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Mood disorders

Harel E.1, 1, Antler D.1, Katz D.1, Pushkarski E.1, Ais E.1, Schvartz A.1, Levkovitz H.1,
1Beer Yaakov mental Health Center, Faculty of medicine, Tel Aviv university;
Background: Repetitive deep transcranial magnetic stimulation (rdTMS) is efficacious for treatment resistant major depressive disorder (TRD). The efficacy of rdTMS may be optimized by stimulation of both the right and left dorsolateral prefrontal cortex (DLPFC). This study is testing the treatment efficacy in TRD of a novel dual channel rdTMS stimulator that was developed for this purpose. Methods: For this open study we recruited 38 outpatients diagnosed with TRD ranging from 18-65 years of age and rated on the HDRS-21≥25., Twenty seven participants completed all study requirements. The rdTMS dual channel stimulator is the Brainsway Multiway deep TMS device: Two channels: a. 10 Hz over the left PFC. b. 1 Hz over the right PFC. Each patient received 20 treatment sessions, five times a week for 4 consecutive weeks. Primary and secondary efficacy outcome measures were the change in the Hamilton Depression Rating Scale (HDRS-21) score and response/remission rates at week 5, respectively Results: HDRS-21 score decreased from an average of 27.22 to 14.22 (P<0.001). Twenty-seven patients completed 4 weeks of treatment. Of them, 13 (48%) showed treatment response (indicating their HDRS-21 score has decreased over 50% from their initial score) and six (22%) showed remission (indicating an HDRS-21 score of less than 10 at the end of the study). Discussion: This open study shows promising results for bilateral simultaneous rdTMS treatment of TRD using a dual channel stimulator. Further randomized controlled studies are necessary for verifying this treatment’s efficacy.
1,2, Shbiro L.1,2, Mechoulam R.3, Gil Z.4,5, Weller A.1,2, Shoval G.4,5,
1Psychology Department, Bar-Ilan University, Ramat Gan, Israel. ; 2Gonda Brain Research Center, Bar-Ilan University, Ramat Gan, Israel.; 3Institute for Drug Research, Medical Faculty, Hebrew University, Jerusalem, 91120, Israel.; 4Geha Mental Health Center, Petah Tiqva, Israel.; 5Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;
Major depressive disorder is a leading cause of disability worldwide; hence, it is necessary to find an appropriate medication. Cannabidiol (CBD), the key non-psychoactive component of the sativa plant, that does not cause negative symptoms, has been shown to have anxiolytic effects, and in a few papers also antidepressive effects. Recently, we showed that oral 30 mg/kg CBD had a pro-hedonic effect on the saccharin preference test. Another compound, CBD acid-methyl ester (CBDA-ME), has been suggested to have more potent effects, but has not been behaviorally tested. Whether administered chronically or after brief sub-chronic administration, antidepressant drugs typically decrease the duration of immobility in the Forced Swim Test (FST). Using the FST, we first examined the effect of orally administered 30 mg/kg CBD in adult male rats from the Wistar-Kyoto (WKY) strain, a genetic animal model of depression. Next, we examined the effect of lower doses of CBDA-ME (0, 0.1, 1, 5 mg/kg). Their control strain was Wistar rats. CBD decreased time floating (immobility) and increased time swimming. Furthermore, 1 mg/kg of CBDA-ME induced the same pattern of effects. In order to explore the effect of CBDA-ME on anhedonia-like behavior we used the saccharin preference test (SPT). As hypothesized, WKY rats showed increased intake of the sweet solution in the SPT after oral administration of 0.1 of CBDA-ME. This provided support for a pro–hedonic effect of CBDA-ME on anhedonia-like behavior, a characteristic of depression as well as of many other mental illnesses. These results provide support for positive effects of acute oral administration of CBD and of much lower doses of CBDA-ME, suggesting therapeutic promise while avoiding potential side effects.
Shvartzman Y.1, Krivoy A.1,2,3, Valevski A.1,2, Weizman A.1,2,3, 1,2,3,
1Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.; 2Geha Mental Health Center, Petach-Tikva, Israel. ; 3Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Petach-Tikva, Israel.;
Objectives: The wide use of antidepressants (ADs) in bipolar disorder I (BD-I) depression is inconsistent with the weak evidence for their effectiveness and safety in this state. Furthermore, there is a paucity of studies on the risk-benefit ratio of AD maintenance treatment in BD-I. We compared the 6-months and 1-year rehospitalization rates of patients with BD-I depression who were discharged with mood stabilizers (MS) or atypical antipsychotics (AAP) with or without AD. Methods: A total of 98 patients with BD-I who were hospitalized with depressive episodes between 2005 and 2013 were retrospectively followed for 6-months and 1-year rehospitalization rates according to treatment at discharge: MS/AAP with or without AD. Durations to rehospitalization were compared between treatment groups. Multivariable survival analyses adjusted for covariates known to influence rehospitalization were conducted. Results: Six-months and 1-year rehospitalization rates were significantly lower in the adjunctive-AD treatment group compared to the no-AD group (9.2% vs. 36.4%, P=.001 and 12.3% vs. 42.4%, P=.001, respectively). Durations to rehospitalization within 6-months and 1-year were significantly longer in the adjunctive-AD treatment group (169.9 vs 141 days, P=.001 and 335.6 vs 252.3 days, P=.001, respectively). Adjunctive-AD treatment at discharge reduced significantly the adjusted risk of rehospitalization within 6-months (HR=0.081, 95% CI: 0.016-0.412, P=.002) and 1-year (HR=0.149, 95% CI: 0.041-0.536, P=.004). Moreover, adjunctive-AD treatment, while reducing adjusted rehospitalization risk for depressive episode did not increase manic episode rehospitalization rates. Conclusions: Adjunctive-AD therapy to MS/AAP may be more effective than MS/AAP monotherapy in preventing rehospitalization during the 1-year period after BD-I depression.
Einat H.1,2,3, Kara N.1,2, Luczak T.3, Agam G.2, Anderson G.3,
1School of Behavioral Sciences, Tel Aviv-Yaffo Academic College; 2Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev; 3College of Pharmacy, University of Minnesota;
Background: Autophagy, a cell survival promoting process, was recently suggested to be involved in the therapeutic action of antidepressant and mood stabilizing drugs. Previous data from our lab demonstrated that repeated administration of compounds that enhance autophagy via different pathways, including rapamycin and trehalose result in antidepressant-like effects and in changes in autophagy-related protein in the frontal cortex of mice. To further understand possible implications of autophagy manipulations in bipolar disorder and its treatment we examined the effects of rapamycin in a strain specific model of mania and examined the behavioral consequences of a conditional deletion of Atg5, a gene required for autophagy in mice. Methods: For the pharmacological study we administered sub-chronic doses of rapamycin to black Swiss mice and tested them behaviorally. For the molecular study we created a conditional knockout mouse model by crossing Atg5flox/flox mice with a mouse strain carrying Cre recombinase under the control of the CamK2a promoter. Atg5 gene deletion was induced by tamoxifen treatment in 6 week old mice. Two or four weeks after treatment mice were examined in a battery of behavioral tests related to basic neuromotor measures and to affective-like change. Results: (1) rapamycin induced antimanic like effects. (2) Conditional KO of Atg5 had no effects on basic neuromotor measures but had a time after induction-dependent effect to induce manic-like behavior in the sweet solution preference test, the forced swim test, the tail suspension test and the amphetamine-induced hyperactivity test. Discussion: These results further support the relationship between autophagy and affective disorders and the possibility that autophagy enhancement could provide a novel target for the development of mood stabilizing drugs.
1, Edut S.2, Richter-Levin G.2, Akirav I.1,
1Department of Psychology, University of Haifa; 2Department of Neurobiology, University of Haifa;
Over half of all patients who suffer from neuropathic pain develop mood disorders such as depression and anxiety but the mechanisms underlying this comorbidity are not fully understood. Nowadays, there is growing evidence for the efficiency of the use of cannabis in alleviating symptoms of both depression and chronic pain. In this study we examined the emotional component of neuropathic pain. Rats with sciatic nerve ligation (SNL) model of neuropathic pain (NP) were chronically adminsitered with vehicle or the endocannabinoid agonist URB597 for two weeks and tested for depressive-like symptoms and performance in appetative and aversive memory tasks. We found that compared to controls, NP rats showed reduced preference to saccharin (i.e., anhedonia), increased learned helplesness, hypolocomotion and impaired performance in the appetative and aversive memory tasks. The cannabinoid agonist URB597ameliotaed the NP induced depression-like symptoms and the impaired perfromance in the aversive memory task, but not in the appetative memory task. URB597 had no effect on pain levels as measured by the Von Frey test.These results indicate that neuropathic pain can induce depressive-like behavior, which can be alleviated by the use of the cannabinoid agonist URB597. This suggests that the endocannabinoid system is implicated in the emotional component of neuropathic pain.
1, Lotan A.1, Pillar N.2, Lifschytz T.1, Mernick B.1, Wolf G.1, Ben-Ari H.1, Oved K.2, Shomron N.2, Lerer B.1,
1Biological Psychiatry Laboratory, Hadassah - Hebrew University Medical Center, Jerusalem, Israel; 2Functional Genomics Laboratory, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel ;
Chronic stress (CS) plays a key role in neuropsychiatric disorders of the elderly. However, the biological pathways involved, including the role of miRNAs, are poorly understood. The present study was designed to test the hypothesis that CS induces differential cognitive-behavioral effects and expression patterns of MiRNAs in young adult and old mice. Young adult (3 month) and old (21 month) female RCC-C57BL/6 mice (n=80) were exposed to either CS or control condition for 9 weeks, followed by cognitive-behavioral tests administered while CS was ongoing. Hippocampi of 12 mice were analyzed on a microarray chip. Old mice were more susceptible to the deleterious effects of CS reflected by significant (p<0.05) age by exposure interaction on two-way ANOVA: Old mice displayed a greater degree of weight loss and decreased cognitive functioning on the radial arm water maze and novel object recognition tests. In young females CS was not associated with weight loss but with modest improvement on RAWM and NOR test and decreased anxiety on the EPM. Using DESeq2, 580 miRNAs were analyzed. A higher expression profile was observed for miRNA-375 in the young CS group compared to the young control group (padj<0.05) and the old CS group (padj<0.05). The data suggest that CS has differential effects depending on age. Old mice were susceptible in terms of developing negative cognitive-behavioral effects whereas young mice displayed striking resilience. We hypothesize that selective expression of miRNA- 375 in young mice exposed to CS could help protect them against potentially deleterious effects of stress while positive effects that CS exposure has been shown to exert, could be supported. These findings have implications for a better understanding of the pathways of miRNAs triggered by CS in old and young individuals. Supported by: Israel Ministry of Science, Technology and Space, Japan-Israel Scientific Research Cooperation.
Kozakevich E.1, Lebovitz M.2, Simhon O.2, Franko M.2, Doron R.1,2,
1Dep. of Education and Psychology, The Open University; 2School of Behavioral Sciences, Tel Aviv-Yaffo Academic College;
Depression and anxiety are highly prevalent and considered of major public health concern worldwide. However, current pharmacological treatments for depression and anxiety are of limited efficacy and associated with various side effects, such as weight gain and sexual dysfunction. Thus, there is high demand for efficacious and safe treatments. In our previous studies, we have investigated the behavioral effect of the new herbal treatment (NHT) which consists of four Chinese herbs. It was found that both NHT and its primary herb induced anxiolytic- and antidepressant-like effects while precluding sexual dysfunction. The aim of the present study was to examine whether treatment with fractions isolated from NHT’s primary herb cause side-effects. To this end, mice were exposed to 4-week-long unpredictable chronic mild stress (UCMS), after which they were randomly assigned to 6 treatment groups: NHT (30mg/kg), escitalopram (15mg/kg), C-20 (3mg/kg), C-20 (30mg/kg), C-50 (3mg/kg) and vehicle. Following 3-weeks of treatment, anxiety- and depressive-like behaviors as well as sexual behavior and memory function were evaluated. Our results indicate that treatment with C-20 (3mg/kg) and C-50 (3mg/kg) induced beneficial anxiolytic- and antidepressant-like effects compared to vehicle, while the effects of C-50 were the most profound. In respect to side-effects, memory performance in the Morris water maze was not impaired by any of the treatments, including the fractions, compared to vehicle. Importantly, sexual function remained intact following treatment with the different fractions, as opposed to escitalopram. Taken together, these results show that C-50 (3mg/kg) herbal fraction is at least as efficacious as NHT and escitalopram in terms of anxiolytic- and antidepressant effects. In addition, treatment with the fraction did not cause memory deficits or sexual dysfunction. Thus, the benefit of the herbal fraction over escitalopram is in the preclusion of sexual dysfunction. Taken together, this c-50 herbal fraction may serve as a safer alternative to current conventional drugs for anxiety and depression. Key words: herbal treatment, Unpredictable Chronic Mild Stress, Selective Serotonin Reuptake Inhibitor, side effects.
1, Kara N.1,2, Einat H.1,2,
1School of Behavioral Sciences, Tel Aviv-Yaffo Academic College; 2Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev;
Background: One of the problem areas of animal models of neuropsychiatric disorders is unclear reproducibility including external validity or generalizability. External validity can be evaluated by replications where aspects of the experiment are manipulated. Alternatively, it can be evaluated using systemic reviews and meta-analyses of available data, a standard practice in clinical research that is nearly ignored in animal models research. The present study reports a meta-analysis of the effects of antidepressant in the mouse forced swim test (FST), a standard screening models for antidepressant action. Methods: A comprehensive search of the literature identified papers that examined the effects of prototypic antidepressants from different groups in the standard protocol of the FST. Included were studies of imipramine, tranylcypromine, fluoxetine, bupropion and lithium. Effect sizes were estimated using Cohen’s d and effect size homogeneity was evaluated by the Q statistic. Results: (1) Despite the abundance of studies utilizing the FST in a variety of contexts, the number of studies that examine the effects of standard antidepressants, or used standard antidepressants as positive control was limited. (2) Across strains, for bupropion, tranylcypromine and lithium, as well as for the low dose range of fluoxetine and possibly the low dose range of imipramine, effects sizes across studies were not significantly different from each other (as shown by the q-statistics). (3) When there were enough experiments performed with a drug to allow separate examination of low and high doses, the effect sizes of the higher dose is qualitatively higher than the effect size of the lower dose. Discussion: these findings offer important support for the external validity of the FST, showing (1) an established antidepressant-like effect, (2) relatively stable effect sizes (3) dose response that is expressed across experiments and strains.
1, Koren O.2, Salmon-Divon M.1, Rodin D.1, Navon-Venezia S.1, Pinhasov A.1,
1Dept. of Molecular Biology, Ariel University, Ariel, Israel; 2Faculty of Medicine Bar-Ilan University, Zefat, Israel;
Background: Recent studies have demonstrated that commensal, probiotic, and pathogenic bacteria in the gastrointestinal tract can activate central nervous system (CNS) signaling systems, possibly through neural, endocrine and immune pathways, thus influencing brain function and behavior. This emerging concept of the microbiome–gut–brain axis suggests modulation of the gut microbiome as a potential novel therapeutic strategy for CNS disorders. In our laboratory, we selectively bred mice, from the WT sabra strain, with strong features of dominance (Dom) and submissiveness (Sub) that represent opposite poles of the behavioral spectrum. We hypothesized that Dom and Sub mice with opposing behavioral phenotypes may possess differential gut microbiomes and that modulation of the gut microbiome may alter depressive-like behavior. Results: Using 16S rRNA gene sequencing, we found Dom and Sub mice's gut microbiome to be comprised of significantly different ratios between bacterial phyla, attributed mainly to Bacteroidetes and Firmicutes. At the same time, the gut microbiome of WT mice, which represent a heterogeneous population displaying a mixed behavioral profile, was found to include Facteroidetes and Firmicutes bacteria, at a ratio approximately the average between that of Dom and Sub mice. WT sabra mice, transplanted with Sub and Dom-associated gut microbiota, exhibited changes in depressive-like behavior. Conclusions: Dom and Sub mice may be used for further investigation of the effects of the gut microbiome upon behavior. Targeted modulation of the microbiome may induce behavioral changes, leading to a better understanding of the role of the microbiome–gut–brain axis upon behavior.
1, Keren N.1, Kara N.1,2, Shemesh G.1, Einat H.1,2,
1School of Behavioral Sciences, Tel Aviv-Yaffo Academic College; 2Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev;
Background: Lithium is the prototypic drug for the treatment of bipolar disorder. Despite its unique therapeutic profile, only a subset of patients shows a therapeutic response to treatment whereas others do not respond or show only partial response. This variability of response was suggested to be influenced by a complex network of genetic, epigenetic and environmental factors. One biological mechanism that had been repeatedly connected with lithium effects is stress. Significant research was done to study the effects of lithium of the outcome of different types of stress from cellular to organism levels. However, not only that lithium influences the outcomes of stress but it is also possible that stress influences the outcomes of lithium treatment. We previously demonstrated that animals that were chronically exposed to significant stress in the Unpredictable Chronic Mild Stress model or using chronic restrain showed a stronger response to the therapeutic-like effects of lithium in a number of tests related to bipolar disorder. The current study was designed to examine if such interaction is also apparent when milder stress is applied. Methods: ICR mice were used to examine (1) the effects of single versus group housing on the response to chronic lithium in the open field (OF) and the forced swim test (FST). (2) The effects of 3 weeks housing in constant dim light versus 12/12 hours light/dark cycle on the response to lithium in the OF, the FST and the elevated plus-maze (EPM). Results: (1) mice maintained in single housing show stronger lithium response in the FST compared with group housed mice. (2) The response to lithium in the FST was not influenced by constant dim light but affected the response to lithium in the EPM. Discussion: Combined with our previous results, the current data supports the possibility that lithium is more effective in stressed compared with non-stressed animals.
1, Belzung C.2, Carmi N.1, Keren N.1, Kara N.1,3, Einat H.1,3,
1School of Behavioral Sciences, Tel Aviv-Yaffo Academic College, Tel-Aviv; 2INSERM 930 & Department of Neurosciences Université François-Rabelais de Tours, France; 3Dept. of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beersheba ;
Background: The variability of individual responses to lithium treatment is a significant hurdle in the attempts to design the best treatment plans for bipolar patients. Unfortunately, only a subset of patients shows an excellent therapeutic response to lithium treatment whereas others do not respond or show only partial response. This variability of response was suggested to be influenced by a complex network of genetic, epigenetic and environmental factors. One biological mechanism that had been repeatedly connected with lithium effects is stress. To explore the possibility that stress can influence the effects of lithium, a previous study tested the interactions between mild stressors (single housing and light manipulations) and the effects of lithium whereas the current study was designed to test the interactions between more significant stressors and response to lithium in mice. Methods: ICR mice were used to examine (1) the effects of daily one hour restraint for three weeks on the response to chronic lithium in the open field (OF) and the forced swim test (FST). (2) The effects of exposure to the unpredictable chronic mild stress procedure on the response to lithium in a battery of behavioral tests including coat state, novelty suppressed feeding, grooming (splash) test, the forced swim test and the tail suspension test. Results: Whereas lithium and stress induced behavioral changes in many of the tests, a clear interaction between them was not frequent. However, in these infrequent events the effects of lithium appear to be stronger in stressed mice. Discussion: Combined with our results regarding mild stressors, the current data supports the possibility that lithium is more effective in stressed compared with non-stressed animals but that the interaction is limited to some but not all facets of behavior.
1,
1Department of Psychology and the Gonda Brain Research Center, Bar-Ilan University;
Animal models have greatly contributed to investigating the etiology of diseases and their underlying neurobiological mechanisms. Thus the availability of animal models for suicidality would potentially be valuable. Naturalists have basically failed to identify suicidal behavior in nonhuman species in field situations. Two key factors in suicidal behavior that cannot be readily modeled in animals are will and intention. However, antecedents, risk factors and biological mechanisms are some of the relevant aspects of suicidal behavior that may be modeled. Researchers have identified potential neuromechanisms, biomarkers and genes involved in suicidal behavior. Valid animal models would allow us to explore the role of these candidate mechanisms in suicidal behavior. To validate an animal model of behavior, a correspondence between the candidate model and the human phenomenon must be observed. This similarity should include, in principle, face validity, predictive validity and construct validity. The different attempts at modelling suicidality in animals will be presented; those based on stress-induced, self-destructive behaviors and those proposing that defeat and entrapment can lead to severe "helplessness" that, in turn, increases both morbidity and mortality, in animals. A more recent approach focuses on several main risk factors for suicidal behavior that can be modeled and manipulated in animals, including aggression, impulsivity, irritability and helplessness behavior (Malkesman et al., 2009). This modelling approach may be useful also for exploring the mechanisms underlying the risks of antidepressant use in in children, adolescents and young adults.
Shemesh N.1.2.3.4, Damri O.1.2.3.4, Las G.1.3, Agam G.1.2.3.4,
1Department of Clinical Biochemistry and Pharmacology; 2Psychiatry Research Unit; 3Faculty of Health Sciences, Ben-Gurion University of the Negev ; 4Mental Health Center, Beer-Sheva, Israel ;
Bipolar disorder (BPD) is a mental disorder with high heritability characterized by mood swings between depression and mania affecting the ability to function, resulting in cognitive and functional impairments and disruption in the life of the patients and their families. The etiology/pathophysiology of BPD illnesses is still unknown. Mitochondria are the main source of reactive oxygen species (ROS) in the cell. Rotenone, a mitochondrial complex I inhibitor, has widely been employed to induce an in vivo and in vitro Parkinson`s disease model causing extreme alteration in mitochondrial homeostasis, blocking autophagic flux by promoting increase in ROS (O2•− in particular) and by impairing lysosomal integrity. A parallel mitochondrial toxin is 3-nitropropionic acid (3NP), a complex II inhibitor. We are employing various concentrations of these two toxins on human neuronal cells (SH-SY5Y) to model very mild mitochondrial dysfunction assumed to occur in BPD. The mitochondrial parameters (mass, membrane potential and ROS) are monitored. Results: Cells were incubated with different concentrations of rotenone/3NP (10-105 pM; 1-103 nM, respectively) for 6, or 24 or 48 hrs. Cell viability was significantly decreased in a gradual manner both by rotenone and 3NP. There was a gradual increase in mitochondrial mass as a function of rotenone concentration only following 48 hrs. Mitochondrial membrane potential gradually decreased as a function of rotenone concentration. ROS levels were not affected. Conclusions: The decrease in cell viability and in mitochondrial membrane potential suggest that rotenone and 3NP treatment of SH-SY5Y cells may serve as a cell model for the mild mitochondrial dysfunction reported in BPD. The gradual increase in mitochondrial mass induced by rotenone might reflect a compensatory effort of the cells.
Erdman A.1, Jalon I.1,3, Abend R.1,4, Shmuel D.2, Peremen Z.6, Levokovitz H.2, Hendler T.1,3,4,5, Harel E.1,2,
1Tel Aviv Center for Brain Function, Tel Aviv Sourasky Medical Center, Tel Aviv University; 2Beer Yaakov Mental Health Center; 3Sagol School of Neuroscience, Tel Aviv University; 4School of Psychological Sciences, Tel Aviv University ; 5Faculty of Medicine, Tel Aviv University ; 6ELMindA;
Objective: This pilot research aimed to identify potential bio-markers that reliably predict the otherwise variable outcomes to deep repetitive Transcranial Magnetic Stimulation (rTMS) treatment in Major Depressive Disorder (MDD) patients. Methods: Thirteen MDD patients underwent functional Magnetic Resonance Imaging (fMRI) while performing two different tasks: 1. Gambling task 2. Implicit emotional regulation task. We used Region of Interest analysis within two limbic regions (“limbic A” and “limbic B”) known to display an impaired function in MDD patients during motivational and emotional regulation tasks, and explored whether these could predict treatment effectiveness. Following the fMRI scan, MDD patients were treated with four weeks of daily rTMS sessions. Results: Examination of the percent signal change (PSC) within the two limbic regions raised a significant reverse correlation in each task. In the gambling task a correlation was found between the “limbic A” PSC and the measured change in the Quick Inventory of Depressive Symptomatology (QIDS) questionnaire; In the emotional regulation task, a correlation was found between “limbic B” PSC and the change measured in the QIDS. Eventually, we combined these two predictors into one linear regression model and found each of them has a unique and significant predictability of treatment efficacy. Discussion: This study is the first to use multi-node limbic activity to predict response to rTMS treatment for MDD. These preliminary results suggest that these limbic emotional responses can be used as bio-markers for treatment success and thus should be considered when selecting rTMS treatment for MDD patients. Moreover, these results may suggest that rTMS treatment affects limbic reactivity in MDD, a hypothesis that should be further explored. However, these results should be interpreted carefully considering the small sample size and the lack of correlation with the more commonly used clinical outcome measure; the HDRS.
soul ,MD O.1, Fenchel ,MSc D.1, Yoffe ,MA R.2, Davidsim ,MD M.1,3, Weiser ,MD M.1,3,
1Department of Psychiatry , Sheba Medical Center, Israel; 2Depatment of mental health, Ministry of health, Israel; 3Department of psychiatry, Sackler school of medicine, Tel aviv university, Israel;
Introduction: Employment is an important positive prognostic factor in psychiatry. Previous studies have shown that people with mental illness have a reduced capacity to work and are less likely to be employed full time. Unemployment reaches up to 95% in people suffering from severe mental illness. Objective: To demonstrate the occupational impairment in relation to a single and recurrent hospitalization due to a depressive episode. Methods: A national database containing consecutive admissions to all psychiatric facilities, including inpatient and day hospitals in Israel between 1990 and 2008, was linked to the database of the National Insurance Institute, which includes information on the income reported for the month of December during 1990–2010. In order to protect patients’ anonymity, data were encrypted before being transferred to the investigators for analysis. We examined the percentage of minimal wage gain in patients with a discharge diagnosis of depression, compared to that of the general population. Results: The proportion of patients diagnosed with depression who are earning above minimal wage was lower in comparison with the general population. Lower rates of income were found in people hospitalized due to recurrent depressive episode when compared to those hospitalized due to a single episode. Findings were similar in all age groups and in both men and women. Conclusions: Our findings support the hypothesis that people hospitalized due to depression are less likely to reach gainful employment and to return to productive life, especially after multiple admissions.
1, Gvirts H.1, Shamay-Tsoory S.1,
1University of Haifa, Department of Psychology;
Loneliness is a subjective unpleasant experience that occurs when social relations are deficient. It is an extremely prevalent human phenomenon, with harmful effects on physical and mental health. Lonely people demonstrate a host of social deficits that make it harder for them to engage in a meaningful relationship. A potential important component of the failure to be fully engaged in social interactions may be related to difficulties in reaching alignment or synchronization with others. Studies show that not being able to synchronize effectively can result in lowered sense of affinity and connection, lower engagement and lower satisfaction from the interaction. These all relate directly to the experience of lonely people. However, to the best of our knowledge, no study to date has examined directly the ability of lonely people to be synchronized. In the present study, we employ a novel paradigm to measure real-time motor synchronization among interacting participants using a computer game. Each participant uses four arrows to move a circle inside a common square arena, while seeing the movements of the other player. To examine the relationship between synchrony and loneliness we recently carried out a preliminary study with 40 participants (20 dyads) who performed the sync task and completed the UCLA loneliness scale. As hypothesized, the mean loneliness score of the dyads (the average loneliness score of both players) was significantly negatively correlated with their ability to synchronize. Moreover, in the group of dyads with a high loneliness score movement correlation between participants was significantly lower in comparison to the group of dyads with a low loneliness score. These preliminary findings help shed light on the behavioral underpinnings of lonely people’s social behavior. They pave the way to additional behavioral as well as neural investigations, as the sync game setup allows it to be used during neuroimaging as well as neuro-stimulation studies.
Levy S.1, Heruti I.1, Avitsur-Hamiel R.1,
1The Academic College of Tel Aviv Yaffo;
Serious nonfatal injuries are common occurrences that can have substantial implications for personal and social functioning. Serious injuries are frequently associated with lasting mental health issues such as depression, panic disorder, generalized anxiety disorder, and substance abuse. The goal of the present study was to examine long-lasting implications of injury to general health and wellbeing. In addition, the moderating role of stress perception on the association between injury and general health were assessed. Two-hundred and forty (48.9%) injured (0.5-10 years post injury) and 251 non-injured subjects completed a self-report health inventory questionnaire regarding their health status during the 6 months prior to study, the short-form Medical Outcome Study (MOS) questionnaire and the Perceived Stress Scale (PSS). Results show that injured subjects reported worse medical outcomes in 3 out of 5 MOS subscales: General health, physical functioning and health beliefs, as well as in the total scale. In addition, injured men reported higher incidence of upper respiratory infections and fever compared to non-injured men, while in women, injury was not associated with increased incidence of illness. Moreover, correlations between perceived stress and self-reported medical outcomes were higher in injured subjects compared to non-injured, suggesting that injury moderates the association between stress and wellbeing. The results of the current study indicate that physical injuries are associated with long-lasting implications for health and wellbeing. In men, severe injury is also associated with increased incidence of illness, suggesting a role for gender in mediating the effects of physical injury. This study highlights several factors that contribute to health and wellbeing following physical injury and may assist in providing better multi-disciplinary care for the injured.
1,
1The Academic College of Tel Aviv-Yaffo;
Maternal depression during pregnancy is associated with unfavorable outcomes for the offspring. Pregnant women suffering from mood disturbances commonly use selective serotonin reuptake inhibitor (SSRI) antidepressants. The beneficial effects of SSRI on the core symptoms of depression are well documented. However, evidence suggest that SSRIs readily cross the placental barrier and impact the developing fetal brain. The goal of the present study was to examine the effects of prenatal stress, as a model for maternal depression, and prenatal exposure to fluoxetine, on the response to an immune challenge in mice. Pregnant dams were injected with either saline or fluoxetine throughout pregnancy. Offspring were administered with lipopolysaccharide (LPS) and circulating levels of proinflammatory cytokines were assessed. Prenatal fluoxetine augmented interleukin (IL)-1beta response while suppressing TNF-alpha and IL-6 secretion in an age-and sex-dependent manner. Moreover, sickness behavior induced by LPS was blunted by prenatal fluoxetine. A separate study examined the effects of prenatal stress in combination with fluoxetine on the response to LPS. Prenatal stress significantly augmented the behavioral response to the immune challenge. Prenatal fluoxetine did not prevent these responses, and, in many cases, augmented them. Lastly, an additional study assessed the effect of prenatal fluoxetine on the response to stress. Prenatal fluoxetine augmented most aspects of corticosterone response to continuous or acute stress. The dexamethasone suppression test revealed that prenatal fluoxetine induced a state of glucocorticoid resistance indicating that the negative feedback control of the hypothalamic-pituitary-adrenal (HPA) axis was disrupted. These findings provide the first indication for altered response to an immune challenge following in utero SSRI treatment and suggest a role for the HPA axis in modulating the effects of prenatal SSRI. This study may contribute to the understanding of the effects of prenatal environment on the development of the neuroendocrine and immune systems and the interplay between these systems. Furthermore, these findings may assist in understanding the limitations and precautions that should be taken in the use of SSRIs during pregnancy.
1, Bruchim-Samuel M.2, Gavish E.1, Halpern O.2, Yadid G.1,2,
1Faculty of Life Sciences; 2Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan, Israel ;
Major depressive disorder is a severe psychiatry disease which affects approximately 5% of the population in any given year. Despite the notable progress that has been made in understanding the mechanism of depression, the efficacy of current treatments remains inadequate, and a considerable percentage of patients exhibit low response rate to the antidepressant treatments. Electrical Deep Brain Stimulation (DBS) of the subgenual-cingulate-cortex was previously shown to have a significant long lasting effect of alleviating the symptoms ofdepression. This region in human parallels the medial prefrontal cortex in rats and is known to have a direct connection to the VTA .Recent studies suggested that stimulation of the ventral tegmental area (VTA), decreased depressive-like symptoms in a genetic rat model of depression (Flinders Sensitive Line rats). The pattern of the stimulation was designed to simulate the burst firing of a healthy rat, suggesting that the abnormalities are caused by dysfunctional network system. Herein, we aimed to study the effect of laterally stimulating the ventro-medial Pre-Frontal Cortex (vmPFC) on the VTA electrophysiology functionalityin FSL rats. We found that chronic (5 days) bilateral low frequency stimulation of the vmPFC (15min per day) caused a significant long-term improvement of depressive-like behavior in the Forced Swim Test ,the saccharin consumption test and normalized the VTA local field potential activity (LFP) in comparison to unilateral stimulation and sham rats as a control group. We suggest that bilateral deep brain stimulation is more effective than unilateral stimulation, depends on the pattern of stimulation, in the vmPFC in improving depressive-like symptoms in a rat model of depression.
1,
Background Lithium is the prototype of mood-stabilizing drugs. The inositol-depletion hypothesis proposes that lithium attenuates phosphatidylinositol signaling. Knockout mice of two genes negatively-regulated by lithium (IMPA1 or Slc5a3), each encoding for an inositol metabolism-related protein were previously characterized as exhibiting a lithium-like neurochemical and behavioral phenotype. Results We performed a microarray study searching for pathways affected by chronic lithium treatment and by the knockout of each of these genes. Bioinformatics analysis indicated up-regulation of mitochondrial-function in the frontal-cortex of all three groups. As a potential behavioral correlate of the bioinformatics results we examined the effect of rotenone, a mitochondrial-function inhibitor, in the forced-swim test and the amphetamine-induced hyperlocomotion paradigm. The observed interrelationship between lithium and rotenone, namely, that the two drugs counteracted each other's effects in both behavioral tests, is consistent with the result of the bioinformatics analysis. Further, a proteomics analysis in the frontal-cortex of lithium-treated mice and IMPA1-knockout mice was carried out to test whether the upregulation of mitochondrial genes is reflected at the protein level. Twelve proteins were similarly affected by lithium-treatment and IMPA1-knockout, eight of them related to mitochondrial-function and/or autophagy. Since lithium's induction of autophagy in-vitro has been shown to be mediated by inositol-depletion we further assessed autophagy markers levels. Both lithium-treatment and IMPA1-knockout resulted in elevated beclin-1/p62 ratio indicative of increased autophagy, corroborating our proteomics results. Conclusions The results suggest the involvement of mitochondrial-function and autophagy in the mood-stabilizing effect of lithium in an inositol-metabolism mediated manner.
Harel E.1, Erdamn A.2, Jalon I.3, Shmuel D.1, Levkovitz H.1, Abend R.4, Hendler T.3,
1Beer Yaakov Mental Health Center, Tel Aviv University; 2Bar Ilan University; 3Center for Brain Functions, Tel Aviv Sourasky Medical Center; 4National Institute of Mental Health NIMH;
Background: A typical phenomenon in depression is the tendency for ruminative thinking, a persistent thought pattern revolving around self-referntial negative affect. Another consistent finding in depression is aberrant ventral striatal (VS) activity when anticipating and receiving rewards. A tendency for negative self-referential thought may influence how external rewards are anticipated and processed. However, to date, no study examined the neural link between rumination and VS activity during reward-related processing. This study aimed at exploring this link using functional magnetic resonance imaging (fMRI) in healthy and depressed participants with different levels of trait rumination. Methods: We scanned a sample composed of 51 healthy participants and 17 participants diagnosed with major depressive disorder while performing a gambling task that includes an anticipatory phase prior to receiving an uncertain monetary reward or loss outcome. Participants also completed the Beck Depression Inventory (BDI) and the Ruminative Response Scale (RRS) assessing trait depression and rumination, respectively. Results: Across the sample, RRS scores correlated negatively with VS activity during outcome anticipation. This correlation remained significant even after controlling for BDI scores, suggesting its specificity to rumination. Furthermore, a hierarchical multiple regression analysis showed that RRS scores moderated the association between VS activity during outcome anticipation and, specifically, reward outcome processing, even after controlling for demographic variables and depression symptom severity. Discussion: Our results suggest a link between negative, self-referential thought tendencies and processing of external rewards. These findings may contribute to elucidating the association between depression, rumination, and aberrant reward-related processes.
Deranieh R.1,2, Greenberg M.1,2,
1Wayne State University Department of Biological Sciences; 2Weizmann Institute of Science Belkin Visiting Professor;
Depletion of inositol has profound effects on cell function and has been implicated in the therapeutic effects of drugs used to treat bipolar disorder. We have previously shown that valproate (VPA) depletes inositol in yeast and human cells by inhibiting myo-inositol 3-phosphate synthase, the enzyme that catalyzes the first and rate-limiting step of inositol biosynthesis. More recently, we have determined that VPA and inositol depletion decreases V-ATPase activity and proton pumping in isolated vacuolar vesicles. Perturbation of the V-ATPase is a consequence of altered PI3,5P2 homeostasis under inositol-limiting conditions. Both PI3,5P2 and the V-ATPase are required for endocytic trafficking. We now demonstrate that VPA delays endocytosis in yeast and mammalian cells, and propose inhibition of endocytosis as a novel mechanism whereby VPA may elicit its GABAergic effect.

Anxiety and obsessive-compulsive disorders

1, Warhaftig G.1, khermesh K.1, Gal-Mark N.1, Levanon E.1, Yadid G.1,2,
1Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel; 2Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan, Israel;
5HT2CRs are Serotonin receptors that are broadly expressed in the CNS and play roles in varied behavioral and physiological processes including emotion and reward. The 5HT2CR mRNA undergoes adenosine-to-inosine RNA editing at five positions (sites A–E) resulting in expression of differently edited isoforms in specific brain regions. 5HT2CR RNA editing has been shown to modulate receptor functions including 5-HT potency, agonist binding affinity, constitutive activity, and G-protein-coupling activity. In this study we examined the RNA editing of the 5HT2CR in a rat model for Post-traumatic-stress-disorder (PTSD), in the central amygdala. The central amygdala is a key structure mediating the effects of stress on the consolidation and recall of traumatic memories. We found significant differences in the frequency of the VNV cluster (partially edited isoform) and the INI cluster (unedited isoform) between the resilient and susceptible groups. Consequently, treating the susceptible rats with a 5HT2CR specific antagonist had long lasting effect on PTSD-like behavior improvement. These results provide potential mechanistic explanation for susceptibility to traumatic events that may develop PTSD. It is intriguing to think this study may suggest a new site to medical intervention.
1,2, Perlman I.4, Chesler D.4, Schnaider Beeri M.5,6,7, Cooper I.1,6, Doron R.3,4,
1BBB-Group, The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel; 2Gonda Brain Research Center, Bar Ilan University, Ramat-Gan, Israel; 3Department. of Education and Psychology, The Open University; 4School of Behavioral Science, The Academic College, Tel Aviv Yaffo; 5The Interdisciplinary Center, Hertzlia, Israel; 6The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel; 7Department of Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, NY, 10029, ;
The blood-brain barrier (BBB) is a barrier that hinders the entry of most molecules into the brain. Disruption in the BBB can lead to multiple brain pathologies. It was demonstrated that frequent BBB disruption in the human cerebral cortex was associated with molecular, clinical, and physiological stress-associated indices. It was also shown that chronic mild stress decreased the activity of superoxide dismutase, thereby increasing oxidants which in turn disrupt the tight junction proteins of the BBB. The aim of this study was to examine the effect of acute and chronic mild stress on the BBB. For that we used unpredictable chronic mild stress (UCMS) paradigm and detected BBB disruption using sodium fluorescein (NaF) injection. ICR mice were randomly assigned to the following four groups: 4-weeks UCMS (N=11), 2-weeks UCMS (N=11), acute stress (30 min; N=14) and non-stressed mice (N=10-14). After exposure to stress, mice were i.v. injected with NaF for 10 min. Thereafter, Mice were perfused with saline and heparin and their brains were harvested and dissected. Brain dissections were homogenized with PBS. Whole brain lysate was precipitated and the fluorescence intensity in each sample was measured.. The results demonstrated a significant decrease in the entry of NaF to the brains of stressed mice in comparison to non-stressed mice. Specifically, mice exposed to 4-weeks UCMS exhibited lower concentrations of NaF in the brain cortex, cerebellum and hippocampus. Mice exposed to 2-weeks UCMS exhibited lower concentrations of NaF in the cerebellum. Mice exposed to acute stress exhibited decreased levels of NaF in the cerebellum and hypothalamus. Whole brain BBB permeability was decreased in 56% following 4-weeks UCMS, 26% following 2-week UCMS and 5% following acute stress. Significant differences in the permeability were shown in the cerebellum, hippocampus, cortex and in other not specific brain area (rest). Based on these findings, it is suggested that stress-induced closure of the BBB in specific brain regions may point to the existence of a protective mechanism in response to stress in which the BBB becomes less permeable to blood circulating substances.
Department of Psychology, Akirav I.Department of Psychology,
1Department of Psychology;
The most common self-reported reason for using cannabis is rooted in its ability to reduce feelings of stress, tension, and anxiety. Studies from our lab suggest that acute cannabinoid administration in proximity to trauma exposure can prevent the effects of the trauma on PTSD-like symptoms. Clinical studies suggest that chronic post-trauma treatment with cannabinoids may attenuate PTSD symptoms. Nevertheless, it has been suggested that direct activation of cannabinoids CB1 receptors over an extended period of time may lead to downregulation of CB1 receptors which may in turn result in a depression-like phenotype in certain individuals and increase risk of addiction. In our study, rats were chronically administered i.p. with vehicle or the cannabinoid CB1/2 receptor agonist WIN55,212-2 (WIN) for 12 days. After an abstinence period of 24 hours or 10 days, they were exposed to the shock and reminders model of PTSD. One month after trauma exposure, rats were tested for anxiety- and depression-like symptoms. We found that in traumatized rats, chronic pre exposure to WIN exacerbated the effects of the trauma on PTSD-like symptoms (i.e., extinction and startle response), when the abstinence period before trauma exposure lasted 10 days. When the abstinence period between the last WIN injection and trauma exposure was 24 hours, there was no exacerbation of symptoms, probably resulting from a residue of cannabinoids in the brain during trauma exposure. The findings suggest that chronic pre-trauma exposure to cannabinoids does not have a therapeutic effect and in some cases chronic pre-exposure may exacerbate the effects of the trauma.
1, 2, Kim J.5, Richter-Levin G.2, 3, 4,
1Psychology Department, Tel-Hai College; 2Psychology Department, University of Haifa; 3Neurobiology Department, University of Haifa; 4Institute for the Study of Affective Neuroscience (ISAN), University of Haifa; 5Department of Psychology, University of Washington;
The involvement of the amygdala in fear learning is a consensus in the field of neuroscience for decades. In an attempt to extend our knowledge about the amygdala functions in fear, we have tested to what extent amygdala is solely involved in fear conditioning. In a series of experiments we were able to demonstrate for the first time that the amygdala, specifically the BLA, direct both innate and learned fear responses in the rat. Further, we assessed the involvement of other brain regions (beside the amygdala) in contributing to the complex affective valence experienced by animals while encountering negative contextual conditions. We could demonstrate that both negative (BLA) and positive (NAcc)-affect related brain regions undergo plasticity simultaneously to optimize animal behavior under variable environmental conditions. Adding to previous data on top-down modulation of such affective brain circuitry, we found that a bottom-up modulation by the midbrain (dPAG) has a significant contribution. This work presents a system-level approach for addressing the emotional brain dynamic responses to aversive stimuli and to lingering emotional states. The approach revealed functional aspects in emotional systems that could not be studied in the traditional approach which examines separately negative or positive affect systems. These findings leave much to be studied but suggest a method that takes into account the complexity of the emotional brain.
1,
1Tel-Aviv Brüll Community Mental Health Center (Ramat-Chen);
Background: Inadequate prenatal care has been associated with adverse perinatal outcomes. Information regarding compliance of women with different psychiatric diagnoses with specific prenatal tests is lacking. We sought to compare compliance with prenatal care visits (PCV), oral glucose tolerance test (OGTT) and serum alfa-fetoprotein (aFP) in women with psychiatric disorders (WPD) and healthy controls. Method: Subjects were 5,395 women (1,043 WPD and 4,352 controls), members of Clalit Health Services (CHS, Tel-Aviv district, Israel), who gave birth during 2004-2014. We used Generalized Estimating Equations with binary-logistic models, considering consecutive pregnancies as repeated measures with unbalanced design. The diagnostic subgroup was the main independent variable, assessed once with and once without age, socioeconomic status and multiple gestation variables, yielding crude and adjusted odds ratios (cOR and aOR, respectively). Results: There was an increased risk for non-compliance with OGTT in women with depression (aOR=1.4, p=.002, 95% CI=1.1-1.7), schizophrenia (aOR=1.8, p=.01, 95% CI= 1.1-2.9), but not anxiety (aOR p>.40; cOR=1.2, p=.03, 95% CI=1.0-1.6). Women with anxiety were more compliant with aFP than controls (aOR=0.6, p=.001, 95% CI=0.5-0.8). Women with depression and schizophrenia did not differ from controls in compliance with aFP. WPD were at risk for both absence of PCV (aOR=4.6, p<.0005, 95% CI=2.7-8.0) and high utilization of PCV (>20 visits, aOR=2.8, p<.0005, 95% CI=2.1-3.7). Conclusion: WPD tended to under-utilize tests perceived for the wellbeing of the mother (OGTT) and over-utilize tests for the wellbeing of the fetus (aFP). WPD exhibited patterns of both very low and very high utilization of PCV.
1,3, Caspi A.1,3, Kimel Naor S.2, Bengal O.2, Czerniak .1,3, Noy S.1,3, Mintz M.4, Plotnik M.2,3,
1Psychiatry Department, The Chaim Sheba Medical Center, Tel Hashomer; 2The Advanced Thecnology Unit, The Rehaboilitation Hospital, Chaim Sheba Medical ; 3Sackler Faculty of Medicine, , Tel Aviv University, Tel Aviv, Israel; 4The School of Psychology Science, Tel Aviv University ;
Objectives: Several studies have shown an association between panic disorder and vestibular symptoms alongside reduced balance capabilities. These studies were mainly based on balance evaluation questionnaires. The aim of this study was to investigate the postural stability during static and dynamic balance in PD patients using VR and compare the results to the balance evaluation questionnaire that was previously used. Method: Eleven young healthy subjects (age: 31.3±6.3y, 5 women) and 11 young subjects diagnosed with PD (36.9±10.3y, 8 women). All participants were evaluated using psychiatric questionnaires, and assessed for functional balance. Four computerized moveable platform tests were performed: (1) Baseline - standing with eyes open (EO) - (2) as #1 with eyes closed (EC); (3), (4) as #1&2 while performing “serial 7 subtraction” (DT). The order of tests was randomized for each patient. Results: Participants with PD had higher scores on the anxiety level evaluations (more anxiety) and significantly lower scores on the functional balance questionnaires. (DHI: controls 0.09±0.3 PD 5.3±4.4; P=0.0035 and Mini-BEST: controls 31.4±0.9 PD 29.4±2.1; P=0.0186), ABC scores showed a significant difference between PD patients and controls. The dynamic physical measures were not significantly different between the groups. Conclusions: Our results show a significant difference between patients and controls in the anxiety levels and balance questionnaires. However, we found no difference between PD and controls in the static, dynamic and DT physical tests. This shows that PD patients have no objective balance impairment, and tend to subjectively report more balance impairments than normal controls due to their underestimation of self-abilities, a known characteristic of PD patients. Key words: Balance assessment, panic disorder, Virtual Reality.
Gross M.1, Kenigsbuch-Sredni D.2, Sredni B.3 , Pinhasov A.1,
1Department of Molecular Biology, Ariel University; 2Interdisciplinary Department, Faculty of Social Sciences, Bar-Ilan University; 3C.A.I.R. Institute, The Safdié AIDS and Immunology Research Center, Bar-Ilan University;
Integrin alpha-v-beta3 is a common cell-surface-adhesion receptor expressed in the presynaptic membrane, whose partial deletion was shown to downregulate reuptake of serotonin by SERT. Integrin alpha-v-beta3 has been shown to be functionally inhibited by Ammonium trichloro (dioxoethylene -O,O') tellurate, or AS101. Given the role of serotonergic signaling in regulation of mood and affect, we hypothesized that AS101 may influence pathways regulating anxiety. Thus, we tested AS101 in modulation of anxiety-like behavior using the selectively bred Submissive (Sub) mouse strain. Mice received daily i.p. injection of AS101 (125 µg/kg or 200 µg/kg) or vehicle for 3 weeks, with the injection itself serving as the source of stress, after which their anxiety-like behavior was measured in the Elevated Plus Maze (EPM). Animals were then culled for measurement of serum corticosterone levels by ELISA and hippocampal expression of Brain Derived Neurotrophic Factor (BDNF) by RT-PCR. Chronic administration of AS101 significantly reduced anxiety-like behavior of Sub mice in the EPM, according to both time spent and entries to open arms. At the same time, AS101 markedly reduced serum corticosterone levels of the treated mice, and elevated their hippocampal BDNF expression. Crosstalk between the HPA axis and hippocampal BDNF signaling with the serotonergic systems modulated by AS101 via integrin alpha-v-beta3 and may suggest a mechanism by which AS101 buffers the anxiogenic response to injection stress in Sub mice.
Mernick B.1, Gendler T.1, Tsuk Y.1, Goldberger S.1, Shechner T.1,
1Developmental Psychopathology Laboratory, Department of Psychology, University of Haifa;
Behavioral inhibition (BI) is a temperament associated with increased childhood risk for the emergence of adolescent anxiety disorders (AAD). During development, BI children show heightened social reticence, rejection, and anxiety-related behaviors. Classical methods that developmental scientists use to measure BI, entail in-vivo behavioral observation of young children’s social interactions with naive peers or adults. As clinical researchers renew their focus on the critical period of early adolescence, during which the BI risk-factor manifests in psychopathology, it is crucial that valid means for assessing BI during preadolescence. This study includes data on two unique measures of the BI phenotype in preadolescence: the Hebrew Behavioral Inhibition Questionnaire (BIQ) and our novel in-vivo dyadic interaction with a strange adult behavioral observation task (BOS). PART I: The BIQ is a scale that is used to measure BI by means of parent reporting. We produced a Hebrew translation of the BIQ and collected 227 responses from parents of children ages 4 to 15. Results indicated that BIQ demonstrated good internal consistency and test-retest reliability. BIQ also showed convergent validity and discriminant validity. Finally, mother reports of BI were significantly correlated to child reports of BI via the BIQ. PART II: The BOS study is an adaptation of existing behavioral-observation-techniques, to assess BI in dyadic interactions between pre/adolescent participant (ages 8-16 years) and an unfamiliar adult confederate. The protocol was adopted from versions of existing in-vivo behavioral observation paradigms. Specifically, we will be applying a combined protocol based on the get-to-know-you-task (Usher et al., 2015) stranger-situation assessment (Asendorpf, 1987a; G. E. Bishop, 2002). Preliminary data from this ongoing laboratory study will be brought to bear in this discussion for BI assessment during the acute periods of late-childhood and early adolescence.
1,2,3, Modai S.2, Farberov L.2, Lin T.1, Sharon H.1,2, Gilam A.2, Volk N.4, Admon R.5, Edry L.2, Fruchter E.6, Wald I.7, Bar-Haim Y.3,7, Tarrasch R.3,8, Chen A.4, Shomron N.2,3, Hendler T.1,2,3,7,
1Functional Brain Center, Sourasky Medical Center; 2Sackler Faculty of Medicine, Tel Aviv University; 3Sagol School of Neuroscience, Tel-Aviv University; 4Department of Neurobiology, Weizmann Institute of Science; 5Department of Psychology, University of Haifa; 6Division of Mental Health, Medical Corps, IDF; 7School of Psychological Sciences, Tel Aviv University; 8School of Education, Tel Aviv University;
Stress research has progressively become more integrative in nature, seeking to unfold crucial relations between the different phenotypic levels of stress manifestations. This study sought to unravel stress-induced variations in expression of human microRNAs sampled in peripheral blood mononuclear cells and further assess their relationship with neuronal and psychological indices. We obtained blood samples from 49 healthy male participants before and three hours after performing a social stress task, while undergoing functional magnetic resonance imaging (fMRI). A seed-based functional connectivity (FC) analysis was conducted for the ventro-medial prefrontal cortex (vmPFC), a key area of stress regulation. Out of hundreds of microRNAs, a specific increase was identified in microRNA-29c (miR-29c) expression, corresponding with both the experience of sustained stress via self-reports, and alterations in vmPFC functional connectivity. Explicitly, miR-29c expression levels corresponded with both increased connectivity of the vmPFC with the anterior insula (aIns), and decreased connectivity of the vmPFC with the left dorso-lateral prefrontal cortex (dlPFC). Our findings further revealed that miR-29c mediates an indirect path linking enhanced vmPFC-aIns connectivity during stress with subsequent experiences of sustained stress. The correlative patterns of miR-29c expression and vmPFC FC, along with the mediating effects on subjective stress sustainment and the presumed localization of miR-29c in astrocytes, together point to an intriguing assumption; miR-29c may serve as a biomarker in the blood for stress-induced functional neural alterations reflecting regulatory processes. Such a multi-level model may hold the key for future personalized intervention in stress psychopathology.
1, 2, Mukrian M.3,
1Bar Ilan University, Department of Psychology; 2NYU School of Medicine, Department of Psychiatry; 3Hadassah Ein-Karem Medical Center, Jerusalem;
Objectives: Pregnancy Loss (PL) and Stillbirth are recognized as a very difficult life experiences. However, to date, PL research in Israel has been very scarce. This study aimed to examine the prevalence and predictors (socio-demographic, marital and birth-related factors) of Post-Traumatic Stress Disorder (PTSD), Major Depressive Disorder (MDD) and Post-Traumatic Growth (PTG) following PL. Methods: Participants were 99 women, ages 24-49 (M=35.07, SD=5.28), who have experienced PL. The mean pregnancy week of loss was 27.29. 86.7% experienced stillbirth. Participants completed self-report questionnaires assessing birth-related variables, socio-demographics, PTSD (assessed via PCL-5), MDD (BDI), PTG (PTGI), Dyadic Adjustment (DAS) and Dyadic Self-Disclosure (SDI). Results: We have found relatively high rates of both PTSD (32.7%) and MDD (29.6%) among women following PL. High PTSD-MDD comorbidity rates were also found. Interestingly, a negative association was found between the number of previous pregnancy losses and the severity of MDD, perhaps indicating an inoculation process. The number of children a woman had while in the study was negatively associated with PTSD. Both PTSD and MDD were negatively associated with the levels of dyadic consensus, self-disclosure, and affectional expression. Finally, post-traumatic growth was positively associated with PTSD levels, perhaps indicating that finding meaning in one's traumatic experience mostly occurs for those suffering the most. Conclusions: Late PL entails a heavy burden of both PTSD and MDD, presumably since most women at the advanced stages of pregnancy are already strongly attached to their unborn child. The quality of the spousal relationship following PL is an important protective factor. In addition, post-traumatic growth may also occur following PL, as is the case for other studied traumas (e.g., combat). There is a pressing need for novel interventions in both individual and couple's therapy following PL.
1,
1Department of Psychology, University of Haifa;
Individuals display heterogeneous responses to traumatic experiences, including resilience, rapid recovery or development of psychopathology such as posttraumatic stress disorder (PTSD) and depression. Resilience to trauma may be characterized by robust reward function that protects individuals from developing psychopathology. Deficits in reward functioning and anhedonic symptoms are present in about two-thirds of PTSD patients, independent of comorbid major depressive disorder. The endocannabinoid system plays important roles in neuropsychiatric disorders. In a series of studies we have demonstrated that enhancing endocannabinoid signaling after exposure to severe stress prevents PTSD-like (e.g., enhanced startle response, impaired extinction, enhanced negative feedback of the HPA axis) and depression-like (learned helplessness, anhedonia) symptoms. Post-stress endocannabinoid enhancement also prevents plasticity impairments in the nucleus accumbens and hippocampus and the functional alterations of cannabinoid CB1 receptors in the fear circuit (i.e., amygdala, hippocampus and prefrontal cortex). Based on our findings, we suggest that components of the endocannabinoid system are dysregulated in the vulnerability phenotype, and that a resilient phenotype is promoted by enhancing endocannabinoid signaling.
Manjoch H.1,
1Ben-Gurion University of the Negev, Department of Psychology, Beer Sheva, Israel ;
Objective: Perceived social support is the most intensively studied resilience factor, yet, research suggests that some individuals do not benefit from it. The aim of this study was to investigate the interaction between the protective effect of social support and personality in terms of psychological and physiological stress responses. Methods: Sixty-five female students completed a battery of questionnaires assessing personality and interpersonal variables, and then arrived to the lab to participate in the study. There, they were randomly allocated to one of two imagery tasks, designed to induce positive support or no support, before being exposed to a standardized psychosocial stressor (Trier Social Stress Test). Physiological stress was measured via heart rate (HR), and time- and frequency-domain heart rate variability (HRV) parameters throughout the procedure. Subjective stress experience was repeatedly assessed before and after stress via anxiety and mood questionnaires. Results: The results show that individual differences moderate the buffering effect of social support. Specifically, we found that an induction of perceived social support reduced physiological stress, but only among individuals with low fear and avoidance of social interactions. We also found that an induction of perceived social support reduced physiological stress, but only among individuals with high levels of attachment anxiety. Conversely, we found an inverse pattern of results regarding self-reported negative mood: participants’ ratings of negative mood were opposite to their physiological stress response. Conclusion: Our results show that the protective effect of social support is altered by individuals’ mental representations and interpersonal relationships. Furthermore, these results are compatible with substantial research demonstrating lack of compatibility between psychological and physiological stress response, raising interesting questions and possible explanations as to the source of this discrepancy.
Ginat-Frolich R.1, Klein Z.1, 1, Shechner T.1,
1University of Haifa;
Fear overgeneralization is characteristic of various psychopathologies. Thus, a novel perceptual discrimination training task was designed to moderate fear-overgeneralization. We hypothesized that basic perceptual improvement would enhance discrimination between threat and safety cues. 70 adults completed a fear-conditioning task. Psychophysiological (EMG, SCR) and self-report measures were collected. Participants were then randomized to complete a training or placebo task. Pairs of novel geometric shapes were constructed for the training task. In each trial, a target shape from the pair appeared on the screen (4s), followed by a fixation point (2s). Participants were then presented with two shapes and asked to identify the shape that differed from the target image. The placebo task used the same shapes, with each image appearing on one side of the screen. Participants needed to indicate the location of the image. Following both tasks, an assessment task was administered and participants were asked whether pairs of novel shapes were identical or different. Finally, a generalization test consisting of 11 morphs (GSs) ranging in perceptual similarity from the CS+ to the CS- was conducted. Participants had to assess the risk level of each morph on a 7-point Likert scale. Successful fear-conditioning was observed in both physiological and behavioral measures (ps<.03). Further, group differences emerged in the assessment task, F(1,64)=38.62, p<.001, with the training group achieving more correct responses than the placebo group. In the generalization test, a larger quadratic trend emerged for the training group [estimate=0.1393] than for the placebo group [estimate=0.0790]. Similarly, GSs in the training group were more closely related to the CS- than were those in the placebo group. Both findings indicate better threat-safety discrimination in the training group. These results offer preliminary evidence for the effectiveness of a novel training task on fear learning.
1,
1Department of Psychology and the Gonda Brain Research Center, Bar-Ilan University;
Background: Bingeing is the consumption of larger amounts of food in a briefer period of time than would normally be consumed under similar circumstances. In rats, trait binge-eating (BE) like behavior has been characterized by BE prone (BEP) versus BE resistant (BER) behavioral profiles. BEP require palatable food (PF) to trigger an abnormal eating response, probably reflecting a gene x environment interaction similarly observed in human BE. We hypothesized that trait BE (an impulsive-like behavior) will predict the pattern of “conflict behavior”, as assessed by levels of PF eating, given expectation of later negative consequences. Two innovations (1) delayed negative impact (2) internal aversive consequences. Method: 52 female Wistar rats were divided to BER/P eating patterns. Rats from both groups ingested either lactose or glucose, before PF session. Lactose groups were conditioned to anticipate digestive discomfort in association with PF. Procedure included 5 test days, 4 hours each (last test was for long term retention). Each day, PF ingestion was examined over the 4hr period and during the 1st and 2nd 2hr periods. Results: While BERs significantly reduced PF ingestion throughout test days in response to lactose ingestion, this effect was significantly smaller or not evident in BEPs. On test day 5 (no lactose administered), rats previously ingesting lactose reduced PF intake compared to rats previously ingesting glucose, indicating a week-long memory for the lactose-discomfort. This memory inhibited PF feeding by the BER rats only until the discomfort failed to appear after 2hr, representing anticipated “conditioned” abdominal discomfort. In addition, rank order of BE predicted PF consumption in the lactose condition on day 4 at the first and last 2hr and on the first 2hr of day 5. Conclusion: These results support the hypothesis that individual differences in trait BE may reflect and predict individual differences in impulse control and conflict resolution
1, Simhon O.1, Rehavi M.2,3, Simhon Tenenbaum Y.2, Doron R.1,4,
1School of Behavioral Science, the Academic College of Tel-Aviv Yaffo, Tel Aviv, Israel; 2Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3The Dr. Miriam and Sheldon G. Adelson Chair and Center for the Biology of Addictive Diseases, Tel Aviv University,Israel; 4Department of Education and Psychology, The Open University, Ra'anana, Israel;
Anxiety during pregnancy is becoming more prevalent. Adverse events during pregnancy may have negative developmental impact on the fetus. In particular, prenatally stressed offspring are more susceptible to mood disorders throughout their life. The growing rate of depression and anxiety has given rise to greater use of selective serotonin reuptake inhibitors (SSRI) during pregnancy and the post-partum period, although their safety with regards to fetal development is still controversial as the evidence is inconclusive. Contention regarding the use and possible deleterious effects of SSRIs during pregnancy or immediately after has led us to search for alternative herbal treatments. Crataegus pinnatifida was selected from a host of Chinese herbs based on studies showing that it has an anxiolytic and anti-depressive effect, as well as the ability to down-regulate the hypothalamic pituitary adrenal axis and raises monoamine levels in the brain. The study aimed to investigate the effect of prenatal stress on anxiety-like behaviors and brain-derived neurotrophic factor (BDNF) levels in offspring, and to examine whether this effect might be ameliorated by lactation-based escitalopram or herbal treatment. The study was designed to mimic the situation where infants are nursed by mothers treated with SSRIs for post-partum depression/anxiety. To this end, 40 pregnant dams were randomly assigned to either control or restraint stress during the last week of pregnancy. All dams were subjected to treatment (escitalopram, herbal, Vehicle, No-treatment) during nursing (n=5/group). Anxiety-like behavior of dams and offspring (n=317) was evaluated using elevated plus maze and open field tests. Blood and brain samples were collected to assess escitalopram levels in the serum and BDNF levels in the brain. Results indicate that prenatal stress lead to an increase in anxiety-like behaviors among offspring and dams, and these were normalized by either escitalopram or herbal treatment
1, Steinmetz A.2, Melamud N.2, Hirshhoren-Lavie L.2, Emunah-Hazani R.1, Frid L.1, Simhon O.2, Franko M.2, Simhon Y.3,4, Rehavi M.3,4, Doron R.1,2,
1Department of Education and Psychology, The Open University of Israel, Raanana, Israel; 2School of Behavioral Sciences, Academic College of Tel Aviv-Yaffo, Tel- Aviv, Israel; 3The Dr. Miriam and Sheldon G. Adelson Chair in Biology of Addictive Diseases, Sackler Faculty of Medicine, TAU, Israel; 4Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel;
Depression and anxiety are highly prevalent and considered of major public health concern worldwide. Selective serotonin reuptake inhibitors (SSRIs), the current first-line treatment for anxiety and depression, are of limited efficacy and slow onset. SSRIs’ clinical response is manifested only after 3-4 weeks of treatment, a period in which symptoms may even be exacerbated. Thus, efficacious fast-onset drugs that will also have sustained effect are in great demand. SSRIs’ delayed onset has been attributed to adaptive regulation induced by serotonin (5-HT) receptors, most notably 5-HT1a. Consistently, complementary treatment with 5-HT receptor agonists or partial agonists was found to expedite SSRIs’ therapeutic outcome. JH is an herbal agent that acts as a partial agonist of 5HT1a receptors and was found to induce anxiolytic-like effects. The aim of the current study was to examine the anxiolytic-like effect induced by the combination between JH and slow-onset conventional and herbal treatments. The herbal treatments are the novel herbal treatment (NHT) and its primary herb, which both have slow-onset anxiolytic- and antidepressant-like activities. ICR mice were exposed to unpredictable chronic mild stress for 4 weeks. Subsequently, mice were treated for 1 or 3 weeks with JH alone or in combination with NHT, NHT’s primary herb, sertraline, fluoxetine or vehicle. Additional groups included treatment with the slow-onset drugs without JH. Anxiety-like behavior was evaluated using the Elevated Plus Maze. Our results indicate that 1-week treatment with JH in combination with fluoxetine, sertraline, NHT or NHT’s primary herb induced fast-onset anxiolytic-like effects. The combination between JH and the slow-onset drugs for 3 weeks did not alter the anxiolytic-like effect induced by individual treatment with the slow-onset drugs. Further analyses in the near future will include assessing 5HT1a receptor in the prefrontal cortex (PFC) and hippocampal BDNF levels.
Elhaik Goldman S.1,2, Perlman I.4, Chesler D.4, Cooper I.1,5, Schnaider Beeri M.5,6,7 ,
1BBB-Group, The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel; 2Gonda Brain Research Center, Bar Ilan University, Ramat-Gan, Israel; 3Department. of Education and Psychology, The Open University; 4School of Behavioral Science, The Academic College, Tel Aviv Yaffo; 5The Interdisciplinary Center, Hertzlia, Israel; 6Department of Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, NY, 10029, ; 7The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel;
The blood-brain barrier (BBB) is a barrier that hinders the entry of most molecules into the brain. Disruption in the BBB can lead to multiple brain pathogenesis. It was demonstrated that frequent BBB disruption in the human cerebral cortex was associated with molecular, clinical, and physiological stress-associated indices. It was also shown that chronic mild stress decreased the activity of superoxide dismutase thereby induces oxidants which in turn disrupts the tight junction proteins of the BBB. In order to test this hypothesis, we used unpredictable chronic mild stress (UCMS) paradigm and detected BBB disruption using sodium fluorescein (NaF) injection. The ICR mice were subjected into four groups, one group with UCMS for one month (N=11), the second with UCMS for two weeks (N=11), the third with acute stress for 30 min (N=14) and control mice (N=10-14). Mice were subjected to one of the stress procedures and then were injected with NaF. Brains were harvested and dissected following perfusion with saline and heparin. The proteins were precipitated using Tri chloric acid and the fluorescence intensity in each sample was detected using a fluorescence plate reader. The results demonstrated significant decreased leakage of NaF in the stressed ICR mice in comparison to control mice. UCMS one month mice group demonstrated decreased leakage of NaF in the brain cortex, cerebellum and hippocampus. UCMS two weeks mice group demonstrated decreased leakage of NaF in the cerebellum. The acute stress group demonstrated decreased leakage of NaF in the cerebellum and hypothalamus. All brain BBB permeability was decreased in 56% percentage following UCMS for one month, in 26% percentage following UCMS for two weeks and in 5% percentage following acute stress. We also found significant differences in the leakage of NaF between the three type of stress in the cerebellum, hippocampus, cortex and in other not specific brain area (rest). These results suggest that the different types of stress cause a gradual resilience of the BBB. As described, mice under chronic and acute stress have less BBB leakage in different brain areas which might indicate a possible protective mechanism for the BBB under stress.
1,2,
1Sheba Medical Center; 2The Interdisciplinary Center, Herzliya;
Previous research has demonstrated a link between childhood anxiety and sleep problems, but little is known about the link between these difficulties and parental sleep disturbances. Previous studies showed that parents of children with significant sleep disruptions reported decreased mood, parenting stress and fatigue, and parental daytime sleepiness was significantly associated with child's sleep problems. When children experience persistent problems in the process of going to sleep, or when they wake up often during the night, parental attention and active involvement to help the child settle back to sleep is a common strategy to “resolve” the issue. However, research show that this parental behavior often does not lead to a resolution of the problems, and additionally may impact parental functioning. In this context, we conducted a study aimed at exploring the link between anxious children’s sleep difficulties and those of their parents. The results suggested that mothers of children with anxiety disorders exhibited higher levels of sleep disturbances than controls. These difficulties were linked to children's anxiety and sleep problems. When treating children with anxiety, it is therefore important to assess their overall sleep picture, as well as parental sleep difficulties, and when appropriate to add a specific sleep intervention component.

Schizophrenia/Psychosis disorders

1,2, Horovitz T.2, Shlosberg D.1,2, Berger E.1,2, Weizman A.1,2,3, Konas S.1,2,
1Geha Mental Health Center, Petach Tikva, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Israel; 3Felsenstein Medical Research Center, Petach Tikva, Israel;
Background: About 30% of schizophrenic patients do not adequately respond to neuroleptics and are defined as treatment resistant schizophrenia (TRS) patients. For decades now, clozapine treatment has been the treatment of choice for these patients. In recent years it has been substantiated that psychotic states influence inflammatory states and vice versa. Previous works have shown conflicting results regarding the effect of clozapine on inflammatory processes and of inflammatory processes on its clinical efficacy. Methods: A retrospective longitudinal study of all adult inpatients admitted under a psychotic state to Geha mental health center (n=97, 169 admissions; age 40.3±10.55 years; 67% male) and treated with clozapine during a 13 year follow-up period. PANSS scores changes and total days of admission were compared for patients with increased or normal levels of inflammatory markers. Excluded were those with chronic inflammatory diseases and/or treated by anti-inflammatory drugs. Results: patients with high neutrophil/lymphocyte ratio (N/L-r>2.5) were found to have increased PANSS-P score on admission (25.0 vs. 21.8, p=0.04). No differences were found following 1 month. Patients with increased CRP levels (>1) did not have different PANSS scores on admission as compared to the rest of the patients. However, after 1 month of hospitalization they displayed no change in PANSS-P scores while the rest did (4.1% vs -12.5%, p=0.014). No difference in hospitalization length was found for either increased N/L-r or CRP levels. Conclusion: These preliminary results expand the knowledge concerning the relationship between the inflammatory and clinical states to TRS patients. In these hard-to-treat patients, N/L-r might serve as an indicator for the severity of psychotic exacerbations and CRP levels may indicate the expected clinical improvement during hospitalizations. Both tests are cheap, simple to perform and readily available.
1, Goldstein A.1,2, Stryjer R.3,4, Gizunterman A.4,
1Department of Psychology, Bar-Ilan University; 2Gonda Multidisciplinary Brain Research Center Bar-Ilan University; 3Sackler School of Medicine, Tel Aviv University; 4Beer-Yakov and Ness-ziona Mental Health Center;
People suffering from schizophrenia try to cope with immense cognitive difficulties, long after the psychotic episode has occurred. While clinicians today treat schizophrenia mostly with antipsychotic medications, no pharmacological treatment is offered to ease the negative and cognitive symptoms one suffers from. These symptoms, in their various forms, greatly affect the person’s social functioning and may impede his full recovery. Previous studies have supported the beneficial role of minocycline add-on treatment for the relief of positive and negative symptoms, in early-phase schizophrenia, whereas recent focus has been given to explore the medication's effect on cognitive functions as well. Furthermore, minocycline has been examined as a potential modulator in altering social behaviors among healthy individuals. In the current study, we examined whether minocycline treatment can improve symptoms among chronic schizophrenia patients, and whether it can further influence patients' executive functioning and social cognitive skills. We conducted a double-blind pilot clinical trial assessing the feasibility, safety and efficacy of minocycline treatment (200mg/d, 6 weeks) for chronic schizophrenia. Since the clinical study was conducted as a pilot, decisive statistical conclusions cannot be made, though we can observe the trends of results and estimate the potential efficacy minocycline might have in chronic stages of schizophrenia in more extensive studies. We randomly assigned 11 patients to either control (placebo) or experiment (minocycline) groups. Nine patients have completed full participation. Results show patients prescribed with minocycline experienced an improvement in their CGI, PANSS and SANS scores, following treatment. Furthermore, we found higher improvement tendencies among the minocycline group on set shifting and cognitive ToM tasks, but not on empathy measures and other cognitive tasks. Taken together, our results suggest minocycline can be a beneficial add-on treatment for chronic schizophrenia, implying inflammation may still be present in progressed stages of the disorder. Additionally, we observed, for the first time, a potential therapeutic effect of minocycline on social cognitive deficits, associated with the disorder. Our study strengthens previous findings which support the efficacy of minocycline for the treatment of negative and positive symptoms in schizophrenia, and suggests this treatment may also be useful in progressed stages of the disorder.
1, Provenzano F.2, Guo J.2, Chakraborty D.3, Kahan U.2, Mingote S.2,4, Gorham S.2, Maechler P.5, Kaphzan H.3, Rayport S.2,4, Small S.2, Gaisler-Salomon I.1,2,
1Psychology Department, University of Haifa, Haifa, Israel; 2Departments of Neurology or Psychiatry, Columbia University College of Physicians & Surgeons, New York, NY, USA; 3Neurobiology Department, University of Haifa, Haifa, Israel; 4Department of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA; 5Department of Cell Physiology and Metabolism, Geneva University Medical Center, Geneva, Switzerland;
Background: Recent findings suggest that glutamate abnormalities underlie hippocampal hypermetabolism in schizophrenia (SZ). Studies measuring cerebral blood volume (CBV) suggest that hippocampal abnormalities occur first in the Cornu Ammonis 1 (CA1) subregion. Insight from glutamate-based animal models supports the role played by glutamate in SZ-related hippocampal abnormalities, but most models focus on the disruption of postsynaptic receptor function rather than on mechanisms that disrupt glutamate homeostasis and release. Aim: Here we set out to identify hippocampal abnormalities at the functional, molecular and behavioral levels, in mice lacking glutamate dehydrogenase (GDH, encoded by Glud1), a mitochondrial enzyme that converts glutamate to alpha-ketoglutarate, in CNS. Methods: Adult male and female CNS-Glud1 deficient (CNS-Glud1-/-) or control (C-Cre+) mice were used in neuroimaging, electrophysiological, molecular and behavioral studies. Results: We found hypermetabolism along with volume reductions specific to right CA1, and elevated glutamate levels in the right hippocampus of CNS-Glud1-/- mice. Sub-regional characterization identified the dorsal right CA1 as principal region of abnormally elevated mRNA expression of both excitatory and inhibitory markers, and a similar pattern of results emerged from mEPSC /mIPSC measurements in the hippocampal slice. These metabolic, molecular and physiological abnormalities were complemented by context learning deficits. Conclusion: Collectively, our results show that Glud1 deficiency phenocopies key features of hippocampal dysfunction in SZ. These findings could provide a novel model of hippocampal dysfunction in SZ, and thus lead to better understanding of SZ etiology and the role played by the hippocampal circuit in the disease.
1, Weiner I.2, Ben Shachar D.1,
1Laboratory of Psychobiology, Department of Psychiatry, Rappaport Faculty of Medicine, Technion, Haifa, Israel. ; 2School of Psychological Sciences, Tel-Aviv University, Tel-Aviv, Israel;
Background: Heme, which synthesis involves the mitochondria, had recently gained attention for its role in neurological disorders. Heme oxygenase-1 (HO1), the enzyme responsible for heme’s breakdown, is overexpressed in the substantia nigra of Parkinson's patients, hippocampus and cortex of Alzheimer’s patients, and the prefrontal cortex of Schizophrenia (SZ) patients. In this study we seek to investigate heme metabolism in SZ, and its relation to mitochondrial complex I, which is deficient in SZ. Method: Hemin levels were fluorescently measured in whole cell and in mitochondria derived from SZ and control EBV transformed lymphocytes. ALAS1, peif2a/eif2a and HO1 mRNA and protein levels were analyzed by Western blot and qRT-PCR, respectively. In addition, peif2a/eif2a and HO1 were assessed in 4 brain regions of the Poly-IC animal model of SZ. Lastly, inhibition of complex I was mimicked by the addition of rotenone to control cells and oxygen consumption as well as the above parameters were assessed. Results: Hemin levels were decreased in SZ-derived lymphoblast lysates, with no change in their mitochondria. Protein and mRNA levels of HO1 and the phosphorylation of eif2a, heme downstream target, were significantly increased. ALAS1 did not change. In poly-IC brain, peif2a/eif2a was increased in the Hippocampus and the STR, while decreased in the FC. HO1 was significantly increased in the dorsal hippocampus only. Exposure to rotenone decreased dose dependently mitochondrial respiration at 24 and 48h. Short-term exposure to rotenone caused a dose dependent increase, while longer exposure (48h) caused a decrease in hemin levels. Conclusion: Our data suggests that a decrease in heme may be involved in the pathogenesis of SZ. In addition, we demonstrate that deficits in complex I causes alternations in heme levels in healthy subjects' derived cells, offering a possible link between the two processes.
1, Ben-Yehuda R.2, Wiener I.2, Ben-Shachar D.1,
1Laboratory of Psychobiology, Rambam Medical Center, Faculty of Medicine, Technion IIT, Haifa, Israel; 2School of Psychological Sciences, Tel-Aviv University, Tel-Aviv, Israel;
Background: Malfunction of mitochondria, key players in various essential cell processes, has been repeatedly reported in schizophrenia (SZ). Recent studies have reported functional improvement and cellular viability following mitochondrial transplantation in several diseases. Here we aimed to study the effect of isolated active normal mitochondria (IAN-MIT) transfer into the medial prefrontal cortex (mPFC) during adolescence on SZ-related behavior and cellular function in adulthood, using the prenatal immune activation poly I:C rat model of SZ. In this model, the maternal immune response leads to various SZ-relevant deficits in adult offspring. Methods: Pregnant dams were injected with poly I:C or saline. On postnatal days 34-47, their offspring were administered with a single bilateral injection of freshly prepared IAN-MIT or vehicle into the mPFC in a stereotaxic surgery. In adulthood, attentional function was assessed by the latent inhibition (LI) test, and mitochondrial function was evaluated by measuring mitochondrial membrane potential (Δym), cell distribution and network connectivity of animals' fronto-cortical freshly isolated neurons using confocal microscopy of JC-1 stained cells. Results: Medial prefrontal IAN-MIT transfer in adolescence had a prolonged effect on animals behavior and mitochondrial function; it prevented disrupted LI and increased the reduced mitochondrial Δym of adult poly I:C-exposed offspring. However, IAN-MIT transfer did not affect mitochondrial cell distribution and network connectivity. Additionally, control offspring injected with IAN-MIT demonstrated disrupted LI and increased mitochondrial Δym. Conclusion: These findings demonstrate a beneficial effect of IAN-MIT transfer in-vivo, suggesting its therapeutic potential in mitochondrial and brain diseases with bioenergetic and neurodevelopmental abnormalities such as SZ. In addition, this study provides an evidence for a relationship between mitochondrial and attentional functions.
Schizophrenia (SZ) and bipolar disorder (BD) are chronic mental disorders characterized by emotional and cognitive abnormalities, which commonly affect young adults. Both disorders share several similarities, including psychotic symptoms, genetic risks, endophenotypes and life-time worldwide prevalence of about 1%. Their pathophysiology is still unclear and the currently pharmacological treatment is decided based on "trial and error" strategy. Numerous studies have shown abnormalities in multifaceted function of the mitochondria in both disorders. Therefore, we aim to identify a mitochondrial based profile as a guideline for personalized treatment, by studying 22 mitochondrial targets of 7 psychotropic drugs in lymphocytes of healthy subjects (in-vitro). We studied 17 different targets, mitochondrial membrane potential (Δψm) mitochondrial cellular distribution and network connectivity as well as levels of 14 mitochondria-related proteins including those involved in the respiratory chain (NDUFV1, NDUFV2, NDUFS1, COX2, SDH1) autophagy (Beclin1, p62) apoptosis (Caspase 3, BAX, BCL2) and mitochondrial network dynamics (OPA1, MFN1, DRP1, FIS1). In an attempt to verify whether drug effects on the mitochondrial parameters in isolated cells can predict treatment outcome, we correlated pretreatment effect of drug in-vitro with its in-vivo effect after a month of treatment to patient. Results: Psychotropic drugs presented a drug specific effect profile on the above mentioned mitochondrial parameters in lymphocytes of healthy subjects (n=28). Drugs affected the parameters similarly in responding patients and controls. In addition, several mitochondrial parameters showed a high correlation between in-vitro and in-vivo response to haloperidol, LiCl and olanzapine before and after treatment, respectively, in patients responding to treatment. Conclusion: Taken together, our findings suggest mitochondrial function as a potential tool to verify individual response to psychotropic medication and thus may facilitate predicting the optimal drug for each patient (personalized medicine).
1, Yitzhaki O.1, Ifraimov T.2, Damri O.2, Marom C.3, Gurman V.3, Bersudsky Y.3, Agam G.2,3, Ben-Shachar D.1,
1Department of Psychiatry, Ruth and Bruce Rappaport Faculty of Medicine, Technion IIT and Rambam Health Care Campus; 2Department of Clinical Biochemistry and Pharmacology; 3Psychiatry Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. ;
Background: Schizophrenia (SZ) and bipolar disorder (BD) are chronic mental disorders characterized by emotional and cognitive abnormalities, which commonly affect young adults. Both disorders share several similarities, including psychotic symptoms, genetic risks, endophenotypes and life-time worldwide prevalence of about 1%. Their pathophysiology is still unclear and the currently pharmacological treatment is decided based on "trial and error" strategy. Numerous studies have shown abnormalities in multifaceted function of the mitochondria in both disorders. Therefore, we aim to identify a mitochondrial based profile as a guideline for personalized treatment, by studying mitochondrial targets of 7 psychotropic drugs in lymphocytes of healthy subjects (in-vitro). We studied mitochondrial membrane potential (Δψm) mitochondrial cellular distribution and network connectivity as well as levels of 14 mitochondria-related proteins including those involved in the respiratory chain (NDUFV1, NDUFV2, NDUFS1, COX2, SDH1) autophagy (Beclin1, p62) apoptosis (Caspase 3, BAX, BCL2) and mitochondrial network dynamics (OPA1, MFN1, DRP1, FIS1). In an attempt to verify whether drug effects on the mitochondrial parameters can predict treatment outcome we correlated pretreatment effect of drug in-vitro with its in-vivo effect after a month of treatment to patient. Results: Psychotropic drugs presented a drug specific effect profile on the above mentioned mitochondrial parameters in lymphocytes of healthy subjects (n=28). Drugs affected the parameters similarly in responding patients and controls. In addition, several mitochondrial parameters showed a high correlation between in-vitro and in-vivo response to haloperidol, LiCl and olanzapine before and after treatment, respectively, in patients responding to treatment. Conclusion: Taken together, our findings suggest mitochondrial function as a potential tool to verify individual response to psychotropic medication and thus may facilitate predicting the optimal drug for each patient (personalized medicine).
580161156,
1Technino-Israel Institute of Technology;
Our laboratory has been studying the neurobiology of D-serine, a D-amino acid which is increasingly appreciated as an important transmitter/signaling molecule. D-Serine modulates N-methyl D-aspartate receptors (NMDARs) and regulates synaptic plasticity, neurodevelopment, and learning and memory. However, the primary site of D-serine synthesis and release remains controversial, with some arguing that it is a gliotransmitter and others defining it as a neuronal cotransmitter. Recent controlled experiments demonstrate that the biosynthetic enzyme of D-serine, serine racemase (SRR), is expressed almost entirely by neurons, with few astrocytes appearing to contain D-serine. Instead of producing D-serine, we found that astrocytes mainly export L-serine to neurons to fuel the synthesis of D-serine by the neuronal SRR. This metabolic cross-talk, called "serine shuttle", appears to be the main determinant of D-serine production, and possibly glycine levels as well. Genetic studies and knockout mice models now implicate six serine shuttle genes (PHGDH, PSAT1, SLC1A4, SLC7A10, SRR and DAO) in severe neurological problems, mental disability, and in neuropsychatric disease as well. In particular, SRR is one of the 108 chromosomal loci associated with schizophrenia in a large genome wide association study, and patients with schizophrenia display lower D-serine in CSF. We will present results on how the serine shuttle differentially regulates the synthesis of D-serine and glycine and affects NMDAR synaptic plasticity, and learning and memory.
1, Weiner I.1,
1Tel Aviv University;
Schizophrenia is a neurodevelopmental disorder manifested symptomatically after puberty. The recognition that the formal diagnosis of the disorder is preceded by progressive behavioral and neuropathological abnormalities, has kindled an interest in preventive interventions during this "prodromal" period. Clinical studies indicated that atypical antipsychotic drugs (APDs) may reduce risk of progression to first-episode psychosis, but results are controversial. Novel interventions based on pathophysiological mechanisms believed to play a role in schizophrenia such as inflammation and redox dysregulation, are heavily advocated but studies in humans are challenging. Valid animal models of schizophrenia are imperative in this context. Here we used the maternal immune activation (MIA) model which is based on the known association between maternal infection in pregnancy and increased risk of schizophrenia, to test the efficacy of early intervention with two compounds with strong anti-inflammatory and anti-oxidant properties, Omega 3, and N-acetylcysteine (NAC). Offspring of pregnant dams injected on gestational day 15 with the viral mimic poly-I:C or saline, were treated in adolescence (postnatal days [PND] 22-47) with either ω-3 PUFAs- enriched diet or NAC at 900 mg/l in drinking water, and tested in schizophrenia-relevant tasks in adulthood (PND>90). Prenatal poly-I:C led to deficits in selective attention and executive function as indexed by disrupted latent inhibition (LI) and abnormally rapid reversal. Both behavioral abnormalities were prevented by omega3 whereas NAC was partially effective. These results support the notion that anti-inflammatory/anti-oxidant compounds, which may be more benign than APDs, have a potential to prevent the emergence of behavioral abnormalities following prenatal insults.
1, Gothelf D.1,
1Behavioral Neurogenetics Center, Sheba Medical Center & Sagol School of Neuroscience, Tel Aviv University; 2International 22q11.2DS Brain and Behavior Research Consortium (IBBC 22q11.2DS);
Nearly one-third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop a psychotic disorder during life, most of them by early adulthood. Importantly, a full-blown psychotic episode is usually preceded by subthreshold symptoms. In the current study, 760 participants (ages 6–55 years) with a confirmed hemizygous 22q11.2 microdeletion have been recruited through 10 medical sites worldwide, as part of an international research consortium. Of them, 692 were non-psychotic and with complete measurement data. Subthreshold psychotic symptoms were assessed using the Structured Interview for Prodromal Syndromes (SIPS). Nearly one-third of participants met criteria for positive subthreshold psychotic symptoms (32.8%), less than 1% qualified for acute positive subthreshold symptoms, and almost a quarter met criteria for negative/disorganized subthreshold symptoms (21.7%). Adolescents and young adults (13–25 years) showed the highest rates of subthreshold psychotic symptoms. Additionally, higher rates of anxiety disorders and attention deficit/hyperactivity disorder (ADHD) were found among the study participants with subthreshold psychotic symptoms compared to those without. Full-scale IQ, verbal IQ, and global functioning (GAF) scores were negatively associated with participants’ subthreshold psychotic symptoms. This study represents the most comprehensive analysis reported to date on subthreshold psychosis in 22q11.2DS. Novel findings include age-related changes in subthreshold psychotic symptoms and evidence that cognitive deficits are associated with subthreshold psychosis in this population.
1,
1Dept. of Psychology, University of Haifa ;
Glutamate is the most prevalent excitatory neurotransmitter in the central nervous system, and is involved in basic sensory as well as higher cognitive functions. The glutamate synapse is complexly regulated by pre-synaptic, post-synaptic and glia-controlled processes. Glutamate abnormalities are implicated in several CNS disorders, including schizophrenia, depression and epilepsy. The glutamate hypothesis of schizophrenia stems from the fact that noncompetitive blockers of the glutamate NMDA receptor induce schizophrenia-like symptoms in healthy individuals, and several lines of evidence point to abnormal glutamate levels in the prefrontal cortex and hippocampus of afflicted individuals. Animal models can be used to gain better understanding of mechanisms underlying glutamate abnormalities in schizophrenia. Data emerging from animal studies support the role played by abnormal glutamate transmission in schizophrenia-related symptomatology and pathophysiology, and point to glutamate-driven hippocampal hyperactivity as the driver of psychosis, Furthermore, recent studies may identify novel pathways of psychopharmacological intervention targeting the glutamate synapse.
1,2, Hussien W.1,2, Ben-Yosef T.3,4, Damri H.3,4, Levin J.3,4, Bersudsky Y.3,4, Agam G.3,4, Ben-Shachar D.1,2,
1Laboratory of psychobiology, Ruth and Bruce Rappaport Faculty of Medicine, Technion IIT ; 2Department of Psychiatry, Rambam Health Care Campus; 3Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University; 4Beer-Sheva Mental Health Center;
One of the theories regarding the pathogenesis of mental disorders is mitochondrial dysfunction. In addition, mitochondria are affected by many psychotropic drugs. During my "basic science" training, I tested mRNA expression of 14 mitochondrial genes in 11 healthy control subjects as part of a larger study that examined many differences in mitochondrial parameters between treated and untreated control samples. The effects of psychotropic drugs on mRNA expression in control subjects together with the data obtained about other mitochondrial parameters will enable us to create a "profile of effect" for each drug. Those profiles will be used in a following research, which will compare gene expression in patients who responded or failed to respond to a drug in order to identify parameters that predict response to treatment. During my training I took blood sample from the subjects, Isolated the lymphocytes, incubated the cells with the drugs, extracted the mRNA, used qRT-PCR in order to compare different gene expression with and without various drugs and analyzed the results. mRNA expression failed to show a significant difference between treated and untreated samples in line with previous finding of short-term antipsychotic drug and mood stabilizer treatment. In a parallel study, protein levels of the same genes were examined and there were significant differences. This might indicate that the effect of the psychotropic drugs is in the post-transcriptional stage.
Heffetz Giterman L.1, Gross A.1, Lander S.1, Gaisler-Salomon I.1,
1University of Haifa, Psychology Dept.;
Background: Most neurotransmitter glutamate is recycled through the glutamate–glutamine cycle, in which phosphate-activated glutaminase 1 (gene GLS1) converts glutamine to glutamate in neurons. Mice with a targeted disruption of a single copy of the Gls1 gene (GLS1 hets) show a mild reduction in glutamate in several brain regions including the hippocampus and frontal cortex, and are insensitive to the effects of amphetamine, a dopamine agonist which induces a psychosis-like state typically characterized by paranoid delusions. NMDA receptor hypofunction engenders schizophrenia(SZ)-like symptomtology in healthy humans and animal models, and leads to excessive glutamate release. Moreover, neonatal NMDAR blockade, which mimics a neurodevelopmental disruption hypothesized as central to SZ etiology, phenocopies key aspects of SZ in rodents. It is unclear whether GLS1 hets are resilient to early developmental manipulations, and specifically to neonatal NMDA receptor blockade. Aim: We investigated SZ-like behavioral deficits in adult male and female GLS1 hets and their wild-type (WT) controls, following neonatal administration (PND 6-10) of the NMDA receptor antagonist MK-801 (0.1 mg/kg) or saline. Our behavioral battery included locomotor activity in Open Field (OF), the object location task (OLT), the Novel Object Recognition task (NOR), social preference, and reversal learning in the Water T-maze. Results and Conclusion: Our results indicate that neonatal NMDA receptor blockade induces SZ-like behavioral abnormalities in WT, but not GLS1 het, mice. These findings provide further support for the potential of inhibiting GLS1 as a novel treatment strategy for some SZ symptoms.
Cohen R.1, Gross A.1, Lander S.1, Zaidan H.1, Gaisler-Salomon I.1,
1University of Haifa, Psychology Dept.;
Dysregulated glutamatergic neurotransmission has been strongly implicated in the pathology of schizophrenia (SZ). Glutaminase 1 (GLS1) plays a critical role in the recycling of glutamate. GLS1 deficient mice were previously shown to display an attenuated response to the acute and chronic effects of the dopamine-releasing psychotomimetic drug amphetamine. A recent large-scale drug screening study identified ebselen as a potent CNS-available GLS1 inhibitor. Here, we asked whether ebselen (10 mg/kg) would attenuate sensitization to amphetamine (4 mg/kg). Adult 129SVe mice were divided into 4 experimental groups, and received i.p. injections on 4 consecutive days (sensitization) and 7 days later (challenge): SAL-SAL, SAL-AMPH, AMPH-AMPH, AMPH+EBS-AMPH+EBS. We found decreased sensitization to amphetamine in mice that received pre-treatment with ebselen. Ongoing gene expression studies are performed to assess reduction of GLS1 transcripts and altered expression of dopamine markers in the striatum.
1,
1Lev Hasharon MHC;
Religious and spiritual beliefs play a major role in the life of many patients with psychiatric disorders. According to the scientific literature, Religious/spiritual beliefs, as well as the spiritual well being of an individual, are a positive prognostic factor in coping with these psychiatric disorders. Nevertheless, the professional teams (psychiatrists, psychologists ecc.) who take care of these patients, are often not paying enough attention to the "spiritual/religious world" of their patients. The goal of this research was to describe the religious/spiritual beliefs among people with psychiatric disorders, and to examine the correlation between these beliefs and the clinical state of the individual. Another goal of the research, was to examine the level of interest, that the professional teams showed in the "spiritual/religious world" of their patient. The results of the research showed a high percentage of psychiatric patients, who believe in some kind of a religious/spiritual belief. The results also showed a negative correlation, between the level of spiritual/religious belief, and the severity of depressive symptoms, psychotic symptoms and suicidality. Another result was a positive correlation between the "spiritual well being" of an individual and his "general quality of life". Another finding was that professional teams, showed a low level of interest in their patients "spiritual/religious world".
1, Frenhcel D.1, Burshtein S.1, Davidson M.1,2, Weiser M.1,2, Fruchter E.5,6, Ben Yehuda A.5, Yoff R.7, Reichenberg A.4, Sandin S.3,4,
1Department of Psychiatry, Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel; 2Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.; 3Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; 4Department of Psychiatry and Department of Preventive Medicine,Icahn School of Medicine at Mount Sinai,New York, NY, USA; 5IDF Medical Corps, Israel.; 6Department of Psychiatry,Rambam Medical Center,Technion-Israel Institute of Technology,Haifa, Israel.; 7Department of Mental Health, Ministry of Health, Israel.;
Understanding the association between advanced paternal age and schizophrenia Marina Belyak1, MD, Daphna Fenchel1, MSc, Eyal Fruchter5,6, MD, Shimon Burshtein1, MD, Ariel Ben Yehuda5, MD, Rinat Yoff7, MA, Abraham Reichenberg4, PhD, Michael Davidson1,2, MD, Sven Sandin PhD 3,4, Mark Weiser1,2, MD 1Department of Psychiatry, Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel. 2Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. 3Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden. 4Department of Psychiatry and Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 5IDF Medical Corps, Israel. 6Department of Psychiatry, Rambam Medical Center, Haifa, Israel; Rappaport School of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. 7Department of Mental Health, Ministry of Health, Israel. Importance: Previous studies suggest an association between advanced paternal age at birth and risk of schizophrenia. Some investigators have hypothesized that this association is caused by older fathers having more replications of sperm cells and therefore more mutations over time, while others have linked this association to psycho-social and/or genetic characteristics of older fathers. Objective: To examine these competing hypotheses and to understand if this association is due to de novo mutations, characteristics of older fathers, or both. Design: Historical prospective population-based cohort study. Setting: Adolescents assessed by the Israeli army draft board prior to induction into military service and followed for later psychiatric hospitalization. Participants: 920,783 subjects screened in the draft boards of the Israeli Defense Force, with complete data on parental age at birth and socio-economic status (SES). Main Outcomes and Measures: ICD-10 diagnoses from the national psychiatric hospitalization case registry of narrowly defined schizophrenia (F20.0-F20.9) with follow-up up to 30 years after screening by the draft board. Results: A total of 4502 (0.5%) were hospitalized for schizophrenia. In the entire population, paternal age at birth was associated with increased risk of schizophrenia: OR=1.02, 95% CI=1.01-1.03, adjusted for maternal age at birth and SES. Compared to a reference group of paternal age of 25-29 at birth, paternal age of 45 or older at birth was associated with increased risk of schizophrenia: OR=1.58, 95% CI=1.32-1.88, adjusted for maternal age at birth and SES. Advanced paternal age at birth of first child was associated with increased risk of schizophrenia (adjusted OR=1.09, 95% CI=1.07-1.10). When taking into account paternal age at birth of first child, advanced paternal age at birth was not associated with increased risk of schizophrenia (OR=0.94, 95% CI=0.93-0.96). No associations between advanced paternal age at birth and risk of schizophrenia were found when controlling for sibship. Conclusions: Our data does not support the hypothesis that de novo mutations are behind the association between advanced paternal age at birth and schizophrenia, but instead support a role for psycho-social and/or genetic factors of older fathers.

Traumatic Brain Injury

1, 2, Ram O.3, Sadot O.3, Matar M.1, 2, Kaplan Z.1, 2, Douvdevani A.2, 4, Cohen H.1, 2,
1Department of Anxiety and Stress Research Unit, Beer-Sheva Mental Health Center, Ministry of Health, Israel. ; 2Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel. ; 3Department of Mechanical Engineering Ben-Gurion University of the Negev, Beer Sheva, Israel.; 4Department of Clinical Biochemistry, Soroka University Medical Center, Beer Sheva, Israel.;
Blast wave-induced minimal traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) have become one of the most frequent injuries in the military and civilian health care sectors since the increase in worldwide terrorism and warfare. Those injuries tend to become chronic injuries in the absence of early diagnosis and intervention. Accurate diagnosis and the initial care of those injuries are a complex challenge especially in the events of mass casualties, and may led to delay the necessary therapeutic intervention. Therefore, early identification of the affected population is of great clinical importance for treatment planning, and rehabilitation assessment for patients. In this study, we determined the levels of CFD in serum at different intervals after low-pressure blast wave exposure to evaluate its potential utility as a sensitive biomarker of blast-induced (psycho)pathology. Our hypothesis was that CFD levels correlate to the behavioral response patterns, and thus may predict the outcome of blast-wave injured. Non-anesthetized rats were exposed to visual, auditory, olfactory, low pressure blast-wave. Blood was obtained from the rats by sublingual puncture under Isoflurane-anesthetized. Simultaneously, combining of cognitive and behavioral paradigms were used in order to determine the rats' performance. The results showed that blast exposure caused significant time-dependent increases in serum CFD at 2 h post-exposure and was independent of the psychopathology. For most of the rats, the maximum increase was recorded at 2 h, and CFD levels returned to baseline by 5 h post exposure. In rats displaying PTSD-phenotype or mTBI-phenotype, the maximum level of circulating CFD was observed at 2 h post exposure and was still significantly elevated at 5 h after blast exposures, likely indicating a slow clearance after a transient release of CFD into the circulation. CFD levels may be used as a marker to assess psychopathology after blast exposure.
1, Dvir O.1, Rubovitch V.1, Pick C.1,
1Tel Aviv University, Anatomy, Tel Aviv, Israel;
Traumatic brain injury (TBI), a brain dysfunction for which there is no present effective treatment, is often caused by a concussive impact to the head. The impact of diet on brain function and susceptibility to neuropsychiatric and neurodegenerative disorders is increasingly appreciated. In addition, rodents maintained on dietary restriction (DR) perform better on learning tasks than do rodents fed ad libitum (AL). Here, we demonstrate a neuroprotective effect of DR in a mouse model of induced mild TBI (mTBI). Mice were divided into two main groups following a weight drop (30, 50 and 70gr). AL group was fed normally while the DR group was maintained on an alternate day feeding regimen. Cognitive and behavioral performance was assessed 30 days post injury using the Novel Object Recognition (NOR) and the Elevated Plus Maze (EPM) tasks. Results taken from the NOR task show that all groups of mTBI mice (30,50 and 70 gr) maintained on normal diet were significantly impaired post injury compared with the no- mTBI (p<0.03, p<0.001 and p<0.001 respectively) and the mTBI+DR groups (p<0.01, p<0.001 and p<0.007). EPM analysis shows no difference between all groups, indicating that injury failed to cause any anxiety like behavior. Currently we are examining the role of Sirtuin1 in this neuroprotective mechanism, as it is known to have a key role in the biological effect of DR. These results bolster accumulating evidence that DR may be an effective approach for increasing the resistance of the brain to damage.
Niv L.1, Aviv I.1, Pilowsky Peleg T.1,2, Apter A.1, Fennig S.1, Shorer M.1,
1Schneider Children’s Medical Center of Israel, Petach Tikvah, Israel; 2Department of Psychology, The Hebrew University of Jerusalem, Israel; 3;
Background: Mild Traumatic Brain Injury (mTBI) has become a major public health problem; Children are being exposed to various forms of head injury which are common reasons for hospital emergency room presentation. M-TBI is a leading cause of Post-Concussion syndrome (PCS) manifested by sustained physical, cognitive, emotional, and behavioral symptoms in children, adolescents and adults. Although most children who are victims of m-TBI usually recover from the symptoms within a few weeks after injury, about 10 to 20 percent suffer from persistent PCS (PPCS) that can continue for months and even years after the injury . The etiology of PPCS has been controversial for many years, with different views proposing distinct mechanisms underlying the syndrome. As a result, the major problem is how to predict whether a closed head injury will result in permanent psychiatric sequela. If this will be proved to be possible, then prevention measures, rehabilitation and treatment options could be instituted in the early stages of the process. The Current Study Goals: first, to test the hypothesis of previous studies that psycho-social difficulties which were present before the injury predicts higher level of PPCS. Second, to investigate the psychological mechanisms which mediate the psycho-social risk factors influence the prognostication of PCS. Methods: The children and their parents will be evaluated in four time points: Baseline (within 2 weeks after trauma), 3 weeks, 4, and 9 months post-injury. The Baseline assessment will include pre-injury child and family status, pre-trauma signs of psychological, learning and behavior difficulties. The follow up assessments will include neuro-cognitive evaluation, persistent emotional, physical, cognitive, and behavioral difficulties. Feature directions: To evaluate such as DTI, and MEG as predictors of PPCS and their interaction with social and emotional factors. We hope that this will enable identification of vulnerable children earlier on and thus enable timely intervention.
Herzog G.1,2, Ram O.3, Sadot O.3, Kaplan Z.1,2, Cohen H.1,2,
1Department of Anxiety and Stress Research Unit, Beer-Sheva Mental Health Center; 2Ministry of Health and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; 3Department of Mechanical Engineering Ben-Gurion University of the Negev, Beer Sheva, Israel. ;
While posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) are both well-described in the general population, the literature concerning PTSD and/or mTBI in the elderly is scanty and patchy. There are indications that both PTSD and mTBI in old age presents unique features. The brain undergoes a series of structural and functional changes during the aging process. Along with anatomical and functional declines, the cerebral levels of neurotransmitters, neurotrophic factors and nerve growth factor are dramatically reduced in aging brains. Therefore, age at injury is likely to influence the way the brain is able to respond and repair itself as a result of developmental status, extent of anatomical, morphological and cellular senescence. The overall objective of this study was to explore the question of how age at the time of blast exposure (age at injury) affects behavioral and cognitive responses in multiple neurological, behavioral, molecular, morphological and imaging domains over an extended time course. We employed a controlled experimental blast-wave paradigm in which non-anesthetized middle aged male rats (12-13 month) were exposed to visual, auditory, olfactory, and tactile effects of an explosive blast-wave produced by exploding a thin copper wire. Validated cognitive-behavioral paradigms were used to assess both mTBI-, PTSD- and depressive-phenotypes on days 7–14 following the blast. The results demonstrate a degree of heterogeneity in individual responses to the experimental blast-wave, which was different than the patterns of younger animals. At old age, exposure to the experimental blast wave did elicit mTBI-like phenotype, PTSD-like phenotype and combined mTBI-PTSD-like symptoms and also elicit a high percentage of depressive–like phenotype, which not observed in younger rats. A better understanding of the mechanisms of age-related compromise may inform the development of therapeutic interventions to mitigate age-related risk.
Zuckerman A.1, 2, Ram O.3, Sadot O.3, Matar M.1, 2, Kaplan Z.1, 2, Cohen H.1, 2,
1Department of Anxiety and Stress Research Unit, Beer-Sheva Mental Health Center, Ministry of Health, Beer-Sheva, Israel; 2Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; 3Department of Mechanical Engineering Ben-Gurion University of the Negev, Beer Sheva, Israel;
Background: In a previous study, we employed a controlled experimental blast-wave paradigm in which rats were exposed to explosive blast-wave produced by exploding a thin copper wire. We found a degree of heterogeneity in individual responses to this exposure: Whereas most exposed animals did not demonstrate any behavioral or cognitive abnormalities, in a number of rats exposure did elicit either a PTSD-like phenotype or mTBI-like behavior, or combined mTBI-PTSD-like symptoms. Since dysregulation of the HPA axis is thought to underlie trauma-related (psycho-)pathology, we first evaluated the endogenous serum corticosterone levels at different intervals after blast exposure. Subsequently, the efficacy of various doses of exogenous hydrocortisone therapy given immediately after blast-exposure was evaluated. Methods: Non-anesthetized rats were exposed to low pressure blast-wave. Blood was obtained from the rats by sublingual puncture under Isoflurane-anesthetized. Simultaneously, combining of cognitive and behavioral paradigms were used in order to determine the rats' performance. We subsequently evaluated the behavioral and cognitive effects of various doses of exogenous hydrocortisone to non-anesthetized exposed rats 1 hour after exposure. Results: Retrospective analysis revealed that the PTSD-phenotype group exhibited a significantly blunted corticosterone response to blast exposure compared to all other groups. We found that 125 mg/kg hydrocortisone given 1h post blast exposure was effective in reducing the prevalence of PTSD-phenotype. No difference in prevalence of the mTBI-phenotype was noted. Conclusions: Faults in the generation of an adequate and timely endogenous corticosteroid response of the HPA-axis unfavorably alters the trajectory of trauma exposure. Corticosteroid treatment is a feasible avenue for clinical interventions for attenuating PTSD. Our results suggest that mTBI and PTSD may have distinct biological and clinical profiles.

Neurodevelopmental disorders

1, Amir D.1, Eisen A.1, Sobel N.1,
1Department of Neurobiology - Weizmann Institute of Science;
Social chemosignals are volatiles secreted by one individual to affect behavioral, physiological and hormonal state of other individuals. Growing evidence suggests that chemosignals likely play an important role in human social behavior, mostly without conscious awareness. A hallmark of autism spectrum disorder (ASD) is difficulties in social communication. We hypothesized that a portion of the inability to read social cues in ASD may reflect an inability to read social chemosignals. In a series of experiments we tested autonomic non-verbal physiological and behavioral responses to three different chemosignals in high-functioning adults with ASD and in typically developed (TD) controls. We found that "Fear sweat" (sweat obtained from individuals in a state of fear) drove decreased arousal in TD yet increased arousal in ASD (nTD = 13, nASD = 15, F1,24 = 13.5, p < 0.005, Cohen's d' = 1.5). The putative chemosignal hexadecanal significantly reduced the physiological startle response in TD but not in HF-ASD (nTD = 16, nASD = 16, F1,30 = 7.7, p < 0.01, d'=0.98). Finally, the putative chemosignal androstadienone, a sweat-bound molecule that effects arousal, significantly increased physiological arousal in TD but not in ASD (nTD = 23, nASD = 17, F1,38 = 7.8, p < 0.01, Cohen's d' = 0.93). Taken together, these results suggest altered physiological responses to subliminal social chemosignals in ASD
1, Gvirts H.1, Karklinsky M.2, Shamay-Tsoory S.1,
1Haifa University ; 2Weizmann Institute;
Previous research has established the importance of interpersonal synchrony in promoting a range of positive social outcomes such as affiliation, cooperation and rapport, emphasizing its role in the formation of effective social interaction. The present study tested the hypothesis that impaired ability to synchronize with other members of the group characterizes individuals with high autistic traits. We used a novel computerized task in which a group of participants were represented as different colored ball shaped figures moving along a computer screen. The level of synchrony of each participant with the group was tested in both (і) free movement (control condition) and (іі) instructed synchrony (experimental condition). Autistic traits severity was measured using AQ questionnaire. We found a significant interaction effect between the type of condition and the level of autistic traits, indicating that individuals with high autistic traits were less synchronized with the group compared to individuals with low autistic traits in the instructed synchrony condition. These results demonstrate the difficulty of individuals with ASD to synchronize with others in the context of group coordination. Moreover, employing a paradigm that measures interactions of individuals within a group provides a highly ecological setting to study social behavior in ASD and may offer novel insights into the mechanisms that underlie the profound behavioral disturbances observed in ASD.
1,2,
1The Pediatric Neurology and Developmental Unit, Loewenstein Rehabilitation Hospital;
Objective: The aim of the present study was to find whether the prevalence of Sensory Processing Disorder (SPD) symptoms is similar among children with attention-deficit/hyperactivity disorder (ADHD) and typical controls, and whether SPD symptoms affect daily function among children with ADHD. Methods: 77 children, aged 8-11 years (37 children with ADHD and 39 typical controls) were recruited. The Conner's Parent Rating Scale–Revised: Short Form (CPRS-R:S) was used to profile ADHD symptoms. The Short Sensory Profile (SSP) was used to measure sensory processing abilities. The Children Activity Scale for Parents (ChAS-P) was used to evaluate children’s difficulties in daily function. Results: The SSP total score of the ADHD group (142.13±25.98) was significantly lower than that of the control group (180.08±11.68; t=-8.23). In the ADHD group, 65.8% of children had an abnormal SSP score indicating SPD, compared to only 2.6% in the control group (χ2=34.40, p<.001). The daily function of children with ADHD was significantly lower than in typical controls (ChAS-p mean 3.95±0.68; and 4.78, ±.36 in the ADHD and control groups, respectively) (t(75)= -6.71, p<.001). The largest differences were found in the category of activities involving executive functions (3.7 ±.79; and 4.76 ±.44). Children with ADHD and abnormal SSP scores, had a significantly lower daily functional ability than controls (p<.001). In contrast, children with ADHD but normal SSP had only marginally lower daily functional abilities than controls (p=.128). Overall, males had lower mean ChAS-P scores than females, however the differences were statistically-significant only among the children with ADHD. An abnormal SSP score was a weightier factor in the ChAS-P performance for males than females. Conclusion: The present study supports the importance of SPD as a possible specifier of ADHD in children that correlates with functional consequences.
1, Ramaswami G.2, Golumbic Y.3,4, Sher N.5, Malik A.5, 6, Barak M.7, Levanon E.7, Li J.2, Gaisler-Salomon I.1,
1Department of Psychology, University of Haifa, Haifa, Israel; 2Department of Genetics, Stanford University, Stanford, California, USA; 3Faculty of Education in Technology and Science, Technion, Haifa, Israel; 4Faculty of Civil and Environmental Engineering, Technion, Haifa, Israel; 5Bioinformatics Core Unit, University of Haifa, Haifa, Israel; 6Department of Marine Biology, Leon H. Charney School of Marine Sciences, University of Haifa, Haifa, Israel; 7The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel;
Adenosine to inosine (A-to-I) RNA editing is an epigenetic process that entails site-specific modification in pre-mRNA catalyzed by adenosine deaminases acting on RNA (ADAR). The serotonin receptor 2C (Htr2c), where editing occurs at five sites yielding 32 putative mRNA variants, is one of the best-studied examples of A-to-I RNA editing in coding regions. Recently developed techniques allow the detection of multiple editing sites with high accuracy, but a high-throughput investigation of editing in the rat brain has not been performed. Here, we used microfluidics-based multiplex PCR sequencing (mmPCR-seq) to determine age-, region- and stress-induced changes in editing at 146 pre-selected, conserved sites in the rat prefrontal cortex (PFC) and amygdala (AMY). Since we previously showed that the effects of stress on behavior and gene expression can be transmitted across generations, we asked whether changes in RNA editing patterns and ADAR gene expression could be observed in first- and second-generation offspring of female rats exposed to prereproductive stress (PRS). We found that in line with previous studies, editing was higher in adult (P60) compared to neonatal (P0) rats, and this effect was uncoupled from changes in the expression of ADAR enzymes. At P0, editing levels were lower in PFC compared with AMY. Stress had little effect on global editing levels, but increased editing at the Htr2c A site. Htr2c editing was significantly altered in offspring of female rats exposed to PRS across 2 generations, and differences in Htr2c isoform distribution were more robust in first- and second-generation offspring compared to rats directly exposed to stress. In conclusion, mmPCR-seq can be used to accurately detect developmental and region-specific changes in RNA editing in the rat brain. Our findings point to stress-induced alterations in RNA editing that may explain previously observed transmission of behavior and gene expression patterns across generations. Support: IGS ISF 484/10, HZ BSF Rahamimoff 2015
1, Maroun M.1,
1Sagol Dept. of Neurobiology, Faculty of Natural Sciences, Univ. of Haifa;
Obesity is considered a critical factor in the prevalence and development of mental disorders and it is becoming one of the most serious public health challenges of the 21st century. Juvenility is a critical development stage characterized by major hippocampus changes and vulnerability to food. We recently demonstrated that long-term exposure for 3 months to high fat diet (HFD) starting from juvenility to adulthood induced enhancement of amygdala function and impairment of hippocampal function. Interestingly, the same exposure to HFD but at adulthood and for 3 months did not result in changes in hippocampal or amygdala-dependent functions (Boitard et al. 2014). Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis was reported to mediate these effects. Here, we focused on the effects of short- term exposure to HFD in the juvenile or adult animals on changes in long-term potentiation (LTP) in the Schaffer collateral-CA1 pathway (hippocampus), spatial memory (hippocampal dependent memory). Further, we examined the dependency of these effects on glucocorticoid receptors (GRs). Exposure to short-term HFD resulted in enhanced CA1-LTP in adult animals and impaired LTP in juvenile animals CA1. After application of GRs antagonist (RU486) effects of HFD no longer observed; the antagonist abolished the induction of LTP in the adult animals while in the PW it enhanced the induction. In accordance with the electrophysiology results, short-term exposure to HFD enhanced spatial memory in adult rats and disturbed it in juvenile animals. Our results show qualitatively different mechanisms that control the modulatory effects of short term HFD on spatial memory and CA1 plasticity in the two age groups. Additionally, GRs may have an important role in modulating plasticity. These differences in the effects of HFD between young and adult brains may explain the increase in emotional and behavioral disorders in children.
1, Gross M.1, Romi H.1, Pinhasov A.1,
1Ariel University, Department of Molecular Biology , Ariel, Israel;
While glucocorticoids are essential to fetal development and nutrient transfer via the placenta, excessive maternal glucocorticoids may cause maladaptive programming of the Hypothalamus Pituitary Adrenal (HPA) axis in utero, which is implicated in anxiety disorders in adulthood. Among two selectively bred mice strains, Dominant (Dom) or Submissive (Sub) phenotype predicts adaptive or maladaptive HPA axis programming in response to prenatal restraint stress (PNS). In order to test the role of placental glucocorticoid signaling in resistance or sensitivity to PNS, pregnant dams were treated with either DEX (0.1 mg/kg, s.c.) or vehicle one hour prior to PNS on gestational days (GD) 15-17. We assessed alterations in glucocorticoid signaling of Dom and Sub placentas in response to PNS, alongside their ability to cope with acute stress. Placental weight was significantly lower among stressed Sub pregnancies, relative to Dom counterparts, which may be explained by dramatically lowered levels of placental glucocorticoid receptor (GR) among Sub mice exposed to PNS. Furthermore, placental levels of the enzyme 11beta-hydroxysteroid dehydrogenase-2 (HSD2), responsible for deactivation of glucocorticoids, were increased among Dom mice in response to PNS, while Sub placentas showed no change in HSD2 levels. Pre-restraint treatment with DEX rendered an anxiolytic effect upon adult Dom offspring in the Elevated Plus Maze (EPM), as opposed to the expected, anxiogenic effects seen among Sub mice. We conclude that the anxiolytic effects of DEX upon Dom mice born to stressed pregnancies may be mediated by alterations in placental glucocorticoid signaling. Further study of the genomic landscape of Dom mice should reveal biomarkers of resilience to stress.
1, Zachor D.2, Heller I.1, Plotkin A.1, Weissbrod A.1, Snitz K.1, Secundo L.1, Sobel N.1,
1Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel; 2The Autism Center, Department of Pediatrics, Assaf Harofeh Medical Center, Zerifin, Israel;
Internal action models are brain templates for sensory-motor coordination that are suggested to be impaired in Autism spectrum disorder (ASD). However, whether and how impaired internal action models relate to the major phenotype of ASD, namely impaired social communication, remains unclear. Olfaction relies on an internal action model known as the sniff-response, whereby nasal airflow parameters are rapidly modulated in accordance with odorant content. For example, pleasant odors are automatically sampled with strong sniffs, yet unpleasant odors are sampled with weak sniffs. Thus, by measuring nasal airflow (sniffs) alone we obtain a non-verbal measure of olfactory perception and processing. To test the hypothesis that the sniff response is altered in ASD, we delivered pleasant and unpleasant odors while simultaneously precisely measuring nasal airflow in 36 children; 18 with ASD and 18 age and gender matched typically developing (TD) controls. TD children generated a typical adult-like sniff-response, modulating airflow in a valence-dependent manner within 305 milliseconds of odor onset. In contrast, ASD children had a profoundly altered sniff-response, sniffing equally regardless of odor valance. At the single subject level this difference allowed for 81% correct ASD classification based on the sniff-response alone (binomial, p < 0.001). Moreover, the sniff-response was correlated with ASD severity such that increasingly aberrant sniffing was associated with increasingly severe ASD (r = 0.75, p < 0.001). Tellingly, aberrant sniffing was associated with the generalized social (r = 0.72, p < 0.001) but not motor (r = 0.12, p = 0.68) impairment in ASD. These results uncover a novel language-free task-free ASD marker that implies a mechanistic link between the underpinnings of olfaction and ASD. This supports the impaired internal action model of ASD and links it to impaired social communication.
1, Dedikov J.1, Eisenberg N.2, Spinrad T.2, Sadeh A.1,
1School of Psychological Sciences, Tel Aviv University; 2Department of Psychology, Arizona State University ;
Introduction: The infant cry is a strong stimulus “programmed” to elicit parental response. Research has suggested that parental reactivity to crying is a personal characteristic that is likely to influence parents’ responses to their infant and thus influence early development. In a previous cross-sectional study we found that parents of infants with sleep problems are more reactive to crying compared to parents of infant without sleep problems (Sadeh et al., 2016). The present study aims to assess the validity of the PCR construct in a longitudinal study and to assess the associations between this parental characteristic and infant sleep. Methods: This is a longitudinal study in progress, with four assessment points (pregnancy, 3, 6 and 12 months). Until now, 115 couples expecting their first child have been recruited, 30 of which have completed the12-month assessment. Assessments of PCR include responses to video (the IDICV paradigm) and audio recordings (the RICAS paradigm) of crying infants (Sadeh et al., 2016). In the IDICV participants are asked to indicate the point in time when they feel it is essential to intervene and soothe a crying infant. The delay time is used as a measure of cry tolerance. Infant sleep is assessed using actigraphy, sleep logs and parent reports. Results: PCR appears to be a stable individual characteristic with correlations ranging between .45 and.66 for repeated administration of the IDICV across pregnancy, 3 months and 6 months in mothers and fathers (F=10.4, p< .005). In addition, fathers are consistently more tolerant to infant crying than mothers. Preliminary findings demonstrate curvilinear links between PCR and sleep, indicating that both extremes of very low and very high PCR at pregnancy are associated with poorer actigraphic sleep quality at 3 months. Discussion: PCR may play a role in parental behaviors related to infant sleep, such as excessive or insufficient involvement in soothing infants at bedtime, which may contribute to the development of poorer sleep quality.
1, Zidan S.1, Afek S.1, Gaisler-Salomon I.1,
1Department of Psychology, University of Haifa, Haifa, Israel;
We have previously shown that pre-reproductive stress (PRS) to adolescent female rats alters anxiogenic behavior in their first- and second-generation offspring in a sex-dependent manner. PRS also changed corticotropin releasing factor 1 (CRF1) mRNA expression in the frontal cortex and oocytes of the exposed females and in their offspring’s brain at birth. Here, we tested whether maternal treatment with the CRF1 antagonist NBI 27914 (NBI, 5 mg/ml; 5 days) or the antidepressant drug fluoxetine (FLX, 5 mg/kg, 7 days) would reverse the behavioral and CRF1 expression abnormalities induced by PRS. Adolescent female rats (F0) were exposed to a 7-day stress procedure, and were treated subchronically with NBI or FLX prior to mating. Female rats (F0) and their offspring (F1) were weighed regularly, and behavior in dams and offspring was assessed on P60. Brain samples were collected from offspring at birth to examine CRF1 mRNA gene expression. In F0, PRS increased pre-pregnancy weight gain and decreased locomotion in the open field (OF). Both male and female offspring of PRS dams showed abnormalities in the open field (OF), elevated plus maze (EPM), and fear conditioning (FC) paradigms. Maternal drug treatment reversed these abnormalities in female, but not male, offspring. As previously observed, PRS increased CRF1 mRNA in offspring amygdala at birth, and this effect was reversed by maternal NBI treatment but potentiated by FLX. Interestingly, maternal drug treatment alone also affected offspring weight and behavior. These findings suggest that some of the behavioral and HPA axis-related transgenerational effects of pre-gestational trauma may be altered by post-stress drug treatment, and that different mechanisms may mediate the inheritance of stress to male and female offspring. Support: Israel Science Foundation (484/10).
1,2, Barzilay R.1,2,3, Hargil M.2,4, Weizman A.1,2,3, Watemberg N.2,4,
1Geha Mental Health Center, Petah-Tikva, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3Felsenstein Medical Research Center, Rabin Medical Center Campus, Petah-Tikva, Israel; 4Child Neurology, Meir Medical Center, Kfar Saba, Israel;
Objectives: Alteration in peripheral iron indices has been reported in a number of movement disorders, particularly Parkinson’s disease. We hypothesized that iron stores may be diminished in children at an early stage of tic disorder. Methods: Using data retrieved from electronic medical records, A total of 1230 files of child neurology outpatients clinic patients were screened, we compared serum ferritin levels, an indicator of body iron store balance, in drug-naive children diagnosed for the first time with tic disorder (study group; N=47, 32 boys/15 girls, aged 8.66–3.17 years) compared to age- and sex-matched children with headaches (comparison group, n=100, 62 boys/38 girls, aged 9.51–3.15 years) treated in the same pediatric neurological clinic. Results: Mean serum ferritin levels were significantly lower (-32%, p=0.01) in the tic disorder group compared to the headache group. No significant differences were detected in circulatory hemoglobin, iron, transferrin, and platelet count between the two groups. Conclusion: Our findings suggest that body iron stores may be reduced in children with recent-onset tic disorder.
1, Maroun M.1,
1Sagol Dept. of Neurobiology, Faculty of Natural Sciences, Univ. of Haifa;
Recent studies have shown that consuming Western diet that contains high levels of saturated fats can affect learning and memory processes. Juvenility is a period of continuous brain development marked by structural changes and thus is very susceptible to metabolic challenges. We have recently reported that exposure to high-fat diet (HFD) for 3 months starting at juvenility induced enhancement of amygdala function and impairment of hippocampal function. Interestingly, the same exposure to HFD at adulthood and for the same duration did not result in changes in hippocampal or amygdala-dependent functions (Boitard et al. 2015a). In the present study we aimed to address the question whether HFD-induced cognitive and emotional alterations can be achieved by shorter periods of exposure, considering that during juvenility the brain structures that mediate emotional and cognitive processes are undergoing maturation. We thus focused on addressing the impact of short exposure (7-10 days) in juvenile or adult animals on social recognition memory. Furthermore, as oxytocin is one of the most important neuromodulator of social memory we thus investigated its role in mediating HFD-induced effects on social memory. Our results indicate that short-term exposure to HFD impaired social recognition memory in juvenile animals but not in adult animals. Systemic Oxytocin injection impaired the social memory in rats that were fed control diet and reversed the impairment in memory of social recognition in animals that were on HFD. This is the first study to show that acute exposure to HFD in juvenile animals is associated with impairments in social recognition memory and thus show that exposure to western diet at early age can have adverse effects on social memory.
1, Dor-Ziderman Y.3, Gvirts H.4, Bloch Y.1,2,
1The Emotion-Cognition Research Center, Shalvata Mental Health Care Center, Hod-Hasharon; 2Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel, Israel; 3The Leslie and Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar-Ilan University Ramat Gan, Israel; 4Department of Psychology, University of Haifa, Haifa, Israel;
Background: Anxiety disorders are highly comorbid with Attention Deficit hyperactive Disorder (ADHD), and there is a complex interplay between attention and anxiety as a dimension. Both are effected by stimulant medications. While some clinicians base their practice on the fear that stimulants will aggravate anxiety in ADHD patients, recent studies support the opposite. The aim of the current study was to examine if the effects of stimulants on anxiety are specific to ADHD patients, and to have a better understanding of the underlining brain circuits. Methods: This double blind cross over study was conducted on 20 adults with ADHD and 20 adult of a Control group. Anxiety and attention were evaluated repeatedly with questionnaires. Brain activity was recorded with the Magnetoencephalography (MEG) both while performing a cognitive task (2N BACK) and at three rest point expected to present differences in state anxiety: before, after a test trial, and at the end of the evaluation. This was performed on two separate appointments: After receiving 20 mg of methylphenidate on one occasion and after placebo on the other. Results: in adults with ADHD and low state anxiety, the level of anxiety increased after receiving methylphenidate. Subjects in the control group showed no elevation in anxiety following methylphenidate. In terms of MEG readings: High gamma band waves were different in the ADHD and control group and had a positive correlation with cognitive performance in both. In subjects with a high level of trait anxiety the theta/betha ratio rose after the admission of methylphenidate. Discussion: This double blind study showed correlation between admission of methylphenidate and elevated level of state and trait Anxiety, and between the Anxiety level and brain activity. It brings to light questions about the place of Anxiety as a dimension whose importance needs to be appreciated in the understanding and treatment of ADHD.

Neurodegenerative disorders

1,2, Goez D.3, Last D.3, Liraz Zaltsman S.4,5, Sharvit-Ginon I.4,9, Atrakchi-Baranes D.4, Shemesh C.4, Schnaider Beeri M.4,6,7, Mardor Y.3,8,
1BBB-Group, The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel; 2Gonda Brain Research Center, Bar Ilan University, Ramat-Gan, Israel; 3The Advanced Technology Center, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel; 4The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel; 5Pharmacology Division, The Institute for Drug Research, Faculty of Medicine, Hebrew University of Jerusalem, Israel; 6Department of Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; 7The Interdisciplinary Center, Herzliya, Israel; 8Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; 9Department of Psychology, Bar Ilan University, Ramat-Gan, Israel;
Background: Type 2 diabetes (T2D) is associated with increased risk for Alzheimer's disease (AD). There is evidence for impaired blood brain barrier (BBB) in both diseases but its role in the interplay between them is not clear. Here, we investigated the effects of high fat diet (HFD), a model for T2D, on the Tg2576 mouse model of AD in regards to BBB function. Results: We showed that HFD mice had higher weight and more insulin resistance, primarily in Tg2576 mice. HFD also induced hypoactivity in Tg2576 mice and anxiety-like behavior. HFD improved learning of Tg2576 mice tested in a Morris Water Maze in comparison to Tg2576 mice fed with regular diet. MRI scans were performed on all mice at 4, 8 and 12 months of age. Tg2576 mice demonstrated BBB disruption at 8 and 12 months which was reflected in increased gadolinium (Gd) extravasation to the brain. Increased volume of the lateral ventricles was also observed in these mice. However, HFD decreased Gd's extravasation to the brain decreased ventricular volume, thus prevented brain AD common pathology. HFD had no effect on amyloid beta level in the cortex. HFD increased serum HDL-cholesterol levels in both Tg2576 and WT mice and also increased the transcription level of insulin receptor in the hippocampus. Conclusions: Our results suggest that HFD promotes better cognitive function through improvement of BBB disruption and of brain atrophy but not of amyloid beta levels. Cholesterol metabolism and insulin signaling may underlie this protection.
1, Gross M.1, Tikhonov T.1, Nesher E.1, Kirby M.1, Michaelevski I.1, Pinhasov A.1,
1Department of Molecular Biology, Ariel University, Ariel, Israel;
Memory disorders are the central contributors to ageing-related cognitive impairments, which are linked to different patterns of sensitivity to stress. Therefore understanding the influence of stress on mechanisms underlying early manifestation of age-related cognitive impairments is of crucial importance. Utilizing social behavior paradigm, we developed animals with strong dominant and submissive behavior exhibiting resilience or sensitivity to stress, respectively. Based on our findings and current knowledge, we hypothesize that inherent sensitivity to stress elicits molecular events, which may be linked to the accelerated aging processes. In this study, we assessed the lifespan of animals with different adaptability to stress. The cohort of mice included 10 males in each of the 3 strains studied (Wild Type (WT), Dominant (Dom) and Submissive (Sub)). We demonstrated that the lifespan markedly differed between Sub and Dom as well as between Dom and WT groups, while no significant difference between Sub and WT groups was observed. These data indicate stress resilient animals have longer lifespan than stress sensitive counterparts, supporting the evidence that stress is a risk factor in developing early onset of aging as well as age-related cognitive impairments, observed in stress sensitive mice. This present study provide a life expectancy survey analysis in our unique mouse model of resilience and sensitivity to stress that will be useful for understanding the pathophysiology events underlying the ageing process.
1, Toledano R.1,2, Rachmani L.1, Sasson E.1, Doron R.2,3,
1Tel Aviv University School of Medicine; 2The Academic College of Tel Aviv-Jaffa; 3The Open University;
We have previously shown that an ultra-low dose of THC (delta-9 tetrahydrocannabinol) protected the mice brain from a variety of insults (Ref. 1, 2, 3). A single injection of 0.002 mg/kg of THC (3-4 orders of magnitudes lower than doses that induce the conventional cannabinoid effects in mice) prevented the cognitive damage that was induced by either hypoxia, deep anesthesia, MDMA-toxicity, epileptic seizures or neuroinflammation. THC was applied either 1-7 days before or 1-7 days after the insult, thus providing a wide therapeutic time-window. The protective effect of the single injection of ultra-low THC lasted for at least 7 weeks. The protective effect of THC was accompanied by a long-lasting elevation in pERK, pCREB and BDNF in the hippocampus and frontal cortex of the THC-treated mice. In the present study we tested whether the same ultra-low dose of THC reverses age-dependent cognitive decline in mice. Old (18-24 months) mice performed significantly worse than young (3-4 months) mice in a battery of cognitive assays, including Morris Water Maze, Passive Avoidance, Y maze, Object Recognition and Place Recognition tests. Old mice that had been injected once with 0.002 mg/kg THC performed significantly better than vehicle-treated old mice, and performed similar to naive young mice in all the assays. The improvement in cognitive functioning lasted for at least 7 weeks following a single injection of ultra-low THC. Sirtuin 1 (SIRT1) is an NAD-dependent protein deacetylase that has been previously shown to be involved in neuroprotection and neuroplasticity. It was found to mediate the protective effects of resveratrol, of melatonin and of caloric restriction, and was suggested to take part in the pathology of various neurodegenerative diseases. In the current study we found that a single injection of 0.002 mg/kg THC elevated the amount of SIRT1-immunoreactive proteins in the hippocampus, the frontal cortex and the cerebellum of old mice for at least 7 weeks. We further hypothesized that such long-lasting behavioral and biochemical changes might be accompanied by structural changes in the brain. Indeed, MRI (Magnetic Resonance Imaging) revealed structural alterations in the brains of old mice 5 weeks after the injection of 0.002 mg/kg THC: Diffusion Tensor Imaging (DTI) detected a lower mean diffusivity, indicating higher tissue density in various brain regions including the entorhinal cortex, amygdala, cingulate cortex and caudate/putamen. T2 relaxation images demonstrated a larger volume of 3 regions (entorhinal cortex, prefrontal cortex and posterior hippocampus) in brains of THC-treated old mice. These findings suggest that extremely low doses of THC, that devoid any psychotropic effect and do not induce desensitization, may provide a safe and effective treatment for mild cognitive impairments in ageing humans. References: (1) Behav. Brain Res. 220, 194 (2011); (2) Exp. Brain Res. 221, 437 (2012); (3) J. Neurosci. Res. 92, 1669 (2014)
1, Wolf G.1, 6, Lifschytz T.1, Ben-Ari H.1, Kreisel-Merzel T.2, Tatarsky P.1, Valitzky M.3, Avidan E.1, Mernick B.1, 4, Koroukhov N.5, Lotan A.1,
1Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 2Department of Developmental Biology and Cancer Research, Hadassah- Hebrew University Medical School, Jerusalem, Israel ; 3Neurology Laboratory, Department of Neurology, Hadassah- Hebrew University Medical Center, Jerusalem, Israel; 4Developmental Psychopathology Laboratory, Department of Psychology, University of Haifa, Israel; 5Cardiovascular Research Center, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 6Departments of Psychology and Life Sciences, School of Sciences, Achva Academic College, Be'er Tuvia, Israel ;
Bilateral common carotid artery stenosis (BCAS) models the effects of compromised cerebral blood flow on brain structure and function in mice. We compared the effects of BCAS in aged (21 month) and young adult (3 month) female mice, anticipating a differentially more severe effect in the older mice. Four weeks after surgery there was a significant age by time by treatment interaction on the radial-arm water maze (p=0.014): On the first day of the test latencies of old mice where longer compared with the latencies of young mice, independent of BCAS. However, on the second day of the test, latencies of old BCAS mice were significantly longer than old control mice (p=0.049), while latencies of old controls were similar to those of the young mice, indicating more severe impairment of hippocampal dependent learning by BCAS in the older mice. Fluorescence staining of myelin basic protein (MBP) showed minimal white matter damage in young BCAS mice whereas degradation of myelin was most pronounced in the old BCAS group (p<0.0001). Interestingly, the intensity of MBP signal of old control mice was lower compared with young controls (p<0.05), indicating that old age induces changes in myelin consistency. While microglia morphology was assessed as normal in young control and young BCAS mice, microglia of old BCAS mice exhibited the most striking activation in the area of degraded myelin compared to young BCAS (p<0.01) and old control mice (p<0.05) . These findings show a differentially more severe effect of cerebral hypoperfusion on cognitive function, white matter integrity and inflammatory processes in aged mice. Hypoperfusion may exacerbate degradation initiated by aging, which may induce more severe neuronal and cognitive phenotypes. Supported by: Israel Ministry of Science, Technology and Space, Japan-Israel Scientific Research Cooperation.

Addictive Disorders

1, Yanovitz C.1, Kirby M.1, Michaelevski I.1, Yadid G.2, Pinhasov A.1,
1Department of Molecular Biology, Ariel University; 2Leslie and Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar Ilan University;
Recent studies show that social interactions including social inequality, dominance, and social dependence are strongly involved in drug addiction, especially in subordinate individuals who often use drugs as an escape from negative and depressive feelings and stressful situations. The current study made use of selectively-bred stress-resilient, socially-dominant (Dom) and stress-vulnerable, socially-submissive (Sub) mice to investigate the interaction between environmental stress and genetic predisposition to develop addiction to cocaine. In Conditioned Place Preference (CPP) paradigm using cocaine, Sub mice displayed an aversion to drug compared with wild type mice (Sabra), whereas Dom mice displayed drug attraction. Following a 4-week regimen of Chronic Mild Stress (CMS), Sub mice in CPP displayed a marked increase (>400%) in cocaine attraction, whereas Dom mice did not differ in attraction from their non-stressed state. Examination of hippocampal gene expression revealed that CMS alone induced increase in CRF expression in Sub mice (>100%), whereas increases were only seen with cocaine in Dom mice. CMS also universally reduced CRFR1 expression, regardless of drug treatment. Further, CMS-induced decreases in DR1 (>60%) and DR2 (>50%) expression in Sub mice differed markedly from a complete lack of change in Dom mice. Tegmental-hippocampal projections are known to invoke aversion behaviors counteracting limbic drive in response to salient addictive stimuli. Reductions in tegmental-hippocampal tone would alleviate physiological antagonism of mesolimbic circuits. We report here an emerging model of drug addiction which may reside in personality differences with stress-vulnerable individuals developing addictive behavior as a combined result of increased limbic drive and reduced stimulus aversion.
1, Lenchinski T.1, Rubovitch V.1, Katz Y.2, Cohen E.2, Wolf E.2, Schreiber S.3, G. Pick C.1,
1Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.; 2Analytical Laboratory, Department of Identification and Forensic Science, Israel Police, Jerusalem, Israel.; 3Department of Psychiatry, Sourasky Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.;
In recent years, synthetic cannabinoids have become more popular. These psychoactive substances are designed in attempt to mimic the euphoric effects of the natural cannabis. Novel unregulated compounds appear once older compounds become controlled by law authorities around the world. It has been previously reported that synthetic cannabinoids are not just other forms of Δ9-tetrahydrocannabinol (Δ9-THC); the active component of cannabis. These compounds have chemical structures unrelated to Δ9-THC, different metabolism, and often, greater toxicity. This study aimed to investigate the effects of three novel synthetic cannabinoids and pure Δ9-THC on memory function, exploratory behavior and locomotor activity. To attain these goals we performed a battery of behavioral and motor tests starting 50 min post i.p. injection of each drug to adult ICR mice. The synthetic cannabinoids that were used are AB-FUBINACA, AB-CHIMINACA and PB-22. All synthetic cannabinoids and Δ9-THC caused spatial memory deficits and decreased exploratory behavior as was measured in the Y-maze and staircase paradigm respectively. However, all synthetic cannabinoids but not Δ9-THC demonstrated decreased locomotor activity in the staircase test. Moreover, none of the drugs affected muscle strength and balance in exception of a high dose of AB-FUBINACA which significantly lowered the latency time to fall when mice were suspended on a metal rod with their four limbs. However, when mice were suspended on the rod with their two forelimbs, AB-FUBINACA and Δ9-THC caused a decrease in the latency time to fall. These results suggest varied effects among different synthetic cannabinoids and Δ9-THC. Further studies are needed in order to characterize the overall effects and differences between these synthetic cannabinoids and Δ9-THC such as on anxiety, depression or psychosis-like behavior.
1, 2, Malik E.1,2, Schreiber S.1,2, Sason A.1, Adelson M.1,
1Adelson Clinic for Drug Abuse Treatment & Research, Tel-Aviv Medical Center ; 2Sackler Faculty of Medicine, Tel Aviv University;
Aims: To study the prevalence of high perceived stress and characterize its risk factors among methadone maintenance treatment (MMT) patients, as stress dysregulation is known to be normalized during MMT. Methods: Random sample of 107 of the current (January 2015) 326 MMT patients were studied using a Perceived Stress Scale questionnaire. History of adverse events, ASI questionnaire, 21-Ham-D rating scale and urine test results were taken. Results: Of the 107 patients, 25% were females. Mean age of opiate use onset was 22.1±7.2, at admission to MMT 41.2±11.0, and current age 50.4±10.8. Mean stress score was 17.6±9.3 (range 0-38), and a high stress level (scored >18) was found among 48.6%. Higher scores were found among the 31 benzodiazepine abusers (24.0±9.1 vs. 15.0±8.1, p<0.0005), and 19 cocaine abusers (22.4±9.5 vs. 16.5±9.0, p=0.01). Scores were higher among 77 patients living alone (18.9±9.2 vs. 14.2±9.0, p=0.02), among 23 patients with history of self-harm (23.0±7.9 vs. 16.3±9.1, F=10.3, p=0.002), 22 patients with history of suicide attempts (23.8±7.9 vs. 16.1±9.0, p<0.0005) and 22 depressed (Hamilton >18) patients (23.6±8.9 vs. 16.0±8.9, p=0.001). Scores did not relate to gender, age (admission or current) and duration in treatment. Logistic regression for high perceived stressed (scored>18) found benzodiazepine abuse (OR= 4.1, 95%CI 1.4-12.0), history of self-harm (OR= 5.5, 95%CI 1.6-18.8) suicide attempts (OR= 3.8, 95%CI 1.1-13.2) and depressed (OR= 3.7, 95%CI 1.1-12.0) to characterize high perceived stressed patients. Perceived stress score was also related to number of current drug abuse and number of adverse events (Corrected mode F=4.6, p<0.0005, Drug abuse F(d.f=2)=7.5, p=0.001; Adverse events F(d.f=2)=4.3, p=0.02). Specifically, the highest score was among patients with more than 2 adverse events and more than 2 drugs abuse and the lowest score was among those with no adverse events and no drug usage. Conclusions: Half of the MMT patients presented high-perceived stress level which was related to their history of adverse events and current drug abuse. The patients' heterogeneity, which most likely precedes treatment admission, may explain the absence of relation between stress level and duration in treatment. A prospective study is needed in order to measure perceived stress changes (reduction) over treatment (parallel to HPA axis normalization).
1, Schreiber S.1,2, Adelson M.1, Peles E.1,2,
1Adelson Clinic for Drug Abuse, Treatment & Research, Tel-Aviv Sourasky Medical Center; 2Sackler Faculty of Medicine Tel Aviv University ;
Background: Methylphenidate, an amphetamine-like prescription medication for attention deficit hyperactivity disorder (ADHD) was previously found to be abused among about 15% of our MMT patients. Aims: To evaluate the motives, circumstances and patterns, and the knowledge of patients about methylphenidate indication, effects and risk, and to explain patients about the risk. Methods: Structured questionnaire (scored 0-19) about knowledge and usage of methylphenidate were filled before and following a brief explanation about methylphenidate indication, effects and risk given by patients' therapist. Results: Of the 239 participants, 37.7% reported of lifetime usage. Most of the current participants (95%, n= 227) were previously tested for methylphenidate. Of the 227 participants, 43(18.9%) were tested positive, and 81.4% of these 43 currently reported of “ever used” (only 8 of the previously tested positive, currently reported as “never used’). Before explanation, knowledge score was higher among the ever (10.4±4.1) than the never used (8.9±4.4, p=0.01), improving to the same level following explanation (13.6±4.2, Repeated measured, p<0.0005). The question of methylphenidate effect was correctly answered as stimulant by 76.6% of the ever used compared to only 53.4% of the never used, whom 33.1% incorrectly thought it’s an anxiolytic (compared to 19.5% of the ever used) pain relief/ analgesic/unknown (13.6% vs. 3.9%, p=0.004). Higher proportion of BDZ in urine (58.8% vs. 41.1%, p=0.01) and dual diagnosis (any Axis I 56.6% vs. 41.3%, p=0.03) characterized the current 85 patients who reported of being ever users with no other differences. Conclusion: Education is important to eliminate abuse. However some of the methylphenidate usage seems to be due to self- medication, therefore ADHD diagnosis and treatment is recommended.
Bareli T.1, Barnea R.1, Ahdoot H.1, Werhaftig G.1, Maayan R.3, Weizman A.3,4, Yadid G.1,2,
1Neuropharmacology laboratory, Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel ; 2Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center, Israel; 3The Laboratory of Biological Psychiatry, Felsenstein Medical Research Center and Sackler Faculty of Medicine, Israel.; 4Geha Mental Health Center, Petah Tikva, Israel;
Ras-related C3 botulinum toxin substrate (RAC), a part of The Rho family of small GTPases is a key regulator of the actin cytoskeleton rearrangement and play important role in dendritic morphogenesis. Cocaine produces neuronal alterations including structural changes in dendritic spine morphology and amount. Here we report that a combination of two FDA approved drugs, opipramol for anxiety and baclofen for spastic movement disorders, have synergistic effect on cocaine seeking behavior in a rat model for cocaine abuse mediated by RAC1. Several previous studies marked sigma-1 receptor as a promising target for prevent craving. Also, sigma-1 receptor binds in a complex with RAC1 gene that regulates a diverse array of cellular events, including synapses formation and morphology changes of dendritic spines. Hence we used a sigma-1 receptor medication (Opipramol) to treat cocaine-addicted rats. We combine it with Baclofen a GABAb (Gabbr1) receptor agonist that was shown to moderately affect craving. In our study, rats were trained to self-administer cocaine (0.5 mg/Kg; FR1) till maintenance, then underwent extinction till abstinence. Opipramol (12.5 mg/kg, i.p) and Baclofen (0.1 mg/kg, i.p) were co-administrated longitudinally throughout the extinction session. Rats were reinstated by i.p. cocaine injection (10 mg/Kg) and drug seeking behavior was monitored. We found that the combination of opipramol and baclofen significantly decreased active lever responding during extinction. Moreover, they also decreased active lever pressing in the relapse test and normalized the RAC1 mRNA levels relative to sham- operated rats. In another experiment, RAC1 inhibitor injected directly to the NAc core decreased active lever presses in the first day of the extinction. We postulate that a combined activation of sigma1 and Gabb1 receptors can suggest a new approach to treat addicts. RAC1 inhibition may play a critical role in decreasing drug seeking and rehabilitation.
Ahdoot H.1, Croitoru O.1, Sudai E.1, Bareli T.1, Yadid G.1,2,
1Neuropharmacology Laboratory, The Mina & Everard Goodman Faculty of Life Sciences, Israel; 2The Leslie and Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center, Israel;
Aims: Drug addiction is a chronic brain disorder, characterized by the loss of ability to control drug consumption.The mean obstacle in rehabilitation is not the detoxification process but the high rates of relapse that cannot be predicted by any biological or psychological means.Previously, we have found that self-administration (SA) cocaine in a rat model can attenuate neurogenesis in the hippocampus and the neurosteroid DHEA can decrease cocaine craving,parallel to normalization of neurogenesis.In this study we aimed to find a predictive value for relapse by the use of a non-invasive method such as DTI.Methods: Sprague-Dawley rats were trained to SA cocaine (1.5 mg/Kg; FR1) or saline for 1 hour daily until stable maintenance levels were attained.Rats were injected i.p. With DHEA or vehicle 90 mins before exposed to the operant chamber for extinction.MRI was performed followed by DTI analysis of the images. BrdU injected i.p. at day 10 of extinction.The brains were sliced and stained for BrdU & Neun and for s100β.Results: Scanning the rat's brains has shown a marked change in DTI parameters in parallel to their craving and relapse to drug usage.However correlating these measures with neurogenesis showed significance but in an opposite direction.Astrocytes volume was also changed at the end of extinction.These results were correlated with lower cocaine seeking behavior in the relapse test.Discussion & Conclusion:We postulate that cocaine decrease neurogenesis and increase astrogliosis in the DG. DHEA attenuation of cocaine seeking behavior may be due to its beneficial effect on astrocytes that may allow neurogenesis restoration. Moreover ADC measurement demonstrates decrease in total area diffusion in the DG of cocaine SA rats, whereas DHEA treatment normalized ADC values. This can be explained by correlation with astrogliosis and not neurogenesis.The DTI method enables non-invasive examination, which we may predict patient's chances of remaining clean months later
1,2, Schreiber S.1,2, Sason A.1,2, Adelson M.1,
1Adelson Clinic for Drug Abuse, Treatment & Research, Tel Aviv Medical Center; 2Sackler Faculty of Medicine Tel Aviv University ;
Background: Methadone Maintenance Treatment (MMT) is the best treatment for opioid addiction. However, many of the opioid addicts abuse stimulants as well. Aims: To compare characteristics and outcome of MMT patients with and without cocaine abuse on admission to MMT. Methods: Study population included all patients admitted to Adelson clinic between June/1993 and June/2015 and stayed at least 3 months. Patients were divided into 4 groups by their cocaine in urine on admission (1st month) and after one year (13th month, or last month if left earlier). Patients' characteristics and long term outcome (up to 23 years) were compared. Results: Of the 790 patients, 23.3% abused cocaine on admission, and more than half of them stopped it during treatment. Specifically, 536 (67.8%) "Never", 100 (12.7%) "Stop", 84 (10.6%) "Always", and 70 (8.9%) "Start" abusing cocaine while in MMT. Comparing the 4 groups, female gender (25.8% of the whole sample) was the most prevalent 36.9%, among the "always" group. Usage opioids of ≥20 years was among 37.4% of the sample, was most prevalent (52.6%) among "always" group. Mean age of admission was 40.9±10 for all sample, but was the youngest (36.2±9.6) at the "Start" group. The "Stop" group had the lowest opioids (22%), and benzodiazepine (51%) abuse after one year, and the highest one year retention rate (93%). They also had the highest methadone daily dosage (147.8±42.6mg/d) that was comparable with the "Always" group (139.5±37.4mg/), however significantly higher than the 2 other groups (119.8±46.1mg/d). Conclusion: The "stop" group had the best retention and opioid abstinence. Those who fail to stop characterized with more years of opioid usage and more females. Higher methadone dose characterized the cocaine abuser, and it seems to be associate with stop cocaine. Half of the cocaine abusers can achieve abstinence with adequate methadone dose that is needed to reduce cocaine and opioids abuse.
Ami Citri's lab,
1Gal Atlan ,Noa Peretz- Rivlin, Ben Jerry Gonzales, Ami Citri ;
The claustrum is a thin sheet of neurons, hidden between the insula and the striatum. Relative to its volume, the claustrum is the most interconnected structure in the brain, warranting its investigation. Due to its complex structure, very little progress had been made during the past decade regarding its function. Our interest in the claustrum was spurred by the serendipitous identification of a transgenic mouse that enables genetic access to neurons in the claustrum. We identified specific expression of the immediate early gene Egr2 in claustral neurons, allowing us to delicately and accurately manipulate them, thus circumventing the elusive morphology of this structure. Utilizing our unique genetic access, we found that inactivating claustral neurons blocked the development of behavioral sensitization to cocaine, and hindered the performance in selective attention demanding tasks. These results adds up to a number of theories that have been raised regarding the function of this enigmatic brain region. Multiplexed fluorescence single molecule in-situ hybridization conducted in our lab revealed that the EGR2 expressing cells are a sub population of dopamine receptor D1 expressing cells, a finding that sparked our interest in this claustral dopamine reactive ensemble. We performed a real time conditioned place preference experiment using optogenetics in D1-Cre transgenic mice expressing ChR2 in the claustrum and observed a clear preference towards the side of the chamber in which blue light stimulated D1R expressing claustral cells These results begin to unveil distinct molecular characteristics of the claustrum, and create a foothold for further investigation of this mysterious structure’s function in reward and attention behavior.

Cognitive neuroscience

1, Shamay-Tsoory S.1,
1Department of psychology, University of Haifa. ;
The neural mechanisms that facilitate the experience of vicarious social touch are largely unknown. Two neural simulation systems might contribute to processing of vicarious social touch: the inferior frontal gyrus (IFG), which has been previously suggested to be part of a simulation observation-execution neural network and to play a key role in the perception of tactile stimuli and attenuation in the mu\alpha rhythm (8-13Hz), also known as mu suppression, a neural marker that has been related to sensorimotor resonance. In a series of experiments, we found that both the mu suppression over sensory motor cortex, and excitability levels of the IFG are related to vicarious social touch and are modulated by individual levels of empathy. In experiment I, we showed fifty-four participants photos depicting social touch, non-social touch or no touch while their electroencephalography (EEG) activity was recorded. Results showed that highly empathic participants evaluated vicarious social touch as inducing more pleasant emotions and exhibited greater mu suppression upon observation of human social touch compared to less empathic participants. Specifically, both the behavioral and the electrophysiological responses to observed social touch were predicted by levels of personal distress, a measure of emotional contagion. In experiment II, we used anodal transcranial direct current stimulation (tDCS) with forty participants who observed the same photos during tDCS or sham stimulation. The results show that while participants with high levels of emotional empathy showed no change in ratings of vicarious social touch, participants with low levels of emotional empathy rate human touch as more emotional following anodal stimulation of the IFG than following sham stimulation. Combining the findings from the two experiments we reasoned that vicarious social touch is facilitated through known simulation mechanisms but is differentially affected by levels of empathic traits.
1,2, Lifschytz T.1, Lotan A.1, Tararskyy P.1, Lerer B.1,
1Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.; 2Department of Psychology, School of Sciences, Achva Academic College, Be'er Tuvia, Israel;
Chronic stress (CS) induces cognitive enhancement in young adult female mice, while its effects on old females are mainly impairing. Focusing on male mice enables us to reveal similarities and dissimilarities compared with our previous results with females. Young adult (3 months) and old (20 months) C57BL male mice were exposed to chronic stress (CS) or control conditions for 5 weeks, after which they underwent extensive behavioral testing while continuing exposure to CS. CS consisted of psychological stressors delivered weekly, in random order. CS induced significant weight loss in old but not young adult mice, reflected by a triple interaction of age, CS, and time (p=0.04). Age by CS interaction was also demonstrated in stress-induced hyperthermia (p=0.024), indicating that CS increased the response to acute stress in young adult mice and blunted the response in old mice. CS increased the amount of time young adult but not old mice spent in the center of the open field (p=0.023). This interaction may reflect reduced anxiety of CS-exposed young adult mice. Both age (p<0.0001) and CS effects (p=0.002) were found in the radial-arm water maze. Old mice displayed longer latencies compared with young adult mice (p<0.0001), while CS mice displayed shorter latencies compared with control mice (p<0.0001). Taken together, these results suggest that chronic stress induces different outcomes in young adult and old male mice, similar to our observations in females. Young mice appeared resilient to CS, whereas old mice displayed resilience on some aspects and vulnerability on others. It still needs to be elucidated whether CS induced differential effects on brain mechanisms as we have previously observed in female mice (reduced dentate gyrus volume, increased hippocampal BDNF and miR375 expression). Supported by a grant from the Israel Ministry of Science, Technology and Space, Japan-Israel Scientific Research Cooperation Program.
1, Lotan A.1, Wolf G.1, Ben Ari H.1, Tatarskyy P.1, Kreisel Merzel T.2, Mernick B.1,3, Lerer B.1,
1Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 2Department of Developmental Biology and Cancer Research, Hadassah- Hebrew University Medical School, Jerusalem, Israel ; 3Developmental Psychopathology Laboratory, Department of Psychology, University of Haifa, Israel;
Late life depression (LLD) is an age dependent phenomenon that is thought to be influenced by environmental stress and is frequently accompanied by anxiety and cognitive decline. A key question for experimental evaluation is whether stress-related effects on affective, cognitive and molecular phenotypes are indeed age related. We investigated this question in female C57BL/6 mice aged 3 (young) and 23 (old) months that were subjected an 8 week chronic stress (CS) protocol. In the final 3 weeks a battery of cognitive-behavioral tests was administered to evaluate CS effects. Old females were more vulnerable to the effects of CS than young females, showing reduced weight and hyper locomotion in the open field. Young females showed reduced anxiety like behavior and enhanced cognitive functioning, contrary to old females that did not benefit from the stress. These finding were correlated with histological studies. These showed that in young females CS caused an increase in hippocampal dentate gyrus (DG) BDNF levels, and in DG area while old mice did not show such CS effects. Another correlation for the differential effects of CS across age was found in hippocampal miRNA expression analysis; expression profiles in CS exposed young females were significantly higher than in CS exposed old females and there was a specific increase in miR-375. Thus, our studies demonstrated differential behavioral effects of CS across age. Young females may actually benefit from stress, while in old females there are negative effects. The molecular correlates we observed could be related to the age dependence of stress modulated neuropsychiatric disorders. Supported by: Israel Ministry of Science, Technology and Space, Japan-Israel Scientific Research Cooperation
1, Rubinson M.2, Moses E.2, Levit-Binnun N.3, Gothelf D.4,
1Ness ziona mental health center; 2Weizmann institute; 3Interdisciplinary center; 4Sheba medical center;
Background: Attention and hyperactivity disorder (ADHD) has long been thought to reflect circuitry dysfunction. Recently it has shown that there is abnormal widespread brain networks dynamics in individuals with ADHD. However, data about global network connectivity dynamics after methylphenidate (MPH) treatment is lacking. Project aim: To evaluate MPH effect on global network connectivity dynamics in youth with ADHD. Design and methods: Double blind cross-over placebo controlled study. Twenty youths with ADHD and age and sex matched controls were recruited. Neurocognitive computerized tasks battery was administered for each subject twice in one day while simultaneously measuring EEG. In the study group, the second battery of each test day was administered 1 hour after ingestion of Placebo/MPH - alternately. Control group second battery was administered after 1 hour break. Data preprocessing and artifact correction was made using EEGLAB. Network analysis was made using matlab. EEG data and network analysis was made for the data recorded during the Sustained attention response task (SART). Results: Significantly higher scores were measured after MPH treatment compared to placebo within all tasks. Control group revealed significantly higher commission scores ("No-Go" precision) on the second trials in the SART. Global efficiency was significantly lower on second trials in the control group. Same network analysis in the ADHD group revealed significantly higher global efficiency after placebo and no significant change in global efficiency after MPH treatment. Significant post-stimuli global efficiency change from baseline was observed in all conditions. These differences were prominent 900ms following the cognitive stimuli before returning to baseline. Conclusions: We found inverted network patterns in ADHD patients during high cognitive demanding tasks. This network pattern inversion was moderated after MPH treatment, suggesting an MPH effect on ADHD related global connectivity dynamics. These network alterations were time sensitive and may reflect flexibility moderation of the network underlies MPH effect on attention in ADHD.
1,2, Koren A.3,4, Levin C.3,4,
1Departments of Behavioral Sciences, The Center for Psychobiological Research, The Max Stern Yezreel Valley College; 2Department of Psychology, Tel Hai College; 3Pediatric Hematology Unit, Emek Medical Center, Afula; 4The Ruth and Baruch Rappaport School of Medicine, Technion, Israel Institute of Technology, Haifa;
Background: Beta thalassemia major (β-TM) is an inherited hemolytic anemia. Patients with β-TM are transfusion-dependent for life, and develop iron overload with impaired function of vital organs. They are also at risk of developing cognitive and neural impairments. The aim of the present study was to assess cognitive function and to identify potential alterations in scalp-recorded Event-Related Potentials (ERPs) in adults with β-TM compared with matched healthy controls. To date, ERP studies in the field of β-TM are scarce and limited to children. Methods: β-TM patients and healthy controls (n=17 and 25, respectively) participated in the study (age > 18 yr). Attention and response inhibition function and ERPs were examined using a stop-signal task in which participants have to quickly and effectively respond to frequent Go stimuli while withholding their response when a Go stimulus is immediately followed by a stop sign. The ability to inhibit inappropriate or irrelevant responses (i.e. response inhibition) requires a fast control mechanism that prevents the execution of the motor response, and considered a hallmark of executive function control. EEG was recorded continuously using a 64-channel HydroCel Geodesic Sensor Net. Correlations between task performance, ERPs and hemoglobin levels were also examined. Results: results showed impaired cognitive performance in β-TM patients, as indicated by longer response times than controls to both Go stimuli and Stop signal stimuli. Hemoglobin levels were negatively correlated with response times to Go stimuli. Electrophysiological results indicated significant alterations in peak amplitudes of several ERP components; β-TM patients, relative to controls, had greater P1 and P2 to Go stimuli and greater P1, N1 and P300 to Stop signals. Significant moderate to strong correlations were found between hemoglobin levels and amplitude of all ERP components; the lower the hemoglobin level, the greater (more pronounced) the ERPs amplitude. Conclusions: our results indicate impaired attention and response inhibition function in β-TM patients, accompanied by significant alterations in neural activation. The present study represents a novel investigation of cognitive function and related brain dynamics in β-TM in adult. Integrating neurophysiologic and neuropsychological assessment and interventions, designated for adults, into traditional disease management, may be imperative in achieving a better quality of life for these patients.
1,
1University of Haifa;
Models of emotional processing highlight the interactions between emotional and attentional systems. These views are based on evidence that emotional information is prioritized and impact attentional functions, as well as evidence that attention and control mechanisms mediate reactions to aversive stimuli. Most of the views today suggest a balance between bottom-up emotions, triggered automatically by limbic regions, and top-down regulation by cortical regions. However, our findings suggest the existence of bottom up (not only top-down) control. In this talk, I will present evidence that attention mechanisms and anxiety-related personality traits and tendencies modulate behavioral, neural and autonomic (basic motor-related blood pressure) reactions to highly-negative material. This evidence suggests that individual characteristics shape the connectivity within a neural network that is involved in the reactions to emotional stimuli; activation in this neural network is further modulated by attention. These findings have possible clinical implications for individuals that show dysfunctional reactions to emotional stimuli.
1,2, Ben Ari H.1, Lotan A.1, Lifschytz T.1, Tararskyy P.1, Mernick B.1, Lerer B.1,
1Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.; 2Department of Psychology, School of Sciences, Achva Academic College, Be'er Tuvia, Israel;
The Ahi1 gene has been associated with several psychiatric disorders. We have previously demonstrated reduced anxiety of Ahi1+/- mice under basal conditions. The present study was designed to test the role of Ahi1 in responsiveness to chronic stress (CS) using behavioral and histological outcome measures. The sucrose preference test was used to evaluate the efficiency of CS. Only Ahi1+/+ mice displayed reduced sucrose preference (SP) following CS, reflected by a significant effect of genotype (F(1,21) = 6.593, P<0.05) on two-way ANOVA . Post hoc comparisons indicated that CS reduced SP in Ahi1+/+ mice compared with Ahi1+/+ controls (p<0.05) but had no such effect in Ahi1+/- mice. Stress-induced hyperthermia tested the effect of CS on an acute stress response. CS induced a blunted response in Ahi1+/+ mice but had no effect on Ahi1+/- mice, as reflected by triple interaction of genotype, treatment, and time (F(1,63) = 5.001, p<0.05) on two-way ANOVA with repeated measures. In the open field test CS increased the amount of time Ahi1+/+ mice spent in the center of the arena, but had no effect on Ahi1+/- mice, reflected by significant exposure by genotype interaction on two-way ANOVA (F(1,70)=6.21, p<0.05). Testing for neurogenesis, doublecortin straining revealed an increased rate of newly formed neurons in Ahi1+/+ mice following CS, but no similar effect on Ahi1+/- mice, reflected by a main effect of genotype (F(1,23)=6.189, p<0.05) and marginal genotype by exposure interaction (F(1,23)=4.129, p=0.054). Post hoc comparisons indicated increased neurogenesis in Ahi1+/+ mice following CS compared both with Ahi1+/+ controls (p<0.05) and Ahi1+/- CS (p<0.01). Taken together, these results indicate that not only do Ahi1 deficient mice manifest a basal anxiolytic-like phenotype, they are not responsive to CS, suggesting that Ahi1 is involved in detection of fear-inducing stimuli. Supported by a grant from the ISF in the context of a cooperative research program with NNSFC
1,2, Sheppes G.1,2,
1The School of Psychological Sciences, Tel Aviv University; 2Sagol School of Neuroscience;
Although recent conceptual models highlight that emotion regulation (ER) is a complicated process that involves several regulatory stages, empirical studies have focused on an implementation stage involving actual execution of regulatory strategies. Little is known about a post-implementation regulatory stage, which involves monitoring an implemented regulatory strategy across time. In this stage, a particular regulatory strategy is implemented on a particular stimulus that differs in its emotional intensity. Specifically, distraction involves disengaging attention from emotional stimuli by producing unrelated neutral thoughts. By contrast, reappraisal involves engaging attention with the emotional stimuli by producing less negative interpretations. The combination of emotional intensity (high, low) and a regulatory strategy (distraction, reappraisal) constitutes regulatory preferences. Most broadly, in low intensity individuals prefer reappraisal over distraction, because whereas both strategies equally modulate emotion, only reappraisal offers long term benefits. In high intensity individuals prefer distraction over reappraisal because distraction more strongly modulates emotion. The present study examined how regulatory preferences influence post-implementation choices, and the short-term neural consequences of these choices. 28 participants implemented distraction or reappraisal on an image of high or low intensity, and then chose whether to maintain or switch. To uncover short-term neural consequences, we measured the Late Positive Potential (LPP), an electro-cortical component that is attenuated during successful ER, following choice. We expected and found that regulatory preferences strongly predicted choice to maintain the initial implemented strategy. Furthermore, only in high intensity, when distraction is both more preferred and more effective relative to reappraisal, regulatory preferences were associated with adaptive short-term neural consequences.
Naor N.1, Zilberman S.1, Russo M.1, Siboni N.1, Shamay-Tsoory S.1, Okon-Singer H.1,
Empathy represents a fundamental ability that allows for the creation and cultivation of social bonds. As part of the empathic process, individuals use their own emotional state in order to interpret others’ emotions and to accurately judge their intensity. Termed by Carl Rogers, empathic accuracy is the moment to moment change in one's ability to recognize the intensity of others' specific thoughts and feelings. In study one, we show that exposure to stimuli designed to elicit empathy hinders accurate valence recognition of facial expressions, thus demonstrating a bias in recognition of emotional facial expression as a function of empathy for pain. In study two, we further examine whether this bias can be modulated by emotional desensitization, a numbing or blunting of emotional reactions to events which would typically elicit a strong response. To this aim, we assessed the effect of exposure to short films depicting violence from the media on judgments of the intensity of pain in facial expressions.
1, Karklinsky M.2, Shamay-Tsoory S.1,
1Department of psychology, University of Haifa, Israel; 22) Department of computer science and applied mathematics, Weizmann Institute of Science, Israel;
We study how human groups synchronize common movements. Human or animal group movements arise from the actions of each group member, and reflect the group's social and communication patterns. We examine how emerging spatiotemporal movement patterns reflect individual characteristic of the group members, especially their empathic tendencies. We rely on two observations regarding animal group behavior. The flocking patterns of birds suggest that a bird's social position in the hierarchy determines its flight direction, leading or following other birds' directions [Nagi et al., 2010]. In fish, local relations between individuals may define their direction and lead to swarming behavior [Paley et al., 2007]. Our experiment examined whether the basic principles of collective animal behavior may shape how human groups move. Importantly, we were also interested in examining spatial patterns of human group movements is determined by the empathic tendencies of the group. We let 30 groups of 4 subjects play a computer game. Each subject used four arrows to move a circle inside a common square arena, while seeing the movements of the 3 other players. Additionally, all subjects filled in the empathy questionnaire. We tested whether group members interact with others differently according to the distances between their circles. The distances between group members define a time-dependent communication network structure that yields a natural definition of a group's synchronicity measure [Paley et al., 2007]. We present preliminary findings; synchronization between humans may depend on their relative distances. Interestingly, individuals with a high empathy score moved their circles nearer to others'. This suggests that traits of the individuals forming a group, such as their empathic tendencies, come into play when a collective animal-like synchronization behavior emerges.
1,2, Reuveni I.3, Keadan T.2, Canetti L.3,4, Goelman G.2, Bonne O.3,
1Edmond and Lily Safra Center for Brain Sciences (ELSC), The Hebrew University of Jerusalem, Israel; 2MRI Lab, The Human Biology Research Center, Department of Medical Biophysics, Hadassah Hebrew University Medical Center; 3Department of Psychiatry, Hadassah Ein-Kerem Hospital, Israel; 4Department of Psychology, The Hebrew University of Jerusalem, Israel;
We here present the effect of gender on the neural encoding of emotions by large-scale functional connectivity networks. Previous research has demonstrated an effect of gender on regional brain activations in response to emotional stimuli. However, no study to date has examined the influence of gender on the synchronization between remote brain regions in response to different emotions. Synchronized oscillatory neural networks are viewed as a mechanism for generating cerebral integration, which is thought to play a key role in the formation of emotions. Here, 40 young healthy Israeli students (20 females, 20 males) underwent an fMRI scan. Each scan included induction of sustained emotional states (10 minutes each) of sadness, happiness and a neutral state using film clips. Gender differences are examined for each functional connectivity network of each emotion and possible clinical relevance of the findings is discussed.
1, Yechiam E.1,
1Techion - Israel Institute of Technology;
Considered an antidepressant and anti-anxiety agent, Hypericum perforatum affects multiple neurotransmitters in a non-competitive synergistic manner, and may have nootropic potential. We quantitatively reviewed the pre-clinical literature to examine if there is a cognitive-enhancing effect of H. perforatum in healthy rodents. Additionally, within these studies, we compared the effects observed in intact rodents versus those whose performance has been impaired, mostly through stress manipulations. The meta-analysis incorporated studies that examined the effect of H. perforatum versus placebo on memory indices of task performance. All analyses were based on weighting different studies according to their inverse variance. Thirteen independent studies (published 2000-2014) involving 20 experimental comparisons met our inclusion criteria. The results showed a large positive effect of H. perforatum on cognitive performance for intact, healthy rodents (d = 1.11), though a larger effect emerged for stress-impaired rodents (d = 3.10 for restraint stress). The positive effect on intact rodents was observed in tasks assessing reference memory as well as working memory, and was not moderated by the type of memory or motivation (appetitive versus aversive). Thus, while primarily considered as a medication for depression, H. perforatum shows considerable nootropic potential in rodents.
1, Biber Z.1, Alkoby O.1, Goldstein P.1, Okon-Singer H.1,
1University of Haifa;
Essential hypertension (EH) is an important risk factor for cerebrovascular diseases and a major cause of premature death in industrialized societies. A predisposing factor for EH is prehypertension: blood pressure (BP) values at rest that are at the higher end of the normal range. Similar to patients with EH, prehypertensives already show abnormal vascular and heart rate reactivity to stressing stimuli. However, daily life contains many more situations of mild aversive emotions than those involving highly aversive stress. Therefore, abnormal reactivity to mild negative emotion stimulation may constitute an important risk factor for future development of cardiovascular dysfunction. We compared the BP responses to neutral and negative pictures between prehypertensives and normotensive controls. BP reactions were analyzed in a continuous fashion, in contrast to previous studies that averaged BP responses across blocks. The innovative nature of this study required new pre-processing and analysis tools, including specific artifact corrections and non-linear regression models. Our findings showed that both prehypertensives and normotensives exhibited lower BP levels in response to negative compared to neutral pictures, replicating previous results with healthy participants. Furthermore, compared to controls, prehypertensives reacted with a steeper and larger decline in BP levels following negative pictures, followed by longer recovery to baseline levels. To the best of our knowledge, this is the first study to examine BP reactions to mild emotional stimuli among prehypertensives. Considering the high frequency and health risks related to prehypertension, understanding the autonomic reactions to emotional stimuli in this population is of clinical importance. Knowledge derived from this study is further important in order to better understand autonomic reactions to emotions in different populations exhibiting dysfunctional emotions such anxiety or depression.
1,2, Marom-Katz A.2, Okon-Singer H.3, Goldway N.2,6, Sharon H.2,7, Keil A.4, Shamir R.5, Hendler T.2,6,7,
1Psychology Department, University of Californai, Berkeley; 2Tel Aviv Sourasky Medical Center, Functional Brain Center, Tel Aviv, Israel; 3Department of Psychology, University of Haifa, Haifa, Israel; 4Center for the Study of Emotion and Attention, University of Florida, Gainesville, Florida , USA; 5Blavatnik School of Computer Science, Tel-Aviv University, Tel Aviv 69978, Israel; 6Sagol school of Neuroscience, Tel Aviv University, Tel Aviv, Israel; 7Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;
Sleep deprivation has been shown to alter emotional processing possibly associated with reduced frontal regulation. Such impairments can ultimately fail adaptive attempts to regulate emotional processing (also known as cognitive control of emotion) though this hypothesis has not been directly examined. We therefore explored the impact of sleep deprivation on two different cognitive-emotional paradigms, recorded using fMRI and EEG. Both paradigms involved task-irrelevant emotional and neutral distractors presented during a competing cognitive task, thus creating a continuous demand for regulation of emotional processing. We further examined changes to the connectivity patterns of emotional networks prior to these tasks (i.e. during rest) to assess the impact of preexisting alterations in connectivity induced by sleep loss. Results reveal that while participants showed enhanced limbic and electrophysiological reactions to emotional distractors regardless of their sleep state, they were specifically unable to ignore neutral distracting information following sleep deprivation. As a consequence, sleep deprivation resulted in similar processing of neutral and negative distractors thus disabling accurate emotional discrimination. Such abnormal emotional reactivity was further predicted by changes in resting state connectivity of the limbic network, recorded prior to task performance. Furthermore and in accordance with our predictions, sleep deprivation triggered a decrease in prefrontal connectivity patterns in both EEG and fMRI tasks, reflecting a profound decline in cognitive control of emotion. Notably, such a decline was associated with lower REM sleep amounts, supporting a role for REM sleep in affective imbalance. Altogether, our findings suggest that losing sleep impairs emotional reactivity by lowering the threshold for emotional activation and that these changes can further be detected in the intrinsic connectivity of the sleep deprived brain. Such maladaptive loss of emotional neutrality can provide a novel mechanism by which disturbed sleep can bring about the development of anxiety.
Gurevitch G.1,2, Abend R.1,3, 1, Erdman A.1, Knirsh S.1, Weiss M.4, Pereman Z.4, Hendler T.1,2,5,
1 Tel Aviv Center for Brain Functions, Wohl Institute for Advanced Imaging, Tel Aviv Sourasky Medical Center; 2School of Psychological Sciences, Tel Aviv University; 3National Institute of Mental Health, USA; 4ElMindA Ltd.; 5Sagol School of Neuroscience, Tel-Aviv University;
Introduction: Attention Deficit Hyperactivity Disorder (ADHD) is hallmarked by deficits in response inhibition and sustained attention. Numerous fMRI and EEG studies have revealed the right inferior frontal gyrus (rIFG) as one of the underlying neural mechanisms associated with these deficits. Previous studies have shown that applying transcranial direct current stimulation (tDCS), a safe non-invasive method, while performing a task that requires response inhibition can improve performance. In this study we combine these techniques with the hope to achieve a more comprehensive model of ADHD, enabling a prediction for treatment success. Methods: Nine patients clinically diagnosed with ADHD were included in this study. The protocol consisted of pre and post-treatment EEG-fMRI scans measuring rIFG activity followed by 13 treatment sessions as well as pre and post behavioral assessments using the standard ADHD continuous performance task (CPT). Every third treatment session was conducted with EEG and tDCS. Patients were asked to complete a Stop Signal Task (SST) while under stimulation and a Go/NoGo task following stimulation. The remaining two thirds of the treatment sessions were tDCS only and asked the patients to perform the SST under stimulation. The stimulation protocol included 20 minutes of HD-tDCS (max current of 1mA) with five 1mm Ag/AgCl electrodes placed in a montage targeting the rIFG. Results: Analysis of the CPT revealed a significant decrease in reaction time standard deviation following treatment (p=0.01). Task improvement was found to be positively correlated with rIFG activation measured during response inhibition from a different task performed in the pre-treatment fMRI scan (r=0.76, n=6, p=0.07). Conclusion: This study suggests that sustained attention in ADHD can be modulated by rIFG electrical stimulation. These preliminary results demonstrate the potential clinical efficacy of combining stimulation with multi-modal monitoring for ADHD treatment.
1,
1Ben-Gurion University;
Synaesthesia is a condition in which a specific sensory dimension (inducer) elicits another sensation not commonly associated with it (concurrent). Synaesthetes may experience a specific colour when listening or thinking of numbers or letters. Large-scale behavioural studies have provided a rich description of the different synaesthesia phenotypes. Recently, great amount of research has been oriented to uncover whether a single or multiple brain mechanisms underlie these various types of synaesthesias. Interestingly, most of the synaesthetic inducers are conceptual stimuli such as numbers, letters, months and weekdays. Emotion is an important component associated with these conceptual inducers as synaesthetetes may report emotion displeasure when experiencing stimuli, which are incongruent with their association. We studied the anatomical correlates of specific conceptual inducers and their possible impact in emotion-related brain areas. We used Voxel-Based Morphometry (VBM) to compare grey matter (GM) volume in synaesthetes and non-synaesthete controls. Increase in GM was found in areas coding the semantic aspect of numbers (left angular gyrus) and in emotion related areas (amygdala and anterior cingulate cortex). These findings are discussed in line with current neurobiological models of synaesthesia.
1, Guri Y.1, Weisman O.1, Harel T.2, Gothelf D.1,2,
1Sackler Faculty of Medicine, Tel Aviv University, Israel; 2The Behavioral Neurogenetics Center, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Israel;
Background: The 22q11.2 deletion syndrome is the most common known genetic risk factor for the development of schizophrenia. The main goal of this study was to describe longitudinally the subthreshold psychotic syndrome and neurocognitive development in 22q11DS individuals. Additionally, we wished to identify the neurocognitive deficits that predict subthreshold psychotic syndrome. Method: A longitudinal design was implemented at 2 time points (14.7±2.1 months apart), and included 44 participants with 22q11DS, 19 with Williams syndrome (WS) and 30 typically developing controls (TD), age 12 to 36. Evaluation concluded standardized psychiatric measured and the computerized neurocognitive battery (CNB). Results: At baseline, individuals with 22q11DS, had the highest rates for subthreshold negative syndrome, compared to individuals with WS and TD.There was no significant effect of time on neurocognitive domains only for group, 22q11DS was found to have higher efficiency scores than WS, while TD controls had better performance compared to both groups. At baseline, individuals with 22q11DS but not those with WS, showed significant association between the presence of negative subthreshold psychotic and general neurocognitive performance (GNP), Executive Function and Social Cognition domains. In 22q11DS, deficits in GNP and younger age at baseline, predicted negative subthreshold psychotic syndrome at follow-up. Finally, 22q11DS individuals under medication showed more improvement in GNP efficiently score between baseline and follow-up. Conclusions: Our data suggest that neurocognitive deficits are associated with negative subthreshold psychotic syndrome in 22q11DS. In addition to their role in ameliorating psychiatric symptoms, psychiatric medications seem to improve neurocognitive functions in 22q11DS.
Glasner L.1, Shamay-Tsoory S.1,
1Department of Psychology, University of Haifa;
Current literature debates whether a link between contagious yawning and the human mirror neuron system (hMNS) exists. The use of transcranial direct current stimulation (tDCS) to elicit changes in yawn contagion during observation of yawns is one way of examining this issue. Research shows that the right inferior frontal gyrus (rIFG) is a core region of the hMNS and its activation is consistently implicated in emotional contagion and recognition. Evidence regarding the rIFG involvement in contagious yawning has been inconclusive hitherto. Thus, this study set to further elucidate the matter. In our study, participants were presented with four types of videos depicting yawning faces, laughing faces, neutral faces and a non-namable facial movement. The study included a pilot which verified the validity of the videos and the experiment during which participants underwent two tDCS conditions: excitation of the right IFG and sham (literature suggests inhibition to be unreliable in this method). The participants' responses were recorded on video during the sessions and later analyzed. We hypothesized that anodal stimulation will increase yawn occurrence and decrease latency time in the participants compared to the sham condition. Results show a significant decrease in latency time, albeit no difference in the amount of yawns. An increase in the temporal proximity could be interpreted as greater affinity towards another. This could mean that the rIFG is specifically involved in a faster reaction time towards another person which in turn increases the yawn contagion impact. The aim of this study is to expand our knowledge of the neural mechanism underpinning contagious yawning and to possibly reveal a new target for screening and treatment in conditions where emotional contagion is impaired (e.g., autism spectrum disorder, post-traumatic stress disorder, psychopaths and schizophrenia).
Vered R.1,2, Falah E.1,2, Richter Levin G.1,2,3, Levy-Gigi E.1,4,5,
1The Institute for the Study of Affective Neuroscience, University of Haifa, Israel; 2Department of Psychology, University of Haifa, Israel; 3Neurobiology and Etiology Department, University of Haifa, Israel; 4School of Education, Bar- Ilan University, Israel; 5Gonda Multidisciplinary Brain Research Center, Bar- Ilan University, Israel;
Neuroimaging and behavioral studies have shown that highly exposed first responders display impairment in hippocampal related functions. In a previous study conducted in our lab we found different types of impairments among firefighters and Criminal Scene Investigators (CSI) policemen. Specifically, firefighters struggled to learn that a previously negative context is later associated with a positive outcome, whereas CSI policemen showed a selective impairment in reversing the outcome of a negative cue. A possible explanation for these differences may relate to the frequent traumatic exposure in these populations together with their unique training. Specifically, while firefighters are trained to attend the context during traumatic events, CSI police are trained to attend specific objects in the environment. Alternatively, it is possible that the different impairments are due to job selection that may be influenced by cognitive style. To test these alternative explanations 82 civilian participants were exposed to traumatic/natural pictures, trained to attend cue/context and completed a cue-context reversal paradigm. Finally they were assessed on a performance based paradigm to determine their cognitive style (global/analytic). The results revealed a significant influence of training and cognitive style on performance. Specifically, exposure to traumatic pictures together with cue related training made the participants more vulnerable in that very same aspect. In contrast, after natural-cue- related training participants became more vulnerable in aspects of context and global perception. Furthermore, we found a correlation between cognitive style and performance after exposure to trauma. Thus, participants with a more global perception had greater impairments in reversing the outcome of a negative context.
1, Eviatar Z.1, Karni A.2,3,
1Institute of Information Processing and Decision Making, Haifa University; 2Department of Human Biology, Faculty of Science & Science Education; 3Edmond J. Safra Brain Research Center for the Study of Learning Disabilities;
Covert and overt speech production were investigated using a repetition task that aimed to test the effects of input modality. According to the Wernicke-Geschwind model, sensory systems participate in speech production. Initial visual and auditory language stimuli are processed in their respective primary and secondary cortical sensory areas and integrated in the angular gyrus, and from that point, visual and auditory linguistic stimuli are processed by the same mechanisms. The SFC model suggested by Hickok, Houde, and Rong (2011) posits that speech generation involves predictions of sensory consequences to inner sensory representations of the vocal target to be conveyed, based on the state of the vocal muscles. The model assumes that most of speech output is based on inner representations of sensory targets. However, if an auditory stimulus is to be repeated, these inner representations may be not be necessary. Based on these models, auditory sensory input targets were hypothesized to result in differential output patterns compared to visual sensory targets in both response duration measurements and surface electromyography (EMG) measurements of Orbicularis Oris Inferior and Thyrohyoideus muscles. Results revealed that sentence repetition duration was longer in the auditory input condition compared to visual input conditions. Additionally, mean of EMG activity (µV) measured during sentence presentation reveal inhibitory innervation as a function of the output condition. An interaction was revealed during sentence presentation, so that in covert speech production only auditory input elicited a significant inhibitory response, while in overt speech production both auditory and visual input targets elicited significant inhibitory responses. The
1,
1University of Haifa;
The self is grossly divided by cognitive philosophers (e.g. Gallagher, TICS, 2000) to two important concepts: the narrative-self and minimal-self. Narrative-self involves personal identity and continuity across time, it is the conceptual and autobiographic self through the life span, and is a rather coherent self-image that is weaved from past memories and anticipated future in the various stories that we and others tell about ourselves. In contrast, the minimal-self involves a momentary and embodied self, devoid of temporal extension, endowed with a sense of ownership (the sense that I am the one who is undergoing an experience), agency (the sense that I am the one who is causing an action) and 1st person perspective (a point of view). The two notions of self-constitution find confirmation in cognitive neuroscience, each one largely related to different brain regions and networks. It is widely accepted that the default mode network (DMN) supports the narrative-self, or self-related processing. Similarly, regions responsible for multi-sensory integration and interoception are suggested to support the minimal-self, via self-specific processing. Based on the Buddhist philosophy stressing that meditation practice is aimed at direct realization of the illusory nature of the self, it can be argued that meditation training might alter the function or even the structure of networks supporting the self, and in particular the narrative-self. In support of that, accumulating evidence shows alterations in the DMN function during the state of meditation. In this talk I will present functional magnetic resonance imaging (fMRI) and MRI findings showing that networks supporting the narrative-self – namely the DMN - show trait (functional and structural) alterations following prolonged mindfulness meditation. I will also present novel magnetoencephalographic (MEG) data obtained using the neuro-phenomenological approach, showing that the neuroplasticity is not confined only to the networks supporting self-related processing, but also affects the minimal-self and the brain networks which supports it. Taken together, the accumulating evidence shows a marked neuroplasticity in the experience of the two self-concepts, as well as their underlying mechanisms, following long-term meditative training. This might bare therapeutic importance for a wide range of psychopathologies, including anxiety, depression, depersonalization and post trauma.
1,2, Shamay- Tsoory S.1, Gabay S.1,2,
1Department of Psychology, University of Haifa, Israel. ; 2Institute of Information Processing and Decision Making (IIPDM).;
There are mixed findings regarding the effect of emotional stimuli on attention. In the present study we tested the influence of negative valence on spatial attention in the archer fish. Fish have an optic tectum but lack fully developed cortical structures. By using fish as a phylogenetic model we can examine the evolutionary origin of different cognitive processes and examine whether subcortical structures suffice to perform them. We have selected the Archer Fish to serve as our model because of its remarkable ability to shoot down insects found on foliage above the water level, and its ability to learn to distinguish between artificial targets presented on a computer monitor in an experimental setting (Ben-Simon, Ben-Shahar, Vasserman, & Segev, 2012; Vasserman, Shamir, Simon, & Segev, 2010). Gabay et al. (2012) demonstrated that fish have similar reflexive attentional abilities to those of humans. Herein we used the dot probe task while comparing the influence of negative pictures (e.g., dead fish) to scrambled pictures on attention. Both pictures were presented simultaneously. After a varied stimulus onset asynchrony (SOA – 100, 500, 1100) a target was presented either on the same side as the negative picture, or on the side of the scrambled picture. In addition, in a control experiment, neutral (e.g., picture of a fish) and the correspondent scrambled picture were presented before the target. Results indicated that in the 100 ms SOA fish reaction times (RT) were faster for targets presented at the same location as the negative pictures in contrast to targets presented at the location of the scrambled pictures. This was not found for neutral pictures. We conclude that the influence of negative valence on attentional processes in humans has an evolutionary ancestor.

Novel methodologies/tools

1. Eitanim,
11. Eitanim;
The issue of psychiatric patients' rights and freedom is basic in any discussion of the interphase between law, society and medicine. Many examples of the problematics of compulsory treatment and admission in restricting individual freedom have been cited in the literature. The State of Israel first passed the Mental Health Act in 1955, giving the District Psychiatrist the power to admit a mentally ill patient to a psychiatric ward against the individuals' will. If the original law reflected a somewhat paternalistic attitude granting the medical/psychiatric profession considerable authority in the process, the subsequent revision (1991) gave the ultimate decision to commit a patient to a district psychiatric committee (DPC) headed by a professional jurist, also including two psychiatrists. While adding a layer of rights, this process raised questions about the decision quality made by the DPC. In our study we examined the outcomes of the decisions made by the district psychiatric committees and compared them to the outcomes of patients discharged by their doctors. In order to analyze the outcome for discharged patients, we extracted all psychiatric discharges emanating from the district psychiatric committee's determination for the year 2013 (N=972). We also harvested all psychiatric discharges emanating from the 'treating psychiatrists' (TP) decision for 2013 (N=5788). The results we present show that the probability of decision "failure" (readmission) was found to be significantly more in the DPC group than in the TP group. This was a consistent finding, though not always with a sufficiently large sample size to achieve statistical significance, across all time frames, diagnoses and gender. We believe that the present system over legal oversight implementing the DRC should be improved so as to improve the outcome measures. Also, periodic review of the quality indicators, across different locations, should provide for a better way to grade our patients' wellbeing while still guarding their basic human rights.
1,2,
1Lev-Ha’Sharon Medical Mental Health Center; 2Sackler Faculty of Medicine, Tel Aviv University;
For years, psychiatric evaluations and interventions have been mainly psychological and pharmacological in nature. The last decade heralded the advent of somatic therapies in psychiatry. Despite its availability and potential to inform psychiatric work, quantitative electroencephalography (qEEG) fails to be implemented in clinical psychiatric settings. At Lev-Ha’Sharon Medical Mental Health Center, we have recently started to include qEEG in our clinical toolbox, both as a diagnostic aid and a potential basis for neuromodulation interventions. The process of integrating qEEG into clinical work will be discussed with clinical examples.
1,2, Schonherz Y.1, Efron M.1,3, Elazar M.1, Gothelf D.1,4,
1Child and Adolescent Psychiatry Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center; 2Sagol School of Neuroscience, Tel Aviv University; 3ADHD and Learning Disorders Clinic, Edmond & Lili Safra Children's Hospital, Sheba Medical Center; 4Sackler School of Medicine, Tel Aviv University;
Objective: To test the utility of a new smartphone application (i.e., mobile app) in increasing adherence to stimulant medications in children with attention deficit/hyperactivity disorder (ADHD). Method: The study sample included 39 children, aged 9.56 ± 2.41 years, who met criteria for a diagnosis of ADHD according to DSM-5. Participants were either ADHD drug-naïve or already prescribed stimulant medications prior to enrollment to the study. Participants were divided into a study group (i.e., prompted to use the mobile app) and a control group (i.e., treated as usual, without the app). Comprehensive clinical assessment was conducted at baseline, Week 4, and Week 8, using the Clinician Rating Scale (CRS), ADHD Rating Scale (ADHD-RS), and Clinical Global Impression (CGI) Scale. Drug accountability (i.e., adherence to stimulants) was recorded by parents and calculated by a clinician at Week 4 and Week 8. Results: Participants who were prescribed with the app demonstrated higher overall medication adherence over 8-weeks period, and a significant improvement in total CRS score at week 4 and week 8, compared to controls. Conclusion: The current study provides initial support for the utility of the iCON app (and the associated intervention model) in increasing adherence to stimulants among Israeli youth with ADHD.
1, Pinkus A.2, Bairachnaya M.1, Kirby M.1, Drori E.2, Pinhasov A.1,
1Department of Molecular Biology, Laboratory of Behavioral and Molecular Psychiatry, Ariel University; 2Department of Agriculture, Samaria and the Jordan Rift Regional R&D Center;
Psychological disorders involving depression or anxiety as behavioral components require long-term administration of psychotropic agents. Despite therapeutic benefits, a variety of adverse side effects also occur. The unique climate of Samaria positions its exclusive ensemble of plants as very promising regarding their potential medicinal properties, some of which have been used medicinally since antiquity. Whereas the components of herbal medicines and their mechanisms of action remain widely obscure, herbal extracts may offer excellent alternatives or supplements to current clinical treatments. We are developing an in vitro bioassay using two cell lines (SH-SY5Y and PC-12) for herbal extract fraction testing followed by neurochemical profiling of cell culture medium. Cell lines were stimulated to differentiate and express neuron-like features (neurites, neurotransmitter metabolism) in culture using nerve growth factor (PC-12) or retinoic acid (SY-SY5Y). The neurochemical profiling of the cell culture medium included chromatographic separation and UV measurement of 5-hydroxytryptamine (5-HT), 5-hydroxyindole-3-acetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), 4-hydroxy-3-methoxyphenylacetic acid (HVA), epinephrine (E), and norepinephrine (NE). The establishment of a simple bioassay for screening of herbal extracts from plants by the changes in neurochemical profiling contributes to the more comprehensive screening of possible anxiolytic and antidepressant effects of plants extracts / specific herbal extract fractions that can be further assessed using in vivo models.
1, Shamay-Tsoory S.1,
1Department of Psychology, University of Haifa, Israel;
In the animal kingdom, chemosensory information has been long known to convey signals of dominance, communicating information about the sender's social status and general fitness. Increasing evidence suggests that humans may also communicate both trait-dominance and state-dominance via chemical compounds. Androstadienone (androsta-4,16,-dien-3-one), a testosterone derivative chemosignal found in human sweat, seems to be a likely candidate for signaling dominance and aggression in humans. A psychopathology involving concerns pertaining specifically to social dominance is social anxiety. Socially anxious individuals tend to see themselves as being low in the hierarchical rank and others as dominant competitors for social status. These individuals are hypersensitive to signs of dominance and they are prone to respond in maladaptive submissive behaviors. One such behavior is a symptom commonly reported in social anxiety - avoidance of eye contact. Socially anxious individuals tend to avert their gaze and avoid the eye region of their adversary as a sign of submission or in an attempt to prevent feared social catastrophes. The current study aimed to investigate whether androstadienone serves as a chemosignal of dominance in low and high socially anxious (HSA) males. In the first experiment, we expose normosmic, heterosexual male participants to images of male targets depicting dominant, submissive and neutral facial poses. They are then asked to rate the target’s dominance level on a 9-point scale. In the second experiment, participants are exposed to a free-view task of male targets depicting similar dominant and neutral facial poses, while we examine their visual scanpath using an eye-tracker. Participants, divided to two groups according to their social anxiety level, complete these two tasks twice, once under exposure to androstadienone and once under exposure to a blank control solution. We hypothesize that compared to a blank control solution, when exposed to androstadienone, participants, and HSA individuals in particular, will rate the male protagonists as more dominant and show a lower number of fixations and shorter dwell time around the eyes region of the targets. Preliminary results from the first experiment show that HSA rated the dominance of protagonists higher during exposure to androstadienone compared to the control solution. Additional results of this ongoing effort will be presented.
1,2,
1Tel Aviv University, The George S. Wise Faculty of Life Sciences, Department of Molecular Microbiology and Biotechnology; 2Yehuda Abarbanel Mental Health Center;
A growing body of evidence suggests a gut brain axis, including a role for an altered microbiota that is associated with the pathogenesis of both intestinal and extra-intestinal disorders. What was once thought to be strictly CNS related pathology, may have in part a microbiota component. In our study, we investigated the effects of 3 different potentially neuroactive molecules, on microbiota composition. We compared oxytocin (molecule showing inconsistent results in regards to anxiolytic effects), with the antidepressant citalopram (a proven serotonin re-uptake inhibitor (SSRI)), in stressed induced (by corticosterone) and stress free rats. Rather than investigating the drug's effects on behavior we investigated the drug's effects on microbiota and only then correlated it with the behavioral results. Oxytocin treated samples presented with strong association between microbiota and behavioural parameters. Despite relative success in the animal models, oxytocin effects in human’s social domain proved to be weak and/or inconsistent, suggesting the effects of oxytocin are situation and/or individual dependent. This inconsistency across individuals was observed in our study as well, and interestingly we find that those rats that "enjoyed" the "benefits" of oxytocin, also displayed increased microbiota composition shift. This study suggests that variations in response to psychiatric drugs, could be due to intestinal effects, some of which could be mediated by the microbiota. The possibility of a measurable brain-gut axis effect of oxytocin is intriguing and should be explored further in larger animal studies or in humans.
1, Naim-Feil J.2, Peled A.3,4, Grinshpoon A.3, Freche D.1, Moses E.2,
1Sagol Center for Brain and Mind, Baruch Ivcher School of Psychology, Interdisciplinary Center (IDC), Herzliya, Israel; 2Department of Physics of Complex Systems, The Weizmann Institute of Science, Rehovot, Israel; 3Institute for Psychiatric Studies, Sha'ar Menashe Mental Health Center, Hadera, Israel; 4Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel;
We propose that circuit stability (or instability) and dynamics represent an etiopathologically meaningful dimension for the study of psychopathology. To investigate circuit stability in Schizophrenia we employ a perturbation approach, measuring the EEG response to diverse circuit stimulators such as transcranial magnetic stimulation (TMS) or cognitive stimulation. Our findings reveal abnormal dynamics and an inherent instability of the schizophrenia circuitry. We discuss the possible applications of investigating circuit instability and dynamics using EEG with various neural stimulations for early diagnosis and monitoring treatment efficiency.
1,2*, Michaelovsky E.1,2*, Weinberger R.1, Frisch A.1,2, Weizman A.1,2,3, Gothelf D.1,4,
1Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv.; 2Felsenstein Medical Research Center, Petach Tikva.; 3Research Unit, Geha Mental Health Center, Petach Tikva.; 4The Behavioral Neurogenetics Center, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer.;
*This author contributed equally to this study The aim of the study was to compare the methylation pattern between psychotic (P) and non-psychotic (NP) subjects with 22q11.2 deletion. 22q11.2 deletion syndrome is the most common genetic syndrome associated with schizophrenia. DNA samples were bisulfide converted, genomic amplified and hybridized to Illumina Infinium MethylationEPIC BeadChip (WG-317-1001 Illumina). Differentially methylated probes (DMP), differentially methylated region (DMR) and methylation blocks were calculated by ChAMP R pipeline. In addition modules in pathways, showing differential methylation changes between the two clinical phenotypes were calculated using champ.EpiMod function. Extensive QC, normalization, and batch effect correction were performed. Significant >50K DMPs discriminated between the NP and P subjects. The statistical significant DMPs were used to define DMRs. Nineteen DMRs were found in the current study. Of particular interest are six DMRs on chromosome 6 that overlap the HLA locus, supporting of a possible link between HLA methylation and psychosis. These data indicate the putative role of the immune system in 22q11.2 deletion-associated psychosis. Additionally, BLOCK analysis that defines clusters of physically close and co-segregate probes was used to calculate the average methylation of clusters in an attempt to identify differences between the two groups. Over 650 blocks were defined and about 250 of them statistically discriminate between the two groups. Modules in pathways between differentially methylated genes, known to create protein-protein interaction, identified six genes/modules. Such modules may be involved in the pathophysiology of psychosis in the context of 22q11.2 deletion.
1, Abed-al-Rahman E.1, Shamir A.2,3, Azhari R.1,
1Prof. Ephraim Katzir Department of Biotechnology Engineering, ORT Braude College, Karmiel, Israel ; 2Psychobiology Research Laboratory, Mazor Mental Health Center, Akko, Israel; 3The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel;
Background: The blood-brain barrier (BBB) serves as a barrier that restricts transport of potentially toxic substances from the blood to the brain. While being a very effective protection strategy, this barrier restricts the transport and effective action of drugs in the brain in pathological situations, such as neurodegenerative diseases and psychiatric disorders. While small amounts of drugs penetrate to the brain, large concentrations cause serious peripheral side effects. The BBB contains carriers which are responsible for the transport of nutrients to the brain and removal of metabolites. While small lipid-soluble molecules diffuse passively through the BBB, other essential polar nutrients (glucose, amino acids) require specific transporters. Recently it has been shown that nanoparticles (NPs) can cross the BBB using carrier-mediated transport, without causing any damage to the BBB. Aim: To develop a platform for targeting active materials to the BBB and enhancing their passage through the BBB, using carrier mediated transport of NPs. Methodology and Results: Nanoparticles, comprised of an antipsychotic drug and a carrier protein, were produced by a solvent evaporation technique. The average size of the NPs was 8 nanometer, as determined by DLS. Encapsulation efficiency of the drug was up to 60%. Fluorescent NPs were incubated with brain cells from the hCMEC/D3 cell line. Foreskin fibroblsts (GF3 Cell line) were used as control. After a 1 hr incubation period, 90% of hCMEC cells incorporated NPs, as determined by FACS analysis, as compared to less than 1% of GF3 cells. Conclusions: Nanoparticles comprising of a drug and a targeting protein were produced and their incorporation into brain cells was enhanced as compared to a fibroblast cell line. In vivo distribution of the radioligand drug is being conducted in mice. The effectiveness of the drug-loaded NPs will be evaluated on schizophrenic mice models.
1,
1Lev-Hasharon Meical Mental Health Center;
We are witnessing a paradigm shift in psychiatry: the human connectome is emerging as an improved model that connects neurobiological understanding of mental disorders to clinical phenomenology, with the aim of improving classification and clinical reasoning. The essentials of network science will be discussed, followed by a brief introduction of the main human large-scale connectomics. Major depressive symptomatology will be re-formulated based on its common pathoconnectomics. We claim, that among the available non-invasive functional imaging modalities, the old-horse electroencephalography, equipped with modern quantitative computational approaches (e.g. graph theory, FFT/JTFA, LORETA) opens a window to the landscape of connectomics, and thus informs clinical psychiatric work. Examples of EEG derived activity and connectivity measures related to psychiatric symptoms will be presented.
1,
1Mind Clinic - A Center for Advanced Treatments;
Psychiatric disorders are complex disorders. Developments over the past years are challenging traditional models of diagnosis and as a consequence, raising questions regarding the treatment paradigms used for these disorders. One of the stumbling blocks in psychiatric treatments has been the lack of central or peripheral endophenotypes that correlate with diagnosis and treatment outcome. Recent developments in the fields of neuroimaging and EEG are discovering new evidence that integrates symptoms, diagnoses, and treatment outcome. For the practicing clinician EEG studies, and especially quantitative EEG (QEEG), can prove to be a relatively simple, precise, and inexpensive method for strengthening diagnosis and monitoring outcome. In this presentation, the evidence supporting the use of QEEG in the psychiatric setting and its importance in monitoring clinical response to pharmacotherapy and neurostimulation will be discussed.
1, Markus A.1, Lichtenstein-Vidne L.1, Aue T.2, Richter-Levin G.1, Okon-Singer H.1,
1University of Haifa; 2University of Bern;
Anxiety and depression are distinct psychiatric diagnoses. However, significant overlap exists in terms of high comorbidity, shared symptoms and similar treatment. The understanding of the unique mechanisms underlying each condition is necessary considering that more than half of the patients from both populations do not react to treatment or suffer from relapses. Recent evidence suggests that anxiety may be related to dysfunctions in automatic cognitive processes, while depression may be associated with dysfunctions in later and more elaborated stages of cognitive processing. The goal of the current project is to rigorously examine possible differences in cognitive biases using a comprehensive test battery and advanced non-linear analysis tools. Our study is the first to systematically investigate and differentiate various biases between anxiety and depression in a single study. We focus on attention, memory, interpretation, and expectancy biases, and their relations to cognitive control. Each bias is examined by a prevalent paradigm, with modifications allowing it to test both automatic and non-automatic reactions. In addition, cognitive control ability is measured. Preliminary results with participants characterized by high/low sub-clinical levels of depression and/or anxiety (high anxiety: N=23, mixed anxiety-depression: N=27, high depression: N=6 control: N=39) replicate previous findings among controls. Importantly, they further show abnormal pattern of reactions among anxious and depressed participants, as manifested by differences between all four groups both in early stages of processing and in late stages. These differences include different implicit remembering of emotional content, hightend expectancy to negative events and tendency to interpret ambiguous situations as negative. These findings are expected to shed light on deficient processes that differ between anxiety and depression, leading to more targeted therapies.
123445, Peled A.123455,
1Shaar Menashe Mental Health Center;
Sensing Agitation of Inpatients. Mihael Bazhmin, Abstract. In recent years there is an exponential increase in research and technological development in the field of Digital Mental Health.. Simple movement tracking sensors and built-in smartphone functions are being used to collect ongoing psychiatric phenomenology useful for follow-up and treatment by the clinicians. To the best of our knowledge such technology has not been applied to monitor and evaluate inpatients hospitalized in closed psychiatric wards. In this study we investigated motion-tracking (associated with light and temperature measurements) simultaneously measured on multiple psychiatric inpatients. The goal was to investigate whether patient’s activity is informative about their clinical psychiatric conditions, and to identify the advantages and limitations of tracking motion activity in the closed psychiatric wards. We investigated 29 inpatients hospitalized in closed wards at Shaar-Menashe MHC each patient signed a consent form to wear a bracelet watch-like motion (light &amp; Temperature) sensor 24/7. Patents were monitored with regular nursing care follow-up . In addition to regular medical assessments they underwent a twice-weekly special quantifiable structured clinical assessment with the PANSS (Positive and Negative Assessment Scale) and neurological assessments with the NES (Neurological Evaluation Scale). Analysis of raw data-sets can inform further on the condition of the patients. For example, assessments of steps on consecutive days can measure restlessness and akathisia, however these measurements need to be validated clinically. Figure 2 shows peak activity on a certain day, found to correlate with specific non-pathological activity in the ward (helping staff make the beds). Additional information extracted from the datasets will be also presented
Peled A.Technion,
1Tachnion; 2Shaar Menashe;
As typically happens in science, an evolutionary leap occurred with accumulation of new knowledge combined with technological advances. In psychiatry the accumulated knowledge about “Neural Computation” and new technologies titled “Digital Mental Health” are about to revolutionize the field of psychiatry to such an extent that it will be unrecognizable to current generations. We are at the verge of a Copernican leap in psychiatry, new labs, institutes and journals titled “Computational Psychiatry” are popping-up everywhere introducing computational neuroscience into psychiatry. AI (artificial intelligence) simulates brains and can simulate psychopathology as well. Finally digital technologies, that of “Internet of Things” will easily collect phenomenology from patients and is already doing it better then clinicians. In my talk I will give an overview of the relevant novel neuroscientific knowledge, Show implementations of “Digital Mental Health” and introduce a novel Start-Up Application titled “Brain Profiler” designed to change the way psychiatry will be practiced in the near future

Neuroendocrinology

1, Kaplan Z.1, Zohar J.2, Cohen H.1,
1Beer-Sheva Mental Health Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel; 2The Chaim Sheba Medical Center, Sackler Medical School, Tel-Aviv University, Israel;
Background: The basal activity of the hypothalamic–pituitary–adrenal (HPA) axis is highly dynamic and is characterized by both a circadian and an ultradian (pulsatile) pattern of hormone secretion. This ultradian pattern has been found critical for optimal transcriptional, neuroendocrine and behavioral responses, yet there is still much to be discovered. We used an animal model of posttraumatic stress disorder (PTSD) to assess whether stress-induced impairment of behavioral responses is mediated, in part, by aberrant secretion of corticosterone. Method: Blood samples were collected during the light-(inactive)-phase in conscious male rats at 20-min intervals for a period starting at 5h prior to predator scent stress exposure and ending at 6h post exposure. The outcome measures included behavior in an elevated plus-maze and acoustic startle response 7 days after the exposure. Individual animals were classified as having "extreme", "partial" and "minimal" behavioral responses, according to pre-set cut-of criteria for behavioral response patterns. Corticosterone secretion patterns (frequency and amplitude) were retrospectively analyzed. Results: Under basal conditions the amplitude of ultradian oscillations of corticosterone, rather than the mean corticosterone level or the frequency of corticosterone pulsatility, was significantly blunted in individuals that displayed PTSD-phenotype 8 days later. In addition, extreme disruption of behavior at day 8 post exposure (PTSD-phenotype) was also characterized by a blunting of corticosterone response to the stressor. Animals whose behaviors were unaffected or partially affected displayed none of the above changes. Conclusion: Blunted basal corticosterone pulse amplitude is a pre-existing susceptibility or risk factor for PTSD, which may originated from prior (life) experiences and therefore may predict susceptibility to post-exposure PTSD-phenotype in rats.
1, Treadway M.2, Pizzagalli D.3,
1Department of Psychology, University of Haifa, Haifa, Israel, 3498838; 2Department of Psychology, Emory University, Atlanta, GA, 30322; 3Center for Depression, Anxiety and Stress Research, McLean Hospital/Harvard Medical School, Belmont, MA, 02478;
Our understanding of the stress response has advanced over the last decades due to the development of efficient behavioral acute stress-induction procedures in humans. Nevertheless, attempts to uncover linear relationships between individuals’ endocrine and affective responses to stress has yielded disappointing results. In the current study 79 healthy females completed a well-established acute laboratory stress procedure and were then told that they would need to repeat the task, thus aiming to prolong its effect. Saliva and subjective affect, measured at 6 time points throughout the session, revealed stress-induced increase in cortisol release and negative affect up to 45 minutes post-stress completion, suggesting a relatively prolonged acute stress response, as intended. Applying latent class linear mixed modelling on individuals’ patterns of cortisol response revealed that three distinct trajectories of cortisol response best depict variability in the data: hyper-response (n=10), moderate-response (n=21), and mild-response (n=48). Post-hoc analysis demonstrated that all three groups exhibited a significant stress-induced increase in cortisol release and negative affect, yet that both hyper-response and mild-response were associated with more negative affect relative to moderate-response. Structural MRI data from the same participants further revealed that hyper-response and mild-response were also associated with more amygdala gray matter volume relative to moderate-response. Taken together, our results suggest that there may be three distinct trajectories of cortisol response to prolonged acute stress among healthy females, and furthermore, that quadratic relations may better describe the link between these trajectories of cortisol response and affective responses to stress, as well as amygdala structural variability.
1, Shamay-Tsoory S.1,
1Department of Psychology, University of Haifa;
Previous studies suggest that several detectable changes increase women's attractiveness during ovulation; one of those is a change in women's body odor, which is perceived as more attractive during the ovulation. It has been suggested that exposure to women's chemosignals of high fertility, leads to an increased motivation for reproduction, which in turn influence men's behavior in various ways. Thus, it is possible that odors of ovulating women have a role in shaping mating behaviors among men. Given that pair-bonded men react differently to un-familiar women as compared to single men, here we investigated how chemosignals associated with women fertility influence approach and avoidance behavior in pair-bonded and single men. In Experiment 1, 29 single and 38 pair-bond men preformed the Comfortable Interpersonal Distance (CID) task while they were exposed to mixed pools of samples containing body odor from the ovulation and from the luteal phase of 43 women. We found a significant main effect for the odor condition and an interaction between the odor condition and the relationship status. When presented with body odor of higher fertility, pair-bonded men, but not single men, kept more distance from different protagonists (particularly females). In Experiment 2 we exposed 20 single and 22 pair-bonded men to body odors of 20 women, while performing a task that involved rating of attractiveness of female’s faces. We found that although ratings of women's beauty did not differ in the two conditions, highly attractive women were rated as less attractive by the pair-bonded men, during exposure to the high fertility odor. These results suggest that exposure to unfamiliar women's fertility cues may trigger social avoidance in pair-bonded men. This could possibly be a result of an increase in the motivation for reproduction, which is further mediated by changes at the perceiver's endocrinological status.
Rapps K.1,2, Hazut N.1,2, Shbiro L.2,3, Weller A.2,3, Susswein A.1,2,
1Life Sciences; 2Brain Reseach Center; 3Psychology; 4Bar Ilan University, Ramat Gan, Israel ;
Nitric oxide (NO), a naturally released gaseous substance is widely known for its parasympathetic functions of vasodilation and relaxation in endothelial cells. Nitric oxide synthase (NOS) is the enzyme that converts dietary amino acid L-arginine to NO. As a gaseous neurotransmitter, NO is involved in the control of the homeostatic feeding center in the hypothalamus. We now report that NO has a paradoxical effect on feeding behavior, dependent on feeding motivational state; NO’s role appears to be excitatory in animals that are interested in food and/or have a high motivation to eat, while NO’s role is inhibitory in animals uninterested in food i.e. satiated with weak motivation to feed. We found that L-arginine and its derivative NO inhibit feeding in both the marine slug, Aplysia and in rats, while the animals are in steady-state. Treatment with L-arginine (150 mg/kg) in satiated rats inhibited a wide range of appetitive and consummatory behaviors. Locomotion levels were not affected by L-arginine, supporting the specificity of the feeding effect, rather than a systemic parasympathetic effect. With a pretreatment of L-NAME (blocker of NOS, 50 mg/kg), some of L-arginine’s inhibitory feeding effects prevailed. It seems that L-arginine may work through another pathway in addition to the typical NOS- NO pathway to further mediate feeding inhibition. NO’s excitatory effect was demonstrated in a series of experiments with hungry animals exhibiting a high motivation to eat. In some, but not all parameters, treatment with NO donor SNAP (10 mg/kg) or L-arginine (150 mg/kg) increased appetitive and consummatory behaviors. The increased feeding behavior shown here reflects results from earlier studies of ours of animals with high feeding motivation- presented with palatable, high fat food in the experiment. Further study is necessary to understand the pathways and mechanism of L-arginine and NO’s control on feeding.
Hazut N.1,2, Rapps K.1,2, Weller A.3,2, Susswein A.1,2,
1Life Sciences ; 2Brain Research Center ; 3Psychology, Bar Ilan University, Ramat Gan, 52900, Israel ;
Previous data have shown that nitric oxide (NO) mediates some of the orexigenic effects of ghrelin and PYY, and therefore it is “known” that NO excites feeding. However, we have recently found that NO is an inhibitor of feeding when rats are satiated, but nonetheless occasionally snack chow. In this condition, treatment with L-arginine (400 mg/kg and 150 mg/kg, i.p) the precursor from which NO is synthesized, inhibited snacking on chow. Thus, NO has inhibitory effects in satiated animals. NO, that inhibits feeding is likely released as a result of satiating signals. NO inhibition with the nitric oxide synthase blocker L-NAME regulated the number of bouts, and L-arginine decreased the number of bouts. In order to discover which brain areas are involved in the process of NO inhibition of feeding, NADPH diaphorase staining was performed on brains of satiated and hungry rats. Our hypothesis was that more NO is released in brain areas that are related to satiety and feeding ( i.e, PVN ,LH and VMH) of satiated rats when compared to the same brain areas of hungry animals. Using the counting cells software, Image J, we discovered a significant difference in the Lateral Hypothalamus (LH) area when comparing hungry and satiated rat brains: There were significantly (p<0.05) more NOS positive neurons in satiated rats than in hungry rats. To conclude, it seems that NO inhibitory effect in satiated animals involves the LH. Further experiments are needed to discover the full mechanism of NO inhibition of feeding.
1, Vainer E.2, Cohen H.1,2,
1Department of Psychology, Ben-Gurion University, Be'er-Sheva, Israel; 2Anxiety and stress research unit, Mental health center, Be'er-Sheva, Israel;
Converging evidence implicates the regulatory neuropeptides orexins (ORX) in anxiety-related behaviors, via modulation of various stress related systems. Specifically, ORX-containing neurons are critical components of the circuitry that regulates and determines the arousal threshold which is necessary for the initial response to threats and, therefore, play a key role in certain aspects of survival behaviors and generating adaptive stress response. In this study, we evaluated the role of the orexinergic system on behavioral responses to stress and associated bio-physiological responses, in a controlled prospective animal model. ORX-A\B were evaluated in the hypothalamic nuclei 8 days after exposure to predator scent stress. The effects of microinfusion orexin-A (ICV or intra lateral hypothalamus (ILH)) , vs. ACSF or almorexant (a dual orexin receptor antagonist) vs. saline (IP), 30 minutes prior stress exposure on behavioral tests were evaluated 7-days later. Brain levels of ORX-A\B were subsequently assessed. All data were analyzed in relation to individual behavior patterns. Whereas animals with minimal behavioral disruption displayed a lasting upregulation of ORX in the hypothalamic nuclei, those with extreme behavioral responses displayed downregulation in the hypothalamus. Pre-exposure ICV microinjections significantly reduced long-term anxiety-like behaviors in the EPM. Rats treated with almorexant displayed grater prevalence of PTSD-phenotype, when compared to exposed untreated rats. In response to stress, ORX neurons are capable of initiating and maintaining survival behavior by activating arousal, sensory, somatomotor, visceromotor, hormonal, and other systems, which enable the organism to adjust to the (altered) prevailing conditions and subsequently re-establish homeostasis. The orexinergic system is actively involved in the neurobiological response to traumatic stress and may be associated with resilience/recovery after stress exposure.

Neuroinflammation

1, Bustan Y.1, Drapish A.1, Ben-Dor D.1, Avrahami M.1, Weizman A.1,
1Geha Mental Health Center;
The interplay between the immune system and brain's function is of increasing interest. Specifically, accumulating preclinical and clinical data point to a link between inflammation and various aspects of psychopathology. While most clinical data describing the association between inflammation and psychopathology comes from adult patients, there is almost no data from children and adolescents. In this talk, we will present data suggesting an association between laboratory markers of inflammation and clinical correlates in patients admitted to the acute adolescent inpatients unit at Geha Mental Health Center. Our data shows an association between increased neutrophils/lymphocytes ratio, a proxy marker of inflammation, and various behavioral phenotypes of severe mental conditions such as psychosis and mania. The data will be presented in the context of recent literature suggesting that inflammation may contribute to the pathobiology of psychiatric disorders, and the possible relevance to the clinic will be discussed.