Pharmacological augmentation of motor recovery after stroke: antidepressants for non-depressed patients?

Stroke remains the most common cause of adult physical disability worldwide, and standard physical rehabilitation methods have limited effectiveness. Thus, the possibility of augmenting motor recovery after stroke using drugs has obvious attractions.     

Is there an optimal age for recovery from motor cortex lesions? II. behavioural and anatomical consequences of unilateral motor cortex lesions in perinatal, infant, and adult rats

Purpose: The purpose of this study was to compare the behavioural and anatomical effects of unilateral motor cortex ablation in neonatal, infant, and adult rats. Methods: Rats were given unilateral lesions of the motor cortex on the day of birth (P1), at ten days of age (P10), or in adulthood. They were trained on several motor tasks (skilled forelimb reaching, beam traversing, tongue extension), general motor activity, and a test of spatial learning (Morris water task). Results: Although all lesion groups were equally impaired at skilled reaching with the forelimb contralateral to the lesion, rats with P1 lesions also were impaired at traversing a narrow beam and at learning the Morris task. Gross anatomical analyses revealed that the P1 rats had smaller brains than the other groups, a result that may account for the larger behavioural deficits in the P1 group. Analysis of Golgi-Cox stained neurons showed that relative to control groups, all lesion groups showed an increase in dendritic length in the basilar dendrites of layer III pyramidal cells and, paradoxically a decrease in length of the apical dendrites of the same cells. Conclusions: The bilateral alterations in dendritic organization following the motor cortex lesions suggest that there has been a bilateral reor-ganization of intrinsic cortical connectivity following motor cortex lesions at any age. These alterations in connectivity are likely not identical in the young and adult animals, however, because relative to controls, both the young operated groups, but not the adult group, showed a bilat-eral drop in spine density in the basilar dendrites of layer V pyramidal cells. These findings are discussed with respect to the idea that there may be critical ages in development in which animals can use anatomical modifications to compensate for deficits produced by cortical injury.     

Is there an optimal age for recovery from motor cortex lesions? II. behavioural and anatomical consequences of unilateral motor cortex lesions in perinatal, infant, and adult rats

Purpose: The purpose of this study was to compare the behavioural and anatomical effects of unilateral motor cortex ablation in neonatal, infant, and adult rats. Methods: Rats were given unilateral lesions of the motor cortex on the day of birth (P1), at ten days of age (P10), or in adulthood. They were trained on several motor tasks (skilled forelimb reaching, beam traversing, tongue extension), general motor activity, and a test of spatial learning (Morris water task). Results: Although all lesion groups were equally impaired at skilled reaching with the forelimb contralateral to the lesion, rats with P1 lesions also were impaired at traversing a narrow beam and at learning the Morris task. Gross anatomical analyses revealed that the P1 rats had smaller brains than the other groups, a result that may account for the larger behavioural deficits in the P1 group. Analysis of Golgi-Cox stained neurons showed that relative to control groups, all lesion groups showed an increase in dendritic length in the basilar dendrites of layer III pyramidal cells and, paradoxically a decrease in length of the apical dendrites of the same cells. Conclusions: The bilateral alterations in dendritic organization following the motor cortex lesions suggest that there has been a bilateral reor-ganization of intrinsic cortical connectivity following motor cortex lesions at any age. These alterations in connectivity are likely not identical in the young and adult animals, however, because relative to controls, both the young operated groups, but not the adult group, showed a bilat-eral drop in spine density in the basilar dendrites of layer V pyramidal cells. These findings are discussed with respect to the idea that there may be critical ages in development in which animals can use anatomical modifications to compensate for deficits produced by cortical injury.     

Is there an optimal age for recovery from motor cortex lesions? I. Behavioral and anatomical sequelae of bilateral motor cortex lesions in rats on postnatal days 1, 10, and in adulthood

Rats were given bilateral lesions of the motor cortex on the day of birth (P1), tenth day of life (P10), or in adulthood. They were trained on several motor tasks (skilled forelimb reaching, beam traversing, tongue extension), general motor activity, and a test of spatial learning (Morris water task). Although all lesion groups were impaired at skilled reaching, the P10 group was less impaired than either of the other two lesion groups. Furthermore, on the other motor tests the P10 group did not differ from controls whereas both P1 and adult groups were impaired. Only the P1 lesion group was impaired at the acquisition of the Morris water task. Anatomical analyses revealed that the P1 and P10 rats had smaller brains than the other two groups as well as having a generalized decrease in cortical thickness. Dendritic analysis of layer III pyramidal cells in the parietal cortex revealed a decrease in apical arbor in the lesion groups and an increase in the basilar arbor of the P1 and adult lesion animals. The P1 and adult operated groups showed an increase in spine density in the basilar dendrites of layer V pyramidal cells. Finally, analysis of the pattern of corticospinal projections revealed that the P1 animals had a markedly wider field of corticospinal projection neurons than any of the other groups. The widespread anatomical changes in all lesion groups versus the relatively better behavioral recovery after P10 lesions suggests that day 10 represents an optimal period for adapting to brain damage and subsequent brain reorganization.     

Is combined functional magnetic resonance imaging and diffusion tensor tractography a useful tool for evaluation of somatosensory dysfunction recovery after intracerebral hemorrhage?

Diffusion tensor tractography allows the sensory fiber course of the medial lemniscus to be visualized. But diffusion tensor tractography for accurate evaluation of the repair of injured somatosensory tracts in stroke patients has been rarely reported. A 55-year-old female patient presented with severe somatosensory dysfunction of the left side caused by a spontaneous intracerebral hemorrhage on the right side. The somatosensory function of the affected side recovered to a nearly normal state at 7 weeks from onset. Functional magnetic resonance imaging revealed that at 3 weeks from onset, there was no cortical activation by touch at each hand; at 7 weeks, the contralateral cortex centered on the primary sensory cortex was found to be activated during touch and passive movements, and activation by passive movements was increased compared with that at 3 weeks. Diffusion tensor tractography revealed that a medial lemniscus on the affected (right) hemisphere was not observed at 3 weeks from onset, however, at 7 weeks, the unaffected (left) hemisphere passed along the medial lemniscus pathway from the pons to the primary sensory cortex. These findings indicate that combined functional magnetic resonance imaging and diffusion tensor tractography would allow more accurate evaluation of the architecture and integrity of somatosensory tracts and is a useful method to investigate the recovery of somatosensory dysfunction in stroke patients.     

Survival motor neuron: motor neuron insurance for a whole lifespan?

The SMN (survival motor neuron) gene plays an important role in ontogenesis and its dysfunction leads to immatu-rity of skeletal muscles and motor neurons in the spinal cord. As a result of SMN mutations the affected cells die and clinical symptoms of spinal muscular atrophy (SMA) develop. Physiologically, SMN together with gemins is part of a multiprotein complex of particular importance to motor neuron development. Since the SMN gene is necessary for normal motor neuron maturity, a question arises whether its expression is preserved in postnatal life or finishes with the end of ontogenesis. To answer this question we examined expression of SMN and gemins 2, 3 and 4 in spinal cords of Wistar rats at age 1-350 days using immunofluorescence and immunohistochemical methods. In the examined animals expression of SMN appeared in neurons in 20-day old rats and increased with animal age. In rats aged 30-350 days SMN immunoreactivity was similar in all the examined animals. The same phenomenon was observed in assessment of gemin expression. Our study revealed that in rat spinal cord expression of SMN and gemins 2, 3 and 4 is present through a whole animal lifespan and not only in motor but also in sensory and autonomic neurons.     

Mapping cortical hand motor representation using TMS: A method to assess brain plasticity and a surrogate marker for recovery of function after stroke?

ObjectiveStroke is associated with reorganization within motor areas of both hemispheres. Mapping the cortical hand motor representation using transcranial magnetic stimulation may help to understand the relationship between motor cortex reorganization and motor recovery of the affected hand after stroke.MethodsA standardized review of the pertinent literature was performed.ResultsWe identified 20 trials, which analyzed the relationship between the extent and/or location of cortical hand motor representation using transcranial magnetic stimulation and motor function and recovery of the affected hand. Several correlations were found between cortical reorganization and measures of hand motor impairment and recovery.ConclusionA better understanding of the relationships between the extent and location of cortical hand motor representation and the motor impairment and motor recovery of the affected hand after stroke may contribute to a targeted use of non-invasive brain stimulation protocols. In the future motor mapping may help to guide brain stimulation techniques to the most effective motor area in an affected individual.     

Schizotaxia--theoretical construct or a tool for clinical research?

From Kretschmer's trials binding personality traits with risk of psychoses have been described in literature. Still there is lack of one theory linking genetic factors with schizophrenia. In 1962 Meehl, introducing the term "schizotaxia", had been trying to find an answer to such a question. He described schizotaxia as subtle neuronal integration deficit caused by a single genetic factor, which depending on conditions, can give schizotypy or schizophrenia. Actually, this theory has only historical meaning. Recently Tsuang and Faraone reformulated the concept of schizotaxia used in clinical studies. Preliminary results lead to a conclusion that presence of schizotaxia has a detrimental influence on social functioning, which is improving after neuroleptic therapy. Studies confirmed that the risk of schizophrenia in persons with schizotaxia was higher as compared to persons without such characteristics. It is supposed, that paying attention to traits of schizotaxia will improve the possibility of early diagnosis of schizophrenia.     

Primate adult brain cell autotransplantation, a new tool for brain repair?

If successful, autologous brain cell transplantation is an attractive approach to repair lesions and restore function of the central nervous system. We demonstrate that monkey adult brain cells obtained from cortical biopsy and kept in culture for 4 weeks exhibit neural progenitor characteristics. After reimplantation into a lesion area of the donor cerebral cortex, these cells can successfully survive and acquire neuronal characteristics over time. These results open new perspectives in the field of brain repair and may lead to future clinical applications.     

Inhibition of the Ca2?-dependent K? channel, KCNN4/KCa3.1, improves tissue protection and locomotor recovery after spinal cord injury

Spinal cord injury (SCI) triggers inflammatory responses that involve neutrophils, macrophages/microglia and astrocytes and molecules that potentially cause secondary tissue damage and functional impairment. Here, we assessed the contribution of the calcium-dependent K? channel KCNN4 (KCa3.1, IK1, SK4) to secondary damage after moderate contusion lesions in the lower thoracic spinal cord of adult mice. Changes in KCNN4 mRNA levels (RT-PCR), KCa3.1 protein expression (Western blots), and cellular expression (immunofluorescence) in the mouse spinal cord were monitored between 1 and 28 d after SCI. KCNN4 mRNA and KCa3.1 protein rapidly increased after SCI; double labeling identified astrocytes as the main cellular source accounting for this upregulation. Locomotor function after SCI, evaluated for 28 d in an open-field test using the Basso Mouse Scale, was improved in a dose-dependent manner by treating mice with a selective inhibitor of KCa3.1 channels, TRAM-34 (triarylmethane-34). Improved locomotor function was accompanied by reduced tissue loss at 28 d and increased neuron and axon sparing. The rescue of tissue by TRAM-34 treatment was preceded by reduced expression of the proinflammatory mediators, tumor necrosis factor-α and interleukin-1β in spinal cord tissue at 12 h after injury, and reduced expression of inducible nitric oxide synthase at 7 d after SCI. In astrocytes in vitro, TRAM-34 inhibited Ca2? signaling in response to metabotropic purinergic receptor stimulation. These results suggest that blocking the KCa3.1 channel could be a potential therapeutic approach for treating secondary damage after spinal cord injury.     

Enhancing recovery after stroke with noradrenergic pharmacotherapy: a new frontier?

Despite much progress in stroke prevention and acute intervention, recovery and rehabilitation have traditionally received relatively little scientific attention. There is now increasing interest in the development of stroke recovery drugs and innovative rehabilitation techniques to promote functional recovery after completed stroke. Experimental work over the past two decades indicates that pharmacologic intervention to enhance recovery may be possible in the subacute stage, days to weeks poststroke, after irreversible injury has occurred. This paper discusses the concept of "rehabilitation pharmacology" and reviews the growing literature from animal studies and pilot clinical trials on noradrenergic pharmacotherapy, a new experimental strategy in stroke rehabilitation. Amphetamine, a monoamine agonist that increases brain norepinephrine levels, is the most extensively studied drug shown to promote recovery of function in animal models of focal brain injury. Further research is needed to investigate the mechanisms and clinical efficacy of amphetamine and other novel therapeutic interventions on the recovery process.     

Is the ipsilateral cortex surrounding the lesion or the non-injured contralateral cortex important for motor recovery in rats with photochemically induced cortical lesions?

PRIMARY OBJECTIVE: To determine whether the ipsilateral cortex surrounding the lesion or the non-injured contralateral cortex is important for motor recovery after brain damage in the photochemically initiated thrombosis (PIT) model. RESEARCH DESIGN: We induced PIT in the sensorimotor cortex in rats and examined the recovery of motor function using the beam-walking test. METHODS AND PROCEDURES: In 24 rats, the right sensorimotor cortex was lesioned after 2 days of training for the beam-walking test (group 1). After 10 days, PIT was induced in the left sensorimotor cortex. Eight additional rats (group 2) received 2 days training in beam walking, then underwent the beam-walking test to evaluate function. After 10 days of testing, the left sensorimotor cortex was lesioned and recovery was monitored by the beam-walking test for 8 days. MAIN OUTCOMES AND RESULTS: In group 1 animals, left hindlimb function caused by a right sensorimotor cortex lesion recovered within 10 days after the operation. Right hindlimb function caused by the left-side lesion recovered within 6 days. In group 2, right hindlimb function caused by induction of the left-side lesion after a total of 12 days of beam-walking training and testing recovered within 6 days as with the double PIT model. The training effect may be relevant to reorganization and neuromodulation. Motor recovery patterns did not indicate whether motor recovery was dependent on the ipsilateral cortex surrounding the lesion or the cortex of the contralateral side. CONCLUSION: The results emphasize the need for selection of appropriate programs tailored to the area of cortical damage in order to enhance motor functional recovery in this model.