Hiroshi Shirozu

Somatic Mutations in the MTOR gene cause focal cortical dysplasia type IIb

Focal cortical dysplasia (FCD) type IIb is a cortical malformation characterized by cortical architectural abnormalities, dysmorphic neurons, and balloon cells. It has been suggested that FCDs are caused by somatic mutations in cells in the developing brain. Here, we explore the possible involvement of somatic mutations in FCD type IIb.

MRI-guided stereotactic radiofrequency thermocoagulation for 100 hypothalamic hamartomas

OBJECT The aim of this study was to elucidate the invasiveness, effectiveness, and feasibility of MRI-guided stereotactic radiofrequency thermocoagulation (SRT) for hypothalamic hamartoma (HH). METHODS The authors examined the clinical records of 100 consecutive patients (66 male and 34 female) with intractable gelastic seizures (GS) caused by HH, who underwent SRT as a sole surgical treatment between 1997 and 2013. The median duration of follow-up was 3 years (range 1-17 years). Seventy cases involved pediatric patients. Ninety percent of patients also had other types of seizures (non-GS). The maximum diameter of the HHs ranged from 5 to 80 mm (median 15 mm), and 15 of the tumors were giant HHs with a diameter of 30 mm or more. Comorbidities included precocious puberty (33.0%), behavioral disorder (49.0%), and mental retardation (50.0%). RESULTS A total of 140 SRT procedures were performed. There was no adaptive restriction for the giant or the subtype of HH, regardless of any prior history of surgical treatment or comorbidities. Patients in this case series exhibited delayed precocious puberty (9.0%), pituitary dysfunction (2.0%), and weight gain (7.0%), besides the transient hypothalamic symptoms after SRT. Freedom from GS was achieved in 86.0% of patients, freedom from other types of seizures in 78.9%, and freedom from all seizures in 71.0%. Repeat surgeries were not effective for non-GS. Seizure freedom led to disappearance of behavioral disorders and to intellectual improvement. CONCLUSIONS The present SRT procedure is a minimally invasive and highly effective surgical procedure without adaptive limitations. SRT involves only a single surgical procedure appropriate for all forms of epileptogenic HH and should be considered in patients with an early history of GS.

The effect of anodal transcranial direct current stimulation over the primary motor or somatosensory cortices on somatosensory evoked magnetic fields.

OBJECTIVES The purpose of this study was to investigate the effect of anodal transcranial direct-current stimulation (tDCS) applied over the primary motor (M1) or the primary somatosensory (S1) cortices on somatosensory evoked magnetic fields (SEFs) following median nerve stimulation. METHODS Anodal tDCS was applied for 15min on the left motor or somatosensory cortices at 1mA. SEFs were recorded following right median nerve stimulation using a magnetoencephalography (MEG) system before and after the application of tDCS. SEFs was measured and compared before and after tDCS was applied over M1 or S1. RESULTS The source strengths for the P35m and P60m increased after tDCS was applied over M1 and that for the P60m increased after tDCS was applied over S1. The mean equivalent current dipole (ECD) location for the P35m was located significantly anterior to that of the N20m, but only during post 1 (10-20min after tDCS was applied over M1). CONCLUSION Our results indicated that the anodal tDCS applied over M1 affected the P35m and P60m sources on SEF components, while that applied over S1 influenced the P60m source. SIGNIFICANCE We demonstrated anodal tDCS applied over M1 or S1 can modulate somatosensory processing and components of SEFs, confirming the hypothesis for locally distinct generators of the P35m and P60m sources.

Gradient magnetic-field topography for dynamic changes of epileptic discharges

We developed gradient magnetic-field topography (GMFT) for magnetoencephalography (MEG). We plotted the Euclidean norms of gradient magnetic fields occurring at the centers of 102 sensors onto 49-point grids and projected these norms onto the MRI brain surface of a 12-year-old boy who presented with neocortical epilepsy secondary to a left temporal tumor. The peak gradient magnetic field located posterior to the tumor and correlated to MEG dipoles. The gradient magnetic field propagated to the temporo-parietal region and corresponded with spike locations on electrocorticography. GMFT revealed the location and distribution of spikes while avoiding the inverse problem.

Gradient magnetic-field topography reflecting cortical activities of neocortical epilepsy spikes

PURPOSE To compare and validate the gradient magnetic-field topography (GMFT) method of current source localization for understanding epileptic zones against equivalent current dipole (ECD) and intracranial video-EEG (IVEEG) data in patients with intractable neocortical epilepsy. METHODS We used retrospective data from eight patients to determine GMFT at onset (O) and peak (P) of interictal magnetoencephalography (MEG) spikes and mapped GMFT(O) and GMFT(P) locations and distributions using 12 zones in unilateral hemisphere. We compared GMFT with ECD, ictal onset zones (IOZ) and interictal zones on IVEEG, and seizure outcomes. RESULTS We projected GMFT(Os) and (Ps) for all spikes on volume-rendered brain surfaces. We localized ECDs for 6-61% of spikes (mean, 28.4%). GMFT(Ps) (mean, 10.3 zones) extended over more zones than GMFT(Os) (6.3 zones) for each spike (p<0.01). The ECD distributions (2.3 zones) were almost equal to the zones of IOZ and surgical areas. GMFT(O) localizations distributed much more extensively than IOZs and surgical areas in three patients with residual seizures comparing with those in five seizure-free patiens. CONCLUSION We validate the potential of GMFT to study the distribution of MEG spikes. GMFT has an advantage in analyzing the cortical activity and propagation from MEG spikes in neocortical epilepsy.

Ca2+-permeable AMPA receptors associated with epileptogenesis of hypothalamic hamartoma

Hypothalamic hamartoma (HH), composed of neurons and glia without apparent cytologic abnormalities, is a rare developmental malformation in humans. Patients with HH often have characteristic medically refractory gelastic seizures, and intrinsic epileptogenesis within the lesions has been speculated. Herein we provide evidence to suggest that in HH neurons, Ca2+ permeability through α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors is aberrantly elevated. In needle biopsy specimens of HH tissue, field potential recordings demonstrated spontaneous epileptiform activities similar to those observed in other etiologically distinct epileptogenic tissues. In HH, however, these activities were clearly abolished by application of Joro Spider Toxin (JSTX), a specific inhibitor of the Ca2+‐permeable AMPA receptor. Consistent with these physiologic findings, the neuronal nuclei showed disappearance of adenosine deaminase acting on RNA 2 (ADAR2) immunoreactivity. Furthermore, examination of glutamate receptor 2 (GluA2) messenger RNA (mRNA) revealed that editing efficiency at the glutamine/arginine site was significantly low. These results suggest that neurons in HH may bear Ca2+‐permeable AMPA receptors due to dislocation of ADAR2.

Somatic mutations in GLI3 and OFD1 involved in sonic hedgehog signaling cause hypothalamic hamartoma

Hypothalamic hamartoma (HH) is a congenital anomalous brain tumor. Although most HHs are found without any other systemic features, HH is observed in syndromic disorders such as Pallister–Hall syndrome (PHS) and oral‐facial‐digital syndrome (OFD). Here, we explore the possible involvement of somatic mutations in HH.

Inhibitory effect of intensity and interstimulus interval of conditioning stimuli on somatosensory evoked magnetic fields.

Magnetoencephalography (MEG) recordings were performed to investigate the inhibitory effects of conditioning stimuli with various types of interstimulus intervals (ISIs) or intensities on somatosensory evoked magnetic fields (SEFs) using a 306‐ch whole‐head MEG system. Twenty‐three healthy volunteers participated in this study. Electrical stimuli were applied to the right median nerve at the wrist. Six pulse trains with ISIs of 500 ms were presented in Experiment 1. A paired‐pulse paradigm with three kinds of conditioning stimulus (CON) intensities, 500 ms before the test stimulus (TS), was applied in Experiment 2. Finally, three CONs 500 or 1000 ms before TS were presented in Experiment 3. Three main SEF deflections (N20m, P35m, and P60m) were observed, and the source activities of P35m and P60m significantly decreased after the 2nd pulse of a six pulse trains. These source activities also significantly decreased with increasing intensity of CON. In addition, these attenuations of source activities were affected by CON–CON or CON–TS intervals. These results indicated that the source activities were modulated by the intensity and ISIs of CONs. Furthermore, P35m after the stimulation were very sensitive to CONs; however, the attenuation of P60m after the stimulation lasted for a longer period than that of P35m. Our findings suggest that the conditioning stimulation had inhibitory effects on subsequent evoked cortical responses for more than 500 ms. Our results also provide important clues about the nature of short‐latency somatosensory responses in human studies.

Ephaptic transmission is the origin of the abnormal muscle response seen in hemifacial spasm.

OBJECTIVE In patients with hemifacial spasm, stimulation of a branch of the affected facial nerve elicits an abnormal response in the muscles innervated by another branch. We tested the hypothesis that this anomaly results from lateral spread of impulses from one motor axon to another at the site of the nerve compression by the offending artery. METHODS In a preoperative study of 21 patients, we delivered a series of stimuli, in short increments, successively distally along the temporal branch of the facial nerve to record abnormal muscle responses from the orbicularis oculi and mentalis muscles. In intraoperative monitoring of 10 patients during microvascular decompression, we monitored propagating nerve action potentials with a handheld electrode placed on the facial nerve 3mm distal to the vascular compression site. RESULTS With incremental shifts of stimulating points distally, the latency of abnormal muscle responses increased by 0.3±0.1ms/cm. This finding implicates the antidromic motor impulse as the trigger for lateral spread. The nerve action potentials recorded during surgery comprised the initial antidromic signal followed by one or more additional peaks. The latter immediately abated, together with abnormal muscle responses, after microvascular decompression. Thus, the secondary peaks must represent the orthodromic impulses generated by ephaptic transmission. An average inter-peak interval of 1.1ms between the first and secondary peaks is consistent with the estimated conduction time from the stimulation point to the site of vascular compression but not to the facial nucleus and return. CONCLUSION An abnormal muscle response results from lateral spread of impulses between motor axons at the site of vascular compression rather than at the facial nucleus. SIGNIFICANCE This study establishes the mechanism of lateral spread responsible for abnormal muscle responses and contributes to the understanding of pathophysiology underlying hemifacial spasm.

Epileptic network of hypothalamic hamartoma: An EEG-fMRI study

OBJECTIVE To investigate the brain networks involved in epileptogenesis/encephalopathy associated with hypothalamic hamartoma (HH) by EEG with functional MRI (EEG-fMRI), and evaluate its efficacy in locating the HH interface in comparison with subtraction ictal SPECT coregistered to MRI (SISCOM). METHODS Eight HH patients underwent EEG-fMRI. All had gelastic seizures (GS) and 7 developed other seizure types. Using a general linear model, spike-related activation/deactivation was analyzed individually by applying a hemodynamic response function before, at, and after spike onset (time-shift model=-8-+4s). Group analysis was also performed. The sensitivity of EEG-fMRI in identifying the HH interface was compared with SISCOM in HH patients having unilateral hypothalamic attachment. RESULTS EEG-fMRI revealed activation and/or deactivation in subcortical structures and neocortices in all patients. 6/8 patients showed activation in or around the hypothalamus with the HH interface with time-shift model before spike onset. Group analysis showed common activation in the ipsilateral hypothalamus, brainstem tegmentum, and contralateral cerebellum. Deactivation occurred in the default mode network (DMN) and bilateral hippocampi. Among 5 patients with unilateral hypothalamic attachment, activation in or around the ipsilateral hypothalamus was seen in 3 using EEG-fMRI, whereas hyperperfusion was seen in 1 by SISCOM. SIGNIFICANCE Group analysis of this preliminary study may suggest that the commonly activated subcortical network is related to generation of GS and that frequent spikes lead to deactivation of the DMN and hippocampi, and eventually to a form of epileptic encephalopathy. Inter-individual variance in neocortex activation explains various seizure types among patients. EEG-fMRI enhances sensitivity in detecting the HH interface compared with SISCOM.