Thomas J. Whitford

Brain maturation in adolescence: concurrent changes in neuroanatomy and neurophysiology.

Adolescence to early adulthood is a period of dramatic transformation in the healthy human brain. However, the relationship between the concurrent structural and functional changes remains unclear. We investigated the impact of age on both neuroanatomy and neurophysiology in the same healthy subjects (n = 138) aged 10 to 30 years using magnetic resonance imaging (MRI) and resting electroencephalography (EEG) recordings. MRI data were segmented into gray and white matter images and parcellated into large‐scale regions of interest. Absolute EEG power was quantified for each lobe for the slow‐wave, alpha and beta frequency bands. Gray matter volume was found to decrease across the age bracket in the frontal and parietal cortices, with the greatest change occurring in adolescence. EEG activity, particularly in the slow‐wave band, showed a similar curvilinear decline to gray matter volume in corresponding cortical regions. An inverse pattern of curvilinearly increasing white matter volume was observed in the parietal lobe. We suggest that the reduction in gray matter primarily reflects a reduction of neuropil, and that the corresponding elimination of active synapses is responsible for the observed reduction in EEG power. Hum Brain Mapp, 2007.

Diagnosis-related regional gray matter loss over two years in first episode schizophrenia and bipolar disorder.

BACKGROUND We examined gray- and white-matter brain volumes in first episode psychosis (FEP) at initial presentation and at two-year follow-up. We predicted that FEP subjects would show longitudinal reductions in fronto-temporal gray- and white-matter volumes compared with controls. Furthermore, we expected groups to be differentiated by diagnosis-related reductions. METHODS Twenty-five schizophrenia and 8 bipolar disorder FEP patients underwent a structural MRI scan at first presentation and 2 years later. Matched healthy subjects (n = 22) underwent a single identical scan. RESULTS At initial presentation FEP subjects had significantly less gray- and white-matter than healthy subjects. Diagnostic dissociations were revealed both at first presentation and at follow-up. In schizophrenia patients, gray-matter deficits were observed in lateral and medial frontal regions and in bilateral posterior temporal lobe regions, with additional extensive losses over time in lateral fronto-temporal regions and left anterior cingulate gyrus. By contrast, gray matter deficit in bipolar patients was localized to bilateral inferior temporal gyri with additional loss over time observed only in the anterior cingulate cortex. CONCLUSIONS The results are consistent with a dual process model of psychosis, in which the diagnosis-related gray matter loss is determined by neurodevelopmental gray-matter volumetric differences which predate symptom onset, and diagnosis-related neurodegenerative gray-matter loss over time.

Functional disconnections in the direct and indirect amygdala pathways for fear processing in schizophrenia

BACKGROUND Schizophrenia patients show reduced neural activity, relative to controls, in the amygdala and its projection to the medial prefrontal cortex (MPFC) in response to fear perception. In this study we tested the hypothesis that schizophrenia is characterized by abnormal functional connectivity in the amygdala network underlying fear perception. METHODS Functional MRI images were acquired from 14 schizophrenia patients and 14 matched healthy control subjects during an emotion perception task, in which fearful and neutral facial expression stimuli were presented pseudorandomly under nonconscious (using masking) and conscious conditions. Both subtraction and functional connectivity analyses were undertaken using a region of interest approach. RESULTS In response to fearful facial expressions, schizophrenia patients displayed reduced amygdala activity, compared to controls, in both the conscious and nonconscious conditions. The amygdala displayed a reversal of the normal pattern of connectivity with the brainstem, visual cortex, and also with the dorsal and ventral divisions of the MPFC in the schizophrenia patients. CONCLUSIONS The presence of functional disconnections in amygdala pathways suggests that schizophrenia patients have a failure in coordinating their automatic orienting to salient signals and the associated prefrontal monitoring of these signals.

Longitudinal Loss of Gray Matter Volume in Patients with First- Episode Schizophrenia: DARTEL Automated Analysis and ROI Validation

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 Heschls 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.

Schizophrenia, Myelination, and Delayed Corollary Discharges: A Hypothesis

Any etiological theory of schizophrenia must account for at least 3 distinctive features of the disorder, namely its excessive dopamine neurotransmission, its frequent periadolescent onset, and its bizarre, pathognomonic symptoms. In this article, we theorize that each of these features could arise from a single underlying cause--namely abnormal myelination of late-developing frontal white matter fasciculi. Specifically, we suggest that abnormalities in frontal myelination result in conduction delays in the efference copies initiated by willed actions. These conduction delays cause the resulting corollary discharges to be generated too late to suppress the sensory consequences of the willed actions. The resulting ambiguity as to the origins of these actions represents a phenomenologically and neurophysiologically significant prediction error. On a phenomenological level, the perception of salience in a self-generated action leads to confusion as to its origins and, consequently, passivity experiences and auditory hallucinations. On a neurophysiological level, this prediction error leads to the increased activity of dopaminergic neurons in the midbrain. This dopaminergic activity causes previously insignificant events to be perceived as salient, which exacerbates the budding hallucinations and passivity experiences and triggers additional first-rank symptoms such as delusions of reference. The article concludes with a discussion of the implications of the theory and some testable predictions which may form a worthwhile basis for future research.

Diffusion tensor imaging of the corpus callosum: a cross-sectional study across the lifespan

Previous studies have demonstrated strong developmental trends of white matter using in vivo neuroimaging. However, few studies have examined white matter using diffusion tensor imaging across the lifespan. In the present study we examined fractional anisotropy and volume in the corpus callosum in four groups (children, adolescents, young adults, and elderly). Results revealed a curvilinear relationship in the analysis of the fractional anisotropy values for these four groups, with fractional anisotropy values increasing in childhood and adolescence, reaching their peak in young adulthood, followed by a non‐significant decline in the elderly. Volumetric analysis of corpus callosum regions revealed a similar pattern, with an increase in volume from childhood and adolescence through young adulthood, and a non‐significant decrease in volume in the elderly group. These results define the microstructural development of the white matter across the lifespan. Future studies are required to examine the neurobehavioral correlates of these neuroimaging indices.

Duration of posttraumatic stress disorder predicts hippocampal grey matter loss

To examine the impact of environmental stress on grey matter volume in posttraumatic stress disorder (PTSD), we investigated the relationship between duration of PTSD and grey matter volume of hippocampus and anterior cingulate cortex. Twenty-one participants with PTSD and 17 trauma-exposed controls, matched for age and sex and with no history of substance dependence, underwent a T1-weighted structural MRI scan and voxel-based morphometry was employed. After controlling for age, depression and whole-brain volume, analysis of covariance revealed significant reductions in hippocampus and rostral anterior cingulate cortex in PTSD, and there was a significant negative correlation between right hippocampal volume and PTSD duration. This pattern suggests that prolonged PTSD may have cumulative adverse effects on hippocampal volume, highlighting the potential role of genetic–environmental interactions.

Decreased nervonic acid levels in erythrocyte membranes predict psychosis in help-seeking ultra-high-risk individuals.

Decreased nervonic acid levels in erythrocyte membranes predict psychosis in help-seeking ultra-high-risk individuals

Hearing voices: a role of interhemispheric auditory connectivity?

Abstract Objectives. Auditory verbal hallucinations (AVH) are among the most common symptoms in schizophrenia. Earlier studies suggest changes in the structural connectivity of auditory areas involved in the pathophysiology of auditory hallucinations. Combining diffusion tensor imaging (DTI) and fibre tractography provides a unique opportunity to visualize and quantify entire fibre bundles. Methods. Fibre tracts connecting homotopic auditory areas via the corpus callosum were identified with DTI in ten first episode paranoid schizophrenia patients and ten healthy controls. Regions of interest were drawn manually, to guide tractography, and fractional anisotropy (FA) – a measure of fibre integrity – was calculated and averaged over the entire tract for each subject. Results. There was no difference in the FA of the interhemispheric auditory fibres between schizophrenic patients and healthy controls. However, the subgroup of patients hearing conversing voices showed increased FA relative to patients without these symptoms (P = 0.047) and trendwise increased FA relative to healthy controls (P = 0.066). In addition, a trendwise correlation between FA values and AVH symptoms (P = 0.089) was found. Conclusions. Our findings suggest that in addition to local deficits in the left auditory cortex and disturbed fronto-temporal connectivity, the interhemispheric auditory pathway might be involved in the pathogenesis of AVH.

Understanding aberrant white matter development in schizophrenia: an avenue for therapy?

Although historically gray matter changes have been the focus of neuropathological and neuroradiological studies in schizophrenia, in recent years an increasing body of research has implicated white matter structures and its constituent components (axons, their myelin sheaths and supporting oligodendrocytes). This article summarizes this body of literature, examining neuropathological, neurogenetic and neuroradiological evidence for white matter pathology in schizophrenia. We then look at the possible role that antipsychotic medication may play in these studies, examining both its role as a potential confounder in studies examining neuronal density and brain volume, but also the possible role that these medications may play in promoting myelination through their effects on oligodendrocytes. Finally, the role of potential novel therapies is discussed.