Effects of Deep Brain Stimulation and Dopaminergic Medication on Excitatory and Inhibitory Spinal Pathways in Parkinson Disease.

PURPOSE: Abnormal activity within the corticospinal system is believed to contribute to the motor dysfunction associated with Parkinson disease. However, the effect of treatment for parkinsonian motor symptoms on dysfunctional descending input to the motor neuron pool remains unclear. METHODS: We recruited nine patients with PD treated with deep brain stimulation and examined the time course of interaction between a conditioning pulse from transcranial magnetic stimulation and the soleus H-reflex. Patients with Parkinson disease were examined under four treatment conditions and compared with 10 age-matched control subjects. RESULTS: In healthy controls, transcranial magnetic stimulation conditioning led to early inhibition of the H-reflex (76.2% ± 6.3%) at a condition-test interval of -2 ms. This early inhibition was absent when patients were OFF medication/OFF stimulation (132.5% ± 20.4%; P > 0.05) but was maximally restored toward control levels ON medication/ON stimulation (80.3% ± 7.0%). Of note, early inhibition ON medication/ON stimulation tended to be stronger than when medication (85.4% ± 5.9%) or deep brain stimulation (95.7% ± 9.4%) were applied separately. Late facilitation was observed in controls at condition-test intervals ≥5 ms but was significantly reduced (by 50% to 80% of controls) in Parkinson disease OFF stimulation at condition-test intervals ≥15 ms. The late facilitation was akin to control subjects when patients were ON stimulation. CONCLUSIONS: The present pilot study demonstrates that the recruitment of early inhibition and late facilitation is disrupted in untreated Parkinson disease and that medication and deep brain stimulation may act together to normalize supraspinal drive to the motor neuron pool.

Neuropathological changes in dorsal root ganglia induced by pyridoxine in dogs.

BACKGROUND: Pyridoxine (PDX; vitamin B6), is an essential vitamin. PDX deficiency induces various symptoms, and when PDX is misused it acts as a neurotoxicant, inducing severe sensory neuropathy. RESULTS: To assess the possibility of creating a reversible sensory neuropathy model using dogs, 150 mg/kg of PDX was injected subcutaneously into dogs for 7 days and body weight measurements, postural reaction assessments, and electrophysiological recordings were obtained. In addition, the morphology of dorsal root ganglia (DRG) and changes in glial fibrillary acidic protein (GFAP) immunoreactive satellite glial cells and ionized calcium-binding adapter molecule 1 (Iba-1) immunoreactive microglia/macrophages were assessed at 1 day, 1 week, and 4 weeks after the last PDX treatment. During the administration period, body weight and proprioceptive losses occurred. One day after the last PDX treatment, electrophysiological recordings showed the absence of the H-reflex in the treated dogs. These phenomena persisted over the four post-treatment weeks, with the exception of body weight which recovered to the pre-treatment level. Staining (CV and HE) results revealed significant losses of large-sized neurons in the DRG at 1 day and 1 week after PDX treatment cessation, but the losses were recovered at 4 weeks post-treatment. The Iba-1 and GFAP immunohistochemistry results showed pronounced increases in reactive microglia/macrophage and satellite glial cell at 1 day and 1 week, respectively, after the last PDX treatment, and thereafter, immunoreactivity decreased with increasing time after PDX treatment. CONCLUSIONS: The results suggest that PDX-induced neuropathy is reversible in dogs; thus, dogs can be considered a good experimental model for research on neuropathy.

Effects of caffeine on neuromuscular function in a non-fatigued state and during fatiguing exercise.

NEW FINDINGS: What is the central question of the study? What are the effects of caffeine on neuromuscular function in a non-fatigued state and during fatiguing exercise? What is the main finding and its importance? In a non-fatigued state, caffeine decreased the duration of the silent period evoked by transcranial magnetic stimulation. Caffeine-induced reduction of inhibitory mechanisms in the central nervous system before exercise was associated with an increased performance. Individuals who benefit from caffeine ingestion may experience lower perception of effort during exercise and an accelerated recovery of M-wave amplitude postfatigue. This study elucidates the mechanisms of action of caffeine and demonstrates that inter-individual variability of its effects on neuromuscular function is a fruitful area for further work. ABSTRACT: Caffeine enhances exercise performance, but its mechanisms of action remain unclear. In this study, we investigated its effects on neuromuscular function in a non-fatigued state and during fatiguing exercise. Eighteen men participated in this randomized, double-blind, placebo-controlled crossover trial. Baseline measures included plantarflexion force, drop jump, squat jump, voluntary activation of triceps surae muscle, soleus muscle contractile properties, M-wave, α-motoneuron excitability (H-reflex), corticospinal excitability, short-interval intracortical inhibition, intracortical facilitation, silent period evoked by transcranial magnetic stimulation (SP) and plasma potassium and caffeine concentrations. Immediately after baseline testing, participants ingested caffeine (6 mg·kg-1 ) or placebo. After a 1-h rest, baseline measures were repeated, followed by a fatiguing stretch-shortening cycle exercise (sets of 40 bilateral rebound jumps on a sledge apparatus) until task failure. Neuromuscular testing was carried out throughout the fatigue protocol and afterwards. Caffeine enhanced drop jump height (by 4.2%) and decreased the SP (by 12.6%) in a non-fatigued state. A caffeine-related decrease in SP and short-interval intracortical inhibition before the fatiguing activity was associated with an increased time to task failure. The participants who benefitted from an improved performance on the caffeine day reported a significantly lower sense of effort during exercise and had an accelerated postexercise recovery of M-wave amplitude. Caffeine modulates inhibitory mechanisms of the CNS, recovery of M-wave amplitude and perception of effort. This study lays the groundwork for future examinations of differences in caffeine-induced neuromuscular changes between those who are deemed to benefit from caffeine ingestion and those who are not.

Effects of bioengineered scaffold loaded with neurotrophins and locomotor training in restoring H-reflex responses after spinal cord injury.

The combinational effects of a bioengineered scaffold loaded with neurotrophins and rehabilitation training on spasticity observed after spinal cord injury (SCI) has not been studied. We used an animal model of moderate contusion injury at T9/T10 that received bioengineered scaffold poly N-isopropylacrylamide-g-poly ethylene glycol (PNIPAAm-g-PEG) loaded with BDNF/NT3 followed by body weight supported treadmill training (BWSTT) and assessed the efficacy of the combinational bioengineered approaches in treating spasticity. Five animal groups were included: Group 1: Sham, Group 2: Injury (SCI), Group 3: SCI + BWSTT (BWSTT), Group 4: SCI + PNIPAAm-g-PEG loaded with BDNF/NT3 (Transplant), and Group 5: SCI + PNIPAAm-g-PEG loaded with BDNF/NT3 + BWSTT (Combinational). Results indicate no significant changes in the BBB scores of animals among various groups, however, a significant restoration in the rate depression property of H-reflex was observed in both BWSTT and Combinational animals. Transplant group reported no improvement in the rate depression property of H-reflex and were similar to SCI only group. Histological findings report restoration of the chloride cotransporter (KCC2) labeling in both BWSTT and Combinational animals and down-regulation of KCC2 in both SCI and Transplant only animals. Findings from this study confirm that rehabilitation training is critical in restoring H-reflex responses and transplantation therapies alone cannot restore these responses after SCI. Also, although no significant difference was observed between the BWSTT and Combinational animals, comparable improvements in the two groups does open new pathways to exploring unique tissue-engineering approaches with promising clinical application for individuals with SCI.

What is the effect and mechanism of kinesiology tape on muscle activity?

OBJECTIVE: This study aimed to evaluate the effects of kinesiology tape, anesthesia, and kinesiology tape along with anesthesia, on motor neuron excitability. PARTICIPANTS: Participants included 20 healthy men aged 20-35 years, who were examined over 5 sessions. INTERVENTION: The five experimental sessions included: control without applying the kinesiology tape or Eutectic Mixture of Local Anesthetics (EMLA); treatment only with EMLA; only kinesiology tape application; only sham tape application; and treatment with kinesiology tape and EMLA. MAIN OUTCOME MEASURES: The H-reflex recruitment curve of the soleus and lateral gastrocnemius was recorded by a blinded assessor in the 5 separate sessions randomly assigned with 48 h washout periods. The major H-reflex parameters include: the Hmax/Mmax ratio, the H-reflex threshold stimulation intensity (Hth), the intensity of maximum H-reflex (IntensityHmax), the H-reflex ascending slope (Hslp), and the H-reflex ascending slope fixed into the first three points (first Hslp). RESULTS: The H-reflex parameters (H slope, first Hslp, Hth, and IntensityHmax) were facilitated by application of the kinesiology tape with and without EMLA; however, EMLA inhibited the H-reflex parameters (Hmax/Mmax ratio, Hslp, first Hslp, and Hth) in both the soleus and lateral gastrocnemius. The sham tape did not alter the H-reflex recruitment curve parameters. The statistical model revealed a significant difference between the kinesiology tape and the sham tape and control sessions, between kinesiology tape-EMLA and EMLA, and between kinesiology tape-EMLA and control session. CONCLUSIONS: Results suggest that the kinesiology tape facilitates the muscle activity and the underlying mechanism on the gastrosoleus motor neuron pool involves the cutaneous receptors.

Acute Effect of Noradrenergic Modulation on Motor Output Adjustment in Men.

PURPOSE: To determine the role of noradrenergic modulation in the control of motor output, we compared the acute effect of reboxetine (REB), a noradrenaline reuptake inhibitor, to a placebo (PLA) on knee extensors motor performance and cortical and spinal excitability. METHODS: Eleven young men took part in two randomized experiments during which they received either 8 mg of REB or a PLA. The torque produced during a maximal voluntary contraction (MVC) and its variability (i.e., coefficient of variation) during submaximal contractions ranging from 5% to 50% MVC were measured. Paired electrical (PES) and transcranial magnetic stimulation (TMS) were used to assess changes in voluntary activation during MVC, and corticospinal (motor-evoked potential (MEP)) and spinal excitability (Hoffmann (H) reflex) during contraction at 20% MVC. RESULTS: MVC torque and torque steadiness increased respectively by 9.5% and 24% on average in REB compared with PLA condition (P < 0.001). Voluntary activation tested by TMS and PES was greater (~3%; P < 0.05) in REB than PLA condition. The increase in voluntary activation in REB condition was significantly correlated with subjects' initial voluntary activation level when tested by TMS (r = -0.62; P = 0.048) and PES (r = -0.86; P < 0.01). The maximal amplitudes of H reflex and MEP and the slope of their recruitment curves were enhanced by REB (P < 0.05). The ratio between the TMS-induced EMG silent period and the corresponding MEP (silent period/MEP) was reduced in REB condition (P < 0.01). CONCLUSIONS: The present findings indicate that voluntary activation and accuracy in force control can be increased by an enhanced level of noradrenaline concentration. This improvement in motor performance is accompanied by changes located at both cortical and spinal levels.

Feasibility of eliciting the H reflex in the masseter muscle in patients under general anesthesia.

OBJECTIVE: To explore the feasibility of eliciting the brainstem H reflex in the masseter muscle in patients under general anesthesia. METHODS: We electrically stimulated the masseteric nerve, a branch of the trigeminal nerve, and recorded ipsilateral masseteric and temporalis muscle responses. We tested eight patients who presented with trigeminal neuralgia; one patient had a temporal bone tumor and one patient had a brainstem arteriovenous malformation. All responses were elicited when patients were under general anesthesia and before the initiation of surgery. RESULTS: The H reflex in the masseter muscle was reliably elicited in 70% of the patients. The reflexes met the usual criteria for the H reflex because they were elicited below the threshold of the direct M response, and their amplitudes decreased when the M response increased with stronger stimuli. The mean onset latencies of the masseter H reflex and the M response were 5.4±1.3ms and 2.6±0.6ms, respectively. CONCLUSIONS: In the present study, we provide evidence of the feasibility of eliciting the H reflex in the masseter muscles of patients under general anesthesia. SIGNIFICANCE: The H reflex of the masseter muscle may represent a new method available for intraoperative monitoring. Specifically, this method may be important for the monitoring of brainstem functional integrity, particularly in the midbrain and mid-pons, in addition to the trigeminal nerve path.

Cortical and spinal excitability in patients with multiple sclerosis and spasticity after oromucosal cannabinoid spray.

BACKGROUND: Delta-9-tetrahydrocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex®) has been recently approved for the management of treatment-resistant multiple sclerosis (MS) spasticity. Although the symptomatic relief of Sativex® on MS-spasticity has been consistently demonstrated, the pathogenetic implications remain unclear and the few electrophysiological studies performed to address this topic yielded controversial results. We therefore aimed to investigate the mechanisms underpinning the modulation of spastic hypertonia by Sativex®, at both central and spinal levels, through an extensive neurophysiological battery in patients with MS. METHODS: Nineteen MS patients with treatment-resistant spasticity were recruited. Before and after 4weeks of treatment with Sativex® patients were clinically assessed with the Modified Ashworth Scale (MAS) and underwent a large neurophysiological protocol targeting measures of excitability and inhibition at both cortical [e.g., intracortical facilitation (ICF), short (SICI) and long (LICI) intracortical inhibition, cortical silent period (CSP)] and spinal level [e.g., H-reflex, H/M ratio and recovery curve of the H-reflex (HRC)]. A group of 19 healthy subjects served as controls. RESULTS: A significant reduction of the MAS score after 4weeks of Sativex® treatment was detected. Before treatment, an increase in the late facilitatory phase of HRC was recorded in patients compared to the control group, that normalised post treatment. At central level, SICI and LICI were significantly higher in patients compared to healthy subjects. After therapy, a significant strengthening of inhibition (e.g. reduced LICI) and a non-significant facilitation (e.g. marginally increased ICF) occurred, suggesting a modulatory effect of Sativex® on different pathways, predominantly of inhibitory type. Sativex® treatment was well tolerated, with only 3 patients complaining about dizziness and bitter taste in their mouth. DISCUSSION: Our results confirm the clinical benefit of Sativex® on spastic hypertonia and demonstrate that it might modulate both cortical and spinal circuits, arguably in terms of both excitation and inhibition. We suggest that the clinical benefit was likely related to a net increase of inhibition at cortical level that, in turn, might have influenced spinal excitability.

Balance impairments and neuromuscular changes in breast cancer patients with chemotherapy-induced peripheral neuropathy.

OBJECTIVE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer treatment. Resulting sensory and motor dysfunctions often lead to functional impairments like gait or balance disorders. As the underlying neuromuscular mechanisms are not fully understood, we compared balance performance of CIPN patients with healthy controls (CON) to specify differences responsible for postural instability. METHODS: 20 breast cancer patients with CIPN (PAT) and 16 matched CONs were monitored regarding centre of pressure displacement (COP) and electromyographic activity of M. soleus, gastrocnemius, tibialis anterior, rectus femoris and biceps femoris. We calculated antagonistic co-contraction indices (CCI) and elicited soleus H-reflexes to evaluate changes in the elicitability and sensitivity of spinal reflex circuitry. RESULTS: PAT's COP displacement was greater than CON's (p=.013) and correlated significantly with the level of CCIs and self-reported CIPN symptoms. PAT revealed prolonged H-wave latency (p=.021), decreased H-reflex elicitability (p=.001), and increased H-reflex sensitivity from bi- to monopedal stance (p=.004). CONCLUSIONS: We summarise that CIPN causes balance impairments and leads to changes in elicitability and sensitivity of spinal reflex circuitry associated with postural instability. We assume that increased simultaneous antagonistic muscle activation may be used as a safety strategy for joint stiffness to compensate for neuromuscular degradation. SIGNIFICANCE: Sensorimotor training has the potential to influence neuromuscular mechanisms in order to improve balance performance. Therefore, this training modality should be evaluated as a possible treatment strategy for CIPN.

Use of Posterior Root-Muscle Reflexes in Peripheral Nerve Surgery: A Case Report.

It is well established that a mixed-agent general anesthetic regimen of volatile gas and intravenous anesthetic or total intravenous anesthetic (TIVA) is required to obtain adequate transcranial motor-evoked potentials (TcMEPs) to detect and hopefully prevent injury during brain, spinal cord, and peripheral nerve surgery. But even under ideal general anesthetic conditions, TcMEPs are not always detectable in every muscle monitored, and are prone to anesthetic fade, especially when neuropathic or injured tissue is monitored. TcMEP sensitivity to general anesthesia can be especially problematic during peripheral nerve surgery where there is often only one or a few essential muscles required to provide adequate monitoring; thus, maximum fidelity is essential. However, there is an anesthetic-resistant high-fidelity modality available to successfully monitor the motor component of distant peripheral nerves originating from the cauda equina. Percutaneus transabdominal electrical stimulation elicits a relatively anesthetic-resistant, robust motor response in muscles innervated by cauda equina nerve roots. We report the successful use of posterior root-muscle (PRM) reflex to monitor the decompression of the sciatic nerve at its bifurcation in a 22-year-old female with a history of severe sciatic nerve neuropathic pain and muscle weakness following benign thigh tumor resection.

Alteration in neuromuscular function of the plantar flexors following caffeine ingestion.

The aim of this study was to compare the neuromuscular function of the plantar flexors following caffeine or placebo administration. Thirteen subjects (25 ± 3 years) ingested caffeine or placebo in a randomized, controlled, counterbalanced, double-blind crossover design. Neuromuscular tests were performed before and 1 h after caffeine or placebo intake. During neuromuscular testing, rate of torque development, isometric maximum voluntary torque, and neural drive to the muscles were measured. Triceps surae muscle activation was assessed by normalized root mean square of the EMG signal during the initial phase of contraction (0-100 ms, 100-200 ms) and maximal voluntary contraction (MVC). Furthermore, evoked spinal reflex responses of the soleus muscle (H-reflex evoked at rest and during MVC, V-wave) and peak twitch torques were evaluated. The isometric maximum voluntary torque and evoked potentials were not different. However, we found a significant difference between groups for rate of torque development in the time intervals 0-100 ms [41.1 N · m/s (95% CI: 8.3-73.9 N · m/s, P = 0.016)] and 100-200 ms [32.8 N · m/s (95% CI: 2.8-62.8 N · m/s, P = 0.034)]. These changes were accompanied by enhanced neural drive to the plantar flexors. Data suggest that caffeine solely increased explosive voluntary strength of the triceps surae because of enhanced neural activation at the onset of contraction whereas MVC strength was not affected.

Exercise modulates chloride homeostasis after spinal cord injury.

Activity-based therapies are routinely integrated in spinal cord injury (SCI) rehabilitation programs because they result in a reduction of hyperreflexia and spasticity. However, the mechanisms by which exercise regulates activity in spinal pathways to reduce spasticity and improve functional recovery are poorly understood. Persisting alterations in the action of GABA on postsynaptic targets is a signature of CNS injuries, including SCI. The action of GABA depends on the intracellular chloride concentration, which is determined largely by the expression of two cation-chloride cotransporters (CCCs), KCC2 and NKCC1, which serve as chloride exporters and importers, respectively. We hypothesized that the reduction in hyperreflexia with exercise after SCI relies on a return to chloride homeostasis. Sprague Dawley rats received a spinal cord transection at T12 and were assigned to SCI-7d, SCI-14d, SCI-14d+exercise, SCI-28d, SCI-28d+exercise, or SCI-56d groups. During a terminal experiment, H-reflexes were recorded from interosseus muscles after stimulation of the tibial nerve and the low-frequency-dependent depression (FDD) was assessed. We provide evidence that exercise returns spinal excitability and levels of KCC2 and NKCC1 toward normal levels in the lumbar spinal cord. Acutely altering chloride extrusion using the KCC2 blocker DIOA masked the effect of exercise on FDD, whereas blocking NKCC1 with bumetanide returned FDD toward intact levels after SCI. Our results indicate that exercise contributes to reflex recovery and restoration of endogenous inhibition through a return to chloride homeostasis after SCI. This lends support for CCCs as part of a pathway that could be manipulated to improve functional recovery when combined with rehabilitation programs.

Tetanus toxin reduces local and descending regulation of the H-reflex.

INTRODUCTION: Skeletal muscles that are under the influence of tetanus toxin show an exaggerated reflex response to stretch. We examined which changes in the stretch reflex may underlie the exaggerated response. METHODS: H-reflexes were obtained from the tibialis anterior (TA) and flexor digitorum brevis (FDB) muscles in rats 7 days after intramuscular injection of tetanus toxin into the TA. RESULTS: We found effects of the toxin on the threshold, amplitude, and duration of H-waves from the TA. The toxin inhibited rate-dependent depression in the FDB between the stimulation frequencies of 0.5­50 HZ and when a conditioning magnetic stimulus applied to the brain preceded a test electrical stimulus delivered to the plantar nerve. CONCLUSIONS: Tetanus toxin increased the amplitude of the Hwave and reduced the normal depression of H-wave amplitude that is associated with closely timed stimuli, two phenomena that could contribute to hyperactivity of the stretch reflex.

Carbon dioxide alters the Hoffmann reflex independent of hydrogen ions.

The purpose of this study was to examine the effect of changes in capillary blood pH on the resting soleus Hoffmann (H) reflex in the intact human. H-max size, H-wave at 20% of H-max, M-max and H-reflex latency were recorded in 10 subjects (apparently healthy, ages 19-36) before and after exposure to 3 hours of NaHCO(3), CaCO(3), NH(4)Cl (all at 0.3 g/kg) or 10 minutes 7% Carbon dioxide (CO(2)) administration. NaHCO(3) increased capillary blood pH, CaCO(3) did not change capillary blood pH, and NH(4)Cl and 7% CO(2) decreased capillary blood pH. H-max and H-wave at 20% of M-max size were significantly decreased with no change in M-max, and H-reflex latency significantly increased during 7% CO(2) administration only. No other changes in H-maximum size or H-reflex latency in response to dry chemical administration were observed. Seven percent CO(2) administration reduces the size and increases the latency of the H-maximum size as previously found, but other chemicals which alter capillary blood pH do not. CO(2) modulates afferent nerve function, and does so, it appears, independent of changes in capillary blood pH.

Effects of isoflurane anesthesia on F-waves in the sciatic nerve of the adult rat.

INTRODUCTION: Nerve conduction studies provide insights into the functional consequences of axonal and myelin pathology in peripheral neuropathies. We investigated whether isoflurane inhalation anesthesia alters F-wave latencies and F-persistence in the sciatic nerve of adult rats. METHODS: Ten rats were investigated at 3 different isoflurane concentrations followed by ketamine-xylazine injection anesthesia. To assess F-wave latencies, a stimulation paradigm was chosen to minimize H-reflex masking of F-waves. RESULTS: F-wave persistence rates were reduced with 3.5% isoflurane concentration at 4 and 10 Hz supramaximal stimulation and marginally reduced with 2.5% isoflurane when compared with ketamine-xylazine. F-wave amplitudes decreased progressively with rising stimulus frequency in all types of anesthesia and most at 3.5% isoflurane concentration. CONCLUSIONS: The type of anesthesia and the stimulus repetition rate have an impact on some F-wave parameters. Higher isoflurane concentrations and repetition rates are not recommended in experimental studies using rat neuropathy models where F-waves are of interest.

Effects of short-term dexamethasone administration on corticospinal excitability.

PURPOSE: The short-term administration of glucocorticoids increases maximal voluntary force in healthy humans, but the underlying mechanisms remain poorly understood. The present study investigated the glucocorticoid effects on spinal and corticospinal pathways and on electromechanical properties of the tibialis anterior muscle in response to nerve stimulation. METHODS: Twelve healthy men participated in a single-blind randomized study to receive either dexamethasone (8 mg · d(-1), n = 8 subjects) or placebo (n = 4 subjects) for 7 d. Group Ia afferent and corticospinal pathways were assessed, respectively, by recording the amplitude of the Hoffmann (H) reflex and motor-evoked potential (MEP) by transcranial magnetic stimulation. The ankle dorsiflexor torque and EMG activity during a maximal voluntary contraction (MVC) and muscle twitch evoked by electrical stimulation were also assessed before and after the intervention. RESULTS: The MVC torque (+14%) and the associated tibialis anterior EMG (+16%) increased after glucocorticoid treatment (P < 0.05), whereas muscle twitch parameters did not change (P > 0.05). The H-reflex amplitude did not change (P = 0.58), but the MEP threshold was significantly (P = 0.008) reduced after treatment. Moreover, the slope of the MEP input-output relation and the silent period/MEP ratio increased (P = 0.049) and decreased (P = 0.029), respectively, after treatment. The amount of change in MEP amplitude and MVC torque were positively associated (r(2) = 0.59) for the dexamethasone group. CONCLUSION: This is the first study indicating that short-term glucocorticoid administration in healthy subjects increased corticospinal excitability that contributed to enhance MVC torque.

Intrathecal baclofen treatment in dystonic cerebral palsy: a randomized clinical trial: the IDYS trial.

BACKGROUND: Dystonic cerebral palsy is primarily caused by damage to the basal ganglia and central cortex. The daily care of these patients can be difficult due to dystonic movements. Intrathecal baclofen treatment is a potential treatment option for dystonia and has become common practice. Despite this widespread adoption, high quality evidence on the effects of intrathecal baclofen treatment on daily activities is lacking and prospective data are needed to judge the usefulness and indications for dystonic cerebral palsy. The primary aim of this study is to provide level one clinical evidence for the effects of intrathecal baclofen treatment on the level of activities and participation in dystonic cerebral palsy patients. Furthermore, we hope to identify clinical characteristics that will predict a beneficial effect of intrathecal baclofen in an individual patient. METHODS/DESIGN: A double blind placebo-controlled multi-center randomized clinical trial will be performed in 30 children with dystonic cerebral palsy. Patients aged between 4 and 25 years old with a confirmed diagnosis of dystonic cerebral palsy, Gross Motor Functioning Classification System level IV or V, with lesions in the cerebral white matter, basal ganglia or central cortex and who are eligible for intrathecal baclofen treatment will be included. Group A will receive three months of continuous intrathecal baclofen treatment and group B will receive three months of placebo treatment, both via an implanted pump. After this three month period, all patients will receive intrathecal baclofen treatment, with a follow-up after nine months. The primary outcome measurement will be the effect on activities of and participation in daily life measured by Goal Attainment Scaling. Secondary outcome measurements on the level of body functions include dystonia, spasticity, pain, comfort and sleep-related breathing disorders. Side effects will be monitored and we will study whether patient characteristics influence outcome. DISCUSSION: The results of this study will provide data for evidence-based use of intrathecal baclofen in dystonic cerebral palsy.

The use of poly(N-[2-hydroxypropyl]-methacrylamide) hydrogel to repair a T10 spinal cord hemisection in rat: a behavioural, electrophysiological and anatomical examination.

There have been considerable interests in attempting to reverse the deficit because of an SCI (spinal cord injury) by restoring neural pathways through the lesion and by rebuilding the tissue network. In order to provide an appropriate micro-environment for regrowing axotomized neurons and proliferating and migrating cells, we have implanted a small block of pHPMA [poly N-(2-hydroxypropyl)-methacrylamide] hydrogel into the hemisected T10 rat spinal cord. Locomotor activity was evaluated once a week during 14 weeks with the BBB rating scale in an open field. At the 14th week after SCI, the reflexivity of the sub-lesional region was measured. We also monitored the ventilatory frequency during an electrically induced muscle fatigue known to elicit the muscle metaboreflex and increase the respiratory rate. Spinal cords were then collected, fixed and stained with anti-ED-1 and anti-NF-H antibodies and FluoroMyelin. We show in this study that hydrogel-implanted animals exhibit: (i) an improved locomotor BBB score, (ii) an improved breathing adjustment to electrically evoked isometric contractions and (iii) an H-reflex recovery close to control animals. Qualitative histological results put in evidence higher accumulation of ED-1 positive cells (macrophages/monocytes) at the lesion border, a large number of NF-H positive axons penetrating the applied matrix, and myelin preservation both rostrally and caudally to the lesion. Our data confirm that pHPMA hydrogel is a potent biomaterial that can be used for improving neuromuscular adaptive mechanisms and H-reflex responses after SCI.

Serotonin 1A receptors alter expression of movement representations.

Serotonin has a myriad of central functions involving mood, appetite, sleep, and memory and while its release within the spinal cord is particularly important for generating movement, the corresponding role on cortical movement representations (motor maps) is unknown. Using adult rats we determined that pharmacological depletion of serotonin (5-HT) via intracerebroventricular administration of 5,7 dihydroxytryptamine resulted in altered movements of the forelimb in a skilled reaching task as well as higher movement thresholds and smaller maps derived using high-resolution intracortical microstimulation (ICMS). We ruled out the possibility that reduced spinal cord excitability could account for the serotonin depletion-induced changes as we observed an enhanced Hoffman reflex (H-reflex), indicating a hyperexcitable spinal cord. Motor maps derived in 5-HT1A receptor knock-out mice also showed higher movement thresholds and smaller maps compared with wild-type controls. Direct cortical application of the 5-HT1A/7 agonist 8-OH-DPAT lowered movement thresholds in vivo and increased map size in 5-HT-depleted rats. In rats, electrical stimulation of the dorsal raphe lowered movement thresholds and this effect could be blocked by direct cortical application of the 5-HT1A antagonist WAY-100135, indicating that serotonin is primarily acting through the 5-HT1A receptor. Next we developed a novel in vitro ICMS preparation that allowed us to track layer V pyramidal cell excitability. Bath application of WAY-100135 raised the ICMS current intensity to induce action potential firing whereas the agonist 8-OH-DPAT had the opposite effect. Together our results demonstrate that serotonin, acting through 5-HT1A receptors, plays an excitatory role in forelimb motor map expression.