Multimodal 7T imaging reveals enhanced functional coupling between salience and frontoparietal networks in young adult tobacco cigarette smokers.

Tobacco cigarette smoking is associated with disrupted brain network dynamics in resting brain networks including the Salience (SN) and Fronto parietal (FPN). Unified multimodal methods [Resting state connectivity analysis, Diffusion Tensor Imaging (DTI), neurite orientation dispersion and density imaging (NODDI), and cortical thickness analysis] were employed to test the hypothesis that the impact of cigarette smoking on the balance among these networks is due to alterations in white matter connectivity, microstructural architecture, functional connectivity and cortical thickness (CT) and that these metrics define fundamental differences between people who smoke and nonsmokers. Multimodal analyses of previously collected 7 Tesla MRI data via the Human Connectome Project were performed on 22 people who smoke (average number of daily cigarettes was 10 ± 5) and 22 age- and sex-matched nonsmoking controls. First, functional connectivity analysis was used to examine SN-FPN-DMN interactions between people who smoke and nonsmokers. The anatomy of these networks was then assessed using DTI and CT analyses while microstructural architecture of WM was analyzed using the NODDI toolbox. Seed-based connectivity analysis revealed significantly enhanced within network [p = 0.001 FDR corrected] and between network functional coupling of the salience and R-frontoparietal networks in people who smoke [p = 0.004 FDR corrected]. The network connectivity was lateralized to the right hemisphere. Whole brain diffusion analysis revealed no significant differences between people who smoke and nonsmokers in Fractional Anisotropy, Mean diffusivity and in neurite orienting and density. There were also no significant differences in CT in the hubs of these networks. Our results demonstrate that tobacco cigarette smoking is associated with enhanced functional connectivity, but anatomy is largely intact in young adults. Whether this enhanced connectivity is pre-existing, transient or permanent is not known. The observed enhanced connectivity in resting state networks may contribute to the maintenance of smoking frequency.

Functional hyperconnectivity between corticocerebellar networks and altered decision making in young adult cannabis users: Evidence from 7T and multivariate pattern analysis.

Decision-making (DM) impairments are important predictors of cannabis initiation and continued use. In cannabis users, how decision-making abnormalities related to structural and functional connectivity in the brain are not fully understood. We employed a three-method multimodal image analysis and multivariate pattern analysis (MVPA) on high dimensional 7 tesla MRI images examining functional connectivity, white matter microstructure and gray matter volume in a group of cannabis users and non-users. Neuroimaging and cognitive analyses were performed on 92 CU and 92 age- matched NU from a total of 187 7T scans. CU were selected on the basis of their scores on the Semi-Structured Assessment for the Genetics of Alcoholism. The groups were first compared on a decision-making test and then on ICA based functional connectivity between corticocerebellar networks. An MVPA was done as a confirmatory analysis. The anatomy of these networks was then assessed using Diffusion Tensor imaging (DTI) and cortical volume analyses. Cannabis Users had significantly higher scores on the Iowa Gambling task (IGT) [Gambling task Percentage larger] and significantly lower scores on the [Gambling task reward Percentage smaller]. Left accumbens (L NAc) volume was significantly larger in cannabis users. DTI analysis between the groups yielded no significant (FWE corrected) differences. Resting state FC analysis of the left Cerebellum region 9 showed enhanced functional connectivity with the right nucleus accumbens and left pallidum and left putamen in CU. In addition, posterior cerebellum showed enhanced functional connectivity (FWE corrected) with 2 nodes of the DMN and left and right paracingulate (sub genual ACC) and the sub callosal cortex in CU. IGT percentage larger scores correlated with posterior cerebellar functional connectivity in non-user women. A multivariate pattern analysis confirmed this cerebellar hyperconnectivity in both groups. Our results demonstrate for the first time that deficits in DM observed in cannabis users are mirrored in hyper connectivity in corticocerebellar networks. Cortical volumes of some of the nodes of these networks showed increases in users. However, the underlying white matter was largely intact in CU. The observed DM deficits and hyper connectivity in resting networks may contribute to difficulties in quitting and/or facilitating relapse.

Verbal Memory Performance and Reduced Cortical Thickness of Brain Regions Along the Uncinate Fasciculus in Young Adult Cannabis Users.

Introduction: Memory impairment is one of the most commonly reported effects of cannabis use, especially among those who initiate use earlier, perhaps due to the effects of delta-9- tetrahydrocannabinol on cannabinoid (CB1) receptors in the brain. Studies have increasingly investigated whether cannabis use is associated with impairments in verbal memory, and with alterations in brain structures underlying verbal memory. The uncinate fasciculus (UF), a long-range white matter tract, connects regions with densely localized CB1 receptors that are important in verbal memory. This study investigated the impact of cannabis use on UF structures and its association with memory performance in young adult cannabis users (CU) and non-using controls (CON). Materials and Methods: Nineteen CU and 22 CON completed a verbal memory task and a neuroimaging protocol, in which diffusion tensor imaging and structural scans were collected. We compared memory performance, diffusion and tractography measures of the UF, and cortical thickness of regions connected by the UF, between CU and CON. In regions showing a significant group effect, we also examined associations between verbal memory performance, cortical thickness, and age of onset of cannabis use. Results: Compared to non-users, CU had worse memory performance, decreased fiber bundle length in the UF, and decreased cortical thickness of brain regions along the UF such as the entorhinal cortex and fusiform gyrus. Verbal memory performance was significantly associated with age of onset of cannabis use, indicating that those who initiated cannabis use at an earlier age performed worse. Cortical thickness of the entorhinal cortex was significantly correlated with age of first use and memory performance. Conclusion: This study provides evidence that cannabis use, especially when initiated at a young age, may be associated with worse verbal memory and altered neural development along the UF. Reductions in cortical thickness in regions implicated in memory processes may underlie weaknesses in verbal memory performance.

Callosal Abnormalities Across the Psychosis Dimension: Bipolar Schizophrenia Network on Intermediate Phenotypes.

BACKGROUND: The corpus callosum has been implicated in the pathogenesis of schizophrenia and bipolar disorder. However, it is unclear whether corpus callosum alterations are related to the underlying familial diathesis for psychotic disorders. We examined the corpus callosum and its subregion volumes and their relationship to cognition, psychotic symptoms, and age in probands with schizophrenia (SZ), psychotic bipolar disorder (PBD), and schizoaffective disorder; their first-degree relatives; and healthy control subjects. METHODS: We present findings from morphometric and neurocognitive analyses of 1381 subjects (SZ probands, n = 224; PBD probands, n = 190; schizoaffective disorder probands, n = 142; unaffected relatives, n = 483 [SZ relatives, n = 195; PBD relatives, n = 175; schizoaffective disorder relatives, n = 113]; control subjects, n = 342). Magnetization prepared rapid acquisition gradient-echo T1 scans across five sites were obtained using 3-tesla magnets. Image processing was done using FreeSurfer Version 5.1. Neurocognitive function was measured using the Brief Assessment of Cognition in Schizophrenia scale. RESULTS: Anterior and posterior splenial volumes were significantly reduced across the groups. The SZ and PBD probands showed robust and significant reductions, whereas relatives showed significant reductions of intermediate severity. The splenial volumes were positively but differentially correlated with aspects of cognition in the probands and their relatives. Proband groups showed a significant age-related decrease in the volume of the anterior splenium compared with control subjects. Among the psychosis groups, the anterior splenium in probands with PBD showed a stronger correlation with psychotic symptoms, as shown by the Positive and Negative Syndrome Scale. All five subregions showed significantly high familiality. CONCLUSIONS: The splenial volumes were significantly reduced across the psychosis dimension. However, this volume reduction impacts cognition and clinical manifestation of the illnesses differentially.

Hippocampal volume is reduced in schizophrenia and schizoaffective disorder but not in psychotic bipolar I disorder demonstrated by both manual tracing and automated parcellation (FreeSurfer).

This study examined hippocampal volume as a putative biomarker for psychotic illness in the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) psychosis sample, contrasting manual tracing and semiautomated (FreeSurfer) region-of-interest outcomes. The study sample (n = 596) included probands with schizophrenia (SZ, n = 71), schizoaffective disorder (SAD, n = 70), and psychotic bipolar I disorder (BDP, n = 86); their first-degree relatives (SZ-Rel, n = 74; SAD-Rel, n = 62; BDP-Rel, n = 88); and healthy controls (HC, n = 145). Hippocampal volumes were derived from 3Tesla T1-weighted MPRAGE images using manual tracing/3DSlicer3.6.3 and semiautomated parcellation/FreeSurfer5.1,64bit. Volumetric outcomes from both methodologies were contrasted in HC and probands and relatives across the 3 diagnoses, using mixed-effect regression models (SAS9.3 Proc MIXED); Pearson correlations between manual tracing and FreeSurfer outcomes were computed. SZ (P = .0007-.02) and SAD (P = .003-.14) had lower hippocampal volumes compared with HC, whereas BDP showed normal volumes bilaterally (P = .18-.55). All relative groups had hippocampal volumes not different from controls (P = .12-.97) and higher than those observed in probands (P = .003-.09), except for FreeSurfer measures in bipolar probands vs relatives (P = .64-.99). Outcomes from manual tracing and FreeSurfer showed direct, moderate to strong, correlations (r = .51-.73, P < .05). These findings from a large psychosis sample support decreased hippocampal volume as a putative biomarker for schizophrenia and schizoaffective disorder, but not for psychotic bipolar I disorder, and may reflect a cumulative effect of divergent primary disease processes and/or lifetime medication use. Manual tracing and semiautomated parcellation regional volumetric approaches may provide useful outcomes for defining measurable biomarkers underlying severe mental illness.

Medial temporal lobe structures and hippocampal subfields in psychotic disorders: findings from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study.

IMPORTANCE: Structural alterations in the hippocampus and other medial temporal lobe regions have been observed in schizophrenia. How these alterations and hippocampal subfields might differ across the psychosis spectrum remains unclear. OBJECTIVES: To characterize medial temporal lobe structures, including hippocampal subfields, using magnetic resonance imaging and to examine their relation to psychosis and cognitive function across the psychosis spectrum. DESIGN, SETTING, AND PARTICIPANTS: Case-control, cross-sectional neuroimaging study in a large series of probands with psychotic disorders and healthy volunteers as part of the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP). Patients with psychotic disorders (schizophrenia, n = 219; schizoaffective disorder, n = 142; and psychotic bipolar disorder, n = 188) and healthy controls (n = 337) were recruited across ambulatory clinics at university health centers in the B-SNIP consortium. MAIN OUTCOMES AND MEASURES: Medial temporal lobe and hippocampal subfields were quantified with an automated parcellation approach using FreeSurfer software. Memory and other cognitive parameters were assessed using standardized neuropsychological tests. RESULTS: Hippocampal volume reductions were seen in all 3 diagnostic groups when compared with healthy controls; alterations in the entorhinal cortex and parahippocampal regions were limited to schizophrenia and schizoaffective disorders (P < .001). Smaller volumes across the hippocampal subfields were seen in all 3 psychotic disorders, with the most prominent differences being in cornu ammonis 2/3 (P < .001). Hippocampal volumes were positively correlated with psychosis severity, declarative memory, and overall cognitive performance (P < .05). CONCLUSIONS AND RELEVANCE: Alterations in the hippocampus were evident across psychotic disorders. Hippocampal subfields that participate in memory-related processes supporting pattern separation and pattern completion might be abnormal and may underlie the pathophysiology of psychosis.

Gray matter volume as an intermediate phenotype for psychosis: Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP).

OBJECTIVE: The study examined gray matter volume across psychosis diagnoses organized by dimensional and DSM-IV categories from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) sample. METHOD: In total, 351 probands with psychosis (146 with schizophrenia, 90 with schizoaffective disorder, and 115 with psychotic bipolar I disorder), 369 of their first-degree relatives (134 were relatives of individuals with schizophrenia, 106 of individuals with schizoaffective disorder, and 129 of individuals with psychotic bipolar I disorder), and 200 healthy comparison subjects were assessed. Gray matter volumes from 3-T T1-weighted images were analyzed using the VBM8 toolbox for SPM8, and outcomes were determined at a false discovery rate-corrected threshold of p<0.005. RESULTS: Across the psychosis dimension, probands (N=351) and relatives with psychosis spectrum disorders (N=34) showed substantial overlapping gray matter reductions throughout the neocortex, whereas relatives without psychosis spectrum (N=332) had normal gray matter volumes relative to comparison subjects. Across DSM-IV diagnoses, schizophrenia and schizoaffective probands showed overlapping gray matter reductions in numerous cortical and subcortical regions, whereas psychotic bipolar probands showed limited gray matter reductions localized to the frontotemporal cortex relative to comparison subjects. All relative groups had gray matter volumes that did not differ from comparison subjects. CONCLUSIONS: Across the dimensional psychosis categories, these findings indicate extensive neocortical gray matter reductions in psychosis probands and relatives with psychosis spectrum disorders, possibly reflecting lifetime psychosis burden, but normal gray matter in nonpsychotic relatives. Traditional DSM-IV psychosis grouping revealed partially divergent gray matter phenotypes for probands with schizophrenia or schizoaffective disorder (extensive neocortical or subcortical gray matter reductions) relative to those with psychotic bipolar disorder (smaller reductions were limited to frontotemporal regions). The dimensional conceptualization of psychosis appears useful in defining more homogenous disease categories that may help identify underlying psychosis biomarkers and develop a biologically driven diagnostic system and targeted treatments.

Reduced subicular subdivisions of the hippocampal formation and verbal declarative memory impairments in young relatives at risk for schizophrenia.

INTRODUCTION: Smaller hippocampal volumes similar to those found in schizophrenia (SZ) are frequently observed to a lesser extent in non-psychotic first-degree relatives of patients with the illness, compared to control subjects. In this study, subdivisions of the hippocampal formation and their association with verbal and visual learning and memory were assessed in persons at familial high risk (FHR) for SZ. METHODS: MRI scans were acquired using a 3T Siemens scanner of young adult (ages 19-32) FHR subjects (N=46) and controls with no family history of illness (i.e., at low genetic risk LRC; N=31) were processed using FreeSurfer 5.0. Subfields of the hippocampal formation were evaluated using the van Leemput method (Van Leemput et al., 2010). Learning and memory measures were collected by standardized neurocognitive tests. RESULTS: Controlling intracranial volume, significantly reduced left (p<0.025), and right hippocampus (p<0.024) volumes were observed in FHR subjects. Among the subfields, the left (p<0.01) and right subicula (p<0.005) were significantly reduced in the FHR group. Immediate verbal recall of stories was significantly impaired and was significantly correlated with the left and right subicula within the FHR group. CONCLUSIONS: Reduced subiculum volume and its association with verbal memory refines further the association with left and right hippocampus reported in previous FHR studies of schizophrenia. Further research is needed to determine the specific genetic and environmental risk factors that may be related to hippocampal subfield alterations.

Brain metabolite alterations in young adults at familial high risk for schizophrenia using proton magnetic resonance spectroscopy.

BACKGROUND: Proton magnetic resonance spectroscopy ((1)H MRS) enables in-vivo measurement of several relevant brain metabolites and has provided evidence of a range of neurochemical abnormalities in schizophrenia, especially in glutamate and N-acetyl-aspartate (NAA). While individuals at high familial risk for schizophrenia (HR) exhibit some neurobiological findings observed in the disorder, (1)H MRS findings and their clinical correlates are not well characterized in this population. METHODS: We compared 23 adolescent and young adult offspring of schizophrenia patients with 24 age- and sex-matched healthy controls using (1)H MRS. We acquired multi-voxel, short TE (1)H MRS measurements at 1.5T and obtained metabolite concentrations of N-acetyl-aspartate (NAA), combined glutamate and glutamine (Glu+Gln) and choline-containing compounds (GPC+PC) for the left and right thalamus, anterior cingulate gyrus, and caudate. We also assessed the relationship between regional metabolite levels, clinical measures and brain volume in a subset of 16 high-risk and 15 control subjects. RESULTS: Compared to healthy controls, high-risk subjects showed reductions in NAA levels in all three regions (thalamus, caudate, and anterior cingulate cortex), increases in Glu+Gln in the thalamus and caudate, and increases in GPC+PC in the anterior cingulate. In HR, thalamic Glu+Gln concentration was positively correlated and thalamic NAA inversely correlated with measures of schizotypy. Anterior cingulate GPC+PC and caudate Glu+Gln were significantly correlated with attenuated psychotic symptom severity. Anterior cingulate NAA was correlated with executive function. CONCLUSIONS: Our data suggest the occurrence of metabolic alterations in young relatives of schizophrenia patients similar to those seen in patients with established illness. The observed correlations with cognitive deficits and psychosis-related psychopathology suggest that these metabolic measures may have value as biomarkers of 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.

Alterations in brain structures underlying language function in young adults at high familial risk for schizophrenia.

INTRODUCTION: Neuroanatomical and cognitive alterations typical of schizophrenia (SZ) patients are observed to a lesser extent in their adolescent and adult first-degree relatives, likely reflecting neurodevelopmental abnormalities associated with genetic risk for the illness. The anatomical pathways for language are hypothesized to be abnormal and to underlie the positive symptoms of schizophrenia. Examining non-psychotic relatives at high familial risk (FHR) for schizophrenia may clarify if these deficits represent trait markers associated with genetic vulnerability, rather than specific markers resulting from the pathological process underlying schizophrenia. METHODS: T1 MRI scans from a 3T Siemens scanner of young adult FHR subjects (N=46) and controls with no family history of illness (i.e. at low genetic risk LRC; N=31) were processed using FreeSurfer 5.0. We explored volumetric and lateralization alterations in regions associated with language processing. An extensive neuropsychological battery of language measures was administered. RESULTS: No significant differences were observed between groups on any language measures. Controlling intracranial volume, significantly smaller left pars triangularis (PT) (p<0.01) and right pars orbitalis (PO) (p<0.01) volumes and reversal of the L>R pars orbitalis (p<0.001) lateralization were observed in FHR subjects. In addition, the L pars triangularis and R pars orbitalis correlated with performance on tests of linguistic function in the FHR group. CONCLUSIONS: Reduced volume and reversed structural asymmetry in language-related regions hypothesized to be altered in SZ are also found in first degree relatives at FHR, despite normal language performance. To clarify if these findings are endophenotypes for Sz, future studies would need to be performed of ill and well family members no longer within the age range of risk for illness to show these deficits segregate with schizophrenia within families. Moreover, measures of complex language need to be studied to determine if FHR individuals manifest impairments in some aspects of language function.

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.

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, Heschl's 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 Heschl's 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.

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.

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.

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.

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 Heschl's (p=.00), left supramarginal (p=.00) and right angular gyrii (p=.02) were also reduced in HR subjects. The L>R asymmetry of the Heschl's 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 Heschl's gyrii may accompany genetic liability to schizophrenia.