Neuroanatomical predictors of awakening in acutely comatose patients.

OBJECTIVE: Lateral brain displacement has been associated with loss of consciousness and poor outcome in a range of acute neurologic disorders. We studied the association between lateral brain displacement and awakening from acute coma. METHODS: This prospective observational study included all new onset coma patients admitted to the Neurosciences Critical Care Unit (NCCU) over 12 consecutive months. Head computed tomography (CT) scans were analyzed independently at coma onset, after awakening, and at follow-up. Primary outcome measure was awakening, defined as the ability to follow commands before hospital discharge. Secondary outcome measures were discharge Glasgow Coma Scale (GCS), modified Rankin Scale, Glasgow Outcome Scale, and hospital and NCCU lengths of stay. RESULTS: Of the 85 patients studied, the mean age was 58 ± 16 years, 51% were female, and 78% had cerebrovascular etiology of coma. Fifty-one percent of patients had midline shift on head CT at coma onset and 43 (51%) patients awakened. In a multivariate analysis, independent predictors of awakening were younger age (odds ratio [OR] = 1.039, 95% confidence interval [CI] = 1.002-1.079, p = 0.040), higher GCS score at coma onset (OR = 1.455, 95% CI = 1.157-1.831, p = 0.001), nontraumatic coma etiology (OR = 4.464, 95% CI = 1.011-19.608, p = 0.048), lesser pineal shift on follow-up CT (OR = 1.316, 95% CI = 1.073-1.615, p = 0.009), and reduction or no increase in pineal shift on follow-up CT (OR = 11.628, 95% CI = 2.207-62.500, p = 0.004). INTERPRETATION: Reversal and/or limitation of lateral brain displacement are associated with acute awakening in comatose patients. These findings suggest objective parameters to guide prognosis and treatment in patients with acute onset of coma.

Predictors of long-term shunt-dependent hydrocephalus after aneurysmal subarachnoid hemorrhage. Clinical article.

OBJECT: The purpose of this study was to identify predictors of shunt-dependent hydrocephalus after aneurysmal subarachnoid hemorrhage (SAH). METHODS: The authors evaluated the incidence of shunt-dependent hydrocephalus in a consecutive cohort of 580 patients with SAH who were admitted to the Neurological Intensive Care Unit of Columbia University Medical Center between July 1996 and September 2002. Patient demographics, 24-hour admission variables, initial CT scan characteristics, daily transcranial Doppler variables, and development of in-hospital complications were analyzed. Odds ratios and 95% CIs for candidate predictors were calculated using multivariate nominal logistic regression. RESULTS: Admission glucose of at least 126 mg/dl (adjusted OR 1.6; 95% CI 1.0-2.6), admission brain CT scan with a bicaudate index of at least 0.20 (adjusted OR 1.43; 95% CI 1.0-2.0), Fisher Grade 4 (adjusted OR 2.71; 95% CI 1.2-5.7), fourth ventricle hemorrhage (adjusted OR 1.78; 95% CI 1.1-2.7), and development of nosocomial meningitis (adjusted OR 2.2; 95% CI 1.4-3.7) were independently associated with shunt dependency. CONCLUSIONS: These data suggest that permanent CSF diversion after aneurysmal SAH may be independently predicted by hyperglycemia at admission, findings on the admission CT scan (Fisher Grade 4, fourth ventricle intraventricular hemorrhage, and bicaudate index ≥ 0.20), and development of nosocomial meningitis. Future research is needed to assess if tight glycemic control, reduction of fourth ventricle clot burden, and prevention of nosocomial meningitis may reduce the need for permanent CSF diversion after aneurysmal SAH.

Motor learning transiently changes cortical somatotopy.

Learning a complex motor skill is associated with changes in motor cortex representations of trained body parts. It has been suggested that representation changes reflect the storage of a skill, i.e., the motor memory trace. If a reflection of the trace, such modifications should persist after training is stopped for as long as the skill is retained. The objective here was to test the persistence of learning-related changes in the representation of the forelimb of the rat after learning a reaching task using repeated epidural stimulation mapping of primary motor cortex. It is shown that the forelimb representations enlarge after 8 days of training (n=8) but contract while performing arm movements without learning (n=7, p=0.006); hindlimb representations remain unchanged. Enlargement correlated with learning success (r=0.82; p=0.012). Subsequently, after 8 days without training, representation size reverted to baseline while the motor skill was retained. Somatotopy remained unaltered by a second training phase in which performance did not improve further (n=5). These findings suggest that successful acquisition but not storage of a motor skill depends on cortical map changes. The motor memory trace in rats may require changes in motor cortex organization other than those detected by stimulation mapping.

Speed of motor re-learning after experimental stroke depends on prior skill.

Many motor rehabilitation therapies are based on principles of motor learning. Motor learning depends on preliminary knowledge of the trained and other (similar) skills. This study sought to investigate the influence of prior skill knowledge on re-learning of a precision reaching skill after a cortical lesion in rat. One group of animals recovered a previously known skill (skill training, followed by stroke and re-learning training, TST, n = 8). A second group learned the skill for the first time after stroke (ST, n = 6). A control group received prolonged training without stroke (n = 6). Unilateral partial motor cortex lesions were induced photothrombotically after identifying the forelimb representation using epidural stimulation mapping. In TST animals, re-learning after stroke was slower than learning before stroke (post hoc repeated measures ANOVA P = 0.039) and learning in the control group (P = 0.033). De novo learning after stroke (ST group) was not different from healthy learning. These findings show that skill learning can be performed if the motor cortex is partially lesioned; re-learning of a skill after stroke is slowed by prior knowledge of the skill. It remains to be tested in humans whether task novelty positively influences rehabilitation therapy.

Cortical stimulation mapping using epidurally implanted thin-film microelectrode arrays.

Stimulation mapping of motor cortex is an important tool for assessing motor cortex physiology. Existing techniques include intracortical microstimulation (ICMS) which has high spatial resolution but damages cortical integrity by needle penetrations, and transcranial stimulation which is non-invasive but lacks focality and spatial resolution. A minimally invasive epidural microstimulation (EMS) technique using chronically implanted polyimide-based thin-film microelectrode arrays (72 contacts) was tested in rat motor cortex and compared to ICMS within individual animals. Results demonstrate reliable mapping with high reproducibility and validity with respect to ICMS. No histological evidence of cortical damage and the absence of motor deficits as determined by performance of a motor skill reaching task, demonstrate the safety of the method. EMS is specifically suitable for experiments integrating electrophysiology with behavioral and molecular biology techniques.

Hemostatic therapy for intracerebral hemorrhage.

Despite the highest mortality and morbidity of all forms of stroke, few advances have been made in the management of intracerebral hemorrhage (ICH). Besides specialized care in the stroke or neurologic intensive care unit, until very recently no specific therapies have been shown to improve outcome after ICH. Ventilatory support, blood pressure reduction, intracranial pressure monitoring, osmotherapy, fever control, seizure prophylaxis, and nutritional supplementation are the cornerstones of supportive care in the intensive care unit. Recently, a phase II trial of recombinant activated factor VII (NovoSeven; Novo Nordisk, Bagsvaerd, Denmark) reduced hematoma expansion, mortality, and disability when given within 3 hours of ICH onset. A phase III trial to confirm these results is now in progress.

Stages of motor skill learning.

Successful learning of a motor skill requires repetitive training. Once the skill is mastered, it can be remembered for a long period of time. The durable memory makes motor skill learning an interesting paradigm for the study of learning and memory mechanisms. To gain better understanding, one scientific approach is to dissect the process into stages and to study these as well as their interactions. This article covers the growing evidence that motor skill learning advances through stages, in which different storage mechanisms predominate. The acquisition phase is characterized by fast (within session) and slow learning (between sessions). For a short period following the initial training sessions, the skill is labile to interference by other skills and by protein synthesis inhibition, indicating that consolidation processes occur during rest periods between training sessions. During training as well as rest periods, activation in different brain regions changes dynamically. Evidence for stages in motor skill learning is provided by experiments using behavioral, electrophysiological, functional imaging, and cellular/molecular methods.

Characterization of motor skill and instrumental learning time scales in a skilled reaching task in rat.

Successful motor skill learning requires repetitive training interrupted by rest periods. In humans, improvement occurs within and between training sessions reflecting fast and slow components of motor learning [Karni A, Meyer G, Rey-Hipolito C, Jezzard P, Adams MM, Turner R, et al. The acquisition of skilled motor performance: fast and slow experience-driven changes in primary motor cortex. Proc Natl Acad Sci USA 1998;95:861-8]. Here, these components are characterized in male and female rats using a model of skilled forelimb reaching and are compared to time scales of instrumental learning. Twenty female and 14 male adult Long-Evans rats were pre-trained to operate a motorized door (via a sensor in the opposite cage wall) to access a food pellet by tongue. Latencies between pellet removal and door opening were recorded as measures of instrumental learning. After criterion performance was achieved, skilled forelimb reaching was requested by increasing the pellet-window distance to 1.5cm. Reaching success was recorded per trial. Mean latencies decreased exponentially over sessions and no improvement within-session was found. Skill learning over eight training sessions followed an exponential course in females and a sigmoid course in males. Females acquired the skill significantly faster than males starting at higher baseline levels (P < 0.001) but reaching similar plateaus. Within-session improvement was found during the sessions 1-3 in females and 1-4 in males. Performance at the end of session 1 was not carried over to session 2. Learning curves of individual animals were highly variable. These findings confirm in rat that motor skill learning has fast and slow components. No within-session improvement is seen in instrumental learning.

Protein synthesis inhibition blocks consolidation of an acrobatic motor skill.

To investigate whether motor skill learning depends on de novo protein synthesis, adult rats were trained in an acrobatic locomotor task (accelerating rotarod) for 7 d. Animals were systemically injected with cycloheximide (CHX, 0.5 mg/kg, i.p.) 1 h before sessions 1 and 2 or sessions 2 and 3. Control rats received vehicle injections before sessions 1, 2, and 3. Although CHX did not affect improvement of performance within session 1, between-session improvement was impaired. In overtrained animals, comparable injections of CHX had no effect on rotarod performance. These findings suggest that consolidation of motor skills requires protein synthesis.

Motor skill learning depends on protein synthesis in motor cortex after training.

The role of protein synthesis in memory consolidation is well established for hippocampus-dependent learning and synaptic plasticity. Whether protein synthesis is required for motor skill learning is unknown. We hypothesized that skill learning is interrupted by protein synthesis inhibition (PSI). We intended to test whether local protein synthesis in motor cortex or cerebellum is required during skill acquisition and consolidation. Anisomycin (ANI; 100 microg/microl in 1 microl of PBS) injected into motor cortex, posterior parietal cortex, or cerebellum produced 84.0 +/- 1.44% (mean +/- SEM), 85.9 +/- 2.31%, and 87.3 +/- 0.17% of PSI 60 min after administration, respectively. In motor cortex, protein synthesis was still reduced at 24 hr (72.0 +/- 4.68% PSI) but normalized at 48 hr after a second injection given 24 hr after the first. To test for the effects of PSI on learning of a skilled reaching task, ANI was injected into motor cortex contralateral to the trained limb or into ipsilateral cerebellum immediately after daily training sessions 1 and 2. Two control groups received motor cortex injections of vehicle or ANI injections into contralateral parietal cortex. Control and cerebellar animals showed a sigmoid learning curve, which plateaued after day 4. PSI in motor cortex significantly reduced learning during days 1-4. Thereafter, when protein synthesis normalized, learning was reinitiated. ANI injections into motor cortex did not induce a motor deficit, because animals injected during the performance plateau did not deteriorate. This demonstrates that motor skill learning depends on de novo synthesis of proteins in motor cortex after training.

Effects of somatosensory electrical stimulation on neuronal injury after global hypoxia-ischemia.

Electrical stimulation (ES) is used after cardiac arrest (CA) for diagnostic and therapeutic purposes. The effects of ES on brain damage induced by hypoxic-ischemic brain injury (HI) has not been investigated. Stimulation of afferent pathways by ES may increase neural injury by releasing excitatory neurotransmitters (glutamate) and thereby exacerbating excitotoxicity. To test this hypothesis, ES was applied to the median nerve (2 h) of adult male Wistar rats after 5 min of asphyxic CA and cardiopulmonary resuscitation. Control animals received no ES. Assessment of neuronal damage in five regions of interest was performed in survivors (ESn=15, Control n=10, Sham n=3) after 48 h using H&E, Cresyl-Violet, and TUNEL stains, and Caspase-3 and activated ERK 1/2 immunohistochemistry. Ratios of injured to normal cells were calculated. Most injury was found in hippocampus and cerebellum. ES animals showed significantly lower injury ratios in bilateral hippocampus as compared with controls (F=20.8, p<0.00001). TUNEL staining, caspase-3 and activated ERK 1/2 showed no differences between groups. It is concluded that ES during the acute phase of HI does not amplify neuronal damage at 48 h, but may have a protective effect that requires further investigation.

Short and long-term motor skill learning in an accelerated rotarod training paradigm.

Rodent models of motor skill learning include skilled forelimb reaching and acrobatic locomotor paradigms. This study characterizes motor skill learning in the accelerated rotarod task. Thirty Long-Evans rats (300-400 g) were trained on an accelerated rotarod (1cm/s(2)) over eight consecutive sessions (=days, 20 trials each). Improvement in rotarod velocities mastered before falling off the rod was observed within and between sessions (plateau after five sessions). Intrasession improvement was incompletely retained at the beginning of the next day's session. Over several training sessions, intrasession improvement diminished, suggesting a ceiling effect. After 1 week of pause, the rotarod skill was retained. Locomotor exercise in a running wheel for 30 min before the first rotarod session did not affect intrasession improvement. Running-wheel exposure for 6 days did not diminish the rate of rotarod skill learning (steepness of the learning curve) but improved overall performance (upward shift of curve). Video analysis of gait on the rotarod showed that rats developed a motor strategy by modifying their gait patterns during training. The data demonstrate that rotarod improvement is not the result of enhanced general locomotor ability or fitness, which are trained in the running wheel, but requires a change in the motor strategy to master the task. Accelerated rotarod training can be regarded a valid paradigm for motor skill learning over short (intrasession, minutes) and long time frames (intersession, days).

Biphasic cerebral blood flow velocity profile in patients with aneurysmal subarachnoid hemorrhage.

INTRODUCTION: Increases in cerebral blood flow velocity (CBFV) as measured by transcranial Doppler (TCD) sonography are reflective of cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage (SAH). In serial TCD measurements, some patients exhibit CBFV temporal profiles with two peaks (biphasic). The significance of this finding remains unclear. This retrospective case-control study was conducted to investigate the characteristics and possible predictors of biphasic CBFV profiles. METHODS: Biphasic CBFV profiles were identified in serial TCD examinations (every 1-2 days) of 182 consecutive patients admitted for aneurysmal SAH based on CBFV profiles of the middle cerebral artery on the side of higher maximum velocity. Patients undergoing angioplasty were excluded. Patients meeting these criteria (study patients) were compared to control patients matched for age and Hunt and Hess grade. RESULTS: Eighteen patients (9.9%) demonstrated biphasic CBFV profiles. The first CBFV (134 +/- 11 cm/second) peak occurred on post-SAH day 6 +/- 1, and the second peak (148 +/- 12 cm/second) on day 13 +/- 1. Study patients more often exhibited focal (p < 0.05) symptoms at the time of the first peak. No patient deteriorated neurologically at the time of the second peak. No correlation was observed between CBVF and mean arterial pressure or central venous pressure trends. CONCLUSION: Serial TCD assessment identifies patients with SAH and a biphasic CBFV temporal profile. Although the second peak usually is not associated with a worsening of symptoms, these patients were more likely to exhibit clinical symptoms during the first CBFV peak.

Early restitution of electrocorticogram predicts subsequent behavioral recovery from cardiac arrest.

Previous studies have shown that parameters of EEG restitution reflect the severity of global hypoxic-ischemic brain injury. Here, the hypothesis is tested that patterns of EEG restitution during the first 4 hours predict later behavioral recovery. Time course and correlations between behavior, electrocorticogram (EcoG), and neuronal injury were investigated in a rodent model of asphyctic cardiac arrest. Forty Wistar rats were subjected to 5 minutes of asphyxia and cardiopulmonary resuscitation. Behavior was assessed by repeated scoring of neurodeficits and open field activity until euthanasia at 48 hours. Electrocorticographic bursting occurred at 13.2 +/- 4 minutes after resuscitation. Bursts increased in frequency and duration until the EcoG reverted to a continuous signal. The resuscitation-continuous EcoG interval correlated with the first appearance of spontaneous movements (r = 0.80, P < 0.05). Larger intervals were associated with hyperactivity in the open field at 24 hours (r = 0.61, P < 0.05), indicating a more severe behavioral deficit. Larger intervals were also associated with worse 48-hour neurodeficit scores (P < 0.05). Neuronal damage in the hippocampus correlated with the degree of open field hyperactivity at 14 hours (P < 0.05). These findings demonstrate a close temporal and prognostic relationship between electrical and behavioral recovery after hypoxic-ischemic brain injury.

Modulation of rodent cortical motor excitability by somatosensory input.

It is assumed that somatosensory input is required for motor learning and recovery from focal brain injury. In rodents and other mammals, corticocortical projections between somatosensory and motor cortices are modified by patterned input. Whether and how motor cortex function is modulated by somatosensory input to support motor learning is largely unknown. Recent human evidence suggests that input changes motor excitability. Using transcranial magnetic stimulation (TMS), this study tested whether motor cortex excitability is affected by patterned somatosensory stimulation in rodents. Motor potentials evoked in gastrocnemius muscles in response to TMS (MEP(TMS)) and to cervical electrical stimulation (MEP(CES)) were recorded bilaterally. Initially, the first negative peak of the MEP(TMS) was identified as a cortical component because it disappeared after decortication in three animals. Subsequently, we studied the effects of 2 h of electrical stimulation of one sciatic nerve on the cortical component of the MEP(TMS), i.e., on motor cortex excitability. After stimulation, its amplitude increased by 117 +/- 45% ( P<0.01) in the stimulated limb. A significantly smaller effect was found in the unstimulated limb ( P<0.02) and no effect was observed in unstimulated control animals. The subcortically evoked MEP(CES) were not affected by stimulation. It is concluded that somatosensory input increases motor excitability in rat. This increase outlasts the stimulation period and is mediated by supraspinal structures, likely motor cortex. Modulation of motor cortex excitability by somatosensory input may play a role in motor learning and recovery from lesion.