Increased Gray Matter Diffusion Anisotropy in Patients with Persistent Post-Concussive Symptoms following Mild Traumatic Brain Injury

A significant percentage of individuals diagnosed with mild traumatic brain injury (mTBI) experience persistent post-concussive symptoms (PPCS). Little is known about the pathology of these symptoms and there is often no radiological evidence based on conventional clinical imaging. We aimed to utilize methods to evaluate microstructural tissue changes and to determine whether or not a link with PPCS was present. A novel analysis method was developed to identify abnormalities in high-resolution diffusion tensor imaging (DTI) when the location of brain injury is heterogeneous across subjects. A normative atlas with 145 brain regions of interest (ROI) was built from 47 normal controls. Comparing each subject’s diffusion measures to the atlas generated subject-specific profiles of injury. Abnormal ROIs were defined by absolute z-score values above a given threshold. The method was applied to 11 PPCS patients following mTBI and 11 matched controls. Z-score information for each individual was summarized with two location-independent measures: “load” (number of abnormal regions) and “severity” (largest absolute z-score). Group differences were then computed using Wilcoxon rank sum tests. Results showed statistically significantly higher load (p = 0.018) and severity (p = 0.006) for fractional anisotropy (FA) in patients compared with controls. Subject-specific profiles of injury evinced abnormally high FA regions in gray matter (30 occurrences over 11 patients), and abnormally low FA in white matter (3 occurrences over 11 subjects). Subject-specific profiles provide important information regarding the pathology associated with PPCS. Increased gray matter (GM) anisotropy is a novel in-vivo finding, which is consistent with an animal model of brain trauma that associates increased FA in GM with pathologies such as gliosis. In addition, the individualized analysis shows promise for enhancing the clinical care of PPCS patients as it could play a role in the diagnosis of brain injury not revealed using conventional imaging

Auditory verbal hallucinations and the interhemispheric auditory pathway in chronic schizophrenia

Objectives—The interhemispheric auditory pathway has been shown to play a crucial role in the processing of acoustic stimuli, and alterations of structural and functional connectivity between bilateral auditory areas are likely relevant to the pathogenesis of auditory verbal hallucinations (AVHs). The aim of this study was to examine this pathway in patients with chronic schizophrenia regarding their lifetime history of AVHs. Methods—DTI scans were acquired from 33 healthy controls (HC), 24 schizophrenia patients with a history of AVHs (LT-AVH) and 9 schizophrenia patients without any lifetime hallucinations (N-LT-AVH). The interhemispheric auditory fibre bundles were extracted using streamline tractography. Subsequently, diffusivity indices, namely Fractional Anisotropy (FA), Trace, Mode, Axial and Radial Diffusivity, were calculated.Results—FA was decreased over the entire pathway in LT-AVH compared with N-LT-AVH. Moreover, LT-AVH displayed decreased FA and Mode as well as increased Radial Diffusivity in the midsagittal section of the fibre tract. Conclusions—These findings indicate complex microstructural changes in the interhemispheric auditory pathway of schizophrenia patients with a history of AVHs. Alterations appear to be absent in patients who have never hallucinated

Correlations between neuropsychological test and FA severity for PPCS patients.

*<p>Scores with significance level p<0.05 are in a bold font.</p

Correlating FA Severity with digit symbol and duration since injury.

<p>Correlation analysis of the Digit Symbol score and FA Severity (left) shows a negative relationship between the two measures indicating poorer performance on the Digit Symbol test associated with more abnormal FA. Duration since Injury and FA Severity (right) were also negatively correlated suggesting FA abnormalities become fewer as time progresses.</p

Raw z-scores for all subjects.

<p>Scatter plots of the raw z scores for FA for all PPCS patients (top) and their controls (bottom). An ‘x’ represents ROIs that are significantly different than the normative atlas (higher or lower than the Bonferroni corrected z-score threshold of ±3.58). Non-significant regions are represented as dots. When FA is abnormal in the GM of PPCS patients it is always higher than the normative atlas. When it is abnormal in the WM of PPCS patients it is always lower than the normal range. There were many more abnormalities detected in GM than in WM. There were only 2 abnormal regions across all of the NC population.</p

Demographic characteristic of study subjects.

<p>Demographic characteristic of study subjects.</p

Subject-specific abnormality map.

<p>A subject-specific abnormality map of an individual PPCS subject (TB11) shows ROIs with abnormal FA values compared with the normative atlas. These abnormalities were not detected in clinical CT or MRI scans, nor were they detected using a conventional group comparison. Coronal slices spanning the entire brain are presented (Posterior–top left to Anterior–bottom right). Abnormalities are highlighted in color (yellow to red, for lower to higher z-scores) overlaid on top of an FA map of this subject. This subject had the following ROIs highlighted as abnormal: Right Putamen (z = 4.62), Left Lateral Orbitofrontal Cortex, (z = 4.22), Left Superior Temporal Gyrus (z = 4.22), Left Amygdala (z = 3.81), Left Pericalcarine Cortex (z = 3.74), Right Supramarginal Gyrus, FA (z = 3.67) and Left Parahippocampal gyrus (z = 3.60).</p

Description of Individual PPCS subjects.

*<p>MVA = Motor Vehicle Accident; In the FA abnormality summary column z-score are given in parenthesis, the highest severity score is in a bold font, ^t - is affixed to z-scores who did not reach significance.</p

Axial diffusivity (AD) vs. Radial diffusivity (RD) in GM ROIs with abnormally high FA.

<p>There are two patterns that can explain the increased FA evinced in GM of PPCS patients. In Cluster 1 (red) AD is abnormally high and RD is normal, consistent with an animal model of gliosis. In Cluster 2 (blue) both AD and RD are abnormally low, a pattern that was not reported in previous GM studies and which remains to be explained.</p