Gad Lubin

Human vulnerability to stress depends on amygdala's predisposition and hippocampal plasticity

Variations in peoples vulnerability to stressful life events may rise from a predated neural sensitivity as well as from differential neural modifications in response to the event. Because the occurrence of a stressful life event cannot be foreseen, characterizing the temporal trajectory of its neural manifestations in humans has been a real challenge. The current prospective study examined the emotional experience and brain responses of 50 a priori healthy new recruits to the Israeli Defense Forces at 2 time points: before they entered their mandatory military service and after their subsequent exposure to stressful events while deployed in combat units. Over time, soldiers reported on increase in stress symptoms that was correlated with greater amygdala and hippocampus responsiveness to stress-related content. However, these closely situated core limbic regions exhibited different temporal trajectories with regard to the stress effect; whereas amygdalas reactivity before stress predicted the increase in stress symptoms, the hippocampal change in activation over time correlated with the increase in such symptoms. Hippocampal plasticity was also reflected by a modification over time of its functional coupling with the ventromedial prefrontal cortex, and this coupling magnitude was again predicted by predated amygdala reactivity. Together, these findings suggest that variations in humans likelihood to develop symptomatic phenomena following stressful life events may depend on a balanced interplay between their amygdalas predisposing reactivity and hippocampal posteriori intra- and interregional plasticity. Accordingly, an individually tailored therapeutic approach for trauma survivors should target these 2 neural probes while considering their unique temporal prints.

Premorbid Intellectual Functioning and Risk of Schizophrenia and Spectrum Disorders

Evidence from longitudinal studies indicates that lower IQ score in childhood and early adolescence increases risk of schizophrenia and schizophrenia spectrum disorders (SSD). This study investigated the association between premorbid IQ and risk of SSD in a population-based cohort of 17-year-old conscripts. Fifty four thousand males assessed by the Israeli Draft Board during two consecutive years were followed by means of the Israeli National Psychiatric Hospitalization Case Registry for up to 11 years. Tests of verbal and non-verbal reasoning, mathematical knowledge and instructions comprehension and several psychosocial variables were recorded by the Draft Board. Risk for SSD increased with decreasing IQ score. Only poorer non-verbal reasoning conferred a significant increased risk for SSD after taking into account general intellectual ability. IQ was not associated with age of onset. These results confirm the importance of low intellectual functioning as a risk factor for SSD. This is unlikely to be due to prodrome.

Stress-induced reduction in hippocampal volume and connectivity with the ventromedial prefrontal cortex are related to maladaptive responses to stressful military service

Previous studies have shown that people who develop psychopathology such as posttraumatic stress disorder (PTSD) following stress exposure are characterized by reduced hippocampal (HC) volume and impaired HC functional connectivity with the ventromedial prefrontal cortex (vmPFC). Nevertheless, the exact interrelationship between reduced HC volume and HC‐vmPFC connectivity deficits in the context of stress has yet to be established. Furthermore, it is still not clear whether such neural abnormalities are stress induced or precursors for vulnerability. In this study, we combined measurements of MRI, functional MRI (fMRI), and diffusion tensor imaging (DTI) to prospectively study 33 a priori healthy Israeli soldiers both pre‐ and post‐exposure to stress during their military service. Thus, we were able to assess the contributions of structural and functional features of the HC and its connectivity to the onset and progression of maladaptive response to stress (i.e., increased PTSD symptoms post‐exposure). We found that soldiers with decreased HC volume following military service (i.e., post‐exposure) displayed more PTSD‐related symptoms post‐exposure as well as reduced HC‐vmPFC functional and structural connectivity post‐exposure, compared to soldiers with increased HC volume following military service. In contrast, initial smaller HC volume pre‐exposure did not have an effect on any of these factors. Our results therefore suggest that reduction in HC volume and connectivity with the vmPFC together mark a maladaptive response to stressful military service. As stress‐induced HC volume reductions were previously shown to be reversible, these localized biological markers may carry valuable therapeutic potential. Hum Brain Mapp 34:2808–2816, 2013.

Advanced Parental Age at Birth Is Associated With Poorer Social Functioning in Adolescent Males: Shedding Light on a Core Symptom of Schizophrenia and Autism

BACKGROUND Evidence indicates an association between older parents at birth and increased risk for schizophrenia and autism. Patients with schizophrenia and autism and their first-degree relatives have impaired social functioning; hence, impaired social functioning is probably an intermediate phenotype of the illness. This study tested the hypothesis that advanced fathers age at birth would be associated with poorer social functioning in the general population. To test this hypothesis, we examined the association between parental age at birth and the social functioning of their adolescent male offspring in a population-based study. METHODS Subjects were 403486, 16- to 17-year-old Israeli-born male adolescents assessed by the Israeli Draft Board. The effect of parental age on social functioning was assessed in analyses controlling for cognitive functioning, the other parents age, parental socioeconomic status, birth order, and year of draft board assessment. RESULTS Compared with offspring of parents aged 25-29 years, the prevalence of poor social functioning was increased both in offspring of fathers younger than 20 years (odds ratio [OR] = 1.27, 95% confidence interval [CI] = 1.08-1.49) and in offspring of fathers 45 years old (OR = 1.52, 95% CI = 1.43-1.61). Male adolescent children of mothers aged 40 years and above were 1.15 (95% CI = 1.07-1.24) times more likely to have poor social functioning. CONCLUSIONS These modest associations between parental age and poor social functioning in the general population parallel the associations between parental age and risk for schizophrenia and autism and suggest that the risk pathways between advanced parental age and schizophrenia and autism might, at least partially, include mildly deleterious effects on social functioning.

Cognitive test scores in male adolescent cigarette smokers compared to non-smokers: a population-based study

BACKGROUND Although previous studies indicate that people with lower intelligence quotient (IQ) scores are more likely to become cigarette smokers, IQ scores of siblings discordant for smoking and of adolescents who began smoking between ages 18-21 years have not been studied systematically. METHODS Each year a random sample of Israeli military recruits complete a smoking questionnaire. Cognitive functioning is assessed by the military using standardized tests equivalent to IQ. RESULTS Of 20 221 18-year-old males, 28.5% reported smoking at least one cigarette a day (smokers). An unadjusted comparison found that smokers scored 0.41 effect sizes (ES, P < 0.001) lower than non-smokers; adjusted analyses remained significant (adjusted ES = 0.27, P < 0.001). Adolescents smoking one to five, six to 10, 11-20 and 21+ cigarettes/day had cognitive test scores 0.14, 0.22, 0.33 and 0.5 adjusted ES poorer than those of non-smokers (P < 0.001). Adolescents who did not smoke by age 18, and then began to smoke between ages 18-21 had lower cognitive test scores compared to never-smokers (adjusted ES = 0.14, P < 0.001). An analysis of brothers discordant for smoking found that smoking brothers had lower cognitive scores than non-smoking brothers (adjusted ES = 0.27; P = 0.014). CONCLUSION Controlled analyses from this large population-based cohort of male adolescents indicate that IQ scores are lower in male adolescents who smoke compared to non-smokers and in brothers who smoke compared to their non-smoking brothers. The IQs of adolescents who began smoking between ages 18-21 are lower than those of non-smokers. Adolescents with poorer IQ scores might be targeted for programmes designed to prevent smoking.

Impaired Reading Comprehension and Mathematical Abilities in Male Adolescents With Average or Above General Intellectual Abilities Are Associated With Comorbid and Future Psychopathology

Research indicates that persons with learning disorders often suffer from psychopathology. We assessed current and future psychopathology in male adolescents with discrete impairments in reading comprehension (IRC) or arithmetic abilities (IAA) but with average or above-average general intellectual abilities. Subjects were a population-based cohort of 174,994 male adolescents screened by the Israeli Draft Board with average or above-average intellectual abilities but with low scores (8.6th and 10th lowest percentile respectively) on reading or arithmetic tests. They were compared with adolescents who scored in the 10th percentile and above on these tests (comparison group). Relative to the comparison group, male adolescents with IRC, IAA, or IRC and IAA (0.69%), had poorer scores on most behavioral assessments and higher prevalence of current psychopathology: 4.2% (comparison group), 8.0% (IRC), 7.0% (IAA), and 9.8% (IRC and IAA). Adolescents with IRC were also at increased risk for later hospitalization for schizophrenia (hazard ratios = 1.8, 95% confidence interval: 1.3–2.6). Male adolescents with average and above-average general intellectual abilities but with IRC or IAA are more likely to have current and future psychopathology. Impairments in intellectual functioning and abnormal behaviors leading to mental illnesses may share common neurobiological substrates. The results support screening male adolescents with learning disorders for psychopathology.

Acute Stress Disorder and Post-Traumatic Stress Disorder among Medical Personnel in Judea and Samaria Areas in the Years 2000–2003

OBJECTIVE We aimed to evaluate the incidence of acute stress disorder (ASD) and post-traumatic stress disorder (PTSD) among medical staff members serving in Judea and Samaria during 2000-2003. METHODS The study population included 141 medics and 19 medical doctors who provided emergency medical treatment during 23 violent events. Information regarding the incidence of ASD and PTSD was abstracted from Israel Defense Forces mental health files, as was a history of previous exposures to similar events, personal acquaintance with the victims, being under fire during the event, number of victims killed and/or wounded in the event, and length of time in service. RESULTS One medic was affected by PTSD, whereas one medical doctor and 12 medics suffered from ASD. The number of people killed in the event was associated with ASD in medics (p = 0.0002). CONCLUSIONS The prevalence of PTSD within the study population was very low, possibly because of post-trauma treatment and the training process for the medical staff members.

Premorbid behavioral and intellectual functioning in schizophrenia patients with poor response to treatment with antipsychotic drugs

INTRODUCTION Approximately one third of schizophrenia patients show partial or no response to pharmacotherapy. Despite intensive investigations, the phenomenological and biological characteristics of such patients are far from elucidated. This study examined the premorbid behavioral and intellectual functioning of schizophrenia patients who showed poor response to antipsychotic treatment. METHOD One hundred twenty-nine schizophrenia patients who showed poor response to treatment were ascertained from a national register and matched by gender, age and education to 129 patients who showed adequate response. The groups were compared on premorbid measures of behavioral and intellectual functions. RESULTS As a group, treatment-resistant male patients had significantly lower (worse) social functioning [p=0.002], and individual autonomy [p<0.0001] scores before the onset of the illness compared to treatment non-resistant patients. Male and female treatment-resistant patients did not differ from non-resistant patients in premorbid intellectual functioning [p>0.1]. CONCLUSIONS Low premorbid social functioning and individual autonomy, but not intellectual functioning, could serve as predictors of poor treatment response in schizophrenia.

Subtle Cognitive Dysfunction in Nonaffected Siblings of Individuals Affected by Nonpsychotic Disorders

BACKGROUND Previous studies have reported that as a group, individuals affected by psychotic and nonpsychotic disorders perform below norms on cognitive tests. Other studies have indicated that unaffected siblings of individuals affected by psychotic disorders also perform below norms on the same tests. We investigated cognitive performance on a large, population-based sample of individuals, affected at the time of testing by nonpsychotic disorders, and their unaffected siblings. METHODS Subjects were taken from a population-based cohort of 523,375, 16- to 17-year-old male adolescents who had been assessed by the Israeli Draft Board. Cognitive test scores were examined in sib-pairs discordant for nonpsychotic (n = 19,489) and psychotic (n = 888) disorders and compared with 224,082 individuals from sibships with no evidence of mental illness. RESULTS There appears to be a gradient in cognitive performance (worst to best) from individuals currently affected by psychotic illnesses (Cohens d = -.82), followed by individuals currently affected by nonpsychotic illness (Cohens d = -.58), unaffected siblings of individuals affected by psychotic illness (Cohens d = -.37), unaffected siblings of individuals affected by nonpsychotic illness (Cohens d = -.27), and members of sibships with no evidence of mental illness. Unaffected siblings of both psychotic and nonpsychotic individuals from multiple affected sibships (more then one affected sibling) had worse cognitive test scores compared with unaffected siblings from simplex sibships (only one affected sibling). CONCLUSIONS The results support, but do not prove, the notion that cognitive impairment in psychiatric disorders is familial and cuts across diagnostic entities.

Dysthymia in male adolescents is associated with increased risk of later hospitalization for psychotic disorders: a historical-prospective cohort study.

Aim: Retrospective studies indicate that patients with psychotic disorders and schizophrenia often suffer from depressive symptoms before the onset of psychosis. In a historical‐prospective design, we studied the association between dysthymia in adolescence and later hospitalization for psychotic disorders and schizophrenia.