Person:

Thermenos, Heidi

We examined the status of the neural network mediating the default mode of brain function, which typically exhibits greater activation during rest than during task, in patients in the early phase of schizophrenia and in young first-degree relatives of persons with schizophrenia. During functional MRI, patients, relatives, and controls alternated between rest and performance of working memory (WM) tasks. As expected, controls exhibited task-related suppression of activation in the default network, including medial prefrontal cortex (MPFC) and posterior cingulate cortex/precuneus. Patients and relatives exhibited significantly reduced task-related suppression in MPFC, and these reductions remained after controlling for performance. Increased task-related MPFC suppression correlated with better WM performance in patients and relatives and with less psychopathology in all 3 groups. For WM task performance, patients and relatives had greater activation in right dorsolateral prefrontal cortex (DLPFC) than controls. During rest and task, patients and relatives exhibited abnormally high functional connectivity within the default network. The magnitudes of default network connectivity during rest and task correlated with psychopathology in the patients. Further, during both rest and task, patients exhibited reduced anticorrelations between MPFC and DLPFC, a region that was hyperactivated by patients and relatives during WM performance. Among patients, the magnitude of MPFC task suppression negatively correlated with default connectivity, suggesting an association between the hyperactivation and hyperconnectivity in schizophrenia. Hyperactivation (reduced task-related suppression) of default regions and hyperconnectivity of the default network may contribute to disturbances of thought in schizophrenia and risk for the illness.

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 center 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 studied 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.

Siblings of patients diagnosed with schizophrenia are at elevated risk for developing this disorder. The nature of such risk associated with brain abnormalities, and whether such abnormalities are similar to those observed in schizophrenia, remain unclear. Deficits in language processing are frequently reported in increased risk populations. Interestingly, white matter pathology involving fronto-temporal language pathways, including Arcuate Fasciculus (AF), Uncinate Fasciculus (UF), and Inferior Occipitofrontal Fasciculus (IOFF), are frequently reported in schizophrenia. In this study, high spatial and directional resolution diffusion MRI data was obtained on a 3T magnet from 33 subjects with increased familial risk for developing schizophrenia, and 28 control subjects. Diffusion Tractography was performed to measure white matter integrity within AF, UF, and IOFF. To understand these abnormalities, Fractional anisotropy (FA, a measure of tract integrity) and Trace (a measure of overall diffusion), were combined with more specific measures of axial diffusivity (AX, a putative measure of axonal integrity) and radial diffusivity (RD, a putative measure of myelin integrity). Results revealed a significant decrease in Trace within IOFF, and a significant decrease in AX in all tracts. FA and RD anomalies, frequently reported in schizophrenia, were not observed. Moreover, AX group effect was modulated by age, with increased risk subjects demonstrating a deviation from normal maturation trajectory. Findings suggest that familial risk for schizophrenia may be associated with abnormalities in axonal rather than myelin integrity, and possibly associated with disruptions in normal brain maturation. AX should be considered a possible biomarker of risk for developing schizophrenia.

Background—Abnormalities in language and language neural circuitry are observed in schizophrenia (SZ). Similar, but less pronounced language deficits are also seen in young first degree relatives of people with SZ, who are at higher familial risk (FHR) for the disorder than the general population. The neural underpinnings of these deficits in people with FHR are unclear. Methods—Participants were 43 people with FHR and 32 comparable controls. fMRI scans were collected while participants viewed associated and unrelated word pairs, and performed a lexical decision task. fMRI analyses conducted in SPM8 examined group differences in the modulation of hemodynamic activity by semantic association. Results—There were no group differences in demographics, IQ or behavioral semantic priming, but FHR participants had more schizotypal traits than controls. Controls exhibited the expected suppression of hemodynamic activity to associated versus unrelated word pairs. Compared to controls, FHR participants showed an opposite pattern of hemodynamic modulation to associated versus unrelated word pairs, in the left inferior frontal gyrus (IFG), right superior and middle temporal gyrus (STG) and the left cerebellum. Group differences in activation were significant, FWE-corrected for multiple comparisons (p<0.05). Activity within the IFG during the unrelated condition predicted schizotypal symptoms in FHR participants. Conclusions—FHR for SZ is associated with abnormally increased neural activity to semantic associates within an inferior frontal/temporal network. This might increase the risk of developing unusual ideas, perceptions and disorganized language that characterize schizotypal traits, potentially predicting which individuals are at greater risk to develop a psychotic disorder.

Abstract Background: While the etiology of schizophrenia (SZ) is still unclear, it has been characterized as a neurodevelopmental disorder because patients exhibit deviations from normal maturational trajectories that are evident prior to the onset of psychotic symptoms. White matter (WM) has been purported to play a central role in the development of SZ, however, the timing and nature of WM changes in SZ is still poorly understood. This study uses diffusion imaging from three independent Genetic High Risk (GHR) populations spanning the developmental timeline from infancy to young adulthood. The aim of this study is to understand the extent and the time-course of WM maturational pathologies as a function of age and genetic risk for psychosis. Methods: Two datasets of 3T diffusion-weighted images of children aged 7 to 12 (24 HC and 16 at GHR) and young adults aged 19 to 29 (26 HC and 43 GHR) were collected at the Massachusetts Institute of Technology. The third dataset of 3T images of infants aged 2 years (35 HC and 18 GHR) was collected at the University of North Carolina – Chapel Hill. Whole brain two-tensor tractography was performed and 4 bilateral WM tracts (arcuate fasciculus (AF); inferior longitudinal fasciculus (ILF); cingulum bundle (CB); superior longitudinal fasciculus-ii (SLF-ii)), were extracted utilizing an atlas-guided fiber clustering algorithm. The fractional anisotropy of the tissue (FA-t) was obtained. We carried out group comparisons of FA-t between GHR and HCs utilizing Mann-Whitney-U tests and Cohen’s d effect sizes for each WM tract. Results: Preliminary analyses reveal significant reductions in FAt between GHR and HC in the right CB (p = 0.013) in the child GHR population. This is mirrored by medium to large effect sizes in the bilateral CB in GHR children (CB-left, d = 0.51; CB-right, d = 0.79). Reductions in FAt in the adult GHR population within the right CB was the largest effect observed in the adult analysis (CB-right, d = 0.46). Effect sizes in the bilateral CB were minimal in the infant GHR population (CB-left, d = 0.14, CB-right, d = 0.11). Significant decreases were also seen in the right SLF-ii in the adult GHR population (p = 0.012), but not in the infant or child GHR populations, though the reductions in FAt in the child GHR population exhibited a small effect (d = 0.35). All other white matter tracts in the adult analysis showed minor effects ranging from d = 0.033 (ILF-right) to 0.28 (ILF-left). The children and infant population also exhibited small effect sizes for all other tracts, with the child GHR dataset ranging from 0.036 (ILF-left) to 0.41 (ILF-right) and the infant GHR dataset ranging from d = 0.038 (SLF-left) to 0.34 (ILF-left). Discussion Our preliminary results suggest that abnormal WM maturation may occur in the right CB and right SLF-ii in individuals with increased genetic risk for SZ, specifically after early childhood (7 to 12 years) and into adulthood (19 to 29 years). The CB and SLF-ii are highly implicated in working memory performance, an ability that retrospective studies have shown begins to decline during the peripubertal period in those that develop SZ (~7 to 9 years). The lack of structural findings in GHR infants, may suggest that WM alterations are more likely to arise later in development, thereby possibly identifying childhood as a vulnerable period. Taken together, the preliminary results of this study provide possible evidence of subtle divergences from a healthy WM maturational trajectory in the right CB and right SLF-ii in early to late childhood that may persist into adulthood and these deviations may contribute to cognitive phenotypes described in other studies.