Endophenotypic Marker Research Articles

Neurocognitive deficits in obsessive-compulsive disorder: A selective review.

Obsessive–compulsive disorder (OCD) is a debilitating mental illness characterized by an early onset and chronic course. Evidence from several lines of research suggests significant neuropsychological deficits in patients with OCD; executive dysfunction and nonverbal memory deficits have been reported consistently in OCD. These deficits persist despite controlling potential confounders such as comorbidity, severity of illness, and medications. Neuropsychological impairments are independent of illness severity, thus suggesting that the neuropsychological deficits are trait markers of the disease. In addition, these deficits are seen in first-degree relatives of individuals with OCD. These reports suggest that neuropsychological deficits are potential endophenotype markers in OCD. Neuropsychological studies in pediatric OCD are limited; they show impairments of small effect size across multiple domains but with doubtful clinical significance. Preliminary evidence shows that different symptom dimensions of OCD may have unique neuropsychological deficits suggestive of discrete but overlapping neuroanatomical regions for individual symptom dimensions. Overall, neuropsychological deficits further support the role of frontostriatal circuits in the neurobiology of OCD. In addition, emerging literature also suggests the important role of other areas, in particular parietal cortex. Preliminary evidence suggests the possible role of neuropsychological deficits to be markers of treatment response but needs to be examined in future. Longitudinal studies with examination of patients at different time points and examination of their potential utility as predictors of treatment response are needed in future.

21.2 FAMILIAL RISK FOR SCHIZOPHRENIA

BackgroundLarry Seidman, Ph.D. was a key contributor to the Consortium on the Genetics of Schizophrenia (COGS) with its focus on understanding the genetic substrates of quantitative endophenotypes in schizophrenia patients. With his deep knowledge of neurocognition related to psychosis, Larry was able to help steer the COGS-1 family study of over 300 families. The subsequent COGS-2 case-control study used the same well curated, quality controlled extensive battery of testing with 1411 schizophrenia patients and 1500 extensively tested healthy control subjects. Larry was first author on the 2015 paper “Factor structure and heritability of endophenotypes and schizophrenia: findings from the Consortium on the Genetics of Schizophrenia.” It is important to note that related association studies examined the relationship of quantitative endophenotypes and genetic loci, and this is complementary to but distinct from case-control studies. These COGS studies identified a 42-gene network with a NRGL-ERBB4 hub underlying schizophrenia neurocognitive deficits. Thus, these Ns, modest for case-control studies, are quite powerful for gene finding using quantitative endophenotypic markers related to core “thought disorder” neurocognitive deficits in schizophrenia. These quantitative measures are up to 100 X more efficient and 10 X more powerful for gene finding than case-control studies as explained by Blangero, Williams and Almasy as early as 2005. Genes for SZ overlap with genes for key functionally important quantitative endophenotypes as shown by many groups, including COGENT and COGS, so case-control and endophenotype studies are best viewed as complementary in nature.MethodsSeidman et al (2015) examined 12 heritable neurocognitive and neurophysiological domains (including the Penn CNB Battery), as well as three neurophysiological measures reflecting inhibitory reprocessing from EEG and eye movements. Seidman et al’s analysis revealed five distinct factors in the composite COGS battery. These were 1-episodic memory, 2-working memory, 3-perceptual vigilance, 4-visual abstraction and 5-inhibitory processing. The five factors had similar structures across probands, siblings and controls. Also, heritability was significant for all 5 factors. These composite endophenotype factors will be used to enhance our neurobiological and genetic understanding of schizophrenia and its treatment as we move forward, and are related to the Biotype concept of psychosis. Larry Seidman was also an important contributor to the COGS mission as described below.ResultsThe COGS PsychChip GWAS of quantitative endophenotypes has now identified six regions of association with quantitative neurocognitive measures exceeding genome-wide significance (e.g. NRGL3-Abstaction and Mental Flexibility on the CNB). In addition, many associations between endophenotypes and specific loci exceed the suggestive threshold for further investigation.DiscussionThese data will be presented implicating synaptic plasticity and other crucial CNS processes in endophenotype dysfunction in SZ. NB: COGS interrogates the genetic architecture of endophenotypes associated with SZ and its functional outcome, not schizophrenia per se. Still, there is much overlap between risk genes for SZ and neurocognitive endophenotypes. Also neurocognitive endophenotypes are endorsed by the FDA and MATRICS as treatment targets for schizophrenia itself. This allows for data-guided drug and sensory-cognitive remediation of neurocognitive deficits to improve functional outcome in schizophrenia. Using this genomic information to enhance precision based selection of treatment options now seems to be an exciting and viable new treatment pathway.

O4.2. HERITABILITY AND CORRELATION TO SCHIZOPHRENIA SPECTRUM DISORDER OF GLUTAMATE AND OTHER NEUROMETABOLITE LEVELS IN ANTERIOR CINGULATE AND LEFT THALAMUS: A REGISTER BASED MAGNETIC RESONANCE TWIN STUDY

BackgroundGlutamatergic changes in schizophrenia may precede dopaminergic alterations leading to psychopathology as part of a dopaminergic pathway, or they may represent a distinct pathophysiology. It is unknown if these glutamatergic alterations are due to genetic influences, although findings in gene studies implicate the NMDA receptor. Higher levels of glutamate and glutamine have been reported in the thalamus of patients with schizophrenia, while studies of the anterior cingulate cortex (ACC) have reported increased, decreased, and unaltered levels compared to healthy controls.By studying discordant mono- (MZ) and dizygotic (DZ) twins it is possible to estimate heritability and correlation to disease in the same population. This kind of study has only been done once on glutamate levels, but no heritability estimates were reported.1 A study of older healthy twins found N-acetyl aspartate (NAA), choline (Cho), creatinine (Cr), and myo-inositol (MI) levels to be heritable in posterior cingulate cortex.2 Of these metabolites, NAA has generally been found to correlate negatively with schizophrenia. Here we present our final results on heritability, and correlation to liability for schizophrenia spectrum disorder (ICD-10 F2x.x) of the neurometabolite levels in the ACC and the left thalamus.MethodsBy linking The Danish Twin Register and The Danish Psychiatric Central Research Register, 25 complete MZ and 21 complete DZ twin pairs con- or discordant for schizophrenia spectrum disorder (ICD 10 F2x.x) and 29 complete MZ and 20 complete DZ healthy control pairs were included. Thirteen additional twins were scanned without their siblings. Spectra of glutamate, Glx, NAA, Cho, Cr and MI were obtained by [1H]-MR spectroscopy at 3 tesla and analyzed by using LCModel. Additive genetic, common environmental and unique environmental effects on metabolite levels were calculated by structural equation modeling with openMX software. The best fitting model was determined by the Akaike Information Criterion.ResultsIn the ACC heritability estimates were significant for glutamate (29%), Glx (31%), NAA (39%), Cho (38%), Cr (37%) and MI (33%). In the left thalamus we found significant estimates of heritability for glutamate (16%), Glx (31%), Cho (60%), and of common environment for Cr (29%). A significant positive correlation to schizophrenia spectrum liability was found for glutamate in the left thalamus (r=0.16; p = 0.03), and negative correlations were found for NAA (r = -0.16; p = 0.02) and Cr (r = -0.25; p = 0.006) in the ACC. For glutamate in the thalamus and Cr in the ACC the significant correlation to disease was due to overlapping genetic effects influencing both metabolite and disease.DiscussionIn this the first study to estimate heritability of glutamate levels in the brain, the primary findings are that glutamate levels in both the ACC and the left thalamus are heritable, and in the left thalamus also correlated to disease with a significant genetic overlap. This emphasizes glutamate levels in the left thalamus as a potential endophenotypic marker for schizophrenia. NAA and Cr were negatively correlated to disease in the ACC, which could point to disturbances of neuronal health and metabolism. For Cr an overlap of genes influencing both metabolite levels and disease suggests Cr as a possible candidate endophenotype.

Visual working memory encoding in schizophrenia and first-degree relatives: neurofunctional abnormalities and impaired consolidation.

Working memory (WM) deficits in schizophrenia (SCZ) have been linked to impairments in the encoding phase that are associated with aberrant neuronal functioning. Similar abnormalities have been observed in unaffected first-degree relatives (REL) and are thus discussed as candidate endophenotypes. The process of WM consolidation - i.e. the formation of durable WM representations - is assumed to be impaired in SCZ, but no study has investigated WM consolidation and neuronal correlates of visual WM encoding in REL before. We examined whole-brain activation during the encoding phase with an event-related functional magnetic resonance imaging study design in 25 SCZ subjects, 22 REL subjects, and 25 healthy controls. Subjects performed a visual masked change detection task that assessed WM performance and consolidation. SCZ showed deficient WM performance indicating an impairment consolidation process, accompanied by broad neuronal hypoactivation, most prominently in frontal brain regions, as well as increased activity of the anterior cingulate during the encoding phase. REL showed decreased neuronal activity in the middle and medial frontal gyrus and increased activity in the precentral gyrus and insula during encoding, but no significant behavioral deficits were observed. In respect of given consolidation times, REL showed a shift from decreased frontal activity at short time intervals to increased frontal activity at longer time intervals. Findings suggest WM consolidation may be slowed in REL so that the deployment of compensatory neuronal resources during encoding is needed to assure proper WM performance. This supports the view of WM-related neuronal dysfunctions as a potential endophenotypic marker.

Altered Neural Activity during Irony Comprehension in Unaffected First-Degree Relatives of Schizophrenia Patients-An fMRI Study.

Irony is a type of figurative language in which the literal meaning of the expression is the opposite of what the speaker intends to communicate. Even though schizophrenic patients are known as typically impaired in irony comprehension and in the underlying neural functions, to date no one has explored the neural correlates of figurative language comprehension in first-degree relatives of schizophrenic patients. In the present study, we examined the neural correlates of irony understanding in schizophrenic patients and in unaffected first-degree relatives of patients compared to healthy adults with functional MRI. Our aim was to investigate if possible alterations of the neural circuits supporting irony comprehension in first-degree relatives of patients with schizophrenia would fulfill the familiality criterion of an endophenotype. We examined 12 schizophrenic patients, 12 first-degree relatives of schizophrenia patients and 12 healthy controls with functional MRI while they were performing irony and control tasks. Different phases of irony processing were examined, such as context processing and ironic statement comprehension. Patients had significantly more difficulty understanding irony than controls or relatives. Patients also showed markedly different neural activation pattern compared to controls in both stages of irony processing. Although no significant differences were found in the performance of the irony tasks between the control group and the relative group, during the fMRI analysis, the relatives showed stronger brain activity in the left dorsolateral prefrontal cortex during the context processing phase of irony tasks than the control group. However, the controls demonstrated higher activations in the left dorsomedial prefrontal cortex and in the right inferior frontal gyrus during the ironic statement phase of the irony tasks than the relative group. Our results show that despite good task performance, first-degree relatives of schizophrenia patients had alterations in the neural circuits during irony processing. Thus, we suggest that neural alteration of irony comprehension could be a potential endophenotypic marker of schizophrenia.

Family history of alcoholism and the human brain response to oral sucrose.

A heightened hedonic response to sweet tastes has been associated with increased alcohol preference and alcohol consumption in both humans and animals. The principal goal of this study was to examine blood oxygenation level dependent (BOLD) activation to high- and low-concentration sweet solutions in subjects who are either positive (FHP) or negative (FHN) for a family history of alcoholism. Seventy-four non-treatment seeking, community-recruited, healthy volunteers (22.8 ± 1.6 SD years; 43% men) rated a range of sucrose concentrations in a taste test and underwent functional magnetic resonance imaging (fMRI) during oral delivery of water, 0.83 M, and 0.10 M sucrose. Sucrose compared to water produced robust activation in primary gustatory cortex, ventral insula, amygdala, and ventral striatum. FHP subjects displayed greater bilateral amygdala activation than FHN subjects in the low sucrose concentration (0.10 M). In secondary analyses, the right amygdala response to the 0.10 M sucrose was greatest in FHP women. When accounting for group differences in drinks per week, the family history groups remained significantly different in their right amygdala response to 0.10 M sucrose. Our findings suggest that the brain response to oral sucrose differs with a family history of alcoholism, and that this response to a mildly reinforcing primary reward might be an endophenotypic marker of alcoholism risk.

Prospective memory in first-degree relatives of patients with schizophrenia

Objectives: Among various cognitive impairments in schizophrenia, prospective memory (ProM) deficit is unequivocally established. However, there is a paucity of research examining whether ProM impairment can be considered a cognitive endophenotypic marker in schizophrenia. An important step toward this is to assess the status of ProM in first-degree relatives (FDRs) of patients with schizophrenia. Keeping this in view, present study has been conducted to assess event- and time-based ProM in FDRs of patients with schizophrenia. Methods: Twenty patients with schizophrenia, 20 FDRs of these patients, and 20 nonpsychiatric (healthy) controls were administered event- and time-based ProM tasks. Results: Findings show that the FDRs had poorer performance on event-based ProM task in comparison to healthy controls. On time-based task, though the FDRs performed poorly in comparison to healthy controls the difference was statistically non-significant. The patient group performed poorer than healthy controls on both event- and time-based tasks. Conclusions: Findings of the present study indicate that the FDRs of patients with schizophrenia exhibit ProM impairment, though to a lesser degree than the patients with schizophrenia.

Heritability of saccadic eye movements in spinocerebellar ataxia type 2: insights into an endophenotype marker

BackgroundSaccade slowing has been proposed as endophenotype marker in Spinocerebellar Ataxia type 2 (SCA2), nevertheless the heritability of this trait has not been properly demonstrated. Thus the present paper was aimed to assess the heritability of different saccadic parameters in SCA2.MethodsForty-eight SCA2 patients, 25 preclinical carriers and 24 non-SCA2 mutation carriers underwent electronystagmographical assessments of saccadic eye movements as well as neurological examination and ataxia scoring. Estimates of heritability based on the intraclass correlation coefficients were calculated for saccade velocity, accuracy and latency as well as for age at disease onset from 36, 17 and 15 sibling pairs of SCA2 patients, preclinical carriers and controls, respectively.ResultsSaccade velocity was significantly reduced in SCA2 patients and preclinical carriers, whereas decreased saccade accuracy and increased saccade latency were only observed in the patients cohort. Intraclass correlation coefficient for saccade velocity was highly significant in SCA2 patients, estimating a heritability around 94%, whereas for the age at ataxia onset this estimate was around 68%.ConclusionsElectronystagmographical measure of saccade velocity showed higher familial aggregation between SCA2 patients leading the suitability of this disease feature as endophenotype marker, with potential usefulness for the search of modifier genes and neurobiological underpinnings of the disease and as outcome measure in future neuroprotective clinical trials.

Set shifting and visuospatial organization deficits in body dysmorphic disorder

Individuals with body dysmorphic disorder (BDD) over-attend to perceived defect(s) in their physical appearance, often becoming “stuck” obsessing about perceived flaws and engaging in rituals to hide flaws. These symptoms suggest that individuals with BDD may experience deficits in underlying neurocognitive functions, such as set-shifting and visuospatial organization. These deficits have been implicated as risk and maintenance factors in disorders with similarities to BDD but have been minimally investigated in BDD. The present study examined differences in neurocognitive functions among BDD participants (n = 20) compared to healthy controls (HCs; n = 20). Participants completed neuropsychological assessments measuring set-shifting (Cambridge Neuropsychological Test Automated Battery Intra-Extra Dimensional Set Shift [IED] task) and visuospatial organization and memory (Rey-Osterrieth Complex Figure Test [ROCF]). Results revealed a set-shifting deficit among BDD participants compared to HCs on the IED. On the ROCF, BDD participants exhibited deficits in visuospatial organization compared to HCs, but they did not differ in visuospatial memory compared to HCs. Results did not change when accounting for depression severity. Findings highlight neurocognitive deficits as potential endophenotype markers of clinical features (i.e., delusionality). Understanding neuropsychological deficits may clarify similarities and differences between BDD and related disorders and may guide targets for BDD treatment.

P376 Multiple physiological measures under external-erotic stimulation delineate bipolar I and II disorders

Objectives More evidence are needed to separate bipolar disorder types I (BDI) and II (BD II). Characterizing the physiological responses to external-emotional stimuli mediated through cortical to brainstem circuit might help to delineate BD I and BD II. Methods We have invited 38 BD I, 22 BD II and 38 healthy volunteers (controls), to undergo tests of electrooculogram, electromyogram, skin conductance and electrocardiogram under six situational emotional-scenes of pictures and sounds (Disgust, Erotica, Fear, Happiness, Neutral, and Sadness), and their interchanges between background and target presenting orders. We also measured the on-going affective states of these participants. Results BD I displayed an increased electooculographic activity than BD II did when target Happiness, Neutral and Sadness were presented against the background Erotica. BD II displayed a decreased electromyographic activity than the healthy controls did when target Erotica was presented against background Disgust, Fear, Happiness, Neutral, and Sadness. Moreover, these alterations in patients were not related to their on-going affective states. Conclusion BD I displayed stronger ocular activity, and BD II displayed weaker muscle activity when responded the situational sexual stimuli. Significance Our study indicates different subtypes of bipolar disorder respond different to external-erotic stimulation, which might be their different endophenotypic markers.

Cognitive abilities in first-degree relatives of individuals with bipolar disorder

BackgroundAlthough the study of cognition in first degree relatives (FDRs) is not new, findings in this group are still somewhat inconsistent and much of the research examining FDR populations include individuals under the age of 25, who are arguably still at significant risk to go on to develop BD. The present study aimed to establish the value of cognitive performance as a genuine endophenotypic marker of familial risk for bipolar disorder (BD), by examining cognition in FDRs aged 25 years or older. MethodsThe current study compared the cognitive performance of 27 unaffected FDRs to 47 healthy controls (HCs) and 28 BD patients using the MATRICS Consensus Cognitive Battery (MCCB). ResultsResults indicated that FDRs had impaired verbal learning performance, as well as selective impairments on a measure of speed of processing; and a measure of spatial working memory compared to HC. LimitationsLimitations relate to the potential insensitivity of some of the tests in the MCCB for detecting cognitive deficits that have been previously noted in BD and FDR samples using other batteries. ConclusionsFindings from this study implicate verbal learning, processing speed and working memory performance as promising candidate endophenotypes of familial risk for BD.

MAM-E17 rat model impairments on a novel continuous performance task: effects of potential cognitive enhancing drugs

RationaleImpairments in attention and inhibitory control are endophenotypic markers of neuropsychiatric disorders such as schizophrenia and represent key targets for therapeutic management. Robust preclinical models and assays sensitive to clinically relevant treatments are crucial for improving cognitive enhancement strategies.ObjectivesWe assessed a rodent model with neural and behavioral features relevant to schizophrenia (gestational day 17 methylazoxymethanol acetate treatment (MAM-E17)) on a novel test of attention and executive function, and examined the impact of putative nootropic drugs.MethodsMAM-E17 and sham control rats were trained on a novel touchscreen-based rodent continuous performance test (rCPT) designed to closely mimic the human CPT paradigm. Performance following acute, systemic treatment with an array of pharmacological compounds was investigated.ResultsTwo cohorts of MAM-E17 rats were impaired on rCPT performance including deficits in sensitivity (d′) and increased false alarm rates (FARs). Sulpiride (0–30 mg/kg) dose-dependently reduced elevated FAR in MAM-E17 rats whereas low-dose modafinil (8 mg/kg) only improved d′ in sham controls. ABT-594 (5.9–19.4 μg/kg) and modafinil (64 mg/kg) showed expected stimulant-like effects, while LSN2463359 (5 mg/kg), RO493858 (10 mg/kg), atomoxetine (0.3–1 mg/kg), and sulpiride (30 mg/kg) showed expected suppressant effects on performance across all animals. Donepezil (0.1–1 mg/kg) showed near-significant enhancements in d′, and EVP-6124 (0.3–3 mg/kg) exerted no effects in the rCPT paradigm.ConclusionThe MAM-E17 model exhibits robust and replicable impairments in rCPT performance that resemble attention and inhibitory control deficits seen in schizophrenia. Pharmacological profiles were highly consistent with known drug effects on cognition in preclinical and clinical studies. The rCPT is a sensitive and reliable tool with high translational potential for understanding the etiology and treatment of disorders affecting attention and executive dysfunction.

Disruptions in the left frontoparietal network underlie resting state endophenotypic markers in schizophrenia.

Advances in functional brain imaging have improved the search for potential endophenotypic markers in schizophrenia. Here, we employed independent component analysis (ICA) and dynamic causal modeling (DCM) in resting state fMRI on a sample of 35 schizophrenia patients, 20 first-degree relatives and 35 control subjects. Analysis on ICA-derived networks revealed increased functional connectivity between the left frontoparietal network (FPN) and left temporal and parietal regions in schizophrenia patients (P < 0.001). First-degree relatives shared this hyperconnectivity, in particular in the supramarginal gyrus (SMG; P = 0.008). DCM analysis was employed to further explore underlying effective connectivity. Results showed increased inhibitory connections to the left angular gyrus (AG) in schizophrenia patients from all other nodes of the left FPN (P < 0.001), and in particular from the left SMG (P = 0.001). Relatives also showed a pattern of increased inhibitory connections to the left AG (P = 0.008). Furthermore, the patient group showed increased excitatory connectivity between the left fusiform gyrus and the left SMG (P = 0.002). This connection was negatively correlated to inhibitory afferents to the left AG (P = 0.005) and to the negative symptom score on the PANSS scale (P = 0.001, r = -0.51). Left frontoparietotemporal dysfunction in schizophrenia has been previously associated with a range of abnormalities, including formal thought disorder, working memory dysfunction and sensory hallucinations. Our analysis uncovered new potential endophenotypic markers of schizophrenia and shed light on the organization of the left FPN in patients and their first-degree relatives. Hum Brain Mapp 38:1741-1750, 2017. © 2017 Wiley Periodicals, Inc.

Shared atypical brain anatomy and intrinsic functional architecture in male youth with autism spectrum disorder and their unaffected brothers.

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder, yet the search for definite genetic etiologies remains elusive. Delineating ASD endophenotypes can boost the statistical power to identify the genetic etiologies and pathophysiology of ASD. We aimed to test for endophenotypes of neuroanatomy and associated intrinsic functional connectivity (iFC) via contrasting male youth with ASD, their unaffected brothers and typically developing (TD) males. The 94 participants (aged 9-19 years) - 20 male youth with ASD, 20 unaffected brothers and 54 TD males - received clinical assessments, and undertook structural and resting-state functional magnetic resonance imaging scans. Voxel-based morphometry was performed to obtain regional gray and white matter volumes. A seed-based approach, with seeds defined by the regions demonstrating atypical neuroanatomy shared by youth with ASD and unaffected brothers, was implemented to derive iFC. General linear models were used to compare brain structures and iFC among the three groups. Assessment of familiality was investigated by permutation tests for variance of the within-family pair difference. We found that atypical gray matter volume in the mid-cingulate cortex was shared between male youth with ASD and their unaffected brothers as compared with TD males. Moreover, reduced iFC between the mid-cingulate cortex and the right inferior frontal gyrus, and increased iFC between the mid-cingulate cortex and bilateral middle occipital gyrus were the shared features of male ASD youth and unaffected brothers. Atypical neuroanatomy and iFC surrounding the mid-cingulate cortex may be a potential endophenotypic marker for ASD in males.

Schizo-obsessive spectrum disorders: an update.

The presence of obsessive-compulsive symptoms (OCS) and obsessive-compulsive disorders (OCD) in schizophrenia is frequent, and a new clinical entity has been proposed for those who show the dual diagnosis: the schizo-obsessive disorder. This review scrutinizes the literature across the main academic databases, and provides an update on different aspects of schizo-obsessive spectrum disorders, which include schizophrenia, schizotypal personality disorder (SPD) with OCD, OCD with poor insight, schizophrenia with OCS, and schizophrenia with OCD (schizo-obsessive disorder). An epidemiological discussion on the discrepancies observed in the prevalence of OCS and OCD in schizophrenia across time is provided, followed by an overview of the main clinical and phenomenological features of the disorder in comparison to the primary conditions under a spectral perspective. An updated and comparative analysis of the main genetic, neurobiological, neurocognitive, and pharmacological treatment aspects for the schizo-obsessive spectrum is provided, and a discussion on endophenotypic markers is introduced in order to better understand its substrate. There is sufficient evidence in the literature to demonstrate the clinical relevance of the schizo-obsessive spectrum, although little is known about the neurobiology, genetics, and neurocognitive aspects of these groups. The pharmacological treatment of these patients is still challenging, and efforts to search for possible specific endophenotypic markers would open new avenues in the knowledge of schizo-obsessive spectrum.

Saccadic eye movements as markers of schizophrenia spectrum: Exploration in at-risk mental states

Schizophrenia is a neurodevelopmental disease with cognitive and motor impairments. Motor dysfunctions, such as eye movements or Neurological Soft Signs (NSS), are proposed as endophenotypic markers. Antisaccade (AS) and memory-guided saccades (MGS), two markers of inhibitory control mechanism, are altered in both patients with schizophrenia and their relatives, although these tools may have different sensitivities. Recently, emphasis has been put on identifying markers predictive of psychosis transition in subjects with ultra-high-risk psychosis in order to develop targeted prevention. This study investigates AS and MGS in 46 patients with schizophrenia, 23 ultra-high-risk subjects, and 39 full siblings compared to 47 healthy volunteers. NSS were assessed as a marker of abnormal neurodevelopment. The results revealed more errors in MGS in patients, ultra-high-risk subjects and siblings, than in controls, and more specifically ultra-high-risk subjects with high NSS scores. By contrast, the error rate in AS was significantly higher only in patients with schizophrenia compared to controls. These findings suggest that MGS could be more accurate to detect deficient inhibitory processes as a marker of vulnerability before the onset of schizophrenia. The use of the different paradigms (AS, MGS) revealed distinct profiles depending on the stage of the disease, indicating that some alterations could be pure endophenotypic markers of vulnerability for schizophrenia, while others could be markers of the disease progression.

Positive Emotion Specificity and Mood Symptoms in an Adolescent Outpatient Sample.

Research on positive emotion disturbance has gained increasing attention, yet it is not clear which specific positive emotions are affected by mood symptoms, particularly during the critical period of adolescence. This is especially pertinent for identifying potential endophenotypic markers associated with mood disorder onset and course. The present study examined self-reported discrete positive and negative emotions in association with clinician-rated manic and depressive mood symptoms in a clinically and demographically diverse group of 401 outpatient adolescents between 11-18 years of age. Results indicated that higher self reported joy and contempt were associated with increased symptoms of mania, after controlling for symptoms of depression. Low levels of joy and high sadness uniquely predicted symptoms of depression, after controlling for symptoms of mania. Results were independent of age, ethnicity, gender and bipolar diagnosis. These findings extend work on specific emotions implicated in mood pathology in adulthood, and provide insights into associations between emotions associated with goal driven behavior with manic and depressive mood symptom severity in adolescence. In particular, joy was the only emotion associated with both depressive and manic symptoms across adolescent psychopathology, highlighting the importance of understanding positive emotion disturbance during adolescent development.

Structural Network Disorganization in Subjects at Clinical High Risk for Psychosis

Previous network studies in chronic schizophrenia patients revealed impaired structural organization of the brain’s rich-club members, a set of highly interconnected hub regions that play an important integrative role for global brain communication. Moreover, impaired rich-club connectivity has also been found in unaffected siblings of schizophrenia patients, suggesting that abnormal rich-club connectivity is related to familiar, possibly reflecting genetic, vulnerability for schizophrenia. However, no study has yet investigated whether structural rich-club organization is also impaired in individuals with a clinical risk syndrome for psychosis. Diffusion tensor imaging and probabilistic tractography was used to construct structural whole-brain networks in 24 healthy controls and 24 subjects with an at-risk mental state (ARMS). Graph theory was applied to quantify the structural rich-club organization and global network properties. ARMS subjects revealed a significantly altered structural rich-club organization compared with the control group. The disruption of rich-club organization was associated with the severity of negative psychotic symptoms and led to an elevated level of modularity in ARMS subjects. This study shows that abnormal structural rich-club organization is already evident in clinical high-risk subjects for psychosis and further demonstrates the impact of rich-club disorganization on global network communication. Together with previous evidence in chronic schizophrenia patients and unaffected siblings, our findings suggest that abnormal structural rich-club organization may reflect an endophenotypic marker of psychosis.

Adaptation et validation d’une échelle des signes neurologiques mineurs chez l’enfant

BackgroundNeurological soft signs (NSS) include anomalies in motor integration, coordination, sensory integration and lateralization and could be endophenotypic markers in autism spectrum disorders (ASD). Their characterization provides a more precise phenotype of ASD and more homogeneous subtypes to facilitate clinical and genetic research. Few scales for NSS have been adapted and validated in children including children with ASD. Our objective was to perform an adaptation to the child of a scale assessing neurological soft signs and a validation study in both general and clinical populations. MethodsWe have selected the NSS scale of Krebs et al. (2000) already validated in adults. It encompasses 5 dimensions: motor coordination, motor integration, sensory integration, involuntary movement, laterality. After a preliminary study that examined 42 children, several changes have been made to the original version to adapt it to the child and to increase its feasibility, particularly in children with ASD. Then we conducted a validation study by assessing the psychometric properties of this scale in a population of 86 children including 26 children with ASD (DSM 5 Criteria) and 60 typically developing children. Children's ages ranged between 6 and 12 years, and patients and controls were matched for gender, age and intelligence. Patients were assessed using the Autism diagnostic Interview-revised and the Childhood Autism Rating Scale to confirm diagnosis. Typically developing children were assessed using the semi-structured Mini International Neuropsychiatric Interview for Children and Adolescents to eliminate any psychiatric disorder. All children with neurological pathologies (history of cerebral palsy, congenital anomaly of the central nervous system, epilepsy, tuberous sclerosis, neurofibromatosis, antecedent of severe head trauma) and obvious physical deformities or sensory deficits that could interfere with neurological assessment were excluded from the study. Both patients and controls were assessed using the Raven Progressive Matrices to exclude intellectual disability, and the adapted Krebs’ scale for the assessment of NSS. ResultsAdaptation of the scale consisted of a modification in the order of items, in the use of concrete supports for the assessment of laterality and in the elimination of item constructive praxis. The internal consistency was good with a Cronbach alpha of 0.87. Inter-rater reliability was good, kappa coefficient was greater than 0.75 for 16 items, 3 items had a kappa value between 0.74 and 0.60, only 1 item had a kappa coefficient between 0.4 and 0.59. Good inter-rater reliability was also checked for the total score with a value of intra-class correlation coefficient (ICC) of 0.91. Principal component analysis found five factors accounting for 62.96 % of the total variance. About the comparison between patients and controls, significant differences were found for NSS total score (P=0.000) and all subscores. ConclusionThe adaptation for children of the Krebs et al.’ NSS scale proved to be valid, especially in children with ASD.

Atypical visual and somatosensory adaptation in schizophrenia-spectrum disorders.

Neurophysiological investigations in patients with schizophrenia consistently show early sensory processing deficits in the visual system. Importantly, comparable sensory deficits have also been established in healthy first-degree biological relatives of patients with schizophrenia and in first-episode drug-naive patients. The clear implication is that these measures are endophenotypic, related to the underlying genetic liability for schizophrenia. However, there is significant overlap between patient response distributions and those of healthy individuals without affected first-degree relatives. Here we sought to develop more sensitive measures of sensory dysfunction in this population, with an eye to establishing endophenotypic markers with better predictive capabilities. We used a sensory adaptation paradigm in which electrophysiological responses to basic visual and somatosensory stimuli presented at different rates (ranging from 250 to 2550 ms interstimulus intervals, in blocked presentations) were compared. Our main hypothesis was that adaptation would be substantially diminished in schizophrenia, and that this would be especially prevalent in the visual system. High-density event-related potential recordings showed amplitude reductions in sensory adaptation in patients with schizophrenia (N=15 Experiment 1, N=12 Experiment 2) compared with age-matched healthy controls (N=15 Experiment 1, N=12 Experiment 2), and this was seen for both sensory modalities. At the individual participant level, reduced adaptation was more robust for visual compared with somatosensory stimulation. These results point to significant impairments in short-term sensory plasticity across sensory modalities in schizophrenia. These simple-to-execute measures may prove valuable as candidate endophenotypes and will bear follow-up in future work.