Person:

Whitford, T

A fundamental tenet of the “disconnectivity” theories of schizophrenia is that the disorder is ultimately caused by abnormal communication between spatially disparate brain structures. Given that the white matter fasciculi represent the primary infrastructure for long distance communication in the brain, abnormalities in these fiber bundles have been implicated in the etiology of schizophrenia. Diffusion tensor imaging (DTI) is a magnetic resonance imaging (MRI) technique that enables the visualization of white matter macrostructure in vivo, and which has provided unprecedented insight into the existence and nature of white matter abnormalities in schizophrenia. The paper begins with an overview of DTI and more commonly used diffusion metrics and moves on to a brief review of the schizophrenia literature. The functional implications of white matter abnormalities are considered, particularly with respect to myelin's role in modulating the transmission velocity of neural discharges. The paper concludes with a speculative hypothesis about the relationship between gray and white matter abnormalities associated with schizophrenia.

Region of Interest (ROI) longitudinal studies have detected progressive gray matter (GM) volume reductions in patients with first-episode schizophrenia (FESZ). However, there are only a few longitudinal voxel-based morphometry (VBM) studies, and these have been limited in ability to detect relationships between volume loss and symptoms, perhaps because of methodologic issues. Nor have previous studies compared and validated VBM results with manual Region of Interest (ROI) analysis. In the present VBM study, high-dimensional warping and individualized baseline-rescan templates were used to evaluate longitudinal volume changes within subjects and compared with longitudinal manual ROI analysis on the same subjects. VBM evaluated thirty-three FESZ and thirty-six matched healthy control subjects (HC) at baseline (cross-sectionally) and longitudinally evaluated 21 FESZ and 23 HC after an average of 1.5 years from baseline scans. Correlation analyses detected the relationship between changes in regional GM volumes in FESZ and clinical symptoms derived from the Brief Psychiatric Rating Scale, as well as cognitive function as assessed by the Mini-Mental State Examination. At baseline, patients with FESZ had significantly smaller GM volume compared to HC in some regions including the left superior temporal gyrus (STG). On rescan after 1.5 years, patients showed significant GM volume reductions compared with HC in the left STG including Heschl's gyrus, and in widespread brain neocortical regions of frontal, parietal, and limbic regions including the cingulate gyrus. FESZ showed an association of positive symptoms and volume loss in temporal (especially STG) and frontal regions, and negative symptoms and volume loss in STG and frontal regions. Worse cognitive function was linked to widespread volume reduction, in frontal, temporal and parietal regions. The validation VBM analyses showed results similar to our previous ROI findings for STG and Cingulate Gyrus. We conclude FESZ show widespread, progressive GM volume reductions in many brain regions. Importantly, these reductions are directly associated with a worse clinical course. Congruence with ROI analyses suggests the promise of this longitudinal VBM methodology.

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.

The cingulum bundle (CB) connects gray matter structures of the limbic system and as such has been implicated in the etiology of schizophrenia. There is growing evidence to suggest that the CB is actually comprised of a conglomeration of discrete sub-connections. The present study aimed to use Diffusion Tensor tractography to subdivide the CB into its constituent sub-connections, and to investigate the structural integrity of these sub-connections in patients with schizophrenia and matched healthy controls. Diffusion Tensor Imaging scans were acquired from 24 patients diagnosed with chronic schizophrenia and 26 matched healthy controls. Deterministic tractography was used in conjunction with FreeSurfer-based regions-of-interest to subdivide the CB into 5 sub-connections (I1 to I5). The patients with schizophrenia exhibited subnormal levels of FA in two cingulum sub-connections, specifically the fibers connecting the rostral and caudal anterior cingulate gyrus (I1) and the fibers connecting the isthmus of the cingulate with the parahippocampal cortex (I4). Furthermore, while FA in the I1 sub-connection was correlated with the severity of patients' positive symptoms (specifically hallucinations and delusions), FA in the I4 sub-connection was correlated with the severity of patients' negative symptoms (specifically affective flattening and anhedonia/asociality). These results support the notion that the CB is a conglomeration of structurally interconnected yet functionally distinct sub-connections, of which only a subset are abnormal in patients with schizophrenia. Furthermore, while acknowledging the fact that the present study only investigated the CB, these results suggest that the positive and negative symptoms of schizophrenia may have distinct neurobiological underpinnings.

Background—Structural abnormalities in the callosal fibers connecting the heteromodal association areas of the prefrontal and temporoparietal cortices bilaterally have been suggested to play a role in the etiology of schizophrenia. Aims—To investigate for geometric abnormalities in these callosal fibers in schizophrenia patients using a novel Diffusion-Tensor Imaging (DTI) metric of fiber geometry named ShapeNormalized Dispersion (SHD). Methods—DTIs (3T, 51 gradient directions, 1.7 mm isotropic voxels) were acquired from 26 schizophrenia patients and 23 matched healthy controls. The prefrontal and temporoparietal fibers of the corpus callosum were extracted by means of whole-brain tractography, and their mean SHD calculated. Results—The schizophrenia patients exhibited subnormal levels of SHD in the prefrontal callosal fibers when controlling for between-group differences in Fractional Anisotropy. Reduced SHD could reflect either irregularly turbulent or inhomogeneously distributed fiber trajectories in the corpus callosum. Conclusions—The results suggest that the transcallosal misconnectivity believed to be associated with schizophrenia could arise from abnormalities in fiber geometry. These abnormalities in fiber geometry could potentially be underpinned by irregularities in the normative processes of neurodevelopment.

Although diffusion tensor imaging (DTI) studies have reported fractional anisotropy (FA) abnormalities in multiple white matter (WM) regions in schizophrenia, relationship between abnormal FA and negative symptoms has not been fully explored. DTI data were acquired from twenty-four patients with chronic schizophrenia and twenty-five healthy controls. Regional brain abnormalities were evaluated by conducting FA comparisons in the cerebral and each lobar WMs between groups. Focal abnormalities were also evaluated with a voxel-wise tract specific method. Associations between structural WM changes and negative symptoms were assessed using the Scale for the Assessment of Negative Symptoms (SANS). The patient group showed decreased FA in the cerebrum, especially in the frontal lobe, compared with controls. A voxel wise analysis showed FA decreases in almost all WM tracts in schizophrenia. Correlation analyses demonstrated negative relationships between FA in the cerebrum, particularly in the left hemisphere, and SANS global and global rating scores (Anhedonia-Asociality, Attention, and Affective-Flattening), and also associations between FA of left frontal lobe and SANS global score, Anhedonia Asociality, and Attention. This study demonstrates that patients with chronic schizophrenia evince widespread cerebral FA abnormalities and that these abnormalities, especially in the left hemisphere, are associated with negative symptoms.

It has been suggested that some cases of schizophrenia may be caused by an interaction between physiological risk factors and exposure to certain neurotropic infectious agents such as Herpes Simplex Virus type 1 (HSV1). This study investigated whether HSV1 exposure was associated with structural brain abnormalities in individuals who, because of genetic or other factors, were deemed at ultra high risk (UHR) of developing psychosis. Twenty-five UHR individuals with a history of HSV1 exposure (HSV1+), 33 UHR participants without a history of HSV1 exposure (HSV1-) and 19 healthy controls participated in the study. All participants underwent a T1- weighted structural MRI scan, and HSV1 exposure was determined based on the presence of IgG class antibodies in the blood serum. Voxel based morphometry revealed that the HSV1+ participants exhibited volumetric gray matter reductions in the cuneus, relative to both the HSV1- and healthy control participants (p<0.05, small volume corrected for familywise error). The results of the study suggest that a history of HSV1 infection is associated with volumetric gray matter reductions in individuals at ultra-high risk for developing psychosis, and are consistent with previous studies that have identified structural gray matter abnormalities in HSV1-infected patients with established schizophrenia.

Introduction—The Middle Longitudinal Fascicle (MdLF) is a long association fiber connecting the superior temporal gyrus (STG) and temporal pole with the angular gyrus through the white matter of the STG, structures which are known to play a crucial role in the pathology of schizophrenia. Functions of MdLF are thought to be related to language and thought processing in the left hemisphere, and with attention in the right hemisphere. While deficits of these functions are core clinical features of schizophrenia, no study has investigated structural abnormalities of MdLF in schizophrenia. Method—3T diffusion tensor data was acquired from twenty-six patients with schizophrenia and twenty-five healthy control subjects. Streamline tractography technique was used to extract MdLF. Fractional Anisotropy (FA) was compared between two groups. In addition, relationships were investigated between FA in the left MdLF and the Disorganized Thought Factor derived from the Positive and Negative Symptom Scale five factor model, and between FA in the right MdLF and the Poor Attention. Result—Relative to control subjects, the patients with chronic schizophrenia showed significant mean FA reductions in the bilateral MdLF. The FA of the left MdLF demonstrated a significant negative association with the Disorganized thoughts factor, and the FA of the right MdLF showed a significant negative relationship with the Poor Attention. Conclusions—This study provides new evidence for structural deficits in the bilateral MdLF in patients with chronic schizophrenia. It further demonstrates contribution of these abnormalities to the core clinical features - especially to disorganization and attention deficit.

Patients with schizophrenia (SZ) characteristically exhibit supranormal levels of cortical activity to self-induced sensory stimuli, ostensibly because of abnormalities in the neural signals (corollary discharges, CDs) normatively involved in suppressing the sensory consequences of self-generated actions. The nature of these abnormalities is unknown. This study investigated whether SZ patients experience CDs that are abnormally delayed in their arrival at the sensory cortex. Twentyone patients with SZ and 25 matched control participants underwent electroencephalography (EEG). Participants’ level of cortical suppression was calculated as the amplitude of the N1 component evoked by a button press-elicited auditory stimulus, subtracted from the N1 amplitude evoked by the same stimulus presented passively. In the three experimental conditions, the auditory stimulus was delivered 0, 50 or 100 ms subsequent to the button-press. Fifteen SZ patients and 17 healthy controls (HCs) also underwent diffusion tensor imaging (DTI), and the fractional anisotropy (FA) of participants’ arcuate fasciculus was used to predict their level of cortical suppression in the three conditions. While the SZ patients exhibited subnormal N1 suppression to undelayed, self-generated auditory stimuli, these deficits were eliminated by imposing a 50-ms, but not a 100-ms, delay between the button-press and the evoked stimulus. Furthermore, the extent to which the 50-ms delay normalized a patient’s level of N1 suppression was linearly related to the FA of their arcuate fasciculus. These data suggest that SZ patients experience temporally delayed CDs to self-generated auditory stimuli, putatively because of structural damage to the white-matter (WM) fasciculus connecting the sites of discharge initiation and destination.