Search

This study aimed to investigate whether the cerebellum contributes to contraction-induced facilitation (CIF) of contralateral corticospinal excitability. To this end, repetitive cerebellar transcranial magnetic stimulation (TMS) was used to test whether it modulates CIF. Overall, 20 healthy young individuals participated in the study. Single-pulse TMS was applied to the left primary motor cortex to induce motor-evoked potentials (MEP) on electromyography of the right first dorsal interosseous (FDI) muscle to test corticospinal excitability. This measurement was conducted during contraction (10% maximum voluntary contraction [MVC]) and rest (0% MVC) of the FDI muscle. CIF, cerebellar brain inhibition (CBI), cortical silent period (cSP), and resting motor threshold (rMT) were measured before and after low-frequency repetitive TMS (crTMS) of the right cerebellum to downregulate cerebellar output. The CIF (contraction/rest of the MEP), CBI (conditioned/unconditioned MEP) during contraction, cSP, and rMT were not affected by crTMS. At rest, CBI was decreased. These findings indicated that the primary motor cortex function for the increase in corticospinal excitability was not affected by crTMS. This study contributes to our understanding of the role of the cerebellum in motor control. Additionally, it may inform decision-making for the site of cerebellar ataxia treatment using non-invasive brain stimulation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Matsugi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Tuberous sclerosis complex (TSC)-related skeletal abnormalities are understudied. Awareness of skull thickening in patients with TSC is important from the surgical standpoint because a thick skull might complicate craniotomy. This study aimed to discover if patients with TSC are generally prone to skull thickening by retrospectively investigating the frequency and characteristics of skull thickening in these patients., Methods: Patients with TSC ages 10 to 60 years who underwent magnetic resonance imaging in the neurosurgery, dermatology, or pediatrics clinic between 2010 and 2021 were identified. Two control groups were used for comparison: one with patients with unruptured intracranial aneurysms to serve as control without antiseizure medication exposure and one with non-TSC epilepsy as control with antiseizure medication exposure. In all patients, thickness of frontal, parietal, temporal, and occipital bones was measured at a fixed location of each bone on T2-weighted axial images., Results: Inclusion criteria were fulfilled by 29 patients. Frontal and temporal bones of the TSC group were significantly thicker than those of either control group. Skull thickening was significantly associated with intracerebral calcification, but not with age, sex, or antiseizure medication exposure. Focal skull thickening was associated with the presence of a subcortical calcification., Conclusions: Patients with TSC have skull thickening, which is often linked to intracerebral calcification. The presence of skull thickening may require modification of surgical approach during craniotomy. Skull thickening and the underlying intracerebral calcification likely share a common precipitating factor given their relationship. Future studies are warranted to clarify the genetic underpinnings of this relationship and even broader skeletal abnormalities in TSC., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Central post-stroke pain (CPSP) is a common type of central neuropathic pain (CNeP) that can occur following the onset of stroke. The oral gabapentinoid mirogabalin besylate (mirogabalin) is a selective α 2 δ ligand that is effective for the treatment of CNeP, including CPSP. However, it is unknown whether the analgesic effect of mirogabalin on CPSP varies in patients with different background factors., Methods: This was a post hoc subgroup analysis of a multinational, open-label, long-term phase 3 study of mirogabalin for the treatment of CNeP conducted between March 2019 and December 2020. Data from patients with CPSP were stratified by type of stroke (ischemic or hemorrhagic), stroke location (thalamus, putamen, brainstem, or other), presence/absence of motor weakness, median time since stroke (≥ 59 or < 59 months), and median duration of CPSP (≥ 55.5 or < 55.5 months). Efficacy was assessed with the short-form McGill Pain Questionnaire (SF-MPQ), and treatment-emergent adverse events (TEAEs) and adverse drug reactions (ADRs) were recorded., Results: This subanalysis included all 94 patients with CPSP from the phase 3 study; all were Japanese, and the mean age was 65.3 years. The least squares mean change [95% confidence interval] in SF-MPQ visual analog scale (VAS) score from baseline at week 52 (last observation carried forward) was - 17.0 [- 22.1, - 11.9] mm. Among the subgroups, least squares mean changes in SF-MPQ VAS scores were not different. Most TEAEs were mild or moderate; severe TEAEs occurred in six patients (6.4%). Somnolence (25.5%), peripheral edema (13.8%), dizziness (11.7%), and weight gain (6.4%) were the most common ADRs, and the types and frequencies of ADRs were similar among subgroups., Conclusion: Mirogabalin was generally effective and well tolerated in patients with CPSP, regardless of background factors such as stroke type or location, presence/absence of motor weakness, time since stroke, and duration of CPSP., Trial Registration: Trial registration number NCT03901352., (© 2024. The Author(s).)

Thalamic pain can be understood as a network reorganization disorder. This study aimed to investigate functional connectivity (FC) in human patients and a macaque model of thalamic pain. In humans, resting-state FC was compared between patients with thalamic pain and healthy individuals. Furthermore, resting-state FC was compared in macaques, before and after the induction of thalamic pain in the same individuals. FC between the amygdala of the unaffected hemisphere and the brainstem was significantly higher in patients with thalamic pain. More specifically, a significantly higher FC was observed between the basolateral amygdala and the ventral tegmental area, which also significantly predicted the value of a visual analog scale of pain intensity in individual patients. The macaque model of thalamic pain also exhibited a significantly higher FC between the amygdala of the unaffected hemisphere and the brainstem, particularly between the basolateral amygdala and the midbrain. Furthermore, the previously reported significantly higher FC between the amygdala and the mediodorsal nucleus of the thalamus in macaques with thalamic pain was also reproduced in the human patients. Therefore, the present results suggest that the FC changes in the regions associated with emotion, memory, motivation, and reward are part of the underlying mechanisms of thalamic pain onset present in both human patients and model macaques. This cross-species convergence provides new insights into the neurological mechanisms underlying thalamic pain, paving the way for further studies and the development of therapeutic strategies. PERSPECTIVE: This article presents that the FC changes in the regions associated with emotion, motivation, and reward are part of the underlying mechanisms of thalamic pain in humans and macaques., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Boltless implantation of stereo-electroencephalography electrode is a useful alternative especially when anchor bolt is not available such as in country with limited resources or is less appropriate such as placement in patients with thin skull or at the occiput area, despite some drawbacks including potential dislodgement. While the accuracy of implantation using anchor bolt is well-studied, data on boltless implantation remain scarce. This study aimed to reveal the accuracy, permissible error for actual placement of electrodes within the grey matter, and delayed electrode dislodgement in boltless implantation., Methods: A total of 120 electrodes were implanted in 15 patients using a Leksell Stereotactic G Frame with each electrode fixed on the scalp using sutures. Target point error was defined as the Euclidean distance between the planned target and the electrode tip on immediate postimplantation computed tomography. Similarly, delayed dislodgement was defined as the Euclidean distance between the electrode tips on immediate postimplantation computed tomography and delayed MRI. The factors affecting accuracy were evaluated using multiple linear regression. The permissible error was defined as the largest target point error that allows the maximum number of planned gray matter electrode contacts to be actually placed within the gray matter as intended., Results: The median (IQR) target point error was 2.6 (1.7-3.5) mm, and the permissible error was 3.2 mm. The delayed dislodgement, with a median (IQR) of 2.2 (1.4-3.3) mm, was dependent on temporal muscle penetration (P = 5.0 × 10-4), scalp thickness (P < 5.1 × 10-3), and insertion angle (P = 3.4 × 10-3)., Conclusion: Boltless implantation of stereo-electroencephalography electrode offers an accuracy comparable to those using anchor bolt. During the planning of boltless implantation, target points should be placed within 3.2 mm from the gray-white matter junction and a possible delayed dislodgement of 2.2 mm should be considered., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

This study aimed to evaluate the efficacy and safety of navigation-guided repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex in patients with neuropathic pain in the upper limb. This randomized, blinded, sham-controlled, parallel trial included a rTMS protocol (10-Hz, 2000 pulses/session) consisting of five daily sessions, followed by one session per week for the next seven weeks. Pain intensity, as well as pain-related disability, quality of life, and psychological status, were assessed. For the primary outcome, pain intensity was measured daily using a numerical rating scale as a pain diary. Thirty patients were randomly assigned to the active rTMS or sham-stimulation groups. In the primary outcome, the decrease (least square [LS] mean ± standard error) in the weekly average of a pain diary at week 9 compared to the baseline was 0.84 ± 0.31 in the active rTMS group and 0.58 ± 0.29 in the sham group (LS mean difference, 0.26; 95% confidence interval, - 0.60 to 1.13). There was no significant effect on the interaction between the treatment group and time point. Pain-related disability score improved, but other assessments showed no differences. No serious adverse events were observed. This study did not show significant pain relief; however, active rTMS tended to provide better results than sham. rTMS has the potential to improve pain-related disability in addition to pain relief.Clinical Trial Registration number: jRCTs052190110 (20/02/2020)., (© 2024. The Author(s).)

The treatment of neuropathic pain (NeP) often leads to partial or incomplete pain relief, with up to 40 % of patients being pharmaco-resistant. In this chapter the efficacy of neuromodulation techniques in treating NeP is reviewed. It presents a detailed evaluation of the mechanisms of action and evidence supporting the clinical use of the most common approaches like transcutaneous electrical nerve stimulation (TENS), transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), deep brain stimulation (DBS), invasive motor cortex stimulation (iMCS), spinal cord stimulation (SCS), dorsal root ganglion stimulation (DRG-S), and peripheral nerve stimulation (PNS). Current literature suggests that motor cortex rTMS is effective for peripheral and central NeP, and TENS for peripheral NeP. Evidence for tDCS is inconclusive. DBS is reserved for research settings due to heterogeneous results, while iMSC has shown efficacy in a small randomized trial in neuropathic pain due to stroke and brachial plexus avulsion. SCS has moderate evidence for painful diabetic neuropathy and failed back surgery syndrome, but trials were not controlled with sham. DRG-S and PNS have shown positive results for complex regional pain syndrome and post-surgical neuropathic pain, respectively. Adverse effects vary, with non-invasive techniques showing local discomfort, dizziness and headache, and DBS and SCS hardware-related issues. To date, non-invasive techniques have been more extensively studied and some are included in international guidelines, while the evidence level for invasive techniques are less robust, potentially suggesting their use in a case-by-case indication considering patient´s preferences, costs and expected benefits., (Copyright © 2024. Published by Elsevier Inc.)

Intrathecal baclofen (ITB) therapy effectively treats spasticity caused by brain or spinal cord lesions. However, only a few studies compare the course of treatment for different diseases. We investigated the change in daily dose of baclofen per year and its associated adverse events in patients presenting with the three most common etiologies at our institute: hereditary spastic paraplegia, cerebral palsy, and spinal cord injury. The ITB pumps were implanted from July 2007 to August 2019, with a mean follow-up period of 70 months. In patients with hereditary spastic paraplegia, baclofen dosage was reduced after eight years following ITB introduction, and the treatment was terminated in one patient owing to disease progression. In patients with cerebral palsy, the dosage increased gradually, and became constant in the 11th year. Patients with spinal cord injury gradually increased their baclofen dosage throughout the entire observation period. Severity and adverse event rates were higher in patients with cerebral palsy than in others. The degree and progression of spasticity varied depending on the causative disease. Understanding the characteristics and natural history of each disease is important when continuing ITB treatment.

Objectives: To examine the relationship between cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) and tap test response to elucidate the effects of comorbidity of AD in idiopathic normal-pressure hydrocephalus (iNPH)., Design: Case-control study., Setting: Osaka University Hospital., Participants: Patients with possible iNPH underwent a CSF tap test., Measurements: Concentrations of amyloid beta (Aβ) 1-40, 1-42, and total tau in CSF were measured. The response of tap test was judged using Timed Up and Go test (TUG), 10-m reciprocation walking test (10MWT), Mini-Mental State Examination (MMSE), and iNPH grading scale. The ratio of Aβ1-42 to Aβ1-40 (Aβ 42/40 ratio) and total tau concentration was compared between tap test-negative (iNPH-nTT) and -positive (iNPH-pTT) patients., Results: We identified 27 patients as iNPH-nTT and 81 as iNPH-pTT. Aβ 42/40 ratio was significantly lower (mean [SD] = 0.063 [0.026] vs. 0.083 [0.036], p = 0.008), and total tau in CSF was significantly higher (mean [SD] = 385.6 [237.2] vs. 293.6 [165.0], p = 0.028) in iNPH-nTT than in iNPH-pTT. Stepwise logistic regression analysis revealed that low Aβ 42/40 ratio was significantly associated with the negativity of the tap test. The response of cognition was significantly related to Aβ 42/40 ratio. The association between Aβ 42/40 ratio and tap test response, especially in cognition, remained after adjusting for disease duration and severity at baseline., Conclusions: A low CSF Aβ 42/40 ratio is associated with a poorer cognitive response, but not gait and urinary response, to a tap test in iNPH. Even if CSF biomarkers suggest AD comorbidity, treatment with iNPH may be effective for gait and urinary dysfunction.

Background: High-resolution computed tomography (CT), outfitted with a 0.25-mm detector, has superior capability for identifying microscopic anatomical structures compared to conventional CT. This study describes the use of high-resolution computed tomography angiography (CTA) for preoperative microvascular decompression (MVD) assessment and explores the potential effectiveness of three-dimensional (3D) image fusion with magnetic resonance imaging (MRI) by comparing it with traditional imaging methods., Observations: Four patients who had undergone preoperative high-resolution CTA and MRI for MVD at Osaka University Hospital between December 2020 and March 2022 were included in this study. The 3D-reconstructed images and intraoperative findings were compared. One patient underwent conventional CTA, thus allowing for a comparison between high-resolution and conventional CTA in terms of radiation exposure and vascular delineation. Preoperative simulations reflected the intraoperative findings for all cases; small vessel compression of the nerve was identified preoperatively in two cases., Lessons: Compared with conventional CTA, high-resolution CTA showed superior vascular delineation with no significant change in radiation exposure. The use of high-resolution CTA with reconstructed 3D fusion images can help to simulate prior MVD. Knowing the location of the nerves and blood vessels can perioperatively guide neurosurgeons.

This study aimed to investigate abnormalities in inhibitory cortical excitability and motor control during ballistic-targeting movements in individuals with degenerative cerebellar ataxia (DCA). Sixteen participants took part in the study (DCA group [n = 8] and healthy group [n = 8]). The resting motor-threshold and cortical silent period (cSP) were measured in the right-hand muscle using transcranial magnetic stimulation over the left primary motor cortex. Moreover, the performance of the ballistic-targeting task with right wrist movements was measured. The Scale for the Assessment and Rating of Ataxia was used to evaluate the severity of ataxia. The results indicated that the cSP was significantly longer in participants with DCA compared to that in healthy controls. However, there was no correlation between cSP and severity of ataxia. Furthermore, cSP was linked to the ballistic-targeting task performance in healthy participants but not in participants with DCA. These findings suggest that there is excessive activity in the gamma-aminobutyric acid-mediated cortical inhibitory circuit in individuals with DCA. However, this increase in inhibitory activity not only fails to contribute to the control of ballistic-targeting movement but also shows no correlation with the severity of ataxia. These imply that increased excitability in inhibitory cortical circuits in the DCA may not contribute the motor control as much as it does in healthy older adults under limitations associated with a small sample size. The study's results contribute to our understanding of motor control abnormalities in people with DCA and provide potential evidence for further research in this area., (© 2023. Springer Nature Limited.)

Background: Through contrastive analysis, we aimed to identify the white matter brain regions that show microstructural changes in patients with neuropathic pain (NP) after spinal cord injury (SCI)., Methods: We categorized patients with SCI into NP ( n  = 30) and non-NP ( n  = 15) groups. We extracted diffusion tensor maps of fractional anisotropy (FA) and mean (MD), axial (AD), and radial (RD) diffusivity. A randomization-based method in tract-based spatial statistics was used to perform voxel-wise group comparisons among the FA, MD, AD, and RD for nonparametric permutation tests., Results: Atlas-based analysis located significantly different regions ( p  < 0.05) in the appointed brain atlas. Compared to the non-NP group, the NP group showed higher FA in the posterior body and splenium of the corpus callosum and higher AD in the corpus callosum, internal capsule, corona radiata, posterior thalamic radiation, sagittal stratum, external capsule, cingulum, fornix/stria terminalis, superior longitudinal fasciculus, and uncinate fasciculus., Conclusion: The results demonstrated that compared with the non-NP group, NP pathogenesis after SCI was potentially related to higher values in FA that are associated with microstructural changes in the posterior body and splenium of the corpus callosum, which could be regarded as central sensitization or network hyperexcitability., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dong, Hosomi, Mori, Kamijo, Furotani, Yamagami, Ohnishi, Watanabe, Nakamura, Tajima, Kishima and Saitoh.)

This study aimed to investigate the effects of repetitive transcranial magnetic stimulation (rTMS) of the cerebellum on changes in motor performance during a series of repetitive ballistic-targeting tasks. Twenty-two healthy young adults (n = 12 in the active-rTMS group and n = 10 in the sham rTMS group) participated in this study. The participants sat on a chair in front of a monitor and fixed their right forearms to a manipulandum. They manipulated the handle with the flexion/extension of the wrist to move the bar on the monitor. Immediately after a beep sound was played, the participant moved the bar as quickly as possible to the target line. After the first 10 repetitions of the ballistic-targeting task, active or sham rTMS (1 Hz, 900 pulses) was applied to the right cerebellum. Subsequently, five sets of 100 repetitions of this task were conducted. Participants in the sham rTMS group showed improved reaction time, movement time, maximum velocity of movement, and targeting error after repetition. However, improvements were inhibited in the active-rTMS group. Low-frequency cerebellar rTMS may disrupt motor learning during repetitive ballistic-targeting tasks. This supports the hypothesis that the cerebellum contributes to motor learning and motor-error correction in ballistic-targeting movements., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Magnetic resonance imaging-guided focused ultrasound (MRgFUS) has become popular as an incisionless mode of neurosurgical treatment. However, head pain during sonication is common and its pathophysiology remains poorly understood., Objective: To explore the characteristics of head pain occurring during MRgFUS thalamotomy., Methods: Our study comprised 59 patients who answered questions about the pain they experienced during unilateral MRgFUS thalamotomy. The location and features of pain were investigated using a questionnaire including the numerical rating scale (NRS) to estimate maximum pain intensity and the Japanese version of the Short Form of McGill Pain Questionnaire 2 to evaluate the quantitative and qualitative dimensions of pain. Several clinical factors were investigated for possible correlation with pain intensity., Results: Forty-eight patients (81%) reported sonication-related head pain, and the degree of pain was severe (NRS score ≥ 7) in 39 patients (66%). The distribution of sonication-related pain was "localized" in 29 (49%) and "diffuse" in 16 (27%); the most frequent location was the "occipital" region. The pain features most frequently reported were those in the "affective" subscale of the Short Form of McGill Pain Questionnaire 2. Patients with diffuse pain had a higher NRS score and lower skull density ratio than did patients with localized pain. The NRS score negatively correlated with tremor improvement at 6 months post-treatment., Conclusion: Most patients in our cohort experienced pain during MRgFUS. The distribution and intensity of pain varied according to the skull density ratio, indicating that the pain might have had different origins. Our results may contribute to the improvement of pain management during MRgFUS., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Congress of Neurological Surgeons.)

Phantom limb pain is attributed to abnormal sensorimotor cortical representations, although the causal relationship between phantom limb pain and sensorimotor cortical representations suffers from the potentially confounding effects of phantom hand movements. We developed neurofeedback training to change sensorimotor cortical representations without explicit phantom hand movements or hand-like visual feedback. We tested the feasibility of neurofeedback training in fourteen patients with phantom limb pain. Neurofeedback training was performed in a single-blind, randomized, crossover trial using two decoders constructed using motor cortical currents measured during phantom hand movements; the motor cortical currents contralateral or ipsilateral to the phantom hand (contralateral and ipsilateral training) were estimated from magnetoencephalograms. Patients were instructed to control the size of a disk, which was proportional to the decoding results, but to not move their phantom hands or other body parts. The pain assessed by the visual analogue scale was significantly greater after contralateral training than after ipsilateral training. Classification accuracy of phantom hand movements significantly increased only after contralateral training. These results suggested that the proposed neurofeedback training changed phantom hand representation and modulated pain without explicit phantom hand movements or hand-like visual feedback, thus showing the relation between the phantom hand representations and pain. PERSPECTIVE: Our work demonstrates the feasibility of using neurofeedback training to change phantom hand representation and modulate pain perception without explicit phantom hand movements and hand-like visual feedback. The results enhance the mechanistic understanding of certain treatments, such as mirror therapy, that change the sensorimotor cortical representation., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients often experience strong shooting pains after spinal root avulsion. The efficacy of spinal cord stimulation (SCS) for this type of pain is inconsistent; however, dorsal root entry zone (DREZ) lesioning (DREZ-lesion) has often proven to be an effective treatment modality. The authors report two cases in which DREZ-lesion was performed to treat pain after spinal root avulsion after implantation of SCS, but the operations were challenging due to strong adhesions., Observations: The authors present two cases of patients with pain after spinal root avulsion in whom SCS implantation was only temporarily effective. Patients complained of persistent and paroxysmal shooting pains in the upper extremities. SCS removal and DREZ-lesion were performed, but adhesions in the epidural and subdural space contacting the leads were strong, making it difficult to expose the DREZ., Lessons: Although adhesions around the spinal cord can be caused by trauma, the authors believe that in these cases, the adhesions could have been caused by the SCS leads. There are few previous reports confirming the efficacy of SCS in treating pain after spinal root avulsion; therefore, caution is required when considering SCS implantation.

Background: Several medications have been applied to Alzheimer's dementia patients (AD) but their efficacies have been insufficient. The efficacy and safety of 4 weeks of repetitive transcranial magnetic stimulation (rTMS) in Japanese AD were evaluated in this exploratory clinical trial., Methods: Forty-two patients, aged 60-93 years (average, 76.4 years), who were taking medication (> 6 months) and had Mini-Mental State Examination (MMSE) scores ≤ 25 and Clinical Dementia Rating Scale scores (CDR-J) of 1 or 2, were enrolled in this single-center, prospective, randomized, three-arm study [i.e., 120% resting motor threshold (120% RMT), 90% RMT for the bilateral dorsolateral prefrontal cortex, and Sham]. Alzheimer's Disease Assessment Scale-Japanese Cognitive (ADAS-J cog), Montreal Cognitive Assessment (MoCA-J), Clinical Global Impression of Change (CGIC), Neuropsychiatric inventory (NPI), and EuroQOL 5 Dimensions 5-Level (EQ-5D-5L) were administered. The primary endpoint was the mean change from baseline in the MMSE score (week 4). An active rTMS session involved applying 15 trains bilaterally (40 pulses/train at 10 Hz; intertrain interval, 26 s). Participants received ≥ 8 interventions within the first 2 weeks and at least one intervention weekly in the 3rd and 4th weeks. Full Analysis set (FAS) included 40 patients [120% RMT ( n = 15), 90% RMT ( n = 13), and Sham ( n = 12)]., Results: In the FAS, MMSE, ADAS-J cog, MoCA-J, CDR-J, CGIC, NPI, and EQ-5D-5L scores between the three groups were not significantly different. Two patients were erroneously switched between the 120% RMT and 90% RMT groups, therefore, "as treated" patients were mainly analyzed. Post hoc analysis revealed significant treatment efficacy in participants with MMSE scores ≥ 15, favoring the 120% RMT group over the Sham group. Responder analysis revealed 41.7% of the 120% RMT group had a ≥ 3-point improvement in the ADAS-J cog versus 0% in the Sham group (Fisher's exact test, p = 0.045). The MoCA-J showed the same tendency but was not significant. Efficacy disappeared in week 20, based on the ADAS-cog and MoCA-J. No intervention-related serious adverse events occurred., Conclusion: This paper is the first report of using rTMS in Japanese AD patients. The treatment seems safe and moderate-mild stage AD should be target population of pivotal clinical trial with 120% RMT rTMS., Competing Interests: YS, KH, and NM belonged to a joint research department established from sponsorship by Teijin Pharma Limited until Mar 31, 2021. TM belonged to a joint research department established from sponsorship by Teijin Pharma Limited until Sept 30, 2020. YS belongs to Boards of Directors of Japan Neuromodulation Society (no payment), Japan Society for Stereotactic and Functional Neurosurgery (no payment), and Japanese Society for Hypothalamic and Pituitary Tumors (no payment). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Saitoh, Hosomi, Mano, Takeya, Tagami, Mori, Matsugi, Jono, Harada, Yamada and Miyake.)

We investigated whether vermal cerebellar low-frequency repetitive transcranial magnetic stimulation (crTMS) affects motor learning of visually guided postural tracking training (VTT) using foot center of pressure (COP) as well as the stability and sensory contribution of upright standing. Twenty-one healthy volunteers participated (10 in the sham-crTMS group and 11 in the active-crTMS group). For VTT, participants stood on the force plate 1.5 m from the monitor on which the COP and target moved in a circle. Participants tracked the target with their own COP for 1 min, and 10 VTT sessions were conducted. The tracking error (TE) was compared between trials. Active- or sham-crTMS sessions were conducted prior to VTT. At baseline (before crTMS), pre-VTT (after crTMS), and post-VTT, the COP trajectory during upright static standing under four conditions (eyes, open/closed; surface, hard/rubber) was recorded. Comparison of the length of the COP trajectory or path and sensory-contribution-rate showed no significant difference between baseline and pre- and post-VTT. There was a significant decrease in TE in the sham-crTMS but not in the active-crTMS group. VTT and crTMS did not immediately affect the stability and sensory contribution of upright standing; however, crTMS immediately affected motor learning. The vermal cerebellum may contribute to motor learning of voluntary postural control., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Intractable neuropathic pain following spinal cord injury (NP-SCI) reduces a patient's quality of life. Excessive release of ATP into the extracellular space evokes neuroinflammation via purinergic receptor. Neuroinflammation plays an important role in the initiation and maintenance of NP. However, little is known about whether or not extracellular ATP cause NP-SCI. We found in the present study that excess of intracellular ATP at the lesion site evokes at-level NP-SCI. No significant differences in the body weight, locomotor function, or motor behaviors were found in groups that were negative and positive for at-level allodynia. The intracellular ATP level at the lesion site was significantly higher in the allodynia-positive mice than in the allodynia-negative mice. A metabolome analysis revealed that there were no significant differences in the ATP production or degradation between allodynia-negative and allodynia-positive mice. Dorsal horn neurons in allodynia mice were found to be inactivated in the resting state, suggesting that decreased ATP consumption due to neural inactivity leads to a build-up of intracellular ATP. In contrast to the findings in the resting state, mechanical stimulation increased the neural activity of dorsal horn and extracellular ATP release at lesion site. The forced production of intracellular ATP at the lesion site in non-allodynia mice induced allodynia. The inhibition of P2X4 receptors in allodynia mice reduced allodynia. These results suggest that an excess buildup of intracellular ATP in the resting state causes at-level NP-SCI as a result of the extracellular release of ATP with mechanical stimulation., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Although stereotactic ablation surgery is known to ameliorate involuntary movement dramatically, little is known regarding alterations in whole-brain networks due to disruption of the deep brain nucleus. To explore changes in the whole-brain network after thalamotomy, we analyzed structural and functional connectivity alterations using resting-state functional magnetic resonance imaging and diffusion tensor imaging in patients with essential tremor who had undergone focused ultrasound (FUS) thalamotomy., Methods: Seven patients with intractable essential tremors and 7 age-matched healthy controls were enrolled in the study. The tremor score in essential tremor patients was assessed, and resting-state functional magnetic resonance imaging and diffusion tensor imaging were performed before and 3 months after left ventral intermediate nucleus thalamotomy using FUS., Results: There was a significant improvement in the tremor of the right hand after FUS thalamotomy. Seed-based functional connectivity analysis revealed a significant increase in functional connectivity between the left thalamus and the caudal part of the dorsal premotor cortex after FUS thalamotomy. Structural connectivity analysis did not detect statistically significant changes between before and after FUS. There was no correlation between the changes in functional connectivity and tremor score., Conclusions: Although the number of cases is small, our results show that functional connectivity between the thalamus and the premotor cortex increases after the amelioration of tremors by FUS thalamotomy. The lack of correlation between increased functional connectivity and clinical tremor scores suggests that the observed increase in functional connectivity may be a compensatory change in the secondary sensorimotor changes that occur after thalamotomy., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of the present study was to investigate the analgesic effects of repetitive transcranial magnetic stimulation over the primary motor cortex (M1-rTMS) using different stimulation parameters to explore the optimal stimulus condition for treating neuropathic pain., Materials and Methods: We conducted a randomized, blinded, crossover exploratory study. Four single sessions of M1-rTMS at different parameters were administered in random order. The tested stimulation conditions were as follows: 5-Hz with 500 pulses per session, 10-Hz with 500 pulses per session, 10-Hz with 2000 pulses per session, and sham stimulation. Analgesic effects were assessed by determining the visual analog scale (VAS) pain intensity score and Short-Form McGill Pain Questionnaire 2 (SF-MPQ2) score immediately before and immediately after intervention., Results: We enrolled 22 adults (age: 59.8 ± 12.1 years) with intractable neuropathic pain. Linear-effects models showed significant effects of the stimulation condition on changes in VAS pain intensity (p = 0.03) and SF-MPQ2 (p = 0.01). Tukey multiple comparison tests revealed that 10-Hz rTMS with 2000 pulses provided better pain relief than sham stimulation, with greater decreases in VAS pain intensity (p = 0.03) and SF-MPQ2 (p = 0.02)., Conclusions: The results of this study suggest that high-dose stimulation (specifically, 10-Hz rTMS at 2000 pulses) is more effective than lower-dose stimulation for treating neuropathic pain., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

High-frequency repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex for neuropathic pain has been shown to be effective, according to systematic reviews and therapeutic guidelines. However, our large, rigorous, investigator-initiated, registration-directed clinical trial failed to show a positive primary outcome, and its subgroup analysis suggested that the analgesic effect varied according to the site of pain. The aim of this study was to investigate the differences in analgesic effects of rTMS for neuropathic pain between different pain sites by reviewing our previous clinical trials. We included three clinical trials in this mini meta-analysis: a multicenter randomized controlled trial at seven hospitals ( N = 64), an investigator-initiated registration-directed clinical trial at three hospitals ( N = 142), and an exploratory clinical trial examining different stimulation parameters ( N = 22). The primary efficacy endpoint (change in pain scale) was extracted for each patient group with pain in the face, upper limb, or lower limb, and a meta-analysis of the efficacy of active rTMS against sham stimulation was performed. Standardized mean difference (SMD) with 95% confidence interval (CI) was calculated for pain change using a random-effects model. The analgesic effect of rTMS for upper limb pain was favorable (SMD = -0.45, 95% CI: -0.77 to -0.13). In contrast, rTMS did not produce significant pain relief on lower limb pain (SMD = 0.04, 95% CI: -0.33 to 0.41) or face (SMD = -0.24, 95% CI: -1.59 to 1.12). In conclusion, these findings suggest that rTMS provides analgesic effects in patients with neuropathic pain in the upper limb, but not in the lower limb or face, under the conditions of previous clinical trials. Owing to the main limitation of small number of studies included, many aspects should be clarified by further research and high-quality studies in these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mori, Hosomi, Nishi, Dong, Yanagisawa, Khoo, Tani, Oshino, Saitoh and Kishima.)

Introduction: Pain relief from repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) is particularly poor in patients with leg pain. The optimal parameters for relieving leg pain remain poorly understood. The purpose of this study was to explore the optimal stimulation parameters of M1-rTMS for patients with leg pain., Methods: Eleven patients with neuropathic pain in the leg randomly underwent 6 conditions of M1-rTMS with different stimulation intensities, sites, and coil directions, including sham stimulation. The 5 active conditions were as follows: 90% or 110% of the resting motor threshold (RMT) on the M1 hand with an anteroposterior coil direction, 90% or 110% RMT on the M1 foot in the anteroposterior direction, and 90% RMT on the M1 foot in the mediolateral direction. Each condition was administered for 3 days. Pain intensity was evaluated using the Visual Analogue Scale and Short-Form McGill Pain Questionnaire 2 at baseline and up to 7 days after each intervention., Results: Visual Analogue Scale scores were significantly reduced after the following active rTMS conditions: 90% RMT on the M1 hand, 90% RMT on the M1 foot with any coil direction, and 110% RMT on the M1 foot. The Short-Form McGill Pain Questionnaire 2 results were similar to those obtained using the Visual Analogue Scale. The analgesic effect of rTMS with stimulus intensity above the RMT was not superior to that below the RMT., Conclusion: We suggest that the optimal stimulation parameters of rTMS for patients with neuropathic pain in the leg may target the M1 foot or M1 hand with an intensity below the RMT., Competing Interests: N. Mori, N. Mori, D. Dong, and Y. Saitoh were members of the Department of Neuromodulation and Neurosurgery, Osaka University Graduate School of Medicine, which was a joint research department established with sponsorship from Teijin Pharma Limited. This department closed on March 31, 2021. The remaining authors have no conflicts of interest to declare. This study was partly supported by the Japan Agency for Medical Research and Development (AMED) under grant numbers JP17hk0102029, JP19ek0610016, JP19dm0307007, and JP19dm0307008 and the Japan Society for the Promotion of Science KAKENHI under grant numbers JP17K10893, JP18K08993, and JP19K19867.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

Machine learning classifiers for psychiatric disorders using resting-state functional magnetic resonance imaging (rs-fMRI) have recently attracted attention as a method for directly examining relationships between neural circuits and psychiatric disorders. To develop accurate and generalizable classifiers, we compiled a large-scale, multi-site, multi-disorder neuroimaging database. The database comprises resting-state fMRI and structural images of the brain from 993 patients and 1,421 healthy individuals, as well as demographic information such as age, sex, and clinical rating scales. To harmonize the multi-site data, nine healthy participants ("traveling subjects") visited the sites from which the above datasets were obtained and underwent neuroimaging with 12 scanners. All participants consented to having their data shared and analyzed at multiple medical and research institutions participating in the project, and 706 patients and 1,122 healthy individuals consented to having their data disclosed. Finally, we have published four datasets: 1) the SRPBS Multi-disorder Connectivity Dataset 2), the SRPBS Multi-disorder MRI Dataset (restricted), 3) the SRPBS Multi-disorder MRI Dataset (unrestricted), and 4) the SRPBS Traveling Subject MRI Dataset., (© 2021. The Author(s).)

Objective: Spinal cord stimulation (SCS) has been considered an ineffective procedure for patients with central poststroke pain (CPSP). However, recent case series that included small numbers of patients reported the possible efficacy of SCS as a treatment of CPSP. This multicenter retrospective study aimed to examine the outcomes of using SCS to treat patients with CPSP and to explore factors related to outcomes., Methods: The authors reviewed the medical records of patients with CPSP who underwent SCS to collect data regarding their background, surgical information, and outcomes of SCS at trial stimulation and last follow-up after long-term implantation in six study centers. Outcomes were evaluated with a pain score for intensity (range 0-10) and the Patient Global Impression of Changes (PGIC) scale. Factors associated with outcomes were explored with univariable and multivariable analyses., Results: The authors collected data from a total of 166 patients (mean age 63.4 years; mean pain score at baseline 8.2). Of these patients, 163 underwent trial stimulation. The mean pain score decreased by 42.0%, 104 (64%) patients had ≥ 30% decrease in pain score, and 96 (59%) reported much or very much improved condition on the PGIC scale at trial stimulation. Moreover, 106 (64%) patients underwent long-term implantation of SCS devices. The mean decrease in pain score was 41.4%, 63 (59%) patients continued to show ≥ 30% decrease in pain score at last follow-up, and 60 (56%) reported much or very much improved condition on the PGIC scale at last follow-up (median [range] follow-up period 24 [24-63] months). Eleven device-related complications and 10 permanent explantations were observed. Univariable and multivariable analyses suggested that young age, less sensory disturbance, implantation of cervical leads, treatment of upper-limb pain, and extensive treated regions were associated with satisfactory outcomes at last follow-up after long-term implantation., Conclusions: These findings indicate that SCS may modestly benefit patients with CPSP. SCS has therapeutic potential for patients with intractable CPSP owing to the lower invasiveness of the SCS procedure and refractory nature of CPSP. Nevertheless, trial stimulation is necessary because of the high initial failure rate.

Although tremor is one of the most common movement disorders, there are many different types, and proper diagnosis is important for appropriate treatment. Action tremor has a significant impact on daily life, but the effectiveness of medical treatment is insufficient, and surgery is often the treatment of choice. Surgical treatment is effective in suppressing tremor, and a large percentage of tremors can be adequately controlled. Currently available surgical treatments for tremor include the ventral intermediate nucleus of thalamus-deep brain stimulation(DBS), radiofrequency(RF)-thalamotomy, focused ultrasound(FUS)-thalamotomy, and gamma knife thalamotomy. DBS is often considered the first choice for surgical treatment due to the number of past cases in which DBS has been applied, reported evidence, long-term efficacy, safety, adjustability, and the possibility of bilateral treatment, but RF-thalamotomy is also expected to improve efficacy and safety because of recent advancements in coagulation technology and the accumulation of anatomical knowledge regarding the target nucleus. In addition, the number of cases in which FUS-thalamotomy has been applied has been increasing in the past few years due to its minimally invasive nature, which does not require puncture of the brain. As neurosurgeons, we have the responsibility to select and perform appropriate surgical treatment based on sufficient knowledge of tremor to yield beneficial results in patients.

Central poststroke pain (CPSP) develops after a stroke around the somatosensory pathway. CPSP is hypothesized to be caused by maladaptive reorganization between various brain regions. The treatment for CPSP has not been established; however, repetitive transcranial magnetic stimulation (rTMS) to the primary motor cortex has a clinical effect. To verify the functional reorganization hypothesis for CPSP development and rTMS therapeutic mechanism, we longitudinally pursued the structural and functional changes of the brain by using two male CPSP model monkeys (Macaca fuscata) developed by unilateral hemorrhage in the ventral posterolateral nucleus of the thalamus. Application of rTMS to the ipsilesional primary motor cortex relieved the induced pain of the model monkeys. A tractography analysis revealed a decrease in the structural connectivity in the ipsilesional thalamocortical tract, and rTMS had no effect on the structural connectivity. A region of interest analysis using resting-state functional magnetic resonance imaging revealed inappropriately strengthened functional connectivity between the ipsilesional mediodorsal nucleus of the thalamus and the amygdala, which are regions associated with emotion and memory, suggesting that this may be the cause of CPSP development. Moreover, rTMS normalizes this strengthened connectivity, which may be a possible therapeutic mechanism of rTMS for CPSP.

Purpose: Neuropathic pain is a complex and distressing chronic illness in modern medicine. Since 1990s, motor cortex stimulation (MCS) has emerged as a potential treatment for chronic neuropathic pain; however, the precise mechanisms underlying analgesia induced by MCS are not completely understood. The purpose of the present study was to investigate the blood oxygen-level dependent (BOLD) response in the brain during MCS., Methods: We inserted a bipolar tungsten electrode into the primary motor cortex (M1) of adult male Wistar rats. Functional magnetic resonance imaging (fMRI) scans were implemented simultaneously with the electrical stimulation of M1 and the BOLD signals taken from the fMRI were used as an index to reflect the response against MCS., Results: Our results demonstrated that the bilateral M1, ipsilateral caudate-putamen, and ipsilateral primary somatosensory cortex to the stimulation spot were activated after the onset of MCS. The BOLD signal time courses were analysed in these regions and similar temporal characteristics were found., Conclusion: By conducting direct cortical stimulation of the rodent brain to investigate its instant effect using fMRI, we identified encephalic regions directly involved in the instant motor cortical stimulation effects in healthy rat models. This result may be essential in establishing a foundation for further research on the underlying neuropathways associated with the MCS effects.

Parkinson's disease (PD) is a progressive neurological disorder characterised by motor and non-motor deficits. Repetitive transcranial magnetic stimulation (rTMS) over the bilateral primary motor cortex at a high frequency (5 Hz or higher) is reported to be a potential treatment of PD. We aimed to assess the effect of rTMS on eye movement control in patients with PD in their 'on' state. We enrolled 14 patients with PD and assessed motor symptoms (Movement Disorder Society-Sponsored Unified Parkinson's Disease Rating Scale; MDS-UPDRS) and eye movement performances (visually guided saccades, volitional anti-saccades, and small involuntary saccades during fixation) at baseline and after administering bilateral 10 Hz rTMS on leg region of the motor cortex. We confirmed that rTMS improved the MDS-UPDRS motor scores and found that rTMS improved the anti-saccade success rate, which requires adequate inhibition of the reflexive response. The improvement in anti-saccade success rate was correlated with that of the postural instability gait difficulty (PIGD) sub-scores of MDS-UPDRS and lower baseline Japanese version of the Montreal Cognitive Assessment scores. This result is consistent with previous findings that PIGD and inhibitory control deficits share common brain dysfunctions in PD. rTMS may alleviate dysfunctions of that circuit and have a clinical effect.

Objective: To determine whether training with a brain-computer interface (BCI) to control an image of a phantom hand, which moves based on cortical currents estimated from magnetoencephalographic signals, reduces phantom limb pain., Methods: Twelve patients with chronic phantom limb pain of the upper limb due to amputation or brachial plexus root avulsion participated in a randomized single-blinded crossover trial. Patients were trained to move the virtual hand image controlled by the BCI with a real decoder, which was constructed to classify intact hand movements from motor cortical currents, by moving their phantom hands for 3 days ("real training"). Pain was evaluated using a visual analogue scale (VAS) before and after training, and at follow-up for an additional 16 days. As a control, patients engaged in the training with the same hand image controlled by randomly changing values ("random training"). The 2 trainings were randomly assigned to the patients. This trial is registered at UMIN-CTR (UMIN000013608)., Results: VAS at day 4 was significantly reduced from the baseline after real training (mean [SD], 45.3 [24.2]-30.9 [20.6], 1/100 mm; p = 0.009 < 0.025), but not after random training ( p = 0.047 > 0.025). Compared to VAS at day 1, VAS at days 4 and 8 was significantly reduced by 32% and 36%, respectively, after real training and was significantly lower than VAS after random training ( p < 0.01)., Conclusion: Three-day training to move the hand images controlled by BCI significantly reduced pain for 1 week., Classification of Evidence: This study provides Class III evidence that BCI reduces phantom limb pain., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: The cerebellum strongly contributes to vestibulospinal function, and the modulation of vestibulospinal function is important for rehabilitation. As transcranial magnetic stimulation (TMS) and electrical stimulation may induce functional changes in neural systems, we investigated whether cerebellar repetitive TMS (crTMS) and noisy galvanic vestibular stimulation (nGVS) could modulate vestibulospinal response excitability. We also sought to determine whether crTMS could influence the effect of nGVS., Methods: Fifty-nine healthy adults were recruited; 28 were randomly allocated to a real-crTMS group and 31 to a sham-crTMS group. The crTMS was conducted using 900 pulses at 1 Hz, while the participants were in a static position. After the crTMS, each participant was allocated to either a real-nGVS group or sham-nGVS group, and nGVS was delivered (15 min., 1 mA; 0.1-640 Hz) while patients were in a static position. The H-reflex ratio (with/without bilateral bipolar square wave pulse GVS), which reflects vestibulospinal excitability, was measured at pre-crTMS, post-crTMS, and post-nGVS., Results: We found that crTMS alone and nGVS alone have no effect on H-reflex ratio but that the effect of nGVS was obtained after crTMS., Conclusion: crTMS and nGVS appear to act as neuromodulators of vestibulospinal function., (Copyright © 2020 Matsugi, Douchi, Hasada, Mori, Okada, Yoshida, Nishishita, Hosomi and Saitoh.)

Objective: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the intractable long-term side effects of anticancer medications and results in pain and dysesthesia. Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex has been demonstrated to provide effective relief for intractable neuropathic pain. The objective of this study was to investigate the effects of rTMS treatment on CIPN in cancer patients., Materials and Methods: Eleven female patients with breast cancer or gynecologic cancer (mean age 64.8 [standard deviation 7.8]) who had neuropathic pain and/or peripheral sensory neuropathy, with a minimum two grade severity based on the scale of the National Cancer Institutes' Common Terminology Criteria for Adverse Events (version 4.0) were enrolled. Patients received rTMS (5-Hz; 500 pulses/session; figure-8 coil) on their primary motor cortex corresponding to the target extremity. The intensity of pain and dysesthesia for all extremities was evaluated using a visual analog scale for pain, dysesthesia, and the Japanese version of the short-form McGill Pain Questionnaire 2 (SFMPQ2)., Results: rTMS for target extremity significantly decreased the visual analog scale of pain and dysesthesia. The intensity of pain measured by the SFMPQ2 was also decreased in the target extremity. Regarding non-target extremities, only dysesthesia significantly decreased as a result of rTMS. No adverse events were observed., Conclusion: This is an initial report demonstrating the potential of rTMS for the treatment of CIPN. We suggest rTMS could be potentially beneficial and effective as a treatment for pain and dysesthesia in patients with CIPN., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

We conducted a multicenter, randomized, patient- and assessor-blinded, sham-controlled trial to investigate the efficacy of repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) in patients with neuropathic pain (NP). Patients were randomly assigned to receive 5 daily sessions of active or sham rTMS of M1 corresponding to the part of the body experiencing the worst pain (500 pulses per session at 5 Hz). Responders were invited to enroll in an open-label continuous trial involving 4 weekly sessions of active rTMS. The primary outcome was a mean decrease in a visual analogue scale of pain intensity (scaled 0-100 mm) measured daily during the daily sessions in an intention-to-treat population. Secondary outcomes were other pain scores, quality-of-life measures, and depression score. One hundred forty-four patients were assigned to the active or sham stimulation groups. The primary outcome, mean visual analogue scale decreases, was not significantly different (P = 0.58) between the active stimulation group (mean, 8.0) and the sham group (9.2) during the daily sessions. The secondary outcomes were not significantly different between 2 groups. The patients enrolled in the continuous weekly rTMS achieved more pain relief in the active stimulation group compared with the sham (P < 0.01). No serious adverse events were observed. Five daily sessions of rTMS with stimulus conditions used in this trial were ineffective in short-term pain relief in the whole study population with various NP. Long-term administration to the responders should be investigated for the clinical use of rTMS on NP in the future trials.

Objective: To investigate whether gaze stabilization exercises (GSEs) improve eye and head movements and whether low-frequency cerebellar repetitive transcranial magnetic stimulation (rTMS) inhibits GSE trainability., Methods: 25 healthy adults (real rTMS, n = 12; sham rTMS, n = 13) were recruited. Real or sham rTMS was performed for 15 min (1 Hz, 900 stimulations). The center of the butterfly coil was set 1 cm below the inion in the real rTMS. Following stimulation, 10 trials of 1 min of a GSE were conducted at 1 min intervals. In the GSE, the subjects were instructed to stand upright and horizontally rotate their heads according to a beeping sound corresponding to 2 Hz and with a gaze point ahead of them. Electrooculograms were used to estimate the horizontal gaze direction of the right eye, and gyroscopic measurements were performed to estimate the horizontal head angular velocity during the GSE trials. The percentage change from the first trial of motion range of the eye and head was calculated for each measurement. The percent change of the eye/head range ratio was calculated to assess the synchronous changes of the eye and head movements as the exercise increased., Results: Bayesian two-way analysis of variance showed that cerebellar rTMS affected the eye motion range and eye/head range ratio. A post hoc comparison (Bayesian t-test) showed evidence that the eye motion range and eye/head range ratio were reduced in the fifth, sixth, and seventh trials compared with the first trial sham stimulation condition., Conclusions: GSEs can modulate eye movements with respect to head movements, and the cerebellum may be associated with eye-head coordination trainability for dynamic gazing during head movements., Competing Interests: Tokuyukai Medical Corporation runs Kansai Rehabilitation Hospital, and employ N.Y. and S.N. as engineer and researcher. Tokuyukai Medical Corporation provided support in the form of salaries for authors N.Y. and S.N., but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The specific roles of these authors are articulated in the ‘author contributions’ section.

A recent phase I-II, open-label trial of ProSavin, a lentiviral vector delivering the key enzymes in the dopamine biosynthetic pathway to non-dopaminergic striatal neurons, demonstrated safety and improved motor function in parkinsonian patients. However, the magnitude of the effect suggested that optimal levels of dopamine replacement may not have been achieved. OXB-102, a lentiviral vector with an optimized expression cassette for dopamine biosynthesis, has been shown to achieve a significantly higher dopamine yield than ProSavin. We assessed the efficacy of OXB-102 in the MPTP macaque model of Parkinson's disease (PD). At 6 months post-vector administration, all treated animals showed significant improvements in clinical scores and spontaneous locomotor activity compared to controls, with the highest recovery observed in the OXB-102 high-dose (HD) group. Positron emission tomography quantification of 6-[ 18 F]-fluoro-L-m-tyrosine uptake showed a significant increase in amino acid decarboxylase activity for all treated animals, compared with controls, where the OXB-102 HD group showed the highest level of dopaminergic activity. A toxicology study in macaques demonstrated that the vector was safe and well tolerated, with no associated clinical or behavioral abnormalities and no immune response mounted against any transgene products. Overall, these data support the further clinical development of OXB-102 for the treatment of PD.

The β-band oscillation in the subthalamic nucleus (STN) is a therapeutic target for Parkinson's disease. Previous studies demonstrated that l-DOPA decreases the β-band (13-30 Hz) oscillations with improvement of motor symptoms. However, it has not been elucidated whether patients with Parkinson's disease are able to control the β-band oscillation voluntarily. Here, we hypothesized that neurofeedback training to control the β-band power in the STN induces plastic changes in the STN of individuals with Parkinson's disease. We recorded the signals from STN deep-brain stimulation electrodes during operations to replace implantable pulse generators in eight human patients (3 male) with bilateral electrodes. Four patients were induced to decrease the β-band power during the feedback training (down-training condition), whereas the other patients were induced to increase (up-training condition). All patients were blinded to their assigned condition. Adjacent contacts that showed the highest β-band power were selected for the feedback. During the 10 min training, patients were shown a circle whose diameter was controlled by the β-band power of the selected contacts. Powers in the β-band during 5 min resting sessions recorded before and after the feedback were compared. In the down-training condition, the β-band power of the selected contacts decreased significantly after feedback in all four patients ( p < 0.05). In contrast, the β-band power significantly increased after feedback in two of four patients in the up-training condition. Overall, the patients could voluntarily control the β-band power in STN in the instructed direction ( p < 0.05) through neurofeedback.

A brachial plexus root avulsion (BPRA) causes intractable pain in the insensible affected hands. Such pain is partly due to phantom limb pain, which is neuropathic pain occurring after the amputation of a limb and partial or complete deafferentation. Previous studies suggested that the pain was attributable to maladaptive plasticity of the sensorimotor cortex. However, there is little evidence to demonstrate the causal links between the pain and the cortical representation, and how much cortical factors affect the pain. Here, we applied lesioning of the dorsal root entry zone (DREZotomy) and training with a brain-machine interface (BMI) based on real-time magnetoencephalography signals to reconstruct affected hand movements with a robotic hand. The DREZotomy successfully reduced the shooting pain after BPRA, but a part of the pain remained. The BMI training successfully induced some plastic changes in the sensorimotor representation of the phantom hand movements and helped control the remaining pain. When the patient tried to control the robotic hand by moving their phantom hand through association with the representation of the intact hand, this especially decreased the pain while decreasing the classification accuracy of the phantom hand movements. These results strongly suggested that pain after the BPRA was partly attributable to cortical representation of phantom hand movements and that the BMI training controlled the pain by inducing appropriate cortical reorganization. For the treatment of chronic pain, we need to know how to modulate the cortical representation by novel methods.

Object: Spinal cord stimulation (SCS) is an effective albeit invasive and relatively expensive treatment of neuropathic pain. Repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) is a non-invasive treatment of neuropathic pain. The aim of the current study was to investigate whether rTMS can predict the successful outcome of SCS., Methods: The study population consisted of 22 patients with neuropathic pain who had undergone SCS and rTMS. We conducted statistical analyses to identify the factors that predict pain reduction following SCS., Results: Multiple regression analyses showed that only degree of pain relief following rTMS was statistically correlated with success in SCS; on the other hand, age, sex, lesion location, pain duration and laterality, and targeted extremities were not correlated. Using receiver-operating characteristic (ROC) curve analyses of the pain relief following rTMS, the diagnostic sensitivity for successful SCS was 0.60 and the specificity was 0.83., Conclusions: The degree of pain relief following rTMS over M1 is a significant prognostic factor of SCS outcome in patients with intractable neuropathic pain., Significance: The current study provides evidence showing that rTMS, a non-invasive and relatively easy to administer procedure, may aid in the selection of suitable candidates for SCS treatment., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: The aim of this study was to investigate the incidence of and risk factors for postoperative delirium (POD) after deep brain stimulation (DBS) surgery in patients with Parkinson disease., Methods: We analyzed the preoperative T1-weighted magnetic resonance imaging data of 71 patients with Parkinson disease who underwent DBS surgery. Multiple regression analysis was performed with age, l-dopa equivalent daily dose, laterality of the surgery, target regions, number of electrode trajectories tried, gray matter volume, and white matter (WM) volume as explanatory variables and the duration (number of days) of POD as the response variable. In addition, regional brain atrophy associated with POD was investigated by means of voxel-based morphometry., Results: Excluding patients with outliers, 61 patients were included in the analyses. POD had occurred in 26 of the 61 patients (42.6%). Age and total WM volume were shown by multiple regression analysis to correlate significantly with the duration of POD (P < 0.05 and < 0.01, respectively). WM was significantly reduced in the temporal stem, and the reduction in volume correlated significantly with the duration of POD (P < 0.001). Gray matter atrophy was not associated with POD., Conclusions: We found that age and WM atrophy in the temporal stem are factors predictive of POD after DBS surgery. In aged patients with temporal stem atrophy, surgical procedures and postoperative management should be carefully explored to reduce the risk of postoperative delirium., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Many reports have shown improvements in motor symptoms after repetitive transcranial magnetic stimulation (rTMS). However, the best stimulation area in the brain has not currently been determined. We assessed the effects of high-frequency rTMS (HF-rTMS) on the motor and mood disturbances in Parkinson's disease (PD) patients and attempted to determine whether the primary motor area (M1), the supplementary motor area (SMA), and the dorsolateral prefrontal cortex (DLPFC) were the best treatment targets. In this randomized, double-blind crossover design study, we investigated the efficacy of 3 consecutive days of HF-rTMS over the M1, SMA, and DLPFC and compared these HF-rTMS to sham stimulations. We used motor and non-motor scales to evaluate the parkinsonian symptoms. The changes in the Unified Parkinson's Disease Rating Scale part III (UPDRS-III) scores after the application of HF-rTMS over the M1 and SMA were significantly greater than those after the sham stimulation. However, after the application of HF-rTMS over the DLPFC, the UPDRS-III scores were similar to those after the sham stimulation. No significant improvements were demonstrated in the mood disturbances after the stimulations over any of the targets. In conclusion, the application of HF-rTMS over the M1 and SMA significantly improved the motor symptoms in the PD patients but did not alter the mood disturbances., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

OBJECTIVE Electrical motor cortex stimulation can relieve neuropathic pain (NP), but its use requires patients to undergo an invasive procedure. Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) using a figure-8 coil can relieve NP noninvasively, but its ability to relieve lower limb pain is still limited. Deep rTMS using an H-coil can effectively stimulate deep brain regions and has been widely used for the treatment of various neurological diseases; however, there have been no clinical studies comparing the effectiveness of figure-8 coils and H-coils. This study assessed the clinical effectiveness of 5 once-daily stimulations with H-coils and figure-8 coils in patients with NP. METHODS This randomized, double-blind, 3-way crossover trial examined 18 patients with NP who sequentially received 3 types of stimulations in the M1 for 5 consecutive days; each 5-day stimulation period was followed by a 17-day follow-up period before crossing over to the next type of stimulation. During each rTMS session, patients received a 5-Hz rTMS to the M1 region corresponding to the painful lower limb. The visual analog scale (VAS) and the Japanese version of the short-form McGill Pain Questionnaire 2 (SF-MPQ2-J) were used to measure pain intensity. The primary outcome was VAS score reduction immediately after and 1 hour after intervention. RESULTS Both the VAS and SF-MPQ2-J showed significant pain improvement immediately after deep rTMS with an H-coil as compared with the sham group (p < 0.001 and p = 0.049, respectively). However, neither outcome measure showed significant pain improvement when using a figure-8 coil. The VAS also showed significant pain improvement 1 hour after deep rTMS with an H-coil (p = 0.004) but not 1 hour after rTMS using a figure-8 coil. None of the patients exhibited any serious adverse events. CONCLUSIONS The current findings suggest that the use of deep rTMS with an H-coil in the lower limb region of the M1 in patients with NP was tolerable and could provide significant short-term pain relief. Clinical trial registration no.: UMIN000010536 ( http://www.umin.ac.jp/ctr/ ).

Objective: Selective amygdalohippocampectomy (SAH) can be used to obtain satisfactory seizure control in patients with mesial temporal lobe epilepsy (MTLE). Several SAH procedures have been reported to achieve satisfactory outcomes for seizure control, but none yield fully satisfactory outcomes for memory function. We hypothesized that preserving the temporal stem might play an important role. To preserve the temporal stem, we developed a minimally invasive surgical procedure, 'neuronavigation-assisted trans-inferotemporal cortex SAH' (TITC-SAH)., Methods: TITC-SAH was performed in 23 patients with MTLE (MTLE on the language-non-dominant hemisphere, n = 11). The inferior horn of the lateral ventricle was approached via the inferior or middle temporal gyrus along the inferior temporal sulcus under neuronavigation guidance. The hippocampus was dissected in a subpial manner and resected en bloc together with the parahippocampal gyrus. Seizure control at one year and memory function at 6 months postoperatively were evaluated., Results: One year after TITC-SAH, 20 of the 23 patients were seizure-free (ILAE class 1), 2 were class 2, and 1 was class 3. Verbal memory improved significantly in 13 patients with a diagnosis of hippocampal sclerosis, for whom WMS-R scores were available both pre- and post-operatively. Improvements were seen regardless of whether the SAH was on the language-dominant or non-dominant hemisphere. No major complication was observed., Conclusion: Navigation-assisted TITC-SAH performed for MTLE offers a simple, minimally invasive procedure that appears to yield excellent outcomes in terms of seizure control and preservation of memory function, because this procedure does not damage the temporal stem. TITC-SAH should be one of the feasible surgical procedures for MTLE., Abbreviations: SAH: Amygdalohippocampectomy; MTLE: Mesial temporal lobe epilepsy (MTLE); TITC-SAH: Ttrans-inferotemporal cortex SAH; ILAE: International League Against Epilepsy (ILAE); MRI: Magnetic resonance imaging; EEG: Electroencephalography (EEG); FDG-PET: 8 F-fluorodeoxyglucose (FDG)-positron emission tomography; ECoG: Electrocorticography; MEG: Magnetoencephalography; IMZ-SPECT: N-isopropyl-p( 123 I)-iodoamphetamine single photon emission computed tomography; WMS-R: Wechsler Memory Scale-Revised.

OBJECTIVE Epilepsy surgery is of known benefit for drug-resistant temporal lobe epilepsy (TLE); however, a certain number of patients suffer significant decline in verbal memory after hippocampectomy. To prevent this disabling complication, a reliable test for predicting postoperative memory decline is greatly desired. Therefore, the authors assessed the value of electrical stimulation of the parahippocampal gyrus (PHG) as a provocation test of verbal memory decline after hippocampectomy on the dominant side. METHODS Eleven right-handed, Japanese-speaking patients with medically intractable left TLE participated in the study. Before surgery, they underwent provocative testing via electrical stimulation of the left PHG during a verbal encoding task. Their pre- and posthippocampectomy memory function was evaluated according to the Wechsler Memory Scale-Revised (WMS-R) and/or Mini-Mental State Examination (MMSE) before and 6 months after surgery. The relationship between postsurgical memory decline and results of the provocative test was evaluated. RESULTS Left hippocampectomy was performed in 7 of the 11 patients. In 3 patients with a positive provocative recognition test, verbal memory function, as assessed by the WMS-R, decreased after hippocampectomy, whereas in 4 patients with a negative provocative recognition test, verbal memory function, as assessed by the WMS-R or MMSE, was preserved. CONCLUSIONS Results of the present study suggest that electrical stimulation of the PHG is a reliable provocative test to predict posthippocampectomy verbal memory decline.

The cause of pain in a phantom limb after partial or complete deafferentation is an important problem. A popular but increasingly controversial theory is that it results from maladaptive reorganization of the sensorimotor cortex, suggesting that experimental induction of further reorganization should affect the pain, especially if it results in functional restoration. Here we use a brain-machine interface (BMI) based on real-time magnetoencephalography signals to reconstruct affected hand movements with a robotic hand. BMI training induces significant plasticity in the sensorimotor cortex, manifested as improved discriminability of movement information and enhanced prosthetic control. Contrary to our expectation that functional restoration would reduce pain, the BMI training with the phantom hand intensifies the pain. In contrast, BMI training designed to dissociate the prosthetic and phantom hands actually reduces pain. These results reveal a functional relevance between sensorimotor cortical plasticity and pain, and may provide a novel treatment with BMI neurofeedback.

OBJECTIVE Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established therapy for motor symptoms in patients with pharmacoresistant Parkinson's disease (PD). However, the procedure, which requires multimodal perioperative exploration such as imaging, electrophysiology, or clinical examination during macrostimulation to secure lead positioning, remains challenging because the STN cannot be reliably visualized using the gold standard, T2-weighted imaging (T2WI) at 1.5 T. Thus, there is a need to improve imaging tools to better visualize the STN, optimize DBS lead implantation, and enlarge DBS diffusion. METHODS Gradient-echo sequences such as those used in T2WI suffer from higher distortions at higher magnetic fields than spin-echo sequences. First, a spin-echo 3D SPACE (sampling perfection with application-optimized contrasts using different flip angle evolutions) FLAIR sequence at 3 T was designed, validated histologically in 2 nonhuman primates, and applied to 10 patients with PD; their data were clinically compared in a double-blind manner with those of a control group of 10 other patients with PD in whom STN targeting was performed using T2WI. RESULTS Overlap between the nonhuman primate STNs segmented on 3D-histological and on 3D-SPACE-FLAIR volumes was high for the 3 most anterior quarters (mean [± SD] Dice scores 0.73 ± 0.11, 0.74 ± 0.06, and 0.60 ± 0.09). STN limits determined by the 3D-SPACE-FLAIR sequence were more consistent with electrophysiological edges than those determined by T2WI (0.9 vs 1.4 mm, respectively). The imaging contrast of the STN on the 3D-SPACE-FLAIR sequence was 4 times higher (p < 0.05). Improvement in the Unified Parkinson's Disease Rating Scale Part III score (off medication, on stimulation) 12 months after the operation was higher for patients who underwent 3D-SPACE-FLAIR-guided implantation than for those in whom T2WI was used (62.2% vs 43.6%, respectively; p < 0.05). The total electrical energy delivered decreased by 36.3% with the 3D-SPACE-FLAIR sequence (p < 0.05). CONCLUSIONS 3D-SPACE-FLAIR sequences at 3 T improved STN lead placement under stereotactic conditions, improved the clinical outcome of patients with PD, and increased the benefit/risk ratio of STN-DBS surgery.

Objectives: Intrathecal baclofen (ITB) therapy is an effective treatment for patients with severe spasticity. However, the effect of ITB therapy on respiratory function has not been reported in detail. In this study we quantitatively analyzed the effects of ITB on the respiratory function of patients with spastic tetraplegia., Methods: We retrospectively reviewed 23 patients who were administrated ITB therapy from January 2009 to December 2012. Six of these 23 patients, who had spastic tetraplegia and were able to undergo spirometric testing, were included this study. The spasticity derived from cervical spinal cord injury in four patients and cerebral palsy (CP) in two patients. Patients' Ashworth Scale scores and spirometer measurements obtained before and 1-6 months after the start of ITB therapy were evaluated and compared., Results: Before ITB therapy, %FVC of all six patients was below 80%, and a restrictive respiratory disorder was diagnosed in five patients and a combined respiratory disorder in one patient. Ashworth Scale scores for both the lower and upper extremities improved significantly with ITB therapy. Forced vital capacity (FVC), %FVC, and forced expiratory volume at one sec also improved significantly with ITB therapy., Conclusions: Respiratory disorders were indeed present in our SCI and CP patients with spastic tetraplegia, and the respiratory function of these patients improved with ITB therapy. Our results suggest that ITB therapy is safe and efficacious in patients with spastic tetraplegia and respiratory dysfunction., (© 2016 International Neuromodulation Society.)

Background: We conducted a randomized, double-blind, sham-controlled study to assess the efficacy in motor recovery and safety of daily repetitive transcranial magnetic stimulation (rTMS) in subacute stroke patients., Methods: Forty-one patients were randomly assigned to a real or sham stimulation group. Each patient underwent regular rehabilitation accompanied by a series of 10 daily 5-Hz rTMS of the ipsilesional primary motor cortex (M1) or sham stimulation. The primary outcome was motor recovery evaluated by the Brunnstrom stages (BS). The secondary outcomes were improvement in the Fugl-Meyer Assessment (FMA), grip power, National Institutes of Health Stroke Scale (NIHSS), Functional Independence Measure (FIM), a quantitative measurement of finger tapping movement, and the incidence of adverse events., Results: Thirty-nine patients completed the study and were included in the analyses. The real rTMS group demonstrated additional improvement in the BS hand score at the last follow-up compared to the sham. The grip power, the NIHSS motor score, and the number of finger taps in the affected hand improved in the real stimulation group but not in the sham group. The BS upper limb scores, the FMA distal upper limb score, the NIHSS total score, and the FIM motor score showed improvement from baseline at the earlier time points after the real rTMS. There were no additional improvements in the other scores after the real rTMS compared to the sham. No serious adverse events were observed., Conclusions: Our results suggest that dailyhigh-frequency rTMS of the ipsilesional M1 is tolerable and modestly facilitates motor recovery in the paralytic hand of subacute stroke patients., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Recent studies of spinal cord axon regeneration have reported good long-term results using various types of tissue scaffolds. Olfactory tissue allows autologous transplantation and can easily be obtained by a simple biopsy that is performed through the external nares. We performed a clinical pilot study of olfactory mucosa autograft (OMA) for chronic complete spinal cord injury in eight patients according to the procedure outlined by Lima et al. Our results showed no serious adverse events and improvement in both the American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade and ASIA motor score in five patients. The preoperative post-rehabilitation ASIA motor score improved from 50 in all cases to 52 in case 2, 60 in case 4, 52 in case 6, 55 in case 7, and 58 in case 8 at 96 weeks after OMA. The AIS improved from A to C in four cases and from B to C in one case. Motor evoked potentials (MEPs) were also seen in one patient, reflecting conductivity in the central nervous system, including the corticospinal tract. The MEPs induced with transcranial magnetic stimulation allow objective assessment of the integrity of the motor circuitry comprising both the corticospinal tract and the peripheral motor nerves.We show the feasibility of OMA for chronic complete spinal cord injury.