Identification of Somatotopic Organization and Optimal Stimulation Site Within the Subthalamic Nucleus for Parkinson's Disease.

BACKGROUND: Details of the somatotopy within the subthalamic nucleus (STN) are still poorly understood; however, the STN is a common target of deep brain stimulation (DBS) for Parkinson disease. OBJECTIVE: To examine somatotopic organization within the STN and identify optimal stimulation sites from 77 surgical cases with microelectrode recording. METHODS: STN-DBS was performed for 77 patients with Parkinson disease between 2010 and 2014. We performed passive movements of each joint and captured single neuronal activities to identify movement-related cells (MRCs). The sites of MRCs and active contacts were determined by measuring their distances from the first contact of DBS electrode. Their positional correlations were directly and indirectly analyzed. RESULTS: The number of obtained MRCs was 264, of which 151 responded to multiple joints. The average x-, y-, and z-coordinates of the cells of the upper and lower limbs from the midcommisural point were 13.1 ± 1.1 and 12.7 ± 1.2, 0.22 ± 1.3 and -0.45 ± 1.5, and -2.5 ± 1.1 and -3.0 ± 1.4 mm, respectively. Most MRCs were distributed in the upper third of the STN, in its superior, lateral, and posterior regions, along the DBS electrode routes. Active contacts were observed to lie slightly inferior, medial, and posterior to the average MRC position. CONCLUSION: Somatotopic organization of the STN was easier to observe in the present study than in previous studies. Optimal stimulation sites were located inferior, medial, and posterior to the average MRC location. The sites may correspond to associative or motor parts through which fibers from the supplementary motor area pass.

Efficacy of Dural Sealant System for Preventing Brain Shift and Improving Accuracy in Deep Brain Stimulation Surgery.

The success of deep brain stimulation (DBS) depends heavily on surgical accuracy, and brain shift is recognized as a significant factor influencing accuracy. We investigated the factors associated with surgical accuracy and showed the effectiveness of a dural sealant system for preventing brain shift in 32 consecutive cases receiving DBS. Thirty-two patients receiving DBS between March 2014 and May 2015 were included in this study. We employed conventional burr hole techniques for the first 18 cases (Group I) and a dural sealant system (DuraSeal) for the subsequent 14 cases (Group II). We measured gaps between the actual positions of electrodes and the predetermined target positions. We then retrospectively evaluated the factors involved in surgical accuracy. The average gap between an electrode's actual and target positions was 1.55 ± 0.83 mm in all cases. Postoperative subdural air volume e, the only factor associated with surgical accuracy (r = 0.536, P < 0.0001), was significantly smaller in Group II (Group I: 43.9 ± 27.7, Group II: 12.1 ± 12.5 ml, P = 0.0006). The average electrode position gap was also significantly smaller in Group II (Group I: 1.77 ± 0.91, Group II: 1.27 ± 0.59 mm, P = 0.035). Use of a dural sealant system could significantly reduce intracranial air volume, which should improve surgical accuracy.

Efficacy of Fiber Tractography in the Stereotactic Surgery of the Thalamus for Patients with Essential Tremor.

Several targets and targeting methods are utilized in stereotactic surgery to achieve tremor suppression for patients with intractable tremor. Recent developments in magnetic resonance imaging, including diffusion tensor imaging, have enabled the setting of appropriate targets in stereotactic surgery. In this retrospective study, the optimal target to suppress tremors in stereotactic surgery was explored using diffusion tensor image-based fiber tractography. Four tracts were focused on in this study, namely: the cerebello-thalamo-premotor cortical fiber tract, cerebello-thalamo-primary motor cortical fiber tract, spino-thalamo-somatosensory cortical fiber tract, and pyramidal tract. In 10 patients with essential tremor, we evaluated the thalamotomy lesions and active contacts of the lead in thalamic stimulation by diffusion tensor image-based fiber tractography to reveal which part of the cerebral cortex is most affected by stereotactic surgery. Tremor suppression and adverse events were also evaluated in the patients involved in this study. Consequently, the good tremor suppression was achieved in all patients. There had been no permanent adverse events 3 months after surgery. Twelve lesions in thalamotomy patients or active contacts of the lead in thalamic stimulation patients were on the cerebello-thalamo-premotor cortical fiber tract (12/14 lesions or active contacts: 86%). In conclusion, the cerebello-thalamo-premotor cortical fiber tract may be an optimal target for tremor suppression. Diffusion tensor image-based fiber tractography may enable us to both determine the optimal target to achieve strong tremor suppression and to reduce the number of adverse events by keeping lesions or electrodes away from important fiber tracts, such as the pyramidal tract and spinothalamic fibers.

Perioperative Management Center (PERIO) for Neurosurgical Patients.

Perioperative management is critical for positive neurosurgical outcomes. In order to maintain safe and authentic perioperative management, a perioperative management center (PERIO) was introduced to patients of our Neurosurgery Department beginning in June 2014. PERIO involves a multidisciplinary team consisting of anesthesiologists, dentists/dental hygienists/technicians, nurses, physical therapists, pharmacists, and nutritionists. After neurosurgeons decide on the course of surgery, a preoperative evaluation consisting of blood sampling, electrocardiogram, chest X-ray, and lung function test was performed. The patients then visited the PERIO clinic 7-14 days before surgery. One or two days before surgery, the patients without particular issues enter the hospital and receive a mouth cleaning one day before surgery. After surgery, postoperative support involving eating/swallowing evaluation, rehabilitation, and pain control is provided. The differences in duration from admission to surgery, cancellation of surgery, and postoperative complications between PERIO and non-PERIO groups were examined. Eighty-five patients were enrolled in the PERIO group and 131 patients in the non-PERIO group. The duration from admission to surgery was significantly decreased in the PERIO group (3.6 ± 0.3 days), compared to that in the non-PERIO group (4.7 ± 0.2 days). There was one cancelled surgery in the PERIO group and six in the non-PERIO group. Postoperative complications and the overall hospital stay did not differ between the two groups. The PERIO system decreased the duration from admission to surgery, and it is useful in providing high-quality medical service, although the system should be improved so as not to increase the burden on medical staff.

Anti-high mobility group box 1 antibody exerts neuroprotection in a rat model of Parkinson's disease.

The high mobility group box-1 (HMGB1) exists as an architectural nuclear protein in the normal state, but displays an inflammatory cytokine-like activity in the extracellular space under pathological condition. Inflammation in the pathogenesis of Parkinson's disease (PD) has been documented. In this study, we investigated the involvement of HMGB1 in the pathology and the neuroprotective effects of neutralizing anti-HMGB1 monoclonal antibody (mAb) on an animal model of PD. Adult female Sprague-Dawley rats were initially injected with 6-hydroxydopmaine (6-OHDA, 20 µg/4 µl) into the right striatum, then anti-HMGB1 mAb (1 mg/kg), or control mAb was intravenously administered immediately, at 6 and 24 h after 6-OHDA injection. The treatment with anti-HMGB1 mAb significantly preserved dopaminergic neurons in substantia nigra pars compacta and dopaminergic terminals inherent in the striatum, and attenuated PD behavioral symptoms compared to the control mAb-treated group. HMGB1 was retained in the nucleus of neurons and astrocytes by inhibiting the proinflammation-induced oxidative stress in the anti-HMGB1 mAb-treated group, whereas HMGB1 translocation was observed in neurons at 1 day and astrocytes at 7 days after 6-OHDA injection in the control mAb-treated group. Anti-HMGB1 mAb inhibited the activation of microglia, disruption of blood-brain-barrier (BBB), and the expression of inflammation cytokines such as IL-1ß and IL-6. These results suggested that HMGB1 released from neurons and astrocytes was at least partly involved in the mechanism and pathway of degeneration of dopaminergic neurons induced by 6-OHDA exposure. Intravenous administration of anti-HMGB1 mAb stands as a novel therapy for PD possibly acting through the suppression of neuroinflammation and the attenuation of disruption of BBB associated with the disease.

Intra-Arterial Transplantation of Allogeneic Mesenchymal Stem Cells Mounts Neuroprotective Effects in a Transient Ischemic Stroke Model in Rats: Analyses of Therapeutic Time Window and Its Mechanisms.

OBJECTIVE: Intra-arterial stem cell transplantation exerts neuroprotective effects for ischemic stroke. However, the optimal therapeutic time window and mechanisms have not been completely understood. In this study, we investigated the relationship between the timing of intra-arterial transplantation of allogeneic mesenchymal stem cells (MSCs) in ischemic stroke model in rats and its efficacy in acute phase. METHODS: Adult male Wistar rats weighing 200 to 250 g received right middle cerebral artery occlusion (MCAO) for 90 minutes. MSCs (1 × 10(6) cells/ 1 ml PBS) were intra-arterially injected at either 1, 6, 24, or 48 hours (1, 6, 24, 48 h group) after MCAO. PBS (1 ml) was intra-arterially injected to control rats at 1 hour after MCAO. Behavioral test was performed immediately after reperfusion, and at 3, 7 days after MCAO using the Modified Neurological Severity Score (mNSS). Rats were euthanized at 7 days after MCAO for evaluation of infarct volumes and the migration of MSCs. In order to explore potential mechanisms of action, the upregulation of neurotrophic factor and chemotactic cytokine (bFGF, SDF-1α) induced by cell transplantation was examined in another cohort of rats that received intra-arterial transplantation at 24 hours after recanalization then euthanized at 7 days after MCAO for protein assays. RESULTS: Behavioral test at 3 and 7 days after transplantation revealed that stroke rats in 24h group displayed the most robust significant improvements in mNSS compared to stroke rats in all other groups (p's<0.05). Similarly, the infarct volumes of stroke rats in 24h group were much significantly decreased compared to those in all other groups (p's<0.05). These observed behavioral and histological effects were accompanied by MSC survival and migration, with the highest number of integrated MSCs detected in the 24h group. Moreover, bFGF and SDF-1α levels of the infarcted cortex were highly elevated in the 24h group compared to control group (p's<0.05). CONCLUSIONS: These results suggest that intra-arterial allogeneic transplantation of MSCs provides post-stroke functional recovery and reduction of infarct volumes in ischemic stroke model of rats. The upregulation of bFGF and SDF-1α likely played a key mechanistic role in enabling MSC to afford functional effects in stroke. MSC transplantation at 24 hours after recanalization appears to be the optimal timing for ischemic stroke model, which should guide the design of clinical trials of cell transplantation for stroke patients.

Spinal cord stimulation exerts neuroprotective effects against experimental Parkinson's disease.

In clinical practice, deep brain stimulation (DBS) is effective for treatment of motor symptoms in Parkinson's disease (PD). However, the mechanisms have not been understood completely. There are some reports that electrical stimulation exerts neuroprotective effects on the central nervous system diseases including cerebral ischemia, head trauma, epilepsy and PD, although there are a few reports on neuroprotective effects of spinal cord stimulation (SCS). We investigated the neuroprotective effects of high cervical SCS on PD model of rats. Adult female Sprague-Dawley rats received hour-long SCS (2, 50 or 200 Hz) with an epidural electrode at C1-2 level for 16 consecutive days. At 2 days after initial SCS, 6-hydroxydopamine (6-OHDA) was injected into the right striatum of rats. Behavioral evaluations of PD symptoms were employed, including cylinder test and amphetamine-induced rotation test performed at 1 and 2 weeks after 6-OHDA injection. Animals were subsequently euthanized for immunohistochemical investigations. In order to explore neurotrophic and growth factor upregulation induced by SCS, another cohort of rats that received 50 Hz SCS was euthanized at 1 and 2 weeks after lesion for protein assays. Behavioral tests revealed that the number of amphetamine-induced rotations decreased in SCS groups. Immunohistochemically, tyrosine hydroxylase (TH)-positive fibers in the striatum were significantly preserved in SCS groups. TH-positive neurons in the substantia nigra pars compacta were significantly preserved in 50 Hz SCS group. The level of vascular endothelial growth factor (VEGF) was upregulated by SCS at 1 week after the lesion. These results suggest that high cervical SCS exerts neuroprotection in PD model of rats, at least partially by upregulation of VEGF. SCS is supposed to suppress or delay PD progression and might become a less invasive option for PD patients, although further preclinical and clinical investigations are needed to confirm the effectiveness and safety.

Cognitive functions in Parkinson's disease: relation to disease severity and hallucination.

OBJECTIVE: We wished to relate severity of Parkinson's disease (PD) with cognitive function in relation to cerebral blood flow (CBF). METHODS: Eighty-one consecutive PD patients were enrolled in this study. We used Mini-Mental State Examination (MMSE) and Wechsler Adult Intelligence Scale-Third edition (WAIS-III) to evaluate cognitive functions, and three-dimensional stereotactic ROI template (3DSRT) and Statistical Parametric Mapping (SPM) 8 to evaluate single photon emission CT (SPECT) recordings of regional CBF. RESULTS: The mean MMSE score of PD patients was 27.4 ± 2.4. The scores of most patients were higher than 23/30. On the other hand, the mean Full-scale IQ of PD patients was 88.4 ± 17.3 in WAIS-III, which was lower than that of normal controls. In particular, visuospatial function score of most patients was lower. There was significant correlation between cognitive scores and Hoehn & Yahr stage and hallucinatory episodes. PD Patients with stage III and IV showed significant deterioration in cognitive functions compared to stage II patients. Analysis of CBF revealed relative reductions in perfusion in the cerebral cortex relative to that in normal control. SPM 8 showed that cognitive functions in PD patients were positively correlated with rCBF in the thalamus and cingulate gyrus. CONCLUSIONS: This is the study to demonstrate the cognitive impairments in PD patients using WAIS-III. Visuospatial dysfunction might be caused by decrease in rCBF in the parietal and occipital lobes and dorsolateral prefrontal cortex. The severity of cognitive impairments in PD patients was correlated with disease severity and hallucinatory episodes.

Regenerative medicine for epilepsy: from basic research to clinical application.

Epilepsy is a chronic neurological disorder, which presents with various forms of seizures. Traditional treatments, including medication using antiepileptic drugs, remain the treatment of choice for epilepsy. Recent development in surgical techniques and approaches has improved treatment outcomes. However, several epileptic patients still suffer from intractable seizures despite the advent of the multimodality of therapies. In this article, we initially provide an overview of clinical presentation of epilepsy then describe clinically relevant animal models of epilepsy. Subsequently, we discuss the concepts of regenerative medicine including cell therapy, neuroprotective agents, and electrical stimulation, which are reviewed within the context of our data.

Neuroprotective effects of liraglutide for stroke model of rats.

The number of diabetes mellitus (DM) patients is increasing, and stroke is deeply associated with DM. Recently, neuroprotective effects of glucagon-like peptide-1 (GLP-1) are reported. In this study, we explored whether liraglutide, a GLP-1 analogue exerts therapeutic effects on a rat stroke model. Wistar rats received occlusion of the middle cerebral artery for 90 min. At one hour after reperfusion, liraglutide or saline was administered intraperitoneally. Modified Bederson's test was performed at 1 and 24 h and, subsequently, rats were euthanized for histological investigation. Peripheral blood was obtained for measurement of blood glucose level and evaluation of oxidative stress. Brain tissues were collected to evaluate the level of vascular endothelial growth factor (VEGF). The behavioral scores of liraglutide-treated rats were significantly better than those of control rats. Infarct volumes of liraglutide-treated rats at were reduced, compared with those of control rats. The level of derivatives of reactive oxygen metabolite was lower in liraglutide-treated rats. VEGF level of liraglutide-treated rats in the cortex, but not in the striatum significantly increased, compared to that of control rats. In conclusion, this is the first study to demonstrate neuroprotective effects of liraglutide on cerebral ischemia through anti-oxidative effects and VEGF upregulation.

The neuroprotective and neurorescue effects of carbamylated erythropoietin Fc fusion protein (CEPO-Fc) in a rat model of Parkinson's disease.

Parkinson's disease is characterized by progressive degeneration of dopaminergic neurons. Thus the development of therapeutic neuroprotection and neurorescue strategies to mitigate disease progression is important. In this study we evaluated the neuroprotective/rescue effects of erythropoietin Fc fusion protein (EPO-Fc) and carbamylated erythropoietin Fc fusion protein (CEPO-Fc) in a rat model of Parkinson's disease. Adult female Sprague-Dawley rats received intraperitoneal injection of EPO-Fc, CEPO-Fc or PBS. Behavioral evaluations consisted of rota-rod, cylinder and amphetamine-induced rotation tests. In the neuroprotection experiment, the CEPO-Fc group demonstrated significant improvement compared with the EPO-Fc group on the amphetamine-induced rotation test throughout the four-week follow-up period. Histologically, significantly more tyrosine hydroxylase (TH)-positive neurons were recognized in the substantia nigra (SN) pars compacta in the CEPO-Fc group than in the PBS and EPO-Fc groups. In the neurorescue experiment, rats receiving CEPO-Fc showed significantly better behavioural scores than those receiving PBS. The histological data concerning striatum also showed that the CEPO-Fc group had significantly better preservation of TH-positive fibers compared to the PBS and EPO-Fc groups. Importantly, there were no increases in hematocrit or hemoglobin levels in the CEPO-Fc group in either the neuroprotection or the neurorescue experiments. In conclusion, the newly developed CEPO-Fc might confer neuroprotective and neurorescue benefits in a rat model of Parkinson's disease without the side effects associated with polycythemia. CEPO-Fc might be a therapeutic tool for patients with Parkinson's disease.

BDNF-secreting capsule exerts neuroprotective effects on epilepsy model of rats.

Brain-derived neurotrophic factor (BDNF) is a well neurotrophic factor with neuroprotective potentials for various diseases in the central nervous system. However several previous studies demonstrated that BDNF might deteriorate symptoms for epilepsy model of animals by progression of abnormal neurogenesis. We hypothesized that continuous administration of BDNF at low dose might be more effective for epilepsy model of animals because high dose of BDNF was used in many studies. BDNF-secreting cells were genetically made and encapsulated for transplantation. Rats receiving BDNF capsule showed significant amelioration of seizure stage and reduction of the number of abnormal spikes at 7 days after kainic acid administration, compared to those of control group. The number of BrdU and BrdU/doublecortin positive cells in the hippocampus of BDNF group significantly increased, compared to that of control group. NeuN positive cells in the CA1 and CA3 of BDNF group were significantly preserved, compared to control group. In conclusion, low dose administration using encapsulated BDNF-secreting cells exerted neuroprotective effects with enhanced neurogenesis on epilepsy model of rats. These results might suggest the importance of the dose and administrative way of this neurotrophic factor to the epilepsy model of animals.