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Spatial distribution of thalamic projections to the supplementary motor area and the primary motor cortex: a retrograde multiple labeling study in the macaque monkey.

The exact knowledge on spatial organization of information sources from the thalamus to the supplementary motor area (SMA) and to the primary motor cortex (MI) has not been established. We investigated the distribution of thalamocortical neurons projecting to forelimb representations of the SMA and the MI using a multiple retrograde labeling technique in the monkey. The forelimb area of the SMA, and the distal and proximal forelimb areas of the MI were identified by electrophysiological techniques of intracortical microstimulation and single neuron recording. Injections were made into these three representations with three different dyes in the same animal (horseradish peroxidase conjugated to wheat germ agglutinin, diamidino yellow, and fast blue), and the thalamic neurons were retrogradely labeled. Injections into the SMA densely labeled thalamic neurons in nuclei ventralis lateralis pars oralis (VLo), ventralis lateralis pars medialis (VLm) and ventralis lateralis pars caudalis (VLc), but not in nucleus ventralis posterior lateralis pars oralis (VPLo). Injections into the MI labeled thalamic neurons primarily in VLo, VLc, and VPLo. We found that the distribution of projection neurons to the three areas was largely separate in the thalamus. However, in the middle part of VLo, and in a limited portion of VLc, thalamic neurons projecting to the SMA partially overlapped with those to the distal forelimb area of the MI. They overlapped little with those to the proximal forelimb area of the MI. We noted no overlap between the distributions of thalamic projection neurons to the distal and proximal forelimb areas of the MI. These findings suggest that the SMA and MI receive separate information from the thalamus, while sharing minor sources of common inputs.

Animals↗

A positron emission tomographic study of subthalamic nucleus stimulation in Parkinson disease: enhanced movement-related activity of motor-association cortex and decreased motor cortex resting activity.

BACKGROUND: Long-term high-frequency stimulation of the subthalamic nucleus (STN) improves akinesia in Parkinson disease. The neural correlates of STN stimulation are not well understood. Positron emission tomography can be applied to the in vivo study of the mechanisms of deep brain stimulation. OBJECTIVE: To study changes in regional cerebral blood flow as an index of synaptic activity in patients with Parkinson disease with effective STN stimulation on and off during rest and movement. METHODS: Eight patients with Parkinson disease who had electrodes implanted in the STN underwent 12 measurements of regional cerebral blood flow with water O 15 positron emission tomography at rest and during performance of paced freely selected joystick movements, both with and without STN stimulation (3 scans per experimental condition). Motor performance and reaction and movement times were monitored. Statistical parametric mapping was used to compare changes in regional cerebral blood flow between conditions and differences in activation. RESULTS: All patients showed improvement in reaction and movement times during scans with the stimulator on. As predicted, increases in activation of rostral supplementary motor area and premotor cortex ipsilateral to stimulation were observed when stimulation was on during contralateral movement (P<.001). Unpredicted observations included decreases in regional cerebral blood flow in primary motor cortex at rest induced by STN stimulation. CONCLUSION: Stimulation of the STN reduces the movement-related impairment of frontal motor association areas and the inappropriate motor cortex resting activity in Parkinson disease.

Adult↗

Motor cortex organization after stroke is related to side of stroke and level of recovery.

BACKGROUND AND PURPOSE: The present study hypothesized that side of stroke and level of recovery influence motor system organization after stroke. METHODS: Functional MRI was performed on 14 control subjects and 21 patients with chronic stroke during index finger tapping (control subjects, right; patients, recovered side). RESULTS: On functional MRI, stroke patients with right arm involvement showed (1) significantly smaller activation in contralateral motor cortexes compared with control subjects; (2) smaller ipsilateral (nonstroke) premotor and larger contralateral (stroke-side) sensorimotor activation compared with patients with left arm involvement, although electromyogram across groups was similar; and (3) 2.7-fold-larger contralateral sensorimotor cortex activation, ventrally, in those with full recovery compared with those with partial recovery, despite similar tapping force, frequency, range of motion, and electromyogram between groups. Supplementary motor area activation was unrelated to level of recovery. CONCLUSIONS: After stroke that causes mild to moderate initial impairment and mild residual hand weakness, cortical organization varies with side of injury and with final motor status. The findings may have implications for treatment after stroke.

Arm↗

Expansion of receptive fields in motor cortex by local blockade of GABAA receptors.

Experiments were done in alpha-choralose anesthetized cats to determine whether local disinhibition would expand the sensory receptive field (RF) of motor cortical neurons. Most of the neurons (n = 17) responded only to a rapid high velocity "tap" of the paw or forearm, often requiring movement of a joint, while four cells responded to light touch of the skin. The receptive field of single neurons was re-examined after microiontophoretic ejection of bicuculline (BIC). In all 21 neurons examined, BIC produced an expansion of the RF (mean 4 times before drug). Expansion was seen most often in the proximal-distal axis (17 neurons) but was also commonly seen in the mediolateral axis (9 neurons). The expansion was usually restricted to the dorsal or ventral surface that the original RF was on; in only three neurons in which the pre-drug RF was on the dorsal surface of the paw did the expansion include part or the entire ventral surface. Response thresholds could only be tested in those neurons with touch RFs and showed no evidence of a change within the original RF of these cells. Local disinhibition has previously been shown to allow for the functional linking of motor cortical points, a mechanism that may be involved in the recruitment of movement related muscle synergies. The present results suggest that this may be also accompanied by expansion of the receptive fields. Such a receptive field expansion may be of functional value since motor cortical output neurons would receive sensory input integrated over a larger area of the limb. The role of local inhibitory control of sensory inputs to motor cortex neurons may thus be different than that in sensory cortex where it is thought to restrict receptive field size.

Animals↗

Depolarization-induced effects of Ca2+-calmodulin-dependent protein kinase injection, in vivo, in single neurons of cat motor cortex.

Intracellular injection of calcium-calmodulin-dependent protein kinase followed by depolarization and depolarization-elicited impulse activity increased input resistance of neurons of the motor cortex of cats. Protein kinase alone or depolarization in the absence of protein kinase did not produce this effect. An analogous increase of input resistance can be produced in the type B photoreceptor of Hermissenda by applying protein kinase and sufficient depolarization to increase calcium conductance and internal Ca2+ concentration. Given previous studies linking changes in both types of neurons to the development of conditioning, the results suggest the possibility of shared biochemical steps in mechanisms of neuronal adaptation by vertebrate and invertebrate species.

Animals↗

Transcranial electrical and magnetic motor cortex stimulation: studies in intact man.

The new method of transcranial electrical and magnetic brain stimulation was tested in 41 normal subjects. Stimulation on the scalp excites corticospinal neurones in the motor cortex while stimulation over the spine excites spinal nerve roots. The difference between EMG response latencies after both stimulations represents conduction in the central motor pathways and is called central motor latency (CML). The aim of out experiments was to investigate certain methodological aspects of the technique in order to standardize the procedure. Recordings were done from slightly contracted abductor digiti minimi and tibialis anterior muscles after electrical stimulation on the scalp and from the relaxed and contracted abductor digiti minimi and biceps brachii muscles after magnetic brain stimulation. Stimulation over the spine (C7/T1 interspace in case of upper limb muscles stimulation and T12/L1 interspace in case of tibialis anterior stimulation) was always electrical. Using a rather weak non-commercial magnetic stimulator we were not able to activate lower limb muscles, neither we succeeded to evoke responses from the relaxed arm muscles in all subjects. Electrical scalp stimulation proved successful in all cases. Muscle response after cortical stimulation in contracting muscles and shorter latencies and provided more accurate estimate of conduction time in the central motor pathways than responses in the relaxed muscles. Latencies should be measured from several superimposed responses and not from averaged ones. The intensity of stimulation over the neck did not affect CML. We nevertheless suggest that the strongest stimulus intensities should not be used in order to avoid CML overestimation.

Adult↗

Long-term potentiation and long-term depression of horizontal connections in rat motor cortex.

This paper reviews studies that investigate conditions resulting in long-lasting modifications of synaptic efficacy in horizontal connections within layers II/III of adult rat motor cortex using the in vitro slice preparation. Long-term potentiation (LTP) was induced by high frequency theta burst stimulation (TBS) when local synaptic inhibition was transiently suppressed by bicuculline methiodide application at the recording site immediately prior to TBS of the horizontal pathway. Without bicuculline, TBS failed to produce LTP. LTP could also be induced without Bic application by conjoint TBS of horizontal and vertical (ascending) inputs. By contrast, long-term depression (LTD) of horizontal transmission was induced by 10 min of 2 Hz stimulation. Depressed horizontal connections nevertheless retained the capability for synaptic strength increases. These studies indicate that synaptic modification across horizontally connected neurones is regulated both by the arrangement of their intrinsic circuits and by the availability of mechanisms for modification at individual synapses. Activity dependent forms of synaptic plasticity operating within horizontal connections may form a spatial substrate and mechanism for experience-dependent regulation of cortical representations.

Animals↗

Effects of antipsychotic medication on electromyographic responses to transcranial magnetic stimulation of the motor cortex in schizophrenia.

OBJECTIVE: To assess the effect of antidopaminergic antipsychotic medication on the electromyographic (EMG) responses of thenar muscles to transcranial magnetic stimulation (TMS) of the motor cortex in schizophrenic patients. METHODS: A group of nine drug naive schizophrenic patients was compared with a group of nine schizophrenic patients established on neuroleptic medication. Surface EMG recordings were made from the thenar muscles while patients maintained a weak isometric voluntary contraction. TMS was applied using a 9 cm circular stimulating coil centred over the vertex. The EMG responses to up to 50 magnetic stimuli were rectified and averaged. RESULTS: There was no difference in threshold TMS strength for eliciting compound motor evoked potentials (cMEPs), or in their latency, in drug naive and medicated patients. In some patients the silent period (SP) was clearly made up of two parts and the percentage of control levels of voluntary EMG was measured in each component. During the early component of the SP there was a weaker (P<0.05) suppression of EMG in the medicated patients (mean 73.9 (SEM) 5.5% of control levels) compared with the drug naive patients (54.7 (SEM) 7.3% of control levels). This resulted in the latency of maximum suppression of voluntary EMG being longer (P<0.05) in the medicated patients (38.3 (2.4) ms) than in the drug naive patients (28.2 (0.7) ms). During the late component of the SP voluntary EMG was reduced to similar levels (P>0.05) in both medicated (48.2 (7.7)% of control levels) and drug naive (58 (7.8)% of control levels) patients. CONCLUSION: The results are discussed with reference to the disrupted inhibition seen in the early part of the SP in Parkinson's disease and drug induced parkinsonism. The future uses of motor responses to TMS as a marker for the status of antipsychotic medication are considered.

Adult↗

A sense of movement elicited in paralyzed distal arm by focal magnetic coil stimulation of human motor cortex.

Two magnetic coils (MCs) of special design (Cadwell Laboratories) were used to elicit movements predominantly of one or a few digits by percutaneous stimulation of human motor cortex. When cortically elicited movements were ischemically blocked, the MC still elicited a discrete sense of digit movement; a sense of movement map was constructed by stimulating at different scalp sites. Our findings support the existence of corollary discharge.

Arm↗

The effect of short-duration bursts of high-frequency, low-intensity transcranial magnetic stimulation on the human motor cortex.

OBJECTIVE: To explore the effect of applying a short burst of high-frequency repetitive transcranial magnetic stimulation (rTMS) to the human motor cortex as a preparatory investigation before attempting theta burst stimulation in humans. METHODS: Five or 15 pulses of 50 Hz rTMS were given at 50-80% active motor threshold (AMT). The time course of changes in motor-evoked potential (MEP) size and short interval intracortical inhibition (SICI) were evaluated from 20 to 300 ms after the end of each burst in the relaxed first dorsal interosseous muscle of 15 healthy volunteers. RESULTS: No subjects noted any adverse effects. MEPs were enhanced and SICIs were reduced at 20 ms after a burst of either 5 or 15 pulses at 70 or 80% AMT, but not at 50% AMT. Subsequent experiments used a 5 pulse burst at 80% AMT. The threshold for producing SICI increased from 60 to 80% AMT when tested 10 or 20 ms after the end of the burst. MEPs were enhanced for 100 ms, whereas SICI was reduced for 200-300 ms. CONCLUSIONS: A short burst of low-intensity 50 Hz rTMS over the hand motor area transiently increases MEP amplitude with a longer lasting decrease in SICI. SIGNIFICANCE: This means that it may be possible in future experiments to apply theta burst conditioning safely to the human cortex.

Adult↗

Role of the cerebellum and motor cortex in the regulation of visually controlled locomotion.

An account is given of the current state of knowledge of the contributions of the cerebellum and the forelimb motor cortex (MC) to the neural control of walking movements in the cat. The main emphasis is on information obtained by recording from single MC and cerebellar neurones in chronically instrumented cats engaged in walking on the rungs of a horizontal ladder, a form of locomotion that is heavily dependent on visual input and for which the integrity of MC is essential. Evidence from the authors' laboratory and from other studies is presented which establishes that MC neurones, including pyramidal tract neurones, show higher levels of activity during ladder walking than during overground walking (i.e., when less constraint exists over the locus of footfall) and that this increase is greatest in late swing-early stance in the contralateral forelimb, consistent with one role of MC being to help determine the locus of footfall. However, many MC neurones develop peak activity at other times in the step cycle, and a comparison with recordings during treadmill walking suggests MC may also help regulate stance duration when walking speed is an important performance variable. Recordings from Purkinje cells and cerebellar nuclear neurones show that during ladder walking step-related activity is widespread in the vermal, paravermal, and crural regions of cortex and in the interposed and dentate nuclei. Nuclear cell activity is so timed that it could be contributing to producing the locomotor rhythms evident in MC cells, although this is not yet proven. Results are also presented and discussed relating to MC and cerebellar neuronal responses that occur when a step onto an unstable rung results in an unexpected external perturbation of the forelimb step cycle. MC responses begin with onset latency as short as 20 ms so that MC may assist spinal reflex mechanisms to produce a post hoc compensatory change in motor output. However, work in progress suggests that corresponding responses in paravermal cerebellum are weak and infrequent, so provisionally it seems that the MC responses are initiated via pathways that do not pass through the cerebellum. By contrast, current work involving a paradigm in which a ladder rung is motor driven to a new position as the animal approaches (thereby providing a visual cue that an adaptive change in gait will soon be required) is revealing in lateral cerebellar neurones, including dentate neurones, changes in discharge that are time locked to the execution of an adapted pace. In addition, there are prominent earlier responses, which begin at short latency after the onset of rung movement. These apparently visual responses have characteristics that encourage the speculation that they may represent a cerebellar signal that "primes for action" other more directly motor regions of the central nervous system.

Animals↗

Single pulse stimulation of the human subthalamic nucleus facilitates the motor cortex at short intervals.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for Parkinson's disease (PD). The mechanism is poorly understood. High-frequency STN DBS has been reported to affect motor cortex excitability in a complex way, but the timing between STN stimuli and changes in motor cortical (M1) excitability has not been investigated. We examined the time course of changes in motor cortical excitability following single pulse STN DBS. We studied 14 PD patients with implanted DBS electrodes in the STN, 2 patients with electrodes in internal globus pallidus (GPi), and 1 patient with an electrode in the sensory thalamus. Transcranial magnetic stimulation (TMS) was delivered to the M1 ipsilateral to the DBS with induced currents either in the anterior-posterior direction in the brain to evoke indirect (I) waves or in the lateral-medial direction to activate corticospinal axons directly. Single pulse stimulation through the DBS contacts preceded the TMS by 0-10 ms. Surface EMG was recorded from the contralateral first dorsal interosseous muscle. Three milliseconds after STN stimulation, the motor evoked potential (MEP) amplitudes produced by anterior-posterior current were significantly larger than control responses, while the responses to lateral-medial currents were unchanged. Similar facilitation also occurred after GPi stimulation, but not with thalamic stimulation. Single pulse STN stimulation facilitates the M1 at short latencies. The possible mechanisms include antidromic excitation of the cortico-STN fibers or transmission through the basal ganglia-thalamocortical pathway.

Adult↗

Activity-dependent modulation of synaptic transmission in the intact human motor cortex revealed with transcranial magnetic stimulation.

Activity-dependent modulation of cortical synaptic transmission is a fundamental mechanism involved in learning and memory storage. This modulation has been widely studied in in vitro brain slices and in vivo animal models. More recently, transcranial magnetic stimulation has allowed detection of activity-dependent excitability modulation occurring in the intact human primary motor cortex (MI) after execution of different kinds of motor tasks. Both increased and decreased MI excitability have been described after exercise. While increased MI excitability is generally considered direct expression of cortical synaptic plasticity, a controversy still exists as to whether decreased MI excitability reflects fatigue of central nervous system (CNS) structures or cortical neuronal reorganization taking place after exercise. Here, we extend previous findings in order to provide further support for the latter hypothesis. Abduction- adduction movements of the thumb performed for 1 min at 2 Hz frequency rate produce a 55% decrease in MI excitability of mean 30 min duration. Similar decrements in amplitude and duration of motor evoked potentials (MEPs) are not reached if the same task is performed once again during the maximal inhibition phase (10 min post-exercise) produced by a previous activation. Moreover, the same task performed at a lower (1 Hz) frequency rate produces no significant MEP changes but can transiently reverse activity-dependent depression obtained after previous 2 Hz movements. Repeated execution of the same task (2 Hz), each being performed after recovery from a previously induced MEP depression, ceases to produce an MEP decrement, suggesting adaptation in MI excitability modulation. This adaptation is long lasting and task-specific, since a different motor task (1 min circular movement of the thumb) restores activity-dependent modulation. Overall, these findings suggest that the dynamic modulation of MEPs occurring after execution of different kinds of simple motor skills reflects some form of activity-dependent, plastic neuronal reorganization instead of CNS fatigue. Possible anatomo-functional mechanisms involved in this activity-dependent modulation of MI excitability are discussed.

Adult↗

A hidden sensory function for motor cortex.

Sensory perception has traditionally been attributed to the activation of sensory cortices. However, by inducing an illusory perception of movement, Naito and colleagues show in this issue of Neuron that the illusory perception of movement is related to activation of primary motor cortex.

Evoked Potentials, Motor↗

Bilateral influences from the motor cortex on lumbar ventral horn interneurons.

Microelectrode recordings were made of discharges of ventral horn interneurons (VHIN) in segments L6-7 of the spinal cord during bilateral stimulation of the motor cortex in cats. The overwhelming majority of VHIN was shown to be activated by influences from the contralateral cortex, and about half of them also by ipsilateral influences. Clear correlation was established between convergence of afferent and cortical influences: Neurons with inputs from ipsilateral afferents only were activated, irrespective of their other characteristics, by descending influences from the contralateral cortex only, whereas bilateral cortical influences converged on cells with bilateral afferent connections. It is suggested that VHIN with bilateral segmental and supraspinal connections are important integrative elements in the mechanism of bilateral coordination of motor responses of different degrees of complexity.

Afferent Pathways↗

Modular organization of directionally tuned cells in the motor cortex: is there a short-range order?

We investigated the presence of short-range order (<600 microm) in the directional properties of neurons in the motor cortex of the monkey. For that purpose, we developed a quantitative method for the detection of functional cortical modules and used it to examine such potential modules formed by directionally tuned cells. In the functional domain, we labeled each cell by its preferred direction (PD) vector in 3D movement space; in the spatial domain, we used the position of the tip of the recording microelectrode as the cell's coordinate. The images produced by this method represented two orthogonal dimensions in the cortex; one was parallel ("horizontal") and the other perpendicular ("vertical") to the cortical layers. The distribution of directionally tuned cells in these dimensions was nonuniform and highly structured. Specifically, cells with similar PDs tended to segregate into vertically oriented minicolumns 50-100 microm wide and at least 500 microm high. Such minicolumns aggregated across the horizontal dimension in a secondary structure of higher order. In this structure, minicolumns with similar PDs were approximately 200 microm apart and were interleaved with minicolumns representing nearly orthogonal PDs; in addition, nonoverlapping columns representing nearly opposite PDs were approximately 350 microm apart.

Animals↗

Repetitive bilateral arm training and motor cortex activation in chronic stroke: a randomized controlled trial.

CONTEXT: Reorganization in central motor networks occurs during early recovery from hemiparetic stroke. In chronic stroke survivors, specific rehabilitation therapy can improve upper extremity function. OBJECTIVE: To test the hypothesis that in patients who have chronic motor impairment following stroke, specific rehabilitation therapy that improves arm function is associated with reorganization of cortical networks. DESIGN, SETTING, AND PATIENTS: A randomized controlled clinical trial conducted in a US ambulatory rehabilitation program with 21 patients (median [IQR], 50.3 [34.8-77.3] months after unilateral stroke). Data were collected between 2001 and 2004. INTERVENTIONS: Patients were randomly assigned to bilateral arm training with rhythmic auditory cueing (BATRAC) (n = 9) or standardized dose-matched therapeutic exercises (DMTE) (n = 12). Both were conducted for 1 hour, 3 times a week, for 6 weeks. MAIN OUTCOME MEASURES: Within 2 weeks before and after the intervention, brain activation during elbow movement assessed by functional magnetic resonance imaging (fMRI) and functional outcome assessed using arm function scores. RESULTS: Patients in the BATRAC group but not in the DMTE group increased hemispheric activation during paretic arm movement (P = .03). Changes in activation were observed in the contralesional cerebrum and ipsilesional cerebellum (P = .009). BATRAC was associated with significant increases in activation in precentral (P<.001) and postcentral gyri (P = .03) and the cerebellum (P<.001), although 3 BATRAC patients showed no fMRI changes. Considering all patients, there were no differences in functional outcome between groups. When only BATRAC patients with fMRI response were included (n = 6), BATRAC improved arm function more than DMTE did (P = .02). CONCLUSIONS: These preliminary findings suggest that BATRAC induces reorganization in contralesional motor networks and provide biological plausibility for repetitive bilateral training as a potential therapy for upper extremity rehabilitation in hemiparetic stroke.

Aged↗

Motor cortex stimulation in neuropathic pain. Correlations between analgesic effect and hemodynamic changes in the brain. A PET study.

To investigate brain mechanisms whereby electrical stimulation of the motor cortex (MCS) may induce pain relief in patients with neuropathic pain, cerebral blood flow (CBF) changes were studied using H2O PET in 19 consecutive patients treated with MCS for refractory neuropathic pain. Patients were studied in three conditions, (a) before MCS (Baseline, stimulator stopped 4 weeks before), (b) during a 35-min period of MCS and (c) during a 75-min period after MCS had been discontinued (OFF). Compared to Baseline, turning on the stimulator was associated with CBF increase in the contralateral (anterior) midcingulate cortex (aMCC, BA24 and 32) and in the dorso-lateral prefrontal (BA10) cortices. The most important changes of CBF were observed in the 75 min after discontinuation of MCS (OFF). This post-stimulation period was associated with CBF increases in a large set of cortical and subcortical regions (from posterior MCC (pMCC) to pregenual (pg) ACC, orbitofrontal cortex, putamen, thalami, posterior cingulate and prefrontal areas) and in the brainstem (mesencephalon/periaqueductal grey (PAG) and pons). CBF changes in the post-stimulation period correlated with pain relief. Functional connectivity analysis showed significant correlation between pgACC and PAG, basal ganglia, and lower pons activities, supporting the activation of descending ACC-to-PAG connections. MCS may act in part through descending (top-down) inhibitory controls that involve prefrontal, orbitofrontal and ACC as well as basal ganglia, thalamus and brainstem. These hemodynamic changes are lengthened and might therefore underlie the long-lasting clinical effects that largely outlast the actual stimulation periods.

Brain↗