Functional imaging of perceptual learning in human primary and secondary somatosensory cortex.

Cellular mechanisms underlying synaptic plasticity are in line with the Hebbian concept. In contrast, data linking Hebbian learning to altered perception are rare. Combining functional magnetic resonance imaging with psychophysical tests, we studied cortical reorganization in primary and secondary somatosensory cortex (SI and SII) and the resulting changes of tactile perception before and after tactile coactivation, a simple type of Hebbian learning. Coactivation on the right index finger (IF) for 3 hr lowered its spatial discrimination threshold. In parallel, blood-oxygen level-dependent (BOLD) signals from the right IF representation in SI and SII enlarged. The individual threshold reduction was linearly correlated with the enlargement in SI, implying a close relation between altered discrimination and cortical reorganization. Controls consisting of a single-site stimulation did not affect thresholds and cortical maps. Accordingly, changes within distributed cortical networks based on Hebbian mechanisms alter the individual percept.

The NMDA antagonist memantine affects training induced motor cortex plasticity--a study using transcranial magnetic stimulation.

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.

Effect of high-dose creatine therapy on symptoms of exercise intolerance in McArdle disease: double-blind, placebo-controlled crossover study.

BACKGROUND: In a recent study, we showed that administration of low-dose creatine (Cr) (60 mg/kg daily) improved work capacity in patients with McArdle disease. OBJECTIVE: To assess the efficacy of high-dose Cr therapy in McArdle disease. DESIGN: Randomized, double-blind, placebo-controlled crossover study. PATIENTS: Nineteen patients with McArdle disease. INTERVENTION: Treatment with Cr, 150 mg/kg daily. Each treatment phase with Cr or placebo lasted 5 weeks. MAIN OUTCOME MEASURES: The patient's daily rating of symptoms of exercise intolerance. At the end of each treatment phase, serum creatine and serum creatine kinase levels, phosphorus 31 magnetic resonance spectroscopy, and surface electromyograms were assessed. RESULTS: Clinical end points revealed increases in the intensity of exercise-induced pain in working muscles (mean treatment-induced difference [d], 0.30 in log(score); 95% confidence interval [CI], 0.05-0.55; P =.02), the limitation of daily activities (d, 0.59; 95% CI, 0.22-0.97;P =.005), and body mass index (d, 0.33 kg/m2, 95% CI, 0.10-0.56 kg/m2; P =.008) with Cr use. Surface electromyograms revealed a smaller increase in the electromyographic amplitude over time during muscle contraction with Cr use (d, -13.52%/min; 95% CI, -23.71%/min to -3.34%/min; P =.01). There were no significant changes in phosphorus 31 magnetic resonance spectroscopy variables. CONCLUSIONS: Administration of high-dose Cr worsened the main clinical symptoms of exercise intolerance in McArdle disease. These neurologic adverse effects represent a major dose-limiting factor in Cr therapy for McArdle disease. Taken together with results of a previous study, the indication for symptomatic therapy with Cr needs to be clarified. An effective Cr dosage without adverse effects may be between 60 and 150 mg/kg daily.

Quantitative sensory testing, neurophysiological and psychological examination in patients with complex regional pain syndrome and hemisensory deficits.

Based on bed-side neurological testing, it has recently been shown that 33% of chronic complex regional pain syndrome (CRPS) type I patients exhibit sensory impairments, which extend past the painful area of the affected limb in a hemisensory distribution (Pain, 80 (1999) 95). In the present study, the clinically observed changes in touch and temperature sensations on the side of the body ipsilateral to the affected limb were investigated quantitatively. Neurophysiological and psychological examinations were conducted to detect changes in the peripheral and central nervous system as well as psychopathological abnormalities. In 40 patients with CRPS, a bed-side neurological examination was performed. Quantitative sensory testing was conducted at five locations on each side of the body. The evaluation of touch thresholds was performed using von Frey filaments (n=40). To measure cool, warm and heat pain thresholds quantitatively, a thermal stimulator using a Peltier-element was used (n=28). With respect to clinical findings, the initiating trauma and severity of abnormalities on nerve conduction testing, three patients were diagnosed as having a reliable CRPS II (causalgia) and five patients a possible CRPS II. Thirty-two patients were diagnosed as having a CRPS I.On clinical examination, 15 patients revealed generalized sensory deficits on the side of the body ipsilateral to the affected limb (hemisensory deficit, n=12; sensory impairment in the upper quadrant of the body, n=3). Patients with these generalized sensory deficits had a significantly longer illness duration (P<0.05) and a significantly higher percentage of mechanical allodynia/hyperalgesia than patients with spatially restricted sensory deficits (n=25) (P<0.05). In patients with generalized sensory impairment, thresholds for touch, warm and cold sensations, and for heat pain were significantly increased at all five locations tested ipsilaterally compared with the contralateral body side, except for the cool threshold on the chest and the heat pain threshold distally on the affected limb. In patients with sensory deficits limited to the affected limb, the touch threshold was significantly higher only in the distal part of the affected limb when compared with the contralateral limb. In these patients, thermal testing revealed almost no differences in cool, warm and heat pain thresholds when comparing both sides. Repeated thermal testing conducted in five patients with generalized sensory impairment reproduced the significant differences between both sides for cool, warm and heat pain thresholds. However, the correlation between the results obtained in the first and second examinations was poor. Neurophysiological recordings revealed pathological results in 46% for nerve conduction studies, 24% for somatosensory evoked potentials and 39% for sympathetic skin response. For all methods applied, there was no statistically significant difference in the incidence of pathological results between patients with generalized and patients with spatially restricted sensory abnormalities. Psychological examination using the structured clinical interview on DSM-IV (SKID) demonstrated a high frequency of affective and anxiety disorders, however, without significant differences between both groups.We conclude that hemisensory impairment in patients with CRPS Type I is probably related to functional disturbances in processing of noxious events in the thalamus and may be a clinical correlate of subcortical brain plasticity in chronic pain.

Expression of chemokine receptor CXCR3 on cerebrospinal fluid T-cells is related to active MRI lesion appearance in patients with relapsing-remitting multiple sclerosis.

We evaluated CXCR3 expression on T-cells and levels of its ligand CXCL10 in blood and cerebrospinal fluid (CSF) of 22 patients with relapsing-remitting multiple sclerosis (RR-MS) in association with magnetic resonance imaging (MRI) disease activity. CXCL10 was strongly released intrathecally, but did not change in association with MRI activity. CXCR3 expression on T-cells was lower in the peripheral blood (PB) of RR-MS patients compared to healthy controls and was increased in the CSF of RR-MS patients undergoing acute attacks, as illustrated by Gd-enhancing lesions on MRI, compared to patients without enhancing lesion. Our results suggest that MRI-documented disease activity is associated with an increase of CXCR3 positive T-cells in the CSF, possibly due to the migration of activated T-cells from the circulation into the CSF.

Fluoxetine facilitates use-dependent excitability of human primary motor cortex.

OBJECTIVES: In poststroke patients, fluoxetine, a selective serotonin-reuptake inhibitor, as an adjunct to physical therapy provided a better functional recovery from motor deficits. The aim of this study was to investigate the effect of a single dose of 20 mg fluoxetine on motor learning and associated cortical changes in healthy right-handed subjects in order to get deeper insight into its facilitating influence on human motor cortex. METHODS: Subjects performed a motor task consisting of a simultaneous co-contraction of the abductor pollicis brevis (APB) and the deltoid muscle with and without fluoxetine in a placebo-controlled double-blinded crossover study design. Immediately before and after motor learning motor output maps of the APB muscle were assessed in order to get insight into plastic changes of the muscle representation. RESULTS: We found a significantly improved motor performance under both conditions without having substantial differences between placebo and fluoxetine. After the completion of the motor task there was a medial shift of the APB muscle motor output map. Only after the administration of fluoxetine the sum of MEP amplitudes (SOA) increased and the motor output map enlarged. CONCLUSIONS: These findings provide evidence for a use-dependent facilitating effect of fluoxetine on cortical excitability but not on motor performance. SIGNIFICANCE: Our findings are not in line with previous experiments in poststroke patients. However, long-term treatment with fluoxetine may additionally improve motor function by upregulating serotonergic receptors. Further studies investigating the influence of long-term treatment on cortical excitability and psychophysics may therefore provide deeper insight into a possible therapeutical efficiency of fluoxetine in poststroke patients.

Reorganization in the ipsilateral motor cortex of patients with lower limb amputation.

The aim of the present study was to assess reorganization in the motor cortex of patients with lower limb amputation. We studied seven patients with traumatic lower limb amputation, and six healthy controls, using transcranial magnetic stimulation mapping, with recordings from the quadriceps femoris muscle on both sides. Motor threshold, sum of amplitudes, area and the amplitude-weighted centre of gravity (COG) of the motor output map were assessed. We found a significant lateral displacement of the COG on the hemisphere contralateral to the healthy leg, whereas other parameters did not differ significantly between sides. This finding might be indicative of cortical reorganization in the hemisphere ipsilateral to the amputation. It is discussed with respect to an altered peripheral input to this hemisphere, and to transcallosal interactions from the deafferented hemisphere.

Comparison of driving simulator performance and neuropsychological testing in narcolepsy.

Daytime sleepiness and cataplexy can increase automobile accident rates in narcolepsy. Several countries have produced guidelines for issuing a driving license. The aim of the study was to compare driving simulator performance and neuropsychological test results in narcolepsy in order to evaluate their predictive value regarding driving ability. Thirteen patients with narcolepsy (age: 41.5+/-12.9 years) and 10 healthy control patients (age: 55.1+/-7.8 years) were investigated. By computer-assisted neuropsychological testing, vigilance, alertness and divided attention were assessed. In a driving simulator patients and controls had to drive on a highway for 60 min (mean speed of 100 km/h). Different weather and daytime conditions and obstacles were presented. Epworth Sleepiness Scale-Scores were significantly raised (narcolepsy patients: 16.7+/-5.1, controls: 6.6+/-3.6, P < or = 0.001). The accident rate of the control patients increased (3.2+/-1.8 versus 1.3+/-1.5, P < or = 0.01). Significant differences in concentration lapses (e.g. tracking errors and deviation from speed limit) could not be revealed (9.8+/-3.5 versus 7.1+/-3.2, pns). Follow-up investigation in five patients after an optimising therapy could demonstrate the decrease in accidents due to concentration lapses (P < or = 0.05). Neuropsychological testing (expressed as percentage compared to a standardised control population) revealed deficits in alertness (32.3+/-28.6). Mean percentage scores of divided attention (56.9+/-25.4) and vigilance (58.7+/-26.8) were in a normal range. There was, however, a high inter-individual difference. There was no correlation between driving performance and neuropsychological test results or ESS Score. Neuropsychological test results did not significantly change in the follow-up. The difficulties encountered by the narcolepsy patient in remaining alert may account for sleep-related motor vehicle accidents. Driving simulator investigations are closely related to real traffic situations than isolated neuropsychological tests. At the present time the driving simulator seems to be a useful instrument judging driving ability especially in cases with ambiguous neuropsychological results.

Repetitive visual stimulation: a neuropsychological approach to the treatment of cortical blindness.

Cortical visual disturbances can occur after traumatic or ischemic brain lesion. Patients mostly suffer from hemianopia. Different treatment approaches in patients with hemianopia are being debated with respect to their effectiveness. For more severely disabled patients with cortical blindness or residual rudimentary vision (RRV) no systematic therapeutic approaches have been reported. In a case study the positive effects of a recently developed repetitive photic stimulation therapy in a patient with RRV after a bioccipital ischemic infarction are presented. The application of this new therapy over several months, supported by treatment with amphetamines led to a statistically significant improvement of different visual functions and a reoccurrence of visual abilities important in daily life. The pathophysiological basis and possible neurorehabilitative consequences that arise from these results are discussed with respect to similar findings in animal experiments.

A prospective study to evaluate the impact of 31P-MRS to determinate mitochondrial dysfunction in skeletal muscle of ALS patients.

Impaired mitochondrial energy production probably plays a role in motor neuron death in amyotrophic lateral sclerosis (ALS) and has been found not only in motor neurons but also in skeletal muscle of patients with ALS. 31P magnetic resonance spectroscopy (31P-MRS) has the potential to reflect the energy metabolism of skeletal muscle in vivo. We sought to determine whether an altered mitochondrial energy metabolism of the muscle cell in patients with SALS can be detected by 31P-MRS, and to this end we recorded 31P-MR spectra of the gastrocnemius muscle of patients with ALS under a standardized isometric muscle exercise protocol. In a prospective setting we compared ten patients with sporadic ALS and 38 age-matched controls. The patients were characterized by a disease duration of approximate 18 months and classified as having probable to definite ALS by means of the revised El Escorial criteria. The time constant of oxidative PCr recovery after aerobic (tau1) and ischaemic muscle contraction (tau2) was used to determine the capacity of mitochondrial ATP formation. We found that mitochondrial impairment in skeletal muscle of patients with ALS could not be confirmed by 31P-MRS and therefore cannot be used as a surrogate factor of the disease.

Motor cortex activation by transcranial magnetic stimulation in ataxia patients depends on the genetic defect.

In patients with degenerative ataxia, various abnormalities in motor cortex activation by transcranial magnetic stimulation (TMS) have been observed, including a reduction of intracortical facilitation and a lengthening of the silent period. However, the groups of patients examined in previous studies were heterogeneous, involving patients with autosomal-dominant and idiopathic cerebellar ataxia, and showing different clinical features. The aim of our present study was to investigate whether differences in motor cortex activation by TMS could be observed in genetically defined subtypes of degenerative ataxia. We examined six patients with Friedreich's ataxia, three patients with spinocerebellar ataxia (SCA) type 1, seven patients with SCA2, 12 patients with SCA3, nine patients with SCA6 and 14 healthy controls. In all subjects, motor threshold, central motor conduction time, cortical silent period after TMS, and intracortical inhibition and facilitation (as assessed by TMS using a paired pulses paradigm) were determined. Additionally, F wave amplitudes evoked by electrical peripheral nerve stimulation were measured. We found a significant reduction of intracortical facilitation in SCA2 and SCA3 patients. Furthermore, motor threshold was elevated in SCA1, central motor conduction time was lengthened in patients with Friedreich's ataxia and SCA1, and F wave amplitudes were enlarged in all the genetic subgroups except for SCA6. Silent period and intracortical inhibition did not differ between patients and controls. We conclude that changes of intracortical facilitation induced by TMS and other excitability parameters of the motor system are not a common phenomenon in degenerative ataxia, but are restricted to specific subtypes. This points to differences in the underlying pathophysiological processes in genetic subtypes of ataxia.

Pharmacological suppression of plastic changes in human primary somatosensory cortex after motor learning.

The strict division between motor and somatosensory systems might be less distinct than previously thought. Many brain mapping studies have described changes of somatosensory cortex (S-I) after the execution of a motor task, which supports the idea of a profound interconnectedness in the sensorimotor system. Here we report experiments in which we investigated by means of somatosensory evoked potentials (SSEPs) mapping the reorganizational capacities in primary somatosensory cortex before and after a Hebbian repetitive co-contraction task of the thumb and arm. We investigated the susceptibility of S-I plasticity to the pharmacological modulation of the GABA-neurotransmitter system by application of the GABA(A) agonist lorazepam. We found that repetitive training induced stable motor learning characterized by a significant improvement of performance. The time differences between the onset of contraction of the deltoid muscle and the abductor pollicis brevis were progressively shortened. The process of motor learning was accompanied by plastic changes in the primary somatosensory cortex as indicated by a significant increase in the dipole strength and a significant shift of the median nerve dipole on the hemisphere contralateral to the exercised side. Moreover, the individual shifts of median nerve dipole location were correlated with the individual improvement in motor performance. After administration of lorazepam, motor learning was significantly suppressed. The behavioural effect was accompanied by an abolition of the N20 dipole shift and an unchanged dipole strength. The results imply that motor learning leads to a profound reorganization in S-I which is subject to pharmacological suppression with the GABA agonist lorazepam.

Breakdown of adenine nucleotide pool in fatiguing skeletal muscle in McArdle's disease: a noninvasive 31P-MRS and EMG study.

Energy metabolism and electrical muscle activity were studied in the calf muscles of 19 patients with proven McArdle's disease and in 25 healthy subjects. Phosphorus magnetic resonance spectroscopy and surface electromyography (S-EMG) were performed during two isometric muscle contractions of 3 min at 30% maximum voluntary contraction, one performed during normal perfusion and the other during applied ischemia. After about 1 min of ischemic muscle contraction in diseased muscle a significant acceleration in phosphocreatine breakdown was observed, along with a significant decrease in adenosine triphosphate. During both contractions the absence of glycolysis was shown by a significant alkalinization. Furthermore, in patients we observed a greater increase in the S-EMG amplitude than in control subjects. We conclude that early on during moderate exercise, a small number of muscle fibers reach metabolic depletion, indicated by a reduction in the adenine nucleotide pool. An increasing number of motor units, which are still in a high-energy state, are continuously recruited to compensate for muscle fatigue. This functional compartmentation may contribute to the pathophysiology of exercise intolerance in McArdle's disease.

Homozygous mutations in caveolin-3 cause a severe form of rippling muscle disease.

Heterozygous missense mutations in the caveolin-3 gene (CAV3) cause different muscle disorders. Most patients with CAV3 alterations present with rippling muscle disease (RMD) characterized by signs of increased muscle irritability without muscle weakness. In some patients, CAV3 mutations underlie the progressive limb-girdle muscular dystrophy type 1C (LGMD1C). Here, we report two unrelated patients with novel homozygous mutations (L86P and A92T) in CAV3. Both presented with a more severe clinical phenotype than usually seen in RMD. Immunohistochemical and immunoblot analyses of muscle biopsies showed a strong reduction of caveolin-3 in both homozygous RMD patients similar to the findings in heterozygous RMD. Electron microscopy studies showed a nearly complete absence of caveolae in the sarcolemma in all RMD patients analyzed. Additional plasma membrane irregularities (small plasmalemmal discontinuities, subsarcolemmal vacuoles, abnormal papillary projections) were more pronounced in homozygous than in heterozygous RMD patients. A stronger activation of nitric oxide synthase was observed in both homozygous patients compared with heterozygous RMD. Like in LGMD1C, dysferlin immunoreactivity is reduced in RMD but more pronounced in homozygous as compared with heterozygous RMD. Thus, we further extend the phenotypic variability of muscle caveolinopathies by identification of a severe form of RMD associated with homozygous CAV3 mutations.