Yann Quidé

Task-related fronto-striatal functional connectivity during working memory performance in schizophrenia

Working memory (WM) deficits and associated brain dysfunction are among the most well replicated candidate endophenotypic processes in schizophrenia. However, previous studies demonstrate inconsistent over- and under-activation of dorsolateral and ventrolateral prefrontal cortices (DLPFC; VLPFC), inferior parietal lobule (IPL) during WM performance, as well as subcortical structures including the striatum, and dysfunctional connectivity among fronto-striatal regions in schizophrenia. However, no previous study has investigated task-related functional connectivity (FC) of DLPFC and striatal regions using a seed-based method; here we employed this method to assess patterns of cortical and subcortical functional connectivity among WM structures during a standard 2-back WM task performed by 28 schizophrenia (SZ) and 28 healthy controls (HC). Initial group comparisons of blood oxygenation level dependent (BOLD) responses during the WM task revealed significantly greater bilateral activity in the striatum in SZ relative to HC, but there was no significant group difference in WM cortical activity (right DLPFC, VLPFC or IPL). Analyses of FC within the cortico-subcortical WM network in the HC group revealed positive performance-related FC between the right DLPFC and the right caudate, and between the right VLPFC and the right IPL; this pattern was absent in SZ. In contrast, SZ patients showed negative performance-related functional connectivity between the left putamen and the right VLPFC. Direct group comparisons in functional connectivity showed significantly greater performance-related FC between the VLPFC and bilateral putamen, as well as unilaterally between the VLPFC and the right IPL, in HC. Results suggest a critical dysfunction of cortico-striatal connectivity underpinning information retrieval for SZ patients during WM performance.

Working memory processing of traumatic material in women with posttraumatic stress disorder

BACKGROUND Posttraumatic stress disorder (PTSD) is associated with medial frontal and amygdala functional alterations during the processing of traumatic material and frontoparietal dysfunctions during working memory tasks. This functional magnetic resonance imaging (fMRI) study investigated the effects of trauma-related words processing on working memory in patients with PTSD. METHODS We obtained fMRI scans during a 3-back task and an identity task on both neutral and trauma-related words in women with PTSD who had been sexually abused and in healthy, nonexposed pair-matched controls. RESULTS Seventeen women with PTSD and 17 controls participated in the study. We found no behavioural working memory deficit for the PTSD group. In both tasks, deactivation of posterior parietal midline regions was more pronounced in patients than controls. Additionally, patients with PTSD recruited the left dorsolateral frontal sites to a greater extent during the processing of trauma-related material than neutral material. LIMITATIONS This study included only women and did not include a trauma-exposed non-PTSD control group; the results may, therefore, have been influenced by sex or by effects specific to trauma exposure. CONCLUSION Our results broadly confirm frontal and parietal functional variations in women with PTSD and suggest a compensatory nature of these variations with regard to the retreival of traumatic memories and global attentional deficits, respectively, during cognitively challenging tasks.

Diurnal cortisol variation and cortisol response to an MRI stressor in schizophrenia and bipolar disorder

Markers of HPA axis function, including diurnal cortisol rhythm and cortisol responses to stress or pharmacological manipulation, are increasingly reported as disrupted in schizophrenia (SZ) and bipolar disorder (BD). However, there has been no direct comparison of cortisol responses to stress in SZ and BD in the same study, and associations between cortisol dysfunction and illness characteristics remain unclear. In this study we used spline embedded linear mixed models to examine cortisol levels of SZ and BD participants at waking, during the first 45min after waking (representing the cortisol awakening response; CAR), during the period of rapid cortisol decline post the awakening response, and in reaction to a stressor (MRI scan), relative to healthy controls (HC). Contrary to expectations, neither SZ nor BD showed differences in waking cortisol levels, CAR, or immediate post-CAR decline compared to HC; however, waking cortisol levels were greater in BD relative to SZ. In response to the MRI stressor, the SZ group showed a significant absence of the expected increase in cortisol responsivity to stress, which was seen in both the BD and HC groups. Clinical factors affecting the CAR differed between SZ and BD. In SZ, higher antipsychotic medication dosage was associated with a steeper incline of the CAR, while greater positive symptom severity was associated with a more blunted CAR, and greater levels of anxiety were associated with the blunted cortisol response to stress. In BD, longer illness duration was associated with a steeper incline in CAR and lower levels of waking cortisol. These results suggest that cortisol responses may normalize with medication (in SZ) and longer illness duration (in BD), in line with findings of aberrant cortisol levels in the early stages of psychotic disorders.

Effects of childhood trauma on working memory in affective and non-affective psychotic disorders.

Childhood trauma is a significant risk factor for the development of psychotic disorders, and may influence executive brain functions. We thus set out to investigate the long-term effects of childhood trauma exposure on brain function of adult chronic patients diagnosed with schizophrenia, schizoaffective disorder and (psychotic) bipolar-I disorder while performing a standard 2/0-back working memory task. Participants were 50 cases diagnosed with schizophrenia/schizoaffective disorder (SCZ), 42 cases with bipolar-I disorder (BD), and 47 healthy controls (HC). Among this sample, 56 clinical cases (SCZ = 32; BD = 24) and 17 HC reported significant levels of childhood trauma, while 36 clinical cases (SCZ = 18; BD = 18) and 30 HC did not. Effects of childhood trauma on working memory-related brain activation were examined in combined samples of clinical cases (independently of diagnosis) relative to HCs, as well as within each diagnostic category. Case–control analyses revealed increased activation of the left inferior parietal lobule as a main effect of trauma exposure. In addition, trauma exposure interacted with a diagnosis of SCZ or BD to reveal trauma-related increased activation in the cuneus in clinical cases and decreased activation in this region in controls. Disorder-specific functional alterations were also evident in the SCZ sample, but not BD. Childhood trauma exposure elicits aberrant function of parietal regions involved in working memory performance regardless of clinical status, as well as task-relevant visual regions that participates to attentional processes. Childhood trauma may therefore contribute to alterations in attention in SCZ and BD while performing an n-back working memory task.

Childhood trauma-related alterations in brain function during a Theory-of-Mind task in schizophrenia

Childhood trauma is a risk factor for schizophrenia that affects brain functions associated with higher cognitive processes, including social cognition. Alterations in Theory-of-Mind (ToM), or mentalizing skills, are a hallmark feature of schizophrenia, and are also evident in individuals exposed to childhood trauma. However, the impact of childhood trauma exposure on brain function during social cognition in schizophrenia remains unclear. We thus examined the association between childhood trauma and brain function during the performance of a ToM task in 47 patients diagnosed with schizophrenia or schizoaffective disorder. All participants completed the Childhood Trauma Questionnaire (CTQ) and underwent functional magnetic resonance imaging while performing an established visual-cartoon affective ToM task. Whole-brain multiple regression analysis was performed on ToM-related brain activation, with CTQ total score as regressor of interest, while accounting for the effects of age, sex, diagnosis, symptom severity, behavioural performance, intelligence and medications levels. First, using a small-volume correction approach within a mask made of key regions for ToM [including bilateral temporo-parietal junctions (TPJ), medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC)/precuneus], total CTQ scores were positively associated with activation of the PCC/precuneus. Second, exploratory analyses for the rest of the brain (i.e., ROIs masked-out), revealed a positive association between trauma exposure and activation of the dorsomedial prefrontal cortex (dmPFC), and a negative association with activation of the anterior section of the TPJ. These results suggest that childhood trauma exposure may, at least partially, contribute to functional alterations of brain regions essential for effective mental state inference in schizophrenia.

Neurocognitive, emotional and neuroendocrine correlates of exposure to sexual assault in women

BACKGROUND Survivors of sexual assault are vulnerable to long-term negative psychological and physical health outcomes, but few studies have investigated changes in cognition, emotional processing and brain function in the early stages after sexual assault. We used a multimodal approach to identify the cognitive and emotional correlates associated with sexual assault in women. METHODS Twenty-seven female survivors of sexual assault were included within 4 weeks of the traumatic event, and they were compared with 20 age-matched controls. Participants underwent functional MRI while performing cognitive/emotional tasks (n-back, emotional go/no-go, mental imagery). We also measured diurnal salivary cortisol and conducted neuropsychological assessments of attention and memory abilities. RESULTS Relative to the control group, the survivors group had lower levels of morning cortisol and showed attentional deficits. We observed no between-group differences in brain activation during the n-back or mental imagery tasks. During the emotional go/no-go task, however, the survivors group showed a lack of deactivation in the dorsal anterior cingulate cortex when processing emotional material, relative to neutral material. Exploratory analyses in the survivors group indicated that symptom severity was negatively associated with cerebellar activation when positive emotional (happy) content interfered with response inhibition, and positively associated with cerebellar activation when thinking of positive (happy) memories. LIMITATIONS The small sample size was the main limitation of this study. CONCLUSION Dysfunctions in the dorsal anterior cingulate cortex and the cerebellum may represent early functional brain modifications that alter higher cognitive processes when emotional material is involved.

S59. CHILDHOOD TRAUMA IS ASSOCIATED WITH SOCIAL COGNITION AND SCHIZOTYPAL PERSONALITY TRAITS IN PSYCHOTIC AND HEALTHY POPULATIONS

Abstract Background Childhood trauma is a transdiagnostic risk factor for adult psychiatric disorders, including schizophrenia and bipolar-I disorder. Recent meta-analytic and epidemiological studies suggest a 3-fold increase in risk for psychotic symptoms in adulthood, following childhood trauma exposure. However, associations between trauma exposure and schizotypal personality traits, as well as cognitive and social cognitive abilities, have been less well studied in clinical populations spanning the psychotic-mood spectrum. Methods Participants were 79 schizophrenia cases, 84 bipolar disorder cases, and 75 healthy control participants who completed the Childhood Trauma Questionnaire (CTQ), the Schizotypal Personality Questionnaire (SPQ), and a standard battery of cognitive tests (to measure executive functions, working memory, attention, immediate and delayed memory), as well as social cognitive tests of facial emotion processing (the Ekman 60 faces task) and Theory-of-Mind (The Awareness of Social Inference Test; TASIT). The CTQ measures childhood trauma exposure on 5 domains (physical abuse, emotional abuse, sexual abuse, physical neglect, emotional neglect); clinically significant levels of childhood trauma exposure on at least one domain (according to specified thresholds for each domain) were evident in 54 schizophrenia cases, 55 bipolar disorder cases, and 26 healthy individuals. Trauma-exposed and non-exposed groups were compared on schizotypal personality features (referred to as ‘schizotypy’), cognitive and social cognitive abilities. Results In both the clinical groups and healthy controls, trauma-exposed participants reported higher levels of schizotypy, especially suspiciousness, relative to non-exposed individuals; this was revealed in the context of higher overall schizotypy levels in both schizophrenia and bipolar disorder, relative to healthy controls. Similarly, while the schizophrenia group showed lower social cognitive and cognitive performances relative to both the bipolar disorder and healthy control groups, trauma-exposed individuals showed deficits in social cognitive, but not general cognitive abilities, regardless of case versus control status. Discussion These findings suggest that childhood trauma exposure has long-term effects on schizotypy, especially suspiciousness, and complex social cognitive abilities in both healthy and psychotic populations. However, there was no interaction of clinical group with trauma exposure in relation to schizotypal personality dimensions, and the influence of early life trauma on cognitive functions was not distinguishable from the effects of psychotic illness in adulthood. It is possible that traumagenic processes contribute to paranoid ideation and social cognitive disturbances that contribute to psychosis-proneness in the general population, consistent with historical models of schizotypy as latent liability for schizophrenia and related psychotic disorders.

Glucocorticoid receptor gene (NR3C1) DNA methylation in association with trauma, psychopathology, transcript expression, or genotypic variation: A systematic review

&NA; The glucocorticoid receptor gene (NR3C1) is a critical component of the stress response system. Cytosine methylation of NR3C1 has been repeatedly associated with trauma and mental disorders, including major depression, post‐traumatic stress disorder, anxiety, and personality disorders, suggesting that NR3C1 methylation may play a role in stress‐related psychopathology. We systematically reviewed 55 studies examining NR3C1 DNA methylation in association with trauma exposure, psychopathology, gene expression, and/or common genetic variants. Overall, a number of NR3C1 CpG sites were significantly associated with trauma or psychopathology, but significant findings were often inconsistent across studies. This lack of consistency is likely influenced by significant methodological variability ‐ experimentally and analytically ‐ across studies. Selected common genetic variants show no significant effect on NR3C1 CpG methylation. In contrast, there was ample evidence linking increased methylation of NR3C1 to reduced expression of this gene. The inverse association between methylation and gene expression shown across eight out of ten studies supports the notion that methylation in the promoter region of NR3C1 is associated with transcriptional silencing.

Schizotypal personality traits and social cognition are associated with childhood trauma exposure

OBJECTIVES Childhood trauma is a common risk factor for adult psychiatric disorders, such as schizophrenia (SZ) and bipolar-I disorder (BD). However, its association with schizotypal personality traits, as well as cognitive and social cognitive abilities, is less well studied in these populations. METHODS In a cohort of 79 SZ cases, 84 BD cases, and 75 healthy controls (HCs), clinically significant levels of childhood trauma exposure (according to scores on the Childhood Trauma Questionnaire; CTQ) were evident in 54 SZ, 55 BD, and 26 HC individuals. Trauma-exposed and non-exposed groups were compared on schizotypal personality features (schizotypy) measured with the Schizotypal Personality Questionnaire (SPQ). Cognitive assessments included executive function, working memory, attention, and immediate and delayed memory. Social cognitive measures assessed facial emotion processing and theory-of-mind abilities. RESULTS Trauma-exposed participants showed higher levels of schizotypy, especially suspiciousness, relative to non-exposed individuals, regardless of clinical or HC status. Furthermore, trauma-exposed individuals showed deficits specifically in social cognitive, but not general cognitive abilities, regardless of clinical or HC status. These trauma-related results were found in the context of higher schizotypy levels in both SZ and BD relative to HC, and lower cognitive and social cognitive performance in SZ, relative to BD and HC groups. CONCLUSIONS These findings suggest that childhood trauma exposure impacts long-term schizotypy outcomes, especially paranoid ideation (suspiciousness), as well as complex social cognitive abilities in both healthy and psychotic populations. However, cognitive deficits associated with psychotic illness may not be distinguishable from those related to trauma exposure in previous studies. PRACTITIONER POINTS Findings Childhood trauma exposure is associated with increased schizotypal features (in particular paranoid ideation) and complex social cognitive abilities, independently of the diagnosis of psychotic disorder. Cognitive and social cognitive deficits were larger in schizophrenia compared to bipolar-I cases and healthy controls, but increased schizotypal features were observed in both schizophrenia and bipolar-I disorder relative to healthy controls. Limitations We were unable to distinguish the specific effects of particular childhood trauma exposures due to the high rate of exposure to more than one type of maltreatment. Retrospective assessment of childhood trauma in adulthood cannot be externally validated, and associations with behavioural traits in later life may be confounded by other factors not studied here.

Effects of common GRM5 genetic variants on cognition, hippocampal volume and mGluR5 protein levels in schizophrenia

GRM5 (coding for metabotropic glutamate receptor 5, mGluR5) is a promising target for the treatment of cognitive deficits in schizophrenia, but there has been little investigation of its association with cognitive and brain phenotypes within this disorder. We examined the effects of common genetic variation in GRM5 with cognitive function, hippocampal volume, and hippocampal mGluR5 protein levels in schizophrenia patients relative to healthy controls. Two independent GRM5 variants rs60954128 [C>T] and rs3824927 [G>T] were genotyped in a schizophrenia case/control cohort (n=249/261). High-resolution anatomical brain scans were available for a subset of the cohort (n=103 schizophrenia /78 control). All participants completed a standard set of neuropsychological tests. In a separate postmortem cohort (n=19 schizophrenia/20 controls), hippocampal mGluR5 protein levels were examined among individuals of different GRM5 genotypes. Schizophrenia minor allele carriers of rs60954128 had reduced right hippocampal volume relative to healthy controls of the same genotype (−12.3%); this effect was exaggerated in males with schizophrenia (−15.6%). For rs3824927, compared to major allele homozygotes, minor allele carriers with schizophrenia had lower Intelligence Quotients (IQ). Examination in hippocampal postmortem tissue showed no difference in mGluR5 protein expression according to genotype for either rs60954128 or rs3824927. While these genetic variants in GRM5 were associated with cognitive impairments and right hippocampal volume reduction in schizophrenia, they did not affect protein expression. Further study of these mechanisms may help to delineate new targets for the treatment of cognitive deficits in schizophrenia, and may be relevant to other disorders.