The NMDA antagonist memantine affects training induced motor cortex plasticity – a study using transcranial magnetic stimulation [ISRCTN65784760]

BACKGROUND: Training of a repetitive synchronised movement of two limb muscles leads to short-term plastic changes in the primary motor cortex, which can be assessed by transcranial magnetic stimulation (TMS) mapping. We used this paradigm to study the effect of memantine, a NDMA antagonist, on short-term motor cortex plasticity in 20 healthy human subjects, and we were especially interested in possible differential effects of different treatment regimens. In a randomised double-blinded cross over study design we therefore administered placebo or memantine either as a single dosage or as an ascending dosage over 8 days. Before and after one hour of motor training, which consisted of a repetitive co-contraction of the abductor pollicis brevis (APB) and the deltoid muscle, we assessed the motor output map of the APB muscle by TMS under the different conditions. RESULTS: We found a significant medial shift of the APB motor output map after training in the placebo condition, indicating training-induced short-term plastic changes in the motor cortex. A single dosage of memantine had no significant effect on this training-induced plasticity, whereas memantine administered in an ascending dosage over 8 days was able to block the cortical effect of the motor training. The memantine serum levels after 8 days were markedly higher than the serum levels after a single dosage of memantine, but there was no individual correlation between the shift of the motor output map and the memantine serum level. Besides, repeated administration of a low memantine dosage also led to an effective blockade of training-induced cortical plasticity in spite of serum levels comparable to those reached after single dose administration, suggesting that the repeated administration was more important for the blocking effect than the memantine serum levels. CONCLUSION: We conclude that the NMDA-antagonist memantine is able to block training-induced motor cortex plasticity when administered over 8 days, but not after administration of a single dose. This differential effect might be mainly due to the prolonged action of memantine at the NMDA receptor. These findings must be considered if clinical studies are designed, which aim at evaluating the potency of memantine to prevent "maladaptive" plasticity, e.g. after limb amputation

Polarity-Specific Cortical Effects of Transcranial Direct Current Stimulation in Primary Somatosensory Cortex of Healthy Humans

Transcranial direct current stimulation (tDCS) is a noninvasive stimulation method that has been shown to modulate the excitability of the motor and visual cortices in human subjects in a polarity dependent manner in previous studies. The aim of our study was to investigate whether anodal and cathodal tDCS can also be used to modulate the excitability of the human primary somatosensory cortex (S1). We measured paired-pulse suppression (PPS) of somatosensory evoked potentials in 36 right-handed volunteers before and after anodal, cathodal or sham stimulation over the right non-dominant S1. Paired-pulse stimulation of the median nerve was performed at the dominant and non-dominant hand. After anodal tDCS, PPS was reduced in the ipsilateral S1 compared to sham stimulation, indicating an excitatory effect of anodal tDCS. In contrast, PPS in the stimulated left hemisphere was increased after cathodal tDCS, indicating an inhibitory effect of cathodal tDCS. Sham stimulation induced no pre-post differences. Thus, tDCS can be used to modulate the excitability of S1 in polarity-dependent manner, which can be assessed by paired-pulse suppression. An interesting topic for further studies could be the investigation of direct correlations between sensory changes and excitability changes induced by tDCS

A Randomized and Controlled Crossover Study Investigating the Improvement of Walking and Posture Functions in Chronic Stroke Patients Using HAL Exoskeleton – The HALESTRO Study (HAL-Exoskeleton STROke Study)

Background: The exoskeleton HAL (hybrid assistive limb) has proven to improve walking functions in spinal cord injury and chronic stroke patients when using it for body-weight supported treadmill training (BWSTT). Compared with other robotic devices, it offers the possibility to initiate movements actively. Previous studies on stroke patients did not compare HAL-BWSTT with conventional physiotherapy (CPT). Therefore, we performed a crossover clinical trial comparing CPT and HAL-BWSTT in chronic stroke patients with hemiparesis, the HALESTRO study. Our hypothesis was that HAL-training would have greater effects on walking and posture functions compared to a mixed-approach CPT.Methods: A total of 18 chronic stroke patients participated in this study. Treatment consisted of 30 CPT sessions and of 30 sessions of BWSTT with a double leg type HAL exoskeleton successively in a randomized, crossover study design. Primary outcome parameters were walking time and speed in 10-meter walk test (10MWT), time in timed-up-and-go test (TUG) and distance in 6-min walk test (6MWT). Secondary outcome parameters were the functional ambulatory categories (FAC) and the Berg-Balance Scale (BBS). Data were assessed at baseline, at crossover and at the end of the study, all without using and wearing HAL.Results: Our study demonstrate neither a significant difference in walking parameters nor in functional and balance parameters. When HAL-BWSTT was applied to naïve patients, it led to an improvement in walking parameters and in balance abilities. Pooling all data, we could show a significant effect in 10MWT, 6MWT, FAC and BBS, both therapies sequentially applied over 12 weeks. Thereby, FAC improve from dependent to independent category (3 to 4). One patient dropped out of the study due to intensive fatigue after each training session.Conclusion: HAL-BWSTT and mixed-approach CPT were effective therapies in chronic stroke patients. However, compared with CPT, HAL training with 30 sessions over 6 weeks was not more effective. The combination of both therapies led to an improvement of walking and balance functions. Robotic rehabilitation of walking disorders alone still lacks the proof of superiority in chronic stroke. Robotic treatment therapies and classical CPT rehabilitation concepts should be applied in an individualized therapy program

Cortical disinhibition occurs in chronic neuropathic, but not in chronic nociceptive pain

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to examine the relationship between chronic neuropathic pain after incomplete peripheral nerve lesion, chronic nociceptive pain due to osteoarthritis, and the excitability of the motor cortex assessed by transcranial magnetic stimulation (TMS). Hence in 26 patients with neuropathic pain resulting from an isolated incomplete lesion of the median or ulnar nerve (neuralgia), 20 patients with painful osteoarthritis of the hand, and 14 healthy control subjects, the excitability of the motor cortex was tested using paired-pulse TMS to assess intracortical inhibition and facilitation. These excitability parameters were compared between groups, and the relationship between excitability parameters and clinical parameters was examined.</p> <p>Results</p> <p>We found a significant reduction of intracortical inhibition in the hemisphere contralateral to the lesioned nerve in the neuralgia patients. Intracortical inhibition in the ipsilateral hemisphere of neuralgia patients and in both hemispheres of osteoarthritis patients did not significantly differ from the control group. Disinhibition was significantly more pronounced in neuralgia patients with moderate/severe pain intensity than in patients with mild pain intensity, whereas the relative compound motor action potential as a parameter of nerve injury severity did not correlate with the amount of disinhibition.</p> <p>Conclusions</p> <p>Our results suggest a close relationship between motor cortex inhibition and chronic neuropathic pain in the neuralgia patients, which is independent from nerve injury severity. The lack of cortical disinhibition in patients with painful osteoarthritis points at differences in the pathophysiological processes of different chronic pain conditions with respect to the involvement of different brain circuitry.</p

Improvement of Tactile Discrimination Performance and Enlargement of Cortical Somatosensory Maps after 5 Hz rTMS

Repetitive transcranial magnetic stimulation (rTMS) is increasingly used to investigate mechanisms of brain functions and plasticity, but also as a promising new therapeutic tool. The effects of rTMS depend on the intensity and frequency of stimulation and consist of changes of cortical excitability, which often persists several minutes after termination of rTMS. While these findings imply that cortical processing can be altered by applying current pulses from outside the brain, little is known about how rTMS persistently affects learning and perception. Here we demonstrate in humans, through a combination of psychophysical assessment of two-point discrimination thresholds and functional magnetic resonance imaging (fMRI), that brief periods of 5 Hz rTMS evoke lasting perceptual and cortical changes. rTMS was applied over the cortical representation of the right index finger of primary somatosensory cortex, resulting in a lowering of discrimination thresholds of the right index finger. fMRI revealed an enlargement of the right index finger representation in primary somatosensory cortex that was linearly correlated with the individual rTMS-induced perceptual improvement indicative of a close link between cortical and perceptual changes. The results demonstrate that repetitive, unattended stimulation from outside the brain, combined with a lack of behavioral information, are effective in driving persistent improvement of the perception of touch. The underlying properties and processes that allow cortical networks, after being modified through TMS pulses, to reach new organized stable states that mediate better performance remain to be clarified

Transcranial Magnetic Stimulation for the treatment of tinnitus: Effects on cortical excitability

<p>Abstract</p> <p>Background</p> <p>Low frequency repetitive transcranial magnetic stimulation (rTMS) has been proposed as an innovative treatment for chronic tinnitus. The aim of the present study was to elucidate the underlying mechanism and to evaluate the relationship between clinical outcome and changes in cortical excitability. We investigated ten patients with chronic tinnitus who participated in a sham-controlled crossover treatment trial. Magnetic-resonance-imaging and positron-emission-tomography guided 1 Hz rTMS were performed over the auditory cortex on 5 consecutive days. Active and sham treatments were separated by one week. Parameters of cortical excitability (motor thresholds, intracortical inhibition, intracortical facilitation, cortical silent period) were measured serially before and after rTMS treatment by using single- and paired-pulse transcranial magnetic stimulation. Clinical improvement was assessed with a standardized tinnitus-questionnaire.</p> <p>Results</p> <p>We noted a significant interaction between treatment response and changes in motor cortex excitability during active rTMS. Specifically, clinical improvement was associated with an increase in intracortical inhibition, intracortical facilitation and a prolongation of the cortical silent period. These results indicate that intraindividual changes in cortical excitability may serve as a correlate of response to rTMS treatment.</p> <p>Conclusion</p> <p>The observed alterations of cortical excitability suggest that low frequency rTMS may evoke long-term-depression like effects resulting in an improvement of subcortical inhibitory function.</p

Learning new sensorimotor contingencies:Effects of long-term use of sensory augmentation on the brain and conscious perception

Theories of embodied cognition propose that perception is shaped by sensory stimuli and by the actions of the organism. Following sensorimotor contingency theory, the mastery of lawful relations between own behavior and resulting changes in sensory signals, called sensorimotor contingencies, is constitutive of conscious perception. Sensorimotor contingency theory predicts that, after training, knowledge relating to new sensorimotor contingencies develops, leading to changes in the activation of sensorimotor systems, and concomitant changes in perception. In the present study, we spell out this hypothesis in detail and investigate whether it is possible to learn new sensorimotor contingencies by sensory augmentation. Specifically, we designed an fMRI compatible sensory augmentation device, the feelSpace belt, which gives orientation information about the direction of magnetic north via vibrotactile stimulation on the waist of participants. In a longitudinal study, participants trained with this belt for seven weeks in natural environment. Our EEG results indicate that training with the belt leads to changes in sleep architecture early in the training phase, compatible with the consolidation of procedural learning as well as increased sensorimotor processing and motor programming. The fMRI results suggest that training entails activity in sensory as well as higher motor centers and brain areas known to be involved in navigation. These neural changes are accompanied with changes in how space and the belt signal are perceived, as well as with increased trust in navigational ability. Thus, our data on physiological processes and subjective experiences are compatible with the hypothesis that new sensorimotor contingencies can be acquired using sensory augmentation