Neurocognitive endophenotypes for bipolar disorder

Objectives:  Neurocognitive deficits have been proposed as vulnerability markers or endophenotypes for the development of bipolar I disorder (BD I). However, few research studies have examined whether neurocognitive deficits also exist in first-degree relatives of individuals with BD I.
Methods:  This prospective study examined neurocognitive function in individuals with BD I, their first-degree relatives and a normal control group using a comprehensive battery of neurocognitive tests.
Results:  Results indicated that individuals with bipolar disorder and their unaffected relatives demonstrated neuropsychological deficits in comparison to the normal control group in the domains of visuospatial/constructional abilities, executive function, visual learning and memory, and motor speed. In general, the unaffected relatives demonstrated an intermediate level of performance in comparison to the normal control and bipolar group. After adjustment for mood symptoms, significant differences were present for the visuospatial/constructional, executive function, and motor domains. Individuals with bipolar disorder also demonstrated a differential right versus left hemisphere deficit with respect to neurocognitive tasks.
Conclusions:  Results suggest that deficits on specific neuropsychological tests, most notably Digit Symbol, Block Design and Judgment of Line Orientation, may be indicative of cognitive endophenotypes for bipolar disorder. Replication studies are needed to further identify these deficits as endophenotypes for BD I.     

Executive dysfunctions as potential markers of familial vulnerability to bipolar disorder and schizophrenia

Attentional and executive impairments have been found both in patients with schizophrenia and in their unaffected first-degree relatives, suggesting that they might be considered as familial vulnerability markers. Several studies have shown that the performance of bipolar patients does not significantly differ from that of schizophrenic patients, so that executive and attentional deficits might not be specific to schizophrenia. In the present study, we aimed to identify executive dysfunctions in schizophrenia and bipolar disorder that might be vulnerability trait markers specific to one or common to both of these diseases. We assessed cognitive performance of euthymic bipolar and schizophrenic patients, their unaffected first-degree relatives and a healthy control group, using neuropsychological tasks to test different components of executive function: the Verbal Fluency Test, the Stroop Word Colour Test, the Wisconsin Card Sorting Test and the Trail Making Test. The two groups of patients and their unaffected relatives demonstrated disproportionately increased slowness on the Stroop test in comparison to the normal healthy group. Patients with schizophrenia performed poorly on all the tests in comparison to the normal healthy subjects, while no other impairment was observed in the bipolar patients and in the relatives of schizophrenic and bipolar patients. Enhanced susceptibility to interference and reduced inhibition could be transnosographical markers for a shared familial vulnerability common to schizophrenia and bipolar disorders.     

Heritability of Trail Making Test performance in multiplex schizophrenia families: implications for the search for an endophenotype

The impairment of the Trail Making Test (TMT) performance as a measure of executive function deficits has been found both in patients with schizophrenia and in their unaffected first-degree relatives, suggesting that it might be considered as a familial vulnerability marker, but its heritability estimates are not well known. This study investigated the genetic heritability of impairments in TMT performance using a sample of 80 schizophrenia patients, 145 unaffected first-degree relatives and 127 healthy controls from families with multiple members with schizophrenia. Consistent with previous reports in the literature, relatives performed in between healthy controls and schizophrenia patients. Based on these results, a variance component-analysis provided small, but significant additive heritability estimates for performance indices relating performance in TMT-version A to TMT-version B. These results showed that this significant but small evidence of heritability on the one hand suggests an association with genetic predisposition to schizophrenia, but that TMT performance is also associated with epigenetic or environmental factors.     

Neurocognitive performance in subjects at ultrahigh risk for schizophrenia: a comparison with first-episode schizophrenia

Objective

The aim of the present study was to explore the neurocognitive performance of patients at ultrahigh risk (UHR) compared with patients with first-episode (FE) schizophrenia and healthy control (HC) subjects.

Method

Twenty-seven subjects at UHR for schizophrenia, 25 patients in their FE of schizophrenia, and 33 HCs were included. All participants completed a neurocognitive battery, including tests of general intelligence, attention and working memory, executive function, and verbal and visual memory.

Results

Of the 3 groups, the FE subjects performed poorest at all neurocognitive tests, encompassing the broad range of impairments. The UHR subjects had a similar pattern of neuropsychological dysfunction but less severe than that of FE patients. The UHR subjects were particularly impaired on measures of attention and working memory, executive function, and verbal memory compared with the HCs.

Conclusion

These findings are consistent with the view that the neurocognitive impairments of schizophrenia are neurodevelopmental in nature and, although less severe, those impairments are mostly in place before the onset of the first frank psychotic episode. Neurocognitive impairments may play an important role in the pathogenesis of early psychosis and could help to clarify individuals at UHR for schizophrenia.     

A comparison of euthymic bipolar patients with unaffected first-degree relatives and healthy controls in terms of neuropsychological functions

Objective. Cognitive dysfunction in bipolar disorder (BD) is well established in the literature. The neurocognitive deficits have been considered to be endophenotypic markers of BD, and studies have examined whether neurocognitive deficits exist in first-degree relatives of individuals with BD I. We hypothesized that performance in tests of neurocognitive function would be impaired in euthymic BD I patients and their unaffected first-degree relatives compared to that of healthy controls. Methods. We compared the performance of bipolar patients, their first-degree relatives, and healthy controls in a battery of neurocognitive tests to reveal possible endophenotypes of BD. A diagnostic interview and neuropsychological test battery were administered to 30 BD I patients, 55 of their unaffected first-degree relatives and 32 healthy controls. Results. The patients and their first-degree relatives were significantly impaired in executive function assessed using the Wisconsin Card Sorting Test (WCST) and Trail Making Test-B (TMT-B) relative to the controls (WCST; perseverative errors: p < 0.0005, categories completed: p = 0.002, TMT-B; p = 0.002). There were no significant differences between the groups in terms of attention, psychomotor speed, verbal memory, or learning. Conclusion. Our study suggests that the deficits in executive function may be endophenotypic markers of genetic vulnerability to BD I.     

Facial emotion perception differs in young persons at genetic and clinical high-risk for psychosis

A large body of literature has documented facial emotion perception impairments in schizophrenia. More recently, emotion perception has been investigated in persons at genetic and clinical high-risk for psychosis. This study compared emotion perception abilities in groups of young persons with schizophrenia, clinical high-risk, genetic risk and healthy controls. Groups, ages 13–25, included 24 persons at clinical high-risk, 52 first-degree relatives at genetic risk, 91 persons with schizophrenia and 90 low risk persons who completed computerized testing of emotion recognition and differentiation. Groups differed by overall emotion recognition abilities and recognition of happy, sad, anger and fear expressions. Pairwise comparisons revealed comparable impairments in recognition of happy, angry, and fearful expressions for persons at clinical high-risk and schizophrenia, while genetic risk participants were less impaired, showing reduced recognition of fearful expressions. Groups also differed for differentiation of happy and sad expressions, but differences were mainly between schizophrenia and control groups. Emotion perception impairments are observable in young persons at-risk for psychosis. Preliminary results with clinical high-risk participants, when considered along findings in genetic risk relatives, suggest social cognition abilities to reflect pathophysiological processes involved in risk of schizophrenia.     

首发精神分裂症患者神经认知功能的遗传学分析

目的 探索精神分裂症患者及其亲属共同存在的神经认知功能损害,并对22号染色体上儿茶酚氧位甲基转移酶(COMT)基因和脯氨酸脱氢酶(PRODH)基因的5个候选单核苷酸多态性(SNP)位点进行相关的遗传学分析。方法 采用14个神经心理测验(共29项)对235例首发精神分裂症患者(患者组)、322名未患病亲属(亲属组)和133名正常对照(正常对照组)进行有关智力、注意、记忆、言语功能和执行功能等评定,比较各组间的神经认知功能有无差异,并对上述神经认知功能测验与COMT和PRODH基因的5个候选SNP进行定量性状的传递不平衡测试。结果 (1)患者组所有测验的成绩均差于正常对照组,差异有显著性(P<0.01和P<0.05),而亲属组的记忆、注意、言语功能和执行功能界于患者与正常对照之间;(2)PRODH1 195G/A与即刻逻辑记忆测验(P=0.03)、言语流畅性测验的正确数(P=0.03)和连线测验B的犯规数(P=0.01)相关,PRODH1945G/A与数字符号测验(P:0.01)、连线测验A的错误数(P:0.02)、HANOI塔测验的总分(P=0.01)、威斯康星卡片分类测验(WCST)的总错误数(P=0.01)、WCST的非持续错误数(P:0.02)和WCST的总分类数(P=0.02)相关。结论 精神分裂症患者在记忆、注意、言语功能和执行功能等方面存在广泛的神经认知功能损害,这种损害可能是精神分裂症的遗传“内表     

Specific executive/attentional deficits in patients with schizophrenia or bipolar disorder who have a positive family history of psychosis

Neurocognitive impairments are well documented in patients with schizophrenia and their healthy first-degree biological relatives. Less is known about neuropsychological performance in bipolar disorders, but some studies indicate that, compared to schizophrenia, bipolar disorder displays a similar profile pattern with less severe deficits. The genetic and environmental contributions to the development of neurocognitive deficits are also unclear. This study explored the effect of a family history (FH) of psychotic disorders in first-degree relatives on a variety of cognitive domains (abstraction and flexibility, verbal fluency, verbal memory, motor activity and visual-motor processing/attention) in 30 patients with schizophrenia, and 24 type I bipolar patients. After adjusting the results for age, gender, education level and pre-morbid intelligence, patients with schizophrenia or bipolar disorder with positive FH (n=18) performed significantly worse than patients with negative FH (n=36) on the visual-motor processing/attention domain. These findings were independent of the specific diagnosis. Moreover, when logistic regression analysis was performed, poor Digit Symbol performance was the only predictor of belonging to the positive FH group. Our results are compatible with the existence of some common genetic factors between the illnesses, as well as the involvement of identical, or at least similar, disordered brain systems in both disorders. These findings are discussed within the context of the continuum model of psychosis.     

Neurocognitive function and outcome in first-episode schizophrenia: a 10-year follow-up of an epidemiological cohort

The natural history of neurocognitive impairments in schizophrenia is unclear. We aimed to characterise this in an epidemiological first-episode cohort and relate it to long-term outcome. All but 1 of 112 first-episode psychosis cases ascertained from a geographical catchment area were traced at 10-12 years. Neurocognitive and multi-dimensional outcome assessments were made at interview in 49 cases with schizophrenia and related disorders. Twenty-four of these had completed the same neurocognitive battery at index admission. Comparisons with normative data showed impaired executive function in a proportion of the first episode (FE) sample at baseline. Significant deterioration was seen over the follow-up period in three of nine sub-tests: object assembly, picture completion and memory for designs. Neurocognitive impairments at outcome, but not baseline, correlated with clinical outcome. Poor outcome was associated with a decline in performance on visuo-spatial tasks and a failure to improve on frontal-temporal tasks during the follow-up period. Executive deficits may be present in the FE, but do not progress over 10-12 years. Visuo-spatial function is spared in the FE but may deteriorate over time. Changes in both these patterned deficits are predictive of clinical outcome.     

Neurocognitive profile in adolescents with early-onset schizophrenia: clinical correlates.

BACKGROUND: Neurocognitive impairments have been documented in adolescents with early-onset schizophrenia (EOS; onset by age 18) and are important treatment targets. Information concerning the severity, pattern, and clinical correlates of these deficits in EOS remains limited. METHODS: Tests assessing motor skills, attention, memory, visuospatial abilities and executive functioning were administered to 54 clinically stabilized adolescents with EOS and 52 age- and sex-matched healthy controls. Childhood-onset patients (onset by age 13) were compared to those with an adolescent onset of illness. Patients' neurocognitive profiles were compared to those of controls. Relationships between neurocognitive deficits and demographic and clinical characteristics were explored. RESULTS: Neurocognitive profiles did not differ between childhood- and adolescent-onset participants. Patients showed a generalized neurocognitive deficit of 2.0 SDs compared to controls, with relative deficit in executive functioning and relative sparing of language and visuospatial abilities. Degree of generalized neurocognitive impairment was associated with premorbid adjustment and negative symptom severity (Adjusted R(2) = .39). CONCLUSIONS: Results document both a significant generalized deficit and a relative deficit of executive functioning in adolescents with EOS. The overall pattern is similar to that observed in severely ill first-episode adult patients. The impairments across multiple neurocognitive domains suggest widespread brain dysfunction in EOS.     

Do schizotypal symptoms mediate the relationship between genetic risk for schizophrenia and impaired neuropsychological performance in co-twins of schizophrenic patients?

BACKGROUND: Neurocognitive deficits and symptoms of schizotypal personality disorder are both elevated in the first-degree relatives of schizophrenic patients, but their relationship to each other and their potential common genetic source remain unclear. METHODS: Fifty unaffected co-twins of schizophrenic patients and 123 control twins were assessed with a neuropsychological battery and structured clinical interviews. RESULTS: Working memory was influenced by genetic risk for schizophrenia but not schizotypal symptoms. Nearly all other domains were influenced by schizotypy symptoms but only in the co-twins of schizophrenic patients. Schizotypy symptoms in the absence of a family history did not seem to be related to impaired neurocognitive functioning. CONCLUSIONS: Schizotypy symptoms in those with genetic risk for schizophrenia are associated with increased risk for cognitive deficits. Some neurocognitive deficits might covary with subpsychotic symptoms due to a shared genetic factor. Community-ascertained schizotypal individuals might not be appropriate for modeling underlying genetic risk for schizophrenia.     

Shared executive dysfunctions in unaffected relatives of patients with autism and obsessive-compulsive disorder.

BACKGROUND: Executive dysfunctions have been studied as a potential endophenotype associated with the genetic basis of autism. Given that recent findings from clinical and molecular genetic studies suggest that autism and obsessive-compulsive disorder (OCD) could share a common pattern of heritability, we assessed executive functions as a possible common cognitive endophenotype in unaffected family members of individuals with either autism or OCD. METHODS: Five tests assessing executive functions (Tower of London, verbal fluency, design fluency, trail making and association fluency) were proposed to 58 unaffected first-degree relatives (parents and siblings) of probands with autism and 64 unaffected first-degree relatives of OCD patients. Results were compared with those of 47 healthy controls matched for age, sex, and level of education. RESULTS: In the Tower of London test, both groups of unaffected relatives showed significantly lower scores and longer response times compared with controls. No differences were observed between autism and OCD relatives and healthy controls in the four other tasks (verbal fluency, design fluency, trail making test and association fluency). CONCLUSIONS: Our findings show the existence of executive dysfunction in the unaffected first-degree relatives of probands with OCD, similar to those observed in the relatives of patients with autism. These results support and extend previous cognitive studies on probands indicating executive dysfunctions in autism and OCD. Planning and working memory processes could thus represent a common cognitive endophenotype in autism and OCD that could help in the identification of genes conferring vulnerability to these disorders.     

Generalized and specific neurocognitive deficits in prodromal schizophrenia.

BACKGROUND: Neurocognitive deficits are considered to be central to the pathophysiology of schizophrenia, and the neurodevelopmental model suggests that such deficits precede full-blown psychosis. The present study examined performance on a broad neuropsychological battery of young subjects considered to be at clinical high risk for schizophrenia, who were subsequently followed to determine clinical outcome. METHODS: Subjects were 38 clinical high-risk patients (58% male patients; mean age = 16.5) and 39 sex- and age-matched healthy control subjects. At baseline, all high-risk patients had attenuated (subpsychotic) schizophrenialike positive symptoms. Clinical follow-up data of at least 6 months duration was available on 33 patients, of whom 12 developed nonaffective psychotic disorders. RESULTS: At baseline, clinical high-risk patients had significantly impaired global cognitive performance relative to control subjects and to estimates of their own prior intellectual functioning. Measures of verbal memory and executive functioning/working memory showed significantly greater impairments; visuospatial functioning was relatively spared. Prodromal patients who later developed psychosis had significantly lower verbal memory scores at baseline compared with patients who remained nonpsychotic. CONCLUSIONS: Verbal memory deficits may be an important risk marker for the development of schizophrenia-spectrum psychotic disorders, possibly indicating the presence of a prefrontal-hippocampal neurodevelopmental abnormality. Generalized neurocognitive impairment may be a nonspecific vulnerability marker.     

Impaired verbal memory in young adults with unipolar and bipolar depression

Aim: Early stages of severe mood disorders may be accompanied by neurocognitive changes. Specifically, deficits in verbal memory have been linked to depression in young people. This study examined whether young adults with unipolar compared with bipolar depression showed similar neurocognitive deficits. Methods: A total of 57 young adults (16–32 years) were assessed in this study. Twenty with unipolar and 20 with bipolar depression, all currently depressed, were compared with 17 healthy controls. Neuropsychological assessment included psychomotor speed, attention for routine mental operations, attentional switching, executive control and verbal learning and memory. Results: Both unipolar and bipolar subjects showed significant impairments in verbal memory and attentional switching compared with controls. Both mood disorder groups showed no impairments in psychomotor speed, attention for routine mental operations and executive control. Effects size calculations show that the unipolar and bipolar groups do not differ from each other across a range of neurocognitive measures. Conclusion: Neurocognitive deficits in young adults with current depressive syndromes appear to differ from those typically seen in older patients. In early adulthood, both unipolar and bipolar depression may be distinguished by poor verbal memory, despite intact speed of processing, attention and executive functions. This study suggests that there is utility in neuropsychological testing for young adults in the early stages of severe mood disorders. In order to prevent neurobiological changes inherent to the disease, pharmacological and non-pharmacological interventions that target verbal memory deficits may be optimally delivered early in the disease course.     

The executive control of attention differentiates patients with schizophrenia, their first-degree relatives and healthy controls

Attentional and executive impairments have been reported in patients with schizophrenia and in their healthy first-degree relatives. However, its nature remains unclear and discrepancies between studies have been observed. These might be due to differences in the clinical severity of the illness or in sociodemographic factors. The objective of the present work was to explore the efficiency of three attention networks: alerting, orienting and executive control (conflict inhibition) defined anatomically, using patients, their relatives and controls, assessing the possibility to use them as endophenotypes. We used three tests, the Attention Network Test (ANT), the Wisconsin Card Sorting Test (WCST) and the Stroop Test, and compared 52 patients with schizophrenia, 55 of their first-degree relatives and 53 unrelated healthy controls, taking into account demographic variables (age, sex and years of education) and clinical symptoms of schizophrenia. Patients had a longer overall mean reaction-time (p < 0.001), and took longer to resolve the ANT conflict (ANTc) (p = 0.04) than the control group. In the schizophrenia group, the SSPI disorganization score was significantly correlated to the ANTc performance. Additionally, first-degree relatives of patients with schizophrenia also performed significantly worse than controls in attention performance test. Our findings support a specific deficit in executive control of attention in patients with schizophrenia. This deficit was shown to be correlated with the intensity of the disorganization score in patients. Relative presented an intermediate phenotype between patients and controls; the ANT reaction time (but not the ANTc) may thus be considered as possible endophenotype marker for schizophrenia.     

Social cognition in first-degree relatives of people with schizophrenia: A meta-analysis

Social cognition is affected in people with schizophrenia, but whether this is the case for healthy relatives of these patients is less clear. The presence of social cognition impairments in relatives would suggest a potential genetic role of social cognition in schizophrenia. To determine whether social cognition is affected in first-degree relatives of people with schizophrenia and examine the impact of potential moderator variables, a meta-analysis of studies investigating at least one domain of social cognition (mentalizing, emotional processing, social perception, social knowledge and/or attributional style) in adult first-degree relatives of patients with schizophrenia was performed. Our inclusion criteria were satisfied by 29 studies, of which 11 evaluated mentalizing, 20 emotional processing, and two social perception. Moderate mean effect sizes were obtained for these three components. Across all studies, effect sizes were significantly correlated with IQ and age differences between groups, calling for careful group matching for future studies. Overall, the results from this meta-analysis highlight that social cognition is globally affected in first-degree relatives of people with schizophrenia, suggesting that social cognition deficits in schizophrenia may be related to a genetic vulnerability for the disorder.     

Social Cognition Deficits Among Individuals at Familial High Risk for Schizophrenia

Social cognition in young relatives of schizophrenia probands (N = 70) and healthy controls (N = 63) was assessed using the Penn Emotion Recognition Test-40 to examine the presence of social cognitive deficits in individuals at risk for the disorder. Measures of neurocognitive function and prodromal psychopathology were collected to assess the cognitive and clinical correlates of social cognitive impairments in at-risk relatives. Results indicated that when compared with healthy controls, individuals at familial high risk for schizophrenia were significantly more likely to overattribute emotions to neutral faces, with such individuals frequently misinterpreting neutral faces as negative. In addition, at-risk individuals had significantly greater reaction times when completing emotion recognition tasks, regardless of valence. Impairments in neurocognition were largely independent of social cognitive performance, and emotion recognition impairments persisted after adjusting for deficits in neurocognitive function. Further, social cognitive impairments in the interpretation of neutral faces were significantly associated with greater positive and general prodromal psychopathology, whereas neurocognitive impairments were only associated with disorganization. These results suggest that impairments in social cognition may be unique endophenotypes for schizophrenia.     

Executive function in parents of patients with familial versus sporadic bipolar disorder

ObjectiveStudies investigating the cognitive function of healthy relatives of patients with bipolar disorder are conflicting, and the neurocognitive profile of relatives of bipolar disorder probands is still unclear. We aimed to evaluate executive function in unaffected parents of familial and sporadic patients with bipolar disorder.MethodsThe study included 24 unaffected familial parents (FP) of patients with bipolar disorder, 26 unaffected sporadic parents (SP) of patients with bipolar disorder and 26 controls matched with the parents for gender, age and duration of education (76 subjects in total). All of the subjects were interviewed with the Structured Clinical Interview for DSM-IV-Axis I. Executive function was assessed using the California Verbal Learning Test (CVLT), the Trail Making Test (TMT), the Wisconsin Card Sorting Test (WCST) and the Stroop test.ResultsIn comparison to their respective matched controls, FP performed significantly worse on the CVLT, TMT, WCST and Stroop test, whereas SP performed significantly worse only on WCST perseverative errors and Stroop color test. FP performed significantly worse than SP on the CVLT, TMT, and WCST.ConclusionThe present study investigated relatives with and without a family history of bipolar disorder separately and found that executive function was impaired in parents with a positive family history of bipolar disorder. These findings bring more evidence suggesting that deficits in prefrontal executive function and verbal memory are associated with familial vulnerability to bipolar disorder and that executive function and verbal memory impairments may represent a potential endophenotype of bipolar disorder.     

Action blind: Disturbed self-other integration in schizophrenia

Recent research using individual task settings suggests that a major problem in schizophrenia is a dysfunctional theory of mind system leading to false mental state attributions. However, if a more low-level deficit to integrate own and other's actions (action blindness) is present in schizophrenia is still unknown. Using a Social Simon task, we tested if schizophrenia patients have a deficit in self-other integration. Further, we tested for a possible genetic bias of this dysfunction by studying clinically unaffected first-degree relatives of schizophrenia patients. While schizophrenia patients showed no Social Simon effect, we found a reliable Social Simon effect in healthy participants and first-degree relatives of schizophrenia patients. Joint task performance differed statistically between patients and healthy controls. We did not find any differences in the size of the Social Simon effects of relatives and healthy controls. The present findings suggest that schizophrenia patients have severe problems with self-other integration, which may lead to problems in social interactions. Since first-degree relatives of schizophrenia patients showed a reliable Social Simon effect, the evidence for a genetic bias of this social dysfunction in schizophrenia however is weak.     

Impaired Motor Cortex Responses in Non-Psychotic First-Degree Relatives of Schizophrenia Patients: A Cathodal tDCS Pilot Study

BackgroundSchizophrenia has recently been described as a disorder of impaired plasticity and dysconnectivity. Several lines of evidence suggest that alterations in glutamatergic neurotransmission underlie different symptom domains of schizophrenia. Little is known about the impact of genetic liability on cortical plasticity and connectivity in schizophrenia.ObjectiveTo compare N-methyl-d-aspartate receptor (NMDAR)-dependent cortical plasticity and connectivity in schizophrenia patients and unaffected first-degree relatives to that in healthy subjects.MethodsCortical plasticity can be induced in the motor cortex with cathodal transcranial direct current stimulation (tDCS). Animal and human research indicates that this long-term depression-like plasticity (LTD-like) is NMDAR dependent, and that these plasticity shifts can last for several hours. tDCS-induced plasticity was assessed by measuring motor-evoked potentials (MEPs) generated by applying transcranial magnetic stimulation (TMS) to both hemispheres in healthy controls, chronically ill schizophrenia patients and unaffected first-degree relatives.ResultsCompared to healthy controls, both first-degree relatives and schizophrenia patients showed abolished motor-cortical LTD-like plasticity of the stimulated hemisphere. On the non-stimulated hemisphere, plasticity was again abolished in schizophrenia patients, whereas first-degree relatives had a reversed plasticity.ConclusionsNon-psychotic and clinically unaffected first-degree relatives showed an alteration and a reversal of LTD-like cortical plasticity, indicating functional alterations of glutamatergic transmission as a result of a genetic liability for developing schizophrenia. These results provide new evidence for the association between plasticity dysregulation and functional cortical connectivity, and the importance of these networks in the pathophysiology of schizophrenia.