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Hand motor cortical area reorganization in stroke: a study with fMRI, MEG and TCS maps.

The anatomical and functional correlates of the hand sensorimotor areas was investigated in a stroke patient with a malacic lesion in the left fronto-parieto-temporal cortex. The patient presented hemiplegia and motor aphasia 12 months earlier, followed by an excellent motor recovery. Transcranial magnetic stimulation mapping, functional magnetic resonance and magnetoencephalography were used as methods of functional imaging and all yielded consistent results. In particular, an asymmetrical enlargement and posterior shift of the sensorimotor areas localized in the affected hemisphere were found with all three techniques. Aspects related to brain 'plasticity' for functional recovery are discussed.

Cerebrovascular Disorders↗

Somatotopy in the human motor cortex hand area. A high-resolution functional MRI study.

Fine-scale somatotopic encoding in brain areas devoted to sensorimotor processing has recently been questioned by functional neuroimaging studies which suggested its absence within the hand area of the human primary motor cortex. We re-examined this issue by addressing somatotopy both in terms of functional segregation and of cortical response preference using oxygenation-sensitive magnetic resonance imaging at high spatial resolution. In a first step, spatial representations of self-paced isolated finger movements were mapped by using motor rest as a control state. A subsequent experimental design studied the predominance of individual finger movements by using contrasting finger movements as the control task. While the first approach confirmed previous reports of extensive overlap in spatial representations, the second approach revealed foci of differential activation which displayed an orderly mediolateral progression in accordance with the classical cortical motor homunculus. We conclude that somatotopy within the hand area of the primary motor cortex does not present as qualitative functional segregation but as quantitative predominance of certain movement or digit representation embedded in an overall joint hand area.

Adult↗

Responses of neurones of the pontine nuclei to stimulation of the sensorimotor, visual and auditory cortex of rats.

The aim of this study was to investigate the degree of convergence of corticofugal neurones from various cortical areas onto single neurones of the pontine nuclei (PN). Eighty-five% of the PN neurones responded to electrical stimulation of at least one of the following cortical areas: sensorimotor, visual, auditory. Slightly less than half of these neurones displayed a convergent input from two or three of functionally different cortical areas. The sensorimotor cortex, particularly the face areas, provided the most important input to the PN; stimulation of the visual cortex was less effective and stimulation of the auditory cortex rarely excited PN neurones. The electrophysiological results suggest that considerable cross-link exists between the anatomically defined cortico-pontine projection columns.

Animals↗

Functional MRI at 4.7 tesla of the rat brain during electric stimulation of forepaw, hindpaw, or tail in single- and multislice experiments.

Stimulation of peripheral nerves activates corresponding regions in sensorimotor cortex. We have applied functional magnetic resonance imaging (fMRI) techniques to monitor activated brain regions by means of measuring changes of blood oxygenation level-dependent contrast during electric stimulation of the forepaw, hindpaw, or tail in rats. During alpha-chloralose anesthesia, artificial respiration, and complete muscle relaxation, stimulations were delivered at 3 Hz via subcutaneous bipolar electrodes with 500-microseconds-current pulses of 0.2-2.0 mA. Single- or multislice gradient echo images were collected during recording sessions consisting of five alternating rest and stimulation periods. Stimulation of the right and left forepaws and hindpaws repeatedly led to robust activation of the contralateral sensorimotor cortex. There was a significant correlation (P < 0.05) between current pulse strength and amount of activation of the sensory cortex during forepaw stimulation. The center of the main cortical representation of the forepaw was situated 3.4 mm lateral to the midline and 5 mm posterior to the rhinal fissure. The main representation of the hindpaw was 2.0 mm lateral to the midline and 6 mm posterior to the rhinal fissure. Tail stimulation gave rise to a strikingly extended bilateral cortical activation, localized along the midline in medial parietal and frontal cortex 4 and 5 mm posterior to the rhinal fissure. In conclusion, the experiments provide evidence that peripheral nerve stimulation induces a fMRI signal in the respective division of the somatosensory cortex in a stimulus-related manner. The marked cortical activation elicited by tail stimulation underlines the key importance of the tail.

Afferent Pathways↗

Causes of neuromuscular weakness in the intensive care unit: a study of ninety-two patients.

The spectrum of neuromuscular disorders among intensive care unit (ICU) patients has shifted toward disorders acquired within the ICU and away from "traditional" neuromuscular disorders that lead to ICU admission. We sought to assess this spectrum by determining the causes and relative frequencies of neuromuscular disorders that led to electromyography (EMG) examinations in our ICU population. Ninety-two patients were studied over a 4 1/2-year period. Twenty-six (28%) had neuromuscular disorders (mainly Guillain-Barré syndrome, myopathy, and motor neuron disease) that led to ICU admission. Among patients who developed weakness in the ICU, there was a predominance of organ transplant patients and patients with the systemic inflammatory response syndrome and multiorgan dysfunction. Thirty-nine (42%) developed acute myopathy (consistent with critical illness myopathy in most), and 13% developed acute axonal sensorimotor polyneuropathy (mainly critical illness polyneuropathy). Patients with acute myopathy and acute axonal sensorimotor polyneuropathy had similar functional outcomes. We conclude that among patients who underwent EMG in our ICU population, acute myopathy is three times as common as acute axonal polyneuropathy, and the outcomes from acute myopathy and acute axonal polyneuropathy may be similar.

Critical Illness↗

Quantitative study of the coexpression of Fos and N-methyl-D aspartate (NMDA) receptor subunits in otolith-related vestibular nuclear neurons of rats.

The expression of NMDA receptor subunits (NR1 and NR2A/B) was demonstrated immunocytochemically in otolith-related neurons within the vestibular nuclear complex and its subnuclei of conscious Sprague-Dawley adult rats. All experimental animals were subjected to constant velocity off-vertical axis rotation (OVAR). The rotating gravity vector during OVAR sequentially activates hair cells on all sectors of the utricular maculae; neurons so activated within the vestibular nuclei were denoted by the expression of Fos protein. Control animals, i.e., labyrinthectomized rats subjected to OVAR and normal rats that remained stationary, showed only a few sporadically scattered labeled neurons. In the brainstem of normal rats subjected to OVAR, a high density of Fos-immunoreactive (Fos-ir) neurons was found in the vestibular nuclear complex (namely, spinal vestibular nucleus, SpVe; medial vestibular nucleus, Mve; superior vestibular nucleus, SuVe) and subnuclei (namely, group x and group y), whereas a lower density was found in the lateral vestibular nucleus (LVe). A double-immunofluorescence study indicated that both NR1 and NR2A/B subunits were highly expressed in Fos-ir neurons within the vestibular nuclei. Fos/NR1 or Fos/NR2A/B double-labeled neurons constitute over three-quarters of the total number of Fos-ir neurons in SpVe, MVe, LVe, SuVe, and groups x and y. Our findings suggest that NMDA-type ionotropic glutamate receptors play a key role in the OVAR-induced neuronal activation of the vestibular nuclei, thus providing a morphological basis for further study of glutamatergic central otolith neurons and their involvement in sensorimotor regulation and autonomic functions of rats.

Animals↗

Cerebellothalamocortical and pallidothalamocortical projections to the primary and supplementary motor cortical areas: a multiple tracing study in macaque monkeys.

The goal of the present study was to clarify whether the primary motor cortex (M1) and the supplementary motor cortex (SMA) both receive, via the motor thalamus, input from cerebellar and basal ganglia output nuclei. This is the first investigation that explores the problem by direct comparison, in the same animal, of thalamic zones that 1) project to M1 and SMA and 2) receive cerebellar-nuclear (CN) and pallidal (GP) afferents. These four zones were mapped in two monkeys by means of two retrograde tracers for M1 and SMA injections and of two anterograde tracers for CN and GP injections. All injections were performed under electrophysiological control (microstimulation and multiunit recordings). Injections in cortical areas were restricted to the hand/arm representation; in the SMA, the tracer deposit was within the "SMA-proper" (or "area F3") and did not include its rostral extension ("pre-SMA" or "area F6"). It was found that zones of all four types formed a number of highly complex patches of labeling that were usually not confined to one cytoarchitectonically defined thalamic nucleus. The overlap of clusters of labeled terminals and perikarya was evaluated morphometrically (area measurements) on a number of coronal sections along the anteroposterior extent of the motor thalamus. In line with previous studies, the thalamic territories innervated by CN and GP afferents rarely overlapped. However, zones projecting to M1 and/or to SMA included thalamic regions receiving CN as well as GP projections, providing the first evidence of such overlap from individual animals. The present observations support the previous conclusion from this laboratory (based on transsynaptic labeling) that the SMA receives, apart from its strong pallidal transthalamic input, a CN transthalamic input. These present findings that both M1 and SMA are recipients of transthalamic inputs from GP and CN thus support the concept that a mixed subcortical input consisting of weighted contributions from cerebellum, basal ganglia, substantia nigra, and spinothalamic tract is directed to each functional component of the sensorimotor cortex.

Animals↗

Mice with the deleted neurofilament of low-molecular-weight (Nefl) gene: 1. Effects on regional brain metabolism.

Neuronal intermediate filaments consist of the NFL subunit linked with NFM and NFH, and their alterations have been proposed as a pathogenesic cause in motor neuron diseases. Depletion of the Nefl gene in mice mimicks the reduced NFL mRNA levels seen in amyotrophic lateral sclerosis and causes perikaryal accumulation of neurofilament proteins and axonal hypotrophy in motoneurons. NFL -/- mice were evaluated for regional brain metabolism by means of quantitative histochemical estimation of cytochrome oxidase (COx) activity. The NFL null mice displayed enzymatic activity alterations in numerous hindbrain regions, mainly the cerebellum, connected regions of the brainstem (red nucleus, vestibular nuclei, and reticular formation), and cranial nerve nuclei. All of the affected regions presented elevated COx activity, except for the Purkinje cells of the cerebellum and the magnocellular red nucleus, where enzymatic activity was lower. NFL-disrupted mice displayed functional alterations in brainstem sensorimotor regions affected in amyotrophic lateral sclerosis.

Amyotrophic Lateral Sclerosis↗

Dominance of the short-latency component in perturbation induced electromyographic responses of long-trained monkeys.

The effects of prolonged training of adult monkeys subjected to random, brief perturbations of alternating elbow flexions and extensions were studied over a period of four years. The training was intensive at first, for about one year, and then irregular, with long pauses, during the following three years. As a consequence of the prolonged training with the brief perturbations, the M2 component of the electromyographic (EMG) response of the biceps and triceps muscles became gradually smaller, and finally disappeared. The M1 component, on the other hand, progressively increased in amplitude and continued to do so after the loss of the M2, until it finally dominated the EMG response. The training had similar effects on the response of the biceps muscle to longer perturbations, but, only under certain conditions, did it affect the triceps muscle response. All changes occurred at earlier stages of the training in the flexor than in the extensor muscle. These observations demonstrate a long-term functional plasticity of the sensorimotor system of adult animals and suggest a growing role for fast segmental mechanisms in the reaction to external disturbances as motor learning progresses. Changes at various levels of the stretch reflex system could underlie the enlargement of the M1 component, while the lack of the M2 component should, at least partially, reflect a reduced cortical effect on alpha-motoneurones and/or changes in spinal systems processing afferent information.

Animals↗

Effects of haloperidol, clozapine, and quetiapine on sensorimotor gating in a genetic model of reduced NMDA receptor function.

RATIONALE: Reduced N-methyl D-aspartate (NMDA) receptor function is hypothesized to contribute to the pathophysiology of schizophrenia. In order to model chronic and developmental NMDA receptor hypofunction, a mouse line was developed that expresses low levels of the NMDA R1 (NR1) subunit of the NMDA receptor. These mice show increased acoustic startle reactivity and deficits in prepulse inhibition (PPI) of acoustic startle. OBJECTIVES: The present study tested the hypothesis that these altered acoustic startle responses in the NR1 hypomorphic (NR1-/-) mice would be affected by antipsychotic drug treatment. METHODS: Mice were injected with drugs 30 min before assessment of acoustic startle responses with and without prepulse stimuli. RESULTS: Haloperidol (0.5 or 1.0 mg/kg) did not reduce the increased startle reactivity in the NR1-/- mice, but did increase PPI in both the mutant and wild type mice. Clozapine (3 mg/kg) and quetiapine (20 mg/kg) reduced startle magnitude and increased PPI in both the wild type and mutant mice. The antidepressant drug imipramine (10 and 20 mg/kg) had minimal effects on startle amplitude in NR1-/- or wild type mice. However, for the 20-mg/kg dose of imipramine, a significant increase in PPI was observed in the wild type animals, but not in the mutant mice. CONCLUSIONS: The results demonstrate that PPI can be increased in a mouse model of chronic NMDA receptor hypofunction by typical and atypical antipsychotic drugs. The similar effects of typical and atypical antipsychotic drugs to increase PPI in the wild type and mutant mice indicates that the assessment of behavior of the NR1 hypomorphic mice in the PPI paradigm offers no advantage over the wild type controls for identifying new clozapine-like drugs.

Acoustic Stimulation↗

Spatiotemporal modeling of cerebral evoked magnetic fields to median nerve stimulation.

We measured somatosensory evoked magnetic fields during median nerve stimulation in 6 normal subjects. We applied multiple dipole models to study the spatiotemporal structure of early somatosensory evoked magnetic fields (SEFs), as well as the number, 3-dimensional location and time activity of their underlying neuronal sources. Two dipole sources were necessary to model the first 40 msec of SEFs explaining 85% of the data variance. Source 1 was located deeper than source 2, showed primarily a tangential orientation, and accounted for a larger part of the variance; source 2 showed no consistent orientation across subjects. Both sources showed biphasic time activities corresponding to the previously described N20-P30 and P25-N35 components. Spatiotemporal modeling could identify sources which could not be modeled consistently above noise by single moving dipoles (P25 component), revealed small latency differences of the two sources in some subjects suggesting parallel activation of these sources, and allowed separation of sources overlapping considerably both in space and time. We conclude that spatiotemporal modeling of SEFs may be useful to study functional anatomy of human sensorimotor cortex non-invasively.

Electric Stimulation↗

The computational leech.

The local bending reflex of the leech computes a well-defined sensorimotor input-output function in which each of several unique patterns of sensory input elicits a unique pattern of motoneuron activity. Interneurons in the reflex respond to most input patterns and contribute to most motor patterns, suggesting a distributed processing mechanism for the reflex. This suggestion is supported by models in which connection strengths are adjusted by a neural network optimization algorithm to reproduce the local bending input-output function. In addition, computational parallels between the local bending network and the perceptron, a major class of artificial neural networks, brings the functional role of local bending interneurons into question and suggests new physiological experiments.

Animals↗

Primary neurologic screening and motor coordination of Dstdt-J mutant mice (dystonia musculorum) with spinocerebellar atrophy.

The autosomal recessive dystonia musculorum (Dst(dt-J)) mutation causes degenerative lesions of peripheral and central sensory pathways. A test battery of motor, sensory, postural, and autonomic functions was used to compare young control and homozygous Dst(dt-J) mice. The Dst(dt-J) mutants were severely impaired for muscle strength, limb coordination, and postural reflexes. As a result of a loss in motor control, the mutants were hypoactive in the open-field and fell quickly from the stationary beam. In sensory tests, the acoustic startle response was impaired, but not tactile reflexes and contact righting, attesting to preserved labyrinthine function and non-lemniscal pathways. Dst(dt-J) mutants were also distinguishable from controls on the basis of tremor, a paler skin, piloerection, and half-open eyes, as well as low body weight and fecal boli. Grooming episodes were less frequent in the mutants but without any reduction in grooming time. The neurologic screening battery delineated the functional integrity of some sensorimotor pathways in a spinocerebellar mutant whose severe phenotype prevents a more elaborate evaluation.

Analysis of Variance↗

Visuomotor neurons: ambiguity of the discharge or 'motor' perception?

The cortical motor system has been classically considered as the unitary, output stage of the brain processing of sensory information. According to this idea, the motor cortex - the acting brain - receives the result of the perceptual processing (visual, acoustical, tactile, etc.) elaborated by the 'associative cortex'. During the last two decades this perspective has been challenged by a series of anatomical, hodological, and neurophysiological data. This converging evidence delineates a dramatically changed picture. Far from being unitary, the cortical motor system appears to be constituted by a constellation of distinct areas, each of those endowed with specific functional properties and linked by reciprocal connections with distinct sectors of the parietal cortex. Furthermore, several 'motor' neurons in addition to their motor discharge, are also activated by somatosensory and visual stimulation (somatomotor and visuomotor neurons). In the present paper we will discuss the functional properties of those sensorimotor neurons located in the ventral part of the monkey premotor cortex. On the basis of electrophysiological data, we will propose that the apparent parodox stemming from the coexistence within the same neuron of motor and sensory properties can be solved by postulating that the motor system not only executes actions but also internally represents them in terms of 'motor ideas'. These motor ideas may provide the neurobiological basis for space representation, understanding of actions made by others and, possibly, semantic categorization of objects.

Animals↗

Histamine elicits neuronal excitatory response of red nucleus in the rat via H2 receptors in vitro.

Perfusing slices with histamine (1-100 microM) produced an excitatory response in rat rubral neurons (118/132, 89.4%). The histamine-induced excitation was not blocked by the low-Ca2+/high-Mg2+ medium (n=10), supporting a direct postsynaptic action of the amine. Histamine H2 receptor antagonist ranitidine effectively blocked the excitatory response of rubral neurons to histamine (n=26), but H1 receptor antagonist triprolidine did not (n=24). The excitatory effect of histamine could be mimicked by dimaprit, a highly selective H2 receptor agonist (n=24), and the dimaprit-elicited excitation of the rubral neurons could be blocked by ranitidine (n=16), but not by triprolidine (n=9). In addition, H1 receptor agonist 2-pyridylethylamine could not elicit any response in rubral neurons (n=12). These results indicate that histamine excites red nucleus neurons through H2 receptors and suggest that the histaminergic afferent fibers may play an important functional role in the sensorimotor integration through the red nucleus.

Animals↗

Thalamic neuronal activity in rats with mechanical allodynia following contusive spinal cord injury.

Pain and allodynia following spinal cord injury are poorly understood and difficult to treat. Since there is evidence that supraspinal mechanisms are important in such pain, we have studied the role of the thalamus in an experimental model of spinal injury. Extracellular recordings were obtained from neurones of the thalamic nucleus ventralis postero-lateralis (VPL) in normal rats and those which had sustained a contusive spinal cord injury to the thoraco-lumbar junction 7 days previously. Behavioural testing with von Frey hairs established that 11 spinally injured rats showed exaggerated vocal responses to normally innocuous mechanical stimulation (allodynia) whereas eight were non-allodynic. Thalamic VPL neurones in spinally injured rats (both allodynic and non-allodynic) exhibited a dysrhythmia in that a significantly higher proportion fired spontaneously in an oscillatory mode when compared with neurones in uninjured rats. Thus this dysrhythmia was linked to spinal injury, not to allodynia. The evoked responses of VPL thalamic neurones to brushing the skin, however, were significantly elevated in allodynic rats when compared with those in uninjured rats and neuronal afterdischarges to these stimuli (which were absent in uninjured rats) were more common in allodynic than in non-allodynic rats. We have previously reported that a proportion of spinal neurones in allodynic spinally injured rats show increased evoked responses and afterdischarges following brushing the skin and hence the enhanced thalamic responses may reflect a greater spinal input. In view of the increasing evidence that thalamo-cortical rhythmical firing is linked to sensorimotor and cognitive brain functions, we propose that pain following brushing the skin results from an exaggerated spinal input being processed by a dysrhythmic thalamus. Thus both spinal and thalamic mechanisms may be important in the genesis of pain and allodynia following spinal cord injury.

Action Potentials↗

Ovarian hormone influences on the density of immunoreactivity for tyrosine hydroxylase and serotonin in the primate corpus striatum.

The serotonergic and dopaminergic inputs to the corpus striatum in human and non-human primates participate in diverse sensorimotor, cognitive, and affective functions, are implicated in dysfunction in diseases such as Parkinson's disease and schizophrenia, and are targets for many of the drugs used to treat these disorders. Sex differences in the incidence and/or clinical course of these disorders and in the effectiveness of related dopaminergic and serotonergic drug therapies suggest that primate striatal indolamines and catecholamines are also influenced by gonadal hormones. However, while well studied in rats, relatively little is known about precisely how gonadal steroids modulate stratial dopamine and serotonin systems in primates. To begin to address this issue, the present studies explored the effects of ovarian steroids on the serotonergic and dopaminergic innervation densities of the caudate, putamen, and the nucleus accumbens in young adult rhesus monkeys. Using densitometry to quantify immunoreactivity for serotonin and for the catecholamine-synthesizing enzyme tyrosine hydroxylase, innervation densities were compared in identified, functionally specialized striatal subdomains across animals that were either ovariectomized or ovariectomized and supplemented with estradiol and/or progesterone, i.e. in a primate model of surgical menopause, with and without hormone replacement therapy. These analyses revealed clear examples of structure-, hemisphere-, and replacement regimen-specific effects of changes in circulating steroids on the densities of each afferent system examined. Further, the predominantly stimulatory effects observed occurred in striatal areas analogous to those suspected as sites of localized dopamine and/or serotonin compromise in Parkinson's disease and schizophrenia. Thus, the hormone actions identified in this study could hold relevance for some of the sex differences identified in relation to these disorders, including the findings of decreased incidence and/or symptom severity in women that have led to hypotheses of protective effects for estrogen.

Animals↗

Preoperative regimens of magnesium facilitate recovery of function and prevent subcortical atrophy following lesions of the rat sensorimotor cortex.

Following brain injury, there is a reduction of intra- and extracellular levels of magnesium (Mg++), which may contribute to the severity of the lesion-induced behavioral impairments. Injections of magnesium prior to or after brain injury attenuate these behavioral impairments. The present study extends these findings by manipulating the number of injections and the time period between the injections and the time of injury. Rats were given either two or five daily preoperative injections of MgCl2 (1 mmol/kg, i.p.), or saline (1 ml/kg, i.p.) with the final injection given 24 h prior to electrolytic lesions of the somatic sensorimotor cortex (SMC). Following SMC lesions the rats exhibited contralateral deficits in forelimb placing and locomotor placing. Rats treated with either two or five preoperative injections of MgCl2 showed a reduction in the initial magnitude of the contralateral deficits and an accelerated rate of recovery compared to saline-treated rats. In addition, analysis of striatal atrophy revealed that MgCl2 treatment prevented atrophy in the ipsilateral posterior striatum compared to rats treated with saline. These data suggest that preoperative injections of MgCl2 produce facilitation of sensorimotor recovery and reduce subcortical atrophy. Moreover, to observe the beneficial effects of MgCl2, the timing of injections need not be tied to the period immediately around the brain injury. The present data may indicate that daily supplements of magnesium may partially protect against some of the deleterious effects of brain injury.

Animals↗