Jack E. Sherman

Longitudinal changes in patients with traumatic brain injury assessed with diffusion-tensor and volumetric imaging ☆

Traumatic brain injury (TBI) is associated with brain volume loss, but there is little information on the regional gray matter (GM) and white matter (WM) changes that contribute to overall loss. Since axonal injury is a common occurrence in TBI, imaging methods that are sensitive to WM damage such as diffusion-tensor imaging (DTI) may be useful for characterizing microstructural brain injury contributing to regional WM loss in TBI. High-resolution T1-weighted imaging and DTI were used to evaluate regional changes in TBI patients compared to matched controls. Patients received neuropsychological testing and were imaged approximately 2 months and 12.7 months post-injury. Paradoxically, neuropsychological function improved from Visit 1 to Visit 2, while voxel-based analyses of fractional anisotropy (FA), and mean diffusivity (MD) from the DTI images, and voxel-based analyses of the GM and WM probability maps from the T1-weighted images, mainly revealed significantly greater deleterious GM and WM change over time in patients compared to controls. Cross-sectional comparisons of the DTI measures indicated that patients have decreased FA and increased MD compared to controls over large regions of the brain. TBI affected virtually all of the major fiber bundles in the brain including the corpus callosum, cingulum, the superior and inferior longitudinal fascicules, the uncinate fasciculus, and brain stem fiber tracts. The results indicate that both GM and WM degeneration are significant contributors to brain volume loss in the months following brain injury, and also suggest that DTI measures may be more useful than high-resolution anatomical images in assessment of group differences.

Corticotropin-releasing factor modulates defensive-withdrawal and exploratory behavior in rats.

The role of corticotropin-releasing factor (CRF), an endogenous neuropeptide, in modulating species-typical responses was examined in an unfamiliar open field containing a small chamber. Rats placed in this small chamber spent most of their time withdrawn in it. However, rats given an intracerebroventricular injection (20 micrograms) of alpha-helical CRF(9-41), a CRF receptor antagonist, emerged from the chamber and explored the unfamiliar open field. Additional studies showed that after 1 exposure to the test environment, vehicle-treated rats increased their time spent in the open field and returned intermittently to the chamber. This result suggests that reexposure reduces the threatening impact of an unfamiliar open field. Importantly, CRF (300 ng) injected centrally, but not peripherally, before reexposure to the test environment significantly reduced exploration in the open field and increased a pattern of defensive-withdrawal into the chamber. Data suggest that whether defensive-withdrawal or exploratory behavior is exhibited may depend on CRF actions in brain systems that mediate the perception of threat in the environment.

The opioid/nonopioid nature of stress-induced analgesia and learned helplessness.

Exposure to a variety of stressors produces a subsequent analgesic reaction. This stress-induced analgesia (SIA) is sometimes opioid in nature (reversed by opiate antagonists and cross-tolerant with morphine) and sometimes nonopioid. Both 30 min of intermittent footshock and 60-80 five-sec tailshocks have been shown to produce opioid SIA, whereas 3 min of continuous footshock and 5-40 tailshocks produce nonopioid SIA. We report that both of the opioid SIA procedures produce a learned helplessness effect as assessed by shuttlebox escape acquisition and an analgesia that is reinstatable 24 hr. later. The nonopioid procedures produce neither a learned helplessness effect nor a reinstatable analgesia. It is argued that these data implicate the learning of uncontrollability in the activation of opioid systems.

Aversion instead of preference learning indicated by nicotine place conditioning in rats

Although nicotine is a drug of abuse for millions of smokers, it has been difficult to demonstrate clearly the motivational properties of nicotine with rats using the conditioned place preference (CPP) paradigm. The first experiment attempted to replicate CPPs reported by other researchers using nicotine doses of 0.4, 0.8, and 1.2 mg/kg. There was a trend for all three doses to produce aversions, but it was significant only for the 0.8 mg/kg dose. Exposures to the CS alone extinguished aversions, but a “priming” dose (0.2 mg/kg) of nicotine given after extinction produced aversions only in animals exposed to 1.2 mg/kg. Experiment 2 tested whether preexposure to morphine or nicotine would sensitize animals to nicotines reinforcing effects. In this experiment, rats were exposed to either six nicotine (0.6 mg/kg) or morphine (1.0 mg/kg) dosings prior to preference conditioning. Neither preferences nor aversions were observed in any group following subsequent conditioning with 0.6 mg/kg nicotine. The results suggest that previous observations of preference effects may have been due to specific procedural factors or may have depended on negative reinforcement due to stress reduction.

ICV-CRH alters stress-induced freezing behavior without affecting pain sensitivity

Freezing is an adaptive response often induced by stressful, fear-eliciting stimuli. Three experiments with rats investigated the effects of intracerebroventricular (ICV) administration of corticotropin-releasing hormone (CRH) on freezing behavior and pain sensitivity. Experiments 1 and 3 demonstrated that ICV-CRH (300 ng) enhanced shock-elicited freezing. In Experiment 1, ICV-CRH also enhanced recovery from shock-elicited freezing, suggesting that the peptide has a biphasic effect. Experiments 2 and 3 established that CRH-induced freezing was not caused by heightened pain sensitivity. Interestingly, in Experiment 2, hot-plate exposure produced increased freezing that was attenuated by ICV-CRH. Thus, the direction of the ICV-CRH effect on freezing was found to depend on the nature of the stressor. These results suggest that endogenous CRH systems modulate stress-induced freezing.

Gait training efficacy using a home-based practice model in chronic hemiplegia

OBJECTIVE The efficacy of a home practice model for gait training was evaluated in 18 hemiplegic subjects 2.3 years (range, 1 to 5) after stroke. DESIGN Uncontrolled case series. SETTING Referral center. SUBJECTS Patients at least 1 year poststroke referred to an outpatient rehabilitation program. INTERVENTION Patients were taught home programs in two or more 2- to 5-day blocks averaging 35 physical therapy (PT) contact hours (range, 9.5 to 62.5); training extended over a mean of 22 months (range, 10 to 65). Training emphasized weight bearing, balance, segmental control, stretching, and bracing. MAIN OUTCOME MEASURES Gait changes were measured using the newly developed Wisconsin Gait Scale (WGS). The patient-rated Falls Efficacy Scale (FES) was administered before and after training to 8 subjects, and the Health Status Questionnaire (HSQ) was retrospectively administered to all subjects to appraise subjective pretraining to posttraining changes and current psychological status. RESULTS The average WGS score significantly improved (p < .05). Patients perceived that gait training increased the quality of their functional activities (p < .05). In a subset of patients, the FES showed that fear of falling was decreased (p < .05). Perception of well-being was comparable to a normative nonstroke reference population except for physical functioning. Compared to the only other published series (using traditional outpatient programming), the current model was of comparable cost. CONCLUSION Despite the literature indicating a plateau in mobility function by 6 months after stroke, postacute training of gait in hemiplegic subjects using a home-based training model results in improved gait and the perception of improved function. Additionally, we provide validation for the newly developed Wisconsin Gait Scale, an instrument of gait measurement that may assist in comparing outcomes.

The effects of ICV-CRH on novelty-induced behavior ☆

To assess whether centrally administered corticotropin-releasing hormone (CRH) modulates behavioral and antinociceptive effects of exposure to a novel environment, vehicle or 0.03, 0.3, or 3.0 micrograms of CRH was administered intracerebroventricularly (ICV) to rats, which were then tested under novel or familiar conditions. Novelty decreased sleeping and grooming and increased rearing, walking, and latency to respond on the hot-plate test of analgesia. CRH increased grooming and walking, decreased rearing and sleeping, and had no effect in the hot-plate test. The lowest dose was without effect on any measure; otherwise, CRH effects generally were dose-dependent. There was no evidence that CRH selectively enhanced or interfered with novelty-induced behavioral changes; it influenced behavior to the same degree in both test conditions. However, test condition selectively modulated the degree of peptide-induced self-gnawing and burrowing.

Morphine analgesia: enhancement by shock-associated cues

Recent research has shown that rats exposed to repeated stress display enhanced morphine analgesia. This study examined the possible contribution of classically conditioned analgesia to this effect. First, drug-naive rats exposed to nine daily sessions of stress, each consisting of a single 45-s exposure to footshock, subsequently displayed enhanced analgesic responsiveness to morphine 1 and 10 days after stress (Experiments 1, 2, and 5). This enhancement was also observed in morphine-experienced rats 1 and 8 days after stress (Experiment 1). Second, the effect of footshock stress on morphine analgesia was found to be specific to the environment in which stress was administered (Experiments 2 and 3). Rats tested in the same distinctive environment in which stress was administered displayed enhanced morphine analgesia; rats shocked elsewhere did not differ from nonshocked controls (Experiment 2). Third, conditioned analgesia was found under the same conditions that yielded enhanced morphine analgesia (Experiments 2 and 4). Lastly, both this conditioned analgesia and the acute analgesia elicited by the footshock stressor were found to be attenuated by naloxone (Experiments 5 and 6). These data are consistent with the hypothesis that the enhanced morphine analgesia observed after repeated footshock stress reflects the contribution of an opioid mediated , conditioned analgesia elicited by cues formerly paired with the stressor.

ICV-CRH potently affects behavior without altering antinociceptive responding

To explore the hypothesized integrative function of corticotropin releasing hormone (CRH) in the stress response, stress-related behaviors including antinociception were studied in rats after either intracerebroventricular (ICV) or peripheral administration of CRH. The effects of low-dose (0.3 microgram) and high-dose (3.0 micrograms) ICV-CRH were compared to those of vehicle, employing a within-S design. The two doses yielded comparable behavioral changes suggestive of increased arousal and stress. These changes were characterized by significant increases in grooming, walking, burrowing, self-gnawing, and pica, and decreases in rearing and sleeping. None of these effects of ICV-CRH were obtained with peripheral administration of the same doses. The hot-plate test of analgesia failed to show a significant effect of ICV-CRH or peripherally administered CRH. A between-S experiment incorporating both the tail-flick and the hot-plate tests of analgesia compared ICV-CRH (3.0 micrograms) with vehicle. ICV-CRH did not affect antinociceptive responding in either of these tests. In contrast, ICV morphine (10 micrograms) yielded potent analgesia in both tests. Thus, with doses of ICV-CRH yielding clear evidence of stress-related behavior, no evidence of analgesia was obtained. These findings question the possible role of central CRH systems in antinociceptive processes.

Tongue-Based Biofeedback for Balance in Stroke: Results of an 8-Week Pilot Study

OBJECTIVE To assess balance recovery and quality of life after tongue-placed electrotactile biofeedback training in patients with stroke. DESIGN Prospective multicenter research design. SETTING Outpatient rehabilitation clinics. PARTICIPANTS Patients (N=29) with chronic stroke. INTERVENTIONS Patients were administered 1 week of therapy plus 7 weeks of home exercise using a novel tongue based biofeedback balance device. MAIN OUTCOME MEASURES The Berg Balance Scale (BBS), Timed Up and Go (TUG), Activities-Specific Balance Confidence (ABC) Scale, Dynamic Gait Index (DGI), and Stroke Impact Scale (SIS) were performed before and after the intervention on all subjects. RESULTS There were statistically and clinically significant improvements from baseline to posttest in results for the BBS, DGI, TUG, ABC Scale, and some SIS domains (Mobility, Activities of Daily Living/Instrumental Activities of Daily Living, Social, Physical, Recovery domains). Average BBS score increased from 35.9 to 41.6 (P<.001), and DGI score, from 11.1 to 13.7 (P<.001). Time to complete the TUG decreased from 24.7 to 20.7 seconds (P=.002). Including the BBS, DGI, TUG, and ABC Scale, 27 subjects improved beyond the minimal detectable change with 95% certainty (MDC-95) or minimal clinically important difference (MCID) in at least 1 outcome and 3 subjects improved beyond the MDC-95 or MCID in all outcomes. CONCLUSIONS Electrotactile biofeedback seems to be a promising integrative method to balance training. A future randomized controlled study is needed.