Occasional essay: upper motor neuron syndrome in amyotrophic lateral sclerosis

The diagnosis of amyotrophic lateral sclerosis (ALS) requires recognition of both lower (LMN) and upper motor neuron (UMN) dysfunction.1 However, classical UMN signs are frequently difficult to identify in ALS.2 LMN involvement is sensitively detected by electromyography (EMG)3 but, as yet, there are no generally accepted markers for monitoring UMN abnormalities,4 the neurobiology of ALS itself, and disease spread through the brain and spinal cord,.5 Full clinical assessment is therefore necessary to exclude other diagnoses and to monitor disease progression. In part, this difficulty regarding detection of UMN involvement in ALS derives from the definition of ‘the UMN syndrome’. Abnormalities of motor control in ALS require reformulation within an expanded concept of the UMN, together with the neuropathological, neuro-imaging and neurophysiological abnormalities in ALS. We review these issues here

The contribution of reorganised motor pathways to recovery of arm and hand function after stroke

Stroke often disrupts the descending motor pathways controlling the upper limb with severe consequences for patients' hand function. Although some recover they are often slow and clumsy when using the affected hand. The mechanism underlying recovery is an unsettled question. Transcranial magnetic stimulation (TMS) was used to determine the changes in the connectivity and function of the corticospinal tract (CST) that are associated with improved motor performance in the recovering arm and hand. The study comprised four parts: 1. Task dependency of responses to TMS in recovered stroke patients. Eight patients, who had recovered some degree of hand function were tested for task dependence of short-latency EMG responses to TMS. Normal subjects were also tested. 2. Longitudinal investigation of recovery of voluntary movement of arm and hand after stroke. The relationship between the recovery of hand and arm function in a group of acute stroke patients (n=21) and the presence of short latency contralateral and ipsilateral EMG responses to TMS in four different upper limb muscles was investigated. 3. Ipsilateral responses in normal subjects. The results of the longitudinal study prompted further investigation of the presence of ipsilateral responses in proximal and distal muscles in fifteen normal subjects. 4. The contribution of CS input to production of force in proximal and distal upper limb muscles. Because patients did not always have responses to TMS in recovered proximal muscles, two further studies were carried out to clarify the contribution of CS input to production of force in proximal and distal upper limb muscles. First, the effect of voluntary contraction on response amplitudes in deltoid, biceps and ID1 were compared. Second, the effect of increasing stimulus intensity on recruitment of low threshold motor units was assessed for deltoid and ID1. In addition the change in response amplitude with increasing voluntary activity in the affected and unaffected shoulder muscles of three patients were compared

Behavioral and muscular deficits induced by Muscimol injection into the primate primary motor cortex during a reach-to-grasp task

Le contrôle moteur fin et précis des doigts est une habileté importante dans la vie quotidienne pour écrire ou manger par exemple. Ce contrôle moteur est pris en charge par le cortex moteur primaire (M1) qui transmet le signal neuronal à la moelle épinière via la voie corticospinale. Le macaque rhésus est un excellent modèle pour étudier ce système moteur car, comme chez l’humain, il possède cette voie cortico-motoneuronale directe. Bien que les déficits du contrôle moteur de la main suite à des inactivations de M1 aient été étudiés sur des modèles de singes, peu d’études ont décrit les changements musculaires sous-tendant ces déficits. Le but de cette étude était d’évaluer les effets d’une inactivation partielle de M1 sur le comportement et l’activation du patron musculaire du membre supérieur chez le macaque rhésus. Pour ce faire, nous avons effectué des injections intra-corticales de Muscimol, un agoniste du GABA, pour inactiver temporairement l’aire de représentation de la main de M1. Des singes ont été entrainés à réaliser une tâche d’atteinte et de préhension qui requière l’utilisation du pouce et de l’index pour attraper une pastille de nourriture. En parallèle, les activités électromyographiques (EMG) des muscles proximaux et distaux du membre supérieur contralatéral aux sites d’injections ont été enregistrées. L’inactivation partielle de M1 entraine différents déficits moteurs comme une diminution du taux de succès, une perte des mouvements indépendants des doigts, une première flexion de l’index plus lente, et l’apparition de nouvelles stratégies de préhension pour attraper la pastille. Dans le cas de trouble sévère, les singes ont présentés tous ces déficits comportementaux. Ces troubles moteurs étaient sous-tendus par des activités musculaires anormales. En effet, les analyses EMG ont mis en évidence des changements dans les latences et les patrons d’activations musculaires des muscles proximaux et distaux au cours de la phase d’atteinte, d’ajustement et de préhension. Dans le cas de trouble modéré, les patrons d’activations musculaires étaient préservés malgré certain déficits visibles. Cependant, les patrons d’activations musculaires étaient altérés si la tâche demandait une rotation de l’avant-bras et de la main. Ces résultats montrent que les déficits comportementaux et les changements musculaires dépendent de la sévérité des troubles moteurs et/ou de la difficulté de la tâche (i.e. une rotation de l’avant-bras).Fine digit movements contribute to many different aspects of our daily life and require appropriate muscle coordination. The main pathway through which M1 sends motor commands to spinal motor neurons is via the corticospinal tract. The rhesus macaque, like humans, have this direct corticomotoneuronal pathway of M1, making it a useful model to study this system. Although the effect of M1 inactivation on the control of the hand in term of behavioral changes has been studied in monkeys, little is known of how muscle activation patterns of the upper limb during reaching and grasping in monkeys becomes altered. The goal of this study was to evaluate the effect of a partial inactivation of the primary motor cortex (M1) in rhesus macaques on both behavioral performance and muscle activations. To do so we performed intra-cortical injections of Muscimol, a GABA agonist, to inactivate the hand area of M1. Monkeys performed a reach-to-grasp task that required a precision grip to retrieve a food pellet from a well. Electromyographic (EMG) activity of the proximal and distal muscles of the contralateral upper limb were recorded and quantified relative to the behavioral performance. We found that depending on the severity of the impairment, the Muscimol injection could induce several different movement abnormalities, such as decrease in the success rate, loss of independent finger movements, longer duration of the first flexion of the index finger, and use of alternate types of grasp to retrieve the food pellet. In cases of severe impairment, monkeys displayed all these movement abnormalities concurrently. In addition, we observed that behavioral deficits were associated with muscle discoordination. Indeed, EMG analysis revealed that the latencies and the muscle activation patterns were altered during the reach, hand preshaping and the grasp phases of the movement. These inappropriate EMG activities were visible on both proximal and distal muscles of the upper limb. In cases of mild impairment, monkeys had fewer behavioral deficits, but still showed some changes in the temporal muscle activation patterns. In contrast to the severe cases, the muscle activation patterns were more preserved. Interestingly, in the mild cases, the muscle activation patterns were altered if a rotation of the forearm was required by the task. Thus, we found that behavioral and muscular activation changes were dependent on the severity of the impairment and/or the difficulty of the task (i.e. required a rotation of the forearm)

Response of single spinal motoneurones to transcranial magnetic simulation in healthy subjects and patients with upper motor neurone disorders

The problem addressed by this study was: How does the human corticospinal tract influence the discharge of spinal motoneurones and what are the effects of neurological disease? The method employed was to study the firing probability of 78 tonically active single motor units of the upper limb following transcranial magnetic stimulation. This was performed in healthy subjects and in a group of patients with different upper motor neurone (UMN) disorders. The inducing current flowed in an anticlockwise direction through a circular coil which was positioned tangentially at the vertex. Two peaks were produced in the peri-stimulus time histogram. The primary peak (PP) had an onset latency in healthy subjects ranging from 13 ms (deltoid and biceps) to 31 ms (first dorsal interosseous muscle) (FDI) and had a short duration of 4.6 ±1.7 ms (mean ± SD). PP frequently consisted of 1-3 sub-peaks, with a mean intermodal interval of 1.4 ms for FDI and 2.9 ms for forearm and upper arm muscles. This interval probably reflects the maximal rise time of one in a sequence of excitatory postsynaptic potentials (EPSPs) at the motoneurone. An increase either in the interval between the stimulus and the preceding voluntary discharge, or in the intensity of stimulation, raised the probability of discharges occurring within PP and influenced their latency. The secondary peak (SP) had an onset latency in FDI ranging from 56-90 ms and a long duration of 20.9 ±12.0 ms. Evidence suggests that SP was caused by the rising phase of a late EPSP mediated via a pathway which included a peripheral afferent component. When compared with healthy subjects, PP in UMN patients was found to be either normal, absent, delayed and dispersed (by up to 28 ms and 21 ms, respectively) or found to consist of sub-peaks with abnormally long inter- modal intervals. These findings suggest specific mechanisms including cortical inexcitability, variable degrees of slowing in the velocity of propagation in descending fibres, frequency dependent conduction block, delay between EPSPs caused by the operation of more than one pathway and ineffective spatial or temporal summation at the spinal motoneurone

Prognostic value of cortically induced motor evoked activity by TMS in chronic stroke: caveats from a very revealing single clinical case

Background: We report the case of a chronic stroke patient (62 months after injury) showing total absence of motor activity evoked by transcranial magnetic stimulation (TMS) of spared regions of the left motor cortex, but near-to-complete recovery of motor abilities in the affected hand. Case presentation: Multimodal investigations included detailed TMS based motor mapping, motor evoked potentials (MEP), and Cortical Silent period (CSP) as well as functional magnetic resonance imaging (fMRI) of motor activity, MRI based lesion analysis and Diffusion Tensor Imaging (DTI) Tractography of corticospinal tract (CST). Anatomical analysis revealed a left hemisphere subinsular lesion interrupting the descending left CST at the level of the internal capsule. The absence of MEPs after intense TMS pulses to the ipsilesional M1, and the reversible suppression of ongoing electromyographic (EMG) activity (indexed by CSP) demonstrate a weak modulation of subcortical systems by the ipsilesional left frontal cortex, but an inability to induce efficient descending volleys from those cortical locations to right hand and forearm muscles. Functional MRI recordings under grasping and finger tapping patterns involving the affected hand showed slight signs of subcortical recruitment, as compared to the unaffected hand and hemisphere, as well as the expected cortical activations. Conclusions: The potential sources of motor voluntary activity for the affected hand in absence of MEPs are discussed. We conclude that multimodal analysis may contribute to a more accurate prognosis of stroke patients

Neuroplasticity of Ipsilateral Cortical Motor Representations, Training Effects and Role in Stroke Recovery

This thesis examines the contribution of the ipsilateral hemisphere to motor control with the aim of evaluating the potential of the contralesional hemisphere to contribute to motor recovery after stroke. Predictive algorithms based on neurobiological principles emphasize integrity of the ipsilesional corticospinal tract as the strongest prognostic indicator of good motor recovery. In contrast, extensive lesions placing reliance on alternative contralesional ipsilateral motor pathways are associated with poor recovery. Within the predictive algorithms are elements of motor control that rely on contributions from ipsilateral motor pathways, suggesting that balanced, parallel contralesional contributions can be beneficial. Current therapeutic approaches have focussed on the maladaptive potential of the contralesional hemisphere and sought to inhibit its activity with neuromodulation. Using Transcranial Magnetic Stimulation I seek examples of beneficial plasticity in ipsilateral cortical motor representations of expert performers, who have accumulated vast amounts of deliberate practise training skilled bilateral activation of muscles habitually under ipsilateral control. I demonstrate that ipsilateral cortical motor representations reorganize in response to training to acquisition of skilled motor performance. Features of this reorganization are compatible with evidence suggesting ipsilateral importance in synergy representations, controlled through corticoreticulopropriospinal pathways. I demonstrate that ipsilateral plasticity can associate positively with motor recovery after stroke. Features of plastic change in ipsilateral cortical representations are shown in response to robotic training of chronic stroke patients. These findings have implications for the individualization of motor rehabilitation after stroke, and prompt reappraisal of the approach to therapeutic intervention in the chronic phase of stroke

Motor system plasticity induced by non-invasive stimuli

MD ThesisPrecisely timed paired stimulation protocols can change cortical and subcortical excitability. In the first study, induction of plastic changes in the long-latency stretch reflex (LLSR) by pairing non-invasive stimuli was attempted, at timings predicted to cause spiketiming dependent plasticity (STDP) in the brainstem. LLSR in human elbow muscles depends on multiple pathways; one possible contributor is the reticulospinal tract. The stimuli used are known to activate reticulospinal pathways. In healthy human subjects, reflex responses in flexor muscles were recorded following extension perturbations at the elbow. Subjects were then fitted with a portable device which delivered auditory click stimuli, and electrical stimuli to biceps muscle. The LLSR was significantly enhanced or suppressed in the biceps muscle depending on the intervention protocol. No changes were observed in the unstimulated brachioradialis muscle. Although contributions from the spinal or cortical pathways cannot be excluded, the results were consistent with STDP in reticulospinal circuits. In the second study, baseline TMS responses were recorded from two intrinsic hand muscles, flexor digitorum superficialis (FDS) and extensor digitorum communis (EDC). In the first phase, paired associative stimulation (PAS) was delivered by pairing motor point stimulation of FDS or EDC with TMS. Responses were then remeasured. Increases were greatest in the hand muscles, smaller in FDS, and non-significant in EDC. In the second phase, intermittent theta-burst rapid-rate TMS was applied instead of PAS. In this case, all muscles showed similar increases in TMS responses. This study showed that potential plasticity in motor cortical output has a gradient: hand muscles > flexors > extensors. However, this was only seen in a protocol which requires integration of sensory input (PAS), and not when plasticity was induced purely by cortical stimulation (rapid rate TMS). In the third study, motor imagery was paired with TMS in healthy human subjects. They were asked to imagine wrist flexion or extension movement, while TMS was delivered to the motor cortex. Six different protocols were tested, but only flexor imagination with TMS and extensor imagination with TMS showed significant facilitation following the test. Flexor imagination with TMS increased motor evoked potential (MEP) in all four Abstract 2 muscles with maximum changes towards flexor, whereas extensor imagination with TMS increased MEP only in extensor. Above changes in the cortical or subcortical excitability evoked by non-invasive stimulation protocols were consistent with long term potentiation and long-term depression mediated plastic change