Michael L. Lipton

Diffusion-Tensor Imaging Implicates Prefrontal Axonal Injury in Executive Function Impairment Following Very Mild Traumatic Brain Injury

PURPOSE To determine whether frontal white matter diffusion abnormalities can help predict acute executive function impairment after mild traumatic brain injury (mTBI). MATERIALS AND METHODS This study had institutional review board approval, included written informed consent, and complied with HIPAA. Diffusion-tensor imaging and standardized neuropsychologic assessments were performed in 20 patients with mTBI within 2 weeks of injury and 20 matched control subjects. Fractional anisotropy (FA) and mean diffusivity (MD) images (imaging parameters: 3.0 T, 25 directions, b = 1000 sec/mm(2)) were compared by using whole-brain voxelwise analysis. Spearman correlation analyses were performed to evaluate associations between diffusion measures and executive function. RESULTS Multiple clusters of lower frontal white matter FA, including the dorsolateral prefrontal cortex (DLPFC), were present in patients (P < .005), with several clusters also demonstrating higher MD (P < .005). Patients performed worse on tests of executive function. Lower DLPFC FA was significantly correlated with worse executive function performance in patients (P < .05). CONCLUSION Impaired executive function following mTBI is associated with axonal injury involving the DLPFC.

A Decade of DTI in Traumatic Brain Injury: 10 Years and 100 Articles Later

SUMMARY: The past decade has seen an increase in the number of articles reporting the use of DTI to detect brain abnormalities in patients with traumatic brain injury. DTI is well-suited to the interrogation of white matter microstructure, the most important location of pathology in TBI. Additionally, studies in animal models have demonstrated the correlation of DTI findings and TBI pathology. One hundred articles met the inclusion criteria for this quantitative literature review. Despite significant variability in sample characteristics, technical aspects of imaging, and analysis approaches, the consensus is that DTI effectively differentiates patients with TBI and controls, regardless of the severity and timeframe following injury. Furthermore, many have established a relationship between DTI measures and TBI outcomes. However, the heterogeneity of specific outcome measures used limits interpretation of the literature. Similarly, few longitudinal studies have been performed, limiting inferences regarding the long-term predictive utility of DTI. Larger longitudinal studies, using standardized imaging, analysis approaches, and outcome measures will help realize the promise of DTI as a prognostic tool in the care of patients with TBI.

Multifocal White Matter Ultrastructural Abnormalities in Mild Traumatic Brain Injury with Cognitive Disability: A Voxel-Wise Analysis of Diffusion Tensor Imaging

The purpose of the present study is to identify otherwise occult white matter abnormalities in patients suffering persistent cognitive impairment due to mild traumatic brain injury (TBI). The study had Institutional Review Board (IRB) approval, included informed consent and complied with the U.S. Health Insurance Portability and Accountability Act (HIPAA) of 1996. We retrospectively analyzed diffusion tensor MRI (DTI) of 17 patients (nine women, eight men; age range 26-70 years) who had cognitive impairment due to mild TBI that occurred 8 months to 3 years prior to imaging. Comparison was made to 10 healthy controls. Fractional anisotropy (FA) and mean diffusivity (MD) images derived from DTI (1.5 T; 25 directions; b = 1000) were compared using whole brain histogram and voxel-wise analyses. Histograms of white matter FA show an overall shift toward lower FA in patients. Areas of significantly decreased FA (p < 0.005) were found in the subject group in corpus callosum, subcortical white matter, and internal capsules bilaterally. Co-located elevation of mean diffusivity (MD) was found in the patients within each region. Similar, though less extensive, findings were demonstrated in each individual patient. Multiple foci of low white matter FA and high MD are present in cognitively impaired mild TBI patients, with a distribution that conforms to that of diffuse axonal injury. Evaluation of single subjects also reveals foci of low FA, suggesting that DTI may ultimately be useful for clinical evaluation of individual patients.

Soccer Heading Is Associated with White Matter Microstructural and Cognitive Abnormalities

PURPOSE To investigate the association of soccer heading with subclinical evidence of traumatic brain injury. MATERIALS AND METHODS With institutional review board approval and compliance with HIPAA guidelines, 37 amateur soccer players (mean age, 30.9 years; 78% [29] men, 22% [eight] women) gave written informed consent and completed a questionnaire to quantify heading in the prior 12 months and lifetime concussions. Diffusion-tensor magnetic resonance (MR) imaging at 3.0 T was performed (32 directions; b value, 800 sec/mm(2); 2 × 2 × 2-mm voxels). Cognitive function was measured by using a computerized battery of tests. Voxelwise linear regression (heading vs fractional anisotropy [FA]) was applied to identify significant regional associations. FA at each location and cognition were tested for a nonlinear relationship to heading by using an inverse logit model that incorporated demographic covariates and history of concussion. RESULTS Participants had headed 32-5400 times (median, 432 times) over the previous year. Heading was associated with lower FA at three locations in temporo-occipital white matter with a threshold that varied according to location (885-1550 headings per year) (P < .00001). Lower levels of FA were also associated with poorer memory scores (P < .00001), with a threshold of 1800 headings per year. Lifetime concussion history and demographic features were not significantly associated with either FA or cognitive performance. CONCLUSION Heading is associated with abnormal white matter microstructure and with poorer neurocognitive performance. This relationship is not explained by a history of concussion.

Diffusion tensor imaging abnormalities in patients with mild traumatic brain injury and neurocognitive impairment.

Objective: To determine if diffusion tensor imaging can differentiate patients with chronic cognitive impairment after mild traumatic brain injury (TBI) from normal controls. Methods: Ten patients with persistent cognitive impairment after mild TBI were evaluated at least 2 years after injury. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were measured at white matter regions susceptible to axonal injury after TBI. Comparison was made to 10 normal controls. Results: Fractional anisotropy was significantly lower (4.5%; P = 0.01) and ADC higher (7.1%; P = 0.04) in patients at the left side of the genu of the corpus callosum. The mild TBI group also demonstrated a significant increase in FA within the posterior limb of the internal capsule bilaterally (left, 5.1%; P = 0.03; right, 1.9%; P = 0.04). Conclusions: These results demonstrate low FA and high ADC in the genu of the corpus callosum of mild TBI patients with persistent cognitive impairment, suggesting that permanent white matter ultrastructural damage occurs in mild TBI, and that such damage may be associated with persistent cognitive disability. Further longitudinal studies are warranted to elucidate the full importance of the findings.

Ipsilateral Hand Input to Area 3b Revealed by Converging Hemodynamic and Electrophysiological Analyses in Macaque Monkeys

Functional magnetic resonance imaging (fMRI) of the hand representation in primary somatosensory cortex (area 3b) of macaque monkeys revealed an ipsilateral hand input undetected by most previous studies. Ipsilateral responses had a hemodynamic signature indistinguishable from that of contralateral hand responses. We explored the neural mechanisms of the fMRI effects using a second derivative analysis of field potentials [current source density (CSD) analysis] combined with action potential profiles, sampled from area 3b using linear array multielectrodes. In contrast to the predominantly excitatory contralateral response, the colocated ipsilateral response appeared dominated by inhibition, suggesting that ipsilateral inputs may have modulatory effects on contralateral input processing. Our findings confirm bimanual convergence at the earliest stage of cortical somatosensory processing in primates. They also illustrate the value of combined CSD and fMRI analyses in monkeys for defining hidden aspects of sensory function and for investigating the neuronal processes generating fMRI signals.

Is Functional MR Imaging Assessment of Hemispheric Language Dominance as Good as the Wada Test?: A Meta-Analysis

PURPOSE To perform a systematic review and meta-analysis to quantitatively assess functional magnetic resonance (MR) imaging lateralization of language function in comparison with the Wada test. MATERIALS AND METHODS This study was determined to be exempt from review by the institutional review board. A systematic review and meta-analysis were performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A structured Medline search was conducted to identify all studies that compared functional MR imaging with the Wada test for determining hemispheric language dominance prior to brain surgery. Studies meeting predetermined inclusion criteria were selected independently by two radiologists who also assessed their quality using the Quality Assessment of Diagnostic Accuracy Studies tool. Language dominance was classified as typical (left hemispheric language dominance) or atypical (right hemispheric language dominance or bilateral language representation) for each patient. A meta-analysis was then performed by using a bivariate random-effects model to derive estimates of sensitivity and specificity, with Wada as the standard of reference. Subgroup analyses were also performed to compare the different functional MR imaging techniques utilized by the studies. RESULTS Twenty-three studies, comprising 442 patients, met inclusion criteria. The sensitivity and specificity of functional MR imaging for atypical language dominance (compared with the Wada test) were 83.5% (95% confidence interval: 80.2%, 86.7%) and 88.1% (95% confidence interval: 87.0%, 89.2%), respectively. CONCLUSION Functional MR imaging provides an excellent, noninvasive alternative for language lateralization and should be considered for the initial preoperative assessment of hemispheric language dominance. Further research may help determine which functional MR methods are most accurate for specific patient populations.

Embracing chaos: the scope and importance of clinical and pathological heterogeneity in mTBI

Mild traumatic brain injury (mTBI) manifests a wide array of clinical features, indicating great heterogeneity of its underlying pathologic features. mTBI diversity is related to pre-injury inter-individual differences and differences in the characteristics of each injury. This review summarizes key features of mTBI patients, their injuries and outcomes to give context to the scope of complexity inherent in this disorder. These differences are underscored by heterogeneity in postmortem pathology and in vivo imaging studies. Recognition, understanding and accounting for disease heterogeneity in mTBI are needed to enhance diagnosis and patient management, as approaches that do not account for inter-individual variation in pathology and patient characteristics relevant to real-life clinical trial participants, may entirely miss therapeutic targets. Refining our approach to TBI diagnosis, in light of inter-individual differences, can facilitate the development of effective prognostic tools and algorithms. New paradigms, which embrace heterogeneity of mTBI, in both preclinical and clinical investigation as well the appreciation of this variability in clinical care, offer much promise for enhancing outcomes and mitigating the burden of mTBI on its victims.

Laminar Profile and Physiology of the α Rhythm in Primary Visual, Auditory, and Somatosensory Regions of Neocortex

The functional significance of the α rhythm is widely debated. It has been proposed that α reflects sensory inhibition and/or a temporal sampling or “parsing” mechanism. There is also continuing disagreement over the more fundamental questions of which cortical layers generate α rhythms and whether the generation of α is equivalent across sensory systems. To address these latter questions, we analyzed laminar profiles of local field potentials (LFPs) and concomitant multiunit activity (MUA) from macaque V1, S1, and A1 during both spontaneous activity and sensory stimulation. Current source density (CSD) analysis of laminar LFP profiles revealed α current generators in the supragranular, granular, and infragranular layers. MUA phase-locked to local current source/sink configurations confirmed that α rhythms index local neuronal excitability fluctuations. CSD-defined α generators were strongest in the supragranular layers, whereas LFP α power was greatest in the infragranular layers, consistent with some of the previous reports. The discrepancy between LFP and CSD findings appears to be attributable to contamination of the infragranular LFP signal by activity that is volume-conducted from the stronger supragranular α generators. The presence of α generators across cortical depth in V1, S1, and A1 suggests the involvement of α in feedforward as well as feedback processes and is consistent with the view that α rhythms, perhaps in addition to a role in sensory inhibition, may parse sensory input streams in a way that facilitates communication across cortical areas. SIGNIFICANCE STATEMENT The α rhythm is thought to reflect sensory inhibition and/or a temporal parsing mechanism. Here, we address two outstanding issues: (1) whether α is a general mechanism across sensory systems and (2) which cortical layers generate α oscillations. Using intracranial recordings from macaque V1, S1, and A1, we show α band activity with a similar spectral and laminar profile in each of these sensory areas. Furthermore, α generators were present in each of the cortical layers, with a strong source in superficial layers. We argue that previous findings, locating α generators exclusively in the deeper layers, were biased because of use of less locally specific local field potential measurements. The laminar distribution of α band activity appears more complex than generally assumed.

Hippocampal correlates of pain in healthy elderly adults A pilot study

Background: Few neuroimaging investigations of pain in elderly adults have focused on the hippocampus, a brain structure involved in nociceptive processing that is also subject to involution associated with dementing disorders. The goal of this pilot study was to examine MRI- and magnetic resonance spectroscopy (MRS)–derived hippocampal correlates of pain in older adults. Methods: A subset of 20 nondemented older adults was drawn from the Einstein Aging Study, a community-based sample from the Bronx, NY. Pain was measured on 3 time scales: 1) acute pain right now (pain severity); 2) pain over the past 4 weeks (Short Form–36 Bodily Pain); 3) chronic pain over the past 3 months (Total Pain Index). Hippocampal data included volume data normalized to midsagittal area and N-acetylaspartate to creatine ratios (NAA/Cr). Results: Smaller hippocampal volume was associated with higher ratings on the Short Form–36 Bodily Pain (rs = 0.52, p = 0.02) and a nonsignificant trend was noted for higher ratings of acute pain severity (rs = −0.44, p = 0.06). Lower levels of hippocampal NAA/Cr were associated with higher acute pain severity (rs = −0.45, p = 0.05). Individuals with chronic pain had a nonsignificant trend for smaller hippocampal volumes (t = 2.00, p = 0.06) and lower levels of hippocampal NAA/Cr (t = 1.71, p = 0.10). Conclusions: Older adults who report more severe acute or chronic pain have smaller hippocampal volumes and lower levels of hippocampal N-acetylaspartate/creatine, a marker of neuronal integrity. Future studies should consider the role of the hippocampus and other brain structures in the development and experience of pain in healthy elderly and individuals with Alzheimer disease.