Imaging biomarkers of vascular and axonal injury are spatially distinct in chronic traumatic brain injury.

Traumatic Brain Injury (TBI) is associated with both diffuse axonal injury (DAI) and diffuse vascular injury (DVI), which result from inertial shearing forces. These terms are often used interchangeably, but the spatial relationships between DAI and DVI have not been carefully studied. Multimodal magnetic resonance imaging (MRI) can help distinguish these injury mechanisms: diffusion tensor imaging (DTI) provides information about axonal integrity, while arterial spin labeling (ASL) can be used to measure cerebral blood flow (CBF), and the reactivity of the Blood Oxygen Level Dependent (BOLD) signal to a hypercapnia challenge reflects cerebrovascular reactivity (CVR). Subjects with chronic TBI (n = 27) and healthy controls (n = 14) were studied with multimodal MRI. Mean values of mean diffusivity (MD), fractional anisotropy (FA), CBF, and CVR were extracted for pre-determined regions of interest (ROIs). Normalized z-score maps were generated from the pool of healthy controls. Abnormal ROIs in one modality were not predictive of abnormalities in another. Approximately 9-10% of abnormal voxels for CVR and CBF also showed an abnormal voxel value for MD, while only 1% of abnormal CVR and CBF voxels show a concomitant abnormal FA value. These data indicate that DAI and DVI represent two distinct TBI endophenotypes that are spatially independent.

Alive inside.

This article provides an ethical analysis of the U.S. practice guideline update on disorders of consciousness. Our analysis focuses on the guideline's recommendations regarding the use of investigational neuroimaging methods to assess brain-injured patients. Complex and multifaceted ethical issues have emerged because these methods alter the clinical understanding of consciousness. We address issues of false hope, patient suffering, and cost. We argue that, in spite of these concerns, there is significant benefit to using neuroimaging to assess brain-injured patients in most cases.

The Search for Consciousness.

In recent years, rapid technological developments in the field of neuroimaging have provided new methods for assessing residual cognition, detecting consciousness, and even communicating with patients who clinically appear to be in a vegetative state. Here, I highlight some of the major implications of these developments, discuss their scientific, clinical, legal, and ethical relevance, and make my own recommendations for future directions in this field.

Exploration of gray matter correlates of cognitive training benefit in adolescents with chronic traumatic brain injury.

Sustaining a traumatic brain injury (TBI) during adolescence has a profound effect on brain development and can result in persistent executive functioning deficits in daily life. Cognitive recovery from pediatric-TBI relies on the potential of neuroplasticity, which can be fostered by restorative training-programs. However the structural mechanisms underlying cognitive recovery in the immature brain are poorly understood. This study investigated gray matter plasticity following 2 months of cognitive training in young patients with TBI. Sixteen adolescents in the chronic stage of moderate-severe-TBI (9 male, mean age = 15y8m ±â€¯1y7m) were enrolled in a cognitive computerized training program for 8 weeks (5 times/week, 40 min/session). Pre-and post-intervention, and 6 months after completion of the training, participants underwent a comprehensive neurocognitive test-battery and anatomical Magnetic Resonance Imaging scans. We selected 9 cortical-subcortical Regions-Of-Interest associated with Executive Functioning (EF-ROIs) and 3 control regions from the Desikan-Killiany atlas. Baseline analyses showed significant decreased gray matter density in the superior frontal gyri p = 0.033, superior parietal gyri p = 0.015 and thalamus p = 0.006 in adolescents with TBI compared to age and gender matched controls. Linear mixed model analyses of longitudinal volumetric data of the EF-ROI revealed no strong evidence of training-related changes in the group with TBI. However, compared to the change over time in the control regions between post-intervention and 6 months follow-up, the change in the EF-ROIs showed a significant difference. Exploratory analyses revealed a negative correlation between the change on the Digit Symbol Substitution test and the change in volume of the putamen (r = -0.596, p = 0.015). This preliminary study contributes to the insights of training-related plasticity mechanisms after pediatric-TBI.

Vascular Abnormalities within Normal Appearing Tissue in Chronic Traumatic Brain Injury.

Magnetic resonance imaging (MRI) is a powerful tool for visualizing traumatic brain injury(TBI)-related lesions. Trauma-induced encephalomalacia is frequently identified by its hyperintense appearance on fluid-attenuated inversion recovery (FLAIR) sequences. In addition to parenchymal lesions, TBI commonly results in cerebral microvascular injury, but its anatomical relationship to parenchymal encephalomalacia is not well characterized. The current study utilized a multi-modal MRI protocol to assess microstructural tissue integrity (by mean diffusivity [MD] and fractional aniosotropy [FA]) and altered vascular function (by cerebral blood flow [CBF] and cerebral vascular reactivity [CVR]) within regions of visible encephalomalacia and normal appearing tissue in 27 chronic TBI (minimum 6 months post-injury) subjects. Fifteen subjects had visible encephalomalacias whereas 12 did not have evident lesions on MRI. Imaging from 14 age-matched healthy volunteers were used as controls. CBF was assessed by arterial spin labeling (ASL) and CVR by measuring the change in blood-oxygen-level-dependent (BOLD) MRI during a hypercapnia challenge. There was a significant reduction in FA, CBF, and CVR with a complementary increase in MD within regions of FLAIR-visible encephalomalacia (p < 0.05 for all comparisons). In normal-appearing brain regions, only CVR was significantly reduced relative to controls (p < 0.05). These findings indicate that vascular dysfunction represents a TBI endophenotype that is distinct from structural injury detected using conventional MRI, may be present even in the absence of visible structural injury, and persists long after trauma. CVR may serve as a useful diagnostic and pharmacodynamic imaging biomarker of traumatic microvascular injury.

Imaging of Cerebrovascular Function in Chronic Traumatic Brain Injury.

Traumatic cerebrovascular injury (TCVI) is a common pathologic mechanism of traumatic brain injury (TBI) and presents an attractive target for intervention. The aims of this study were to assess cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) using magnetic resonance imaging (MRI) to assess their value as biomarkers of TCVI in chronic TBI, characterize the spatial distribution of TCVI, and assess the relationships between each biomarker and neuropsychological and clinical assessments. Forty-two subjects (27 chronic TBI, 15 age- and gender-matched healthy volunteers) were studied cross-sectionally. CBF was measured by arterial spin labeling and CVR by assessing the MRI-blood oxygen level-dependent signal with hypercapnia challenge. A focused neuropsychological battery adapted from the TBI Common Data Elements and neurobehavioral symptom questionnaires were administered at the time of the imaging session. Chronic TBI subjects showed a significant reduction in mean global, gray matter (GM), and white matter (WM) CVR, compared with healthy volunteers (p < 0.001). Mean GM CVR had the greatest effect size (Cohen's d = 0.9). CVR maps in chronic TBI subjects showed patchy, multifocal CVR deficits. CBF discriminated poorly between TBI subjects and healthy volunteers and did not correlate with CVR. Mean global CVR correlated best with chronic neurobehavioral symptoms among TBI subjects. Global, GM, and WM CVR are reliable and potentially useful biomarkers of TCVI in the chronic stage after moderate-to-severe TBI. CBF is less useful as biomarker of TCVI. CVR correlates best with chronic TBI symptoms. CVR has potential as a predictive and pharmacodynamic biomarker for interventions targeting TCVI.

Postmortem Autopsy-Confirmation of Antemortem [F-18]FDDNP-PET Scans in a Football Player With Chronic Traumatic Encephalopathy.

Currently, only presumptive diagnosis of chronic traumatic encephalopathy (CTE) can be made in living patients. We present a modality that may be instrumental to the definitive diagnosis of CTE in living patients based on brain autopsy confirmation of [F-18]FDDNP-PET findings in an American football player with CTE. [F-18]FDDNP-PET imaging was performed 52 mo before the subject's death. Relative distribution volume parametric images and binding values were determined for cortical and subcortical regions of interest. Upon death, the brain was examined to identify the topographic distribution of neurodegenerative changes. Correlation between neuropathology and [F-18]FDDNP-PET binding patterns was performed using Spearman rank-order correlation. Mood, behavioral, motor, and cognitive changes were consistent with chronic traumatic myeloencephalopathy with a 22-yr lifetime risk exposure to American football. There were tau, amyloid, and TDP-43 neuropathological substrates in the brain with a differential topographically selective distribution. [F-18]FDDNP-PET binding levels correlated with brain tau deposition (rs = 0.59, P = .02), with highest relative distribution volumes in the parasagittal and paraventricular regions of the brain and the brain stem. No correlation with amyloid or TDP-43 deposition was observed. [F-18]FDDNP-PET signals may be consistent with neuropathological patterns of tau deposition in CTE, involving areas that receive the maximal shearing, angular-rotational acceleration-deceleration forces in American football players, consistent with distinctive and differential topographic vulnerability and selectivity of CTE beyond brain cortices, also involving midbrain and limbic areas. Future studies are warranted to determine whether differential and selective [F-18]FDDNP-PET may be useful in establishing a diagnosis of CTE in at-risk patients.

The value of 11C-methionine PET in the early differentiation between tumour recurrence and radionecrosis in patients treated for a high-grade glioma and indeterminate MRI. / Utilidad de la PET con 11C-metionina en la diferenciación precoz entre recurrencia tumoral y radionecrosis de pacientes tratados de glioma de alto grado con RM indeterminada.

OBJECTIVE: To evaluate the contribution of 11C-Methionine PET in the early differentiation between tumour recurrence and radionecrosis in patients treated for a high grade glioma. METHOD: The study included 30 patients with glioma (III/IV grade) treated with surgery/radiotherapy/chemotherapy (5-8 months) and with an indeterminate MRI. All patients underwent a 11C-Methione PET (within 15 days of MRI) and studies were visually analysed (intensity and morphology of uptake), quantified (SUV max/SUV mean background), and coregistered to MRI (3D-Flair). Patient management was decided by the neuro-oncology committee to clinical and imaging follow-up, second-line treatment, or surgery. RESULTS: There were 23 11C-Methionine PET studies visually positive. Morphology of uptake was focal in 15, diffuse in 4, and ring-shaped in 4. Three out of the focal uptake cases underwent resection (Histopathology +). Sixteen underwent second-line therapy (11 responded; 5 progressed). The 4 cases with ring-shaped uptake were followed-up, and progression was found in 2 (true-positive), and disease-free in 2 (follow-up of 6 and 7 months, respectively) (false-positive). Seven out of 11C-Methionine studies PET were visually negative, and all of them were disease-free (follow-up of 3-12 months). SUV lesion/background was 2.79±1.35 in tumour recurrence, and 1.53±0.39 in radionecrosis (P<.05). Taking into account a SUV lesion/background threshold of 2.35, the sensitivity and specificity values were 90.5% and 100%, respectively. CONCLUSION: Visual analysis, quantitative and PET/MRI coregistration of 11C-Methionine PET showed their complementary role in patients with indeterminate MRI results, thus allowing early differentiation between tumour recurrence and radionecrosis, and helping in the individual therapy approach.

Function-structure connectivity in patients with severe brain injury as measured by MRI-DWI and FDG-PET.

A vast body of literature exists showing functional and structural dysfunction within the brains of patients with disorders of consciousness. However, the function (fluorodeoxyglucose FDG-PET metabolism)-structure (MRI-diffusion-weighted images; DWI) relationship and how it is affected in severely brain injured patients remains ill-defined. FDG-PET and MRI-DWI in 25 severely brain injured patients (19 Disorders of Consciousness of which 7 unresponsive wakefulness syndrome, 12 minimally conscious; 6 emergence from minimally conscious state) and 25 healthy control subjects were acquired here. Default mode network (DMN) function-structure connectivity was assessed by fractional anisotropy (FA) and metabolic standardized uptake value (SUV). As expected, a profound decline in regional metabolism and white matter integrity was found in patients as compared with healthy subjects. Furthermore, a function-structure relationship was present in brain-damaged patients between functional metabolism of inferior-parietal, precuneus, and frontal regions and structural integrity of the frontal-inferiorparietal, precuneus-inferiorparietal, thalamo-inferioparietal, and thalamofrontal tracts. When focusing on patients, a stronger relationship between structural integrity of thalamo-inferiorparietal tracts and thalamic metabolism in patients who have emerged from the minimally conscious state as compared with patients with disorders of consciousness was found. The latter finding was in line with the mesocircuit hypothesis for the emergence of consciousness. The findings showed a positive function-structure relationship within most regions of the DMN. Hum Brain Mapp 37:3707-3720, 2016. © 2016 Wiley Periodicals, Inc.

Blood-Brain Barrier Dysfunction as a Hallmark Pathology in Chronic Traumatic Encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative condition associated with repetitive mild traumatic brain injury. In recent years, attention has focused on emerging evidence linking the development of CTE to concussive injuries in athletes and military personnel; however, the underlying molecular pathobiology of CTE remains unclear. Here, we provide evidence that the blood-brain barrier (BBB) is disrupted in regions of dense perivascular p-Tau accumulation in a case of CTE. Immunoreactivity patterns of the BBB-associated tight junction components claudin-5 and zonula occludens-1 were markedly discontinuous or absent in regions of perivascular p-Tau deposition; there was also immunohistochemical evidence of a BBB in these foci. Because the patient was diagnosed premortem clinically as having progressive supranuclear palsy (PSP), we also compromised that the CTE alterations appear to be distinct from those in the brain of a patient with PSP. This report represents the first description of BBB dysfunction in a pathologically proven CTE case and suggests a vascular component in the postconcussion cascade of events that may ultimately lead to development of a progressive degenerative disorder. BBB dysfunction may represent a correlate of neural dysfunction in live subjects suspected of being at risk for development of CTE.

Tau imaging in the study of ageing, Alzheimer's disease, and other neurodegenerative conditions.

In vivo tau imaging allows a deeper understanding of tau deposition in the brain, providing insights into the causes, diagnosis and treatment of primary and secondary tauopathies such as Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, chronic traumatic encephalopathy, and some variants of frontotemporal lobar degeneration. The cross-sectional and longitudinal assessment of the temporal and spatial patterns of tau deposition in the brain will allow a better understanding of the role tau plays in ageing as well as its relationship with cognition, genotype, and neurodegeneration. It is likely that selective tau imaging could be used as a diagnostic and prognostic biomarker of disease progression, as well as a surrogate marker for monitoring of efficacy and patient recruitment for disease-specific therapeutic trials.

Early Computed Tomography Frontal Abnormalities Predict Long-Term Neurobehavioral Problems But Not Affective Problems after Moderate to Severe Traumatic Brain Injury.

Behavioral problems are serious consequences of moderate to severe traumatic brain injury (TBI) and have a negative impact on outcome. There may be two types: neurobehavioral problems, manifesting as inadequate social behavior resulting from prefrontal system damage, and affective behavioral problems, resulting from emotional distress as a reaction to the brain injury. In the present study we investigated whether these two types of behavioral problems, as indicated by proxies, could be distinguished in a group of chronic TBI patients and whether early indicators of prefrontal damage on imaging could predict long-term neurobehavioral problems. Computed tomography (CT) imaging data on admission were used to identify frontal lesions. Three hundred twenty-three moderate to severe TBI survivors received 2 to 16 years post-trauma an aftercare survey with seven questions asking for changes in behavior and affect, presented both to patients and their proxies. One hundred eighty-six patients (59%) answered the behavioral questions; 42% had frontal lesions on CT. Ordinal common factor analysis on proxy scores yielded two factors, with behavior and affective items clearly separated and the anger item mediocre related to both factors. Three scales were created: Behavior, Affective and Anger. Frontal patients scored significantly higher on the Behavior and Anger scales. Logistic regression analysis showed a fourfold increase of long-term neurobehavioral problems in patients with frontal lesions. Long-term neurobehavioral problems were significantly correlated to one-year outcome and return to work in the long term. We conclude that in patients with moderate to severe TBI neurobehavioral and affective problems can be distinguished. Early CT frontal abnormalities predict long-term neurobehavioral problems, but not affective problems.

In vivo characterization of chronic traumatic encephalopathy using [F-18]FDDNP PET brain imaging.

Chronic traumatic encephalopathy (CTE) is an acquired primary tauopathy with a variety of cognitive, behavioral, and motor symptoms linked to cumulative brain damage sustained from single, episodic, or repetitive traumatic brain injury (TBI). No definitive clinical diagnosis for this condition exists. In this work, we used [F-18]FDDNP PET to detect brain patterns of neuropathology distribution in retired professional American football players with suspected CTE (n = 14) and compared results with those of cognitively intact controls (n = 28) and patients with Alzheimer's dementia (AD) (n = 24), a disease that has been cognitively associated with CTE. [F-18]FDDNP PET imaging results in the retired players suggested the presence of neuropathological patterns consistent with models of concussion wherein brainstem white matter tracts undergo early axonal damage and cumulative axonal injuries along subcortical, limbic, and cortical brain circuitries supporting mood, emotions, and behavior. This deposition pattern is distinctively different from the progressive pattern of neuropathology [paired helical filament (PHF)-tau and amyloid-ß] in AD, which typically begins in the medial temporal lobe progressing along the cortical default mode network, with no or minimal involvement of subcortical structures. This particular [F-18]FDDNP PET imaging pattern in cases of suspected CTE also is primarily consistent with PHF-tau distribution observed at autopsy in subjects with a history of mild TBI and autopsy-confirmed diagnosis of CTE.

Voyage au bout de la nuit: Aß and tau imaging in dementias.

The last decade has witnessed the development and characterization of tracers for the evaluation of neuropathology in vivo. The introduction of these tracers, namely ß-amyloid (Aß) and later tau, are providing the tools to change the landscape and refine our understanding of Aß and tau deposition in the brain, allowing to investigate the causes, refine diagnosis and improve treatment of major neurodegenerative conditions such as Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE) and frontotemporal lobar degeneration (FTLD). Aß and tau imaging allow examination of the regional and global changes of these disease markers over time as well as their relationship with other relevant parameters such as cognitive performance and neurodegenerative changes. Aß and tau imaging will enable to establish the role Aß and tau play -and interplay- in aging and disease. Aß and tau imaging value resides in being not only diagnostic, prognostic or progression markers, but also surrogate markers of disease, crucial for patient recruitment and efficacy evaluation of disease-specific therapies.

Tauopathy PET and amyloid PET in the diagnosis of chronic traumatic encephalopathies: studies of a retired NFL player and of a man with FTD and a severe head injury.

Single, severe traumatic brain injury (TBI) which elevates CNS amyloid, increases the risk of Alzheimer's disease (AD); while repetitive concussive and subconcussive events as observed in athletes and military personnel, may increase the risk of chronic traumatic encephalopathy (CTE). We describe two clinical cases, one with a history of multiple concussions during a career in the National Football League (NFL) and the second with frontotemporal dementia and a single, severe TBI. Both patients presented with cognitive decline and underwent [(18)F]-Florbetapir positron emission tomography (PET) imaging for amyloid plaques; the retired NFL player also underwent [(18)F]-T807 PET imaging, a new ligand binding to tau, the main constituent of neurofibrillary tangles (NFT). Case 1, the former NFL player, was 71 years old when he presented with memory impairment and a clinical profile highly similar to AD. [(18)F]-Florbetapir PET imaging was negative, essentially excluding AD as a diagnosis. CTE was suspected clinically, and [(18)F]-T807 PET imaging revealed striatal and nigral [(18)F]-T807 retention consistent with the presence of tauopathy. Case 2 was a 56-year-old man with personality changes and cognitive decline who had sustained a fall complicated by a subdural hematoma. At 1 year post injury, [(18)F]-Florbetapir PET imaging was negative for an AD pattern of amyloid accumulation in this subject. Focal [(18)F]-Florbetapir retention was noted at the site of impact. In case 1, amyloid imaging provided improved diagnostic accuracy where standard clinical and laboratory criteria were inadequate. In that same case, tau imaging with [(18)F]-T807 revealed a subcortical tauopathy that we interpret as a novel form of CTE with a distribution of tauopathy that mimics, to some extent, that of progressive supranuclear palsy (PSP), despite a clinical presentation of amnesia without any movement disorder complaints or signs. A key distinguishing feature is that our patient presented with hippocampal involvement, which is more frequently seen in CTE than in PSP. In case 2, focal [(18)F]-Florbetapir retention at the site of injury in an otherwise negative scan suggests focal amyloid aggregation. In each of these complex cases, a combination of [(18)F]-fluorodeoxyglucose, [(18)F]-Florbetapir and/or [(18)F]-T807 PET molecular imaging improved the accuracy of diagnosis and prevented inappropriate interventions.

F-18 FDG PET imaging of chronic traumatic brain injury in boxers: a statistical parametric analysis.

PURPOSE: The participation in concussive susceptible sports such as boxing may cause chronic traumatic brain injury. The objective of this study was to determine whether there are unique patterns of reduced brain glucose metabolism in professional and amateur boxers. METHOD: We compared the fluorine-18 fluorodeoxyglucose (F-18 FDG) PET brain scans of boxers (group) (N=19) with those of controls (group) (N=7) using both statistical parametric mapping and region of interest analysis. RESULTS: Boxers showed decreased F-18 FDG uptake by 8-15% in the following brain areas: posterior cingulate cortex, parieto-occipito, frontal lobes (Broca's area) bilaterally, and the cerebellum (P<0.005) as compared with controls. CONCLUSION: Our results suggest that F-18 FDG PET scans of boxers suspected of chronic traumatic brain injury show unique patterns of hypometabolism, and that these patterns may reflect the mechanisms of repeated traumatic brain injury unique to boxers.

Transcranial color-coded duplex sonography allows to assess cerebral perfusion pressure noninvasively following severe traumatic brain injury.

OBJECTIVE: Assess optimal equation to noninvasively estimate intracranial pressure (eICP) and cerebral perfusion pressure (eCPP) following severe traumatic brain injury (TBI) using transcranial color-coded duplex sonography (TCCDS). DESIGN AND SETTING: This is an observational clinical study in a university hospital. PATIENTS: A total of 45 continuously sedated (BIS < 50), normoventilated (paCO(2) > 35 mmHg), and non-febrile TBI patients. METHODS: eICP and eCPP based on TCCDS-derived flow velocities and arterial blood pressure values using three different equations were compared to actually measured ICP and CPP in severe TBI patients subjected to standard treatment. Optimal equation was assessed by Bland-Altman analysis. RESULTS: The equations: ICP = 10:927 x PI(pulsatility index) - 1:284 and CPP = 89:646 - 8:258 PI resulted in eICP and eCPP similar to actually measured ICP and CPP with eICP 10.6 +/- 4.8 vs. ICP 10.3 +/- 2.8 and eCPP 81.1 +/- 7.9 vs. CPP 80.9 +/- 2.1 mmHg, respectively. The other two equations, eCPP = (MABP x EDV)/mFV + 14 and eCPP = mFV / (mFV - EDV)] x (MABP - RRdiast), resulted in significantly decreased eCPP values: 72.9 +/- 10.1 and 67 +/- 19.5 mmHg, respectively. Superiority of the first equation was confirmed by Bland-Altman revealing a smallest standard deviations for eCPP and eICP. CONCLUSIONS: TCCDS-based equation (ICP = 10.927 x PI - 1.284) allows to screen patients at risk of increased ICP and decreased CPP. However, adequate therapeutic interventions need to be based on continuously determined ICP and CPP values.

Pilot case study of the therapeutic potential of hyperbaric oxygen therapy on chronic brain injury.

BACKGROUND: Recently, the effect of hyperbaric oxygen (HBO(2)) therapy was explored in the treatment of chronic TBI. It has been speculated that idling neurons in the penumbra zone remain viable several years after injury and might be reactivated by enhanced oxygenation. We studied the therapeutic potential of HBO(2) therapy in a 54-year-old man who had sustained traumatic brain injuries one year before testing that resulted in permanent neurological symptoms. METHODS: Two treatment series separated by a one-year inter-session interval were administered. Treatment series consisted of 20 and 60 daily one-hour exposures to 100% oxygen at 2 ATA. Electrophysiological (event-related potentials), metabolic and behavioral (sensorimotor and neuropsychological) measurements were obtained to evaluate the effects of hyperbaric oxygen therapy on neurocognitive functioning. RESULTS: Following the initial treatment, the patient showed improvements in sensorimotor functions, as well as enhanced P300 amplitude in the damaged hemisphere. Although most of these gains were no longer observed one year after treatment, these were reinstated with an additional series of 60 exposures. Neuropsychological improvements were also observed after the completion of the second series of treatments. CONCLUSION: The present single-case study provides preliminary evidence of neuropsychological and electrophysiological improvements after series of 20 and 60 treatments, although the first dosage appeared to be insufficient to produce permanent benefits. Longitudinal studies using different treatment parameters should be conducted if we are to systematically investigate long-term improvements resulting from HBO(2) therapy.

Effects of the dopaminergic agent and NMDA receptor antagonist amantadine on cognitive function, cerebral glucose metabolism and D2 receptor availability in chronic traumatic brain injury: a study using positron emission tomography (PET).

PRIMARY OBJECTIVE: This study was performed to assess effects of amantadine (AMH), a dopaminergic agent and NMDA antagonist, on chronic traumatic brain injury (TBI). The primary hypotheses were that amantadine treatment would result in executive function improvement and increased activity in pre-frontal cortex. RESEARCH DESIGN: An open-label design was used. METHODS: Twenty-two subjects underwent neuropsychological testing pre- and post-12 week treatment. Six subjects also underwent PET scanning. INTERVENTION: Amantadine 400 mg was administered per day. RESULTS: Significant improvements on tests of executive function were observed with treatment. Analysis of PET data demonstrated a significant increase in left pre-frontal cortex glucose metabolism. There was a significant positive correlation between executive domain scores and left pre-frontal glucose metabolism. CONCLUSIONS: This is the first known study to assess amantadine in chronic TBI using PET and the data are consistent with the hypotheses. The conduction of further studies is warranted.

Better without (lateral) frontal cortex? Insight problems solved by frontal patients.

A recently proposed theory on frontal lobe functions claims that the prefrontal cortex, particularly its dorso-lateral aspect, is crucial in defining a set of responses suitable for a particular task, and biasing these for selection. This activity is carried out for virtually any kind of non-routine tasks, without distinction of content. The aim of this study is to test the prediction of Frith's 'sculpting the response space' hypothesis by means of an 'insight' problem-solving task, namely the matchstick arithmetic task. Starting from Knoblich et al.'s interpretation for the failure of healthy controls to solve the matchstick problem, and Frith's theory on the role of dorsolateral frontal cortex, we derived the counterintuitive prediction that patients with focal damage to the lateral frontal cortex should perform better than a group of healthy participants on this rather difficult task. We administered the matchstick task to 35 patients (aged 26-65 years) with a single focal brain lesion as determined by a CT or an MRI scan, and to 23 healthy participants (aged 34-62 years). The findings seemed in line with theoretical predictions. While only 43% of healthy participants could solve the most difficult matchstick problems ('type C'), 82% of lateral frontal patients did so (Fisher's exact test, P < 0.05). In conclusion, the combination of Frith's and Knoblich et al.'s theories was corroborated.