Ryo Urushihara

Comparison of monophasic versus biphasic stimulation in rTMS over premotor cortex: SEP and SPECT studies

OBJECTIVE To optimize the clinical uses of repetitive transcranial magnetic stimulation (rTMS), we compared the effects of rTMS on somatosensory-evoked potentials (SEPs) and regional cerebral blood flow (rCBF) using different phases (monophasic vs. biphasic) or frequencies (0.2Hz vs. 0.8Hz) of stimulation. METHODS In the first experiment, different phases were compared (0.2Hz monophasic vs. 0.2Hz biphasic). Biphasic 1Hz or sham condition served as controls. The second experiment was to explore the effect of frequencies (0.2Hz vs. 0.8Hz) using the monophasic stimulation. Substhreshold TMS was applied 250 times over the left premotor cortex. Single photon emission computed tomography (SPECT) was performed before and after monophasic 0.2Hz or biphasic 1Hz rTMS. RESULTS Monophasic rTMS of both 0.2 and 0.8Hz significantly increased the ratio of N30 amplitudes as compared with sham rTMS, whereas biphasic stimulation showed no significant effects. SPECT showed increased rCBF in motor cortices after monophasic 0.2Hz rTMS, but not after biphasic 1Hz stimulation. CONCLUSIONS Monophasic rTMS exerted more profound effects on SEPs and rCBF than biphasic rTMS over the premotor cortex. SIGNIFICANCE Monophasic rTMS over the premotor cortex could be clinically more useful than biphasic rTMS.

Mesolimbic dopaminergic system is involved in diurnal blood pressure regulation.

Parkinsons disease (PD) patients with autonomic failure show no nocturnal decrease in blood pressure (BP). At present, it is not clear if this symptom is attributable to the disturbance of the dopaminergic (DA) system that is responsible for PD. In the present study, we determined that the mesolimbic DA system is involved in diurnal profiles of the mean BP (MBP) by destroying the A10 DA system in rats with 6-hydroxydopamine. In control rats, a clear dip in the MBP and heart rate (HR) occurs during the light, that is, resting period, analogous to the nocturnal dip in normal humans. This normal daytime decrease in MBP and HR was disturbed by inducing a lesion of the ventral tegmental area (VTA) DA neurons, although the rhythms of wake-sleep duration and behavioral activity remained relatively intact. On the basis of this evidence, the absence of a nocturnal dip in BP in PD patients is attributed to impairment of the mesolimbic DA system.

Chapter 37 Abnormal sensorimotor integration in hand dystonia

Publisher Summary This chapter explores sensory gating in dystonia. Dystonia is defined as a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. One characteristic of focal dystonia is a sensory trick by which sensory input to a certain area of the body can reduce abnormal contractions in nearby muscles. This suggests that adjusting the link between sensory input and movement allows motor commands to be issued more effectively from the brain. Gating by a central command to move was abnormal in dystonia. To explore sensorimotor interaction, the chapter examines inhibition induced by low-frequency, subthreshold repetitive transcranial magnetic stimulation (rTMS) in the motor cortices and the change of somatosensory-evoked potentials (SEPs). Regulation of the sensory system in movement is a critical issue in motor control. Direct motor commands can be executed by reducing the influence of sensory input (gating). The PMC is susceptible to the inhibitory effect of subthreshold low-frequency rTMS in dystonia. The chapter concludes that PMC may play an important role in sensorimotor interaction in dystonia.

Successful treatment of stiff person syndrome with sequential use of tacrolimus

Stiff person syndrome (SPS) is a rare neurological disease with features of an autoimmune disease. SPS is characterised by severe progressive muscle stiffness of the spine and lower extremities with superimposed muscle spasms triggered by external stimuli such as noise, touch and emotional distress.1 Patients with SPS respond to high doses of muscle relaxants, such as diazepam and baclofen, several anticonvulsants, and gabapentin. Previous studies have reported that several causal treatments with corticosteroids, plasmapheresis, intravenous immunoglobulin (Ig) and new immunomodulating agents can reduce stiffness and lower sensitivity to stimuli and stress in patients with SPS.2 ,3 Because SPS is a chronic disease, patients generally require long-term treatments, which may be effective but difficult to take for long periods. Tacrolimus (Prograf, FK506) is a macrolide molecule belonging to the same immunosuppressant class as cyclosporine. Tacrolimus has a lower molecular weight and is 100-fold more potent in inhibiting T cell proliferation than cyclosporine. It acts through inhibition of the calcium-calcineurin (CaN) pathway and exerts its immunosuppressive effect by reducing the proliferation of activated T cells.4 We now report the successful treatment of patients with SPS using tacrolimus as the immunosuppressive agent. ### Patients We assigned two patients with SPS who had incomplete responses to conventional therapies and fulfilled the defined clinical criteria (online supplementary table 1).3 ### Clinical evaluations At baseline and each month thereafter, a neurologist used the distribution of stiffness index, the most consistent indicator of stiffness among patients and within patients, to evaluate the patients with SPS.3 Scores on this index range from 0 to 6 and reflect the extent of stiffness. The same neurologist also assessed the patients for changes in frequency of spasms with use of the heightened-sensitivity scale, which has been a reproducible and consistent means of assessing the number of factors triggering spasms.3 …

CSF cystatin C and diffusion tensor imaging parameters as biomarkers of upper motor neuron degeneration in amyotrophic lateral sclerosis

OBJECTIVES The establishment of biomarkers for amyotrophic lateral sclerosis (ALS) will be useful for early diagnosis and may provide evidence about pathogenesis. To elucidate whether high-field magnetic resonance (MR) findings and multimodal analysis of cerebrospinal fluid (CSF) levels of cystatin C could be indicators of upper motor neuron (UMN) involvement in ALS. PATIENTS AND METHODS Patients with ALS (n = 20), multiple sclerosis (n = 15), immune mediated chronic polyneuropathy (n = 17), and acute polyneuropathy (n = 12) were included in this retrospective study. Clinical indices including UMN signs were assessed, and 3.0-Tesla diffusion tensor imaging and MR spectroscopy were performed in patients with ALS. CSF levels of cystatin C were measured using enzyme-linked immunosorbent assay. RESULTS MR findings indicated that decreased anisotropy, increased diffusion, and increased myo-inositol/creatine ratio were also significantly correlated with UMN involvement in patients with ALS. The CSF cystatin C levels were significantly lower in patients with ALS than in the other three groups. The reduction of CSF cystatin C levels was significantly correlated with clinical UMN involvement (r = -0.505, p =  0.023). CONCLUSIONS Reduced cystatin C in CSF can reflect UMN involvement as shown in high-field MR of ALS, potentially providing a new biomarker for UMN degeneration in ALS.

Multimodal analysis based on high-field magnetic resonance and motor evoked potentials: A case report of multiple sclerosis

Magnetic resonance imaging is widely used in the evaluation of multiple sclerosis (MS). Diffusion tensor imaging can provide information about structural changes in MS that is inaccessible with other magnetic resonance imaging techniques.

136. Long-term effect of repetitive transcranial magnetic stimulation (rTMS) over the premotor cortex for upper limb dystonia

Subclinical rhythmic electrographic discharges of adults (SREDA) is a rare pattern reported in fewer than 0.05% of patients. We documented SREDA-like discharges in a patient with Parkinson’s disease (PD). A 59-year-old woman was admitted to our hospital due to slowly progressive motor disturbance of her left arm. On examination, she had left-dominant rigidity without autonomic and cognitive dysfunctions. Brain MRI showed a mild diffuse cerebral atrophy and SPECT revealed the hypoperfusion in the right thalamus and bifrontal areas. Her symptoms improved by L-DOPA, and thus we diagnosed her with PD. She underwent EEGs twice. In both tests, we found the repetitive discharges characterized by an abrupt onset during hyperventilation: occipital dominant theta waves preceded by delta waves appeared and evolved repeatedly, lasting 4–5 min. While these discharges were observed, her consciousness was alert and she had no symptoms. These discharges seemed to be SREDA, however, they lasted for long time and showed slower frequencies.

Acute Effect of Subthreshold Low-frequency Repetitive Transcranial Magnetic Stimulation over the Premotor Cortex in Writer's Cramp

Writers cramp, or focal hand dystonia, is characterized by involuntary coactivation of antagonist or unnecessary muscles while writing or performing other tasks. Recent studies of changes in cerebral blood flow during writing have demonstrated a reduction in the activation of the primary motor cortex (MC) and hyperactivity of the parts of frontal nonprimary motor areas. Therefore, any measures that decrease the activities of nonprimary motor areas like the premotor cortex (PMC) or supplementary motor area (SMA) might improve dystonic symptoms. We explore this possibility of acute effect, Nine patients with writers cramp and seven age-matched control subjects were recruited. After the preliminary experiments, we used subthreshold low-frequency (0.2 Hz) repetitive transcranial magnetic stimulation (rTMS), which exerts an inhibitory action on the cortex. We compared the silent periods and computer-assisted ratings of handwriting before and after rTMS applied to the MC, SMA, or PMC. Stimulation of the PMC but not the MC significantly improved the rating of handwriting (mean tracking error from the target, P=0.004; pen pressure, P=0.01) and prolonged the silent period (P=0.02) in the patient group. This increased susceptibility of the PMC in dystonia suggests that lack of inhibition in the MC is secondary to the hyperactivity of PMC neurons. Further physiological studies disclosed that the amplitude of frontal N30 component was significantly increased after rTMS over the PMC in control subjects (p=0.014) but not in dystonic patients, and 99mTc-ECD SPECT showed the different activation pattern in between control subjects (Brodmann area 9 and 6 including PMC and prefrontal cortex) and patients (parietal and cerebellar cortices). These findings support the idea that cortical network pattern induced by rTMS is quite different in the two groups. It is not clear whether the activated areas seen in dystonia is due to primary or compensatory mechanism, but our findings suggest the PMC plays an important role in the pathophysiology of dystonia. Additionally we showed 0.2 Hz rTMS over the premotor cortex was rather effective than ordinary 1 Hz stimulation over the MC, demonstrating that different frequency and stimulation site is to be explored in each disease depending on its own pathophysiology.

FC22.3 Mechanism of therapeutic effects of low-frequency monophasic rTMS over premotor cortex in writer’s cramp

Background: Patients with Parkinson’s disease (PD) may present mirror movements (MM). Transcranial magnetic stimulation data indicate that this reflect an abnormal enhancement of the ‘physiological mirroring’ that can be observed in healthy adults during complex and effortful tasks. It was hypothesized that, in PD, enhanced mirroring is caused by a failure of basal ganglia output to support the cortical network that is responsible for the execution of strictly unimanual movements. If so, it is likely that subtle alterations of voluntary unimanual motor control are also present in PD patients without overt MM. Objective: To test this hypothesis by using surface electromyographic (EMG) techniques in 12 mildly to moderately affected PD patients without overt MM, and in two control groups (12 age-matched and 10 young healthy volunteers). Methods: Subjects performed unilateral phasic thumb abduction during a sustained tonic contraction of the opposite abductor pollicis brevis. All patients were tested on dopaminergic therapy. On a separate day, 7 out of 12 patients were re-tested after withdrawal of medication. Results: During this task, involuntary mirror-like increase in surface EMG of the tonically abducting thumb was significantly larger in PD patients than in age-matched or young healthy volunteers. Off therapy, mirroring was slightly greater than on medication, although this difference was not significant. Conclusion: Our findings suggest that dysfunction of unimanual motor control is a general feature of PD. It is likely that this deficient movement lateralization contributes to an impairment of nonsymmetrical bimanual movements in PD.