Impaired scaling of preparatory postural responses to repeated balance perturbations in Parkinsonian patients with comorbid white matter disease.

BACKGROUND: Postural instability may result from altered sequencing of automatic motor programs for anticipatory postural corrections and/or impaired motor learning in Parkinson Disease (PD) patients. Comorbid white matter disease is a major determinant of axial motor impairment, leading to poorer stability than nigrostriatal dopaminergic denervation per se. OBJECTIVE: To assess differences in anticipatory control of postural stability function between subjects affected by PD with comorbid leukoaraiosis (LPD), idiopathic Parkinson disease (IPD) and elderly healthy subjects (EHS) as control group. METHODS: Eight patients with IPD, eight patients with LPD and eight age/weight matched elderly healthy subjects (EHS) were tested in standing position by measuring the Center of Pressure (CoP) along the anteroposterior axis (CoP-Y) while subjects were expecting three repeated backward surface translation. RESULTS: LPD patients positioned the CoP-Y significantly backward while waiting for the second and third platform translations, with respect to their COP-Y position in preparation for the first translation. The IPD and EHS showed no significant differences in the COP-Y position among the repeated perturbation trials. CONCLUSIONS: LPD patients show inability to rescale an effective preparatory postural pattern to known, repeated postural perturbations suggesting impaired sensory-motor strategies in anticipating perturbations. Anticipatory postural patterns remain effective in IPD patients.

Role of brain hemispheric dominance in anticipatory postural control strategies.

Most of the cerebral functions are asymmetrically represented in the two hemispheres. Moreover, dexterity and coordination of the distal segment of the dominant limbs depend on cortico-motor lateralization. In this study, we investigated whether postural control may be also considered a lateralized hemispheric brain function. To this aim, 15 young subjects were tested in standing position by measuring center of pressure (COP) shifts along the anteroposterior axis (COP-Y) during dynamic posturography before and after continuous Theta Burst Stimulation (cTBS) intervention applied to the dominant or non-dominant M1 hand area as well as to the vertex. We show that when subjects were expecting a forward platform translation, the COP-Y was positioned significantly backward or forward after dominant or non-dominant M1 stimulation, respectively. We postulate that cTBS applied on M1 may have disrupted the functional connectivity between intra- and interhemispheric areas implicated in the anticipatory control of postural stability. This study suggests a functional asymmetry between the two homologous primary motor areas, with the dominant hemisphere playing a critical role in the selection of the appropriate postural control strategy.

More than at the neuromuscular synapse: actions of botulinum neurotoxin A in the central nervous system.

Botulinum neurotoxin type A (BoNT/A) is a metalloprotease that produces a sustained yet transitory blockade of transmitter release from peripheral nerve terminals. Local delivery of this neurotoxin is successfully employed in clinical practice to reduce muscle hyperactivity such as in spasticity and dystonia, and to relieve pain with long-lasting therapeutic effects. However, not all BoNT/A effects can be explained by an action at peripheral nerve terminals. Indeed, it appears that BoNT/A is endowed with trafficking properties similar to the parental tetanus neurotoxin and thus be able to directly affect the CNS. In this review, we present and discuss novel compelling evidence for a direct central effect of BoNT/A in both dorsal and ventral horns of the animal and human spinal cord after peripheral injection of the neurotoxin, with important consequences on pain and motor control. This new knowledge is expected to radically change the approach to the use of BoNT/A in the future. As BoNT/A central action appears to also contribute to functional improvement, for instance in human spastic gait, the challenge will be to develop new subtypes or BoNT derivatives with deliberate, cell-specific central effects in order to fully exploit the spectrum of BoNT/A therapeutic activity.

Differential effects of acute cortisol administration on deep and shallow episodic memory traces: a study on healthy males.

We aimed at investigating rapid effects of plasma cortisol elevations on the episodic memory phase of encoding or retrieval, and on the strength of the memory trace. Participants were asked either to select a word containing the letter "e" (shallow encoding task) or to judge if a word referred to a living entity (deep encoding task). We intravenously administered a bolus of 20mg of cortisol either 5 min before encoding or 5 min before retrieval, in a between-subjects design. The study included only male participants tested in the late afternoon, and neutral words as stimuli. When cortisol administration occurred prior to retrieval, a main effect of group emerged. Recognition accuracy was higher for individuals who received cortisol compared to placebo. The higher discrimination accuracy for the cortisol group was significant for words encoded during deep but not shallow task. Cortisol administration before encoding did not affect subsequent retrieval performance (either for deep or shallow stimuli) despite a facilitatory trend. Because genomic mechanisms take some time to develop, such a mechanism cannot apply to our findings where the memory task was performed shortly after the enhancement of glucocorticoid levels. Therefore, glucocorticoids, through non-genomic fast effects, determine an enhancement in episodic memory if administered immediately prior to retrieval. This effect is more evident if the memory trace is laid down through deep encoding operations involving the recruitment of specific neural networks.

Meaningful improvement in walking performance after Botulinum neurotoxin A (BoNT-A) in chronic spastic patients.

BACKGROUND: Botulinum neurotoxin A (BoNT-A) may reduce lower limb spasticity but its role in improving walking ability remains to be established. OBJECTIVE: To investigate the efficacy of simultaneous BoNT-A injections into several targeted spastic muscles of different joints on gait speed and on functional gains in gait performance in chronic stroke and MS patients. METHODS: Twenty patients affected by stroke or multiple sclerosis were tested before, one and three months after BoNT-A administration. Gait was evaluated by the 10 Meter Walk Test; patients were stratified into functional ambulation classes accordingly. Spasticity was assessed using the modified Ashworth Scale. RESULTS: At final assessment, spasticity was reduced in hip adductors and ankle plantar-flexors, gait speed improved and, 1/3rd of patients transitioned to a higher ambulation class. The pre-post difference in Level of Spasticity of the hips was a predictor for an increase in gait speed. CONCLUSIONS: A meaningful improvement in walking performance can be obtained in chronic spastic patients after BoNT-A injection into several muscles, specifically the hip adductors.

Predictors of long-term recovery in complex activities of daily living before discharge from the stroke unit.

BACKGROUND AND PURPOSE: There is a need for individuating those post-stroke patients who may benefit from an optimal and customised rehabilitation plan aiming at early reintegration in community life participation. This study investigated whether the gain of independence in complex Activities of Daily Living (ADL) may be predicted before the discharge from the stroke unit using simple bedside determinants. METHODS: In 104 first-ever stroke patients with no previous disability, ten determinants at 10 days after stroke were selected. Multivariable logistic regression analysis was applied to identify the prognostic determinants able to predict independence in complex ADL, as measured by modified Rankin Scale grade ≤2. RESULTS: The model shows that having a Barthel Index ≥9, a Motricity Index- Upper Limb ≥75, an age ≤70 and being a male resulted in 100% probability of achieving independence in complex ADL. If three of the four determinants were present, the probability was more than 90%. With the presence of two of the four determinants, the probability ranged from 87% to 28%. With the presence of only one determinant, the probability was 13%. CONCLUSIONS: Accurate prediction of independence in complex ADL can be made before the discharge from the stroke unit. The strength of the paretic upper limb, age, gender, and the ability of performing basic ADL are the significant variables. The probability of favorable prognosis depends on the presence and on the robustness of each single determinant.

Beyond muscular effects: depression of spinal recurrent inhibition after botulinum neurotoxin A.

The natural target of the botulinum neurototoxin type A (BoNT-A) is the neuromuscular junction. When injected into a muscle, BoNT-A is internalized by motoneurone terminals where it functions as an endopeptidase, cleaving protein components of the synaptic machinery responsible for vesicle docking and exocytosis. As a result, BoNT-A induces a characteristic flaccid paralysis of the affected muscle. In animal models, BoNT-A applied in the periphery can also influence central activity via retrograde transport and transcytosis. An analogous direct central effect in humans is still debated. The present study was designed to address whether BoNT-A modifies the activity of the spinal recurrent inhibitory pathways, when injected at muscular level, in humans. To avoid methodological bias, the recurrent inhibition from an injected muscle (soleus) was investigated on an untreated muscle (quadriceps), and stimulation parameters (producing recurrent inhibition) were monitored on a third non-injected muscle but innervated by the same nerve as the soleus (flexor digitorum brevis). The experiments were performed on 14 post-stroke patients exhibiting spasticity in ankle plantarflexors, candidates for BoNT-A. One month after BoNT-A, the level of recurrent inhibition was depressed. It is suggested that the depression of recurrent inhibition was induced by BoNT-A, injected peripherally, through axonal transport and blockade of the cholinergic synapse between motoneurone recurrent collaterals and Renshaw cells.

Cortisol-induced effects on human cortical excitability.

BACKGROUND: Cortisol may fulfill all criteria for a neuromodulator. However, it is not known whether it may rapidly influence motor system activity in humans. OBJECTIVE: Circulating cortisol levels were manipulated by administration of a single intravenous dose of hydrocortisone or saline solution, on separate days, to study changes in corticospinal and motor cortical excitability. METHODS: Motor-evoked potentials (MEPs) to single- and paired-pulse transcranial magnetic stimulation from the resting first dorsal interosseous muscle, and cortisol plasma levels were assessed before and after either a bolus of 20 mg of hydrocortisone or saline solution in seven healthy subjects. RESULTS: Mean cortisol plasma level rapidly rose, peaked between 5 and 10 minutes after hydrocortisone injection, to slowly decay afterward. Mean MEP amplitude significantly increased from preinjection levels, and mean standard deviation of MEPs significantly increased between 8-12 minutes postinjection. Short-intracortical inhibition, tested during the same period, was significantly decreased. No significant changes in the above measures were observed after saline solution administration. CONCLUSIONS: Our results suggest that high circulating levels of cortisol rapidly increase corticospinal excitability and reduce gamma aminobutyric acid activity, as measured by short-intracortical inhibition, in humans. These effects, lasting about 10 minutes, were observed within 15 minutes from the pharmacological intervention. They are therefore compatible with a nongenomic mechanism. These findings are important in view of the notion that a decrease in intracortical gamma aminobutyric acid activity appears to be a prerequisite for motor learning and plastic processes in the human motor cortex.

Progesterone - new therapy in mild carpal tunnel syndrome? Study design of a randomized clinical trial for local therapy.

BACKGROUND: Local corticosteroid injection for carpal tunnel syndrome (CTS) provides greater clinical improvement in symptoms one month after injection compared to placebo but significant symptom relief beyond one month has not been demonstrated and the relapse of symptoms is possible.Neuroprotection and myelin repair actions of the progesterone was demonstrated in vivo and in vitro study.We report the design of a randomized controlled trial for the local injection of cortisone versus progesterone in "mild" idiopathic CTS. METHODS: Sixty women with age between 18 and 60 years affected by "mild" idiopathic CTS, diagnosed on the basis of clinical and electrodiagnostic tests, will be enrolled in one centre. The clinical, electrophysiological and ultasonographic findings of the patients will be evaluate at baseline, 1, 6 and 12 months after injection.The major outcome of this study is to determine whether locally-injected progesterone may be more beneficial than cortisone in CTS at clinical levels, tested with symptoms severity self-administered Boston Questionnaire and with visual analogue pain scale.Secondary outcome measures are: duration of experimental therapy; improvement of electrodiagnostic and ultrasonographic anomalies at various follow-up; comparison of the beneficial and harmful effects of the cortisone versus progesterone. CONCLUSION: We have designed a randomized controlled study to show the clinical effectiveness of local progesterone in the most frequent human focal peripheral mononeuropathy and to demonstrate the neuroprotective effects of the progesterone at the level of the peripheral nervous system in humans.

Evidence for two concurrent inhibitory mechanisms during response preparation.

Inhibitory mechanisms are critically involved in goal-directed behaviors. To gain further insight into how such mechanisms shape motor representations during response preparation, motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) and H-reflexes were recorded from left hand muscles during choice reaction time tasks. The imperative signal, which indicated the required response, was always preceded by a preparatory cue. During the postcue delay period, left MEPs were suppressed when the left hand had been cued for the forthcoming response, suggestive of a form of inhibition specifically directed at selected response representations. H-reflexes were also suppressed on these trials, indicating that the effects of this inhibition extend to spinal circuits. In addition, left MEPs were suppressed when the right hand was cued, but only when left hand movements were a possible response option before the onset of the cue. Notably, left hand H-reflexes were not modulated on these trials, consistent with a cortical locus of inhibition that lowers the activation of task-relevant, but nonselected responses. These results suggest the concurrent operation of two inhibitory mechanisms during response preparation: one decreases the activation of selected responses at the spinal level, helping to control when selected movements should be initiated by preventing their premature release; a second, upstream mechanism helps to determine what response to make during a competitive selection process.

Role of Renshaw cells in amyotrophic lateral sclerosis.

In this article the role of Renshaw cell involvement in experimental amyotrophic lateral sclerosis (ALS) is discussed, with an emphasis on the anatomy, physiology, and possible role in motor control of Renshaw cells. These cells are located in lamina VII of the spinal cord, are excited by motor axon collaterals, and inhibit homonymous and synergistic motoneurons in a negative-feedback fashion (recurrent inhibition). Early dysfunction and/or loss of Renshaw cells has been suggested to occur in experimental ALS, and the hypothesis has been put forward that this may be the event that makes motoneurons more susceptible to glutamatergic toxicity in ALS. However, Renshaw cell properties and connectivity-in particular, the lack of recurrent inhibition in the more distal muscles of the limbs where, on the contrary, initial wasting is prominent in human ALS-make it unlikely that impairment of Renshaw cells is a general feature of the human form of the disease.

Prulifloxacin as a trigger of myasthenia gravis.

Fluoroquinolones has been rarely associated with exacerbation of myasthenia gravis (MG). We present a case of MG following a treatment with prulifloxacin, a new broad-spectrum oral fluoroquinolone. Fluoroquinolones of any generation may interfere with neuromuscular transmission and should be avoided in patients with MG.

A reappraisal of the central effects of botulinum neurotoxin type A: by what mechanism?

Botulinum neurotoxin A (BoNT/A) is a metalloprotease that enters peripheral motor nerve terminals and blocks the release of acetylcholine via the specific cleavage of the synaptosomal-associated protein of 25-kDa. Localized injections of BoNT/A are widely employed in clinical neurology to treat several human diseases characterized by muscle hyperactivity. It is generally assumed that the effects of BoNT/A remain localized to the injection site. However, several neurophysiological studies have provided evidence for central effects of BoNT/A, raising the issue of how these actions arise. Here we review these data and discuss the possibility that retrograde axonal transport of catalytically active BoNT/A may explain at least some of its effects at the level of central circuits.

Effects of posture-related changes in motor cortical output on central oscillatory activity of pathological origin in humans.

Changes in shoulder position influence motor cortical outflow to Abductor Digiti Minimi (ADM) muscle in healthy humans. We examined whether these changes may affect finger tremor of central origin. Subjects had their shoulder positioned in two different configurations: 30 degrees horizontal adduction (ANT) and 30 degrees horizontal abduction (POST) with respect to neutral position at 0 degrees in the horizontal plane. In healthy subjects, patients with Parkinsonian tremor (PT) and essential tremor (ET), transcranial magnetic stimulation (TMS) of the motor cortex was performed under resting and active conditions in ANT and POST. PT, ET and physiological tremor (PhT) were studied by accelerometric recordings from the little finger and by EMG activity from ADM and Extensor Carpi Radialis (ECR) in ANT and POST. In healthy and ET subjects, ADM motor evoked responses (MEPs) to TMS were smaller under resting, but larger under active conditions in POST. In PT patients, MEPs showed no difference at rest in ANT but were lower during ADM activation in POST. PT decreased, whereas ET increased in POST. These changes were paralleled by a decrease in PT EMG power and an increase in ET EMG power in POST. In PhT, there was no difference in tremor amplitude between ANT and POST. PT decrease and ET increase in POST parallel the changes in motor cortical outflow to ADM induced by modification of shoulder position under active conditions. This may be evidence for altered premotor-motor interaction at cortical level in PT, and for a role of the motor cortex in generating ET.

Dynamic changes in cortical and spinal activities with different representations of isometric motor actions and efforts.

BACKGROUND: Positioning the shoulder joint from 30 degrees adduction (anterior [ANT]) to 30 degrees abduction (posterior [POST]) in the horizontal plane modifies the corticospinal output to hand and forearm muscles in humans. OBJECTIVE: We investigated the mechanisms by which the central nervous system (CNS) maintains force output under conditions of increased effort and reduced corticospinal activity. METHODS: Ten healthy subjects were studied with the shoulder joint fully supported and passively kept either in ANT or POST. Changes in motor-evoked potentials (MEPs) to transcranial magnetic stimulation (TMS), intracortical inhibition (ICI), intracortical facilitation (ICF), H-reflex and F-waves were studied at force levels corresponding to 10% maximum voluntary contraction (MVC) of abductor digiti minimi (ADM) in ANT for both shoulder positions. In addition, premovement changes in ADM MEP size were assessed in a choice reaction time paradigm in the two shoulder positions. RESULTS: ADM MEPs were larger in POST than in ANT either during or before ADM voluntary contraction, pointing to increased corticospinal excitability in both conditions. ICI and ICF were increased and decreased, respectively, indicating a general disfacilitation on primary motor cortical (M1) output to ADM in POST. F-waves and H-reflexes were increased and decreased, respectively, indicating postsynaptic facilitation and increased presynaptic inhibition at spinal cord level in POST. CONCLUSIONS: A larger cortical output is produced in POST to maintain the same force levels as in ANT. A contributory role of premotor regions is hypothesized.

Heightened seizure susceptibility associated with brain dermoid cyst and the administration of human chorionic gonadotropin (hCG).

It is known that the intramuscular injection of human chorionic gonadotropin (hCG) lowers the threshold for motor evoked responses (MEPs) in the first dorsal interosseous (FDI) muscle to transcranial magnetic stimulation (TMS) in humans. We describe the case of a patient with a clinically silent left-sided nasofrontal dermoid cyst who, while being treated with hCG/LH for hypogonadotropic hypogonadism, presented with simple partial seizures, ipsilateral to the cyst, with secondary generalization. Motor cortex excitability was studied by single and paired TMS and MEPs were recorded from FDI. Resting motor threshold (RMT), active motor threshold (AMT), MEP size, intracortical inhibition (ICI) and intracortical facilitation (ICF) were tested during and after suspension of hormonal therapy. RMT and AMT were lower, MEP size was larger, ICI was decreased while ICF was slightly diminished during treatment. Overall, this indicated a reduced intracortical inhibition during hormonal therapy. It is concluded that treatment with hCG/LH may favour seizure onset in the presence of potentially epileptogenic lesions such as an intracranial dermoid cyst.

Intermanual Differences in movement-related interhemispheric inhibition.

Interhemispheric inhibition (IHI) between motor cortical areas is thought to play a critical role in motor control and could influence manual dexterity. The purpose of this study was to investigate IHI preceding movements of the dominant and nondominant hands of healthy volunteers. Movement-related IHI was studied by means of a double-pulse transcranial magnetic stimulation protocol in right-handed individuals in a simple reaction time paradigm. IHI targeting the motor cortex contralateral (IHI(c)) and ipsilateral (IHI(i)) to each moving finger was determined. IHI(c) was comparable after the go signal, a long time preceding movement onset, in both hands. Closer to movement onset, IHI(c) reversed into facilitation for the right dominant hand but remained inhibitory for left nondominant hand movements. IHI(i) displayed a nearly constant inhibition with a trough early in the premovement period in both hands. In conclusion, our results unveil a more important modulation of interhemispheric interactions during generation of dominant than nondominant hand movements. This modulation essentially consisted of a shift from a balanced IHI at rest to an IHI predominantly directed toward the ipsilateral primary motor cortex at movement onset. Such a mechanism might release muscles from inhibition in the contralateral primary motor cortex while preventing the occurrence of the mirror activity in ipsilateral primary motor cortex and could therefore contribute to intermanual differences in dexterity.

Adaptive changes in postural strategy selection in chronic low back pain.

Chronic low back pain (CLBP) patients achieve postural stability during challenging stance conditions by increasing sway speed. We investigated the mechanisms underlying this behavior, and whether postural strategy selection may be influenced by short-term experience of postural perturbation. Thirteen CLBP patients and thirteen age-matched controls underwent posturography tests. Subjects were asked to stand quietly: (a) with eyes open and eyes closed, and (b) while expecting a series of four backward translations of the support surface. Data from condition (a) was subjected to sway density analysis (SDA). This computes the number of consecutive spaces and respectively time samples during which center of pressure (COP) displacements remained inside a 2.5 mm radius. Three parameters of this analysis were considered: the mean number of peaks (MP), reflecting the time spent by COP in regions of stability, the mean time between peaks (MT) relating to the rate of production of posturographic commands, and the mean spatial distance (MD), reflecting the distance between stable regions. In condition (b) the mean COP positions were analyzed during the time (500 ms) preceding each translation. The MD was significantly increased in the CLBP group as compared to controls (P < 0.01), while the MP and MT did not present any significant difference. The expectation of backward translations initially produced a different COP positioning between the two groups (P < 0.0001) which decreased with repetition of platform translations (controls: PDelta1-4 < 0.002; patients: PDelta1-4 < 0.005). The findings show that the timing and the rate of the balance motor commands is comparable between the two groups. On the other hand, there is greater distance between regions of stability in the patient group. Such modification of motor control patterns might be the consequence of a reweighting of sensory input, possibly due to a deterioration of its reliability. Platform translation findings show that both groups aimed at optimizing their posture selection strategy based on prior testing experience. CLBP patients make use of a different postural motor strategy to maintain quiet stance. This is probably the consequence of an imprecise internal estimate of body sway, due to reduced accuracy in the sensory integration process.

Spinal use-dependent plasticity of synaptic transmission in humans after a single cycling session.

The spinal cord is able to express use-dependent plasticity, as demonstrated in spinalized cats following treadmill training. In humans, spinal use-dependent plasticity is inferred from modifications in the size of H reflex, which are often more prominent after skilled motor training. Plasticity can develop at synaptic connections between afferent fibres and/or descending tracts and motoneurones or interneurones interposed in the spinal pathways. Here we explore whether skilled training induces a change in synaptic efficacy at the synapse between Ia afferents and soleus (Sol) motoneurones. Synaptic efficacy can be modulated presynaptically through changes of the probability of transmitter release (homosynaptic depression, HD). The frequency-related depression of the Sol H reflex, thought to reflect HD, was tested at rest, before and after one single skilled (14 subjects) or non-skilled (9 subjects) cycling training session. Performance improved in both groups but to a larger extent with skilled training, while HD increased immediately after and the day following skilled training in the absence of changes with non-skilled training. These results support the view that spinal cord function is able to encode a local motor memory.