Person:

Shenton, Martha

Background—Abnormalities within language-related anatomical structures have been associated with clinical symptoms and with language and memory deficits in schizophrenia. Recent studies suggest disruptions in functional connectivity within the Inferior Frontal Gyrus (IFG) network in schizophrenia. However, due to technical challenges, anatomical connectivity abnormalities within this network and their involvement in clinical and cognitive deficits have not been studied. Material and Methods—Diffusion and anatomical scans were obtained from 23 chronic schizophrenia patients and 23 matched controls. The IFG was automatically segmented, and its white matter connections extracted and measured with newly-developed stochastic tractography tools. Correlations between anatomical structures and measures of semantic processing were also performed. Results—White Matter connections between the IFG and posterior brain regions followed two distinct pathways: dorsal and ventral. Both demonstrated left lateralization, but ventral pathway abnormalities were only found in schizophrenia. IFG volumes also showed left lateralization andabnormalities in schizophrenia. Further, despite similar laterality and abnormality patterns, IFG volumes and white matter connectivity were not correlated with each other in either group. Interestingly, measures of semantic processing correlated with white matter connectivity in schizophrenia and with gray matter volumes in controls. Finally, hallucinations were best predicted by both gray matter and white matter measures together. Conclusions—Our results suggest abnormalities within the ventral IFG network in schizophrenia, with white matter abnormalities better predicting semantic deficits. The lack of a statistical relationship between coexisting gray and white matter deficits might suggest their different origin and the necessity for a multimodal approach in future schizophrenia studies.

Background—Several theories of schizophrenia have emphasized the role of aberrant neural timing in the etiology of the disease, possibly as a consequence of conduction delays caused by structural damage to the white-matter fasciculi. Consistent with this theory, increased interhemispheric transmission times (IHTTs) to unilaterally-presented visual stimuli have been reported in patients with schizophrenia. The present study investigated whether or not these IHTT abnormalities could be underpinned by structural damage to the visual fibers of the corpus callosum. Methods—30 schizophrenia patients and 22 matched controls underwent Event Related Potential (ERP) recording, and a subset of 19 patients and 16 controls also underwent 3T Diffusion-Tensor Imaging (DTI). Unilateral visual stimuli (squares, 2 × 2 degrees) were presented 6 degrees lateral to either side of a central fixation point. IHTTs (ipsilateral minus contralateral latencies) were calculated for the P1 and N1 components at occipital-temporal sites in current source densitytransformed ERPs. The visual fibers of the corpus callosum were extracted with streamline tractography and the diffusion metrics of Fractional Anisotropy (FA) and Mode calculated. Results—While both subject groups exhibited highly significant IHTTs across a range of posterior electrode pairs, and significantly shorter IHTTs from left-to-right hemisphere than vice versa, no significant groupwise differences in IHTT were observed. However, participants’ IHTTs were linearly related to their FA and Mode, with longer IHTTs being associated with lower FA and more prolate diffusion ellipsoids. Conclusions—These results suggest that IHTTs are estimable from DTI measures of white matter integrity. In light of the range of diffusion abnormalities that have been reported in patients with schizophrenia, particularly in frontal fasciculi, these results support the conjecture that schizophrenia is ultimately underpinned by abnormalities in neural timing.

Patients with 22q11.2 deletion syndrome (22q11.2DS) represent a population at high risk for developing schizophrenia, as well as learning disabilities. Deficits in visuo-spatial memory are thought to underlie some of the cognitive disabilities. Neuronal substrates of visuo-spatial memory include the inferior fronto-occipital fasciculus (IFOF) and the inferior longitudinal fasciculus (ILF), two tracts that comprise the ventral visual stream. Diffusion Tensor Magnetic Resonance Imaging (DT-MRI) is an established method to evaluate white matter (WM) connections in vivo. DT-MRI scans of nine 22q11.2DS young adults and nine matched healthy subjects were acquired. Tractography of the IFOF and the ILF was performed. DT-MRI indices, including Fractional anisotropy (FA) (measure of WM changes), axial diffusivity (AD, measure of axonal changes) and radial diffusivity (RD, measure of myelin changes) of each of the tracts and each group were measured and compared. The 22q11.2DS group showed statistically significant reductions of FA in IFOF in the left hemisphere. Additionally, reductions of AD were found in the IFOF and the ILF in both hemispheres. These findings might be the consequence of axonal changes, which is possibly due to fewer, thinner, or less organized fibers. No changes in RD were detected in any of the tracts delineated, which is in contrast to findings in schizophrenia patients where increases in RD are believed to be indicative of demyelination. We conclude that reduced axonal changes may be key to understanding the underlying pathology of WM leading to the visuo-spatial phenotype in 22q11.2DS.

Background: Using diffusion tensor imaging (DTI), we previously reported abnormalities in two critical white matter tracts in schizophrenia, the uncinate fasciculus (UF) and the cingulum bundle (CB), both related to fronto–temporal connectivity. Here, we investigate these two bundles in unmedicated subjects with schizotypal personality disorder (SPD). Methods: Fifteen male SPD subjects and 15 male control subjects were scanned with line-scan DTI. Fractional anisotropy (FA) and mean diffusivity (Dm) were used to quantify water diffusion, and cross-sectional area was defined with a directional threshold method. Exploratory correlation analyses were evaluated with Spearman’s rho, followed by post hoc hierarchical regression analyses. Results: We found bilaterally reduced FA in the UF of SPD subjects. For CB, there was no significant group difference for FA or Dm measures. Additionally, in SPD, reduced FA in the right UF was correlated with clinical symptoms, including ideas of reference, suspiciousness, restricted affect, and social anxiety. In contrast, left UF area was correlated with measures of cognitive function, including general intelligence, verbal and visual memory, and executive performance. Conclusions: These findings in SPD suggest altered fronto–temporal connectivity through the UF, similar to findings in schizophrenia, and intact neocortical–limbic connectivity through the CB, in marked contrast with what has been reported in schizophrenia.

Hemisphere asymmetry was explored in normal healthy subjects and in patients with schizophrenia using a novel voxel-based tensor analysis applied to fractional anisotropy (FA) of the diffusion tensor. Our voxel-based approach, which requires precise spatial normalization to remove the misalignment of fiber tracts, includes generating a symmetrical group average template of the diffusion tensor by applying nonlinear elastic warping of the demons algorithm. We then normalized all 32 diffusion tensor MRIs from healthy subjects and 23 from schizophrenic subjects to the symmetrical average template. For each brain, six channels of tensor component images and one T2-weighted image were used for registration to match tensor orientation and shape between images. A statistical evaluation of white matter asymmetry was then conducted on the normalized FA images and their flipped images. In controls, we found left-higher-than-right anisotropic asymmetry in the anterior part of the corpus callosum, cingulum bundle, the optic radiation, and the superior cerebellar peduncle, and right-higher-than-left anisotropic asymmetry in the anterior limb of the internal capsule and the anterior limb’s prefrontal regions, in the uncinate fasciculus, and in the superior longitudinal fasciculus. In patients, the asymmetry was lower, although still present, in the cingulum bundle and the anterior corpus callosum, and not found in the anterior limb of the internal capsule, the uncinate fasciculus, and the superior cerebellar peduncle compared to healthy subjects. These findings of anisotropic asymmetry pattern differences between healthy controls and patients with schizophrenia are likely related to neuro-developmental abnormalities in schizophrenia.

Two of the most frequently investigated regions in diffusion tensor imaging studies in chronic schizophrenia are the uncinate fasciculus (UF) and cingulum bundle (CB). The purpose of the present study was to determine whether UF and CB white matter integrity were altered at the early stage of illness and specific to schizophrenia. Fifteen schizophrenia subjects and 15 affective psychosis within 4 years of first hospitalization (12 patients with schizophrenia and 12 patients with affective psychosis during their first hospitalization), and 15 psychiatrically healthy controls underwent line-scan diffusion tensor imaging. Fractional anisotropy (FA) and mean diffusivity (D(m)) were used to quantify water diffusion, and cross-sectional area was defined with a directional threshold method. Bilaterally reduced FA, but not D(m), was present in the UF of schizophrenia compared with healthy controls. Affective psychosis was intermediate between schizophrenia subjects and healthy controls, but not significantly different from either. For CB, there was no significant group difference for FA or D(m). These findings suggest that UF, but not CB, white matter integrity is altered at the early stage of illness in schizophrenia although it may not be specific to schizophrenia. The CB abnormalities reported in chronic schizophrenia may develop during the later course of the disease.

Background—Previous studies have shown that frontostriatal networks, especially those involving dorsolateral prefrontal cortex (DLPFC) and ventrolateral prefrontal cortex (VLPFC) mediate cognitive functions some of which are abnormal in schizophrenia. This study examines white matter integrity of the tracts connecting DLPFC/VLPFC and striatum in patients with firstepisode schizophrenia (FESZ), and their associations with cognitive and clinical correlates. Methods—Diffusion tensor and structural magnetic resonance images were acquired on a 3T GE Echospeed system from 16 FESZ and 18 demographically comparable healthy controls. FreeSurfer software was used to parcellate regions of interest. Two-tensor tractography was applied to extract fibers connecting striatum with rostral middle frontal gyrus (rMFG) and inferior frontal gyrus (IFG), representing DLPFC and VLPFC respectively. DTI indices, including fractional anisotropy (FA), trace, axial diffusivity (AD) and radial diffusivity (RD), were used for group comparisons. Additionally, correlations were evaluated between these diffusion indices and the Wisconsin Card Sorting Task (WCST) and the Brief Psychiatric Rating Scale (BPRS). Results—FA was significantly reduced in the left IFG-striatum tract, whereas trace and RD were significantly increased in rMFG-striatum and IFG-striatum tracts, bilaterally. The number of WCST categories completed correlated positively with FA of the right rMFG-striatum tract, and negatively with trace and RD of right rMFG-striatum and right IFG-striatum tracts in FESZ. The BPRS scores did not correlate with these indices. Conclusions—These data suggest that white matter tract abnormalities between rMFG/IFG and striatum are present in FESZ and appear to be significantly associated with executive dysfunction but not with symptom severity.

Voxel-Based Morphometry (VBM) is a hypothesis-free, whole-brain, voxel-by-voxel analytic method that attempts to compare imaging data between populations. Schizophrenia studies have utilized this method to localize differences in Diffusion Tensor Imaging (DTI) derived Fractional Anisotropy (FA), a measure of white matter integrity, between patients and healthy controls. The number of publications has grown, although it is unclear how reliable and reproducible this method is, given the subtle white matter abnormalities expected in schizophrenia. Here we analyze and combine results from 23 studies published to date that use VBM to study schizophrenia in order to evaluate the reproducibility of this method in DTI analysis. Coordinates of each region reported in DTI VBM studies published thus far in schizophrenia were plotted onto a Montreal Neurological Institute atlas, and their anatomical locations were recorded. Results indicated that the reductions of FA in patients with schizophrenia were scattered across the brain. Moreover, even the most consistently reported regions were reported independently in less than 35% of the papers studied. Other instances of reduced FA were replicated at an even lower rate. Our findings demonstrate striking inconsistency, with none of the regions reported in much more than a third of the published papers. Poor replication rate suggests that the application of VBM to DTI data may not be the optimal way for studying the subtle microstructural abnormalities that are being hypothesized in schizophrenia.

Background: Superior temporal gyrus (STG) volume reduction is one of the most consistent findings in schizophrenia. The goal of this study was to conduct the first diffusion tensor imaging (DTI) study to investigate altered structural integrity in STG gray and white matter in patients with chronic schizophrenia compared with healthy controls. Methods: Magnetic resonance imaging (MRI) and DTI were acquired in 21 male patients with schizophrenia and 22 age-, handedness-, and parental social economic status-matched male comparison subjects. After manual segmentation of gray and white matter, mean diffusivity and fractional anisotropy were measured within STG. Correlational analyses were also conducted to test possible associations between DTI and clinical measures, including positive and negative symptoms of schizophrenia. Results: Compared with controls, patients demonstrated reduced volume, bilaterally, in STG gray matter but not in white matter. For DTI measures, patients showed increased mean diffusivity, bilaterally, in STG gray matter, and in left-sided STG white matter. In addition, mean diffusivity in left-sided STG white matter showed statistically significant correlations with auditory hallucinations and attentional impairments in patients. Conclusions: These findings suggest a disruption of tissue integrity in STG gray and white matter in schizophrenia. In addition, increased water diffusivity in left-side STG, which was associated with auditory hallucinations and attentional impairments, suggests the possibility of a disconnection among auditory/language processing regions in schizophrenia.

Background—Whilst the neuroanatomical underpinnings of the functional brain disconnectivity observed in patients with schizophrenia remain elusive, white matter fiber bundles of the brain are a likely candidate given that they represent the infrastructure for long-distance neural communication. Methods—This study investigated for diffusion abnormalities in 19 patients with chronic schizophrenia (SZ), relative to 19 matched controls, across tractography-defined segments of the Corpus Callosum. Diffusion-weighted images were acquired with 51 non-collinear gradients on a 3T scanner (1.7mm isotropic voxels). The Corpus Callosum was extracted by means of whole-brain tractography and automated fiber-clustering, and was parcellated into six segments on the basis of fiber trajectories. The diffusion indices of Fractional Anisotropy (FA) and Mode were calculated for each segment. Results—Relative to the healthy controls, the SZ patients exhibited Mode increases in the Parietal fibers, suggesting a relative absence of crossing fibers. SZ patients also exhibited FA reductions in the Frontal fibers, which were underpinned by increased in Radial Diffusivity, consistent with myelin abnormalities. Significant correlations were observed between patients' degree of Reality Distortion and their FA and Radial Diffusivity, such that the most severely psychotic patients were the least abnormal in terms of their Frontal fiber diffusivity. Conclusions—The SZ patients exhibited a variety of diffusion abnormalities in the Corpus Callosum, which were related to the severity of their psychotic symptoms. To the extent that diffusion abnormalities influence axonal transmission velocities, these results provide support for those theories that emphasize neural timing abnormalities in the etiology of schizophrenia.