Paula E. Pelavin

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.

Human middle longitudinal fascicle: variations in patterns of anatomical connections.

Based on high-resolution diffusion tensor magnetic resonance imaging (DTI) tractographic analyses in 39 healthy adult subjects, we derived patterns of connections and measures of volume and biophysical parameters, such as fractional anisotropy (FA) for the human middle longitudinal fascicle (MdLF). Compared to previous studies, we found that the cortical connections of the MdLF in humans appear to go beyond the superior temporal (STG) and angular (AG) gyri, extending to the temporal pole (TP), superior parietal lobule (SPL), supramarginal gyrus, precuneus and the occipital lobe (including the cuneus and lateral occipital areas). Importantly, the MdLF showed a striking lateralized pattern with predominant connections between the TP, STG and AG on the left and TP, STG and SPL on the right hemisphere. In light of the results of the present study, and of the known functional role of the cortical areas interconnected by the MdLF, we suggested that this fiber pathway might be related to language, high order auditory association, visuospatial and attention functions.

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.

Fractional anisotropy and radial diffusivity: Diffusion measures of white matter abnormalities in the anterior limb of the internal capsule in schizophrenia

INTRODUCTION Higher cognitive functioning is mediated by frontal-subcortical cognitive and limbic feedback sub-loops. The thalamo-cortical projection through the anterior limb of the internal capsule (ALIC) serves as the final step in these feedback sub-loops. We evaluated abnormalities in the ALIC fiber tract in schizophrenia using both structural MRI and diffusion tensor imaging (DTI). METHODS 20 chronic schizophrenia patients and 22 male, normal controls group matched for handedness, age, and parental SES, underwent structural and DTI brain imaging on a 1.5 Tesla GE system. We manually measured ALIC volume normalized for intracranial contents (ICC) using structural brain images and then registered these high resolution structural brain scan derived ALIC label maps to DTI space allowing for the measurement in the ALIC of diffusion indices including, fractional anisotropy (FA) mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD). RESULTS We found in the ALIC of chronic schizophrenia subjects, compared with normal controls, bilaterally lower FA and bilaterally higher RD, but no differences in AD, MD, or relative volume. Cognitive correlations in schizophrenia patients showed, in particular, that higher left ALIC FA correlated positively with better verbal and nonverbal declarative/episodic memory performance. DISCUSSION Using a novel approach to assess both diffusion and volume measures in the ALIC in schizophrenia, we found abnormalities in measures of diffusion, but not volume, supporting their importance as sensitive indices of abnormalities in white matter fiber bundles in schizophrenia. Our findings also support the role of ALIC white matter tract FA abnormalities in declarative/episodic memory in schizophrenia.

Gray matter volume reduction in rostral middle frontal gyrus in patients with chronic schizophrenia

The dorsolateral prefrontal cortex (DLPFC) is a brain region that has figured prominently in studies of schizophrenia and working memory, yet the exact neuroanatomical localization of this brain region remains to be defined. DLPFC primarily involves the superior frontal gyrus and middle frontal gyrus (MFG). The latter, however is not a single neuroanatomical entity but instead is comprised of rostral (anterior, middle, and posterior) and caudal regions. In this study we used structural MRI to develop a method for parcellating MFG into its component parts. We focused on this region of DLPFC because it includes BA46, a region involved in working memory. We evaluated volume differences in MFG in 20 patients with chronic schizophrenia and 20 healthy controls. Mid-rostral MFG (MR-MFG) was delineated within the rostral MFG using anterior and posterior neuroanatomical landmarks derived from cytoarchitectonic definitions of BA46. Gray matter volumes of MR-MFG were then compared between groups, and a significant reduction in gray matter volume was observed (p<0.008), but not in other areas of MFG (i.e., anterior or posterior rostral MFG, or caudal regions of MFG). Our results demonstrate that volumetric alterations in MFG gray matter are localized exclusively to MR-MFG. 3D reconstructions of the cortical surface made it possible to follow MFG into its anterior part, where other approaches have failed. This method of parcellation offers a more precise way of measuring MR-MFG that will likely be important in further documentation of DLPFC anomalies in schizophrenia.

Anisotropy of transcallosal motor fibres indicates functional impairment in children with periventricular leukomalacia.

Aim  In children with bilateral spastic cerebral palsy (CP), periventricular leukomalacia (PVL) is commonly identified on magnetic resonance imaging. We characterized this white matter condition by examining callosal microstructure, interhemispheric inhibitory competence (IIC), and mirror movements.

Olfactory sulcal depth and olfactory bulb volume in patients with schizophrenia: an MRI study

The current report used structural magnetic resonance imaging (MRI) to objectively measure olfactory bulb volume and olfactory sulcal depth in patients diagnosed with chronic schizophrenia and healthy controls. Additional measures were obtained to assess olfactory function. The olfactory bulb and sulcus were manually traced on structural 3T MRIs for 25 right-handed male patients diagnosed with chronic schizophrenia and 25 matched male healthy controls. A sub-set of subjects received the University of Pennsylvania Smell Identification Test (UPSIT). Olfactory bulb volume was significantly decreased in patients with schizophrenia compared to healthy controls, as was their performance on the UPSIT. Additionally, a positive correlation was seen in patients between right bulb volume and UPSIT scores. Overall, our findings support earlier research studies showing morphometric and functional changes in the olfactory system in patients with schizophrenia.

Decreased axial diffusivity within language connections: A possible biomarker of schizophrenia risk

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.

Auditory Verbal Hallucinations and the Interhemispheric Auditory Pathway in Chronic Schizophrenia

Abstract 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 nine 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.

Cingulum bundle integrity associated with delusions of control in schizophrenia: Preliminary evidence from diffusion-tensor tractography

BACKGROUND Delusions of control are among the most distinctive and characteristic symptoms of schizophrenia. Several theories have been proposed that implicate aberrant communication between spatially disparate brain regions in the etiology of this symptom. Given that white matter fasciculi represent the anatomical infrastructure for long-distance communication in the brain, the present study investigated whether delusions of control were associated with structural abnormalities in four major white matter fasciculi. METHODS Ten schizophrenia patients with current delusions of control, 13 patients with no clinical history of delusions of control, and 12 healthy controls underwent a Diffusion-Tensor Imaging (DTI) scan. Deterministic tractography was used to extract the corpus callosum, superior longitudinal fasciculus, arcuate fasciculus, and cingulum bundle. The structural integrity of these four fasciculi was quantified with fractional anisotropy (FA) and compared between groups. RESULTS The patients with delusions of control exhibited significantly lower FA in all four fasciculi, relative to the healthy controls. Furthermore, the patients with delusions of control also exhibited significantly lower FA in the cingulum bundle relative to patients without a history of this symptom, and this difference remained significant when controlling for between-group differences in global SAPS score and medication dosage. CONCLUSIONS The results suggest that structural damage to the cingulum bundle may be involved in the etiology of delusions of control, possibly because of its role in connecting the action initiation areas of the premotor cortex with the cingulate gyrus.