Excess intracellular ATP causes neuropathic pain following spinal cord injury.

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.

Altered Thalamic Connectivity Due to Focused Ultrasound Thalamotomy in Patients with Essential Tremor.

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.

[Stereotactic Surgery for Tremor].

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.

Lumbar Catheter Misplacement into the Spinal Subdural Epiarachnoid Space Causing Lumboperitoneal Shunt Malfunction: Report of Two Cases.

Lumboperitoneal (LP) shunting is a standard treatment for idiopathic normal pressure hydrocephalus (iNPH), with equivalent efficacy to ventriculoperitoneal (VP) shunting, and it is associated with a favorable outcome in approximately 75% of patients with iNPH. Despite the advantages, LP shunting can result in problems associated with the lumbar catheter, the obstruction of which has not been well described. This report presents two cases of LP shunt malfunction caused by lumbar catheter misplacement into the spinal subdural epiarachnoid space (SSES), and by subsequent obstruction. A 67-year-old man and a 69-year-old woman with iNPH underwent LP shunt placement without intraoperative fluoroscopy. Shortly after the surgery, they experienced a temporary improvement of their symptoms which was, however, followed by recurrence within a few months. This was suggestive of shunt malfunction. Although shunt pumping tests were normal, shuntography and subsequent computed tomography (CT) revealed lumbar catheter misplacement into the SSES. Shunt revisions, in which only the lumbar catheters were exchanged, were performed with intraoperative fluoroscopy and shuntography. Their symptoms have improved again following the revisions. In the present cases, lumbar catheter misplacement into the SSES caused LP shunt malfunction, and shuntography and CT were useful to detect the abnormality. Moreover, unrecognized lumbar catheter misplacement into the SSES might potentially have occurred in some patients considered as "non-responders" to LP shunting; hence, shuntography may be useful in those patients.

Pilot study of repetitive transcranial magnetic stimulation in patients with chemotherapy-induced peripheral neuropathy.

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.

Risk Factors for Postoperative Delirium After Deep Brain Stimulation Surgery for Parkinson Disease.

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.

Efficacy of deep rTMS for neuropathic pain in the lower limb: a randomized, double-blind crossover trial of an H-coil and figure-8 coil.

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/ ).

Navigation-assisted trans-inferotemporal cortex selective amygdalohippocampectomy for mesial temporal lobe epilepsy; preserving the temporal stem.

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: 8F-fluorodeoxyglucose (FDG)-positron emission tomography; ECoG: Electrocorticography; MEG: Magnetoencephalography; IMZ-SPECT: N-isopropyl-p(123I)-iodoamphetamine single photon emission computed tomography; WMS-R: Wechsler Memory Scale-Revised.

A Pilot Clinical Study of Olfactory Mucosa Autograft for Chronic Complete Spinal Cord Injury.

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.

Three-dimensional SPACE fluid-attenuated inversion recovery at 3 T to improve subthalamic nucleus lead placement for deep brain stimulation in Parkinson's disease: from preclinical to clinical studies.

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.

Electrical stimulation of the parahippocampal gyrus for prediction of posthippocampectomy verbal memory decline.

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.

Modulating the pain network--neurostimulation for central poststroke pain.

Central poststroke pain (CPSP) is one of the most under-recognized consequences of stroke, occurring in up to 10% of patients, and is also one of the most difficult to treat. The condition characteristically develops after selective lesions to the spinothalamic system, most often to the ventral posterior thalamus. Here, we suggest that CPSP is best characterized as a disorder of brain network reorganization, and that this characterization offers insight into the inadequacy of most current pharmacological treatments. Accordingly, we review the progress in identification of nonpharmacological treatments, which could ultimately lead to mechanism-based therapeutics. Of the invasive neurostimulation treatments available, electrical motor cortex stimulation seems to be superior to deep brain stimulation of the thalamus or brainstem, but enthusiasm for clinical use of the procedure is limited by its invasiveness. The current preference is for noninvasive transcranial magnetic stimulation, which, though effective, requires repeated application, causing logistical difficulties. Although CPSP is often severe and remains difficult to treat, future characterization of the precise underlying neurophysiological mechanisms, together with technological innovation, should allow new treatments to evolve.

Modulation of neuronal activity after spinal cord stimulation for neuropathic pain; H(2)15O PET study.

Spinal cord stimulation (SCS) is an effective therapy for chronic neuropathic pain. However, the detailed mechanisms underlying its effects are not well understood. Positron emission tomography (PET) with H(2)(15)O was applied to clarify these mechanisms. Nine patients with intractable neuropathic pain in the lower limbs were included in the study. All patients underwent SCS therapy for intractable pain, which was due to failed back surgery syndrome in three patients, complex regional pain syndrome in two, cerebral hemorrhage in two, spinal infarction in one, and spinal cord injury in one. Regional cerebral blood flow (rCBF) was measured by H(2)(15)O PET before and after SCS. The images were analyzed with statistical parametric mapping software (SPM2). SCS reduced pain; visual analog scale values for pain decreased from 76.1+/-25.2 before SCS to 40.6+/-4.5 after SCS (mean+/-SE). Significant rCBF increases were identified after SCS in the thalamus contralateral to the painful limb and in the bilateral parietal association area. The anterior cingulate cortex (ACC) and prefrontal areas were also activated after SCS. These results suggest that SCS modulates supraspinal neuronal activities. The contralateral thalamus and parietal association area would regulate the pain threshold. The ACC and prefrontal areas would control the emotional aspects of intractable pain, resulting in the reduction of neuropathic pain after SCS.

Movement induces suppression of interictal spikes in sensorimotor neocortical epilepsy.

Epileptic activities are known to be modulated by cortical excitability, which is altered with normal brain functioning such as movement. However, the relationship between the epileptic activity and movement has not been well studied. Here, we investigated movement-induced modulation of interictal spikes to reveal the relationship between epileptic activity and the movement-induced modulation of cortical activity. Two patients (three cases) with focal cortical dysplasia (FCD) of the pre- and/or post-central gyrus performed voluntary movements of their hands or mouths. During the movement, the interictal spikes of the sensorimotor cortex, which were measured by electrocorticograms (ECoG), were significantly reduced. This reduction strongly correlated with the event-related desynchronization (ERD) of the cortical oscillatory activity at the lower frequency bands (<25 Hz) during movement. The epileptic activity was suggested to be modulated by the movement, which correlates with the ERD of the cortical oscillatory activity.