Involvement of glutamate neurotransmission in the development of excessive wheel running in Lewis rats.

Physical activities such as long-distance running can form a habit and might be related to drug-induced addictive behaviors. We investigated possible modulations of N-methyl-D-aspartate (NMDA) receptor subunits during voluntary wheel running in brain regions implicated in reward and addiction. It was observed that Lewis rats progressively increased their amount of daily running, reaching maximum levels of 4-6 km/day. After 3 weeks of running, mRNA levels coding for NR2A and NR2B subunits were increased in the ventral tegmental area, while only NR2A mRNA levels were found to be elevated in the frontal cortex. Long-term wheel running was also associated with increased binding of specific NMDA receptor antagonist [3H]CGP39653 in the frontal cortex. Moreover, pharmacological inhibition of glutamate release by repeated administration of phenytoin (20 mg/kg IP for 21 days) significantly suppressed daily running. These results suggest that glutamatergic neurotransmission might be related to neurobiological mechanisms underlying the compulsive character of voluntary wheel running.

Acupuncture and transcutaneous nerve stimulation in stroke rehabilitation: a randomized, controlled trial.

BACKGROUND AND PURPOSE: In small trials with control groups that receive no intervention, acupuncture has been reported to improve functional outcome after stroke. We studied effects of acupuncture and transcutaneous electrical nerve stimulation on functional outcome and quality of life after stroke versus a control group that received subliminal electrostimulation. METHODS: In a multicenter randomized controlled trial involving 7 university and district hospitals in Sweden, 150 patients with moderate or severe functional impairment were included. At days 5 to 10 after acute stroke, patients were randomized to 1 of 3 intervention groups: (a) acupuncture, including electroacupuncture; (b) sensory stimulation with high-intensity, low-frequency transcutaneous electrical nerve stimulation that induces muscle contractions; and (c) low-intensity (subliminal) high-frequency electrostimulation (control group). A total of 20 treatment sessions were performed over a 10-week period. Outcome variables included motor function, activities of daily living function, walking ability, social activities, and life satisfaction at 3-month and 1-year follow-up. RESULTS: At baseline, patients in each group were closely similar in all important prognostic variables. At 3-month and 1-year follow-ups, no clinically important or statistically significant differences were observed between groups for any of the outcome variables. The 3 treatment modalities were all conducted without major adverse effects. CONCLUSIONS: When compared with a control group that received subliminal electrostimulation, treatment during the subacute phase of stroke with acupuncture or transcutaneous electrical nerve stimulation with muscle contractions had no beneficial effects on functional outcome or life satisfaction.

Reduction of visuo-spatial neglect with vestibular galvanic stimulation.

The purpose of the present investigation was to determine the effect of galvanic vestibular stimulation on visuo-spatial neglect without inducing nystagmus and associated discomfort. Fourteen patients with right-hemisphere stroke with neglect were assessed with two visuo-motor tasks ("Line crossing" and "Star cancellation") on three occasions. Seven of the subjects received galvanic vestibular stimulation during the second condition (Experiment 1), whereas the other seven received stimulation during the third assessment (Experiment 2). Between-group comparisons of stimulation effects were performed by analyzing change on visuo-spatial neglect from the first to the second condition in the two experimental groups. A significantly larger effect was demonstrated on the "Line crossing" task in Experiment 1. This finding suggests a stimulation effect beyond practice/spontaneous recovery, and may provide new possibilities in rehabilitation research because the stimulation can be given without discomfort.

Sensorimotor function and neuropathology five to six weeks after hypoxia-ischemia in seven-day-old rats.

Various therapeutic interventions after hypoxia-ischemia (HI) have been shown to reduce brain injury in the short-term perspective, but it remains uncertain whether such findings are accompanied by long-term functional and structural improvements. HI was induced in 7-d-old rats as follows. The left carotid artery was ligated, and the rat was exposed to 100 min of hypoxia (7.70% oxygen in nitrogen). At postnatal d 42 the rats were assessed using four sensorimotor tests. The results were correlated with the extent of brain damage expressed as volume of deficit of the left hemisphere as percent of the right hemisphere. In the grip-traction test, the time to falling was 2.2 times shorter in the HI animals compared with controls (p < 0.01). Asymmetries of limb-placing and foot-faults (p < 0.001) were detected in HI animals, and the motor function was abnormal in the postural reflex test (p < 0.001). We found a moderate correspondence between functional and neuropathologic outcome (r = 0.842, p < 0.001). A set of four easily performed sensorimotor tests is presented for the long-term evaluation of neurologic function in the 7-d-old rat model of HI.

Neural grafting to experimental neocortical infarcts improves behavioral outcome and reduces thalamic atrophy in rats housed in enriched but not in standard environments.

BACKGROUND AND PURPOSE: The purpose of this study was to evaluate whether grafting of fetal neocortical tissue 1 week after focal brain ischemia improved behavioral outcome and reduced secondary thalamic atrophy. METHODS: One week after distal ligation of the right middle cerebral artery in spontaneously hypertensive male rats, blocks of fetal neocortex (embryonic day 17) were homografted to rats housed in standard or enriched environments. Control infarcted nongrafted rats were housed in the enriched environment. Behavioral outcome was repeatedly tested until the rats were killed 20 weeks after the ligation. Ten days earlier, a mixture of 2% Fluoro-Gold and 10% biotinylated dextran amine was injected into the transplants for retrograde and anterograde tracing of graft-host connections. RESULTS: Grafted and nongrafted rats with enriched housing performed significantly better than grafted rats with standard housing on a rotating pole and a prehensile traction test. Grafted "enriched" rats were moreover significantly better than grafted "standard" rats and nongrafted enriched rats in a rotation test and a postural and locomotor tail position test. In the latter test, nongrafted enriched rats performed significantly better than grafted standard rats. The lesion-induced atrophy in posterior thalamus with its major sensorimotor cortex relay nuclei was significantly reduced in grafted enriched rats compared with nongrafted enriched rats. Afferent and efferent graft-host connections were identified in both grafted groups. Graft volumes did not differ. CONCLUSIONS: Neural grafting enhanced functional outcome and reduced thalamic atrophy only when combined with housing in enriched environments.

Secondary thalamic lesions after ligation of the middle cerebral artery: an ultrastructural study.

Earlier light microscopic, immunocytochemical and morphometric investigations indicate that noxious substances transported with the vasogenic edema from hemispheric infarcts influence the character, timing and extent of the secondary thalamic lesions. The object of the present study was to analyze the ultrastructure of the secondary damage and the cytolytic nerve cell change which ensues in the thalamus within a week after the infarction. Adult spontaneously hypertensive rats (SHR) were studied either 7 days after permanent ligation of the right middle cerebral artery (MCA) (n = 4) or 7 days after a 2-h temporary occlusion of the MCA (n = 4). Light microscopy revealed damage in the ipsilateral thalamic nuclei and the electron microscopic analysis showed that the cytolytic nerve cell degeneration was somatodendritic. Central chromatolysis was not observed. Somatodendritic nerve cell degeneration, as found in the secondary thalamic lesions in the present study, has been described in excitotoxic brain damage as well as in chronic, edematous lesions in stroke-prone spontaneously hypertensive rats. The possibility that the cytolytic thalamic nerve cell lesion is influenced by excitatory, noxious substances spreading with the edema fluid from the infarct has, thus, to be considered.

Influence of an enriched environment and cortical grafting on functional outcome in brain infarcts of adult rats.

The purpose of this work was to study if enriched housing conditions and fetal neocortical transplantation could enhance the functional outcome after focal brain ischemia in adult rats. The right middle cerebral artery (MCA) was ligated in 34 inbred, spontaneously hypertensive male rats, which were then randomly divided into three groups. Groups A and B were transferred to an enriched environment, i.e., a large cage with opportunities for various activities but not forcing the rats to do any particular tasks; group C was kept in standard laboratory cages. Three weeks after the MCA occlusion blocks of fetal neocortical tissue (Embryonic Day 17) were transplanted to the infarct cavity in groups B and C. Rats in group A (n = 11) and group B (n = 11) performed equally well and significantly better than rats in group C (n = 10) when placed on an inclined plane and when traversing a rotating pole 6 and 9 weeks after the MCA occlusion and in a leg placement test at 9, but not 6 and 12 weeks. Skilled forelimb function did not differ between the groups. Infarct size and thalamic atrophy did not differ between the groups and graft size was similar in group B and C. There was no correlation between infarct size and motor function in any of the tests in rats housed in an enriched environment. Since the environment can significantly alter functional outcome without reducing infarct size we suggest that more attention should be given to the role of the laboratory environment and to long term behavioral outcome in experimental stroke.

The nasal route of cerebrospinal fluid drainage in man. A light-microscope study.

The drainage routes from the subarachnoid space to the nasal mucosa were investigated in autopsy material. Indian ink, applied post-mortem to the olfactory groove, promptly filled the perineurial spaces around the olfactory nerve branches in the dura, the lamina cribrosa and the submucosal tissue in the nose. In a case of recent subarachnoid haemorrhage, the perineurial spaces even around the most distal olfactory nerve branches were congested with blood and there was an abundant accumulation of red corpuscles in the apical part of the nasal mucosa. Iron-containing pigment was found in the perineurial spaces of proximal and distal olfactory nerve branches as well as in the nasal mucosal stroma in cases with older haemorrhagic lesions. The findings show that the perineurial spaces provide an efficient drainage route from the subarachnoid space to the nasal mucosa in cases with haemorrhagic cerebral lesions. A complementary drainage route for the cerebrospinal fluid was indicated by the presence of indian ink, red corpuscles and iron pigment in arachnoid villi, which penetrated the lamina cribrosa and ended in the nasal submucosal tissue. Iron in the deep cervical lymph nodes should not be taken as evidence of transport from the CNS, since iron pigment was also found in cases without intracranial haemorrhage.

Sensory stimulation promotes normalization of postural control after stroke.

BACKGROUND AND PURPOSE: In a randomized study of hemiparetic stroke patients with a median age of 75 years, functional recovery was significantly better in those who received additional sensory stimulation (n = 38), including electrostimulation, than in control patients (n = 40) given the same physiotherapy and occupational therapy; group differences for balance, mobility, and activities of daily living were significant. The present study was designed to investigate postural control in patients who survived more than 2 years after stroke onset. METHODS: The 48 survivors (mean, 2.7 years; range, 2.0 to 3.8 years), 22 from the treatment group and 26 from the control group, were compared with 23 age-matched healthy subjects. Subjects were perturbed by vibrators applied to calf muscles or with galvanic vestibular stimulation. We evaluated postural control in terms of sway variances or sway velocities and the dynamics of postural control as a feedback system using system identification with a model previously validated for human postural control. RESULTS: Significantly more patients of the treatment group than of the control group maintained stance during perturbations (P < .01). Among patients capable of maintaining stance during perturbation, the control patients were characterized by significant divergence from normal values in two of the three characteristic parameters of dynamic postural control (ie, swiftness and stiffness; P < .05) compared with the treatment subgroup or age-matched subjects. CONCLUSIONS: The course of sensory stimulation enhanced recovery of postural function, an enhancement still significant 2 years after the lesion and treatment. The differences and near normalization of characteristic parameters of dynamic postural control among treated patients suggest that improved recovery after sensory stimulation may be achieved by patients regaining normal or near normal dynamics of human postural control.

Oedema-related tissue damage after temporary and permanent occlusion of the middle cerebral artery.

Eleven adults spontaneously-hypertensive male rats (SHR) were studied 22 h or 7 days after a 2 h unilateral occlusion of the right middle cerebral artery (MCA). Another 11 SHR were studied after 24 h or 7 days of permanent MCA ligation. The brain infarcts were significantly larger (P < 0.05) after permanent occlusion than after a 2 h occlusion. More extensive and widespread vasogenic oedema, emanating from the infarcts, was visualized immunohistochemically in the temporarily-ligated animals and the relative number of astrocytes in their contralateral hemispheres was greater, thereby indicating that the vasogenic oedema influences the degree of gliosis. An immunopositivity for albumin but not for fibrinogen extended via the white matter into the ipsilateral thalamic nuclei, where cytolytic nerve cell damage, severely shrunken and karyorrhectic nerve cells as well as gliosis were found one week after permanent and temporary MCA ligation. The histological changes in the thalamus indicated a difference in timing between lateral and medial parts of the lesion as well as between temporarily- and permanently-ligated SHR. These findings together with the close spatial correlation with albumin immunoreactivity indicate that the spread of extravasated plasma constituents or degradation products with the oedema bulk flow from the infarct influences the timing, character and extent of thalamic lesions after cerebral infarction.

Can sensory stimulation improve the functional outcome in stroke patients?

After obtaining informed consent, we randomized 78 patients with severe hemiparesis of the left or right side within 10 days of stroke onset: 40 to a control group receiving daily physiotherapy and occupational therapy, and 38 to a group that, in addition, we treated with sensory stimulation (acupuncture) twice a week for 10 weeks. The median age was 76 years for both groups. Motor function, balance, and ADL (Barthel's Index) were assessed before the start of treatment and at 1 and 3 months after stroke onset; ADL was also assessed after 12 months. We assessed the quality of life (QL) using the Nottingham Health Profile 3, 6, and 12 months after stroke onset. Patients given sensory stimulation recovered faster and to a larger extent than the controls, with a significant difference for balance, mobility, ADL, QL, and days spent at hospitals/nursing homes. Whether acupuncture per se is responsible for the differences requires further study.

The relationship between plasma protein extravasation and remote tissue changes after experimental brain infarction.

Extravasated endogenous serum albumin and fibrinogen were identified immunohistochemically in coronal brain sections from normotensive Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) after permanent ligation of the right middle cerebral artery. Infarcts were seen in all the SHR but only in 6 out of 14 WKY. Six hours after ligation, extravasated proteins were located primarily within the borders of the infarcts whereas after 24 h and later there was an increasing spread in the white matter. After 7 days, a protein immunoreactivity was seen far outside the infarcted areas, mainly in the white matter and occasionally extending somewhat into the contralateral side. Three weeks after permanent ligation, the immunoreactivity for plasma proteins had a similar extension but was less intense than after 7 days. A gliosis was noted within the protein-positive regions. From 72 h and onwards the immunoreactivity for albumin but not for fibrinogen extended via the white matter into the ipsilateral thalamic nuclei, where marked, mainly cytolytic nerve cell damage and gliosis was found. The close spatial correlation with albumin immunopositivity and the histological features of the thalamic lesions indicate that the propagation of extravasated plasma constituents or degradation products from the infarct may influence the character, timing and extent of remote tissue changes after cerebral infarction.

Calcium antagonists: effects on cerebral blood flow and blood-brain barrier permeability in the rat.

1 Because they affect isolated cerebral arteries, some calcium antagonists have been studied on the intact cerebral circulation of the rat.2 Global cerebral blood flow ((133)Xe clearance technique) was measured in anaesthetized rats. Neither perhexiline (0.1 mug/kg to 1.0 mg/kg, i.v.) nor diltiazem (0.06-0.6 mg/kg, i.v.) had any significant effect on resting cerebral blood flow when measured 5 min after each dose. A high dose of nifedipine (1.0 mg/kg, i.v.) was administered during induced hypocapnia. Nifedipine failed to modify the hypocapnic vasoconstriction of the cerebral vasculature when compared to vehicle-treated rats.3 The possibility of discrete changes in regional cerebral blood flow was investigated. Local cerebral blood flow was measured in a number of brain regions by the [(14)C]-ethanol technique 15 min after the administration of nifedipine (20 or 100 mug/kg, i.v.). Nifedipine had no apparent effect on regional blood flow in the rat brain.4 Acute arterial hypertension increases protein leakage into the brain, a phenomenon susceptible to drugs that act on endothelial pinocytosis which is known to be calcium-dependent. The increase in protein extravasation, induced by the intravenous administration of either angiotensin II or adrenaline, was unchanged in rats previously treated with either nimodipine (20 mug/kg, i.v.) or nifedipine (50 mug/kg, i.v.) when dissolved in ethanol alone. However, nifedipine (20 mug/kg, i.v.) when dissolved in a solution of polyethylene glycol and ethanol further enhanced the hypertension-induced increase in brain albumin permeability.5 In conclusion, we have been unable to demonstrate any apparent effects of various calcium antagonists on the intact cerebral circulation of the rat, despite the number of different experimental models used.