Sumit N. Niogi

Extent of Microstructural White Matter Injury in Postconcussive Syndrome Correlates with Impaired Cognitive Reaction Time: A 3T Diffusion Tensor Imaging Study of Mild Traumatic Brain Injury

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) may be a useful index of microstructural changes implicated in diffuse axonal injury (DAI) linked to persistent postconcussive symptoms, especially in mild traumatic brain injury (TBI), for which conventional MR imaging techniques may lack sensitivity. We hypothesized that for mild TBI, DTI measures of DAI would correlate with impairments in reaction time, whereas the number of focal lesions on conventional 3T MR imaging would not. MATERIALS AND METHODS: Thirty-four adult patients with mild TBI with persistent symptoms were assessed for DAI by quantifying traumatic microhemorrhages detected on a conventional set of T2*-weighted gradient-echo images and by DTI measures of fractional anisotropy (FA) within a set of a priori regions of interest. FA values 2.5 SDs below the region average, based on a group of 26 healthy control adults, were coded as exhibiting DAI. RESULTS: DTI measures revealed several predominant regions of damage including the anterior corona radiata (41% of the patients), uncinate fasciculus (29%), genu of the corpus callosum (21%), inferior longitudinal fasciculus (21%), and cingulum bundle (18%). The number of damaged white matter structures as quantified by DTI was significantly correlated with mean reaction time on a simple cognitive task (r = 0.49, P = .012). In contradistinction, the number of traumatic microhemorrhages was uncorrelated with reaction time (r = −0.08, P = .71). CONCLUSION: Microstructural white matter lesions detected by DTI correlate with persistent cognitive deficits in mild TBI, even in populations in which conventional measures do not. DTI measures may thus contribute additional diagnostic information related to DAI.

Diffusion tensor imaging of mild traumatic brain injury.

Mild traumatic brain injury (mTBI) remains a challenge to accurately assess with conventional neuroimaging. Recent research holds out the promise that diffusion tensor imaging (DTI) can be used to predict recovery in mTBI patients. Unlike computed tomography or conventional magnetic resonance imaging, DTI is sensitive to microstructural axonal injury, the neuropathology that is thought to be most responsible for the persistent cognitive and behavioral impairments that often occur after mTBI. Through the use of newer DTI analysis techniques such as automated region of interest analysis, tract-based voxel-wise analysis, and quantitative tractography, researchers have shown that frontal and temporal association white matter pathways are most frequently damaged in mTBI and that the microstructural integrity of these tracts correlates with behavioral and cognitive measures. Future longitudinal DTI studies are needed to elucidate how symptoms and the microstructural pathology evolve over time. Moving forward, large-scale investigations will ascertain whether DTI can serve as a predictive imaging biomarker for long-term neurocognitive deficits after mTBI that would be of value for triaging patients to clinical trials of experimental cognitive enhancement therapies and rehabilitation methods, as well as for monitoring their response to these interventions.

Effective gene therapy for an inherited CNS disease in a large animal model.

Genetic diseases affecting the brain typically have widespread lesions that require global correction. Lysosomal storage diseases are good candidates for central nervous system gene therapy, because active enzyme from genetically corrected cells can be secreted and taken up by surrounding diseased cells, and only small amounts of enzyme (<5% of normal) are required to reverse storage lesions. Injection of gene transfer vectors into multiple sites in the mouse brain has been shown to mediate widespread reversal of storage lesions in several disease models. To study a brain closer in size to the human brain, we evaluated the extent of storage correction mediated by a limited number of adeno‐associated virus vector injections in the cat model of human α‐mannosidosis. The treated cats showed remarkable improvements in clinical neurological signs and in brain myelination assessed by quantitative magnetic resonance imaging. Postmortem examination showed that storage lesions were greatly reduced throughout the brain, even though gene transfer was limited to the areas surrounding the injection tracks. The data demonstrate that widespread improvement of neuropathology in a large mammalian brain can be achieved using multiple injection sites during one operation and suggest that this could be an effective treatment for the central nervous system component of human lysosomal enzyme deficiencies. Ann Neurol 2005;57:355–364

Visual tracking synchronization as a metric for concussion screening

Our goal was to determine whether performance variability during predictive visual tracking can provide a screening measure for mild traumatic brain injury (mTBI). Seventeen subjects with chronic postconcussive syndrome and 9 healthy control subjects were included in this study. Eye movements were recorded with video-oculography as the subject visually tracked a target that moved through a circular trajectory. We compared the variability of gaze positional errors relative to the target with the microstructural integrity of white matter tracts as measured by the fractional anisotropy (FA) parameter of diffusion tensor imaging. Gaze error variability was significantly correlated with the mean FA values of the right anterior corona radiata (ACR) and the left superior cerebellar peduncle, tracts that support spatial processing and sustenance of attention, and the genu of the corpus callosum. Because the ACR and the genu are among the most frequently damaged white matter tracts in mTBI, the correlations imply that gaze error variability during visual tracking may provide a useful screening tool for mTBI. Gaze error variability was also significantly correlated with attention and working memory measures in neurocognitive testing; thus, measurement of visual tracking performance is promising as a fast and practical screening tool for mTBI.

Individual Differences in Distinct Components of Attention are Linked to Anatomical Variations in Distinct White Matter Tracts.

Inter-subject variations in white matter tract properties are known to correlate with individual differences in performance in cognitive domains such as attention. The specificity of such linkages, however, is largely unexplored at the level of specific component operations of attention associated with distinct anatomical networks. This study examines individual performance variation within three functional components of attention – alerting, orienting, and conflict processing – identified by the Attention Network Task (ANT), and relates each to inter-subject variation in a distinct set of white matter tract regions. Diffusion tensor imaging data collected at 3T was used to calculate average fractional anisotropy within a set of individualized a priori defined regions of interest using the Reproducible Objective Quantification Scheme (ROQS) (Niogi and McCandliss, 2006; Niogi et al., 2007). Results demonstrate three functionally distinct components of attention that each correlate distinctly with three white matter tract regions. Structure–function correlations were found between alerting and the anterior limb of the internal capsule, orienting and the splenium of the corpus callosum, and conflict and the anterior corona radiata. A multiple regression/dissociation analysis demonstrated a triple dissociation between these three structure-function relationships that provided evidence of three anatomically and functionally separable networks. These results extend previous findings from functional imaging and lesion studies that suggest these three components of attention are subserved by dissociable networks, and suggest that variations in white matter tract microstructure may modulate the efficiency of these cognitive processes in highly specific ways.

White matter microstructures underlying mathematical abilities in children

The role of gray matter function and structure in mathematical cognition has been well researched. Comparatively little is known about white matter microstructures associated with mathematical abilities. Diffusion tensor imaging data from 13 children (7–9 years) and two measures of their mathematical competence were collected. Relationships between childrens mathematical competence and fractional anisotropy were found in two left hemisphere white matter regions. Although the superior corona radiata was found to be associated with both numerical operations and mathematical reasoning, the inferior longitudinal fasciculus was correlated with numerical operations specifically. These findings suggest a role for microstructure in left white matter tracts for the development of mathematical skills. Moreover, the findings point to the involvement of different white matter tracts for numerical operations and mathematical reasoning.

Diffusion tensor imaging segmentation of white matter structures using a Reproducible Objective Quantification Scheme (ROQS).

Reproducible Objective Quantification Scheme (ROQS) is a novel method for regional white matter measurements of diffusion tensor imaging (DTI) parameters that overcomes the limitations of previous approaches for analyzing large cohorts of subjects reliably. ROQS is a semi-automated technique that exploits the fiber orientation information from the diffusion tensor in conjunction with a binary masking and chain-linking algorithm to segment anatomically distinct white matter tracts for subsequent quantitative analysis of DTI parameters such as fractional anisotropy and apparent diffusion coefficient. When applied to 3-T whole-brain DTI of normal adult volunteers, ROQS is shown to segment the corpus callosum much faster than manual region of interest (ROI) delineation, and with better reproducibility and accuracy.

Concussion in Sports

Context: Recently, concussion has become a topic of much discussion within sports. The goal of this review is to provide an overview of the literature concerning the definition of concussion, management of initial injury, return to play, and future health risks. Evidence Acquisition: This article reviews the most recent findings on recognizing and managing sports-related concussion, which has become a significant health risk. We reviewed articles from the literature discussing concussion and its effects. Results: Though concussion patients typically have negative head imaging, imaging is warranted in those with severe mechanism, significant loss of consciousness, focal neurologic deficit, or worsening symptoms. The existence of “second-impact syndrome,” whereby a first minor head injury predisposes an athlete to later catastrophic injury, remains controversial; however, it is clear that concussion has significant effects on a patient and should be considered carefully in return-to-play decisions. Conclusions: A comprehensive understanding of concussion and its related risks is important in making return-to-play decisions as well as health care and league policy.

Longitudinal Resting State Functional Connectivity Predicts Clinical Outcome in Mild Traumatic Brain Injury

Mild traumatic brain injury (mTBI) affects about 42 million people worldwide. It is often associated with headache, cognitive deficits, and balance difficulties but rarely shows any abnormalities on conventional computed tomography (CT) or magnetic resonance imaging (MRI). Although in most mTBI patients the symptoms resolve within 3 months, 10-15% of patients continue to exhibit symptoms beyond a year. Also, it is known that there exists a vulnerable period post-injury, when a second injury may exacerbate clinical prognosis. Identifying this vulnerable period may be critical for patient outcome, but very little is known about the neural underpinnings of mTBI and its recovery. In this work, we used advanced functional neuroimaging to study longitudinal changes in functional organization of the brain during the 3-month recovery period post-mTBI. Fractional amplitude of low frequency fluctuations (fALFF) measured from resting state functional MRI (rs-fMRI) was found to be associated with symptom severity score (SSS, r = -0.28, p = 0.002). Decreased fALFF was observed in specific functional networks for patients with higher SSS, and fALFF returned to higher values when the patient recovered (lower SSS). In addition, functional connectivity of the same networks was found to be associated with concurrent SSS, and connectivity immediately after injury (<10 days) was capable of predicting SSS at a later time-point (3 weeks to 3 months, p < 0.05). Specific networks including motor, default-mode, and visual networks were found to be associated with SSS (p < 0.001), and connectivity between these networks predicted 3-month clinical outcome (motor and visual: p < 0.001, default-mode: p < 0.006). Our results suggest that functional connectivity in these networks comprise potential biomarkers for predicting mTBI recovery profiles and clinical outcome.

Clinical Findings in a Multicenter MRI Study of Mild TBI

Background: Uncertainty continues to surround mild traumatic brain injury (mTBI) diagnosis, symptoms, prognosis, and outcome due in part to a lack of objective biomarkers of injury and recovery. As mTBI gains recognition as a serious public health epidemic, there is need to identify risk factors, diagnostic tools, and imaging biomarkers to help guide diagnosis and management. Methods: One hundred and eleven patients (15–50 years old) were enrolled acutely after mTBI and followed with up to four standardized serial assessments over 3 months. Each encounter included a clinical exam, neuropsychological assessment, and magnetic resonance imaging (MRI). Chi-square and linear mixed models were used to assess changes over time and determine potential biomarkers of mTBI severity and outcome. Results: The symptoms most frequently endorsed after mTBI were headache (91%), not feeling right (89%), fatigue (86%), and feeling slowed down (84%). Of the 104 mTBI patients with a processed MRI scan, 28 (27%) subjects had white matter changes which were deemed unrelated to age, and 26 of these findings were deemed unrelated to acute trauma. Of the neuropsychological assessments tested, 5- and 6-Digit Backward Recall, the modified Balance Error Scoring System (BESS), and Immediate 5-Word Recall significantly improved longitudinally in mTBI subjects and differentiated between mTBI subjects and controls. Female sex was found to increase symptom severity scores (SSS) at every time point. Age ≥ 25 years was correlated with increased SSS. Subjects aged ≥ 25 also did not improve longitudinally on 5-Digit Backward Recall, Immediate 5-Word Recall, or Single-Leg Stance of the BESS, whereas subjects < 25 years improved significantly. Patients who reported personal history of depression, anxiety, or other psychiatric disorder had higher SSS at each time point. Conclusions: The results of this study show that 5- and 6-Digit Backward Recall, the modified BESS, and Immediate 5-Word Recall should be considered useful in demonstrating cognitive and vestibular improvement during the mTBI recovery process. Clinicians should take female sex, older age, and history of psychiatric disorder into account when managing mTBI patients. Further study is necessary to determine the true prevalence of white matter changes in people with mTBI.