Tejas S. Bhojraj

Premorbid cognitive deficits in young relatives of schizophrenia patients

Neurocognitive deficits in schizophrenia (SZ) are thought to be stable trait markers that predate the illness and manifest in relatives of patients. Adolescence is the age of maximum vulnerability to the onset of SZ and may be an opportune “window” to observe neurocognitive impairments close to but prior to the onset of psychosis. We reviewed the extant studies assessing neurocognitive deficits in young relatives at high risk (HR) for SZ and their relation to brain structural alterations. We also provide some additional data pertaining to the relation of these deficits to psychopathology and brain structural alterations from the Pittsburgh Risk Evaluation Program (PREP). Cognitive deficits are noted in the HR population, which are more severe in first-degree relatives compared to second-degree relatives and primarily involve psychomotor speed, memory, attention, reasoning, and social-cognition. Reduced general intelligence is also noted, although its relationship to these specific domains is underexplored. Premorbid cognitive deficits may be related to brain structural and functional abnormalities, underlining the neurobiological basis of this illness. Cognitive impairments might predict later emergence of psychopathology in at-risk subjects and may be targets of early remediation and preventive strategies. Although evidence for neurocognitive deficits in young relatives abounds, further studies on their structural underpinnings and on their candidate status as endophenotypes are needed.

Verbal fluency deficits and altered lateralization of language brain areas in individuals genetically predisposed to schizophrenia

Alterations of verbal fluency may correlate with deficits of gray matter volume and hemispheric lateralization of language brain regions like the pars triangularis (PT) in schizophrenia. Examining non-psychotic individuals at high genetic risk (HR) for schizophrenia may clarify if these deficits represent heritable trait markers or state dependent phenomena. We assessed adolescent and young adult HR subjects (N=60) and healthy controls (HC; N=42) using verbal fluency tests and Freesurfer to process T1-MRI scans. We hypothesized volumetric and lateralization alterations of the PT and their correlation with verbal fluency deficits. HR subjects had letter verbal fluency deficits (controlling for IQ), left PT deficits (p=.00), (controlling ICV) and reversal of the L>R PT asymmetry noted in HC. Right Heschls (p=.00), left supramarginal (p=.00) and right angular gyrii (p=.02) were also reduced in HR subjects. The L>R asymmetry of the Heschls gyrus seen in HC was exaggerated and asymmetries of L>R of supramarginal and R>L of angular gyri, seen in HC were attenuated in HR subjects. L>R asymmetry of the PT predicted better verbal fluency across the pooled HR and HC groups. Young relatives of schizophrenia patients have verbal fluency deficits, gray matter volume deficits and reversed asymmetry of the pars triangularis. A reversed structural asymmetry of the PT in HR subjects may impair expressive language abilities leading to verbal fluency deficits. Volumetric deficits and altered asymmetry in inferior parietal and Heschls gyrii may accompany genetic liability to schizophrenia.

Gray matter loss in young relatives at risk for schizophrenia: relation with prodromal psychopathology.

The maturation of neocortical regions mediating social cognition during adolescence and young adulthood in relatives of schizophrenia patients may be vulnerable to heritable alterations of neurodevelopment. Prodromal psychotic symptoms, commonly emerging during this period in relatives, have been hypothesized to result from alterations in brain regions mediating social cognition. We hypothesized these regions to show longitudinal alterations and these alterations to predict prodromal symptoms in adolescent and young adult relatives of schizophrenia patients. 27 Healthy controls and 23 relatives were assessed at baseline and one-year follow-up using scale of prodromal symptoms and gray matter volumes of hypothesized regions from T1-MRI images. Regional volumes showing deficits on ANCOVA and repeated-measures ANCOVAs (controlling intra cranial volume, age and gender) were correlated with prodromal symptoms. At baseline, bilateral amygdalae, bilateral pars triangulares, left lateral orbitofrontal, right frontal pole, angular and supramarginal gyrii were smaller in relatives compared to controls. Relatives declined but controls increased or remained stable on bilateral lateral orbitofrontal, left rostral anterior cingulate, left medial prefrontal, right inferior frontal gyrus and left temporal pole volumes at follow-up relative to baseline. Smaller volumes predicted greater severity of prodromal symptoms at both cross-sectional assessments. Longitudinally, smaller baseline volumes predicted greater prodromal symptoms at follow-up; greater longitudinal decreases in volumes predicted worsening (increase) of prodromal symptoms over time. These preliminary findings suggest that abnormal longitudinal gray matter loss may occur in regions mediating social cognition and may convey risk for prodromal symptoms during adolescence and early adulthood in individuals with a familial diathesis for schizophrenia.

Grey matter and cognitive deficits in young relatives of schizophrenia patients

Grey-matter volumetric and cognitive deficits in young, high-risk relatives of schizophrenia patients may be vulnerability markers of the illness. Although these markers may be correlated, it is unclear if their distributions in relatives overlap. We examined convergence of these markers in 94 young first and second-degree relatives (HR) and 81 healthy controls. Subjects were assessed using WCST, CPT-IP and Benton-Hamscher tests and on grey-matter volumes of brain regions related to language, attention and executive function using FreeSurfer to process T1-MR-images. K-means clustering using cognitive performance scores split relatives into sub-samples with better (HR+C, n=35) and worse (HR-C, n=59) cognition after controlling for age and gender. All regional volumes and language related regional laterality-indices were compared between HR-C, HR+C and control subjects, controlling for age, gender and intra-cranial volume. Volumes of caudate nuclei, thalami, hippocampi, inferior frontal gyri, Heschls gyri, superior parietal cortices, supramarginal gyri, right angular gyrus, right middle frontal gyrus and right superior frontal gyrus, leftward laterality of supramarginal and inferior frontal gyri and rightward laterality of the angular gyrus were reduced in HR-C compared to controls. Volumes of Heschls gyri, left supramarginal gyrus, inferior frontal gyri, hippocampi and caudate nuclei HR-C were smaller in HR-C compared to HR+C. HR+C showed deficits compared to controls only for the superior parietal and right angular volumes. Premorbid neuroanatomical and laterality alterations in schizophrenia may selectively manifest in cognitively compromised relatives. Overlapping structural and cognitive deficits may define a hyper vulnerable sub-sample among individuals at familial predisposition to schizophrenia.

A broad cortical reserve accelerates response to cognitive enhancement therapy in early course schizophrenia

OBJECTIVES Cognitive rehabilitation can improve cognition in schizophrenia and prevent disability. It is unknown, however, whether a greater neurobiologic reserve, as measured by cortical volumes, will predict a favorable response to rehabilitation. We investigated this question in early course schizophrenia patients treated with Cognitive Enhancement Therapy (CET). METHODS Outpatients in the early course of schizophrenia or schizoaffective disorder were randomly assigned to CET (n=29) or an Enriched Supportive Therapy control (n=21) and treated for two years. Cortical surface area and gray matter volume data were collected before treatment using structural magnetic resonance imaging. Neurocognition and social cognition were assessed before, and after one and two years of treatment. Moderator analyses examined the impact of pre-treatment cortical surface area and gray matter volume on differential neurocognitive and social-cognitive response to CET. RESULTS Pre-treatment, whole brain cortical surface area and gray matter volume significantly moderated the effects of CET on social cognition, but not neurocognition. Greater neurobiologic reserve predicted a rapid social-cognitive response to CET in the first year of treatment; patients with less neurobiologic reserve achieved a comparable social-cognitive response by the second year. While nearly every regional measurement significantly contributed to this accelerated social-cognitive treatment response, effects were the strongest in the temporal cortex. CONCLUSIONS A broad cortical surface area and gray matter reserve is associated with an accelerated social-cognitive response to CET in early schizophrenia, yet the benefits of cognitive rehabilitation are achieved in those with less initial cognitive resources after a longer duration of treatment.

Abnormalities of the corpus callosum in non-psychotic high-risk offspring of schizophrenia patients

Alterations in the structure of the corpus callosum (CC) have been observed in schizophrenia. Offspring of schizophrenia parents have 10-15 times higher risk for developing schizophrenia. We examined CC volume in offspring at genetic high-risk (HR) subjects. Since the sub-regions of the CC are topographically mapped to cortical brain regions, we hypothesized that HR subjects may show a decrement in total volume and differential volume decreases in sub-regions of the CC. The offspring of schizophrenia parents (HR; n=70; 36 males) and healthy volunteers with no family or personal history of psychotic disorders (healthy controls (HC); n=73; 37 males) matched for age, gender and education were selected for the study. Magnetic resonance images were collected using a GE 1.5 T scanner and processed using FreeSurfer image analysis software. The CC was divided into five neuroanatomically based partitions. The volume of total CC and the five sub-regions were measured blind to clinical information. With covariation for intracranial volume, HR subjects had significantly reduced total CC, more prominently observed in the anterior splenium. An age-related increase in CC volume was found in the anterior and posterior splenium of healthy controls but not in HR subjects. The volume reduction was greater in male than female HR subjects. The volume reduction in the CC may reflect a reduction in axonal fibers crossing the hemispheres and/or myelination between the left and right temporo-parietal cortices. The absence of an age-related volume increase suggests an abnormal developmental trajectory that may underlie susceptibility to schizophrenia.

Do inter-regional gray-matter volumetric correlations reflect altered functional connectivity in high-risk offspring of schizophrenia patients?

BACKGROUND Schizophrenia patients and their relatives show aberrant functional connectivity in default network regions (DRs) such as the medial prefrontal, lateral temporal, cingulate and inferior parietal cortices and executive regions such as the dorsolateral prefrontal cortex (DLPFC). Gray-matter volumetric alterations may be related to these functional connectivity deficits. Also, gray-matter volume inter-regional correlations may reflect altered inter-regional functional connectivity. AIMS To examine our prediction of alterations of gray-matter volumes and inter-regional volume correlations for DRs and the DLPFC in offspring of schizophrenia patients (OS). METHODS We assessed 64 adolescent and young adult OS and 80 healthy controls (HC) using T1-MRI. Regional gray-matter volumes and inter-regional volume correlations between the DRs and between the DLPFC and DRs on each side were compared across groups. RESULTS Compared to HC, OS had reductions in several DRs and the DLPFC after controlling age, gender, and intra-cranial volume, and correcting for multiple comparisons. OS had stronger (more positive) gray-matter volume inter-correlations between DRs and between DRs and the DLPFC. CONCLUSIONS Volumetric deficits in the default network and in the DLPFC may be related to familial diathesis in schizophrenia and to functional connectivity abnormalities in those at familial risk. Increased inter-correlations between DRs and between DR and DLPFC gray-matter volumes may serve as surrogate indices of abnormal functional connectivity.

Progressive alterations of the auditory association areas in young non-psychotic offspring of schizophrenia patients

BACKGROUND Schizophrenia may involve progressive alterations of structure and hemispheric lateralization of auditory association areas (AAA) within the superior temporal gyrus. These alterations may be greater in male patients. It is unclear if these deficits are state-dependent or whether they predate illness onset and reflect familial diathesis. AIMS We sought to compare AAA cortical thickness, surface area and lateralization across adolescent and young adult non-psychotic offspring of schizophrenia patients (OS) and healthy controls at baseline and one year follow-up. We also assessed the moderating effect of gender on these measures. METHODS Fifty-six OS and thirty-six control subjects were assessed at baseline and at follow-up on AAA surface area and thickness using FreeSurfer to process T1-MRI-images. We used repeated measures ANCOVAs, controlling intra cranial volume and age with assessment-time and side as within-subject factors and gender and study group as between-subject factors. RESULTS Surface area deficit in OS was greater on the left than on the right, as reflected in a lower surface area laterality-index (left-right/left + right × 100) in OS compared to controls. Left, but not right surface area and surface area laterality-index showed a longitudinal decline in OS compared to controls. Male OS declined more than controls on surface area and thickness. CONCLUSIONS Left AAA surface area may progressively decline in young non-psychotic offspring at familial diathesis for schizophrenia causing a continuing reversal of the leftward AAA lateralization. Progressive surface area reduction and thinning of AAA may be more prominent in young non-psychotic male offspring at risk for schizophrenia.

Alterations in the cerebral white matter of genetic high risk offspring of patients with schizophrenia spectrum disorder

Alterations in white matter (WM) may be seen in young relatives at risk and may underlie vulnerability to schizophrenia. We were interested in exploring which of the WM regions were altered in adolescent offspring at familial risk for schizophrenia. We examined structural alterations in the offspring of subjects with schizophrenia or schizoaffective disorder (HR; n=65; 36 males) and healthy controls (HC; n=80: 37 males) matched for age and education. MRI images were collected using a GE 1.5 T scanner at the University of Pittsburgh Medical Center. Image processing was done using FreeSurfer (MGH) by an experienced rater blind to clinical data. We used multivariate analysis of covariance, with intracranial volume (p>0.05) and age as covariates. High Risk offspring had significant reductions in total WM, hemispheric WM and WM within left parietal and left cingulate cortices. Male offspring had more pronounced right hemisphere WM reductions than females.

Involuntary movements and their correlates in first‐episode psychoses

Involuntary movements (IMs) are seen in schizophrenia and are widely considered to be side-effects of neuroleptic medications (1,2). Although dopamine-blocking antipsychotics may be related to IMs, IMs are often manifested in medication-naive patients and were frequently reported in the preneuroleptic era (3–5). IMs are reported in medication-free chronically ill (6–8) and medication-naive first-episode patients (9–14). Previous studies report IMs in neuroleptic-naive psychosis up to 14% (5), suggesting that IMs could be state-independent, core features. It, however, remains unclear whether IMs represent medication-induced phenomena or whether they are the core phenotypic trait-related features of schizophrenia (15). Some studies suggest that the severity of IMs may correlate with the degree of negative (3,16) or positive symptoms (10), albeit inconsistently (17). Working memory impairments and negative symptoms may correlate with IMs in patients treated for chronic schizophrenia 18), suggesting a role for frontostriatal neural systems in the pathophysiology of IMs. Although the relationship between IMs, negative symptoms and neurocognitive deficits, one of the core features of schizophrenia (19), has not been studied previously in untreated patients with first-episode psychoses, those studies examining IMs in untreated schizophrenia patients are limited by a small sample size (10,14) and by the lack of standardised assessment scales (13). We examined IMs in a relatively large group of medication-free first-episode psychosis patients and studied their relationships to positive and negative symptoms and executive function (Box 1). We hypothesised that the patients will have IMs and these would correlate with more severe negative symptoms as well as executive function impairment. Box 1. Involuntary Movements in Medication-free First-episode Psychosis Patients and Their Relationship to Positive and Negative Symptoms and Executive Functions Methods The subjects included individuals who were involved in a longitudinal study of first-episode psychosis [for details of the methods see Keshavan et al. (20)]. About 178 previously untreated patients with psychosis were evaluated with a thorough medical, neurological and psychiatric evaluations. Of these, 162 were diagnosed with schizophrenia or schizoaffective disorder (104 males; 24.8 + 7.81 years), and 16 were diagnosed with other psychotic disorders (12 males; 34.72 ± 9.24 years). Patients were recruited from the in-patient and out-patient services of the Western Psychiatric Institute and Clinic, Pittsburgh. All subjects were interviewed by experienced clinical raters (Debra Montrose PhD, Kevin Eklund RN or Elizabeth Radomsky PhD) using the Structured Clinical Interview for Diagnostic and Statistical Manual, fourth edition (DSM-IV) (21). Diagnoses were derived by consensus diagnostic evaluations and were formally confirmed after at least 6 months follow-up. These patients were aged 15–45 years, had minimal prior exposure to neuroleptics, and met the DSM-IV criteria for a non-organic psychotic disorder. Exclusion criteria were significant neurological or medical illness, mental retardation as diagnosed by DSM-IV, head injury with loss of consciousness, current substance abuse or substance dependence within the previous 6 months. All participants provided informed consent after full explanation of the study. The study was approved by the University of Pittsburgh Institutional Review Board. Involuntary movements were evaluated by an experienced clinician Kevin Eklund, RN), trained by the senior investigator (Matcheri S Keshavan) using abnormal involuntary movements scale (AIMS). Executive dysfunction was examined using the perseverative errors on the Wisconsin Card Sort Test (WCST). The Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms were completed close to the time of the neuropsychological evaluations without knowledge of the findings from cognitive investigations. Similarly, neuropsychological testing was done blind to knowledge of clinical ratings. Correlational analyses were conducted using Spearman rank-order correlations. Results AIMS scores were elevated (0.43 ± 1.6) in the schizophrenia patients compared to the other psychoses (0.25 ± 1). We found the rate of involuntary movements (score of 1 or more on any of the anatomical item of AIMS) to be 10.49% in the subset of 162 patients with first-episode Schizophrenia, which contrasts with 6.25% in the group with other Psychoses. No correlation was found between the AIMS scores and the positive symptoms (ρ = 0.11, p = 0.13) or the neurological soft signs (ρ = 0.92, p = 0.36). The negative symptoms showed a strong correlation with the AIMS total score (ρ = 0.24, p = 0.001), which is in consonance with the results found in previous studies (5). The AIMS total score was positively correlated to the perseverative errors on the WCST, in those patients in whom (n = 136) the data were available (ρ = 0.19, p = 0.04). This correlation remained significant if only patients with a diagnosis of schizophrenia or schizoaffective disorder were included in the analyses (ρ = 0.17, p = 0.047). We found increased AIMS scores in a small proportion of previously untreated patients with first-episode psychoses suggesting that IMs might be at least partially, a disease-induced state-dependent change, independent of the effect of antipsychotic medications. AIMS scores were correlated with negative symptoms (but not positive symptoms) consistent with prior literature (9); a novel observation is that IMs correlated with increased perseverative errors on the WCST. The perseverative errors in the WCST and their relationship to IMs (albeit small but significant) point towards the possible involvement of the prefrontal and striatal structures (which are implicated in the executive function deficits) in the pathogenesis of the IMs in psychotic disorders. The strengths of this study include a relatively large sample of minimally treated patients with first-episode psychosis who were well characterised with psychopathologic and neurocognitive assessments. However, our study was limited by the absence of AIMS data in a group of well-matched controls. Future studies need to confirm these observations and systematically examine the relationship between IMs and neurobiological indices of frontostriatal pathology in the early course of psychiatric disorders.