Kathirkamanthan Shanmuganathan

Default Mode Network Interference in Mild Traumatic Brain Injury – A Pilot Resting State Study

In this study we investigated the functional connectivity in 23 Mild TBI (mTBI) patients with and without memory complaints using resting state fMRI in the sub-acute stage of injury as well as a group of control participants. Results indicate that mTBI patients with memory complaints performed significantly worse than patients without memory complaints on tests assessing memory from the Automated Neuropsychological Assessment Metrics (ANAM). Altered functional connectivity was observed between the three groups between the default mode network (DMN) and the nodes of the task positive network (TPN). Altered functional connectivity was also observed between both the TPN and DMN and nodes associated with the Salience Network (SN). Following mTBI there is a reduction in anti-correlated networks for both those with and without memory complaints for the DMN, but only a reduction in the anti-correlated network in mTBI patients with memory complaints for the TPN. Furthermore, an increased functional connectivity between the TPN and SN appears to be associated with reduced performance on memory assessments. Overall the results suggest that a disruption in the segregation of the DMN and the TPN at rest may be mediated through both a direct pathway of increased FC between various nodes of the TPN and DMN, and through an indirect pathway that links the TPN and DMN through nodes of the SN. This disruption between networks may cause a detrimental impact on memory functioning following mTBI, supporting the Default Mode Interference Hypothesis in the context of mTBI related memory deficits.

A longitudinal evaluation of diffusion kurtosis imaging in patients with mild traumatic brain injury

Abstract Primary objective: To investigate longitudinal diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) changes in white and grey matter in patients with mild traumatic brain injury (mTBI). Research design: A prospective case-control study. Methods and procedures: DKI data was obtained from 24 patients with mTBI along with cognitive assessments within 10 days, 1 month and 6 months post-injury and compared with age-matched control (n = 24). Fractional anisotropy (FA), mean diffusivity (MD), radial diffusion (λr), mean kurtosis (MK) and radial kurtosis (Kr) were extracted from the thalamus, internal capsule and corpus callosum. Main outcomes and results: Results demonstrate reduced Kr and MK in the anterior internal capsule in patients with mTBI across the three visits, and reduced MK in the posterior internal capsule during the 10 day time point. Correlations were observed between the change in MK or Kr between 1–6 months and the improvements in cognition between the 1 and 6 month visits in the thalamus, internal capsule and corpus callosum. Conclusions: These data demonstrate that DKI may be sensitive in tracking pathophysiological changes associated with mTBI and may provide additional information to conventional DTI parameters in evaluating longitudinal changes following TBI.

Prognostic Value of Diffusion Tensor Imaging Parameters in Severe Traumatic Brain Injury

Diffusion tensor imaging (DTI) has recently emerged as a useful tool for assessing traumatic brain injury (TBI). In this study, the prognostic value of the relationship between DTI measures and the clinical status of severe TBI patients, both at the time of magnetic resonance imaging (MRI), and their discharge to acute TBI rehabilitation, was assessed. Patients (n=59) admitted to the trauma center with severe closed head injuries were retrospectively evaluated after approval from the institutions institutional review board, to determine the prognostic value of DTI measures. The relationship of DTI measures, including apparent diffusion coefficient (ADC), fractional anisotropy (FA), axial (λ‖) and radial diffusivity (λ⊥) from the whole brain white matter, internal capsule, genu, splenium, and body of the corpus callosum, were compared with neurological status at MRI and at discharge to acute TBI rehabilitation. Whole brain white matter averages of ADC, λ‖, and λ⊥, and their coefficient of variation (CV) were significantly correlated with the Glasgow Coma Scale (GCS) score on the day of MRI. The average λ‖ was significantly correlated with GCS scores on the day of MRI in all measured brain regions. Outcomes were associated with whole brain white matter averages of ADC and λ‖, and the CVs of FA, ADC, λ‖, and λ⊥; and the averages and CVs of FA and λ‖ in all corpus callosum regions. The inclusion of regional and global DTI measures improved the accuracy of prognostic models, when adjusted for admission GCS score and age (p<0.05). Whole brain white matter and regional DTI measures are sensitive markers of TBI, and correlate with neurological status both at MRI and discharge to rehabilitation. The addition of DTI measures adjusted for age, gender, and admission GCS score significantly improved prognostic models.

Longitudinal and prognostic evaluation of mild traumatic brain injury: A 1H-magnetic resonance spectroscopy study.

In the majority of patients with mild traumatic brain injury (mTBI), brain tissue impairment is undetectable by computed tomography and/or structural magnetic resonance imaging. Even in confirmed cases of head injury, conventional neuroimaging methods lack sensitivity in predicting neuropsychological outcomes of patients. The objectives of this study were to (1) cross-sectionally determine deviations in the neurometabolic profile of patients with mTBI from healthy controls at different stages of mTBI using tightly controlled examination windows, and (2) determine associations between acute neurometabolic markers of mTBI and chronic neurocognitive performance. Patients were examined at the early subacute (n=43; 5.44 ± 3.15 days post-injury (DPI)), late subacute (n=33; 37.00 ± 12.26 DPI) and chronic (n=27; 195.30 ± 19.60 DPI) stages of mTBI. Twenty-one neurologically intact subjects were used as controls. Proton magnetic resonance spectroscopy imaging ((1)H-MRSI) was used to obtain metabolic measurements from different brain regions. The Automated Neuropsychological Assessment Metrics (ANAM) was used for cognitive evaluation of patients at the chronic stage of mTBI. Measurements in the thalamus and centrum semiovale (CSV) emerged as the most indicative of injury and were used to predict neurocognitive outcome. The major findings of this study are (1) decreases in Cho/Cre (choline-to-creatine ratio) measured in the thalamus (p=0.042) and CSV (p=0.017) at the late subacute stage of mTBI; (2) positive associations of early subacute Cre measurements in the CSV with chronic ANAM scores measuring performance in delayed (r=0.497, p=0.019) and immediate (r=0.391, p=0.072) code substitution. These findings show that metabolic measurements in the thalamus and CSV can potentially serve as diagnostic and prognostic markers of mTBI.

Disruptions in Resting State Functional Connectivity and Cerebral Blood Flow in Mild Traumatic Brain Injury Patients

Mild traumatic brain injury (mTBI) is often occult to conventional imaging techniques. However, there is growing evidence that mTBI patients who lack evidence of structural intracranial injury may develop post-concussive syndrome (PCS). We investigated longitudinal alterations in resting state functional connectivity (rs-FC) in brain networks in a population of 28 patients compared to 28 matched control participants. Rs-FC and cerebral blood flow (CBF) within the nodes of the Default Mode Network (DMN) and Task Positive Network (TPN) were assessed at three time points including acute, sub-acute, and chronic stages following mTBI. Participants received the Automated Neuropsychological Assessment Metrics (ANAM) to assess cognitive performance. Main findings indicate that despite normalized cognitive performance, chronic mTBI patients demonstrate increased rs-FC between the DMN and regions associated with the salience network (SN) and TPN compared to the control populations, as well as reduced strength of rs-FC within the DMN at the acute stage of injury. In addition, chronic mTBI patients demonstrate an imbalance in the ratio of CBF between nodes of the DMN and TPN. Furthermore, preliminary exploratory analysis suggests that compared to those without chronic PCS, patients with chronic PCS reveal an imbalance in the ratio of CBF between the DMN nodes and TPN nodes across multiple stages of recovery. Findings suggest that the altered network perfusion with the associated changes in rs-FC may be a possible predictor of which mTBI patients will develop chronic PCS.

Intramedullary lesion expansion on magnetic resonance imaging in patients with motor complete cervical spinal cord injury

OBJECT The authors performed a study to determine if lesion expansion occurs in humans during the early hours after spinal cord injury (SCI), as has been established in rodent models of SCI, and to identify factors that might predict lesion expansion. METHODS The authors studied 42 patients with acute cervical SCI and admission American Spinal Injury Association Impairment Scale Grades A (35 patients) and B (7 patients) in whom 2 consecutive MRI scans were obtained 3-134 hours after trauma. They recorded demographic data, clinical information, Injury Severity Score (ISS), admission MRI-documented spinal canal and cord characteristics, and management strategies. RESULTS The characteristics of the cohort were as follows: male/female ratio 37:5; mean age, 34.6 years; and cause of injury, motor vehicle collision, falls, and sport injuries in 40 of 42 cases. The first MRI study was performed 6.8 ±2.7 hours (mean ± SD) after injury, and the second was performed 54.5 ± 32.3 hours after injury. The rostrocaudal intramedullary length of the lesion on the first MRI scan was 59.2 ± 16.1 mm, whereas its length on the second was 88.5 ± 31.9 mm. The principal factors associated with lesion length on the first MRI study were the time between injury and imaging (p = 0.05) and the time to decompression (p = 0.03). The lesions rate of rostrocaudal intramedullary expansion in the interval between the first and second MRI was 0.9 ± 0.8 mm/hour. The principal factors associated with the rate of expansion were the maximum spinal cord compression (p = 0.03) and the mechanism of injury (p = 0.05). CONCLUSIONS Spinal cord injury in humans is characterized by lesion expansion during the hours following trauma. Lesion expansion has a positive relationship with spinal cord compression and may be mitigated by early surgical decompression. Lesion expansion may be a novel surrogate measure by which to assess therapeutic effects in surgical or drug trials.

Comparative effectiveness of surgical versus nonoperative management of unilateral, nondisplaced, subaxial cervical spine facet fractures without evidence of spinal cord injury: clinical article.

OBJECT Facet joints are major stabilizers of cervical motion allowing for effortless and pain-free multidimensional cervical spine movements without significant linear or rotational translation, thus minimizing any chance for spinal cord or nerve root impingement. Unilateral, nondisplaced subaxial facet fractures do not meet the conventional criteria for spinal instability under physiological loads. Limited evidence indicates that even with no or minimal displacement, 20%-80% of these fractures fail nonoperative management. The risk factors for instability in isolated nondisplaced subaxial facet fractures remain uncertain. In this retrospective study of prospectively collected data, the authors attempted to identify the predictors of failure in the management of isolated, nondisplaced subaxial facet fractures admitted to their Level I trauma center over a 10-year period. METHODS Demographic, clinical, imaging, and follow-up data for 25 patients with unilateral nondisplaced subaxial facet fractures who were managed surgically (n = 10) or nonoperatively (n = 15) were statistically analyzed. RESULTS The mean age of the patients was 38 years, 19 were male, and 21 of the fractures were the result of either motor vehicle accidents or falls. The mean motor score on the American Spinal Injury Association scale was 99.2, and the mean Subaxial Injury Classification (SLIC) severity score was 3 (operated 3.5, nonoperated 2.3). Allen mechanistic classification included 22 compressive-extension Stage 1 and 2 distractive-extension Stage 1 fractures. Subaxial facet fractures involved C-7 in 17 patients (68%), C-6 in 7 (28%), and C-3 in 1 (4%). The anatomical plane of fracture through the lateral mass was sagittal in 12 patients, axial in 8, and coronal in 3 patients. Nondisplaced floating lateral mass injuries were noted in 2 patients. The mean instability score, considering 7 components of the discoligamentous complex on MRI, was 3.2 (operated 3.6, nonoperated 3.0). Ten (40%) of 25 patients in this investigation did not have successful management, 9 in the nonoperated and 1 in the operated group (p = 0.018). Unsuccessful management was significantly greater in younger patients (p = 0.0008), possibly indicating selection bias (p = 0.07, Wilcoxon ranksum test). Fracture plane, instability, and SLIC scores did not play a significant role in treatment failure in this study. CONCLUSIONS In this study, surgery was superior to nonoperative management of isolated, nondisplaced, or minimally displaced subaxial cervical spine facet fractures.

Predictors of intramedullary lesion expansion rate on MR images of patients with subaxial spinal cord injury

OBJECT Studies of preclinical spinal cord injury (SCI) in rodents indicate that expansion of intramedullary lesions (IMLs) seen on MR images may be amenable to neuroprotection. In patients with subaxial SCI and motor-complete American Spinal Injury Association (ASIA) Impairment Scale (AIS) Grade A or B, IML expansion has been shown to be approximately 900 μm/hour. In this study, the authors investigated IML expansion in a cohort of patients with subaxial SCI and AIS Grade A, B, C, or D. METHODS Seventy-eight patients who had at least 2 MRI scans within 6 days of SCI were enrolled. Data were analyzed by regression analysis. RESULTS In this cohort, the mean age was 45.3 years (SD 18.3 years), 73 patients were injured in a motor vehicle crash, from a fall, or in sport activities, and 77% of them were men. The mean Injury Severity Score (ISS) was 26.7 (SD 16.7), and the AIS grade was A in 23 patients, B in 7, C in 7, and D in 41. The mechanism of injury was distraction in 26 patients, compression in 22, disc/osteophyte complex in 29, and Chance fracture in 1. The mean time between injury onset and the first MRI scan (Interval 1) was 10 hours (SD 8.7 hours), and the mean time to the second MRI scan (Interval 2) was 60 hours (SD 29.6 hours). The mean IML lengths of the first and second MR images were 38.8 mm (SD 20.4 mm) and 51 mm (SD 36.5 mm), respectively. The mean time from the first to the second MRI scan (Interval 3) was 49.9 hours (SD 28.4 hours), and the difference in IML lengths was 12.6 mm (SD 20.7 mm), reflecting an expansion rate of 366 μm/ hour (SD 710 μm/hour). IML expansion in patients with AIS Grades A and B was 918 μm/hour (SD 828 μm/hour), and for those with AIS Grades C and D, it was 21 μm/hour (SD 304 μm/hour). Univariate analysis indicated that AIS Grade A or B versus Grades C or D (p < 0.0001), traction (p= 0.0005), injury morphology (p < 0.005), the surgical approach (p= 0.009), vertebral artery injury (p= 0.02), age (p < 0.05), ISS (p < 0.05), ASIA motor score (p < 0.05), and time to decompression (p < 0.05) were all predictors of lesion expansion. In multiple regression analysis, however, the sole determinant of IML expansion was AIS grade (p < 0.005). CONCLUSIONS After traumatic subaxial cervical spine or spinal cord injury, patients with motor-complete injury (AIS Grade A or B) had a significantly higher rate of IML expansion than those with motor-incomplete injury (AIS Grade C or D).

Prognostic Ability of Diffusion Tensor Imaging Parameters among Severely Injured Traumatic Brain Injury Patients

Diffuse axonal injury (DAI) represents the most common primary intra-axial form of traumatic brain injury (TBI), comprising approximately half of all such injuries. Patients presenting with DAI follow a highly variable clinical course, with initial status frequently discrepant from long-term neurological outcome. Diffusion Tensor Imaging (DTI) is sensitive to disruptions in neuronal structure that may not be appreciated on CT or conventional MRI and may serve as an important prognostic imaging marker. In this study, we retrospectively evaluated the data from 84 patients to determine if the whole brain DTI parameters (axial diffusivity λ1, radial diffusivity λ PERP , apparent diffusion coefficient ADC, and fractional anisotropy FA) are predictive of their clinical outcome as determined by discharge Glasgow Coma Scale (GCS). The first group consisted of 52 severely injured patients (GCS≤8) that either died (n=10), had poor outcome (n=12) or good outcome (n=27). The second group was comprised of mildly injured patients (GCS≥14 during entire hospitalization) that served as the reference group. Whole brain measurements of the DTI parameters were measured on each patient, and using non-parametric statistics, the measures from within each group were compared. Significant differences were found in ADC, λ1, and λ PERP between the three outcome groups. Further, these measures were shown to be significantly related to GCS at scan. Using ordinal logistic regression models adjusted for age, gender, and admission GCS, DTI parameters were shown to significantly predict outcomes in severe TBI patients (death, poor outcome, good outcome, or mild injury). Evaluation of TBI patients may be improved using DTI measures as they correlate well with clinical measures, reflect the severity of injury, and can predict outcome. This method may provide a valuable independent tool to predict clinical outcomes in DAI.