Auditory event-related potentials, neurocognition, and global functioning in drug naïve first-episode schizophrenia and bipolar disorder.

BACKGROUND: Deficits in event-related potential (ERP) including duration mismatch negativity (MMN) and P3a have been demonstrated widely in chronic schizophrenia (SZ) but inconsistent findings were reported in first-episode patients. Psychotropic medications and diagnosis might contribute to different findings on MMN/P3a ERP in first-episode patients. The present study examined MMN and P3a in first episode drug naïve SZ and bipolar disorder (BPD) patients and explored the relationships among ERPs, neurocognition and global functioning. METHODS: Twenty SZ, 24 BPD and 49 age and sex-matched healthy controls were enrolled in this study. Data of clinical symptoms [Positive and Negative Symptoms Scale (PANSS), Young Manic Rating Scale (YMRS), Hamilton Depression Rating Scale (HAMD)], neurocognition [Wechsler Adult Intelligence Scale (WAIS), Cattell's Culture Fair Intelligence Test (CCFT), Delay Matching to Sample (DMS), Rapid Visual Information Processing (RVP)], and functioning [Functioning Assessment Short Test (FAST)] were collected. P3a and MMN were elicited using a passive auditory oddball paradigm. RESULTS: Significant MMN and P3a deficits and impaired neurocognition were found in both SZ and BPD patients. In SZ, MMN was significantly correlated with FAST (r = 0.48) and CCFT (r = -0.31). In BPD, MMN was significantly correlated with DMS (r = -0.54). For P3a, RVP and FAST scores were significant predictors in SZ, whereas RVP, WAIS and FAST were significant predictors in BPD. CONCLUSIONS: The present study found deficits in MMN, P3a, neurocognition in drug naïve SZ and BPD patients. These deficits appeared to link with levels of higher-order cognition and functioning.

Dynamic and progressive changes in thalamic functional connectivity over the first five years of psychosis.

The early stage of psychosis (ESP) is a critical period where effective intervention has the most favorable impact on outcomes. Thalamic connectivity abnormalities have been consistently found in psychosis, and are associated with clinical symptoms and cognitive deficits. However, most studies consider ESP patients as a homogeneous population and fail to take the duration of illness into account. In this study, we aimed to capture the progression of thalamic connectivity changes over the first five years of psychosis. Resting-state functional MRI scans were collected from 156 ESP patients (44 with longitudinal data) and 82 healthy controls (24 with longitudinal data). We first performed a case-control analysis comparing thalamic connectivity with 13 networks in the cortex and cerebellum. Next, we modelled the shape (flat, linear, curvilinear) of thalamic connectivity trajectories by comparing flexible non-linear versus linear models. We then tested the significance of the duration of illness and diagnosis in trajectories that changed over time. Connectivity changed over the ESP period between the thalamus and default mode network (DMN) and fronto-parietal network (FPN) nodes in both the cortex and cerebellum. Three models followed a curvilinear trajectory (early increase followed by a subsequent decrease), while thalamo-cerebellar FPN connectivity followed a linear trajectory of steady reductions over time, indicating different rates of change. Finally, diagnosis significantly predicted thalamic connectivity. Thalamo-cortical and thalamo-cerebellar connectivity change in a dynamic fashion during the ESP period. A better understanding of these changes may provide insights into the compensatory and progressive changes in functional connectivity in the early stages of illness.

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.

Frontal P3 event-related potential is related to brain glutamine/glutamate ratio measured in vivo.

BACKGROUND: The auditory P3 event-related potential (ERP) is thought to index cognitive processing relevant to attention and working memory processes. Drug challenge studies suggest that glutamate neurotransmission plays an important role in modulating P3 ERP. However, while direct links between glutamate activity and P3 ERP response in humans are suspected, mechanistic details remain largely unknown. We investigated here the relationships between P3 ERP and indices of glutamatergic processing measured in vivo with proton magnetic resonance spectroscopy ((1)H MRS). We hypothesized that a higher index of glutamatergic processing (glutamine/glutamate ratio; abbreviated Gln/Glu) in the anterior cingulate (ACC) and in the parietal-occipital (POC) cortices would associate with larger frontal P3a and parietal P3b amplitudes, respectively. METHODS: Frontal P3a (Fz) and parietal P3b (Pz) were collected from 32 healthy participants who performed an auditory oddball task. Resting glutamate (Glu), glutamine (Gln), and Gln/Glu (an index of glutamatergic processing) measures were obtained on a 4T MR scanner using J-resolved MR spectroscopy. Linear regression and partial correlations were used for statistical analysis. RESULTS: Significant positive correlations were found between frontal P3a amplitude and ACC Gln/Glu ratio (partial R=0.57; P=0.001) and between frontal P3a amplitude and ACC Gln concentration (partial R=0.43; P=0.02). Relationships between parietal P3b and the glutamate indices in the POC were not significant. CONCLUSIONS: These results indicate a specific connection between an index of glutamate neurotransmitter function in ACC and frontal P3 ERP, providing a novel insight into the neurochemistry underlying scalp recorded EEG response. Abnormalities in glutamate neurotransmission have been observed in schizophrenia and other psychiatric conditions and may underlie illness related deficits of P3 ERP.

Sensory gating deficits in the attenuated psychosis syndrome.

BACKGROUND: Individuals with an "Attenuated Psychosis Syndrome" (APS) have a 20-40% chance of developing a psychotic disorder within two years; however it is difficult to predict which of them will become ill on the basis of their clinical symptoms alone. We examined whether P50 gating deficits could help to discriminate individuals with APS and also those who are particularly likely to make a transition to psychosis. METHOD: 36 cases meeting PACE (Personal Assessment and Crisis Evaluation) criteria for the APS, all free of antipsychotics, and 60 controls performed an auditory conditioning-testing experiment while their electroencephalogram was recorded. The P50 ratio and its C-T difference were compared between groups. Subjects received follow-up for up to 2 years to determine their clinical outcome. RESULTS: The P50 ratio was significantly higher and C-T difference lower in the APS group compared to controls. Of the individuals with APS who completed the follow-up (n=36), nine (25%) developed psychosis. P50 ratio and the C-T difference did not significantly differ between those individuals who developed psychosis and those who did not within the APS group. CONCLUSION: P50 deficits appear to be associated with the pre-clinical phase of psychosis. However, due to the limitations of the study and its sample size, replication in an independent cohort is necessary, to clarify the role of P50 deficits in illness progression and whether this inexpensive and non-invasive EEG marker could be of clinical value in the prediction of psychosis outcomes amongst populations at risk.

Patterns of deficits in brain function in bipolar disorder and schizophrenia: a cluster analytic study.

Historically, bipolar disorder and schizophrenia have been considered distinct disorders with different etiologies. Growing evidence suggests that overlapping genetic influences contribute to risk for these disorders and that each disease is genetically heterogeneous. Using cluster analytic methods, we empirically identified homogeneous subgroups of patients, their relatives, and controls based on distinct neurophysiologic profiles. Seven phenotypes were collected from two independent cohorts at two institutions. K-means clustering was used to identify neurophysiologic profiles. In the analysis of all participants, three distinct profiles emerged: "globally impaired", "sensory processing", and "high cognitive". In a secondary analysis, restricted to patients only, we observed a similar clustering into three profiles. The neurophysiological profiles of the Schizophrenia (SZ) and Bipolar Disorder (BPD) patients did not support the Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnostic distinction between these two disorders. Smokers in the globally impaired group smoked significantly more cigarettes than those in the sensory processing or high cognitive groups. Our results suggest that empirical analyses of neurophysiological phenotypes can identify potentially biologically relevant homogenous subgroups independent of diagnostic boundaries. We hypothesize that each neurophysiology subgroup may share similar genotypic profiles, which may increase statistical power to detect genetic risk factors.

The genetic and environmental influences of event-related gamma oscillations on bipolar disorder.

OBJECTIVES: Gamma oscillations have been proposed to play an important role in neural information coding. There have been a limited number of electrophysiology studies in evoked gamma band responses (GBRs) in bipolar disorder (BPD). It is also unclear whether GBR deficits, if present, are potential endophenotypes for BPD as little is known about the heritability of GBRs. The present study aimed to examine whether GBRs derived from two auditory tasks, the oddball task and the dual-click paradigm, are potential BPD endophenotypes. METHODS: A total of 308 subjects were included in this study: 198 healthy controls, 59 BPD patients (22 monozygotic BPD twins and 37 BPD patients from 31 families), and 51 unaffected relatives. The evoked gamma responses were calculated using a Morlet wavelet transformation. Structural equation modelling was applied to obtain the genetic (heritability) and environment estimates in each GBR variable and their (genetic) overlap with BPD. RESULTS: The heritability estimates of GBR to standard stimuli were 0.51 and 0.35 to target stimuli in the oddball task. However, neither response type was impaired in BPD patients or their unaffected relatives. The heritability estimates of GBR to S1 stimuli were 0.54 and 0.50 to S2 stimuli in the dual-click paradigm. BPD patients had reduced gamma power and suppression to S1 stimuli but their unaffected relatives did not. CONCLUSIONS: Evoked GBRs are heritable traits. However, GBR deficits are not observed in clinically unaffected relatives nor associated with BPD. Gamma responses do not appear to satisfy criteria for being BPD endophenotypes.

The early auditory gamma-band response is heritable and a putative endophenotype of schizophrenia.

BACKGROUND: Reduced power and phase locking of the early auditory gamma-band response (EAGBR) have been reported in schizophrenia, but findings are equivocal. Further, little is known about genetic (heritability) and environmental influences on the EAGBR or its potential as an endophenotype of schizophrenia. The present study used a twin design to examine whether EAGBR power and phase locking are heritable and reduced in schizophrenic patients and their unaffected co-twins and thus putative endophenotypes of schizophrenia. METHODS: The study sample included a total of 194 individuals, consisting of 15 monozygotic [MZ] twin pairs concordant for schizophrenia, 9 MZ twin pairs discordant for schizophrenia, and 42 MZ and 31 dizygotic (DZ) control pairs. Evoked power and phase-locking factor of the EAGBR were computed on Morlet wavelet-transformed electroencephalogram responses to standard tones during an auditory oddball target detection task. Structural equation modeling was applied to estimate heritability and genetic and environmental correlations with schizophrenia for the EAGBR measures. RESULTS: Both evoked power and phase-locking phenotypes were heritable traits (power: h(2) = 0.65; phase locking: h(2) = 0.63). Impaired EAGBR measures were significantly associated with schizophrenia. Patients with schizophrenia and their unaffected identical co-twins exhibited significantly reduced EAGBR power compared with control subjects. In each phenotype, shared genetic factors were likely the source of the observed associations with schizophrenia. CONCLUSIONS: Our results support EAGBR measures as putative endophenotypes of schizophrenia, likely reflecting an ubiquitous local cortical circuit deficit.

Auditory P300 in patients with bipolar disorder and their unaffected relatives.

OBJECTIVES: There is evidence that genetic susceptibility may be shared between bipolar disorder (BD) and schizophrenia, but electrophysiological phenotypes which have been extensively used in studies of genetic susceptibility for schizophrenia remain far less explored in bipolar illness. This study assesses whether auditory P300 latency delays and amplitude reductions, which have been demonstrated in patients with schizophrenia and their unaffected first-degree relatives, are associated with familial liability to psychotic bipolar illness. METHODS: The P300 auditory evoked potential was obtained using an oddball task from 37 participants with BD who had a history of psychotic symptoms, 38 of their unaffected first-degree relatives and 42 healthy unrelated comparison subjects. Patients and relatives came from families multiply affected with BD or another functional psychotic disorder. P300 amplitude and latency at midline sites were compared between the groups, using linear regression analyses and robust variance estimators for clustered data, including age and gender as covariates. RESULTS: Bipolar disorder patients with a history of psychosis and their unaffected relatives showed significantly delayed P300 latency at Pz compared to controls. The groups did not differ in P300 amplitude. CONCLUSIONS: P300 latency delays are associated with both psychotic BD and familial liability for this illness. Sample size limited our ability to test for multimodal distribution of P300 measures among relatives, which might be expected if only a subgroup inherits any deficits. In future it will be of interest to directly compare groups of families with psychotic and non-psychotic forms of BD to explore further the role of psychotic symptoms with regard to P300 measures in the disorder. Our results indicate that delayed P300 latency is a promising candidate endophenotype for psychotic BD, as well as schizophrenia, and may reflect the impact of shared susceptibility genes for both types of psychosis.

Physiology of schizophrenia, bipolar disorder, and schizoaffective disorder.

OBJECTIVE: Endophenotypes have been proposed to identify the genetic and biological substrates of complex disorders. Three physiological inhibitory endophenotypes of large effect size in schizophrenia include suppression of P50 auditory evoked responses, inhibition of leading (small anticipatory) saccades during smooth pursuit eye movements, and cancellation of reflexive saccades in the antisaccade eye movement task. The aim of this study was to determine if the pattern of endophenotype abnormalities within individuals with schizophrenia differed from that within individuals with bipolar disorder. A second aim was to determine whether subjects with schizoaffective disorder, bipolar type, were neurophysiologically more similar to subjects with schizophrenia or subjects with bipolar disorder. METHOD: Endophenotypes were recorded for subjects diagnosed with schizophrenia (N=29), bipolar disorder (DSM-IV-TR) (N=40), and schizoaffective disorder, bipolar type (N=18). Data from normal comparison subjects were used to establish normal performance. RESULTS: Logistic regression determined that P50 ratio and frequency of leading saccades identified subjects with schizophrenia and bipolar disorder with a sensitivity of 95% and a specificity of 83%. The schizoaffective disorder group was split, with six subjects physiologically classified as schizophrenia-like and 12 subjects as bipolar-like. Those classified as schizophrenia-like were significantly younger at illness onset and had higher symptom ratings. CONCLUSION: A composite endophenotype of P50 ratio and frequency of leading saccades is consistent with the current clinical nosology of schizophrenia and bipolar disorder and parses patients with schizoaffective disorder, bipolar type, into two subgroups.

Substantial shared genetic influences on schizophrenia and event-related potentials.

OBJECTIVE: Several components of event-related potentials--P50 suppression, P300 amplitude and latency, and mismatch negativity--have been proposed as potential endophenotypes for schizophrenia on the basis of family studies. The present study used a twin design to estimate the extent of genetic overlap between these indices and the liability to schizophrenia. METHOD: The authors measured mismatch negativity, P300, and P50 suppression in 16 monozygotic twin pairs concordant for schizophrenia, nine monozygotic twin pairs discordant for schizophrenia, and 78 healthy comparison twin pairs. The study design was based on a power calculation. Structural equation modeling was used to quantify the genetic and environmental contributions to the phenotypic covariance between schizophrenia and each of the event-related potential indices. RESULTS: Significant phenotypic correlation with schizophrenia was found for each of the event-related potential components. Genetic factors were the main source of the phenotypic correlations. P50 suppression had the greatest genetic correlation with schizophrenia, followed by P300 amplitude, P300 latency, and mismatch negativity. CONCLUSIONS: All four event-related potential indices are potentially valid endophenotypes for schizophrenia, but P50 suppression and P300 amplitude show the closest genetic relationship to schizophrenia.

Magnetic resonance imaging of the thalamus and adhesio interthalamica in twins with schizophrenia.

CONTEXT: Abnormalities of the thalamus are thought to be central to the pathophysiology of schizophrenia. These abnormalities include altered structure and shape of the thalamus itself and possibly changes to the adhesio interthalamica (or massa intermedia), the gray matter bridge connecting the 2 thalamic lobes. However, it is not clear to what extent these abnormalities are determined by the genetic liability for schizophrenia. OBJECTIVE: To investigate thalamic volume and the presence of the adhesio interthalamica in monozygotic (MZ) twins concordant or discordant for schizophrenia. DESIGN: Study of MZ twins. SETTING: Patients were drawn from inpatient and outpatient clinics. Twin controls were recruited from a volunteer twin register and through media advertisements. PARTICIPANTS: A total of 123 twins participated: 19 MZ twin pairs concordant for schizophrenia, 15 MZ schizophrenic twins and 16 MZ nonschizophrenic twins drawn from 17 pairs discordant for schizophrenia, and 27 MZ twin pairs without schizophrenia. Groups were matched for age, sex, handedness, level of education, parental socioeconomic status, and ethnicity. MAIN OUTCOME MEASURES: The volume of the thalamus (including right and left hemispheres) was measured (in cubic centimeters) and the presence of the adhesio interthalamica was ascertained from structural magnetic resonance images. RESULTS: Concordant twin pairs displayed significantly reduced thalamic volume compared with control twins, even when covarying for effects of whole-brain volume, age, and sex. There was a significant linear decrease in thalamic volume (control greater than discordant nonschizophrenic greater than discordant schizophrenic greater than concordant). In all groups, right thalamus was larger than left thalamus. There was no difference across groups in the frequency of the adhesio interthalamica. CONCLUSIONS: Volumetric thalamic abnormalities in schizophrenia occur in twin pairs concordant for schizophrenia. These abnormalities may mark the substantial genetic contribution to the illness seen in concordant twin pairs, whereas the adhesio interthalamica is unlikely to be affected in schizophrenia.

P50 auditory evoked potential suppression in bipolar disorder patients with psychotic features and their unaffected relatives.

BACKGROUND: Diminished suppression of the P50 response, a consistent finding in schizophrenia, has also been reported in patients with psychotic bipolar disorder. It is a promising endophenotype for schizophrenia, but its relationship to genetic liability in bipolar disorder is unknown. We therefore assessed whether diminished P50 suppression is associated with familial risk for psychotic bipolar disorder. METHODS: The P50 response was collected in a conditioning (C)--testing (T) paradigm from 42 outpatients with bipolar 1 disorder who had experienced psychotic symptoms and 44 of their unaffected first-degree relatives, all from families multiply affected with bipolar disorder or another non-organic psychotic disorder; 48 healthy control subjects were also studied. The T/C ratio was compared between the groups, with linear regression analyses and robust variance estimators for clustered data. RESULTS: Both patients (estimated mean difference in T/C ratio to control subjects, 32, 95% confidence interval [CI] 15-48, p=.001) and unaffected relatives (20, 95% CI 7-32, p=.002) demonstrated higher T/C ratio, thus indicating diminished P50 suppression compared with control subjects. CONCLUSIONS: To our knowledge, this is the first report of diminished P50 gating in unaffected relatives of psychotic bipolar disorder patients from multiply affected families. Our results suggest that impaired P50 gating is a putative endophenotype for psychotic bipolar disorder and thus might reflect the impact of susceptibility genes across psychosis.

Varied effects of atypical neuroleptics on P50 auditory gating in schizophrenia patients.

OBJECTIVE: Sensory gating deficits found in schizophrenia can be assessed by using a paired auditory stimulus paradigm to measure auditory evoked response. The ratio of the P50 response amplitude of the second or test stimulus to that of the first or conditioning stimulus is expressed as a percentage. Normal subjects generally suppress the second response and typically have ratios of less than 40%. Subjects with schizophrenia and half their first-degree relatives have deficits in sensory gating, with P50 ratios that are generally greater than 50%. Treatment with typical neuroleptics does not reverse this deficit. However, previous studies have shown that treatment with clozapine, an atypical neuroleptic, ameliorates this deficit in clinically responsive patients. This study sought to determine whether other atypical neuroleptics improve P50 ratios. METHOD: P50 evoked potential recordings were obtained from 132 patients with schizophrenia and 177 healthy comparison subjects. Eighty-eight patients were being treated with atypical neuroleptics (clozapine [N=26], olanzapine [N=31], risperidone [N=22], and quetiapine [N=9]). Thirty-four patients were taking typical neuroleptics, and 10 were unmedicated. RESULTS: Healthy subjects exhibited P50 suppression that was significantly better than the schizophrenia patients receiving typical neuroleptics (mean=19.8% [SD=21.0%] versus 110.1% [SD=87.9%]). Patients receiving atypical neuroleptics had a mean P50 ratio that fell between these two means (mean=70.4%, SD=53.7%). When patients treated with different atypical neuroleptics were compared, only the clozapine group had mean P50 ratios that were in the normal range. All other groups exhibited auditory P50 response inhibition that was significantly poorer than that of the healthy subjects. CONCLUSIONS: Improvement in P50 gating appears to be greatest in patients treated with clozapine.