Contribution of transcranial magnetic stimulation in restless legs syndrome: pathophysiological insights and therapeutical approaches

Transcranial magnetic stimulation (TMS) may offer a reliable means to characterize significant pathophysiologic and neurochemical aspects of restless legs syndrome (RLS). Namely, TMS has revealed specific patterns of changes in cortical excitability and plasticity, in particular dysfunctional inhibitory mechanisms and sensorimotor integration, which are thought to be part of the pathophysiological mechanisms of RLS rather than reflect a non-specific consequence of sleep architecture alteration.If delivered repetitively, TMS is able to transiently modulate the neural activity of the stimulated and connected areas. Some studies have begun to therapeutically use repetitive TMS (rTMS) to improve sensory and motor disturbances in RLS. High-frequency rTMS applied over the primary motor cortex or the supplementary motor cortex, as well as low-frequency rTMS over the primary somatosensory cortex, seem to have transient beneficial effects. However, further studies with larger patient samples, repeated sessions, an optimized rTMS setup, and clinical follow-up are needed in order to corroborate preliminary results.Thus, we performed a systematic search of all the studies that have used TMS and rTMS techniques in patients with RLS.     

Psychometric properties of the Repetitive Behavior Scale-Revised for individuals with autism spectrum disorder in Japan

Restricted and repetitive behaviors (RRBs) constitute a core symptom of autism spectrum disorder (ASD). The Repetitive Behavior Scale-Revised (RBS-R) is a widely used questionnaire administered by parents or caregivers to assess RRBs in individuals with ASD. This study evaluated the psychometric properties of the RBS-R Japanese Version (RBS-R-J). The ASD and non-ASD groups comprised 274 and 36 participants, respectively. We examined corrected item-total correlation, Cronbach's alpha, and RBS-R-J scores of different diagnostic groups, as well as correlations between RBS-R-J scores and intelligence quotient (IQ), autistic symptoms, adaptive/maladaptive functioning, aberrant behaviors, and sensory processing. All items showed moderate corrected item-total correlations. Cronbach's alpha coefficient was .93. We found significant differences in the mean RBS-R-J scores of the low-functioning ASD group and the intellectual disabilities group, and of low-functioning and high-functioning ASD groups. RBS-R-J scores negatively correlated with IQ and scores on the Sensory Profile (Japanese version) and Adaptive Behavior Composite of the Maladaptive Behavior Index of the Vineland Adaptive Behavior Scales-Second Edition (VABS-II; Japanese version), but positively correlated with scores on the peak and current symptoms subscales of the Pervasive Developmental Disorders Autism Society Japan Rating Scale, the VABS-II, and the Aberrant Behavior Checklist-Community (Japanese version). From these results, we conclude that RBS-R-J showed good reliability, diagnostic validity, and convergent validity, indicating that it is a reliable, valid instrument for use among ASD individuals in clinical and research settings.     

Excitation of locus coeruleus neurons by an adenosine 3',5'-cyclic monophosphate-activated inward current: extracellular and intracellular studies in rat brain slices

The firing rate of locus coeruleus (LC) neurons in rat brain slices was increased reversibly by agents that either elevate intracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP) or mimic its actions (e.g., forskolin, and activator of adenylate cyclase, 8-Br-cAMP, a membrane permeable analog of cAMP, and Ro20-1724, a preferential inhibitor of cAMP-phosphodiesterase). Intracellular recordings showed that 8-Br-cAMP and forskolin induce a depolarization of LC neurons, accompanied by a decrease in input resistance. The 8-Br-cAMP- and forskolin-elicited depolarization persisted in the presence of cobalt, a calcium channel blocker. Steady-state current-voltage curves revealed that in the voltage range of -50 to -120 mV, 8-Br-cAMP and forskolin induced an inward current, which did not reverse at the potassium equilibrium potential and could not be blocked by tetrodotoxin. Partial replacement of sodium with Tris or choline markedly reduced the depolarization elicited by 8-Br-cAMP. We conclude that 8-Br-cAMP and forskolin act through a common mechanism to increase the firing rate of locus coeruleus neurons by inducing a cAMP-activated inward current, carried out at least in part by sodium ions.     

Intensity-dependent regional cerebral blood flow during 1-Hz repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers studied with H215O positron emission tomography: I. Effects of primary motor cortex rTMS.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) affects the excitability of the motor cortex and is thought to influence activity in other brain areas as well. We combined the administration of varying intensities of 1-Hz rTMS of the motor cortex with simultaneous positron emission tomography (PET) to delineate local and distant effects on brain activity. METHODS: Ten healthy subjects received 1-Hz rTMS to the optimal position over motor cortex (M1) for producing a twitch in the right hand at 80, 90, 100, 110, and 120% of the twitch threshold, while regional cerebral blood flow (rCBF) was measured using H(2)(15)O and PET. Repetitive transcranial magnetic stimulation (rTMS) was delivered in 75-pulse trains at each intensity every 10 min through a figure-eight coil. The regional relationship of stimulation intensity to normalized rCBF was assessed statistically. RESULTS: Intensity-dependent rCBF increases were produced under the M1 stimulation site in ipsilateral primary auditory cortex, contralateral cerebellum, and bilateral putamen, insula, and red nucleus. Intensity-dependent reductions in rCBF occurred in contralateral frontal and parietal cortices and bilateral anterior cingulate gyrus and occipital cortex. CONCLUSIONS: This study demonstrates that 1-Hz rTMS delivered to the primary motor cortex (M1) produces intensity-dependent increases in brain activity locally and has associated effects in distant sites with known connections to M1.     

Novel antiepileptic drug levetiracetam decreases dyskinesia elicited by L-dopa and ropinirole in the MPTP-lesioned marmoset.

Long-term dopamine replacement therapy of Parkinson's disease leads to the occurrence of dyskinesias. Altered firing patterns of neurons of the internal globus pallidus, involving a pathological synchronization/desynchronization process, may contribute significantly to the genesis of dyskinesia. Levetiracetam, an antiepileptic drug that counteracts neuronal (hyper)synchronization in animal models of epilepsy, was assessed in the MPTP-lesioned marmoset model of Parkinson's disease, after coadministration with (1) levodopa (L-dopa) or (2) ropinirole/L-dopa combination. Oral administration of levetiracetam (13-60 mg/kg) in combination with either L-dopa (12 mg/kg) alone or L-dopa (8 mg/kg)/ropinirole (1.25 mg/kg) treatments was associated with significantly less dyskinesia, in comparison to L-dopa monotherapy during the first hour after administration. Thus, new nondopaminergic treatment strategies targeting normalization of abnormal firing patterns in basal ganglia structures may prove useful as an adjunct to reduce dyskinesia induced by dopamine replacement therapy without affecting its antiparkinsonian action.     

Quadro-pulse stimulation is more effective than paired-pulse stimulation for plasticity induction of the human motor cortex

OBJECTIVE: Repetitive paired-pulse transcranial magnetic stimulation (TMS) at I-wave periodicity has been shown to induce a motor-evoked potential (MEP) facilitation. We hypothesized that a greater enhancement of motor cortical excitability is provoked by increasing the number of pulses per train beyond those by paired-pulse stimulation (PPS). METHODS: We explored motor cortical excitability changes induced by repetitive application of trains of four monophasic magnetic pulses (quadro-pulse stimulation: QPS) at 1.5-ms intervals, repeated every 5s over the motor cortex projecting to the hand muscles. The aftereffects of QPS were evaluated with MEPs to a single-pulse TMS, motor threshold (MT), and responses to brain-stem stimulation. These effects were compared to those after PPS. To evaluate the QPS safety, we also studied the spread of excitation and after discharge using surface electromyograms (EMGs) of hand and arm muscles. RESULTS: Sizes of MEPs from the hand muscle were enhanced for longer than 75min after QPS; they reverted to the baseline at 90min. Responses to brain-stem stimulation from the hand muscle and cortical MEPs from the forearm muscle were unchanged after QPS over the hand motor area. MT was unaffected by QPS. No spreads of excitation were detected after QPS. The appearance rate of after discharges during QPS was not different from that during sham stimulation. CONCLUSIONS: Results show that QPS can safely induce long-lasting, topographically specific enhancement of motor cortical excitability. SIGNIFICANCE: QPS is more effective than PPS for inducing motor cortical plasticity.     

Changes in somatosensory evoked responses by repetition of the median nerve stimulation

OBJECTIVE: We investigate the synaptic factor for the recovery function of evoked responses using a repetitive stimulation technique. METHODS: Somatosensory evoked cortical magnetic field (SEF) was recorded following stimulation of the median nerve using single to 6-train stimulation in 8 healthy subjects. The SEF responses after each stimulus in the train stimulation were extracted by subtraction of the waveforms. RESULTS: An attenuation of the SEF components was recognized after the second of the stimuli, but there was no significant attenuation with the third or later stimulations. The root mean square (RMS) of the 1M (peak latency at 20 ms after stimulation) and 4M (70 ms) components were smaller than that of the single stimulation during the train stimulation, while the 2M (30 ms) and 3M (45 ms) components were not attenuated, but the 3M was facilitated at the fourth to sixth stimulation. CONCLUSION: The synaptic factor was not responsible for the attenuation of the SEF components during repetitive stimulation in healthy subjects. The SEF change disclosed a functional difference among the SEF components during the train stimulation, especially among the later components.     

Detecting cumulative trauma disorders in workers performing repetitive tasks

On-site testing of 157 poultry processors disclosed that 50% had three or more abnormal upper extremity findings out of a total of 22 possibles. The average worker had five to six abnormal findings. Impaired pinch strength, decreased vibration sensitivity in the fingertips, and reports of current numbness were the most prevalent. Of workers with signs, 25% reported no symptoms, whereas only 8% of workers reported symptoms but had no signs. The investigators concluded that this measurement method has utility for assessments of worker populations to determine prevalence of CTDs and, potentially, for preclinical detection of these disorders to permit early intervention, reduce medical costs, and minimize disability. The need for accurate measurement to enhance early detection and prevention is discussed.     

不同重复经颅磁刺激模式对脑卒中后上肢运动功能障碍干预效果的网状Meta分析

背景 上肢运动功能障碍是脑卒中后常见的后遗症之一,严重影响患者日常生活能力。重复经颅磁刺激（rTMS）作为常见的神经电生理技术对治疗脑卒中后上肢运动功能障碍有较好的疗效,但临床对不同rTMS干预模式的选择仍缺乏循证依据。目的 采用网状Meta分析方法比较rTMS的4种模式对脑卒中后上肢运动功能障碍患者的临床疗效。方法 计算机检索PubMed、Embase、Cochrane Library、Web of Science、中国生物医学文献数据库、中国知网、万方数据知识服务平台、维普网中有关rTMS治疗脑卒中后上肢运动功能障碍的随机对照试验,并通过追溯Meta分析的参考文献作为补充。检索时间均为建库至2022年2月,采用主题词和自由词结合方式进行。2名研究者进行文献筛选、资料提取及质量评价。采用RevMan 5.0软件和Stata 16.0软件进行统计学分析。结果 最终纳入17篇文献,790例患者,共涉及6种干预措施：高频rTMS(HF-rTMS)、低频rTMS(LF-rTMS)、间断性theta节律刺激（iTBS）、连续性theta节律刺激（cTBS）、假刺激、常规疗法。网状Meta分析结...     

Transcranial magnetic stimulation: new insights into representational cortical plasticity

In the last decade, transcranial magnetic stimulation (TMS) has been used increasingly as a tool to explore the mechanisms and consequences of cortical plasticity in the intact human cortex. Because the spatial accuracy of the technique is limited, we refer to this as plasticity at a regional level. Currently, TMS is used to explore regional reorganization in three different ways. First, it can map changes in the pattern of connectivity within and between different cortical areas or their spinal projections. Important examples of this approach can be found in the work on motor cortex representations following a variety of interventions such as immobilization, skill acquisition, or stroke. Second, TMS can be used to investigate the behavioural relevance of these changes. By applying TMS in its "virtual lesion" mode, it is possible to interfere with cortical function and ask whether plastic reorganization within a distinct cortical area improves function. Third, TMS can be used to promote changes in cortical function. This is achieved by using repetitive TMS (rTMS) to induce short-term functional reorganization in the human cortex. The magnitude and the direction of rTMS-induced plasticity depend on extrinsic factors (i.e. the variables of stimulation such as intensity, frequency, and total number of stimuli) and intrinsic factors (i.e. the functional state of the cortex targeted by rTMS). Since conditioning effects of rTMS are not limited to the stimulated cortex but give rise to functional changes in interconnected cortical areas, rTMS is a suitable tool to investigate plasticity within a distributed functional network. Indeed, the lasting effects of rTMS offer new possibilities to study dynamic aspects of the pathophysiology of a variety of diseases and may have therapeutic potential in some neuropsychiatric disorders. Electronic Publication