Acute thalamic connectivity precedes chronic post-concussive symptoms in mild traumatic brain injury.

Chronic post-concussive symptoms are common after mild traumatic brain injury (mTBI) and are difficult to predict or treat. Thalamic functional integrity is particularly vulnerable in mTBI and may be related to long-term outcomes but requires further investigation. We compared structural MRI and resting state functional MRI in 108 patients with a Glasgow Coma Scale (GCS) of 13-15 and normal CT, and 76 controls. We examined whether acute changes in thalamic functional connectivity were early markers for persistent symptoms and explored neurochemical associations of our findings using PET data. Of the mTBI cohort, 47% showed incomplete recovery 6 months post-injury. Despite the absence of structural changes, we found acute thalamic hyperconnectivity in mTBI, with specific vulnerabilities of individual thalamic nuclei. Acute fMRI markers differentiated those with chronic post-concussive symptoms, with time- and outcome-dependent relationships in a sub-cohort followed longitudinally. Moreover, emotional and cognitive symptoms were associated with changes in thalamic functional connectivity to known serotonergic and noradrenergic targets, respectively. Our findings suggest that chronic symptoms can have a basis in early thalamic pathophysiology. This may aid identification of patients at risk of chronic post-concussive symptoms following mTBI, provide a basis for development of new therapies and facilitate precision medicine application of these therapies.

Thalamic subfield iron accumulation after acute mild traumatic brain injury as a marker of future post-traumatic headache intensity.

OBJECTIVE: To explore alterations in thalamic subfield volume and iron accumulation in individuals with post-traumatic headache (PTH) relative to healthy controls. BACKGROUND: The thalamus plays a pivotal role in the pathomechanism of pain and headache, yet the role of the thalamus in PTH attributed to mild traumatic brain injury (mTBI) remains unclear. METHODS: A total of 107 participants underwent multimodal T1-weighted and T2* brain magnetic resonance imaging. Using a clinic-based observational study, thalamic subfield volume and thalamic iron accumulation were explored in 52 individuals with acute PTH (mean age = 41.3; standard deviation [SD] = 13.5), imaged on average 24 days post mTBI, and compared to 55 healthy controls (mean age = 38.3; SD = 11.7) without history of mTBI or migraine. Symptoms of mTBI and headache characteristics were assessed at baseline (0-59 days post mTBI) (n = 52) and 3 months later (n = 46) using the Symptom Evaluation of the Sports Concussion Assessment Tool (SCAT-5) and a detailed headache history questionnaire. RESULTS: Relative to controls, individuals with acute PTH had significantly less volume in the lateral geniculate nucleus (LGN) (mean volume: PTH = 254.1, SD = 43.4 vs. controls = 278.2, SD = 39.8; p = 0.003) as well as more iron deposition in the left LGN (PTH: T2* signal = 38.6, SD = 6.5 vs. controls: T2* signal = 45.3, SD = 2.3; p = 0.048). Correlations in individuals with PTH revealed a positive relationship between left LGN T2* iron deposition and SCAT-5 symptom severity score at baseline (r = -0.29, p = 0.019) and maximum headache intensity at the 3-month follow-up (r = -0.47, p = 0.002). CONCLUSION: Relative to healthy controls, individuals with acute PTH had less volume and higher iron deposition in the left LGN. Higher iron deposition in the left LGN might reflect mTBI severity and poor headache recovery.

Concussion Prone Scenarios: A Multi-Dimensional Exploration in Impact Directions, Brain Morphology, and Network Architectures Using Computational Models.

While individual susceptibility to traumatic brain injury (TBI) has been speculated, past work does not provide an analysis considering how physical features of an individual's brain (e.g., brain size, shape), impact direction, and brain network features can holistically contribute to the risk of suffering a TBI from an impact. This work investigated each of these features simultaneously using computational modeling and analyses of simulated functional connectivity. Unlike the past studies that assess the severity of TBI based on the quantification of brain tissue damage (e.g., principal strain), we approached the brain as a complex network in which neuronal oscillations orchestrate to produce normal brain function (estimated by functional connectivity) and, to this end, both the anatomical damage location and its topological characteristics within the brain network contribute to the severity of brain function disruption and injury. To represent the variations in the population, we analyzed a publicly available database of brain imaging data and selected five distinct network architectures, seven different brain sizes, and three uniaxial head rotational conditions to study the consequences of 74 virtual impact scenarios. Results show impact direction produces the most significant change in connections across brain areas (structural connectome) and the functional coupling of activity across these brain areas (functional connectivity). Axial rotations were more injurious than those with sagittal and coronal rotations when the head kinematics were the same for each condition. When the impact direction was held constant, brain network architecture showed a significantly different vulnerability across axial and sagittal, but not coronal rotations. As expected, brain size significantly affected the expected change in structural and functional connectivity after impact. Together, these results provided groupings of predicted vulnerability to impact-a subgroup of male brain architectures exposed to axial impacts were most vulnerable, while a subgroup of female brain architectures was the most tolerant to the sagittal impacts studied. These findings lay essential groundwork for subject-specific analyses of concussion and provide invaluable guidance for designing personalized protection equipment.

Early Stage Longitudinal Subcortical Volumetric Changes following Mild Traumatic Brain Injury.

Objective: To investigate early brain volumetric changes from acute to 6 months following mild traumatic brain injury (mTBI) in deep gray matter regions and their association with patient 6-month outcome.Methods: Fifty-six patients with mTBI underwent MRI and behavioral evaluation at acute (<10 days) and approximately 1 and 6 months post injury. Regional volume changes were investigated in key gray matter regions: thalamus, hippocampus, putamen, caudate, pallidum, and amygdala, and compared with volumes from 34 healthy control subjects. In patients with mTBI, we further assessed associations between longitudinal regional volume changes with patient outcome measures at 6 months including post-concussive symptoms, cognitive performance, and overall satisfaction with life.Results: Reduction in thalamic and hippocampal volumes was observed at 1 month among patients with mTBI. Such volume reduction persisted in the thalamus until 6 months. Changes in thalamic volumes also correlated with multiple symptom and functional outcome measures in patients at 6 months.Conclusion: Our results indicate that the thalamus may be differentially affected among patients with mTBI, resulting in both structural and functional deficits with subsequent post-concussive sequelae and may serve as a biomarker for the assessment of efficacy of novel therapeutic interventions.

The diffusion-tensor imaging reveals alterations in water diffusion parameters in acute pediatric concussion.

Wide-spread visualization methods which are computed tomography (CT) and magnetic resonance imaging (MRI) are not sensitive to mild traumatic brain injury (mTBI). However, mTBI may cause changes of cerebral microstructure that could be found using diffusion-tensor imaging. The aim of this study is to reveal the impact of acute mTBI (no more than 3 days after trauma) on diffusion parameters in corpus callosum, corticospinal tract, and thalamus in children (aged 14-18). Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were analyzed. Significant increase in FA and decrease in ADC were observed in thalamus. The trend to an increase in FA is observed in corpus callosum.

Interest of blood biomarkers to predict lesions in medical imaging in the context of mild traumatic brain injury.

Mild traumatic brain injury (mTBI) is one of the common causes of emergency department visits around the world. Up to 90% of injuries are classified as mTBI. Cranial computed tomography (CCT) is a standard diagnostic tool for adults with mTBI. Alternatively, children can be admitted for inpatient observation with CCT scans performed only on those with clinical deterioration. The use of blood biomarkers is a supplementary tool for identifying patients at risk of intracerebral lesions who may need imaging. This review provides a contemporary clinical and laboratory framework for blood biomarker testing in mTBI management. The S100B protein is used routinely in the management of mTBI in Europe together with clinical guidelines. Due to its excellent negative predictive value, S100B protein is an alternative choice to CCT scanning for mTBI management under considered, consensual and pragmatic use. In this review, we propose points to help clinicians and clinical pathologists use serum S100B protein in the clinical routine. A review of the literature on the different biomarkers (GFAP, UCH-L1, NF [H or L], tau, H-FABP, SNTF, NSE, miRNAs, MBP, ß trace protein) is also conducted. Some of these other blood biomarkers, used alone (GFAP, UCH-L1) or in combination (GFAP + H-FABP ± S100B ± IL10) can improve the specificity of S100B.

Injury of the dentato-rubro-thalamic tract in a patient with intentional tremor after mild traumatic brain injury: a case report.

OBJECTIVES: We imaged the dentato-rubro-thalamic tract (DRTT) and cortico-ponto-cerebellar tract (CPCT) using diffusion tensor tractography (DTT) to evaluate the cortico-cerebellar-cortical circuit in a patient with tremor in both hands after mild TBI. We found bilateral DRTT injury in the DTT. METHOD: A 50-year-old male presented with action tremor in both hands 1 week after mild TBI. One month before the visit, the patient had a head injury from a fall on a bus. The patient lost consciousness for 1 min and experienced post-traumatic amnesia for approximately 5 min after the accident. His Glasgow Coma Scale score was 15. The action tremor presented with a frequency of 3 Hz in both hands. No specific lesion was observed with a conventional brain MRI. RESULTS: DTT, performed 1.5 months after TBI, showed that the right DRTT was not reconstructed and the left DRTT had thinned. However, CPCT integrity was well-preserved in both hemispheres. The tremor disappeared after oral treatment with 30 mg/day indenol. The patient's tremor would have been caused by disruption of the bilateral DRTT following mild TBI. CONCLUSION: DRTT and CPCT analysis using DTT would be useful for diagnosing abnormal movement problems, including tremor and ataxia, in patients following mild TBI.

Altered hypothalamic functional connectivity in post-traumatic headache after mild traumatic brain injury.

BACKGROUND: Post-traumatic headache (PTH) is one of the most frequent symptoms following mild traumatic brain injury (mTBI). Neuroimaging studies implicate hypothalamic function connectivity (FC) disruption as an important factor in pain disorders. However, it is unknown whether there are alterations in the hypothalamus-based resting state FC within PTH following mTBI at the acute stage and its relationship with headache symptom measurement. METHODS: Forty-four mTBI patients with PTH, 27 mTBI patients without PTH and 43 healthy controls who were well matched for age, gender, and years of education were enrolled in this study. All participants underwent resting-state functional magnetic resonance imaging (fMRI) scanning as well as headache symptom measurement and cognitive assessment. Hypothalamic resting state networks were characterized by using a standard seed-based whole-brain correlation method. The bilateral hypothalamic FC was compared among the three groups. Furthermore, the correlations between hypothalamic resting state networks and headache frequency, headache intensity and MoCA scores was investigated in mTBI patients with PTH using Pearson rank correlation. RESULTS: Compared with mTBI patients without PTH, mTBI patients with PTH at the acute stage presented significantly decreased left hypothalamus-based FC with the right middle frontal gyrus (MFG) and right medial superior frontal gyrus (mSFG), and significantly decreased right hypothalamus-based FC with the right MFG. Decreased FC of the right MFG was significantly positively associated with headache frequency and headache intensity (r = 0.339, p = 0.024; r = 0.408, p = 0.006, respectively). Decreased FC of the right mSFG was significantly positively associated with headache frequency and headache intensity (r = 0.740, p < 0.0001; r = 0.655, p < 0.0001, respectively). CONCLUSION: Our data provided evidence of disrupted hypothalamic FC in patients with acute mTBI with PTH, while abnormal FC significantly correlated with headache symptom measurement. Taken together, these changes may play an essential role in the neuropathological mechanism of mTBI patients with PTH.

Structural abnormalities in thalamo-prefrontal tracks revealed by high angular resolution diffusion imaging predict working memory scores in concussed children.

Because of their high prevalence, heterogeneous clinical presentation, and wide-ranging sequelae, concussions are a challenging neurological condition, especially in children. Shearing forces transmitted across the brain during concussions often result in white matter damage. The neuropathological impact of concussions has been discerned from animal studies and includes inflammation, demyelination, and axonal loss. These pathologies can overlap during the sub-acute stage of recovery. However, due to the challenges of accurately modeling complex white matter structure, these neuropathologies have not yet been differentiated in children in vivo. In the present study, we leveraged recent advances in diffusion imaging modeling, tractography, and tractometry to better understand the neuropathology underlying working memory problems in concussion. Studying a sample of 16 concussed and 46 healthy youths, we used novel tractography methods to isolate 11 working memory tracks. Along these tracks, we measured fractional anisotropy, diffusivities, track volume, apparent fiber density, and free water fraction. In three tracks connecting the right thalamus to the right dorsolateral prefrontal cortex (DLPFC), we found microstructural differences suggestive of myelin alterations. In another track connecting the left anterior-cingulate cortex with the left DLPFC, we found microstructural changes suggestive of axonal loss. Structural differences and tractography reconstructions were reproduced using test-retest analyses. White matter structure in the three thalamo-prefrontal tracks, but not the cingulo-prefrontal track, appeared to play a key role in working memory function. The present results improve understanding of working memory neuropathology in concussions, which constitutes an important step toward developing neuropathologically informed biomarkers of concussion in children.

Dynamic Blood-Brain Barrier Regulation in Mild Traumatic Brain Injury.

Whereas the diagnosis of moderate and severe traumatic brain injury (TBI) is readily visible on current medical imaging paradigms (magnetic resonance imaging [MRI] and computed tomography [CT] scanning), a far greater challenge is associated with the diagnosis and subsequent management of mild TBI (mTBI), especially concussion which, by definition, is characterized by a normal CT. To investigate whether the integrity of the blood-brain barrier (BBB) is altered in a high-risk population for concussions, we studied professional mixed martial arts (MMA) fighters and adolescent rugby players. Additionally, we performed the linear regression between the BBB disruption defined by increased gadolinium contrast extravasation on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) on MRI and multiple biomechanical parameters indicating the severity of impacts recorded using instrumented mouthguards in professional MMA fighters. MMA fighters were examined pre-fight for a baseline and again within 120 h post-competitive fight, whereas rugby players were examined pre-season and again post-season or post-match in a subset of cases. DCE-MRI, serological analysis of BBB biomarkers, and an analysis of instrumented mouthguard data, was performed. Here, we provide pilot data that demonstrate disruption of the BBB in both professional MMA fighters and rugby players, dependent on the level of exposure. Our data suggest that biomechanical forces in professional MMA and adolescent rugby can lead to BBB disruption. These changes on imaging may serve as a biomarker of exposure of the brain to repetitive subconcussive forces and mTBI.

Characterizing the Link Between Glial Activation and Changed Functional Connectivity in National Football League Players Using Multimodal Neuroimaging.

OBJECTIVE: The primary objective of this preliminary study was to examine the impact of NFL play on interregional functional connectivity between two brain regions, the supramarginal gyrus (SMG) and the thalamus, identified as having higher binding of [11C]DPA-713 in NFL players. The authors' secondary objective was to examine the effect of years since play on the interregional connectivity. METHODS: Resting-state functional MRI was used to examine functional brain changes between regions with evidence of past injury in active or recently retired NFL players (defined as ≤12 years since NFL play) and distantly retired players (defined as >12 years since NFL play). Age-comparable individuals without a history of concussion or participation in collegiate or professional collision sports were included as a control group. RESULTS: Compared with healthy control subjects, NFL players showed a loss of anticorrelation between the left SMG and bilateral thalami (mean z score=-2.434, p=0.015). No difference was observed when examining right SMG connectivity. The pattern of connectivity in active and recently retired players mimicked the pattern observed in distantly retired players and older control subjects. CONCLUSIONS: Further study of the clinical significance of this altered pattern of interregional connectivity in active and recently retired NFL players is needed.

Visualization of thalamic calcium influx with quantitative susceptibility mapping as a potential imaging biomarker for repeated mild traumatic brain injury.

A key event in the pathophysiology of traumatic brain injury (TBI) is the influx of substantial amounts of Ca2+ into neurons, particularly in the thalamus. Detection of this calcium influx in vivo would provide a window into the biochemical mechanisms of TBI with potentially significant clinical implications. In the present work, our central hypothesis was that the Ca2+ influx could be imaged in vivo with the relatively recent MRI technique of quantitative susceptibility mapping (QSM). Wistar rats were divided into five groups: naive controls, sham-operated experimental controls, single mild TBI, repeated mild TBI, and single severe TBI. We employed the lateral fluid percussion injury (FPI) model, which replicates clinical TBI without skull fracture, performed 9.4 Tesla MRI with a 3D multi-echo gradient-echo sequence at weeks 1 and 4 post-injury, computed susceptibility maps using V-SHARP and the QUASAR-HEIDI technique, and performed histology. Sham, experimental controls animals, and injured animals did not demonstrate calcifications at 1 week after the injury. At week 4, calcifications were found in the ipsilateral thalamus of 25-50% of animals after a single TBI and 83% of animals after repeated mild TBI. The location and appearance of calcifications on stained sections was consistent with the appearance on the in vivo susceptibility maps (correlation of volumes: r = 0.7). Our findings suggest that persistent calcium deposits represent a primary pathology of repeated injury and that FPI-QSM has the potential to become a sensitive tool for studying pathophysiology related to mild TBI in vivo.

Microstructural alterations of cortical and deep gray matter over a season of high school football revealed by diffusion kurtosis imaging.

OBJECTIVES: To probe microstructural changes that are associated with subconcussive head impact exposure in deep and cortical gray matter of high school football players over a single season. METHODS: Players underwent diffusion kurtosis imaging (DKI) and quantitative susceptibility mapping (QSM) scans. Head impact data was recorded. Association between parametric changes and frequency of frontal head impact was assessed. RESULTS: In deep gray matter, significant decreases in mean kurtosis (MK) and increases in mean diffusivity (MD) over the season were observed in the thalamus and putamen. Correlations between changes in DKI metrics and frequency of frontal impacts were observed in the putamen and caudate. In cortical gray matter, decreases in MK were observed in regions including the pars triangularis and inferior parietal. In addition, increases in MD were observed in the rostral middle frontal cortices. Negative correlations between MK and frequency of frontal impacts were observed in the posterior part of the brain including the pericalcarine, lingual and middle temporal cortices. Magnetic susceptibility values exhibited no significant difference or correlation, suggesting these diffusion changes common within the group may not be associated with iron-related mechanisms. CONCLUSION: Microstructural alterations over the season and correlations with head impacts were captured by DKI metrics, which suggested that DKI imaging of gray matter may yield valuable biomarkers for evaluating brain injuries associated with subconcussive head impact. Findings of associations between frontal impacts and changes in posterior cortical gray matter also indicated that contrecoup injury rather than coup injury might be the dominant mechanism underlying the observed microstructural alterations. ADVANCES IN KNOWLEDGE: Significant microstructural changes, as reflected by DKI metrics, in cortical gray matter such as the rostral middle frontal cortices, and in deep gray matter such as the thalamus were observed in high school football players over the course of a single season without clinically diagnosed concussion. QSM showed no evidence of iron-related changes in the observed subconcussive brain injuries. The detected microstructural changes in cortical and deep gray matter correlated with frequency of subconcussive head impacts. IMPLICATIONS FOR PATIENT CARE: DKI may yield valuable biomarkers for evaluating the severity of brain injuries associated with subconcussive head impacts in contact sport athletes.

Relationships Between Subcortical Shape Measures and Subjective Symptom Reporting in US Service Members With Mild Traumatic Brain Injury.

OBJECTIVE: To assess interactions of subcortical structure with subjective symptom reporting associated with mild traumatic brain injury (mTBI), using advanced shape analysis derived from volumetric MRI. PARTICIPANTS: Seventy-six cognitively symptomatic individuals with mTBI and 59 service members sustaining only orthopedic injury. DESIGN: Descriptive cross-sectional study. MAIN MEASURES: Self-report symptom measures included the PTSD Checklist-Military, Neurobehavioral Symptom Inventory, and Symptom Checklist-90-Revised. High-dimensional measures of shape characteristics were generated from volumetric MRI for 7 subcortical structures in addition to standard volume measures. RESULTS: Several significant interactions between group status and symptom measures were observed across the various shape measures. These interactions were revealed in the right thalamus and globus pallidus for each of the shape measures, indicating differences in structure thickness and expansion/contraction for these regions. No relationships with volume were observed. CONCLUSION: Results provide evidence for the sensitivity of shape measures in differentiating symptomatic mTBI individuals from controls, while volumetric measures did not exhibit this same sensitivity. Disruptions to thalamic nuclei identified here highlight the role of the thalamus in the spectrum of symptoms associated with mTBI. Additional work is needed to prospectively, and longitudinally, assess these measures along with cognitive performance and advanced multimodal imaging methods to extend the utility of shape analysis in relation to functional outcomes in this population.

Aggravation of an injured dentato-rubro-thalamic tract in a patient with mild traumatic brain injury: A case report.

RATIONALE: We report on a patient with mild traumatic brain injury (TBI) by follow-up diffusion tensor tractography (DTT), and observed for approximately nine monthsby serial diffusion tensor tractography (DTT). PATIENT CONCERNS: A 66-year-old male patient was injured in a car crash. Approximately four weeks after the crash, he developed a tremor in the right hand and leg. His symptoms worsened over time. DIAGNOSES: Approximately six months after the crash, he developed a mild tremor in the left hand. Nine months after the crash, he manifested severe tremor in his right hand, mild resting and intentional tremor in his left hand and both legs, and mild trunkal ataxia. INTERVENTIONS: N/A. OUTCOMES: On 3-week DTT, well reconstructed DRTTs were observed in both hemispheres, except for the thinned lower portion of the right DRTT. On 9-month DTT, the right lower DRTT had thinned compared with the 3-week DTT and showed a disruption at the upper portion. The left DRTT showed thinning in the lower portion and tearing in the upper portion compared with 3-week DTT. LESSONS: Aggravation of an injured DRTT was demonstrated in a patient with mild TBI, using serial DTT examination.

GABA alterations in pediatric sport concussion.

OBJECTIVE: To evaluate whether frontal-lobe magnetic resonance spectroscopy measures of γ-aminobutyric acid (GABA) would be altered in a sample of adolescents scanned after sport concussion because mild traumatic brain injury is often associated with working memory problems. METHODS: Eleven adolescents (age 14-17 years) who had sustained a first-time sport concussion were studied with MRI/magnetic resonance spectroscopy within 23 to 44 days after injury (mean 30.4 ± 6.1 days). Age- and sex-matched healthy controls, being seen for sports-related injuries not involving the head and with no history of concussion, were also examined. GABA/creatine + phosphocreatine (Cre) was measured in left-sided frontal lobe and central posterior cingulate regions. The frontal voxel was positioned to overlap with patient-specific activation on a 1-back working memory task. RESULTS: Increased GABA/Cre was shown in the frontal lobe for the concussed group. A decreased relationship was observed in the parietal region. High correlations between GABA/Cre and task activation were observed for the control group in the frontal lobe, a relationship not shown in the concussed participants. CONCLUSIONS: GABA/Cre appears increased in a region colocalized with working memory task activation after sport concussion. Further work extending these results in larger samples and at time points across the injury episode will aid in refining the clinical significance of these observations.

Microstructural changes in the thalamus after mild traumatic brain injury: A longitudinal diffusion and mean kurtosis tensor MRI study.

PRIMARY OBJECTIVE: The primary aim of this study was to assess microstructural changes in the thalamus, hippocampus and corpus callosum with a fast mean kurtosis tensor (MKT) technique, in the acute and sub-acute phase after mTBI. It was hypothesized that MKT would differ between baseline and follow-up in patients. The secondary aim was to relate diffusion measures to symptoms of mTBI. RESEARCH DESIGN: A longitudinal case-control study. METHODS AND PROCEDURES: Twenty-seven patients with mTBI and 27 age- and gender-matched healthy controls were enrolled in the study. Patients were scanned within 2 weeks and 3 months after mTBI, while the controls were scanned once. MAIN OUTCOMES AND RESULTS: MKT decreased significantly (p = 0.02) from baseline to follow-up in the thalamus in patients. Compared to healthy subjects, thalamic MKT values were significantly larger in patients at baseline (p = 0.048). Secondary analysis revealed a significant decrease (p = 0.01) in fractional anisotropy in the splenium of corpus callosum from baseline to follow-up. CONCLUSIONS: The current study indicates microstructural changes in the thalamus and corpus callosum from within 14 days to 3 months after mTBI and suggests MKT as a potential biomarker after mTBI.

A longitudinal study of changes in Diffusion Tensor Value and their association with cognitive sequelae among patients with mild head injury.

BACKGROUND: Diffusion tensor imaging (DTI) is an advanced and sensitive technique that detects sub-threshold pathology in normal imaging brain injury patients. Currently, there are no longitudinal DTI studies to look for time-based changes. The present study has investigated longitudinal imaging and its association with cognitive deficits. METHODS: Twenty-one patients were available for MRI and neuropsychological test (NPT) assessment for all the 3 time points. Initially (<36 hours), all patients presented with GCS 15 and normal scan findings. The DTI (P<0.0001) and NPT scores (P<0.05) were analyzed using repeated-measure of analysis. The tensor values were correlated with specific time-point NPT scores using partial correlation (0.05). RESULTS: Right cerebral-hemisphere showed significant alterations in both anisotropy and diffusivity values overtime. Cingulate gyrus and occipital lobe showed prominent changes in anisotropy value. Significant improvement in thalamo-cortical anisotropy value after 3-4 months after injury was seen. The changes in diffusivity values were mainly seen in frontal, parietal lobe, right inferior fronto-occipital and superior longitudinal fasciculus, and posterior supramarginal gyrus. Time-related changes of tensor values of thalamus, frontal and temporal lobe had persistent and significant association with attention and learning/memory aspects. CONCLUSIONS: The findings of this study suggest that DTI detects and observes natural-recovery of brain regions affected by sub-threshold force.

No Effect of Anodal Transcranial Direct Current Stimulation on Gamma-Aminobutyric Acid Levels in Patients with Recurrent Mild Traumatic Brain Injury.

In patients in the chronic phase after recurrent mild traumatic brain injury (mTBI), alterations in gamma-aminobutyric acid (GABA) concentration and receptor activity have been reported, possibly mediating subtle but persistent cognitive deficits and increased rate of dementia in older age. We evaluated whether anodal transcranial direct current stimulation (atDCS) over the primary motor cortex reduces GABA concentration and GABAB receptor activity in patients with recurrent mTBI. Seventeen patients (mean age 25, two women) in the chronic phase after recurrent mTBI and 22 healthy control subjects (mean age 26, two women) were included. All participants received comprehensive cognitive testing and detailed questionnaires on post-concussive symptoms at baseline. Subsequently, they participated in four experimental sessions, consisting of either magnetic resonance spectroscopy (MRS)/atDCS/MRS, transcranial magnetic stimulation (TMS)/atDCS/TMS, MRS/sham/MRS, or TMS/sham/TMS to determine GABA concentration (from MRS) and GABAB receptor activity (from TMS) after atDCS and after sham stimulation. Patients with mTBI scored significantly lower on verbal fluency tasks compared with healthy control subjects. GABA concentration at baseline was associated with the number of mTBI, although no group differences in GABA concentration and GABAB receptor activity were found. Moreover, no effects of atDCS on GABA concentration and receptor activity were seen in patients with mTBI or healthy control subjects. GABA concentration may increase with the number of mTBI, but atDCS did not modulate GABA concentration and receptor activity, as has been reported previously. Specifics of experimental design and analysis, but also characteristics of the respective samples, may account for these differential findings, and should be addressed in future larger studies.

Controlled Low-Pressure Blast-Wave Exposure Causes Distinct Behavioral and Morphological Responses Modelling Mild Traumatic Brain Injury, Post-Traumatic Stress Disorder, and Comorbid Mild Traumatic Brain Injury-Post-Traumatic Stress Disorder.

The intense focus in the clinical literature on the mental and neurocognitive sequelae of explosive blast-wave exposure, especially when comorbid with post-traumatic stress-related disorders (PTSD) is justified, and warrants the design of translationally valid animal studies to provide valid complementary basic data. We employed a controlled experimental blast-wave paradigm in which unanesthetized animals were exposed to visual, auditory, olfactory, and tactile effects of an explosive blast-wave produced by exploding a thin copper wire. By combining cognitive-behavioral paradigms and ex vivo brain MRI to assess mild traumatic brain injury (mTBI) phenotype with a validated behavioral model for PTSD, complemented by morphological assessments, this study sought to examine our ability to evaluate the biobehavioral effects of low-intensity blast overpressure on rats, in a translationally valid manner. There were no significant differences between blast- and sham-exposed rats on motor coordination and strength, or sensory function. Whereas most male rats exposed to the blast-wave displayed normal behavioral and cognitive responses, 23.6% of the rats displayed a significant retardation of spatial learning acquisition, fulfilling criteria for mTBI-like responses. In addition, 5.4% of the blast-exposed animals displayed an extreme response in the behavioral tasks used to define PTSD-like criteria, whereas 10.9% of the rats developed both long-lasting and progressively worsening behavioral and cognitive "symptoms," suggesting comorbid PTSD-mTBI-like behavioral and cognitive response patterns. Neither group displayed changes on MRI. Exposure to experimental blast-wave elicited distinct behavioral and morphological responses modelling mTBI-like, PTSD-like, and comorbid mTBI-PTSD-like responses. This experimental animal model can be a useful tool for elucidating neurobiological mechanisms underlying the effects of blast-wave-induced mTBI and PTSD and comorbid mTBI-PTSD.