Potential Endophenotype Research Articles

White matter correlates of episodic memory encoding and retrieval in schizophrenia

Episodic memory (EM) impairments in schizophrenia (SZ) are predictive of functional outcome and are a potential endophenotype of the disorder. The current study investigated the neuroanatomical correlates of EM encoding and retrieval in SZ with structural magnetic resonance and diffusion tensor imaging (DTI) measures in 22 patients with SZ and 22 age- and gender-matched healthy controls. Tract-based Spatial Statistics (TBSS) was used to investigate microstructural alterations in white matter (WM), while FreeSurfer surface-based analysis was used to determine abnormalities in grey matter (GM) and WM volumetrics and cortical thickness. Compared to controls, patients demonstrated GM deficits in temporal and parietal regions and lower fractional anisotropy (FA) of WM in diffuse brain regions. Patients also demonstrated reduced functioning in both encoding and retention of auditory-verbal EM. Among patients but not controls, EM encoding correlated with WM volume in the orbitofrontal cortex and increased radial diffusivity in the fornix, whereas EM retrieval correlated with WM volume in posterior parietal cortex. These findings suggest a differential role for frontal and parietal WM in EM encoding and retrieval processes, while myelin integrity of the fornix may play a specific role in mediating EM encoding processes in SZ.

Brain activation differences in schizophrenia during context-dependent processing of saccade tasks.

BackgroundBrain function in schizophrenia has been probed using saccade paradigms and functional magnetic resonance imaging, but little information exists about how changing task context impacts saccade related brain activation and behavioral performance. We recruited schizophrenia and comparison subjects to perform saccade tasks in differing contexts: (1) two single task runs (anti- or pro-saccades alternating with fixation) and (2) one dual task run (antisaccades alternating with prosaccades).ResultsContext-dependent differences in saccade circuitry were evaluated using ROI analyses. Distinction between anti- and pro-saccade activation across contexts (single versus dual task) suggests that the schizophrenia group did not respond to context in the same way as the comparison group.ConclusionsFurther investigation of context processing effects on brain activation and saccade performance measures informs models of cognitive deficits in the disorder and enhances understanding of antisaccades as a potential endophenotype for schizophrenia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12993-016-0103-2) contains supplementary material, which is available to authorized users.

Cognitive deficits in first-degree relatives of bipolar patients: the use of homogeneous subgroups in the search of cognitive endophenotypes.

Previous studies have demonstrated impairments in attention, memory and executive functions in euthymic bipolar patients (BP) as well as their unaffected first-degree relatives, albeit in an attenuated form. Subsequently, cognitive deficits are discussed as a possible endophenotype of bipolar disorder. However, recent studies showed that only a subgroup of BP shows cognitive impairments. The aim of the present study was to investigate cognitive functioning in relatives compared to BP, to find out if the differentiation in a cognitive deficit vs. non-deficit subgroup is valid for relatives of BP, too. Therefore, the performance of 27 unaffected relatives of BP, 27 euthymic BP and 27 HC were compared using a neuropsychological test battery. The results showed that BP exhibited a reduced psychomotor speed and deficits in working memory compared to relatives and HC. Relatives performed significantly slower (psychomotor speed) as compared to HC (p=0.024); performance in the other test measures lie between BP and HC. Furthermore, a detailed evaluation of the data indicated that only subgroups of BP and relatives exhibited cognitive impairments in the implemented tests. However, the deficit and non-deficit groups did not differ in sociodemographic and clinical variables from each other, possibly due to the small sample size. In conclusion, our results suggest that reduced psychomotor speed could serve as a potential endophenotype for bipolar disorder which should be investigated along the developmental trajectory of this disorder, also to examine whether abnormalities therein precede onset of the first mood episode. Furthermore, the division of relatives into subgroups aids in the identification of stable trait markers and high-risk bipolar groups and could enable early prevention strategies. As to that more research using distinct and homogeneous subgroups is necessary.

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.

Reward-related neural dysfunction across depression and impulsivity: A dimensional approach.

Recent theoretical models underline reward sensitivity as a potential endophenotype for major depressive disorder. Neural and behavioral evidence reveals depression is associated with reduced reward sensitivity. However, reward dysfunction is not unique to depression, as it is also common across disorders of poor impulse control. We examined the interrelationships of depression (Depression, Anxiety, and Stress Scale [DASS-21]) and impulsivity (UPPS-P Impulsive Behavior Scale) with reward sensitivity among a large, representative sample (N = 260). ERPs were recorded to isolate two neural indicators of consummatory reward processing: initial evaluation of rewards in the 250-350 ms time window postonset of feedback (reward positivity [RewP]), and salience to monetary outcomes (P3). Significant interactions were observed between depression and impulsivity facets across these two stages of reward processing: depression and positive urgency predicted RewP amplitude to reward outcomes (win vs. loss); depression and one other impulsivity trait, (lack of) premeditation, predicted P3 amplitude to monetary outcomes. Conversely, high symptoms of depression were related to three biobehavioral profiles: (1) blunted RewP in conjunction with high positive urgency, (2) combination of blunted RewP and low (lack of) premeditation, and (3) blunted P3 to monetary wins/losses, in conjunction with low (lack of) premeditation. Findings illustrate that reward-related dysfunctions may be optimally conceptualized when examining the interactions between dimensions of internalizing and externalizing psychopathology.

Editorial: Endophenotypes for Schizophrenia and Mood Disorders: Implications from Genetic, Biochemical, Cognitive, Behavioral, and Neuroimaging Studies.

Editorial: Endophenotypes for Schizophrenia and Mood Disorders: Implications from Genetic, Biochemical, Cognitive, Behavioral, and Neuroimaging Studies.

Emotional intelligence in non-psychotic first-degree relatives of people with schizophrenia

Subtle social cognitive deficits in unaffected relatives of schizophrenia patients have received increasing attention over the last few years, supporting their potential endophenotypic role for this disorder. The current study assessed non-psychotic first-degree relatives' performance on a multidimensional measure of emotional intelligence (EI): the Mayer–Salovey–Caruso Emotional Intelligence Test 2.0 (MSCEIT). Endorsed by the National Institute of Mental Health, the MSCEIT is a valid and reliable instrument for detecting emotion-processing deficits among schizophrenia patients and people high in schizotypy. Method: Thirty-seven first-degree relatives, 37 schizophrenia outpatients and 37 healthy controls completed the MSCEIT, which comprises eight subscales aimed to assess the four branches of EI: Identifying, Facilitating, Understanding and Managing Emotions. Potential associations with cognitive function and schizotypy levels, measured with the Schizotypal Personality Questionnaire–Brief, were further evaluated. Results: Relatives had significantly lower MSCEIT total scores than controls and also significantly lower scores on the Identifying emotions branch. Nevertheless, schizophrenia patients still had the poorest global EI performance. The strongest positive correlations were found in relatives and controls with measures of executive function, processing speed and general intelligence. A higher level of schizotypy correlated significantly with lower MSCEIT scores among controls, but not among relatives. Conclusions: Contrary to expectations in the general population, the current study observed subtle EI impairment in non-psychotic first-degree relatives of schizophrenia patients. These findings support the hypothesis that these EI deficiencies may be potential endophenotypes located between the clinical phenotype and the genetic predisposition for schizophrenia.

Telomere length in subjects with schizophrenia, their unaffected siblings and healthy controls: Evidence of accelerated aging

Schizophrenia (SZ) is associated with broad burden. The clinical manifestations of SZ are related to pathophysiological alterations similar to what is seen in normal aging. Our aim was to evaluate the differences in telomere length (TL), a biomarker of cellular aging, in subjects with SZ (n=36), unaffected siblings (SB, n=36) and healthy controls (HC, n=47). SZ had shorter TL compared to HC, but no difference was found in SB comparing to SZ. These findings indicate that a pathological accelerated aging profile could be present in the course of SZ and further studies are needed to confirm TL as potential endophenotype, especially in at risk populations.

Neuropsychological, electrophysiological and neurological impairments in patients with obsessive compulsive disorder, their healthy siblings and healthy controls: Identifying potential endophenotype(s)

The etiology of obsessive-compulsive disorder (OCD) has not been clarified. This study aimed to investigate the cognitive, neurological, electrophysiological functions which are reflected in executive functions, memory, visuospatial integration; neurological examination and auditory event related potentials (AERP) (N100, N200, P200 and P300) in patients with OCD, their siblings, and control subjects and to determine potential endophenotypic markers. Thirty-three patients with OCD, 18 siblings and 21 controls; matched for age, gender and years of education were included. Yale Brown Obsessive Compulsive Symptoms Checklist Scale, Hamilton Depression-Rating Scale, an exhaustive neuropscyhological test battery and Neurological Evaluation Scale were administered. Their AERP recordings were obtained. Executive functions and visuospatial integration were highly impaired in patients and slightly in their siblings compared to controls. P200 amplitude was sorted as siblings>patients>controls. P300 amplitude was sorted as patients<siblings<controls. Neurological Evaluation Scale scores were lower in patients compared to siblings and controls. The logistic regression analysis showed that, higher P300 amplitude, better performance on block design test and faster completion of Stroop test would predict being in the control group, whereas higher P200 amplitude would predict being in the case (patient and sibling) groups. We suggest that these seem to be the potential endophenotypes of OCD.

CHRNA4 was associated with prepulse inhibition of schizophrenia in Chinese: a pilot study

ABSTRACTIntroduction: Prepulse inhibition (PPI) of the auditory startle reflex, as an operational measurement used to evaluate the function of brain sensorimotor gating, appears to be a sensitive potential endophenotype for schizophrenia. CHRNA4 is highly expressed in the central nervous system and has been demonstrated to be significantly associated with schizophrenia by previous studies. The purpose of the current study was to evaluate the effect of CHRNA4 on PPI and acoustic startle parameters in schizophrenia.Methods: 77 patients with schizophrenia and 62 controls were administered the test PPI, and 3 single nucleotide polymorphisms (SNPs) (rs3746372, rs1044396, and rs3787140) of CHRNA4 were genotyped in these subjects.Results: Patients with schizophrenia showed significantly lower levels of PPI at the 120 ms prepulse intervals and longer peak latency than controls, and the GG genotype of rs3746372 and the TT genotype of rs1044396 were associated with decreased PPI levels in schizophrenia but not in controls.Conclusion: PPI may be influenced by the polymorphisms of the CHRNA4 in schizophrenia and it may be a potential endophenotype of schizophrenia. An independent replication would greatly increase the value of this study.

Multidimensional assessment of impulsivity in schizophrenia, bipolar disorder, and major depressive disorder: testing for shared endophenotypes.

Impulsivity is associated with bipolar disorder as a clinical feature during and between manic episodes and is considered a potential endophenotype for the disorder. Schizophrenia and major depressive disorder share substantial genetic overlap with bipolar disorder, and these two disorders have also been associated with elevations in impulsivity. However, little is known about the degree of overlap among these disorders in discrete subfacets of impulsivity and whether any overlap is purely phenotypic or due to shared genetic diathesis. We focused on five subfacets of impulsivity: self-reported attentional, motor, and non-planning impulsivity, self-reported sensation seeking, and a behavioral measure of motor inhibition (stop signal reaction time; SSRT). We examined these facets within and across disorder proband and co-twin groups, modeled heritability, and tested for endophenotypic patterning in a sample of twin pairs recruited from the Swedish Twin Registry (N = 420). We found evidence of moderate to high levels of heritability for all five subfacets. All three proband groups and their unaffected co-twins showed elevations on attentional, motor, and non-planning impulsivity. Schizophrenia probands (but not their co-twins) showed significantly lower sensation seeking, and schizophrenia and bipolar disorder probands (but not in their co-twins) had significantly longer SSRTs, compared with healthy controls and the other groups. Attentional, motor, and non-planning impulsivity emerged as potential shared endophenotypes for the three disorders, whereas sensation seeking and SSRT were associated with phenotypic affection but not genetic loading for these disorders.

Resting vagal activity in schizophrenia: meta-analysis of heart rate variability as a potential endophenotype.

Cardiac vagal tone, indexed by heart rate variability (HRV), is a proxy for the functional integrity of feedback mechanisms integrating central and peripheral physiology. To quantify differences in HRV in individuals with schizophrenia compared with healthy controls. Databases were systematically searched for studies eligible for inclusion. Random effect meta-analyses of standardised mean differences were calculated for vagal activity indicated by high-frequency HRV and the root mean square of successive R-R interval differences (RMSSD). Thirty-four studies were included. Significant main effects were found for high-frequency HRV (P = 0.0008; Hedges' g = -0.98, 95% CI -1.56 to -0.41, k = 29) and RMSSD (P<0.0001; g = -0.91, 95% CI -1.19 to -0.62, k = 24), indicating lower vagal activity in individuals with schizophrenia than in healthy controls. Considerable heterogeneity was evident but effects were robust in subsequent sensitivity analyses. Given the association between low HRV, threat processing, emotion regulation and executive functioning, reduced vagal tone may be an endophenotype for the development of psychotic symptoms.

Neurophysiological evidence of impaired self-monitoring in schizotypal personality disorder and its reversal by dopaminergic antagonism.

BackgroundSchizotypal personality disorder (SPD) is a schizophrenia-spectrum disorder characterized by odd or bizarre behavior, strange speech, magical thinking, unusual perceptual experiences, and social anhedonia. Schizophrenia proper has been associated with anomalies in dopaminergic neurotransmission and deficits in neurophysiological markers of self-monitoring, such as low amplitude in cognitive event-related brain potentials (ERPs) like the error-related negativity (ERN), and the error positivity (Pe). These components occur after performance errors, rely on adequate fronto-striatal function, and are sensitive to dopaminergic modulation. Here we postulated that analogous to observations in schizophrenia, SPD individuals would show deficits in self-monitoring, as measured by the ERN and the Pe. We also assessed the capacity of dopaminergic antagonists to reverse these postulated deficits.MethodsWe recorded the electroencephalogram (EEG) from 9 SPD individuals and 12 healthy controls in two separate experimental sessions while they performed the Eriksen Flanker Task, a classical task recruiting behavioral monitoring. Participants received a placebo or 1 mg risperidone according to a double-blind randomized design.ResultsAfter placebo, SPD individuals showed slower reaction times to hits, longer correction times following errors and reduced ERN and Pe amplitudes. While risperidone impaired performance and decreased ERN and Pe in the control group, it led to behavioral improvements and ERN amplitude increases in the SPD individuals.ConclusionsThese results indicate that SPD individuals show deficits in self-monitoring analogous to those in schizophrenia. These deficits can be evidenced by neurophysiological measures, suggest a dopaminergic imbalance, and can be reverted by dopaminergic antagonists.

Genetic effects on source level evoked and induced oscillatory brain responses in a visual oddball task

Stimuli in simple oddball target detection paradigms cause evoked responses in brain potential. These responses are heritable traits, and potential endophenotypes for clinical phenotypes. These stimuli also cause responses in oscillatory activity, both evoked responses phase-locked to stimulus presentation and phase-independent induced responses. Here, we investigate whether phase-locked and phase-independent oscillatory responses are heritable traits. Oscillatory responses were examined in EEG recordings from 213 twin pairs (91 monozygotic and 122 dizygotic twins) performing a visual oddball task. After group Independent Component Analysis (group-ICA) and time-frequency decomposition, individual differences in evoked and induced oscillatory responses were compared between MZ and DZ twin pairs. Induced (phase-independent) oscillatory responses consistently showed the highest heritability (24–55%) compared to evoked (phase-locked) oscillatory responses and spectral energy, which revealed lower heritability at 1–35.6% and 4.5–32.3%, respectively. Since the phase-independent induced response encodes functional aspects of the brain response to target stimuli different from evoked responses, we conclude that the modulation of ongoing oscillatory activity may serve as an additional endophenotype for behavioral phenotypes and psychiatric genetics.

Resting-state cerebellar-cerebral networks are differently affected in first-episode, drug-naive schizophrenia patients and unaffected siblings.

Dysconnectivity hypothesis posits that schizophrenia is a disorder with dysconnectivity of the cortico-cerebellar-thalamic-cortical circuit (CCTCC). However, it remains unclear to the changes of the cerebral connectivity with the cerebellum in schizophrenia patients and unaffected siblings. Forty-nine patients with first-episode, drug-naive schizophrenia patients, 46 unaffected siblings of schizophrenia patients and 46 healthy controls participated in the study. Seed-based resting-state functional connectivity approach was employed to analyze the data. Compared with the controls, the patients and the siblings share increased default-mode network (DMN) seed – right Crus II connectivity. The patients have decreased right dorsal attention network (DAN) seed – bilateral cerebellum 4,5 connectivity relative to the controls. By contrast, the siblings exhibit increased FC between the right DAN seed and the right cerebellum 6 and right cerebellum 4,5 compared to the controls. No other abnormal connectivities (executive control network and salience network) are observed in the patients/siblings relative to the controls. There are no correlations between abnormal cerebellar-cerebral connectivities and clinical variables. Cerebellar-cerebral connectivity of brain networks within the cerebellum are differently affected in first-episode, drug-naive schizophrenia patients and unaffected siblings. Increased DMN connectivity with the cerebellum may serve as potential endophenotype for schizophrenia.

Trait-related decision making impairment in obsessive-compulsive disorder: evidence from decision making under ambiguity but not decision making under risk.

This study aimed to investigate whether deficits in decision making were potential endophenotype markers for OCD considering different phases of the disease. Fifty-seven non-medicated OCD patients (nmOCD), 77 medicated OCD patients (mOCD), 48 remitted patients with OCD (rOCD) and 115 healthy controls were assessed with the Iowa Gambling Task (IGT), which measured decision making under ambiguity, and the Game of Dice Task (GDT), which measured decision making under risk. While the three patients groups showed impaired performance on the IGT compared with healthy controls, all patients showed intact performance on the GDT. Furthermore, the rOCD patients showed a preference for deck B, indicating that they showed more sensitivity to the frequency of loss than to the magnitude of loss, whereas the mOCD patients showed a preference for deck A, indicating that they had more sensitivity to the magnitude of loss than to the frequency of loss. These data suggested that OCD patients had trait-related impairments in decision making under ambiguity but not under risk, and that dissociation of decision making under ambiguity and under risk is an appropriate potential neurocognitive endophenotype for OCD. The subtle but meaningful differences in decision making performance between the OCD groups require further study.

Motivational Effects of Methylphenidate are Associated with GABRA2 Variants Conferring Addiction Risk.

Background: Variations in the GABRA2 gene, encoding α2 subunits of GABAA receptors, have been associated with risk for addiction to several drugs, but the mechanisms by which variations in non-coding regions of GABRA2 increase risk for addictions are not understood. Mice with deletion of GABRA2 show deficits in the ability of psychostimulants to facilitate responding for conditioned reinforcers, offering a potential explanation.Methods: We report human and mouse studies investigating a potential endophenotype underlying this association. Healthy human volunteers carrying either cocaine-addiction “risk” or “protective” GABRA2 single nucleotide polymorphism (SNPs) were tested for their subjective responses to methylphenidate, and methylphenidate’s ability to facilitate conditioned reinforcement (CRf) for visual stimuli (CS+) associated with monetary reward. In parallel, methylphenidate’s ability to facilitate responding for a visual CRf was studied in wildtype and α2 knockout (α2−/−) mice.Results: Methylphenidate increased the number of CS+ presentations obtained by human subjects carrying protective, but not risk SNPs. In mice, methylphenidate increased responding for a CS+ in wildtype, but not α2−/− mice. Human subjects carrying protective SNPs felt stimulated, aroused and restless following methylphenidate, while individuals carrying risk SNPs did not.Conclusion: Human risk SNP carriers were insensitive to methylphenidate’s effects on mood or in facilitating CRf. That mice with the gene deletion were also insensitive to methylphenidate’s ability to increase responding for CRf, suggests a potential mechanism whereby low α2-subunit levels increase risk for addictions. Circuits employing GABAA-α2 subunit-containing receptors may protect against risk for addictions.

Decreased pain sensitivity among people with schizophrenia: a meta-analysis of experimental pain induction studies.

Patients with schizophrenia report reduced pain sensitivity in clinical studies, but experimental studies are required to establish pain sensitivity as a potential endophenotype. We conducted a systematic review of electronic databases from database inception until April 15, 2015, including experimental studies investigating pain among patients with schizophrenia spectrum disorder vs healthy controls. A random-effect meta-analysis yielding Hedges' g ±95% confidence intervals (CIs) as the effect size (ES) measure was conducted. Primary outcome was a pooled composite of pain threshold and pain tolerance; secondary outcomes included these parameters individually, plus sensory threshold, physiological pain response, and pain intensity or unpleasantness. Across 17 studies, patients with schizophrenia spectrum disorder (n = 387; age, 30.7 ± 6.9 years; females, 31.9%; illness duration, 7.0 ± 5.7 years) were compared with controls (n = 483; age, 29.5 ± 7.4 years; females, 31.0%). Patients had elevated pain threshold/pain tolerance vs controls (ES = 0.583; 95% CI, 0.212-0.954; P = 0.002; studies = 15). Results were similar in antipsychotic-free individuals (ES = 0.599; 95% CI, 0.291-0.907; P < 0.0001; studies = 8), with trend-level significance in antipsychotic-treated individuals (ES = 0.566; 95% CI, -0.007 to 1.125; P = 0.047; studies = 9). Likewise, patients with schizophrenia had increased pain tolerance (ES = 0.566; 95% CI, 0.235-0.897; P = 0.0001; studies = 6), sensory threshold (ES = 1.16; 95% CI, 0.505-1.727; P < 0.0001; studies = 5), and pain threshold (ES = 0.696; 95% CI, 0.407-0.986; P < 0.001; studies = 9), as well as reduced physiological response to noxious stimuli (ES = 0.456; 95% CI, 0.131-0.783; P = 0.006) and pain intensity/unpleasantness ratings (ES = 0.547; 95% CI, 0.146-0.949; P = 0.008). Findings were similarly significant in antipsychotic-free patients with schizophrenia (analysable parameters = 4) and antipsychotic-treated individuals (analysable parameters = 2). Finally, greater psychiatric symptoms moderated increased pain threshold, and younger patient age moderated increased pain tolerance. Decreased pain sensitivity seems to be an endophenotype of schizophrenia spectrum disorders. How this alteration links to other dimensions of schizophrenia and physical comorbidity-related help-seeking behaviour/morbidity/mortality requires further study.

Impaired prefrontal synaptic gain in people with psychosis and their relatives during the mismatch negativity.

The mismatch negativity (MMN) evoked potential, a preattentive brain response to a discriminable change in auditory stimulation, is significantly reduced in psychosis. Glutamatergic theories of psychosis propose that hypofunction of NMDA receptors (on pyramidal cells and inhibitory interneurons) causes a loss of synaptic gain control. We measured changes in neuronal effective connectivity underlying the MMN using dynamic causal modeling (DCM), where the gain (excitability) of superficial pyramidal cells is explicitly parameterised. EEG data were obtained during a MMN task—for 24 patients with psychosis, 25 of their first‐degree unaffected relatives, and 35 controls—and DCM was used to estimate the excitability (modeled as self‐inhibition) of (source‐specific) superficial pyramidal populations. The MMN sources, based on previous research, included primary and secondary auditory cortices, and the right inferior frontal gyrus. Both patients with psychosis and unaffected relatives (to a lesser degree) showed increased excitability in right inferior frontal gyrus across task conditions, compared to controls. Furthermore, in the same region, both patients and their relatives showed a reversal of the normal response to deviant stimuli; that is, a decrease in excitability in comparison to standard conditions. Our results suggest that psychosis and genetic risk for the illness are associated with both context‐dependent (condition‐specific) and context‐independent abnormalities of the excitability of superficial pyramidal cell populations in the MMN paradigm. These abnormalities could relate to NMDA receptor hypofunction on both pyramidal cells and inhibitory interneurons, and appear to be linked to the genetic aetiology of the illness, thereby constituting potential endophenotypes for psychosis. Hum Brain Mapp 37:351–365, 2016. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Theory-of-mind understanding and theory-of-mind use in unaffected first-degree relatives of schizophrenia and bipolar disorder

We assessed theory of mind (ToM) in unaffected first-degree relatives (FDR) of patients with schizophrenia (SC) and bipolar disorder (BD) compared to healthy controls with a revised computerized referential communication task. Results showed that FDR of SC performed worse than FDR of BD and controls on a task requiring ToM-use, but not on a task requiring ToM-understanding. This indicates that deficient ToM-use, rather than ToM-understanding impairments, may represent a potential candidate endophenotype for schizophrenia.