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Primary motor cortex reorganization in a long-term monkey amputee.

The primary motor cortex (M1) was mapped with intracortical microstimulation (ICMS) in a 15 year-old macaque whose right upper extremity was amputated at the shoulder joint prior to 2 years of age. Movements of the right shoulder girdle and stump were evoked by ICMS throughout the left M1 upper extremity region. The size of the left M1 upper extremity region contralateral to the amputated arm was not appreciably different from the size of the right upper extremity region contralateral to the intact arm. Long stimulus trains and/or higher stimulus currents were needed to evoke detectable movements at significantly more loci in the left than in the right M1 upper extremity region. These observations would be consistent with unmasking of a high threshold representation of shoulder musculature that normally exists throughout the central core of the upper extremity region, where it underlies a lower threshold representation of the distal forelimb. Alternatively, invasion of the de-efferented distal forelimb core by surrounding shoulder representation may have occurred. Differences between the limited M1 reorganization observed in the present study and the more extensive reorganization of S1 observed in other studies may reflect fundamental differences between M1 and S1, and/or differences in the extent of de-efferentation versus deafferentation.

Amputation Stumps↗

The growth of non-pyramidal neurons in the primary motor cortex of man: a Golgi study.

In Golgi-Cox-impregnated motor cortex (regio precentralis) of six children (36 weeks of gestation to 13 month after birth) four types of interneurons of laminae II-VI have been investigated qualitatively and quantitatively and finally, compared with interneurons of a child (3 month of age) with Down's Syndrome. All cell measurements have been made by using a computerized digital morphometric system. In order to study the developmental stage of interneurons in our cases we statistically compared analogue neuron types in the brains. As parameters for characterizing non-pyramidal neurons served the pattern of dendritic branching, dendritic length for all dendritic orders within single dendritic fields, and of the whole neuron. The quantitative morphological study of dendritic arborizations revealed that bitufted and large multipolar interneurons had significantly more branching material in the postnatal brains than their prenatal counterparts. These differences were due to the increase of both length and number of branches during perinatal period. Such constant increment in dendritic span and branching provides larger receptive areas and that should improve the development of connections in functional intracortical columns. The quantitative parameter area of dendritic fields and number of branching points of the brain with Down's syndrome revealed in comparison with normal brain of the same age differences such as lower dendritic areas and a higher amount of branching points.

Dendrites↗

Motor cortex stimulation for deafferentation pain.

OBJECT: The authors tested a modified motor cortex stimulation (MCS) protocol for the treatment of deafferentation pain in 15 patients: eight patients with poststroke pain, four with brachial plexus injury, two with phantom limb pain, and one with spinal cord injury. METHODS: Preoperative pharmacological tests were performed with phentolamine, lidocaine, ketamine, thiopental, morphine, and a placebo. In 12 patients we placed a 20- or 40-grid electrode in the subdural space to determine the best stimulation point for pain relief over a few weeks and therefore the optimum position for a permanent internal device. In four patients, the MCS devices were implanted in the interhemispheric fissure to reduce lower-extremity pain. In one patient, the MCS device was placed within the central sulcus, and a 20-grid electrode was placed on the brain surface. In two patients with pain extending from the upper extremity to the hyperbody, dual-electrode devices were implanted to drive two electrodes. In 10 of the 15 patients MCS-induced pain reduction was achieved (four with excellent, two with good, and four with fair alleviation of pain). The result of pharmacological testing indicated that patients with ketamine sensitivity seem to be good candidates for MCS. CONCLUSIONS: Test stimulation with a subdural multigrid electrode was helpful in locating the best stimulation point for pain relief.

Aged↗

Functional activation in motor cortex reflects the direction and the degree of handedness.

Handedness is the clearest example of behavioral lateralization in humans. It is not known whether the obvious asymmetry manifested by hand preference is associated with similar asymmetry in brain activation during movement. We examined the functional activation in cortical motor areas during movement of the dominant and nondominant hand in groups of right-handed and left-handed subjects and found that use of the dominant hand was associated with a greater volume of activation in the contralateral motor cortex. Furthermore, there was a separate relation between the degree of handedness and the extent of functional lateralization in the motor cortex. The patterns of functional activation associated with the direction and degree of handedness suggest that these aspects are independent and are coded separately in the brain.

Adult↗

The patterns and synaptic properties of horizontal intracortical connections in the rat motor cortex.

1. The laminar distribution of synaptic activity in the primary motor cortex, elicited by stimulation of intracortical, horizontal afferents, was studied in young (12-17 days old) and adult rats using the in vitro brain slice preparation. Connectivity patterns were deduced from current-source density (CSD) analyses of field potential depth profiles and were confirmed by anatomic data of retrograde cell labeling after focal injections of a fluorescent tracer. 2. According to the CSD distributions, horizontal axons in layer II/III provide strong monosynaptic input to dendrites of layer II and III pyramidal cells in a distant column, and weaker monosynaptic input to layer V and VI cells by synapsing on dendritic fields at the border of layer III and V and in deep layer V. When these pathways are activated, layer II/III cells may relay excitatory activity to upper and deep layer V, as well as to other cells in layer II/III of the same column. Axons arising from layer V provide monosynaptic input to pyramidal cells in all layers of neighboring columns, by synapsing in two dendritic fields: one in the superficial layers and the other in middle layer V. Activation of these pathways may generate a disynaptic intracolumnar input from layer II/III cells to middle layer V, as well as to other cells in layer II/III. Similar patterns of synaptic activity were elicited by stimulation from 0.45 to 2 mm distal to the recorded column. There were no apparent differences between young and adult rats in the connectivity patterns revealed by the CSD analyses. 3. Tracer injections in layer III resulted in retrograde labeling of cells in layers II/III and V, at distances > 2 mm from the injection site, whereas injections in layer V resulted in retrograde labeling of cells at long distances in layer V and to a lesser extent in layer II/III. These findings indicate that neurons in layer V project, via horizontal axon collaterals, for long distances within layers III and V, whereas the horizontal axon collaterals of layer III cells are restricted, for the most part, to the superficial layers. 4. Suppression of inhibitory activity by bath application of the gamma-aminobutyric acid-A (GABAA) receptor antagonist bicuculline methiodide (BMI) did not alter the pattern of the CSD distributions. All synaptic currents present in the control medium were enhanced by application of BMI, although the effect was more pronounced on the polysynaptic components.(ABSTRACT TRUNCATED AT 400 WORDS)

6-Cyano-7-nitroquinoxaline-2,3-dione↗

Aggregate distribution in frontal and motor cortex in Huntington's disease brain.

Insoluble protein aggregates have been considered a pathological hallmark of Huntington's disease and other polyglutamine disorders. In this study the number of aggregates was assessed in the superior frontal gyrus and motor cortex of seven Huntington's disease patients and was compared with the symptoms (motor/mood) these patients displayed during the course of the disease. Regardless of the pattern of symptoms present in the patients, there was a consistently higher number of nuclear and non-nuclear aggregates in the superior frontal gyrus than in the motor cortex. This suggests that there is a consistent regional difference in the density of aggregates and that this consistency is not reflected in the variable symptomatology between cases.

Adult↗

Structural and functional definition of the motor cortex in the monkey (Macaca fascicularis).

1. The details of the organization of the motor cortex and its anterior and posterior border were investigated in three monkeys by a combination of techniques including intracortical microstimulation (i.c.m.s.), electrophysiological recording of cutaneous and muscle afferent inputs to single cortical neurones, and electrophysiological and anatomical identification of corticospinal neurones; in addition, data from these methods were related to cortical cytoarchitecture.2. Almost 5000 individual cortical loci were tested with i.c.m.s. in the unanaesthetized monkeys. In this paper, we particularly consider the organization of the forelimb motor representation, and its relation to the representation of other parts of the body. I.c.m.s. thresholds of about 5 muA were common for evoking twitch movements and e.m.g. responses in distal forelimb and face, jaw and tongue muscles, but proximal forelimb, trunk and hind-limb movements also sometimes had such low thresholds.3. The fingers were found to be represented nearest the central sulcus, with horseshoe-shaped bands of cortical tissue representing progressively more proximal muscles situated around this central ;finger core'.4. Cytoarchitectonically, the cortex having these low-threshold motor effects was characteristic of area 4. There was also a close fit between the extent of this ;excitable cortex' and the extent of densely spaced corticospinal neurones identified electro-physiologically or with horseradish peroxidase labelling. In subsequent mapping of forelimb afferents to the cortex when the animal was deeply anaesthetized, low-threshold and short-latency responses to muscle nerve stimulation were rarely found in this ;excitable cortex'.5. The anterior border could be clearly established by i.c.m.s. and by the sharp boundary of corticospinal neurones. It was noted that the motor cortex extends rostrally beyond area 4 and its anterior border appears to reside in the posterior part of area 6aalpha (Vogt & Vogt, 1919) although it is difficult to establish the precise transition from area 4 to area 6.6. Posteriorly, the ;micro-excitable cortex' was found to be limited to regions cytoarchitectonically delineated as area 4 and did not include area 3a. On the other hand, low-threshold forelimb proprioceptive afferent inputs appeared restricted to area 3a neurones in the deeply anaesthetized animal. Corticospinal neurones were very dense in area 4, and there was a clear decrease in their occurrence in more caudal areas. However, scattered nests of corticospinal neurones were noted in areas 3a, 3b, 2, 1 and 5. It remains to be seen whether these scattered nests could be directly involved in motor control or whether they may modulate ascending somatosensory transmission, and whether they rely on sensory feed-back or inputs from other central areas for their spinal effects.

Animals↗

Corticomotoneuronal latencies after non-invasive stimulation of the motor cortex in adrenomyeloneuropathy and adrenoleukodystrophy: results in patients and their relatives.

Corticomotoneuronal latencies after non-invasive stimulation of the motor cortex were studied in two patients with adrenomyeloneuropathy (AMN), in one patient with adrenoleukodystrophy (ALD), in two obligate heterozygotes, and in three clinically not affected sisters of the patients with AMN. Corticomotoneuronal latencies were prolonged in the patients as well as in obligate female carriers, but normal in the clinically and biochemically not affected relatives. The noninvasive cortex stimulation was found to be a sensitive method to detect clinical and subclinical deficits in patients and heterozygous carriers.

Adolescent↗

Functional and structural plasticity in motor cortex: implications for stroke recovery.

Several studies have now demonstrated that the motor cortical representations are dynamically maintained in both normal and brain-injured animals. Functional plasticity in the motor cortex of normal animals is accompanied by changes in synaptic morphology; these changes are skill-dependent rather than simply use-dependent. Finally, motor cortical areas undergo substantial functional alterations after focal ischemic infarcts; motor experience is a potent and adaptive modulator of injury-related plasticity. These recent neuroscientific advances set the stage for the development of new, more effective interventions in chronic stroke populations that are based on the basic mechanisms underlying neuroplasticity.

Brain Ischemia↗

Unchanged total number of neurons in motor cortex and neocortex in amyotrophic lateral sclerosis: a stereological study.

Modern stereological methods provide precise and reliable estimates of the number of neurons in specific regions of the brain. The total number of neurons in the neocortex and motor cortex from eight patients suffering from amyotrophic lateral sclerosis (ALS) and nine controls was estimated. No attempt was made to estimate subpopulations of neurons such as the number of giant pyramidal cells of Betz. No difference was found in the average number of neurons in neocortex in ALS and controls, 21.7 and 22.3 x 10(9), respectively, and 1.33 and 1.29 x 10(9) in motor cortex, respectively. In the light of our stereological measurements, results obtained from in-vivo proton magnetic resonance spectroscopy (1H-MRS), suggesting neuronal loss in ALS, may instead be due to neuronal metabolic dysfunction and/or alteration in the size or the volume fraction of the neurons.

Aged↗

[Changes in the excitability of the motor cortex during elaboration of conditioned reflex switching].

In the process of elaboration of conditioned transswitching of classical and instrumental alimentary and acid defensive reflexes, there was a change of excitability in the cortical projection of dog's forepaw. When flexor reaction elicited by stimulation of the motor cortex is used as signal stimulus, the character of functional reorganization in its cortical projection proves to be principally the same as at special elaboration of the motor cortex was used as a signal stimulus the thresholds of flexor reaction increased approximately equally in both experimental situations.

Animals↗

Patterns of abnormal motor cortex excitability in atypical parkinsonian syndromes.

OBJECTIVE: Multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal-ganglionic degeneration (CBGD) are all clinically characterized by an akinetic-rigid syndrome together with a variety of additional signs. We hypothesised that these atypical parkinsonian syndromes (APS) will show distinctive patterns in their motor output upon transcranial magnetic stimulation (TMS) due to their different underlying anatomico-functional deficits. METHODS: We performed single and paired-pulse TMS and assessed inhibitory and excitatory response parameters from the first dorsal interosseus muscles in 13 patients with MSA, 18 with PSP, 13 with CBGD, 15 patients with Parkinson's disease and 17 healthy subjects. RESULTS: PSP and MSA patients had significantly enlarged response amplitudes at rest, reduced intracortical inhibition (ICI) and prolonged ipsi- and contralateral silent periods, whereas CBGD patients showed significantly increased motor thresholds, smaller response amplitudes at rest, shortened contralateral silent period, reduced transcallosal inhibition and a reduced ICI. In 22% of APS patients ipsilateral motor responses occurred in upper limb muscles irrespective of the underlying disease. CONCLUSIONS: Our results indicate that motor cortex disinhibition is predominant in patients with PSP and MSA. In CBGD more severe neuronal cell loss in the motor cortex itself may lead to hypoexcitability of corticospinal and transcallosal pathways.

Adult↗

Magnetic brain stimulation: a tool to explore the action of the motor cortex on single human spinal motoneurones.

The human brain can be stimulated by a single intense magnetic pulse over the scalp. Currents induced within the cranium excite the motor cortex and cause limb muscles to contract. The discharge of single motor units, the firing of which is maintained by voluntary effort, can be modulated by magnetic stimuli. Peri-stimulus time histograms suggest that after a cortical stimulus spinal motoneurones are induced to fire by a sequence of EPSPs arising from a train of impulses transmitted monosynaptically over fast-conducting corticospinal fibres. In multiple sclerosis both dispersion of this descending volley and partial transmission failure can impair motoneurone excitation and may explain motor symptoms in these patients.

Brain↗

Motor cortex stimulation for amyotrophic lateral sclerosis. Time for a therapeutic trial?

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) of the brain can modulate neurotransmission. The aim of this preliminary study was to investigate whether rTMS of the motor cortex at low (1 Hz) or high (20 Hz) frequencies can have any beneficial effect in a transgenic rat model of amyotrophic lateral sclerosis (ALS) and in a few patients with ALS. METHODS: The effects of chronic rTMS were evaluated in 20 transgenic rats overexpressing the human G93A mutant superoxide dismutase 1 gene. Several cycles of rTMS were also performed in 4 ALS patients and the rate of progression of the disease before and during rTMS treatment was compared. RESULTS: No effects of rTMS was observed in transgenic rats. The rTMS treatment was well tolerated by the patients. All ALS patients continued to deteriorate. However, in the patients exposed to low-frequency rTMS the rate of progression during treatment was slightly slower than that evaluated before treatment; an opposite tendency was observed in patients exposed to high frequencies. CONCLUSIONS: Though we cannot be sure whether the effects observed in the patients can be attributed to rTMS, further investigation using low-frequency motor cortex stimulation on a larger group of ALS patients is warranted. SIGNIFICANCE: The results of the pilot study in humans might open up a new therapeutic perspective in ALS based on neuromodulation.

Amyotrophic Lateral Sclerosis↗

Stable ratio of ipsilateral to contralateral sensory motor cortex activity despite varying effort and peripheral nerve block.

BACKGROUND: Ipsilateral sensory motor cortex (SMC) activation can occur during hand movements following cerebral injury. We studied the effect of increasing task difficulty and temporary peripheral paralysis on patterns of motor system activation. METHODS: Six healthy subjects completed a functional MRI paradigm of right finger abduction with four stages; light resistance, strong resistance, imagined movement and attempted abduction after ulnar nerve blockade. Activation maps compared images acquired during rest and task, while region of interest analysis measured numbers of activated pixels. RESULTS: All subjects showed some ipsilateral SMC activation. Across all subjects and all tasks involving hand movement, contralateral activation was proportional to ipsilateral activation (2.1:1; r=0.86). CONCLUSIONS: The relationship between ipsilateral and contralateral SMC activation remained stable despite differing effort or hand paralysis. The contralateral and ipsilateral SMC appear to act in a coordinated fashion during unilateral hand movements.

Adult↗

Effects of low frequency and low intensity repetitive paired pulse stimulation of the primary motor cortex.

OBJECTIVE: Following a previous report [Bestmann et al. Clin Neurophysiol 2004;115:755-64] that pairs of subthreshold pulses of transcranial magnetic stimulation (TMS) can show temporal summation, we explored whether repeated application of pairs of stimulation could produce long-lasting after effects on the excitability of the human motor cortex. METHODS: Twelve healthy subjects received 25 min repetitive paired pulse magnetic stimulation (paired rTMS) given at a frequency of about 0.6 Hz over the left primary motor cortex (500 paired stimuli in total). The interval between the paired stimuli was 3 ms and the intensity of both stimuli was 80% of active motor threshold. The resting and active motor threshold, MEP recruitment curve, short interval intracortical inhibition (SICI) and facilitation, and the duration of the cortical silent period (SP) were tested for the right first interosseous muscle (FDI) before and two times after the end of 25 min paired rTMS. RESULTS: Prolonged subthreshold paired rTMS produced a significant decrease in excitability in the corticospinal projection to FDI: resting motor threshold was significantly increased and MEP recruitment was significantly decreased, SICI was significantly increased at 2 and 4 ms and the SP was significantly increased in duration. CONCLUSIONS: Prolonged low frequency paired rTMS at subthreshold intensity can modulate cortical excitability by producing inhibitory effects that outlast the period of stimulation.

Adolescent↗

Cerebellar loops with motor cortex and prefrontal cortex of a nonhuman primate.

We used transneuronal transport of neurotropic viruses to examine the topographic organization of circuits linking the cerebellar cortex with the arm area of the primary motor cortex (M1) and with area 46 in dorsolateral prefrontal cortex of monkeys. Retrograde transneuronal transport of the CVS-11 (challenge virus strain 11) strain of rabies virus in cerebello-thalamocortical pathways revealed that the arm area of M1 receives input from Purkinje cells located primarily in lobules IV-VI of the cerebellar cortex. In contrast, transneuronal transport of rabies from area 46 revealed that it receives input from Purkinje cells located primarily in Crus II of the ansiform lobule. Thus, both M1 and area 46 are the targets of output from the cerebellar cortex. However, the output to each area of the cerebral cortex originates from Purkinje cells in different regions of the cerebellar cortex. Anterograde transneuronal transport of the H129 strain of herpes simplex virus type 1 (HSV1) revealed that neurons in the arm area of M1 project via the pons to granule cells primarily in lobules IV-VI, whereas neurons in area 46 project to granule cells primarily in Crus II. Together, the findings from rabies and HSV1 experiments indicate that the regions of the cerebellar cortex that receive input from M1 are the same as those that project to M1. Similarly, the regions of the cerebellar cortex that receive input from area 46 are the same as those that project to area 46. Thus, our observations suggest that multiple closed-loop circuits represent a fundamental architectural feature of cerebrocerebellar interactions.

Animals↗

Enhanced synchrony among primary motor cortex neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine primate model of Parkinson's disease.

Primary motor cortex (MI) neurons discharge vigorously during voluntary movement. A cardinal symptom of Parkinson's disease (PD) is poverty of movement (akinesia). Current models of PD thus hypothesize that increased inhibitory pallidal output reduces firing rates in frontal cortex, including MI, resulting in akinesia and muscle rigidity. We recorded the simultaneous spontaneous discharge of several neurons in the arm-related area of MI of two monkeys and in the globus pallidus (GP) of one of the two. Accelerometers were fastened to the forelimbs to detect movement, and surface electromyograms were recorded from the contralateral arm of one monkey. The recordings were conducted before and after systemic treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rendering the animals severely akinetic and rigid with little or no tremor. The mean spontaneous MI rates during periods of immobility (four to five spikes/sec) did not change after MPTP; however, in this parkinsonian state, MI neurons discharged in long bursts (sometimes >2 sec long). These bursts were synchronized across many cells but failed to elicit detectable movement, indicating that even robust synchronous MI discharge need not result in movement. These synchronized population bursts were absent from the GP and were on a larger timescale than oscillatory synchrony found in the GP of tremulous MPTP primates, suggesting that MI parkinsonian synchrony arises independently of basal ganglia dynamics. After MPTP, MI neurons responded more vigorously and with less specificity to passive limb movement. Abnormal MI firing patterns and synchronization, rather than reduced firing rates, may underlie PD akinesia and persistent muscle rigidity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗