Publications by authors named "Akio Takahashi"

52 Publications

Thalamic anterior part of the ventral posterolateral nucleus and central lateral nucleus in the genesis of central post-stroke pain.

Acta Neurochir (Wien) 2021 May 14. Epub 2021 May 14.

Department of Neurosurgery, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.

Background: The genesis of central post-stroke pain (CPSP) is important but difficult to understand. We evaluated the involvement of the thalamic anterior part of the ventral posterolateral nucleus (VPLa) and central lateral nucleus (CL) in the occurrence of CPSP.

Method: Stereotactic thalamotomy was performed on the posterior part of the ventral lateral nucleus (VLp)-VPLa and CL in 9 patients with CPSP caused by deep-seated intracerebral hemorrhage. Computed tomography (CT) did not reveal definite thalamic lesion in 5 patients but did in 4 patients. Electrophysiological studies of these thalamic nuclei were carried out during the surgery. Anatomical studies using CT were performed in another 20 patients with thalamic hemorrhage who had clear consciousness but had sensory disturbance at onset.

Results: Neural activities were preserved and hyperactive and unstable discharges (HUDs) were often recognized along the trajectory in the thalamic VLp-VPLa in 5 patients without thalamic lesion. Surgical modification of this area ameliorated pain, particularly movement-related pain. Neural activities were hypoactive in the other 4 patients with thalamic lesion. However, neural activities were preserved and HUDs were sometimes recognized in the CL. Sensory responses were seen, but at low rate, in the sensory thalamus. Anatomical study showed that the thalamic lesion was obviously smaller in the patients with developing pain in the chronic stage.

Conclusions: Change in neural activities around the cerebrovascular disease lesion in the thalamic VPLa or CL might affect the perception of sensory impulses or sensory processing in those thalamic nuclei, resulting in the genesis of CPSP.
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http://dx.doi.org/10.1007/s00701-021-04743-0DOI Listing
May 2021

Cognitive and developmental outcomes after pediatric insular epilepsy surgery for focal cortical dysplasia.

J Neurosurg Pediatr 2020 Aug 7:1-9. Epub 2020 Aug 7.

Departments of1Neurosurgery and.

Objective: Cognitive risk associated with insular cortex resection is not well understood. The authors reviewed cognitive and developmental outcomes in pediatric patients who underwent resection of the epileptogenic zone involving the insula.

Methods: A review was conducted of 15 patients who underwent resective epilepsy surgery involving the insular cortex for focal cortical dysplasia, with a minimum follow-up of 12 months. The median age at surgery was 5.6 years (range 0.3-13.6 years). Developmental/intelligence quotient (DQ/IQ) scores were evaluated before surgery, within 4 months after surgery, and at 12 months or more after surgery. Repeated measures multivariate ANOVA was used to evaluate the effects on outcomes of the within-subject factor (time) and between-subject factors (resection side, anterior insular resection, seizure control, and antiepileptic drug [AED] reduction).

Results: The mean preoperative DQ/IQ score was 60.7 ± 22.8. Left-side resection and anterior insular resection were performed in 9 patients each. Favorable seizure control (International League Against Epilepsy class 1-3) was achieved in 8 patients. Postoperative motor deficits were observed in 9 patients (permanent in 6, transient in 3). Within-subject changes in DQ/IQ were not significantly affected by insular resection (p = 0.13). Postoperative changes in DQ/IQ were not significantly affected by surgical side, anterior insular resection, AED reduction, or seizure outcome. Only verbal function showed no significant changes before and after surgery and no significant effects of within-subject factors.

Conclusions: Resection involving the insula in children with impaired development or intelligence can be performed without significant reduction in DQ/IQ, but carries the risk of postoperative motor deficits.
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http://dx.doi.org/10.3171/2020.5.PEDS2058DOI Listing
August 2020

[Unilateral ptosis induced by pure midbrain infarction: a case report].

Rinsho Shinkeigaku 2020 Aug 7;60(8):527-532. Epub 2020 Jul 7.

Department of Neurology, Sapporo Medical University School of Medicine.

We describe herein a case with left-side ptosis induced by pure midbrain infarction in a 49-year-old woman. She also presented with diplopia and right-side cerebellar ataxia. MRI demonstrated new ischemic stroke of the left ventral paramedian midbrain. In this case, ischemia of the left oculomotor fascicles caused the left-side ptosis and diplopia, and ischemia of the left decussation of the superior cerebellar peduncle caused the right-side cerebellar ataxia. These symptoms resulted from inner superior medial mesencephalic branch infraction. This case offers an educational example that can be explained by models proposed in the past and requires knowledge of neuroanatomy and cerebrovasculature.
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http://dx.doi.org/10.5692/clinicalneurol.60.cn-001397DOI Listing
August 2020

Electrical Thalamic Stimulation in the Anterior Part of the Ventral Posterolateral Nucleus for the Treatment of Patients With Central Poststroke Pain.

Neuromodulation 2021 Feb 3;24(2):361-372. Epub 2020 Jul 3.

Department of Neurosurgery, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.

Objectives: The effects of thalamic stimulation of the anterior part of the ventral posterolateral nucleus (VPLa) for central poststroke pain (CPSP) and the pain-related electrophysiological characteristics of this structure were investigated.

Materials And Methods: Nine patients with CPSP manifesting as hemibody pain were enrolled. Stereotactic thalamic VPLa stimulation was implemented, and intraoperative electrophysiological studies on hyperactive and unstable discharges (HUDs) and responses to sensory and electrical stimulation were performed in the sensory thalamus. A preoperative somatosensory-evoked potential (SEP) study was carried out in all nine patients and in eight other patients with localized pain.

Results: The patients were classified into two groups: a HUD-dominant group (group H, n = 5) and a sensory response-dominant group (group R, n = 4). HUDs were frequently encountered in the thalamic VPLa in the former group. The total number of HUDs and the number along the trajectory to the VPLa in group H were significantly larger than those in group R. The improvements on the pain numeric rating scale in group H were significantly higher than those in group R two years after surgery. The amplitude ratio of the SEP N20s in the ipsilateral to the contralateral side of CVD lesion in the study group was significantly lower than in the localized pain group.

Conclusions: Adequate and stable pain relief with thalamic VPLa stimulation is obtainable in patients with CPSP who exhibit hyperactivity and electrical instability along the trajectory to this nucleus. Both responders and nonresponders were found to have severe dysfunction of the lemniscal system.
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http://dx.doi.org/10.1111/ner.13215DOI Listing
February 2021

Status epilepticus during correction of hyponatremia in a patient with Alzheimer's disease: A case report.

SAGE Open Med Case Rep 2020 15;8:2050313X20915416. Epub 2020 Apr 15.

Division of Neurosurgery, National Hospital Organization Shibukawa Medical Center, Shibukawa, Japan.

An 83-year-old Japanese man with Alzheimer's disease was admitted to our hospital for treatment of hyponatremia resulting from water intoxication. During hospitalization, the patient developed focal impaired awareness seizures, focal to bilateral tonic-clonic seizures, and subsequent status epilepticus. Electroencephalogram during focal impaired awareness seizures showed rhythmic 5-9 Hz theta activity in the right frontotemporal region. Electroencephalogram during focal to bilateral tonic-clonic seizures showed bilateral polyspikes. Electroencephalogram during an interseizure period revealed sharp waves in the right frontal region. Continuous intravenous administration of midazolam was the only effective treatment for status epilepticus. The patient died of aspiration pneumonia on day 58. Hyponatremia-associated status epilepticus is rare; in the present case, multifocal epileptogenicity resulting from Alzheimer's disease and hyponatremia-associated elevation of glutamate levels in the synaptic cleft may have contributed to the onset of focal to bilateral tonic-clonic seizures with subsequent status epilepticus.
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http://dx.doi.org/10.1177/2050313X20915416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160763PMC
April 2020

Transient water-electrolyte disturbance after hemispherotomy in young infants with epileptic encephalopathy.

Childs Nerv Syst 2020 05 16;36(5):1043-1048. Epub 2019 Dec 16.

Department of Neurosurgery, National Center of Neurology and Psychiatry, Tokyo, Japan.

Purpose: This study aimed to elucidate the clinical features of water-electrolyte disturbance (WED) as a sequela of hemispherotomy.

Methods: We performed a retrospective chart review to identify the clinical features of diabetes insipidus (DI) as a complication in < 12-month-old patients who underwent hemispherectomy or hemispherotomy for severe epilepsy between 2007 and 2018. Central DI was diagnosed if a patient developed polyuria (urine output > 5 mL/kg/h), abnormally high serum osmolality (> 300 mOsm/kg), high serum sodium level (> 150 mEq/L), either abnormally low urine specific gravity (< 1.005) or low urine osmolality (< 300 mOsm/kg) or both, and effective control of polyuria with arginine vasopressin (AVP). The clinical course of post-hemispherotomy WED, complications other than WED, and seizure outcomes were analyzed.

Results: The review identified that 3 of 23 infants developed WED. All patients developed polyuria within 2 days after surgery, with high serum osmolality and hypotonic urine; AVP was effective in treating these symptoms. The clinical course was compatible with central DI. Two patients subsequently developed hyponatremia in a biphasic or triphasic manner. All patients had multiple seizures that were probably related to WED. Two patients developed asymptomatic cerebral sinovenous thrombosis, possibly because of the surgical procedure and dehydration; anticoagulant treatment was provided. All patients were treated for WED for up to 2 months and had no residual pituitary dysfunction.

Conclusion: Systemic complications other than intracranial ones can occur in patients who have undergone hemispherotomy. Perioperative systemic management of young infants undergoing this procedure should include careful water and electrolyte balance monitoring.
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http://dx.doi.org/10.1007/s00381-019-04452-1DOI Listing
May 2020

Altered Expression of Astrocyte-Related Receptors and Channels Correlates With Epileptogenesis in Hippocampal Sclerosis.

Pediatr Dev Pathol 2019 Nov-Dec;22(6):532-539. Epub 2019 Jun 5.

Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan.

Background: Hippocampal sclerosis (HS) is one of the major causes of intractable epilepsy. Astrogliosis in epileptic brain is a peculiar condition showing epileptogenesis and is thought to be different from the other pathological conditions. The aim of this study is to investigate the altered expression of astrocytic receptors, which contribute to neurotransmission in the synapse, and channels in HS lesions.

Methods: We performed immunohistochemical and immunoblotting analyses of the P2RY1, P2RY2, P2RY4, Kir4.1, Kv4.2, mGluR1, and mGluR5 receptors and channels with the brain samples of 20 HS patients and 4 controls and evaluated the ratio of immunopositive cells and those expression levels.

Results: The ratio of each immunopositive cell per glial fibrillary acidic protein-positive astrocytes and the expression levels of all 7 astrocytic receptors and channels in HS lesions were significantly increased. We previously described unique astrogliosis in epileptic lesions similar to what was observed in this study.

Conclusion: This phenomenon is considered to trigger activation of the related signaling pathways and then contribute to epileptogenesis. Thus, astrocytes in epileptic lesion may show self-hyperexcitability and contribute to epileptogenesis through the endogenous astrocytic receptors and channels. These findings may suggest novel astrocytic receptor-related targets for the pharmacological treatment of epilepsy.
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http://dx.doi.org/10.1177/1093526619855488DOI Listing
April 2020

Stereotactic Selective Thalamotomy for Focal Dystonia with Aid of Depth Microrecording.

World Neurosurg 2018 Sep 14;117:e349-e361. Epub 2018 Jun 14.

Department of Neurosurgery, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.

Objective: Long-term effectiveness of selective ventralis intermedius nucleus (VIM)-ventralis oralis nucleus (VO) thalamotomy with depth microrecording for the treatment of focal dystonia was evaluated. The optimal thalamic areas for controlling focal dystonia were studied based on the electrophysiologic and anatomic data.

Methods: Stereotactic selective VIM-VO thalamotomy with depth microrecording was carried out in 8 patients with focal arm and hand dystonia and in 1 patient with cervical dystonia. Electrophysiologic data on the lateral part of thalamic VIM were studied in patients with focal dystonia. A very small and narrow therapeutic lesion was formed in the shape of a square on the sagittal plane and of an I, rotated V, Y, or inverse Y on the axial plane in the VIM-VO, which covered the kinesthetic response area topographically related to focal dystonia. Patients with arm and hand dystonia were followed up for 4.7 ± 3.0 years and 1 patient with cervical dystonia was followed up for 18.2 years.

Results: Marked improvement of focal dystonia was shown by functional assessment using the Unified Dystonia Rating Scale. Transient dysarthria was recognized in 1 patient. The sequence of body localization of kinesthetic response in the VIM was clearly shown in patients with focal dystonia. Decreases in the amplitude and amplitude ratio of electromyography on the forearm muscles were markedly significant after VIM thalamotomy, but insignificant after VO thalamotomy immediately after VIM thalamotomy.

Conclusions: Marked reduction of electromyographic tonic discharges of focal dystonia was shown after VIM lesioning. Selective VIM-VO thalamotomy showed good and long-term stable effects for focal dystonia.
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http://dx.doi.org/10.1016/j.wneu.2018.06.033DOI Listing
September 2018

Intractable epilepsy due to a rosette-forming glioneuronal tumor with a dysembryoplastic neuroepithelial background.

Neuropathology 2018 Jun 18;38(3):300-304. Epub 2017 Dec 18.

Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan.

A rosette-forming glioneuronal tumor (RGNT) was initially reported as an infratentorial tumor that comprised both small neurocytic rosettes and astrocytic components. However, a few studies have reported supratentorial RGNTs arising in the cerebral hemispheres. Here, we report an unusual case involving a 9-year-old boy with a supratentorial RGNT who presented with intractable epilepsy and behavioral changes. Brain MRI revealed a well-circumscribed space-occupying lesion with septae in the right inferomedial parietal lobe. Electroencephalography showed multifocal spikes over the right frontal, temporal and parietal regions. The seizure frequency decreased dramatically after tumorectomy. Histopathological examination revealed prominent neurocytic rosette formation appearing with the specific glioneuronal element of a dysembryoplastic neuroepithelial tumor (DNT). Although the pathogenesis has not been elucidated, a supratentorial RGNT presenting with epilepsy may exhibit a rosette component, which is the major feature of this tumor, against the background of a specific glioneuronal element mimicking DNT. However, RGNT arising in regions other than the fourth ventricle is rare, and the pathogenesis of epilepsy due to RGNT has not been fully elucidated. Further clinical and histological studies are required to understand the pathology underlying epilepsy caused by RGNT.
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http://dx.doi.org/10.1111/neup.12450DOI Listing
June 2018

Superselective Thalamotomy in the Most Lateral Part of the Ventralis Intermedius Nucleus for Controlling Essential and Parkinsonian Tremor.

World Neurosurg 2018 Jan 17;109:e630-e641. Epub 2017 Oct 17.

Department of Neurosurgery, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.

Objective: The minimum and essential thalamic areas for reducing tremor were investigated in cases treated by superselective thalamotomy in the most lateral part of the ventralis intermedius nucleus (mlp-VIM).

Methods: Stereotactic superselective VIM thalamotomy with depth microrecording was performed in 21 patients with essential tremor (ET) and 15 patients with tremor-dominant Parkinson disease (PD). A very small and narrow (axial plane) therapeutic lesion was formed as a square on the sagittal plane and inverse V on the axial plane in the mlp-VIM, which covered the kinesthetic response area topographically related to tremor. Patients with ET were followed up for 4.7 ± 3.0 years and patients with PD for 7.9 ± 3.9 years.

Results: Almost complete tremor control was achieved in all patients immediately after surgery and continued for up to 8 years. A few adverse events were recognized but disappeared within 1 month without 1 patient with thalamic hemorrhage. The medial border of the therapeutic lesion was significantly more lateral in both patients with ET and patients with PD than the calculated standard target point and was in patients with PD than in patients with ET. The mean width was only about 2.4 mm. The individual differences of the adequate location of the therapeutic lesion were significantly greater in the ET than in the PD group.

Conclusions: The important area for reducing tremor was small and narrow and was located in the mlp-VIM, where the proprioceptive ascending signals from the tremor-dominant body part are conducted. Superselective thalamotomy in the mlp-VIM was safe and effective for the long-term in patients with ET and PD.
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http://dx.doi.org/10.1016/j.wneu.2017.10.042DOI Listing
January 2018

Noninvasive detection of focal brain hyperthermia related to continuous epileptic activities using proton MR spectroscopy.

Epilepsy Res 2017 12 6;138:1-4. Epub 2017 Oct 6.

Department of Radiology, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8551, Japan. Electronic address:

Recent studies using rat models suggested that epileptic discharges (EDs) can induce focal brain hyperthermia, but such ED-related hyperthermia has not been confirmed in humans. We examined hyperthermia of the focus of epilepsy using noninvasive proton magnetic resonance spectroscopy (H-MRS) thermometry. We recruited six pediatric patients with refractory daily seizures, continuous interictal epileptic discharges, and concordant focus lesions on MRI who had undergone comprehensive presurgical exams. H-MRS thermometry calculated the temperatures of the presumed epileptogenic lesions, and we examined the contralateral counterparts in each patient as controls. As a result, the mean temperature of the epileptogenic foci (36.81°C) was significantly higher than that of the controls (36.01°C). The mean difference was 0.81°C (95%CI: 0.22-1.39, p=0.017). H-MRS thermometry may have the ability to noninvasively detect focal brain hyperthermia related to continuous EDs in human subjects, and to contribute to a better understanding and focus detection of epilepsy.
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http://dx.doi.org/10.1016/j.eplepsyres.2017.10.001DOI Listing
December 2017

Surgical strategy to avoid ischemic complications of the pyramidal tract in resective epilepsy surgery of the insula: technical case report.

J Neurosurg 2018 04 9;128(4):1173-1177. Epub 2017 Jun 9.

1Department of Neurosurgery, Epilepsy Center, National Center of Neurology and Psychiatry (NCNP), Kodaira.

Surgical treatment of the insula is notorious for its high probability of motor complications, particularly when resecting the superoposterior part. Ischemic damage to the pyramidal tract in the corona radiata has been regarded as the cause of these complications, resulting from occlusion of the perforating arteries to the pyramidal tract through the insular cortex. The authors describe a strategy in which a small piece of gray matter is spared at the bottom of the periinsular sulcus, where the perforating arteries pass en route to the pyramidal tract, in order to avoid these complications. This method was successfully applied in 3 patients harboring focal cortical dysplasia in the posterior insula and frontoparietal operculum surrounding the periinsular sulcus. None of the patients developed permanent postoperative motor deficits, and seizure control was achieved in all 3 cases. The method described in this paper can be adopted for functional preservation of the pyramidal tract in the corona radiata when resecting epileptogenic pathologies involving insular and opercular regions.
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http://dx.doi.org/10.3171/2017.1.JNS161278DOI Listing
April 2018

Pathologic Active mTOR Mutation in Brain Malformation with Intractable Epilepsy Leads to Cell-Autonomous Migration Delay.

Am J Pathol 2017 May;187(5):1177-1185

Epilepsy Center, National Center of Neurology and Psychiatry, National Institute of Neuroscience, Kodaira, Japan; Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, Kodaira, Japan. Electronic address:

The activation of phosphatidylinositol 3-kinase-AKTs-mammalian target of rapamycin cell signaling pathway leads to cell overgrowth and abnormal migration and results in various types of cortical malformations, such as hemimegalencephaly (HME), focal cortical dysplasia, and tuberous sclerosis complex. However, the pathomechanism underlying abnormal cell migration remains unknown. With the use of fetal mouse brain, we performed causative gene analysis of the resected brain tissues from a patient with HME and investigated the pathogenesis. We obtained a novel somatic mutation of the MTOR gene, having approximately 11% and 7% mutation frequency in the resected brain tissues. Moreover, we revealed that the MTOR mutation resulted in hyperphosphorylation of its downstream molecules, S6 and 4E-binding protein 1, and delayed cell migration on the radial glial fiber and did not affect other cells. We suspect cell-autonomous migration arrest on the radial glial foot by the active MTOR mutation and offer potential explanations for why this may lead to cortical malformations such as HME.
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http://dx.doi.org/10.1016/j.ajpath.2017.01.015DOI Listing
May 2017

Vertical parasagittal hemispherotomy for Sturge-Weber syndrome in early infancy: case report and literature review.

Springerplus 2016 30;5(1):1434. Epub 2016 Aug 30.

Department of Neurosurgery, National Hospital Organization Nara Medical Center, Shichijo 2-789, Nara, 630-8053 Japan.

Introduction: The authors here present a rare case of a 3-month-old infant with unilateral Sturge-Weber syndrome (SWS) who had excellent seizure control and no aggravation of previous existed neurological deficits after vertical parasagittal hemispherotomy (VPH). To our knowledge, this patient with SWS was the youngest one who received VPH.

Case Description: The use of VPH results in a successful treatment of intractable epilepsy in a patient with seizure onset in early infancy. At follow-up, the patient's neurodevelopmental status has been improved since the surgery.

Discussion: It is generally accepted that early-onset seizures in children with SWS are associated with worse neurological and developmental outcomes. However, when surgical treatment should be considered and how it should be performed remain a longstanding controversy. We promote early surgery in children with SWS and early-onset epilepsy.

Conclusion: We suggest that VPH may be a useful adjuvant in the management of SWS with refractory epilepsy in early infancy and this procedure carries low neurological risk.
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http://dx.doi.org/10.1186/s40064-016-3096-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005253PMC
September 2016

The Role of Sister Cities' Staff Exchanges in Developing "Learning Cities": Exploring Necessary and Sufficient Conditions in Social Capital Development Utilizing Proportional Odds Modeling.

Int J Environ Res Public Health 2015 Jun 24;12(7):7133-53. Epub 2015 Jun 24.

Department of Mathematics, Western Washington University, Bellingham, WA 98225, USA.

In the last half century former international adversaries have become cooperators through networking and knowledge sharing for decision making aimed at improving quality of life and sustainability; nowhere has this been more striking then at the urban level where such activity is seen as a key component in building "learning cities" through the development of social capital. Although mega-cities have been leaders in such efforts, mid-sized cities with lesser resource endowments have striven to follow by focusing on more frugal sister city type exchanges. The underlying thesis of our research is that great value can be derived from city-to-city exchanges through social capital development. However, such a study must differentiate between necessary and sufficient conditions. Past studies assumed necessary conditions were met and immediately jumped to demonstrating the existence of structural relationships by measuring networking while further assuming that the existence of such demonstrated a parallel development of cognitive social capital. Our research addresses this lacuna by stepping back and critically examining these assumptions. To accomplish this goal we use a Proportional Odds Modeling with a Cumulative Logit Link approach to demonstrate the existence of a common latent structure, hence asserting that necessary conditions are met.
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http://dx.doi.org/10.3390/ijerph120707133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4515646PMC
June 2015

Expression of astrocyte-related receptors in cortical dysplasia with intractable epilepsy.

J Neuropathol Exp Neurol 2014 Aug;73(8):798-806

From the Epilepsy Center (SS, TO, SH, RH, TS, EN, TK, NS, YK, AT, KS, YS, MS, YG, MI), Departments of Mental Retardation and Birth Defect Research (SS, HD, SN, SH, YG, MI), Neurosurgery (TO, TK, YK, AT), Child Neurology (RH, TS, EN, KS, MS), Radiology (NS), and Laboratory Medicine (YS), National Center of Neurology and Psychiatry, Kodaira, Tokyo; and Department of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi (SS, SH, SK), Japan.

Epilepsy is one of the major neurologic diseases, and astrocytes play important roles in epileptogenesis. To investigate possible roles of astrocyte-related receptors in patients with intractable epilepsy associated with focal cortical dysplasia (FCD) and other conditions, we examined resected epileptic foci from 31 patients, including 23 with FCD type I, IIa, or IIb, 5 with tuberous sclerosis complex, and 3 with low-grade astrocytoma. Control samples were from 21 autopsied brains of patients without epilepsy or neurologic deficits and 5 patients with pathologic gliosis without epilepsy. Immunohistochemical and immunoblot analyses with antibodies against purinergic receptor subtypes P2RY1, P2RY2, P2RY4, potassium channels Kv4.2 and Kir4.1, and metabotropic receptor subtypes mGluR1 and mGluR5 were performed. Anti-glial fibrillary acidic protein, anti-NeuN, and anti-CD68 immunostaining was used to identify astrocytes, neurons, and microglia, respectively. Most glial fibrillary acidic protein-immunopositive astrocyte cells in the brain samples from patients with epilepsy were P2RY1-, P2RY2-, P2RY4-, Kv4.2-, Kir4.1-, mGluR1-, and mGluR5-positive, whereas samples from controls and pathologic gliosis showed lower expression levels of these astrocyte-related receptors. Our findings suggest that, although these receptors are necessary for astrocyte transmission, formation of the neuron-glia network, and other physiologic functions, overexpression in the brains of patients with intractable epilepsy may be associated with activation of intracellular and glio-neuronal signaling pathways that contribute to epileptogenesis.
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http://dx.doi.org/10.1097/NEN.0000000000000099DOI Listing
August 2014

Complex regional pain syndrome in a 15-year-old girl successfully treated with continuous epidural anesthesia.

Brain Dev 2015 Jan 8;37(1):175-8. Epub 2014 Apr 8.

Department of Neurosurgery, NCNP, Kodaira, Tokyo, Japan.

A 15-year-old girl developed severe pain in her right upper limb within a few days after she experienced an astatic epileptic seizure accompanied by falling on her right side. She was treated with fluid infusion through a cannula into her right hand. Swelling, mild flaring, and muscle weakness of the right arm subsequently appeared. Pharmacotherapy and stellate ganglion block were ineffective, and continuous epidural anesthesia was commenced 14 days after the falling event. The pain and accompanying symptoms completely disappeared within 5 days. Early treatment with continuous epidural anesthesia may be a promising option for the management of complex regional pain syndrome during childhood.
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http://dx.doi.org/10.1016/j.braindev.2014.03.002DOI Listing
January 2015

Classification of various muscular tissues using miRNA profiling.

Biomed Res 2013 ;34(6):289-99

Department of Genomic Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan.

MicroRNAs (miRNAs) are endogenous small RNAs of 18-23 nucleotides that regulate gene expression. Recently, plasma miRNAs have been investigated as biomarkers for various diseases. In the present study, we explored whether miRNA expression profiling of various muscle cells may be useful for the diagnosis of various diseases involving muscle necrosis. miRNA expression profiling was assessed by miRNA array and real-time reverse-transcriptase polymerase chain reaction by using a reverse primer of a stem loop structure. Profiling of various muscle cells of mouse, including cardiac muscles, skeletal muscles, and vascular and visceral smooth muscles, indicated that profiling of miR-1, miR-133a, miR-133b, miR-145, miR-206, miR-208a, miR-208b, and miR499 were adequate to discriminate muscle cells. miR-145 was remarkably highly expressed in smooth muscles. miR-208a and miR-499 were highly expressed in cardiomyocytes. miR-133a was highly expressed in fast-twitch skeletal muscles. miR-206 and miR-208b were expressed in the slow-twitch skeletal muscles, and they can likely discriminate fast- and slow-twitch types of skeletal muscle cells. We observed that brown fat adipose cells had an miRNA expression profile very similar to those of skeletal muscle cells in the mouse. Plasma concentrations of miR-133a and miR-145 were extremely useful in diagnosing skeletal muscle necrosis in a mouse model of Duchenne muscular dystrophy and colon smooth muscle necrosis in a rat ischemic colitis model, respectively. In the present study, we investigated the miRNA expression profiles of various muscular tissues. Our results suggest that expression profiling would be useful for the diagnosis of various diseases such as muscular necrosis.
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http://dx.doi.org/10.2220/biomedres.34.289DOI Listing
August 2014

Persistent verbal and behavioral deficits after resection of the left supplementary motor area in epilepsy surgery.

Brain Dev 2014 Jan 8;36(1):74-9. Epub 2013 Feb 8.

Department of Child Neurology, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigachi-cho, Kodaira, Tokyo 187-8551, Japan.

An 8-year-old boy underwent a resection for focal cortical dysplasia at the left supplementary motor area (SMA) for the treatment of intractable epilepsy. The manifestations of SMA syndrome, such as transient mutism and right hemiparesis, resolved within a few weeks. Verbal disfluency and impaired executive function, accompanied by impulsivity and distractibility, persisted for more than 12months. The verbal and behavioral problems caused serious difficulties in the school life of the patient, until they became less evident at 18months after surgery. Tractography performed 18months after surgery revealed a defect in the subportion of fronto-parietal association fibers within the left superior longitudinal fascicles. Verbal influency can persist with unusually long duration after resection of SMA during childhood. Although not discernible on the routine neuroimaging, white matter damage beneath the SMA region could result in serious disabilities in executive function. These complications should be recognized for the prediction and assessment of deficits in children after surgical intervention involving this region.
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http://dx.doi.org/10.1016/j.braindev.2013.01.002DOI Listing
January 2014

Long-term developmental outcome after early hemispherotomy for hemimegalencephaly in infants with epileptic encephalopathy.

Epilepsy Behav 2013 Oct 7;29(1):30-5. Epub 2013 Aug 7.

Department of Child Neurology, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan.

This study aimed to identify the effect of early hemispherotomy on development in a consecutive series of 12 infants with hemimegalencephaly (HME) demonstrating epileptic encephalopathy. Mean age at onset was 20.4 days (range, 1-140), mean age at surgery was 4.3 months (range, 2-9), and mean follow-up time was 78.8 months (range, 36-121). Eleven patients had a history of early infantile epileptic encephalopathy. Vertical parasagittal hemispherotomy was performed without mortality or severe morbidities. At follow-up, seizure freedom was obtained in 8 patients (66.7%), who showed significantly higher postoperative developmental quotient (DQ) (mean, 31.3; range, 7-61) than those with seizures (mean, 5.5; range, 3-8) (p=0.02). Within the seizure-free group, postoperative DQ correlated with preoperative seizure duration (r=-0.811, p=0.01). Our results showed that shorter seizure duration during early infancy could provide better postoperative DQ in infants with HME and epileptic encephalopathy.
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http://dx.doi.org/10.1016/j.yebeh.2013.06.006DOI Listing
October 2013

Surgical management of cortical dysplasia in infancy and early childhood.

Brain Dev 2013 Sep 18;35(8):802-9. Epub 2013 May 18.

Department of Neurosurgery, Epilepsy Center, National Center of Neurology and Psychiatry, Tokyo, Japan.

Purpose: To describe operative procedures, seizure control and complications of surgery for cortical dysplasia (CD) causing intractable epilepsy in infancy and early childhood.

Methods: Fifty-six consecutive children (less than 6years old) underwent resective epilepsy surgery for CD from December 2000 to August 2011. Age at surgery ranged from 2 to 69months (mean 23months) and the follow-up was from 1 to 11years (mean 4years 4months).

Results: Half of the children underwent surgery during infancy at an age less than 10months, and the majority (80%) of these infants needed extensive surgical procedures, such as hemispherotomy and multi-lobar disconnection. Seizure free (ILAE class 1) outcome was obtained in 66% of the cases (class 1a; 55%): 85% with focal resection (n=13), 50% with lobar resection (n=18), 71% with multilobar disconnection (n=7) and 67% with hemispherotomy (n=18). Peri-ventricular and insular structures were resected in 23% of focal and 61% of lobar resections. Repeated surgery was performed in 9 children and 5 (56%) became seizure free. Histological subtypes included hemimegalencephaly (16 patients), polymicrogyria (5 patients), and FCD type I (6 patients), type IIA (19 patients), type IIB (10 patients). Polymicrogyria had the worst seizure outcome compared to other pathologies. Surgical complications included 1 post-operative hydrocephalus, 1 chronic subdural hematoma, 2 intracranial cysts, and 1 case of meningitis. No mortality or severe morbidities occurred.

Conclusions: Early surgical intervention in children with CD and intractable seizures in infancy and early childhood can yield favorable seizure outcome without mortality or severe morbidities although younger children often need extensive surgical procedures.
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http://dx.doi.org/10.1016/j.braindev.2013.04.008DOI Listing
September 2013

Clinical analysis of catastrophic epilepsy in infancy and early childhood: results of the Far-East Asia Catastrophic Epilepsy (FACE) study group.

Brain Dev 2013 Sep 13;35(8):786-92. Epub 2013 Mar 13.

Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan.

Purpose: We studied children younger than 6years old who developed catastrophic epilepsy and were registered in the FACE study group to clarify their clinical characteristics and prevalence of seizure as well as epilepsy types.

Subjects: Subjects were prospectively recruited from children with epilepsy who satisfied the following criteria and underwent intensive examination between 2009 and 2012 in 14 collaborative centers: (1) younger than 6years old and (2) more than 10 seizures/month refractory to all available medical treatments including ACTH therapy, leading to significant psychosocial morbidity.

Methods: We analyzed epilepsy onset age, predominant seizure type, etiology, neuropsychological findings, and syndromic classification according to the pre-determined registration format.

Results: A total of 314 children were enrolled in this study. Epilepsy onset age in 239 cases (80%) was younger than 12months. The most frequent seizure type was epileptic spasms (ES), followed by generalized tonic seizures (GTS), which accounted for 42% and 20%, respectively. West syndrome (WS) was the most frequent epileptic syndrome and accounted for 37%, followed by unclassified epilepsy at 21%, neocortical epilepsy at 19%, Lennox-Gastaut syndrome at 12%, Dravet syndrome at 4%, Rasmussen syndrome at 2%, and others. The two most frequent causes of epilepsy were cortical dysplasia and chromosomal anomalies, as shown in 16% and 6%, respectively. However, the etiology of nearly one half of all patients remained unknown. Psychomotor development was already worse than a moderate degree in 62% of subjects at the first examination.

Conclusion: The highest proportion of catastrophic epilepsy was WS and its related syndromes featuring ES and GTS, followed by neocortical epilepsy, whose psychomotor development was significantly retarded at examinations.
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http://dx.doi.org/10.1016/j.braindev.2013.02.004DOI Listing
September 2013

Posterior disconnection in early infancy to treat intractable epilepsy with multilobar cortical dysplasia: three case report.

Neurol Med Chir (Tokyo) 2013 ;53(1):47-52

Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xian, China.

Extensive multilobar cortical dysplasias occasionally occur in children and can induce seizure onset in early infancy, causing severe epileptic encephalopathy. Surgical interventions in early infancy, such as disconnection of large parts of the brain, are challenging because of the degree of invasiveness and carry greater risks in infants compared with older children. Here we report the successful treatment of intractable epilepsy with multilobar cortical dysplasias in the posterior cortex by posterior disconnection in three infants (age 3 months). The patients showed good postoperative recovery and exhibited excellent seizure control at follow-up evaluation within a year after surgery. Developmental catch-up was also achieved and no early complications have been detected to date. Use of the posterior disconnection technique for early-stage extensive multilobar cortical dysplasias can result in good seizure control and developmental progress with little perioperative morbidity. However, the efficacy of this surgical technique needs to be verified with long-term follow up after surgery.
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http://dx.doi.org/10.2176/nmc.53.47DOI Listing
December 2013

A new species of the genus Ocadia (Testudines: Geoemydidae) from the middle Miocene of Tanegashima Island, southwestern Japan and its paleogeographic implications.

Zootaxa 2013 ;3647:527-40

Department of Zoology, Faculty of Science, Okayama University of Science. Ridai-cho 1-1, Kita-ku, Okayama 700-0005, Japan.

A new geoemydid turtle, Ocadia tanegashimensis (Testudines: Geoemydidae) is described on the basis of a relatively well-preserved shell from the lower middle Miocene of Tanegashima Island, Kagoshima Prefecture, southwestern Japan. This species is clearly distinguished from two congeneric species (extant O. sinensis and O. nipponica from the middle Pleistocene of eastern Japan) due to the presence of the following character states: length of the entoplastron as long as the interhyoplastral suture, the costals dovetailed with one another in outline, the third pleural overlapping only the sixth and seventh peripherals. The present study suggests that the initial intrageneric diversification of Ocadia began not later than the early Miocene in eastern Asia.
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http://dx.doi.org/10.11646/zootaxa.3647.4.3DOI Listing
September 2015

Hemimegalencephaly in a patient with coexisting trisomy 21 and hypomelanosis of Ito.

J Child Neurol 2014 Mar 23;29(3):415-20. Epub 2012 Dec 23.

1Department of Pediatrics and Child Neurology, Oita University Faculty of Medicine, Oita, Japan.

A male infant with trisomy 21 simultaneously showed clinical features of hypomelanosis of Ito and hemimegalencephaly, with related intractable epileptic seizures. The epileptic seizures were refractory to conventional antiepileptic drugs and persisted until the patient underwent functional hemispherotomy. It is well known that patients with hypomelanosis of Ito may also have cortical dysplasia and hemimegalencephaly and that approximately half of these patients have chromosomal abnormalities. However, to our knowledge, there is no previous report of a patient with trisomy 21 associated with hemimegalencephaly. Here, we describe a rare case of coexisting trisomy 21 and hypomelanosis of Ito, associated with hemimegalencephaly.
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http://dx.doi.org/10.1177/0883073812469297DOI Listing
March 2014

Medullary ischemia due to vertebral arteritis associated with Behçet syndrome: a case report.

Asian Pac J Allergy Immunol 2012 Sep;30(3):239-42

Department of Neurosurgery, National Center Hospital, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Here we report an extremely rare case of Behçet syndrome (BS) that showed acute onset of Wallenberg syndrome and was treated successfully by corticosteroids. A 51-year-old woman with BS had a sudden onset of Wallenberg syndrome. Three days after the onset, she was transferred to our institute. In the magnetic resonance imaging (MRI) study on admission, T2-weighted and fluid-attenuated inversion recovery images showed a high intensity area in the left paramedian region of the medulla oblongata. Contrast-enhanced T1-weighted images showed enhancement in the vessel wall of the left vertebral artery. We diagnosed her as having Wallenberg syndrome due to the acute vertebral arteritis associated with BS. After initiation of high-dose steroid therapy, her symptoms gradually improved. Two months after admission, she was discharged from our institute with mild hemihypesthesia. We hypothesized that vertebral arteritis due to BS had caused hypoperfusion of the medullary perforators causing Wallenberg syndrome in our patient.
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September 2012

Late-onset epilepsy in children with acute febrile encephalopathy with prolonged convulsions: A clinical and encephalographic study.

Brain Dev 2013 Jun 13;35(6):531-9. Epub 2012 Sep 13.

Department of Child Neurology, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

The aim of this study is to analyze the characteristics of epilepsies as the sequelae of acute febrile encephalopathy with prolonged convulsions during childhood. Sixteen patients (M:F=9:7) aged 2-13years (mean 6.1years) with history of febrile acute encephalopathy were retrospectively reviewed. These patients experienced febrile encephalopathy at the age of 11months to 4years, with 11 individuals presenting with findings of a biphasic clinical course (n=5), frontal predominant (n=8) lesions, and/or reduced diffusivity in the cerebral white matter on magnetic resonance imaging (MRI; n=3). The remaining 5 patients had unilateral lesions that manifested the phenotype of hemiconvulsion-hemiplegia-epilepsy syndrome (HHES). Epilepsy emerged with a latent period of 2months to 2years after the acute phase of febrile encephalopathy. Head nodding or spasm with subsequent motion arrest and brief tonic seizures were the main seizure phenotypes. Ictal records of epileptic seizures were available in 9 patients. Epileptiform discharges with a focal or uneven distribution appeared at the seizure onset and lasted less than 1s in all patients; these were followed by either generalized attenuation or fast activity in 8 patients with head nodding, spasm, or brief tonic seizures, and by localized fast activity in 1 patient with versive tonic seizures. Notably, the seizure onset area was often located outside the severe lesions on MRI, i.e., in the parietal areas in patients with frontal predominant lesions, and in the spared hemisphere of HHES. Although phenobarbital, zonisamide, carbamazepine, clobazam, clonazepam, and clorazepate were partially effective in some patients, daily seizures persisted in 11 patients. Callosotomy was performed in 2 patients, and beneficial effects were observed in both. These characteristics suggested a broad distribution of augmented excitability in these patients, resulting in the rapid propagation of epileptic activity in the initial phase of ictal phenomena. Thus, this study investigates the most severe subgroup of epilepsy following febrile acute encephalopathy and provides the basis for further exploration of the pathogenesis and treatment of characteristic seizures in this population.
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http://dx.doi.org/10.1016/j.braindev.2012.08.007DOI Listing
June 2013

Novel pathological abnormalities of deep brain structures including dysplastic neurons in anterior striatum associated with focal cortical dysplasia in epilepsy.

J Neurosurg Pediatr 2012 Sep 27;10(3):217-25. Epub 2012 Jul 27.

Departments of Neurosurgery, National Center of Neurology and Psychiatry, Kodaira, Japan.

Object: Some patients are not seizure free even after epileptogenic cortical resection. The authors recently described a case of frontal lobe epilepsy cured after the resection of periventricular white matter and striatum, in which dysplastic neurons were revealed. The authors attempted to confirm similar cases.

Methods: They reviewed the records of 8 children with frontal lobe epilepsy who had daily (7) or monthly (1) seizures and underwent resections including deep brain structures.

Results: Five patients underwent multiple resections. Neuroimaging of the deep structures showed the transmantle sign in 3 patients, ictal hyperperfusion in 6, reduced iomazenil uptake in 2, and spike dipole clustering in 6. All patients became seizure free postoperatively. Focal cortical dysplasia of various types was diagnosed in all patients. Dysmorphic neurons were found in the cortex and subcortical white matter of 5 patients. The striatum was verified in 3 patients in whom dysmorphic neurons were scattered. In the periventricular white matter, prominent astrocytosis was evident in all cases.

Conclusions: Pathological abnormalities such as dysmorphic neurons and astrocytosis in deep brain structures would play a key role in epileptogenesis.
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http://dx.doi.org/10.3171/2012.6.PEDS11325DOI Listing
September 2012

Delayed maturation and differentiation of neurons in focal cortical dysplasia with the transmantle sign: analysis of layer-specific marker expression.

J Neuropathol Exp Neurol 2012 Aug;71(8):741-9

Epilepsy Center, National Center of Neurology and Psychiatry, Tokyo, Japan.

Transmantle dysplasia is a rare type of focal cortical dysplasia (FCD) characterized by expansion of the cortex from the deep white matter to the surface and in which there is a FCD IIA or IIB pathologic pattern. To characterize possible mechanisms underlying this regional disorder of radial migrating cells, we studied the expression patterns of neocortical layer-specific markers using immunohistochemistry in surgical specimens from 5 FCD IIA and 4 FCD IIB cases in children. All neuronal cells expressed the mature neuron marker MAP2/2B but not the microglia markers Iba-1 and CD68. Some layer-specific markers showed distinct expression patterns. TBR1-positive, SATB2-positive, and FOXP1-positive cells were diffusely distributed in the cortex and/or the white matter. TBR1-positive and FOXP1-positive cells were generally more numerous in FCD IIB than in FCD IIA and were mostly in the cortical molecular and upper layers. FOXP1-, FOXP2-, and CUTL1-positive cells also expressed the immature neuron marker, Nestin/PROX1, whereas TBR1-, CTIP2-, and SATB2-positive cells only expressed MAP2/2B. These data highlight differences between FCD IIB and FCD IIA with more cells having the immature marker in upper layer markers in the former. By analyzing layer-specific marker expression patterns, we identified apparent neuronal maturation differences between FCD IIA and FCD IIB in cases of transmantle dysplasia.
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http://dx.doi.org/10.1097/NEN.0b013e318262e41aDOI Listing
August 2012

Abnormal maturation and differentiation of neocortical neurons in epileptogenic cortical malformation: unique distribution of layer-specific marker cells of focal cortical dysplasia and hemimegalencephaly.

Brain Res 2012 Aug 1;1470:89-97. Epub 2012 Jul 1.

Epilepsy Center, National Center of Neurology and Psychiatry, Tokyo, Japan.

Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are major causes of intractable epilepsy in children. The probable pathogenesis of FCD and HMG is the abnormal migration and differentiation of neurons. The aim of the present study was to clarify the abnormal cytoarchitecture, based on neuronal immaturation. Tissue samples were obtained from 16 FCD and seven HME patients, aged between 2 months and 12 years, who had been diagnosed as typical FCD and HME, following surgical treatment for intractable epilepsy. Paraffin-embedded sections were stained with the antibodies of three layer-markers that are usually present only during the fetal period, namely SATB2 (expressed in the upper layer of the normal fetal neocortex), FOXP1 (expressed in the 5th layer), and TBR1 (expressed in the 6th layer). In FCD, SATB2-positive (+) cells located in the middle and deep regions of FCD Ia and Ib, but only in the superficial region of FCD IIa and IIb. FOXP1+ cells diffusely located in the neocortex, especially the upper layer of FCD IIa and IIb. TBR1+ cells mainly located in the middle and deep regions, and also white matter. In FCD IIb, TBR1+ cells were in the superficial region. In HME, SATB2+ and FOXP1+ cells were found diffusely. TBR1+ cells were in the middle and deep regions. On the basis of continued expression of fetal cortical layer-specific markers in FCD and HME brains, the abnormal neocortical formation in both is likely to be the result of disrupted neuronal migration and dysmaturation. The expression pattern is different between FCD and HME.
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http://dx.doi.org/10.1016/j.brainres.2012.06.009DOI Listing
August 2012