Gender and environmental effects on regional brain-derived neurotrophic factor expression after experimental traumatic brain injury.

Alterations in brain-derived neurotrophic factor expression have been reported in multiple brain regions acutely after traumatic brain injury, however neither injury nor post-injury environmental enrichment has been shown to affect hippocampal brain-derived neurotrophic factor gene expression in male rats chronically post-injury. Studies have demonstrated hormone-related neuroprotection for female rats after traumatic brain injury, and estrogen and exercise both influence brain-derived neurotrophic factor levels. Despite recent studies suggesting that exposure post-traumatic brain injury to environmental enrichment improves cognitive recovery in male rats, we have shown that environmental enrichment mediated improvements with spatial learning are gender specific and only positively affect males. Therefore the purpose of this study was to evaluate the effect of gender and environmental enrichment on chronic post-injury cortical and hippocampal brain-derived neurotrophic factor protein expression. Sprague-Dawley male and cycling female rats were placed into environmental enrichment or standard housing after controlled cortical impact or sham surgery. Four weeks post-surgery, hippocampal and frontal cortex brain-derived neurotrophic factor expression were examined using Western blot. Results revealed significant increases in brain-derived neurotrophic factor expression in the frontal cortex ipsilateral to injury for males (P=0.03). Environmental enrichment did not augment this effect. Neither environmental enrichment nor injury significantly affected cortical brain-derived neurotrophic factor expression for females. In the hippocampus ipsilateral to injury brain-derived neurotrophic factor expression for both males and females was half (49% and 51% respectively) of that observed in shams housed in the standard environment. For injured males, there was a trend in this region for environmental enrichment to restore brain-derived neurotrophic factor levels to sham values. However, there were robust increases in hippocampal brain-derived neurotrophic factor expression ipsilateral to the injury for injured females in environmental enrichment compared with both sham and injured females placed in standard housing (P

Reduced cortical injury and edema in tissue plasminogen activator knockout mice after brain trauma.

Tissue plasminogen activator (tPA) may play a deleterious role after brain injury. Here, we compared the response to traumatic brain injury in tPA knockout (KO) and wildtype (WT) mice after controlled cortical impact. At 6 h after trauma, blood-brain barrier permeability was equally increased in all mice. However, by 24 h specific gravity measurements of brain edema were significantly worse in WT mice than in KO mice. At 1 and 2 days post-trauma, mice showed deficits in rotarod performance, but by day 7 all mice recovered motor function and there were no differences between WT and KO mice. At 7 days, cortical lesion volumes were significantly reduced in KO mice compared with WT mice. However, there were no significant differences in CA3 hippocampal neuron survival. These data suggest that tPA amplifies cortical brain damage and edema in this mouse model of traumatic brain injury.

Vigabatrin directed against kindled seizures following cortical insult: impact on epileptogenesis and somatosensory recovery.

The anticonvulsant drug vigabatrin has not been found to be detrimental to the recovery process when administered following focal cortical insult. This finding is in contrast to the negative postinjury consequences of other anticonvulsant drugs (e.g., phenobarbital and diazepam) with more direct activation of the GABA/benzodiazepine receptor complex. Moreover, phenobarbital directed against kindled seizures affects functional recovery more adversely than either the drug or subconvulsive seizures alone. The purpose of the present study was to determine whether vigabatrin (150, 200, and 250 mg/kg) directed against kindled seizures would impact recovery from lesion-induced somatosensory deficits. Vigabatrin was coupled with daily electrical kindling of the amygdala during the first week after a unilateral anteromedial cortex (AMC) lesion. Somatosensory recovery was assessed using bilateral tactile stimulation tests. Animals receiving the highest dose of vigabatrin prior to electrical kindling (250 mg/kg vigabatrin/kindled) remained significantly impaired even after two months of testing relative to vehicle/kindled, kindled/250 mg/kg vigabatrin, which received vigabatrin after electrical kindling, and the 150, 200, and 250 mg/kg vigabatrin/nonkindled groups (p < 0.0001). In contrast, neither vigabatrin (at any of the doses tested) nor subconvulsive kindled seizures impacted the recovery process (p > 0.05) when administered alone (i.e., without the drug + seizure interaction). These data add to the accumulating experimental and clinical evidence suggesting that the neurobehavioral consequences of the interaction between anticonvulsant drugs and subclinical seizures after brain insult are detrimental to functional recovery.

The selective 5-HT(1A) receptor agonist repinotan HCl attenuates histopathology and spatial learning deficits following traumatic brain injury in rats.

The selective 5-HT(1A) receptor agonist Repinotan HCl (BAY x3702) has been reported to attenuate cortical damage and improve functional performance in experimental models of cerebral ischemia and acute subdural hematoma. Using a clinically relevant contusion model of traumatic brain injury, we tested the hypothesis that a 4-h continuous infusion of Repinotan HCl (10 microg/kg/h i.v.) commencing 5 min post-injury would ameliorate functional outcome and attenuate histopathology. Forty isoflurane-anesthetized male adult rats were randomly assigned to receive either a controlled cortical impact (2.7 mm tissue deformation, 4 m/s) or sham injury (Injury/Vehicle=10, Injury/MK-801=10, Injury/Repinotan HCl=10, Sham/Vehicle=10), then tested for vestibulomotor function on post-operative days 1-5 and for spatial learning on days 14-18. Neither Repinotan HCl nor the non-competitive N-methyl-D-aspartate receptor antagonist MK-801, which served as a positive control, improved vestibulomotor function on beam balance and beam walk tasks relative to the Injury/Vehicle group, but both did significantly attenuate spatial learning and memory deficits on a water maze task. Repinotan HCl also reduced hippocampal CA(1) and CA(3) neuronal loss, as well as cortical tissue damage, compared to the Injury/Vehicle group at 4 weeks post-trauma. No significant difference in histological outcome was revealed between the Repinotan HCl- and MK-801-treated groups.These findings extend the therapeutic efficacy of Repinotan HCl to a contusion model of experimental brain injury and demonstrate for the first time that 5-HT(1A) receptor agonists confer neuroprotection and attenuate spatial learning deficits following controlled cortical impact injury. This treatment strategy may be beneficial in a clinical context where memory impairments are common following human traumatic brain injury.

Tyrosine hydroxylase, but not dopamine beta-hydroxylase, is increased in rat frontal cortex after traumatic brain injury.

Chronic frontal lobe functional deficits after traumatic brain injury (TBI) may be associated with altered catecholamine systems in the frontal cortex. To test this, tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) levels were examined by immunohistochemistry and Western blot at 1, 7, 14, and 28 days after TBI or sham surgery. No alterations in DBH levels were observed by Western blot at any time point examined, but there was a significant increase in TH expression 28 days after TBI (optical density 334 +/- 68% or 3.3-fold, ipsilateral and 218 +/- 39% or 2.2-fold, contralateral) relative to the sham controls. The increase in TH may reflect a compensatory response of dopaminergic neurons to upregulate their synthesizing capacity and increase the efficiency of dopamine neurotransmission chronically after TBI.

The temporal patterns of c-Fos and basic fibroblast growth factor expression following a unilateral anteromedial cortex lesion.

Following a unilateral anteromedial cortex lesion, a critical period of 12 h to 6 days exists during which the recovery process is exquisitely vulnerable to manipulation. Certain anti-convulsant drugs, as well as convulsive seizures impede recovery when administered during, but not after, the critical period. The mechanisms underlying these behavioral phenomena have not been delineated. Thus, the present study was designed to determine potential mechanisms underlying and responsible for the critical period. To this end, we measured the immunoreactivity of two important markers of the post-injury response cascade, c-Fos and bFGF, at designated times after a unilateral anteromedial cortex lesion. These temporal patterns of expression in the perilesional cortex and ipsilateral dorsal striatum were mapped onto functional recovery patterns. Within the critical period, c-Fos was dramatically elevated through 48 h after the lesion, while bFGF peaked later, on day 6. Upregulation of these markers preceded recovery from somatosensory deficits, which was most dramatic after post-operative day 9 and complete by day 23. Early post-lesion expression of c-Fos may contribute to lesion-induced bFGF expression, which through its neurotrophic properties could be responsible for subsequent functional recovery. Gaining a similar understanding of the critical period following human traumatic brain injury could be an important first step toward improved treatment strategies and neurobehavioral outcome.

Distinctive amygdala kindled seizures differentially affect neurobehavioral recovery and lesion-induced basic fibroblast growth factor (bFGF) expression.

The differing effects of partial seizures on neurobehavioral recovery following anteromedial cortex (AMC) injury in rats have previously been reported. Specifically, convulsive Stage 1 seizures evoked ipsilateral to the lesion during the 6-day post-lesion critical period delayed recovery, while non-convulsive Stage 0 seizures were neutral. The present study was designed to elaborate on that research by examining several potential mechanisms for the seizure-associated difference observed in functional outcome. Anesthetized rats sustained unilateral AMC lesions followed by implantation of a stimulating electrode in the amygdala ipsilateral (Expt. 1) or contralateral (Expt. 2) to the lesion. Beginning 48 h after surgery, animals were kindled to evoke Stage 0 or Stage 1 seizure activity during the critical period. Kindling trials and afterdischarge (AD) were controlled to ascertain their role in functional outcome. Recovery from somatosensory deficits was assessed over a two-month period. The results revealed that (i) Stage 0 seizures did not impact recovery regardless of whether initiated ipsilateral or contralateral to the lesion, (ii) Stage 1 seizures prevented recovery only when initiated in the ipsilateral hemisphere during the post-lesion critical period, and (iii) the detrimental effect of Stage 1 seizures appears to be independent of the number of kindling trials provided and cumulative AD. Thus, to determine why Stage 1 seizures evoked in the hemisphere ipsilateral to the lesion impeded recovery, a separate group of animals (Expt. 3) were kindled accordingly and processed for c-Fos and basic fibroblast growth factor (bFGF) immunohistochemistry. It was hypothesized that Stage 1 seizures evoked in the injured hemisphere prevent recovery by blocking lesion-induced bFGF expression in structures shown to be important for recovery after cortex lesions (e.g., striatum). The results confirmed our hypothesis and suggest that the seizure-associated inhibition of lesion-induced bFGF may alter the growth factor-mediated plasticity necessary for functional recovery.

Chronic pain disorder following physical injury.

Pain disorders that are primarily associated with psychological factors are of great clinical concern, but they are difficult to study because of the inability to make valid or reliable diagnoses by structured interview alone. The authors confront this difficulty by using an injured subject population that had extensive psychiatric and medical evaluations. Those who developed somatoform pain disorder (SPD) were compared with a control group who did not. The SPD group had distinctive associated factors: more sites of pain, spread of pain beyond area of original injury, and substantially more opiate and benzodiazepine use. Compensation/litigation influenced symptoms more in the SPD group. Psychotherapists often supported the patient's viewpoint that the pain was physical and to be endured.

Phenobarbital administration directed against kindled seizures delays functional recovery following brain insult.

Anti-convulsant drug administration or recurrent seizures can impact functional recovery following brain insult. The nature of that impact depends on a variety of factors, including timing of drug administration and drug mechanism of action, as well as seizure number, timing, and severity. The objective of this study was to determine the functional consequences of anti-convulsant administration directed against seizure activity in brain-damaged animals. To this end, phenobarbital was coupled with daily electrical kindling of the amygdala beginning 48 h after a unilateral anteromedial cortex lesion. Recovery from somatosensory deficits was assessed, as was regional atrophy and basic fibroblast growth factor (bFGF) expression. Animals receiving phenobarbital prior to daily kindling failed to recover within 2 months of testing. In contrast, animals receiving saline prior to kindling as well as phenobarbital-treated non-kindled animals recovered within 2 months after the lesion. Though the exact mechanisms underlying these behavioral phenomena remain uncertain, patterns of bFGF expression among the groups provide some insight. Taken together, results from the present study suggest that anti-convulsant drug administration directed against subclinical seizure activity can be more detrimental to functional recovery than seizures alone or anti-convulsant drug treatment after seizure activity has occurred.

Chronic methylphenidate treatment enhances water maze performance following traumatic brain injury in rats.

Methylphenidate (MPH), a central nervous system stimulant with dopaminergic activity, facilitates neurobehavioral outcome following cortical suction ablation injury, but its potential efficacy following experimental traumatic brain injury (TBI) is unknown. Thus, beginning 24 h after controlled cortical impact injury or sham surgery, male Sprague-Dawley rats were injected (i.p.) once daily for 18 days with either MPH (5 mg/kg) or saline vehicle (VEH) and motor function assessed on post-operative days 1-4, followed by Morris water maze training to find a hidden platform on days 14-18. The MPH treatment regimen was ineffective in accelerating beam-balance or beam-walk recovery, but did significantly decrease swim latencies when compared to VEH-treated controls. The results are consistent with published studies showing improved outcome with MPH therapy. Furthermore, this positive finding with delayed treatment suggests that strategies that enhance catecholamine neurotransmission during the chronic post injury phase may be a useful adjunct in ameliorating some of the neurobehavioral sequelae following TBI in humans.

Evaluation of combined fibroblast growth factor-2 and moderate hypothermia therapy in traumatically brain injured rats.

Both the exogenous administration of fibroblast growth factor-2 (FGF-2) or the induction of moderate hypothermia have been shown to attenuate histopathology and improve functional outcome after traumatic brain injury (TBI). Since combined therapeutic strategies may be more beneficial than single therapies, we examined the potential synergistic effect of FGF-2 combined with moderate hypothermia treatment induced 10 min after TBI on functional and histological outcome following controlled cortical impact (CCI) injury. Fifty male Sprague-Dawley rats were randomized to one sham and four CCI treatment groups: Sham+vehicle (VEH); FGF-2 (45 microg/kg/h for 3 h i.v.)+Normothermia (37+/-0.5 degrees C); FGF-2+Hypothermia (32+/-0.5 degrees C for 3 h); VEH+Norm; VEH+Hypo. Vestibulomotor performance on the beam balance and beam-walk (BW) tasks on post-operative days 1-5 and spatial memory acquisition in the Morris water maze (MWM) on days 14-18 were assessed. After 4 weeks survival, histological evaluations (CA(1) and CA(3) cell counts and lesion volume) were performed. MWM performance improved in all treatment groups, but combined treatment was not more efficacious than either alone. The FGF-2+Hypo group performed significantly better than the other injured treatment groups in the BW task. Lastly, no significant group differences in beam balance or histological outcome were observed. These data suggest a suboptimal and incomplete synergy of combined FGF-2 and hypothermia treatment. These data may indicate that either our dose of FGF-2 or combination therapy was not optimized in our model.

Antecedent tone presentation differentially alters the rate of amygdala kindling: continued exposure is not required for this region-specific effect.

Recently we reported that antecedent tone presentation significantly delays the rate of amygdala kindling when it precedes and overlaps with every kindling trial. The goal of the present study was to determine if there is a minimal number of pairings required for the tone to exert its effects or if continued exposure is required. To investigate this, male Long-Evans hooded rats were implanted with a bipolar electrode in the right amygdala and assigned to a Tone, No Tone, or Tone Discontinued group and kindled once daily. The Tone group was exposed to the auditory stimulus on every kindling trial, while the Tone Discontinued group received it for only the first 5 days and subsequently was kindled in the same manner as the No Tone group (i.e., not exposed to the tone while receiving the kindling stimulation). In agreement with our earlier report, antecedent tone presentation significantly delayed seizure progression for subjects kindled in the central nucleus. However, the antecedent tone also significantly accelerated epileptogenesis for rats kindled in the amygdalostriatal transition area and produced no significant difference for those kindled in the basolateral nucleus. Furthermore, presentation of the tone was not required with every kindling trial in order for these effects to be seen, suggesting that a critical period might exist early in the kindling process during which epileptogenesis is acutely vulnerable to intervention. Additional research is necessary to determine the nature of these interventions and what effects they may have on seizure genesis.

Antecedent tone presentation significantly delays rate of amygdala kindling.

External stimuli may contribute to seizure occurrence in at least two ways. First, the aberrant neuronal activity that precipitates a seizure could be elicited by certain external events; and second, external events could cue the organism to an impending seizure and result in a compensatory response that is, in effect, 'anti-convulsant'. While previous research has been aimed at addressing these issues, the results have been inconclusive. The present study was conducted to clarify and extend this prior work. Adult male Long-Evans hooded rats were chronically implanted with a kindling electrode and randomly assigned to one of two groups. The Tone group was presented with a 2-s auditory stimulus (Tone) beginning one second prior to and overlapping with the 1-s kindling stimulus. Animals in the No Tone group received only the kindling stimulus. Antecedent tone presentation significantly delayed the rate of amygdala kindling. The Tone group required significantly more stimulations to reach a Stage 5 seizure than did the No Tone group. The possibility of this phenomenon providing a means to study the mechanisms underlying anti-epileptogenesis is discussed.

Methylphenidate treatment following ablation-induced hemiplegia in rat: experience during drug action alters effects on recovery of function.

Two experiments examined the effects of single or multiple administrations of methylphenidate (MPH; Ritalin) and differing amounts of beam-walking trials (symptom relevant experience) during the period of drug action on recovery from hemiplegia following unilateral sensorimotor cortex ablation in rat. The first study tested multiple doses of MPH (10 mg/kg) or sterile saline given once daily, followed by four beam-walk (BW) trials at 1, 2, 3, and 6 h on 3 consecutive days. A significant and enduring enhancement of recovery was only observed 24 h after the third administration of MPH, compared to saline controls. In the second study, a single dose of MPH (10 mg/kg) or saline was administered 24 h after ablation, followed by 12 BW trials beginning 1 h and continuing at 15-min intervals until 3 h after MPH or saline administration. A significant and enduring facilitation of BW ability was produced by this single MPH treatment regimen. These data further support the importance of an interaction between symptom-relevant experience and drugs that increase norepinephrine transmission to enhance functional recovery after brain damage.

Noradrenergic pharmacotherapy, intracerebral infusion and adrenal transplantation promote functional recovery after cortical damage.

The research described in this review briefly summarizes evidence that short term pharmacological enhancement of noradrenergic (NA) synaptic activity, combined with symptom relevant experience (SRE), promotes functional recovery of some symptoms of cortical damage in rat, cat and human beings even when treatment is initiated from days to weeks after injury. A summary is provided of the numerous drugs tested in rodent cortical injury models which have been proven useful for predicting beneficial or harmful effects on behavioral outcome in human stroke. The pattern of drug effects indicates a central role for NA in functional recovery. Additionally, studies of the effects of direct intraventricular infusion of monoamine neurotransmitters are reviewed and further support the hypothesized role of NA in recovery from some symptoms of cortical injury. The site of NA/SRE interaction to promote recovery from hemiplegia apparently involves the cerebellar hemisphere contralateral to the cortical injury. Microinfusions of NA into the contra- but not ipsilateral cerebellar hemisphere dramatically enhance recovery. Furthermore, like its systemic action, microinfusion of the alpha 1-NA receptor antagonist, phenoxybenzamine, reinstates hemiplegia. A "permanent" symptom of motor cortex injury in the cat is the complete loss of tactile placing contralateral to the injury which does not spontaneously recover for as long as seven years after ablation. This postural reflex is temporarily restored for 8-12 hours following amphetamine administration. However, this permanently lost reflex can be enduringly restored by transplanting catecholamine secreting adrenal tissue into the wound cavity. The experiment is reviewed in detail and involves chromaffin cell autografts into the frontal cortex ablation wound cavity producing a restoration of tactile placing for the 7-10 month duration of the study. This enduring restoration of tactile placing is considered a result of the release of catecholamines into the CNS from the grafted chromaffin cells found, by histochemical methods, surviving 7-10 months after transplant. Lastly, we attribute these delayed treatment effects to an attenuation of a diaschisis, or remote functional depression, in morphologically intact areas anatomically connected to the area of injury. The widespread reduction of glycolytic and oxidative metabolism, produced by focal cortical injury, is normalized by the same treatment which alleviates symptoms and is worsened by drugs which exacerbate deficits. These data support the hypothesis that providing SRE during a period of enhanced NA synaptic activity produces an enduring functional recovery after cortical injury by attenuating remote functional depression. This treatment for enhancing recovery is especially attractive since it is effective even when begun weeks after cortical damage.

Communication among rehabilitation staff: "mild," "moderate," or "severe" deficits?

Effective communication among members of the various rehabilitation disciplines is considered an essential component of the modern team approach. Inconsistency in the use of terminology within and across disciplines poses a significant barrier to effective communication. To systematically examine the extent of this problem, 132 respondents representing 14 rehabilitation facilities in six states were surveyed regarding their use of the descriptive labels "mild," "moderate," and "severe" as they pertain to level of cognitive impairment. They were also questioned regarding their use of terms to characterize different types of memory. As predicted, the results reflect a lack of consensus regarding the use of such terminology. The implications of this communication failure for rehabilitation staff, family members, patients, and third-party payers are discussed, and recommendations are made for ameliorating this problem.