R.C. Gur

Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium

The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen’s d=−0.46), amygdala (d=−0.31), thalamus (d=−0.31), accumbens (d=−0.25) and intracranial volumes (d=−0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.

P50 abnormalities in schizophrenia: relationship to clinical and neuropsychological indices of attention

While the P50 component (50-60-ms latency) of the auditory evoked potential has been reported as abnormal in schizophrenia, few studies have examined the relationship between this abnormality and clinical or neuropsychological measures. To examine these possible relationships, mid-latency auditory evoked potentials were recorded at the CZ recording site of 47 patients with schizophrenia in response to binaural clicks presented at three stimulus rates: 1, 5 and 10/sec. A sub-sample of patients were then divided into high- (n = 15) and low-P50 abnormality (n = 16) groups based on a median split of the P50 amplitude at a rate of 10/sec (a greater amplitude at this rate suggests a greater abnormality in recovery) of the entire sample. Only those patients with complete neuropsychological and clinical data and who were reasonably matched on demographic dimensions were included. A multivariate analysis of variance of 11 neuropsychological function profile scores showed a significant group x global score interaction (Hotelling t = 3.97, p < 0.005). The high-abnormality group had relatively greater deficits for attention profile scores than for the remaining neuropsychological measures. An analysis of global subscores for SAPS and SANS clinical measures revealed a significant difference only for the SANS attention subscale (p < 0.05). The high-abnormality group was rated as more severe on the attention measure. These convergent findings across both phenomenological and neuropsychological measures suggest that abnormalities in P50 recovery may be linked to deficits in attention processes in schizophrenia.

Psychiatric disorders in 22q11.2 deletion syndrome are prevalent but undertreated.

BACKGROUND Chromosome 22q11.2 deletion syndrome (22q11DS) is a common genetic disorder with high rates of psychosis and other psychopathologies, but few studies discuss treatment. Our aim was to characterize the prevalence and treatment of major psychiatric illnesses in a well-characterized sample of individuals with 22q11DS. METHOD This was a cross-sectional study of 112 individuals aged 8 to 45 years with a confirmed diagnosis of 22q11DS. Each participant was administered a modified Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) and the Structured Interview for Prodromal Syndromes (SIPS). Phenotypes assessed were threshold and subthreshold psychosis, depression, mania, generalized and separation anxiety, obsessions/compulsions, inattention/hyperactivity and substance use. Histories of mental health care and current psychotropic treatment were obtained. RESULTS Psychopathology was common, with 79% of individuals meeting diagnostic criteria for a disorder at the time of assessment. Diagnoses of psychosis were made in 11% of cases, attenuated positive symptom syndrome (APS) in 21%, and 47% experienced significant subthreshold symptoms. Peak occurrence of psychosis risk was during adolescence (62% of those aged 12-17 years). Criteria for a mood disorder were met by 14%, for anxiety disorder 34% and for attention deficit hyperactivity disorder (ADHD) 31%. Mental health care had been received by 63% of individuals in their lifetime, but only 40% continued therapy and 39% used psychotropics. Antipsychotics were used by 42% of participants with psychosis and none of the participants with APS. Half of those at risk for psychosis were receiving no mental health care. CONCLUSIONS Psychopathology is common in 22q11DS but is not adequately treated or clinically followed. Particular attention should be paid to subthreshold psychotic symptoms, especially in adolescents.

Effect of Retrieval Effort and Switching Demand on fMRI Activation During Semantic Word Generation in Schizophrenia

Verbal fluency deficits in schizophrenia are difficult to interpret because the tasks are multi-factorial and groups differ in total words generated. We manipulated retrieval and switching demands by requiring alternation between over-learned sequences in which retrieval is relatively automatic (OS) and semantic categories requiring increased retrieval effort (SC). Controlled processing was also manipulated by including switching and non-switching conditions, and formal thought disorder (FTD) was assessed with the communication disorders index (CDI). The OS/SC semantic fluency paradigm was administered during fMRI to 13 patients with schizophrenia and 14 matched controls. Images were acquired on a 3 Tesla Siemens scanner using compressed image acquisition to allow for cued overt word production. Subjects alternated between OS, SC, OS-switch, SC-switch, and baseline blocks. Images were pre-processed in SPM-2, and a two-stage random effects analysis tested within and between group contrasts. There were no group performance differences. fMRI analysis did not reveal any group differences during the OS non-switching condition. Both groups produced expected activation in bilateral prefrontal and inferior parietal regions. However, during the SC condition patients had greater activation than controls in left prefrontal, right anterior cingulate, right superior temporal, bilateral thalamus, and left parietal regions. There was also evidence of patient over-activation in prefrontal, superior temporal, superior parietal, and visual association areas when a switching component was added. FTD was negatively correlated with BOLD response in the right anterior cingulate, cuneus and superior frontal gyrus during increased retrieval demand, and positively correlated with fMRI activation in the left lingual gyrus, right fusiform gyrus and left superior parietal lobule during increased switching demand. These results indicate that patients are able to successfully perform effortful semantic fluency tasks during non-speeded conditions. When retrieval is relatively automatic there does not appear to be an effect of schizophrenia on fMRI response. However, when retrieval and controlled processing demands increase, patients have greater activation than controls despite unimpaired task performance. This inefficient BOLD response may explain why patients are slower and less accurate on standard self-paced fluency tasks.

Emotion recognition deficits as predictors of transition in individuals at clinical high risk for schizophrenia: a neurodevelopmental perspective.

BACKGROUND Schizophrenia is characterized by profound and disabling deficits in the ability to recognize emotion in facial expression and tone of voice. Although these deficits are well documented in established schizophrenia using recently validated tasks, their predictive utility in at-risk populations has not been formally evaluated. METHOD The Penn Emotion Recognition and Discrimination tasks, and recently developed measures of auditory emotion recognition, were administered to 49 clinical high-risk subjects prospectively followed for 2 years for schizophrenia outcome, and 31 healthy controls, and a developmental cohort of 43 individuals aged 7-26 years. Deficit in emotion recognition in at-risk subjects was compared with deficit in established schizophrenia, and with normal neurocognitive growth curves from childhood to early adulthood. RESULTS Deficits in emotion recognition significantly distinguished at-risk patients who transitioned to schizophrenia. By contrast, more general neurocognitive measures, such as attention vigilance or processing speed, were non-predictive. The best classification model for schizophrenia onset included both face emotion processing and negative symptoms, with accuracy of 96%, and area under the receiver-operating characteristic curve of 0.99. In a parallel developmental study, emotion recognition abilities were found to reach maturity prior to traditional age of risk for schizophrenia, suggesting they may serve as objective markers of early developmental insult. CONCLUSIONS Profound deficits in emotion recognition exist in at-risk patients prior to schizophrenia onset. They may serve as an index of early developmental insult, and represent an effective target for early identification and remediation. Future studies investigating emotion recognition deficits at both mechanistic and predictive levels are strongly encouraged.

Are neurologic examination abnormalities heritable? A preliminary study.

BACKGROUND Neurologic examination abnormalities (NEA) are more prevalent among patients with schizophrenia as well as their unaffected relatives when compared with healthy controls, suggesting that NEA may be endophenotypes for schizophrenia. We estimated the heritability of NEA in moderately sized pedigrees. We also evaluated correlations between NEA and cognitive performance in order to examine their construct validity. METHODS Members of eight extended families, each consisting of two first degree relatives with schizophrenia/schizoaffective disorders, as well as available first- to fifth-degree relatives were examined (n=96 participants). A modification of the Neurological Evaluation Scale (NES) was employed, augmented with localizing signs. Where feasible, we used untransformed data such as error counts and completion time, rather than ordinal measures. Heritability was estimated using the variance component method, implemented in SOLAR. RESULTS Statistically significant heritability (h2) estimates were obtained for several measures (p<0.05, h2+/-standard error: rapid alternating movements, right-sided completion time, 0.99+/-0.19; alternating fist-palm test, completion time, 0.77+/-0.19 s, errors, 0.70+/-0.32; fist-ring test, right-sided completion time, 0.53+/-0.23 s, left-sided completion time, 0.70+/-0.21 s; go-no go task, correct responses, 0.93+/-0.33; audio-visual integration, correct responses, 0.79+/-0.54). For most items, heritability analysis was hampered by insufficient data variability (infrequent errors). Correlational analyses show some degree of divergence among types of NEA, repetitive motor tasks being associated with most domains of cognitive functioning other than executive functioning, and cognitive-perceptual tasks being associated with memory and executive functioning. CONCLUSIONS Significant familial influences on certain aspects of neurologic performance were detected. These heritable measures were also correlated with heritable neurocognitive measures.

Heritability and familiality of neurological soft signs: evidence from healthy twins, patients with schizophrenia and non-psychotic first-degree relatives.

BACKGROUND Neurological soft signs (NSS) have long been considered potential endophenotypes for schizophrenia. However, few studies have investigated the heritability and familiality of NSS. The present study examined the heritability and familiality of NSS in healthy twins and patient-relative pairs. METHOD The abridged version of the Cambridge Neurological Inventory was administered to 267 pairs of monozygotic twins, 124 pairs of dizygotic twins, and 75 pairs of patients with schizophrenia and their non-psychotic first-degree relatives. RESULTS NSS were found to have moderate but significant heritability in the healthy twin sample. Moreover, patients with schizophrenia correlated closely with their first-degree relatives on NSS. CONCLUSIONS Taken together, the findings provide evidence on the heritability and familiality of NSS in the Han Chinese population.

The Computerized Neurocognitive Battery: Validation, aging effects, and heritability across cognitive domains.

OBJECTIVE The Computerized Neurocognitive Battery (CNB) enables efficient neurocognitive assessment. The authors aimed to (a) estimate validity and reliability of the batterys Dutch translation, (b) investigate effects of age across cognitive domains, and (c) estimate heritability of the CNB tests. METHOD A population-representative sample of 1,140 participants (aged 10-86), mainly twin-families, was tested on the CNB, providing measures of speed and accuracy in 14 cognitive domains. In a subsample (246 subjects aged 14-22), IQ data (Wechsler Intelligence Scale for Adults; WAIS) were available. Validity and reliability were assessed by Cronbachs alpha, comparisons of scores between Dutch and U.S. samples, and investigation of how a CNB-based common factor compared to a WAIS-based general factor of intelligence (g). Linear and nonlinear age dependencies covering the life span were modeled through regression. Heritability was estimated from twin data and from entire pedigree data. RESULTS Internal consistency of all tests was moderate to high (median = 0.86). Effects of gender, age, and education on cognitive performance closely resembled U.S. SAMPLES The CNB-based common factor was completely captured by the WAIS-based g. Some domains, like nonverbal reasoning accuracy, peaked in young adulthood and showed steady decline. Other domains, like language reasoning accuracy, peaked in middle adulthood and were spared decline. CNB-test heritabilities were moderate (median h2 = 31%). Heritability of the CNB common factor was 70%, similar to the WAIS-based g-factor. CONCLUSION The CNB can be used to assess specific neurocognitive performance, as well as to obtain a reliable proxy of general intelligence. Effects of aging and heritability differed across cognitive domains.

Impact of Psychiatric Comorbidity and Cognitive Deficit on Function in 22q11.2 Deletion Syndrome

OBJECTIVE Presence of psychiatric comorbidity is associated with poor functioning and is an important consideration in treatment. Many individuals with 22q11.2 deletion syndrome (22q11DS) develop comorbid psychiatric disorders, yet its pattern and impact on functioning have not been formally investigated. In this cross-sectional study, we examined the relationship between comorbid psychopathology and neurocognitive deficits and their association with global functioning. We hypothesized that higher psychiatric burden and psychosis-spectrum features would be associated with reduced functioning and increased neurocognitive deficits. METHOD The cohort included 171 individuals with 22q11DS and mean (SD) age of 17.4 (8.1) years, recruited from a tertiary childrens hospital and nationally through social media between September 2010 and December 2013. Psychiatric diagnoses and functioning were assessed using semistructured interviews and the Global Assessment of Functioning (GAF) scale, respectively. On the basis of psychopathology and number of comorbid diagnoses, participants were assigned to unaffected (n = 32), nonpsychosis spectrum (n = 24), nonpsychosis spectrum-plus (n = 15), psychosis spectrum (n = 29), and psychosis spectrum-plus (n = 71) groups. Executive function, episodic memory, complex cognition, social cognition, and praxis speed were assessed using a computerized neurocognitive battery (CNB). Cognitive profile and GAF scores were compared among the groups, and the association of GAF with cognitive performance and psychopathology was examined. RESULTS We observed high rates of comorbid psychiatric disorders. Approximately 50% of the participants had ≥ 2 diagnoses. Psychosis spectrum disorders were most frequently comorbid with other disorders. GAF score was progressively worse with increased psychiatric burden. Mean (SD) GAF score for the unaffected group (81.1 [8.9]) was significantly different from those of nonpsychosis spectrum (68.6 [12.1]), nonpsychosis spectrum-plus (63.4 [8.8]), psychosis spectrum (58.7 [13.1]), or psychosis spectrum-plus (55.5 [13.3]) (P < .05) groups. All groups performed poorly and were comparable to each other on the CNB (P = .273). Notably, verbal memory (P = .003), spatial processing (P = .001), and parent education level (P < .001) were significantly associated with GAF. CONCLUSIONS Individuals with 22q11DS have high rates of comorbid psychiatric disorders and diffuse cognitive deficits regardless of psychiatric burden. Those with psychotic spectrum disorders and comorbid psychiatric disorders are at an increased risk for poor overall functioning.

Linkage analysis of schizophrenia in African-American families.

While many studies have sought a window into the genetics of schizophrenia, few have focused on African-American families. An exception is the Project among African-Americans to Explore Risks for Schizophrenia (PAARTNERS), which seeks to identify novel and known risk variation for schizophrenia by genetic analyses of African-American families. We report a linkage study of diagnostic status in 217 African-American families using the Illumina Linkage Panel. Due to assumed incomplete and time-dependent penetrance, we performed linkage analysis using two different treatments of diagnosis: (1) treating both affected and unaffected individuals as informative for linkage (using the program SIBPAL) and (2) treating only affected individuals as informative (using the program MERLIN). We also explore three definitions of affected status: narrowly defined schizophrenia; one broadened to include schizoaffective disorder; and another including all diagnoses indicating psychosis. Several regions show a decrease in the evidence for linkage as the definition broadens 8q22.1 (rs911, 99.26 cM; SIBPAL p-value [p] goes from 0.006 to 0.02), 16q24.3 (rs1006547, 130.48 cM; p from 0.00095 to 0.0085), and 20q13.2 (rs1022689, 81.73 cM; p from 0.00015 to 0.032). One region shows a substantial increase in evidence for linkage, 11p15.2 (rs722317, 24.27 cM; p from 0.0022 to 0.0000003); MERLIN results support the significance of the SIBPAL results (p=0.00001). Our linkage results overlap two broad, previously-reported linkage regions: 8p23.3-p12 found in studies sampling largely families of European ancestry; and 11p11.2-q22.3 reported by a study of African-American families. These results should prove quite useful for uncovering loci affecting risk for schizophrenia.