Unaffected Relatives Of Patients Research Articles

Trajectory of reward-related abnormalities in unaffected relatives of patients with bipolar disorder – A longitudinal fMRI study

First-degree relatives of patients with bipolar disorder are at heightened risk of mood episodes, which may be attributed to the existence of endophenotypes i.e., heritable (neuro)biological changes present in patients and their unaffected relatives (UR). In this longitudinal MRI study, we aim to investigate the trajectories of aberrant reward-related functional changes identified in UR vs healthy controls (HC). Sixty-eight UR and 65 HC of similar age and gender distribution underwent MRI at baseline while performing a card guessing task. Of these, 29 UR and 36 HC were investigated with the same protocol following a 16-month period in average. We first identified brain regions showing group differences in the neural response to expected value (EV) and reward prediction error (PE) at baseline and analyzed how the reward-related response in these regions changed over time in UR vs HC. Relative to HC at baseline, UR showed lower EV signal in the right ventrolateral prefrontal cortex (vlPFC) and paracingulate gyrus and lower PE signal in the left vlPFC and dorsomedial PFC. The trajectories of these abnormalities in UR showed a normalization of the prefrontal EV signals, whereas the PE signals which correlated with depressive symptoms remained stable over time. While the UR showed both blunted EV and PE signals, none of these abnormalities increased over time, which is consistent with the observed stable mood symptoms.

Reward Processing as an Indicator of Vulnerability or Compensatory Resilience in Psychoses? Results From a Twin Study

BackgroundFindings of reward disturbances in unaffected relatives of patients with schizophrenia suggest reward disturbances as an endophenotype for schizophrenia. Twin studies, where 1 twin has been diagnosed with a schizophrenia spectrum disorder, can further explore this. MethodsWe used Danish registries to identify twin pairs with at least 1 twin having a schizophrenia spectrum disorder diagnosis and control twin pairs matched on age, sex, and zygosity. The analyses included data from 34 unaffected co-twins (16 females), 42 probands with schizophrenia spectrum disorder (17 females), and 83 control twins (42 females). Participants performed a modified incentive delay task during functional magnetic resonance imaging. Whole-brain group differences were analyzed by performing comparisons between co-twins and control twins. Correlations with cognitive flexibility were tested. ResultsCompared with control twins, co-twins showed no differences in striatal regions, but increased signal in the dorsolateral prefrontal cortex (DLPFC) during missed target contrast was observed. In co-twins, increased DLPFC signal was associated with lower intra-extra dimensional set-shifting scores indicative of higher cognitive flexibility. ConclusionsUnaffected co-twins did not have decreased striatal activity during anticipation as previously reported for patients with schizophrenia. Instead, they showed increased activity in the DLPFC during evaluation of missed target contrast, which correlated with their level of cognitive flexibility. Unaffected co-twins had no diagnosis at a mean age of 40 years. This could indicate that greater cognitive flexibility and increased activity in the right DLPFC during processing of unexpected negative outcome represents a compensatory resilience mechanism in predisposed twins.

Genetic generalized epilepsies in adults - challenging assumptions and dogmas.

Genetic generalized epilepsy (GGE) syndromes start during childhood or adolescence, and four commonly persist into adulthood, making up 15-20% of all cases of epilepsy in adults. These four GGE syndromes are childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy and epilepsy with generalized tonic-clonic seizures alone. However, in ~20% of patients with GGE, characteristics of more than one syndrome are present. Novel insights into the genetic aetiology, comorbidities and prognosis of the GGE syndromes have emerged and challenge traditional concepts about these conditions. Evidence has shown that the mode of inheritance in GGE is mostly polygenic. Neuropsychological and imaging studies indicate similar abnormalities in unaffected relatives of patients with GGE, supporting the concept that underlying alterations in bilateral frontothalamocortical networks are genetically determined. Contrary to popular belief, first-line anti-seizure medication often fails to provide seizure freedom in combination with good tolerability. Nevertheless, long-term follow-up studies have shown that with advancing age, many patients can discontinue their anti-seizure medication without seizure relapses. Several outcome predictors have been identified, but prognosis across the syndromes is more homogeneous than previously assumed. Overall, overlap in pathophysiology, seizure types, treatment responses and outcomes support the idea that GGEs are not separate nosological entities but represent a neurobiological continuum.

Emotional cognition subgroups in unaffected first-degree relatives of patients with mood disorders.

Patients with major depressive disorder (MDD) or bipolar disorder (BD) exhibit difficulties with emotional cognition even during remission. There is evidence for aberrant emotional cognition in unaffected relatives of patients with these mood disorders, but studies are conflicting. We aimed to investigate whether emotional cognition in unaffected first-degree relatives of patients with mood disorders is characterised by heterogeneity using a data-driven approach. Data from 94 unaffected relatives (33 of MDD patients; 61 of BD patients) and 203 healthy controls were pooled from two cohort studies. Emotional cognition was assessed with the Social Scenarios Test, Facial Expression Recognition Test and Faces Dot-Probe Test. Hierarchical cluster analysis was conducted using emotional cognition data from the 94 unaffected relatives. The resulting emotional cognition clusters and controls were compared for emotional and non-emotional cognition, demographic characteristics and functioning. Two distinct clusters of unaffected relatives were identified: a relatively 'emotionally preserved' cluster (55%; 40% relatives of MDD probands) and an 'emotionally blunted' cluster (45%; 29% relatives of MDD probands). 'Emotionally blunted' relatives presented with poorer neurocognitive performance (global cognition p = 0.010), heightened subsyndromal mania symptoms (p = 0.004), lower years of education (p = 0.004) and difficulties with interpersonal functioning (p = 0.005) than controls, whereas 'emotionally preserved' relatives were comparable to controls on these measures. Our findings show discrete emotional cognition profiles that occur across healthy first-degree relatives of patients with MDD and BD. These emotional cognition clusters may provide insight into emotional cognitive markers of genetically distinct subgroups of individuals at familial risk of mood disorders.

Error-Related Brain Activity in Patients With Obsessive-Compulsive Disorder and Unaffected First-Degree Relatives: Evidence for Protective Patterns

BackgroundIndicators of increased error monitoring are associated with obsessive-compulsive disorder (OCD), as shown in electroencephalography and functional magnetic resonance imaging studies. As most studies used strictly controlled samples (excluding comorbidity and medication), it remains open whether these findings extend to naturalistic settings. Thus, we assessed error-related brain activity in a large, naturalistic OCD sample. We also explored which activity patterns might qualify as vulnerability endophenotypes or protective factors for the disorder. To this aim, a sample of unaffected first-degree relatives of patients with OCD was also included. MethodsParticipants (84 patients with OCD, 99 healthy control participants, and 37 unaffected first-degree relatives of patients with OCD) completed a flanker task while blood oxygen level–dependent responses were measured with functional magnetic resonance imaging. Aberrant error-related brain activity in patients and relatives was identified. ResultsPatients with OCD showed increased error-related activity in the supplementary motor area and within the default mode network, specifically in the precuneus and postcentral gyrus. Unaffected first-degree relatives showed increased error-related activity in the bilateral inferior frontal gyrus. ConclusionsIncreased supplementary motor area and default mode network activity in patients with OCD replicates previous studies and might indicate excessive error signals and increased self-referential error processing. Increased activity of the inferior frontal gyrus in relatives may reflect increased inhibition. Impaired response inhibition in OCD has been demonstrated in several studies and might contribute to impairments in suppressing compulsive actions. Thus, increased inferior frontal gyrus activity in the unaffected relatives of patients with OCD may have contributed to protection from symptom development.

EEG microstates are a candidate endophenotype for schizophrenia

Electroencephalogram microstates are recurrent scalp potential configurations that remain stable for around 90 ms. The dynamics of two of the four canonical classes of microstates, commonly labeled as C and D, have been suggested as a potential endophenotype for schizophrenia. For endophenotypes, unaffected relatives of patients must show abnormalities compared to controls. Here, we examined microstate dynamics in resting-state recordings of unaffected siblings of patients with schizophrenia, patients with schizophrenia, healthy controls, and patients with first episodes of psychosis (FEP). Patients with schizophrenia and their siblings showed increased presence of microstate class C and decreased presence of microstate class D compared to controls. No difference was found between FEP and chronic patients. Our findings suggest that the dynamics of microstate classes C and D are a candidate endophenotype for schizophrenia.

Impaired self-recognition in individuals with no full-blown psychotic symptoms represented across the continuum of psychosis: a meta-analysis.

Impairments in self-recognition (i.e. recognition of own thoughts and actions) have been repeatedly shown in individuals with schizophrenia. According to classical clinical characterizations, schizophrenia is included in a continuum encompassing a large range of genetic statuses, psychotic states and symptoms. The current meta-analysis aims to determine whether self-recognition is affected by individuals within the psychosis continuum. Three populations were considered: people with an at-risk mental state for psychosis (ARMS), hallucination-prone individuals and unaffected relatives of patients with schizophrenia. Eleven studies contrasted self-recognition between these three populations (n = 386) and healthy controls (n = 315) and four studies used correlational analysis to estimate comparable effects (n = 629). Eligible studies used experimental paradigms including source-monitoring and self-monitoring. We observed significantly reduced self-recognition accuracy in these populations [g = -0.44 (-0.71 to -0.17), p = 0.002] compared to controls. No influence of the type of population, experimental paradigm or study design was observed. The present analysis argues for self-recognition deficits in populations with no full-blown psychotic symptoms represented across the continuum of psychosis.

Resting-state Functional Connectivity between Dorsolateral Prefrontal Cortex and Left Temporal Language-related Region in Unaffected First-degree Relatives of Schizophrenia Patients

According to the large body of literature data, patients with schizophrenia demonstrate altered (decreased) functional connectivity (FC) between the brain regions involved in executive functions and language (in particular, dorsolateral prefrontal cortex (DLPFC) and left temporal regions). However, the analysis of similar FC in the genetic risk group has not been done, although such data are significant for studying the neurobiological markers of schizophrenia, linked to the genetic architecture of the disorder (its traits or so-called endophenotypes). The aim of this study was to investigate whether FC between the DLPFC and left temporal language-related region was altered in unaffected first-degree relatives of patients with schizophrenia. First-degree unaffected relatives of patients with schizophrenia (12 subjects) and healthy individuals without family history of mental disorders (13 subjects) underwent resting-state functional magnetic resonance imaging at 3T Philips scanner. The FC between the regions of interest (left/right DLPFC, on the one hand, and left temporal region, on the other hand) was compared between groups as well as indexes of Verbal fluency and the Scale of Prodromal Symptoms (SOPS). As compared to controls, the relatives of patients with schizophrenia were characterized by increased FC between the left DLPFC and left temporal language-related region, although they did not differ in the other indexes, and there were no correlations between the indexes and FC. The findings might reflect some compensatory functional processes in unaffected first-degree relatives of schizophrenic patients.

Conditional False Discovery Rate Analysis Of Genome-Wide Association Studies Uncovers Genetic LOCI Shared Between Schizophrenia And Volumes Of Hippocampus, Putamen And Intracranial Volume

Schizophrenia (SCZ) is a severe mental disorder associated with differences in subcortical brain volumes and intracranial volume (ICV). However, the molecular mechanisms underlying these brain abnormalities are poorly understood. Subcortical brain structures regulate a variety of higher-order functions including emotion, movement, cognition, and reward-seeking behavior. Moreover, the majority of dopamine D2-receptors targeted by antipsychotic drugs are located in the basal ganglia, and treatment with antipsychotics may alter the volumes of the basal ganglia and the hippocampus. Hence, elucidating whether SCZ and brain structure volumes share causative factors may provide important insights into SCZ pathogenesis and its relationship to brain structure formation. Both SCZ and brain structure volumes have high heritability estimates (60-80% and 70–90%, respectively), and brain volume alterations are also present in unaffected relatives of patients with SCZ, suggesting that genetic risk underlying SCZ may also influence brain structure volumes. Despite this, a recent study reported no evidence of shared genetic influences between subcortical brain volumes and SCZ after using a battery of (frequentist) statistical tools to analyze genome-wide association study (GWAS) data of these phenotypes (Franke et al, 2016).Here, we used an alternative approach to address the question of genetic overlap, by applying the conditional false discovery rate (cFDR) approach. This statistical framework increases power for discovery by leveraging overlapping signal across GWAS. Importantly, cFDR analysis allows for identifying overlapping loci regardless of their direction of allelic effects. Applying the cFDR methodology, we have previously demonstrated shared genetic variants between SCZ, Alzheimer’s disease, immune-related diseases and related phenotypes, and substantially increased the number of identified risk loci. Here, we analyzed summary data (p-values and z-scores) from GWAS on seven subcortical brain volumes and ICV (n=11,840) from the ENIGMA Consortium (Enhancing NeuroImaging Genetics through Meta-Analysis) and GWAS on SCZ (n=82,315) from PGC (Psychiatric Genomics Consortium). To validate our approach and assess the replicability of the identified variants, we studied them in larger GWAS samples on ICV and hippocampal volume (n≥26,577).We observed polygenic overlap between SCZ and volumes of hippocampus, putamen, and ICV. Based on conjunctional cFDR<0.05, we identified two loci shared between SCZ and ICV implicating genes FOXO3 (rs10457180) and ITIH4 (rs4687658), two loci shared between SCZ and hippocampal volume implicating SLC4A10 (rs4664442) and SPATS2L (rs1653290), and two loci shared between SCZ and volume of putamen implicating DCC (rs4632195) and DLG2 (rs11233632). Three of the six identified loci are novel for SCZ. The loci shared between SCZ and hippocampal volume or ICV had not reached significance in the primary GWAS on brain phenotypes. Proving our point of increased power, two loci did reach genome-wide significance with ICV (rs10457180) and hippocampal volume (rs4664442) in the larger GWAS. In conclusion, the findings indicate that SCZ and volumes of hippocampus, putamen and ICV share genetic influences. The results provide new insights into the common genetic architecture underlying SCZ and brain structure formation, suggesting novel molecular genetic mechanisms.

Six NSCL/P Loci Show Associations With Normal-Range Craniofacial Variation.

Objectives: Orofacial clefting is one of the most prevalent craniofacial malformations. Previous research has demonstrated that unaffected relatives of patients with non-syndromic cleft lip with/without cleft palate (NSCL/P) show distinctive facial features, which can be an expression of underlying NSCL/P susceptibility genes. These results support the hypothesis that genes involved in the occurrence of a cleft also play a role in normal craniofacial development. In this study, we investigated the influence of genetic variants associated with NSCL/P on normal-range variation in facial shape.Methods: A literature review of genome wide association studies (GWAS) investigating the genetic etiology of NSCL/P was performed, resulting in a list of 75 single nucleotide polymorphisms (SNPs) located in 38 genetic loci. Genotype data were available for 65 of these selected SNPs in three datasets with a combined sample size of 7,418 participants of European ancestry, whose 3D facial images were also available. The effect of each SNP was tested using a multivariate canonical correlation analysis (CCA) against 63 hierarchically-constructed facial segments in each of the three datasets and meta-analyzed. This allowed for the investigation of associations between SNPs known to be involved in NSCL/P and normal-range facial shape variations in a global-to-local perspective, without preselecting specific facial shape features or characteristics.Results: Six NSCL/P SNPs showed significant associations with variation in normal-range facial morphology. rs6740960 showed significant effects in the chin area (p = 3.71 × 10−28). This SNP lies in a non-coding area. Another SNP, rs227731 near the NOG gene, showed a significant effect in the philtrum area (p = 1.96 × 10−16). Three SNPs showed significant effects on the shape of the nose. rs742071 (p = 8.71 × 10−14), rs34246903 (p = 6.87 × 10−12), and rs10512248 (p = 8.4 × 10−9). Respectively, these SNPs are annotated to PAX7, MSX1, and PTCH1. Finally, rs7590268, an intron variant of THADA, showed an effect in the shape of the supraorbital ridge (p = 3.84 × 10−7).Conclusions: This study provides additional evidence NSCL/P-associated genetic variants influence normal-range craniofacial morphology, with significant effects observed for the chin, the nose, the supraorbital ridges and the philtrum area.

Olfactory function in patients with nonsyndromic orofacial clefts and their unaffected relatives.

Nonsyndromic orofacial clefting is one of the most frequently occurring congenital conditions. The aim of the study was to investigate the prevalence and nature of reduced olfactory function in patients with nonsyndromic cleft lip and/or cleft palate (NSCL/P) and their unaffected first-degree relatives. Olfactory function was tested using the Sniffin' Sticks identification test in patients with NSCL/P, in their unaffected relatives, and in control subjects. MR imaging was performed to measure olfactory bulb (OB) volumes and olfactory sulcus (OS) depths. A reduced olfactory function was seen in significantly more patients with NSCL/P (p = .002) than in control subjects, regardless of the cleft type. Strikingly, unaffected relatives of patients with NSCL/P also had a higher rate of hyposmia (p = .001). In hyposmic patients, the OB volumes (left: p = .01 and right: p = .003) and the depth of the left OS (p = .02) were significantly smaller than in controls. In hyposmic relatives, both OS depths (left: p = .02 and right: p = .03) were significantly smaller. Patients with NSCL/P and their unaffected relatives have an increased prevalence of reduced olfactory function, associated with changes in the central olfactory structures.

F203. A META-ANALYSIS OF MINOR PHYSICAL ANOMALIES IN FIRST-DEGREE UNAFFECTED RELATIVES OF PATIENTS WITH SCHIZOPHRENIA

BackgroundNeurodevelopmental abnormalities are common in schizophrenia. Minor physical anomalies (MPAs) are associated with abnormalities in neural development. Previous studies clearly demonstrated that MPAs are significantly increased in schizophrenia. However, the available evidence in unaffected relatives of patients with schizophrenia is contradictory.MethodsA literature search was conducted between 1 JAN 1980 and SEP 2017 in PUBMED and SCOPUS. Random-effects model was used. Heterogeneity was tested with Q test and I2. The meta-analysis was conducted using OpenMetaAnalyst software.Results16 studies were included in the meta-analysis. MPAs were significantly more common unaffected first-degree relatives of patients with schizophrenia (d=0.56, CI=0.40–0.73, p<0.001). There was a significant heterogeneity in distribution of effect sizes (Q=42.2, p<0.001). The level of this heterogeneity was medium in range (I2=64 %). In meta-regression analyses, demographic variables were not significantly related with magnitude of the effect size.DiscussionMPAs are associated with risk of schizophrenia. However, the level of heterogeneity suggests that risk of psychosis is associated with neurodevelopmental abnormalities in some but not all individuals. Findings also emphasize that resilience factors might be protecting many neurodevelopmentally impaired relatives of schizophrenia against having a full-blown psychotic disorder.

Serum anti-glycan-antibodies in relatives of patients with inflammatory bowel disease.

BackgroundSerum anti-glycan antibodies are a promising tool for differential diagnosis, disease stratification and prediction of Crohn’s disease (CD). To investigate possible heritability of the markers we assessed the presence of serum anti-glycan antibodies in affected and unaffected relatives of patients with CD.MethodsSerum samples of 169 IBD patients of the German inflammatory bowel disease (IBD) network (140 CD & 29 Ulcerative colitis (UC)), 349 relatives of CD patients, 63 relatives of UC patients and 46 healthy controls were tested for the presence of anti-glycan antibodies by ELISA in a blinded fashion. Clinical data of the IBD patients and controls were available.ResultsA higher proportion of non-affected CD relatives was positive for anti-glycan antibodies compared to healthy subjects. No inheritance of a specific pattern of anti-glycan antibodies could be detected. No difference in marker expression depending on the degree of relationship in the non-affected relatives was noted and the presence of family history did not lead to a difference in marker levels in the affected CD subjects.ConclusionsNon-affected CD relatives had a higher frequency of anti-glycan antibodies compared to healthy subjects. This difference was mild and was found to be true for the overall reactivity to glycan antigens, but not for specific patterns. This may indicate an inherited mechanism resulting in a non-specific increased reactivity to microbial antigens in IBD.

Temporal Discrimination: Mechanisms and Relevance to Adult-Onset Dystonia.

Temporal discrimination is the ability to determine that two sequential sensory stimuli are separated in time. For any individual, the temporal discrimination threshold (TDT) is the minimum interval at which paired sequential stimuli are perceived as being asynchronous; this can be assessed, with high test–retest and inter-rater reliability, using a simple psychophysical test. Temporal discrimination is disordered in a number of basal ganglia diseases including adult-onset dystonia, of which the two most common phenotypes are cervical dystonia and blepharospasm. The causes of adult-onset focal dystonia are unknown; genetic, epigenetic, and environmental factors are relevant. Abnormal TDTs in adult-onset dystonia are associated with structural and neurophysiological changes considered to reflect defective inhibitory interneuronal processing within a network which includes the superior colliculus, basal ganglia, and primary somatosensory cortex. It is hypothesized that abnormal temporal discrimination is a mediational endophenotype and, when present in unaffected relatives of patients with adult-onset dystonia, indicates non-manifesting gene carriage. Using the mediational endophenotype concept, etiological factors in adult-onset dystonia may be examined including (i) the role of environmental exposures in disease penetrance and expression; (ii) sexual dimorphism in sex ratios at age of onset; (iii) the pathogenesis of non-motor symptoms of adult-onset dystonia; and (iv) subcortical mechanisms in disease pathogenesis.

Familial aggregation of MATRICS Consensus Cognitive Battery scores in a large sample of outpatients with schizophrenia and their unaffected relatives.

The increased use of the MATRICS Consensus Cognitive Battery (MCCB) to investigate cognitive dysfunctions in schizophrenia fostered interest in its sensitivity in the context of family studies. As various measures of the same cognitive domains may have different power to distinguish between unaffected relatives of patients and controls, the relative sensitivity of MCCB tests for relative-control differences has to be established. We compared MCCB scores of 852 outpatients with schizophrenia (SCZ) with those of 342 unaffected relatives (REL) and a normative Italian sample of 774 healthy subjects (HCS). We examined familial aggregation of cognitive impairment by investigating within-family prediction of MCCB scores based on probands' scores. Multivariate analysis of variance was used to analyze group differences in adjusted MCCB scores. Weighted least-squares analysis was used to investigate whether probands' MCCB scores predicted REL neurocognitive performance. SCZ were significantly impaired on all MCCB domains. REL had intermediate scores between SCZ and HCS, showing a similar pattern of impairment, except for social cognition. Proband's scores significantly predicted REL MCCB scores on all domains except for visual learning. In a large sample of stable patients with schizophrenia, living in the community, and in their unaffected relatives, MCCB demonstrated sensitivity to cognitive deficits in both groups. Our findings of significant within-family prediction of MCCB scores might reflect disease-related genetic or environmental factors.

A Meta-analytic Review of Auditory Event-Related Potential Components as Endophenotypes for Schizophrenia: Perspectives From First-Degree Relatives.

As endophenotypes bridge the gap between genetics and phenotypic disease expression, identifying reliable markers is important for fostering understanding of pathophysiology. The present aim was to conduct current meta-analyses of 3 key auditory event-related potential (ERP) components that have been held as potential endophenotypes for schizophrenia: P50, P300 amplitude and latency, and mismatch negativity (MMN), reflective of sensory gating, attention and classification speed, and perceptual discrimination ability, respectively. In order to assess endophenotype viability, these components were examined in unaffected relatives of patients with schizophrenia and healthy controls. Effect sizes (ES) were examined between relatives and controls for P50 suppression (10 studies, n = 360 relatives, 473 controls), P300 amplitude (20 studies, n = 868 relatives, 961 controls), P300 latency (17 studies, n = 674 relatives, 792 controls), and MMN (11 studies, n = 377 relatives, 552 controls). Reliable differences in P50 suppression (ES = 0.86, P < .001), P300 amplitude (ES = -0.52, P < .001), and P300 latency (ES = 0.44, P < .05) were found between unaffected relatives and controls. A trend was found between relatives and controls for MMN (ES = 0.21, P = 0.06), and the use of extraneous channels was found to be a significant moderator (P = 0.01). When MMN was analyzed using frontocentral channel Fz, a significant difference was found (ES = 0.26, P < 0.01). The results indicate that P50 suppression, P300 amplitude and P300 latency, and MMN may serve as viable endophenotypes for schizophrenia.

Alterations in neural Theory of Mind processing in euthymic patients with bipolar disorder and unaffected relatives.

Behavioral deficits in the Theory of Mind (ToM) have been robustly demonstrated in bipolar disorder. These deficits may represent an intermediate phenotype of the disease. The aim of this study was: (i) to investigate alterations in neural ToM processing in euthymic patients with bipolar disorder, and (ii) to examine whether similar effects are present in unaffected relatives of patients with bipolar disorder suggesting that ToM functional activation may be, in part, due to genetic risk for the disease. A total of 24 euthymic patients with bipolar disorder, 21 unaffected first-degree relatives, and 81 healthy controls completed a ToM task while undergoing functional magnetic resonance imaging. We observed reduced bilateral activation of the temporoparietal junction (TPJ) and diminished functional fronto-temporoparietal connectivity in patients compared to controls. Relatives tended towards intermediate temporoparietal activity and functional coupling with medial prefrontal areas. There was also evidence for a potentially compensatory enhanced recruitment of the right middle temporal gyrus and stronger connectivity between this region and the medial prefrontal cortex in relatives. These findings provide further evidence of altered neural ToM processing in euthymic patients with bipolar disorder. Further, our findings in relatives lend support to the idea that altered ToM processing may act as an intermediate phenotype of the disorder.

Theory of mind network activity is altered in subjects with familial liability for schizophrenia.

As evidenced by a multitude of studies, abnormalities in Theory of Mind (ToM) and its neural processing might constitute an intermediate phenotype of schizophrenia. If so, neural alterations during ToM should be observable in unaffected relatives of patients as well, since they share a considerable amount of genetic risk. While behaviorally, impaired ToM function is confirmed meta-analytically in relatives, evidence on aberrant function of the neural ToM network is sparse and inconclusive. The present study therefore aimed to further explore the neural correlates of ToM in relatives of schizophrenia. About 297 controls and 63 unaffected first-degree relatives of patients with schizophrenia performed a ToM task during functional magnetic resonance imaging. Consistent with the literature relatives exhibited decreased activity of the medial prefrontal cortex. Additionally, increased recruitment of the right middle temporal gyrus and posterior cingulate cortex was found, which was related to subclinical paranoid symptoms in relatives. These results further support decreased medial prefrontal activation during ToM as an intermediate phenotype of genetic risk for schizophrenia. Enhanced recruitment of posterior ToM areas in relatives might indicate inefficiency mechanisms in the presence of genetic risk.

Schizophrenia and Bipolar Disorder Type II in Heterozygous Twins

Introduction Schizophrenia and bipolar disorder seem to be completely distinct. However, years of intensive investigation on the genetic bases of these disorders suggest that they share common genetic risks. Aim In order to support this hypothesis, we report the cases of two heterozygous twins. One has been diagnosed with SA and the other with bipolar disorder type II (BPII). Case report Sirs Z R and T R are 31 years old. They are from a non-consanguineous marriage. Their parents divorced when they were 13 years old. Their mother would be followed for schizophrenia and she is currently stabilized. Mr. Z R was in school up the third year upper. He is followed in psychiatry for SA since the age of 15 years. He had been hospitalized in the psychiatric department 13 times. The patient is currently well stabilized with risperidone and valproate. Mr. T R is a teacher of mathematics. He is followed from the age of 18 years for BPII. He presented previously 4 major depressive episodes that would have been of medium intensity and 5 hypomanic episodes. He was treated with valproate (500mg/day) with a good treatment adherence. He had been hospitalized once in the psychiatric department for physical and verbal hetero aggressiveness. The final diagnosis over this hospitalization was hypomanic episode with an hysterical personality. Conclusion Schizophrenia and bipolar disorder share common genetic risks, therefore early detection of endophenotypes in unaffected relatives of patients with these disorders should allow the development of strategies to prevent them.

Applying neuroimaging to detect neuroanatomical dysconnectivity in psychosis.

This editorial discusses the application of a novel brain imaging analysis technique in the assessment of neuroanatomical dysconnectivity in psychotic illnesses. There has long been a clinical interest in psychosis as a disconnection syndrome. In recent years graph theory metrics have been applied to functional and structural imaging datasets to derive measures of brain connectivity, which represent the efficiency of brain networks. These metrics can be derived from structural neuroimaging datasets acquired using diffusion imaging whereby cortical structures are parcellated into nodes and white matter tracts represent edges connecting these nodes. Furthermore neuroanatomical measures of connectivity may be decoupled from measures of physiological connectivity as assessed using functional imaging, underpinning the need for multi-modal imaging approaches to probe brain networks. Studies to date have reported a number of structural brain connectivity abnormalities associated with schizophrenia that carry potential as illness biomarkers. Structural connectivity abnormalities have also been reported in well patients with bipolar disorder and in unaffected relatives of patients with schizophrenia. Such connectivity metrics may represent clinically relevant biomarkers in studies employing a longitudinal design of illness course in psychosis.