Identification of an Intravenous Injectable NK1 Receptor Antagonist for Use in Traumatic Brain Injury.

Traumatic brain injuries represent a leading cause of death and disability in the paediatric and adult populations. Moderate-to-severe injuries are associated with blood-brain barrier dysfunction, the development of cerebral oedema, and neuroinflammation. Antagonists of the tachykinin NK1 receptor have been proposed as potential agents for the post-injury treatment of TBI. We report on the identification of EUC-001 as a potential clinical candidate for development as a novel TBI therapy. EUC-001 is a selective NK1 antagonist with a high affinity for the human NK1 receptor (Ki 5.75 × 10-10 M). It has sufficient aqueous solubility to enable intravenous administration, whilst still retaining good CNS penetration as evidenced by its ability to inhibit the gerbil foot-tapping response. Using an animal model of TBI, the post-injury administration of EUC-001 was shown to restore BBB function in a dose-dependent manner. EUC-001 was also able to ameliorate cerebral oedema. These effects were associated with a significant reduction in post-TBI mortality. In addition, EUC-001 was able to significantly reduce functional deficits, both motor and cognitive, that normally follow a severe injury. EUC-001 is proposed as an ideal candidate for clinical development for TBI.

NK1 tachykinin receptor antagonist treatment reduces cerebral edema and intracranial pressure in an ovine model of ischemic stroke.

Following ischemic stroke, substance P (SP)-mediated neurogenic inflammation is associated with profound blood-brain barrier (BBB) dysfunction, cerebral edema, and elevated intracranial pressure (ICP). SP elicits its effects by binding the neurokinin 1 tachykinin receptor (NK1-R), with administration of an NK1-R antagonist shown to ameliorate BBB dysfunction and cerebral edema in rodent and permanent ovine stroke models. Given the importance of reperfusion in clinical stroke, this study examined the efficacy of NK1-R antagonist treatment in reducing cerebral edema and ICP in an ovine model of transient middle cerebral artery occlusion (tMCAo). Anesthetized sheep (n = 24) were subject to 2-hours tMCAo and randomized (n = 6/group) to receive early NK1-R treatment (days 1-3 post-stroke), delayed NK1-R treatment (day 5 post-stroke), or saline vehicle. At 6-days post-stroke animals were re-anaesthetized and ICP measured, followed by MRI to evaluate infarction, edema and BBB dysfunction. Following both early and delayed NK1-R antagonist administration, ICP was significantly reduced on day 6 compared to vehicle animals (p < 0.05), accompanied by a reduction in cerebral edema, midline shift and BBB dysfunction (p < 0.05). This study demonstrates that NK1-R antagonist treatment is an effective novel therapy for cerebral edema and elevated ICP following stroke in an ovine model, warranting future clinical evaluation.

Chronic traumatic encephalopathy (CTE)-features and forensic considerations.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative condition, in which the only known cause is exposure to repeated episodes of blunt head trauma. It most often occurs in professional and amateur athletes who have had frequent and repetitive cranial impacts during contact sports, but may also be found in victims of domestic violence, military personnel exposed to explosive devices and in individuals with severe epilepsy. The pathognomonic pathological findings are of neurofibrillary tangles and pretangles in the depths of the cerebral sulci caused by perivascular accumulation of phosphorylated Tau (pTau). Cases may be high profile requiring an evaluation of whether the neuropathological findings of CTE can be related to injuries previously sustained on the sporting field. Failure to examine the brain or to adequately sample appropriate areas at autopsy may lead to cases being overlooked and to an underestimation of the incidence of this condition in the community. Performing immunohistochemical staining for pTau in three areas from the neocortex has been found to be a useful screening tool for CTE. Ascertaining whether there is a history of head trauma, including exposure to contact sports, as a standard part of forensic clinical history protocols will help identify at-risk individuals so that Coronial consideration of the need for brain examination can be appropriately informed. Repetitive head trauma, particularly from contact sport, is being increasingly recognized as a cause of significant preventable neurodegeneration.

Investigating genetic variants in microRNA regulators of Neurokinin-1 receptor in sudden infant death syndrome.

Sudden infant death syndrome (SIDS) occurs more often in male than in female infants, suggesting involvement of the X-chromosome. Histopathological studies have suggested that altered expression of the Neurokinin-1 receptor may also play a role in the pathogenesis of SIDS. It was hypothesised that genetic variants in three X-chromosome-encoded microRNA (miRNA/miR), known to down-regulate expression of the Neurokinin-1 receptor, may contribute to SIDS. AIM: To identify sequence variants in the miRNAs within a study cohort (27 cases of SIDS and 28 controls) and determine if there was a difference in the frequencies in male and female SIDS infants. METHODS: Genomic DNA prepared from stored blood spots was amplified and sequenced to identify genetic variants in miR500A, miR500B and miR320D2. RESULTS: No novel variants in the miRNAs were identified in our study cohort. We identified one known single-nucleotide polymorphism (SNP) in miR320D2: rs5907732 G/T, in both cases and controls. No significant difference in the SNP frequency was observed between male and female SIDS cases. CONCLUSION: This pilot study suggests that sequence variants in three miRNAs do not contribute to the reported higher prevalence of SIDS in male infants and do not contribute to the pathogenesis of SIDS in our cohort.

Artificial intelligence for diagnosis and Gleason grading of prostate cancer: the PANDA challenge.

Artificial intelligence (AI) has shown promise for diagnosing prostate cancer in biopsies. However, results have been limited to individual studies, lacking validation in multinational settings. Competitions have been shown to be accelerators for medical imaging innovations, but their impact is hindered by lack of reproducibility and independent validation. With this in mind, we organized the PANDA challenge-the largest histopathology competition to date, joined by 1,290 developers-to catalyze development of reproducible AI algorithms for Gleason grading using 10,616 digitized prostate biopsies. We validated that a diverse set of submitted algorithms reached pathologist-level performance on independent cross-continental cohorts, fully blinded to the algorithm developers. On United States and European external validation sets, the algorithms achieved agreements of 0.862 (quadratically weighted κ, 95% confidence interval (CI), 0.840-0.884) and 0.868 (95% CI, 0.835-0.900) with expert uropathologists. Successful generalization across different patient populations, laboratories and reference standards, achieved by a variety of algorithmic approaches, warrants evaluating AI-based Gleason grading in prospective clinical trials.

NK1 antagonists attenuate tau phosphorylation after blast and repeated concussive injury.

Exposure to repeated concussive traumatic brain injury (TBI) and to blast-induced TBI has been associated with the potential development of the neurodegenerative condition known as chronic traumatic encephalopathy (CTE). CTE is characterized by the accumulation of hyperphosphorylated tau protein, with the resultant tau tangles thought to initiate the cognitive and behavioral manifestations that appear as the condition progresses. However, the mechanisms linking concussive and blast TBI with tau hyperphosphorylation are unknown. Here we show that single moderate TBI, repeated concussive TBI and blast-induced mild TBI all result in hyperphosphorylation of tau via a substance P mediated mechanism. Post-injury administration of a substance P, NK1 receptor antagonist attenuated the injury-induced phosphorylation of tau by modulating the activity of several key kinases including Akt, ERK1/2 and JNK, and was associated with improvement in neurological outcome. We also demonstrate that inhibition of the TRPV1 mechanoreceptor, which is linked to substance P release, attenuated injury-associated tau hyperphosphorylation, but only when it was administered prior to injury. Our results demonstrate that TBI-mediated stimulation of brain mechanoreceptors is associated with substance P release and consequent tau hyperphosphorylation, with administration of an NK1 receptor antagonist attenuating tau phosphorylation and associated neurological deficits. NK1 antagonists may thus represent a pharmacological approach to attenuate the potential development of CTE following concussive and blast TBI.

Artificial intelligence assistance significantly improves Gleason grading of prostate biopsies by pathologists.

The Gleason score is the most important prognostic marker for prostate cancer patients, but it suffers from significant observer variability. Artificial intelligence (AI) systems based on deep learning can achieve pathologist-level performance at Gleason grading. However, the performance of such systems can degrade in the presence of artifacts, foreign tissue, or other anomalies. Pathologists integrating their expertise with feedback from an AI system could result in a synergy that outperforms both the individual pathologist and the system. Despite the hype around AI assistance, existing literature on this topic within the pathology domain is limited. We investigated the value of AI assistance for grading prostate biopsies. A panel of 14 observers graded 160 biopsies with and without AI assistance. Using AI, the agreement of the panel with an expert reference standard increased significantly (quadratically weighted Cohen's kappa, 0.799 vs. 0.872; p = 0.019). On an external validation set of 87 cases, the panel showed a significant increase in agreement with a panel of international experts in prostate pathology (quadratically weighted Cohen's kappa, 0.733 vs. 0.786; p = 0.003). In both experiments, on a group-level, AI-assisted pathologists outperformed the unassisted pathologists and the standalone AI system. Our results show the potential of AI systems for Gleason grading, but more importantly, show the benefits of pathologist-AI synergy.

Automated deep-learning system for Gleason grading of prostate cancer using biopsies: a diagnostic study.

BACKGROUND: The Gleason score is the strongest correlating predictor of recurrence for prostate cancer, but has substantial inter-observer variability, limiting its usefulness for individual patients. Specialised urological pathologists have greater concordance; however, such expertise is not widely available. Prostate cancer diagnostics could thus benefit from robust, reproducible Gleason grading. We aimed to investigate the potential of deep learning to perform automated Gleason grading of prostate biopsies. METHODS: In this retrospective study, we developed a deep-learning system to grade prostate biopsies following the Gleason grading standard. The system was developed using randomly selected biopsies, sampled by the biopsy Gleason score, from patients at the Radboud University Medical Center (pathology report dated between Jan 1, 2012, and Dec 31, 2017). A semi-automatic labelling technique was used to circumvent the need for manual annotations by pathologists, using pathologists' reports as the reference standard during training. The system was developed to delineate individual glands, assign Gleason growth patterns, and determine the biopsy-level grade. For validation of the method, a consensus reference standard was set by three expert urological pathologists on an independent test set of 550 biopsies. Of these 550, 100 were used in an observer experiment, in which the system, 13 pathologists, and two pathologists in training were compared with respect to the reference standard. The system was also compared to an external test dataset of 886 cores, which contained 245 cores from a different centre that were independently graded by two pathologists. FINDINGS: We collected 5759 biopsies from 1243 patients. The developed system achieved a high agreement with the reference standard (quadratic Cohen's kappa 0·918, 95% CI 0·891-0·941) and scored highly at clinical decision thresholds: benign versus malignant (area under the curve 0·990, 95% CI 0·982-0·996), grade group of 2 or more (0·978, 0·966-0·988), and grade group of 3 or more (0·974, 0·962-0·984). In an observer experiment, the deep-learning system scored higher (kappa 0·854) than the panel (median kappa 0·819), outperforming 10 of 15 pathologist observers. On the external test dataset, the system obtained a high agreement with the reference standard set independently by two pathologists (quadratic Cohen's kappa 0·723 and 0·707) and within inter-observer variability (kappa 0·71). INTERPRETATION: Our automated deep-learning system achieved a performance similar to pathologists for Gleason grading and could potentially contribute to prostate cancer diagnosis. The system could potentially assist pathologists by screening biopsies, providing second opinions on grade group, and presenting quantitative measurements of volume percentages. FUNDING: Dutch Cancer Society.

Determining the Temporal Profile of Intracranial Pressure Changes Following Transient Stroke in an Ovine Model.

BACKGROUND AND PURPOSE: Cerebral edema and elevated intracranial pressure (ICP) are the leading cause of death in the first week following stroke. Despite this, current treatments are limited and fail to address the underlying mechanisms of swelling, highlighting the need for targeted treatments. When screening promising novel agents, it is essential to use clinically relevant large animal models to increase the likelihood of successful clinical translation. As such, we sought to develop a survival model of transient middle cerebral artery occlusion (tMCAO) in the sheep and subsequently characterize the temporal profile of cerebral edema and elevated ICP following stroke in this novel, clinically relevant model. METHODS: Merino-sheep (27M;31F) were anesthetized and subject to 2 h tMCAO with reperfusion or sham surgery. Following surgery, animals were allowed to recover and returned to their home pens. At preselected times points ranging from 1 to 7 days post-stroke, animals were re-anesthetized, ICP measured for 4 h, followed by imaging with MRI to determine cerebral edema, midline shift and infarct volume (FLAIR, T2 and DWI). Animals were subsequently euthanized and their brain removed for immunohistochemical analysis. Serum and cerebrospinal fluid samples were also collected and analyzed for substance P (SP) using ELISA. RESULTS: Intracranial pressure and MRI scans were normal in sham animals. Following stroke, ICP rose gradually over time and by 5 days was significantly (p < 0.0001) elevated above sham levels. Profound cerebral edema was observed as early as 2 days post-stroke and continued to evolve out to 6 days, resulting in significant midline shift which was most prominent at 5 days post-stroke (p < 0.01), in keeping with increasing ICP. Serum SP levels were significantly elevated (p < 0.01) by 7 days post-tMCAO. CONCLUSION: We have successfully developed a survival model of ovine tMCAO and characterized the temporal profile of ICP. Peak ICP elevation, cerebral edema and midline shift occurred at days 5-6 following stroke, accompanied by an elevation in serum SP. Our findings suggest that novel therapeutic agents screened in this model targeting cerebral edema and elevated ICP would most likely be effective when administered prior to 5 days, or as early as possible following stroke onset.

NK1-r Antagonist Treatment Comparable to Decompressive Craniectomy in Reducing Intracranial Pressure Following Stroke.

Background and Purpose: The morbidity and early mortality associated with stroke is largely attributable to cerebral edema and elevated intracranial pressure (ICP). Existing pharmacotherapies do not target the underlying pathophysiology and are often ineffective in sustainably lowering ICP, whilst decompressive craniectomy (DC) surgery is life-saving yet with surgical/peri-operative risk and increased morbidity in the elderly. Accordingly, there is an urgent need for therapies that directly target the mechanisms of edema genesis. Neurogenic inflammation, mediated by substance P (SP) binding to the tachykinin NK1 receptor (NK1-r), is associated with blood-brain barrier (BBB) disruption, cerebral edema and poor outcome post-stroke. NK1-r antagonist treatment ameliorates BBB dysfunction and cerebral edema in rodent stroke models. However, treatment has not been investigated in a large animal model, an important step toward clinical translation. Consequently, the current study compared the efficacy of NK1-r antagonist treatment to DC surgery in reducing ICP post-stroke in a clinically relevant ovine model. Methods: Anesthetized female Merino sheep (65 ± 6 kg, 18-24 months) underwent sham surgery (n = 4) or permanent middle cerebral artery occlusion (n = 22). Stroke animals were randomized into one of 5 treatments: 1×NK1 bolus (4 h), 2×NK1 bolus (4 h;9 h), 3×NK1 bolus (4 h;9 h;14 h), DC surgery (performed at 4 h) or saline vehicle. ICP, blood pressure and blood gasses were monitored for 24 h post-stroke. At 24 h post-stroke anesthetized animals underwent MRI followed by perfusion and brains removed and processed for histological assessment. Results: 2×NK1, 3×NK1 administration or DC surgery significantly (p < 0.05) reduced ICP compared to vehicle. 1×NK1 was ineffective in sustainably lowering ICP. On MRI, midline shift and cerebral edema were more marked in vehicles compared to NK1-r treatment groups. Conclusion: Two or three boluses of NK1-r antagonist treatment reduced ICP comparable to DC surgery, suggesting it may provide a novel alternative to invasive surgery for the management of elevated ICP.

How to Translate Time: The Temporal Aspects of Rodent and Human Pathobiological Processes in Traumatic Brain Injury.

Traumatic brain injury (TBI) triggers multiple pathobiological responses with differing onsets, magnitudes, and durations. Identifying the therapeutic window of individual pathologies is critical for successful pharmacological treatment. Dozens of experimental pharmacotherapies have been successfully tested in rodent models, yet all of them (to date) have failed in clinical trials. The differing time scales of rodent and human biological and pathological processes may have contributed to these failures. We compared rodent versus human time scales of TBI-induced changes in cerebral glucose metabolism, inflammatory processes, axonal integrity, and water homeostasis based on published data. We found that the trajectories of these pathologies run on different timescales in the two species, and it appears that there is no universal "conversion rate" between rodent and human pathophysiological processes. For example, the inflammatory process appears to have an abbreviated time scale in rodents versus humans relative to cerebral glucose metabolism or axonal pathologies. Limitations toward determining conversion rates for various pathobiological processes include the use of differing outcome measures in experimental and clinical TBI studies and the rarity of longitudinal studies. In order to better translate time and close the translational gap, we suggest 1) using clinically relevant outcome measures, primarily in vivo imaging and blood-based proteomics, in experimental TBI studies and 2) collecting data at multiple post-injury time points with a frequency exceeding the expected information content by two or three times. Combined with a big data approach, we believe these measures will facilitate the translation of promising experimental treatments into clinical use.

The potential role of substance P in brainstem homeostatic control in the pathogenesis of sudden infant death syndrome (SIDS).

Victims of sudden infant death syndrome (SIDS) are believed to have an underlying dysfunction in medullary homeostatic control that impairs critical responses to life threatening challenges such as hypoxia, hypercarbia and asphyxia, often during a sleep period. This failure is thought to result from abnormalities in a network of neural pathways in the medulla oblongata that control respiration, chemosensitivity, autonomic function and arousal. Studies have mainly focused on the role of serotonin, 5-hydroxytyptamine (5HT), although the neuropeptide substance P (SP) has also been shown to play an integral role in the modulation of medullary homeostatic function, often in conjunction with 5-HT. Actions of SP include regulation of respiratory rhythm generation, integration of cardiovascular control, modulation of the baroreceptor reflex and mediation of the chemoreceptor reflex in response to hypoxia. Abnormalities in SP neurotransmission may, therefore, also play a significant role in homeostatic dysfunction of the neurotransmitter network in SIDS. This review focuses on the pathways within the medulla involving SP and its tachykinin NK1 receptor, their potential relationship with the medullary 5-HT system, and possible involvement in the pathogenesis of SIDS.

Neuropathological Developments in Sudden Infant Death Syndrome.

A wide variety of neuropathological abnormalities have been investigated in infants who have died of sudden infant death syndrome (SIDS). Issues which detracted from early studies included failure to use uniform definitions of SIDS and lack of appropriately matched control populations. Development of the triple risk model focused attention on the concept of an inherent susceptibility to unexpected death in certain infants, with research demonstrating a role for the neurotransmitter serotonin within the brainstem. However, it now appears that neuropathological abnormalities in SIDS infants are more complex than a simple serotonergic deficiency in certain medullary nuclei but instead could involve failure of an integrated network of neurochemical transmitters in a variety of subcortical locations. The following overview examines recent research developments looking particularly at the potential role of the peptide neurotransmitter substance P and its neurokinin-1 receptor in multiple nuclei within the brainstem, asymmetry and microdysgenesis of the hippocampus, and decreased orexin levels within dorsomedial, perifornical, and lateral levels in the hypothalamus. Whether such research will lead to identifiable biomarker for infants at risk of SIDS is yet to be established. Use of standardized and consistent methods of classifying and categorizing infant deaths will be pivotal in generating reproducible research results.

Large animal models of stroke and traumatic brain injury as translational tools.

Acute central nervous system injury, encompassing traumatic brain injury (TBI) and stroke, accounts for a significant burden of morbidity and mortality worldwide. Studies in animal models have greatly enhanced our understanding of the complex pathophysiology that underlies TBI and stroke and enabled the preclinical screening of over 1,000 novel therapeutic agents. Despite this, the translation of novel therapeutics from experimental models to clinical therapies has been extremely poor. One potential explanation for this poor clinical translation is the choice of experimental model, given that the majority of preclinical TBI and ischemic stroke studies have been conducted in small animals, such as rodents, which have small lissencephalic brains. However, the use of large animal species such as nonhuman primates, sheep, and pigs, which have large gyrencephalic human-like brains, may provide an avenue to improve clinical translation due to similarities in neuroanatomical structure when compared with widely adopted rodent models. This purpose of this review is to provide an overview of large animal models of TBI and ischemic stroke, including the surgical considerations, key benefits, and limitations of each approach.

The amyloid precursor protein derivative, APP96-110, is efficacious following intravenous administration after traumatic brain injury.

Following traumatic brain injury (TBI) neurological damage is ongoing through a complex cascade of primary and secondary injury events in the ensuing minutes, days and weeks. The delayed nature of secondary injury provides a valuable window of opportunity to limit the consequences with a timely treatment. Recently, the amyloid precursor protein (APP) and its derivative APP96-110 have shown encouraging neuroprotective activity following TBI following an intracerebroventricular administration. Nevertheless, its broader clinical utility would be enhanced by an intravenous (IV) administration. This study assessed the efficacy of IV APP96-110, where a dose-response for a single dose of 0.005mg/kg- 0.5mg/kg APP96-110 at either 30 minutes or 5 hours following moderate-severe diffuse impact-acceleration injury was performed. Male Sprague-Dawley rats were assessed daily for 3 or 7 days on the rotarod to examine motor outcome, with a separate cohort of animals utilised for immunohistochemistry analysis 3 days post-TBI to assess axonal injury and neuroinflammation. Animals treated with 0.05mg/kg or 0.5mg/kg APP96-110 after 30 minutes demonstrated significant improvements in motor outcome. This was accompanied by a reduction in axonal injury and neuroinflammation in the corpus callosum at 3 days post-TBI, whereas 0.005mg/kg had no effect. In contrast, treatment with 0.005m/kg or 0.5mg/kg APP96-110 at 5 hours post-TBI demonstrated significant improvements in motor outcome over 3 days, which was accompanied by a reduction in axonal injury in the corpus callosum. This demonstrates that APP96-110 remains efficacious for up to 5 hours post-TBI when administered IV, and supports its development as a novel therapeutic compound following TBI.

Normative distribution of substance P and its tachykinin neurokinin-1 receptor in the medullary serotonergic network of the human infant during postnatal development.

Substance P (SP) and its tachykinin NK1 receptor (NK1R) function within key medullary nuclei to regulate cardiorespiratory and autonomic control. We examined the normative distribution of SP and NK1R in the serotonergic (5-Hydroxytryptamine, [5-HT]) network of the human infant medulla during postnatal development, to provide a baseline to facilitate future analysis of the SP/NK1R system and its interaction with 5-HT within pediatric brainstem disorders in early life. [125I] labelled Bolton Hunter SP (BH-SP) tissue receptor autoradiography (n = 15), single label immunohistochemistry (IHC) and double label immunofluorescence (IF) (n = 10) were used to characterize the normative distribution profile of SP and NK1R in the 5-HT network of the human infant medulla during postnatal development. Tissue receptor autoradiography revealed extensive distribution of SP and NK1R in nuclei intimately related to cardiorespiratory function and autonomic control, with significant co-distribution and co-localization with 5-HT in the medullary network in the normal human infant during development. A trend for NK1R binding to decrease with age was observed with significantly higher binding in premature and male infants. We provide further evidence to suggest a significant role for SP/NK1R in the early postnatal period in the modulation of medullary cardiorespiratory and autonomic control in conjunction with medullary 5-HT mediated pathways and provide a baseline for future analysis of the potential consequences of abnormalities in these brainstem neurotransmitter networks during development.

Large animal models of traumatic brain injury.

Animal models are essential to gain a deeper understanding of the pathophysiology associated with traumatic brain injury (TBI). Rodent models of TBI have proven highly valuable with respect to the information they have provided over the years, particularly when it comes to the molecular understanding of injury mechanisms. However, there has been a failure to translate the successes in therapeutic treatment of TBI in rodents, which many believe may be related to their different brain anatomy compared with humans. Specifically, the rodent lissencephalic brain within its bony skull responds differently to injury than a human gyrencephalic brain, particularly from a biomechanical and physiological perspective. There is now far greater interest in developing more clinically relevant, large animal models of TBI so as to enhance the possibility of successful clinical translation. The current mini-review highlights the differences between lissencephalic and gyrencephalic brains, emphasizing how these differences might impact studies of TBI. Thereafter follows a summary of the different large animal models, with a critical analysis of their strengths and weaknesses.

The Forensic Implications of Amphetamine Intoxication in Cases of Inflicted Blunt Craniocerebral Trauma.

The effects of D-amphetamine on outcome after blunt craniocerebral trauma are characterized and the potential legal implications discussed. Traumatic brain injury (TBI) was induced under general anesthesia in adult, male Sprague Dawley rats using the impact acceleration model. At 10 min prior to injury, D-amphetamine (5 mg/kg) or saline vehicle was administered subcutaneously; animals were subsequently assessed over a 7-day period post-trauma for motor outcome using a rotarod device. D-amphetamine treated animals performed significantly better (p < 0.001; ANOVA) than vehicle treated controls on their motor assessment, suggesting that D-amphetamine exposure prior to injury either is neuroprotective or enhances motor performance. It is possible, therefore, that an individual who has taken amphetamines may function at a better motor level after head trauma than one who has not been exposed to the drug. Future interpretations of the potential effects of amphetamines on TBI should include this possibility.