Impact of Antipsychotic Treatment on Attention and Motor Learning Systems in First-Episode Schizophrenia

Background: Antipsychotic medications have established clinical benefit, but there are few neuroimaging studies before and after initiating antipsychotic medication to assess drug influence on brain circuitry. Attention and motor learning tasks are promising approaches for examining treatment-related changes in frontostriatal systems. Methods: Twenty-one unmedicated first-episode schizophrenia patients (14 antipsychotic-naïve) participated in functional imaging studies while performing visual attention (prosaccades) and motor learning tasks (predictive saccades). Posttreatment testing was completed in 14 patients after 4–6 weeks of antipsychotic treatment. Matched healthy controls were studied in parallel. Results: Pretreatment, patients had reduced activation in the dorsal neocortical visual attention network. Activation deficits were significantly reduced posttreatment. Higher medication dose was associated with greater caudate activation at follow-up. For the motor learning task, patients’ dorsolateral prefrontal cortex (DLPFC) was unimpaired prior to treatment but showed significantly reduced activation after treatment. Conclusion: Impairments in dorsal cortical attention networks are present in untreated first-episode schizophrenia patients. These impairments are reduced after antipsychotic treatment, suggesting a beneficial effect on neural systems for attention. Treatment-emergent decreases in DLPFC activation observed for the motor learning task are consistent with other clinical and preclinical evidence suggesting that antipsychotics can have adverse effects on prefrontal function.Key words: fMRI, cognition, dorsolateral prefrontal cortex, saccades, caudate, risperidone     

Neurocognitive Graphs of First-Episode Schizophrenia and Major Depression Based on Cognitive Features

Neurocognitive deficits are frequently observed in patients with schizophrenia and major depressive disorder (MDD). The relations between cognitive features may be represented by neurocognitive graphs based on cognitive features, modeled as Gaussian Markov random fields. However, it is unclear whether it is possible to differentiate between phenotypic patterns associated with the differential diagnosis of schizophrenia and depression using this neurocognitive graph approach. In this study, we enrolled 215 first-episode patients with schizophrenia (FES), 125 with MDD, and 237 demographically-matched healthy controls (HCs). The cognitive performance of all participants was evaluated using a battery of neurocognitive tests. The graphical LASSO model was trained with a one-vs-one scenario to learn the conditional independent structure of neurocognitive features of each group. Participants in the holdout dataset were classified into different groups with the highest likelihood. A partial correlation matrix was transformed from the graphical model to further explore the neurocognitive graph for each group. The classification approach identified the diagnostic class for individuals with an average accuracy of 73.41% for FES vs HC, 67.07% for MDD vs HC, and 59.48% for FES vs MDD. Both of the neurocognitive graphs for FES and MDD had more connections and higher node centrality than those for HC. The neurocognitive graph for FES was less sparse and had more connections than that for MDD. Thus, neurocognitive graphs based on cognitive features are promising for describing endophenotypes that may discriminate schizophrenia from depression.     

Impaired Sensorimotor Gating Using the Acoustic Prepulse Inhibition Paradigm in Individuals at a Clinical High Risk for Psychosis

Many robust studies have investigated prepulse inhibition (PPI) in patients with schizophrenia. Recent evidence indicates that PPI may help identify individuals who are at clinical high risk for psychosis (CHR). Selective attention to prepulse stimulus can specifically enhance PPI in healthy subjects; however, this enhancement effect is not observed in patients with schizophrenia. Modified PPI measurement with selective attentional modulation using perceived spatial separation (PSS) condition may be a more robust and sensitive index of PPI impairment in CHR individuals. The current study investigated an improved PSSPPI condition in CHR individuals compared with patients with first-episode schizophrenia (FES) and healthy controls (HC) and evaluated the accuracy of PPI in predicting CHR from HC. We included 53 FESs, 55 CHR individuals, and 53 HCs. CHRs were rated on the Structured Interview for Prodromal Syndromes. The measures of perceived spatial co-location PPI (PSCPPI) and PSSPPI conditions were applied using 60- and 120-ms lead intervals. Compared with HC, the CHR group had lower PSSPPI level (Inter-stimulus interval [ISI] = 60 ms, P < .001; ISI = 120 ms, P < .001). PSSPPI showed an effect size (ES) between CHR and HC (ISI = 60 ms, Cohen’s d = 0.91; ISI = 120 ms, Cohen’s d = 0.98); on PSSPPI using 60-ms lead interval, ES grade increased from CHR to FES. The area under the receiver operating characteristic curve for PSSPPI was greater than that for PSCPPI. CHR individuals showed a PSSPPI deficit similar to FES, with greater ES and sensitivity. PSSPPI appears a promising objective approach for preliminary identification of CHR individuals.     

Age at First Episode Modulates Diagnosis-Related Structural Brain Abnormalities in Psychosis

Brain volume and thickness abnormalities have been reported in first-episode psychosis (FEP). However, it is unclear if and how they are modulated by brain developmental stage (and, therefore, by age at FEP as a proxy). This is a multicenter cross-sectional case-control brain magnetic resonance imaging (MRI) study. Patients with FEP (n = 196), 65.3% males, with a wide age at FEP span (12–35 y), and healthy controls (HC) (n = 157), matched for age, sex, and handedness, were scanned at 6 sites. Gray matter volume and thickness measurements were generated for several brain regions using FreeSurfer software. The nonlinear relationship between age at scan (a proxy for age at FEP in patients) and volume and thickness measurements was explored in patients with schizophrenia spectrum disorders (SSD), affective psychoses (AFP), and HC. Earlier SSD cases (ie, FEP before 15–20 y) showed significant volume and thickness deficits in frontal lobe, volume deficits in temporal lobe, and volume enlargements in ventricular system and basal ganglia. First-episode AFP patients had smaller cingulate cortex volume and thicker temporal cortex only at early age at FEP (before 18–20 y). The AFP group also had age-constant (12–35-y age span) volume enlargements in the frontal and parietal lobe. Our study suggests that age at first episode modulates the structural brain abnormalities found in FEP patients in a nonlinear and diagnosis-dependent manner. Future MRI studies should take these results into account when interpreting samples with different ages at onset and diagnosis.Key words: first-episode psychosis, age at onset, schizophrenia, bipolar disorder, cortical thickness, cortical volume, MRI     

A White Matter Connection of Schizophrenia and Alzheimer’s Disease

Schizophrenia (SZ) is a severe psychiatric illness associated with an elevated risk for developing Alzheimer’s disease (AD). Both SZ and AD have white matter abnormalities and cognitive deficits as core disease features. We hypothesized that aging in SZ patients may be associated with the development of cerebral white matter deficit patterns similar to those observed in AD. We identified and replicated aging-related increases in the similarity between white matter deficit patterns in patients with SZ and AD. The white matter “regional vulnerability index” (RVI) for AD was significantly higher in SZ patients compared with healthy controls in both the independent discovery (Cohen’s d = 0.44, P = 1·10^–5, N = 173 patients/230 control) and replication (Cohen’s d = 0.78, P = 9·10^–7, N = 122 patients/64 controls) samples. The degree of overlap with the AD deficit pattern was significantly correlated with age in patients (r = .21 and .29, P < .01 in discovery and replication cohorts, respectively) but not in controls. Elevated RVI-AD was significantly associated with cognitive measures in both SZ and AD. Disease and cognitive specificities were also tested in patients with mild cognitive impairment and showed intermediate overlap. SZ and AD have diverse etiologies and clinical courses; our findings suggest that white matter deficits may represent a key intersecting point for these 2 otherwise distinct diseases. Identifying mechanisms underlying this white matter deficit pattern may yield preventative and treatment targets for cognitive deficits in both SZ and AD patients.     

Face and object visual working memory deficits in first-episode schizophrenia correlate with multiple neurocognitive performances

BackgroundWorking memory (WM) deficit is considered a core feature and cognitive biomarker in patients with schizophrenia. Several studies have reported prominent object WM deficits in patients with schizophrenia, suggesting that visual WM in these patients extends to non-spatial domains. However, whether non-spatial WM is similarly affected remains unclear.AimThis study primarily aimed to identify the processing of visual object WM in patients with first-episode schizophrenia.MethodsThe study included 36 patients with first-episode schizophrenia and 35 healthy controls. Visual object WM capacity, including face and house WM capacity, was assessed by means of delayed matching-to-sample visual WM tasks, in which participants must distribute memory so that they can discriminate a target sample. We specifically examined their anhedonia experience by the Temporal Experience of Pleasure Scale and the Snaith-Hamilton Pleasure Scale. Cognitive performance was measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).ResultsBoth face and house WM capacity was significantly impaired in patients with schizophrenia. For both tasks, the performance of all the subjects was worse under the high-load condition than under the low-load condition. We found that WM capacity was highly positively correlated with the performance on RBANS total scores (r=−0.528, p=0.005), RBANS delayed memory scores (r=−0.470, p=0.013), RBANS attention scores (r=−0.584, p=0.001), RBANS language scores (r=−0.448, p=0.019), Trail-Making Test: Part A raw scores (r=0.465, p=0.015) and simple IQ total scores (r=−0.538, p=0.005), and correlated with scores of the vocabulary test (r=−0.490, p=0.011) and scores of the Block Diagram Test (r=−0.426, p=0.027) in schizophrenia. No significant correlations were observed between WM capacity and Positive and Negative Syndrome Scale symptoms.ConclusionsOur research found that visual object WM capacity is dramatically impaired in patients with schizophrenia and is strongly correlated with other measures of cognition, suggesting a mechanism that is critical in explaining a portion of the broad cognitive deficits observed in schizophrenia.     

Neuropsychological Performance in Older Patients With Schizophrenia: A Meta-Analysis of Cross-sectional and Longitudinal Studies

Objective: Cognitive deficits are among the most reliable predictors of functional impairment in schizophrenia and a particular concern for older individuals with schizophrenia. Previous reviews have focused on the nature and course of cognitive impairments in younger cohorts, but a quantitative meta-analysis in older patients is pending. Method: A previously used search strategy identified studies assessing performance on tests of global cognition and specific neuropsychological domains in older patients with schizophrenia and age-matched comparison groups. Both cross-sectional and longitudinal studies were included. Potential methodological, demographic, and clinical moderators were analyzed. Results: Twenty-nine cross-sectional (2110 patients, 1738 comparison subjects) and 14 longitudinal (954 patients) studies met inclusion criteria. Patients were approximately 65 years old, with 11 years of education, 53% male and 79% Caucasian. Longitudinal analysis (range 1–6 years) revealed homogeneity with small effect sizes (d = −0.097) being observed. Cross-sectional analyses revealed large and heterogeneous deficits in global cognition (d = −1.19) and on specific neuropsychological tests (d = −0.7 to −1.14). Moderator analysis revealed a significant role for demographic (age, sex, education, race) and clinical factors (diagnosis, inpatient status, age of onset, duration of illness, positive and negative symptomology). Medication status (medicated vs nonmedicated) and chlorpromazine equivalents were inconsequential, albeit underrepresented. Conclusions: Large and generalized cognitive deficits in older individuals with schizophrenia represent a robust finding paralleling impairments across the life span, but these deficits do not decline over a 1–6 year period. The importance of considering demographic and clinical moderators in cross-sectional analyses is highlighted.     

The Impact of Cannabis Use on Cognitive Functioning in Patients With Schizophrenia: A Meta-analysis of Existing Findings and New Data in a First-Episode Sample

Cannabis use is highly prevalent among people with schizophrenia, and coupled with impaired cognition, is thought to heighten the risk of illness onset. However, while heavy cannabis use has been associated with cognitive deficits in long-term users, studies among patients with schizophrenia have been contradictory. This article consists of 2 studies. In Study I, a meta-analysis of 10 studies comprising 572 patients with established schizophrenia (with and without comorbid cannabis use) was conducted. Patients with a history of cannabis use were found to have superior neuropsychological functioning. This finding was largely driven by studies that included patients with a lifetime history of cannabis use rather than current or recent use. In Study II, we examined the neuropsychological performance of 85 patients with first-episode psychosis (FEP) and 43 healthy nonusing controls. Relative to controls, FEP patients with a history of cannabis use (FEP + CANN; n = 59) displayed only selective neuropsychological impairments while those without a history (FEP − CANN; n = 26) displayed generalized deficits. When directly compared, FEP + CANN patients performed better on tests of visual memory, working memory, and executive functioning. Patients with early onset cannabis use had less neuropsychological impairment than patients with later onset use. Together, these findings suggest that patients with schizophrenia or FEP with a history of cannabis use have superior neuropsychological functioning compared with nonusing patients. This association between better cognitive performance and cannabis use in schizophrenia may be driven by a subgroup of “neurocognitively less impaired” patients, who only developed psychosis after a relatively early initiation into cannabis use.     

Disrupted action monitoring in recent-onset psychosis patients with schizophrenia and bipolar disorder

Schizophrenia patients experience cognitive control disturbances, manifest in altered neural signatures during action monitoring. It remains unclear whether error- and conflict-monitoring disturbances co-occur, and whether they are observed in recent-onset psychosis patients with schizophrenia or bipolar disorder. We tested electrophysiological measures of action monitoring in these patients. Seventy-three schizophrenia patients (SZ), 26 bipolar disorder type I patients (BP), each within one year of psychosis onset, and 54 healthy control subjects (HC) underwent EEG during Stroop task performance. In the trial-averaged EEG at three midline scalp electrodes, the error-related negativity (ERN), error positivity (Pe) and conflict-related N450 were measured. Compared to HC (1) SZ exhibited an attenuated ERN and N450, and Pe unchanged and (2) BP exhibited an attenuated ERN but normal Pe and N450. Between patient groups, SZ showed an attenuated N450; ERN and Pe were not significantly different. A small (n=10) SZ subgroup that was not receiving antipsychotic medication showed normal ERPs. Altered error- and conflict-monitoring occur together in the first-episode schizophrenia patients, and these measures are comparable in patients with the first-episode bipolar disorder. Antipsychotic medication may be associated with altered measures of error-monitoring in schizophrenia.     

A comparison of neuropsychological dysfunction in first-episode psychosis patients with unipolar depression, bipolar disorder, and schizophrenia

The severity and profile of cognitive dysfunction in first episode schizophrenia and psychotic affective disorders were compared before and after antipsychotic treatment. Parallel recruitment of consecutively admitted study-eligible first-episode psychotic patients (30 schizophrenia, 22 bipolar with psychosis, and 21 psychotic depression) reduced confounds of acute and chronic disease/medication effects as well as differential treatment and course. Patient groups completed a neuropsychological battery and were demographically similar to healthy controls (n = 41) studied in parallel. Prior to treatment, schizophrenia patients displayed significant deficits in all cognitive domains. The two psychotic affective groups were also impaired overall, generally performing intermediate between the schizophrenia and healthy comparison groups. No profile differences in neuropsychological deficits were observed across patient groups. Following 6 weeks of treatment, no patient group improved more than practice effects seen in healthy individuals, and level of performance improvement was similar for affective psychosis and schizophrenia groups. Although less severe in psychotic affective disorders, similar profiles of generalized neuropsychological deficits were observed across patient groups. Recovery of cognitive function after clinical stabilization was similar in mood disorders and schizophrenia. To the extent that these findings are generalizable, neuropsychological deficits in psychotic affective disorders, like schizophrenia, may be trait-like deficits with persistent functional implications.     

The Effect of Context Processing on Different Aspects of Social Cognition in Schizophrenia

Background: It is well known that individuals with schizophrenia have impaired social cognition. The construct of social cognition involves several components, including perception, interpretation, and the ability to integrate context (Adolphs R. The neurobiology of social cognition. Curr Opin Neurobiol. 2001;11:231–239; Brothers L. The social brain: a project for integrating primate behavior and neurophysiology in a new domain. Concepts Neurosci. 1990;1:27–61). Importantly, a number of studies have suggested that deficits in context processing underlie cognitive dysfunction in schizophrenia (Penn DL, Corrigan PW, Bentall RP, Racenstein JM, Newman L. Social cognition in schizophrenia. Psychol Bull. 1997;121(1):114–132; Green MF, Nuechterlein KH. Should schizophrenia be treated as a neurocognitive disorder? Schizophr Bull. 1999;25:309–319). Thus, the purpose of the current study was to investigate the relationship between context processing and different aspects of social cognition in schizophrenia. Method: Individuals with schizophrenia (n = 41) and the healthy controls (n = 32) participated in this study. The participants completed 2 sections of The Awareness of Social Inference Test: (1) social inference minimal (SI-M) and (2) social inference enriched (SI-E). They also completed face and voice emotion discrimination tasks. In addition, we used the AX-Continuous Performance Test (AX-CPT) to measure context processing and the n-back task to measure working memory more generally. Results: AX-CPT performance in schizophrenia was positively correlated with both SI-M and SI-E performance but not with either the face or the voice discrimination. Furthermore, the correlation between AX-CPT performance and SI-M/SI-E performance was significantly stronger in individuals with schizophrenia than in controls. Conclusion: These results suggest that impairments in context processing are related to inferential components of social cognition in schizophrenia but not to the ability to recognition facial or vocal emotion. As such, deficits in context processing may contribute to deficits in both “hot” and “cold” aspects of cognition in schizophrenia.     

首发精神分裂症与双相障碍及抑郁障碍认知功能比较

目的探讨首发精神分裂症、双相障碍及抑郁障碍患者认知功能差异。方法纳入首发精神分裂症患者61例,双相障碍患者57例,抑郁障碍患者48例,另设正常对照59名。所有研究对象采用重复性神经心理测查系统(Repeatable Battery for the Assessment of Neuropsychological Status,RBANS)评估认知功能,首发精神分裂症组采用阳性和阴性症状量表(positive and negative syndrome scale,PANSS)评定精神病性症状,双相障碍组、抑郁障碍组采用汉密尔顿抑郁量表(Hamilton depression scale,HAMD)、汉密尔顿焦虑量表(Hamilton anxiety scale,HAMA)评估抑郁和焦虑症状,贝克—拉范森躁狂(Bech-Rafaelsen mania scale,BRMS)量表评估躁狂症状。结果 4组对象的RBANS总分(F=5.18,P0.01)、即刻记忆(F=4.09,P0.01)、言语功能(F=9.53,P0.01)、注意(F=3.87,P=0.01)、延时记忆(F=9.86,P0.01)因子得分差异具有统计学意义,其中首发精神分裂症、双相障碍组RBANS总分低于对照组(P0.01),首发精神分裂症、双相障碍、抑郁障碍组即刻记忆、言语功能、延时记忆得分低于对照组(P0.05),双相障碍组言语功能得分低于首发精神分裂症组(P0.01),首发精神分裂症组注意得分低于抑郁障碍及对照组(P0.01)。结论首发精神分裂症、双相障碍、抑郁障碍患者均存在认知功能损伤,首发精神分裂症认知功能缺陷重于抑郁障碍,轻于双相障碍。     

Deficits of entropy modulation of the EEG: A biomarker for altered function in schizophrenia and bipolar disorder?

BackgroundThe synchronized activity of distributed neural assemblies — reflected in the electroencephalogram (EEG) — underpins mental function. In schizophrenia, modulation deficits of EEG spectral content during a P300 task have been replicated. The effects of treatment, chronicity and specificity in these deficits and their possible relationship with anatomic connectivity remain to be explored.MethodsWe assessed spectral entropy modulation of the EEG during a P300 task in 79 patients with schizophrenia (of those, 31 were in their first episode), 29 patients with bipolar disorder and 48 healthy controls. Spectral entropy values summarize EEG characteristics by quantifying the irregularity of spectral content. In a subsample, we calculated the network architecture of structural connectivity using diffusion tensor imaging and graph-theory parameters.ResultsWe found significant spectral entropy modulation deficits with task performance in patients with chronic or first-episode schizophrenia and in patients with bipolar disorder, without significant pre-stimulus spectral entropy differences. The deficits were unrelated to treatment doses, and spectral entropy modulation did not differ between patients taking or not taking antipsychotics, lithium, benzodiazepines or antidepressants. Structural connectivity values were unrelated to spectral entropy modulation. In patients with schizophrenia, spectral entropy modulation was inversely related to negative symptoms and directly related to verbal memory.LimitationsAll patients were taking medication. Patients with bipolar disorder were euthymic and chronic. The cross-sectional nature of this study prevented a more thorough analysis of state versus trait criteria for spectral entropy changes.ConclusionSpectral entropy modulation with task performance is decreased in patients with schizophrenia and bipolar disorder. This deficit was not an effect of psychopharmacological treatment or structural connectivity and might reflect a deficit in the synchronization of the neural assemblies that underlie cognitive activity.     

Antipsychotic Treatment and Mortality in Schizophrenia

Background: It is generally believed that long-term use of antipsychotics increases mortality and, especially, the risk of cardiovascular death. However, there are no solid data to substantiate this view. Methods: We identified all individuals in Sweden with schizophrenia diagnoses before year 2006 (N = 21 492), aged 17–65 years, and persons with first-episode schizophrenia during the follow-up 2006–2010 (N = 1230). Patient information was prospectively collected through nationwide registers. Total and cause-specific mortalities were calculated as a function of cumulative antipsychotic exposure from January 2006 to December 2010. Results: Compared with age- and gender-matched controls from the general population (N = 214920), the highest overall mortality was observed among patients with no antipsychotic exposure (hazard ratio [HR] = 6.3, 95% CI: 5.5–7.3), ie, 0.0 defined daily dose (DDD)/day, followed by high exposure (>1.5 DDD/day) group (HR = 5.7, 5.2–6.2), low exposure (<0.5 DDD/day) group (HR = 4.1, 3.6–4.6), and moderate exposure (0.5–1.5 DDD/day) group (HR = 4.0, 3.7–4.4). High exposure (HR = 8.5, 7.3–9.8) and no exposure (HR = 7.6, 5.8–9.9) were associated with higher cardiovascular mortality than either low exposure (HR = 4.7, 3.7–6.0) or moderate exposure (HR = 5.6, 4.8–6.6). The highest excess overall mortality was observed among first-episode patients with no antipsychotic use (HR = 9.9, 5.9–16.6). Conclusions: Among patients with schizophrenia, the cumulative antipsychotic exposure displays a U-shaped curve for overall mortality, revealing the highest risk of death among those patients with no antipsychotic use. These results indicate that both excess overall and cardiovascular mortality in schizophrenia is attributable to other factors than antipsychotic treatment when used in adequate dosages.Key words: schizophrenia, mortality, antipsychotic     

Abnormal Causal Connectivity by Structural Deficits in First-Episode,Drug-Naive Schizophrenia at Rest

Anatomical deficits and resting-state functional connectivity (FC) alterations in prefrontal-thalamic-cerebellar circuit have been implicated in the neurobiology of schizophrenia. However, the effect of structural deficits in schizophrenia on causal connectivity of this circuit remains unclear. This study was conducted to examine the causal connectivity biased by structural deficits in first-episode, drug-naive schizophrenia patients. Structural and resting-state functional magnetic resonance imaging (fMRI) data were obtained from 49 first-episode, drug-naive schizophrenia patients and 50 healthy controls. Data were analyzed by voxel-based morphometry and Granger causality analysis. The causal connectivity of the integrated prefrontal-thalamic (limbic)-cerebellar (sensorimotor) circuit was partly affected by structural deficits in first-episode, drug-naive schizophrenia as follows: (1) unilateral prefrontal-sensorimotor connectivity abnormalities (increased driving effect from the left medial prefrontal cortex [MPFC] to the sensorimotor regions); (2) bilateral limbic-sensorimotor connectivity abnormalities (increased driving effect from the right anterior cingulate cortex [ACC] to the sensorimotor regions and decreased feedback from the sensorimotor regions to the right ACC); and (3) bilateral increased and decreased causal connectivities among the sensorimotor regions. Some correlations between the gray matter volume of the seeds, along with their causal effects and clinical variables (duration of untreated psychosis and symptom severity), were also observed in the patients. The findings indicated the partial effects of structural deficits in first-episode, drug-naive schizophrenia on the prefrontal-thalamic (limbic)-cerebellar (sensorimotor) circuit. Schizophrenia may reinforce the driving connectivities from the left MPFC or right ACC to the sensorimotor regions and may disrupt bilateral causal connectivities among the sensorimotor regions.Key words: first-episode schizophrenia, causal effect, structural deficits, voxel-based morphometry, Granger causality analysis     

Dysconnectivity Within the Default Mode in First-Episode Schizophrenia: A Stochastic Dynamic Causal Modeling Study With Functional Magnetic Resonance Imaging

We report the first stochastic dynamic causal modeling (sDCM) study of effective connectivity within the default mode network (DMN) in schizophrenia. Thirty-three patients (9 women, mean age = 25.0 years, SD = 5) with a first episode of psychosis and diagnosis of schizophrenia—according to the Diagnostic and Statistic Manual of Mental Disorders, 4th edition, revised criteria—were studied. Fifteen healthy control subjects (4 women, mean age = 24.6 years, SD = 4) were included for comparison. All subjects underwent resting state functional magnetic resonance imaging (fMRI) interspersed with 2 periods of continuous picture viewing. The anterior frontal (AF), posterior cingulate (PC), and the left and right parietal nodes of the DMN were localized in an unbiased fashion using data from 16 independent healthy volunteers (using an identical fMRI protocol). We used sDCM to estimate directed connections between and within nodes of the DMN, which were subsequently compared with t tests at the between subject level. The excitatory effect of the PC node on the AF node and the inhibitory self-connection of the AF node were significantly weaker in patients (mean values = 0.013 and −0.048 Hz, SD = 0.09 and 0.05, respectively) relative to healthy subjects (mean values = 0.084 and −0.088 Hz, SD = 0.15 and 0.77, respectively; P < .05). In summary, sDCM revealed reduced effective connectivity to the AF node of the DMN—reflecting a reduced postsynaptic efficacy of prefrontal afferents—in patients with first-episode schizophrenia.Key words: brain connectivity, default mode network, dysconnectivity, first-episode schizophrenia, functional magnetic resonance imaging (fMRI), resting state, stochastic dynamic causal modeling (DCM)     

Reduced Frontal Glutamate + Glutamine and N-Acetylaspartate Levels in Patients With Chronic Schizophrenia but not in Those at Clinical High Risk for Psychosis or With First-Episode Schizophrenia

Changes in brain pathology as schizophrenia progresses have been repeatedly suggested by previous studies. Meta-analyses of previous proton magnetic resonance spectroscopy (¹H MRS) studies at each clinical stage of schizophrenia indicate that the abnormalities of N-acetylaspartate (NAA) and glutamatergic metabolites change progressively. However, to our knowledge, no single study has addressed the possible differences in ¹H MRS abnormalities in subjects at 3 different stages of disease, including those at ultrahigh risk for psychosis (UHR), with first-episode schizophrenia (FES), and with chronic schizophrenia (ChSz). In the current study, 24 patients with UHR, 19 FES, 25 ChSz, and their demographically matched 3 independent control groups (n = 26/19/28 for the UHR, FES, and ChSz control groups, respectively) underwent ¹H MRS in a 3-Tesla scanner to examine metabolites in medial prefrontal cortex. The analysis revealed significant decreases in the medial prefrontal NAA and glutamate + glutamine (Glx) levels, specifically in the ChSz group as indexed by a significant interaction between stage (UHR/FES/ChSz) and clinical status (patients/controls) (P = .008). Furthermore, the specificity of NAA and Glx reductions compared with the other metabolites in the patients with ChSz was also supported by a significant interaction between the clinical status and types of metabolites that only occurred at the ChSz stage (P = .001 for NAA, P = .004 for Glx). The present study demonstrates significant differences in ¹H MRS abnormalities at different stages of schizophrenia, which potentially correspond to changes in glutamatergic neurotransmission, plasticity, and/or excitotoxicity and regional neuronal integrity with relevance for the progression of schizophrenia.Key words: anterior cingulate cortex, at-risk mental state, biomarkers, frontal lobe, magnetic resonance imaging, neurochemical abnormality     

In Vivo Amygdala Nuclei Volumes in Schizophrenia and Bipolar Disorders

Abnormalities in amygdala volume are well-established in schizophrenia and commonly reported in bipolar disorders. However, the specificity of volumetric differences in individual amygdala nuclei is largely unknown. Patients with schizophrenia disorders (SCZ, N = 452, mean age 30.7 ± 9.2 [SD] years, females 44.4%), bipolar disorders (BP, N = 316, 33.7 ± 11.4, 58.5%), and healthy controls (N = 753, 34.1 ± 9.1, 40.9%) underwent T1-weighted magnetic resonance imaging. Total amygdala, nuclei, and intracranial volume (ICV) were estimated with Freesurfer (v6.0.0). Analysis of covariance and multiple linear regression models, adjusting for age, age², ICV, and sex, were fitted to examine diagnostic group and subgroup differences in volume, respectively. Bilateral total amygdala and all nuclei volumes, except the medial and central nuclei, were significantly smaller in patients relative to controls. The largest effect sizes were found for the basal nucleus, accessory basal nucleus, and cortico-amygdaloid transition area (partial η² > 0.02). The diagnostic subgroup analysis showed that reductions in amygdala nuclei volume were most widespread in schizophrenia, with the lateral, cortical, paralaminar, and central nuclei being solely reduced in this disorder. The right accessory basal nucleus was marginally smaller in SCZ relative to BP (t = 2.32, P = .05). Our study is the first to demonstrate distinct patterns of amygdala nuclei volume reductions in a well-powered sample of patients with schizophrenia and bipolar disorders. Volume differences in the basolateral complex (lateral, basal, and accessory basal nuclei), an integral part of the threat processing circuitry, were most prominent in schizophrenia.     

Intelligence,educational attainment,and brain structure in those at familial high‐risk for schizophrenia or bipolar disorder

First‐degree relatives of patients diagnosed with schizophrenia (SZ‐FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First‐degree relatives of patients diagnosed with bipolar disorder (BD‐FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD‐FDRs are inconsistent. Here, we performed a meta‐analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ‐FDRs, 867 BD‐FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ‐FDRs showed a pattern of widespread thinner cortex, while BD‐FDRs had widespread larger cortical surface area. IQ was lower in SZ‐FDRs (d = −0.42, p = 3 × 10⁻⁵), with weak evidence of IQ reductions among BD‐FDRs (d = −0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group‐effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ‐FDRs and more pronounced effects in BD‐FDRs. To conclude, SZ‐FDRs and BD‐FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ‐FDRs and BD‐FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.