[The Applications of qNMR in Drug Quality Control].

NMR is well known as one of the most important methods for elucidating the structure of organic compounds. Furthermore, it has recently been recognized as a powerful tool for quantitative analysis. The quantitative NMR (qNMR) has become an official analytical method described in detail in the Japanese Pharmacopoeia. And today, it is widely applied in drug development. The qNMR method offers many new advantages over traditional and conventional quantitative analysis methods. For example, this method requires only a few milligrams of the analyte and allows absolute quantitation of the analyte without using a qualified reference standard as a control sample. Then, it can be easily applied to most chemicals without expending significant time and resources on method development. In addition, residual solvent can be determined using qNMR methods. The peak area of an NMR spectrum is directly proportional to the number of protons contributing to the resonance. Based on this principle, the residual solvent can be determined by counting the signal corresponding to the residual solvent in the sample solution. We have applied qNMR as an alternative to GC. Thus, qNMR is an innovative and promising analytical technique that is expected to make significant progress in the future. Recently, the analytical research and quality control departments have been working together to expand this technology to a wide range of areas in the pharmaceutical industry.

Voxel-Based Lesion Mapping of Cryptogenic Stroke in Patients with Advanced Cancer: A Detailed Magnetic Resonance Imaging Analysis of Distribution Pattern.

BACKGROUND: Ischemic stroke is one form of cancer-associated thrombosis that can greatly worsen a patient's performance status. The present investigation aimed to elucidate the characteristic distribution pattern(s) of cryptogenic stroke lesions using a voxel-based lesion-mapping technique and examine the differences in clinical manifestations between cryptogenic and conventional strokes in patients with advanced cancer. METHODS: Data from 43 patients with advanced cancer who developed acute ischemic stroke were retrospectively collected. Stroke etiology was grouped into either cryptogenic or conventional stroke etiology according to the ASCO stroke score. Clinical data were reviewed, and voxel-based lesion mapping using diffusion-weighted imaging (DWI) was performed to visualize the cross-patient spatial distribution of the lesions. RESULTS: Of the 43 patients, 25 were classified as having cryptogenic stroke etiology and 18 were classified as having conventional stroke etiology. Median survival time of patients from stroke onset was 96 days for cryptogenic stroke etiology and 570 days for conventional stroke etiology (P = .01). D-dimer of patients was significantly higher in cryptogenic stoke etiology than in conventional stroke etiology (P = .006). Voxel-based lesion mapping showed that DWI hyperintense lesions accumulated at cortical and internal watershed areas of the cerebrum and at the vascular border zone of the superior cerebellar and posterior inferior cerebellar arteries at the cerebellum. CONCLUSIONS: Voxel-based lesion mapping for cryptogenic stroke in patients with advanced cancer showed that lesions accumulated at vascular border zones within the brain both at the cerebrum and at the cerebellum, but not at perforating arterial territories.

Effects of edaravone on muscle atrophy and locomotor function in patients with ischemic stroke: a randomized controlled pilot study.

BACKGROUND AND OBJECTIVE: Stroke patients with severe leg paralysis are often bedridden in the acute and subacute phase, which increases the risk of disuse muscle atrophy in the chronic phase. The evidence to date indicates that oxidative stress plays an important role in the mechanism of disuse muscle atrophy. Therefore, the aim of this study was to determine if long-term radical scavenger treatment with edaravone following an acute stroke prevents the progression of disuse muscle atrophy and improves leg locomotor function in the chronic phase. METHODS: This randomized controlled pilot study was conducted at 19 acute stroke and rehabilitation centers across Japan. Forty-seven ischemic stroke patients with at least leg motor weakness admitted within 24 hours of onset were randomly assigned to receive continuous intravenous infusions of edaravone 30 mg twice daily for 3 days (short-term group) or 10-14 days (long-term group). The primary endpoints of the study included the degree of leg disuse muscle atrophy, as measured by the percentage change from baseline in femoral muscle circumference 15 cm above the knee, and the improvement in leg locomotor function, as assessed by the maximum walking speed over 10 m, 3 months after the onset of stroke. RESULTS: Three-month follow-up was completed by a total of 41 patients (21 in the short-term group and 20 in the long-term group). On admission, there was no significant difference in the severity of stroke or the grade of leg paresis between the two treatment groups. The grade of disuse muscle atrophy and incidence of gait impairment 3 weeks after stroke onset were also similar between the short- and long-term groups. However, disuse muscle atrophy of the paretic and non-paretic legs was significantly less severe in the long-term versus the short-term treatment group (3.6 ± 5.9% and 1.5 ± 6.0% vs 8.3 ± 5.2% and 5.7 ± 6.4%; p < 0.01 and p < 0.05) 3 months after stroke onset. Additionally, the maximum walking speed over a distance of 10 m was significantly greater in the long-term group (98 ± 67 vs 54 ± 55 cm/sec; p < 0.05). CONCLUSION: Edaravone treatment for up to 14 days suppresses the progression of disuse muscle atrophy and improves leg locomotor function to a greater extent than shorter-term treatment in acute stroke patients. This suggests that the management of stroke may be improved with long-term edaravone therapy by providing myoprotective effects that ameliorate functional outcome in the chronic phase.

Single base substitutions in the capsid region of the norovirus genome during viral shedding in cases of infection in areas where norovirus infection is endemic.

Norovirus (NoV) infections are the major cause of food- and waterborne nonbacterial gastroenteritis in Japan. Some individuals showed long-term excretion of the virus into feces in 29 outbreaks of acute nonbacterial gastroenteritis that occurred in Toyama Prefecture, Japan, in fiscal year 2006. In one of these cases, single base substitutions from A to G in the capsid region of the NoV genome were commonly detected in two individuals during virus shedding by direct sequencing of PCR products. The A-to-G substitution was accompanied by an N-to-S amino acid change. The population of clones that possessed A at the corresponding site was gradually replaced by those with G during the infectious course. Although other substitutions were observed in the complete open reading frame 2 sequence, they were not common in these two individuals. NoVs are capable of evolving in the gastroenteric tract.

Neurological and MRI findings as predictors of progressive-type lacunar infarction.

AIMS: To find neurological or neuroimaging signs to predict neurological deterioration in acute lacunar infarctions. METHODS: Sixty-one consecutive patients with a supratentorial lacunar infarct, who were admitted within 48 h, were studied retrospectively. Progressive-type stroke (PS) was defined as progressive motor deficits that arose within 7 days after onset, by using the motor ratings of the National Institutes of Health Stroke Scale. RESULTS: Sixteen patients (26%) were classified into the PS group. In the PS group, fluctuating or progressing onset (81 vs. 42%, p = 0.009), leg-predominant motor deficits on admission (63 vs. 16%, p = 0.001) and corona radiata lesion on diffusion-weighted MRI (100 vs. 69%, p = 0.013) were all more frequent than in the non-PS group. CONCLUSION: Bedside neurological assessment and MRI findings may allow us to predict PS and start early intensive treatment for preventing further neurological deterioration.

Relationship between detectability of ischemic lesions by diffusion-weighted imaging and embolic sources in transient ischemic attacks.

BACKGROUND/AIMS: The aim of this study is to clarify the relationship between lesion detectability by diffusion-weighted magnetic resonance imaging (DWI) and the etiology of transient ischemic attacks (TIAs). METHODS: A retrospective study was performed on 72 patients with carotid TIAs who underwent DWI studies within 2 weeks after the last episode. RESULTS: Lesions were detected in 24 of 72 patients (33%). The detectability of lesions was 12% (3/25) in the large-artery atherosclerosis (LA) group, 57% (8/14) in the cardioembolism (CE) group, 8% (1/13) in the small-artery occlusion (SA) group, and 60% (12/20) in the other etiology or undetermined etiology (UD) group. Detectabilities in the CE group and the UD group were higher than those in the LA and SA groups. Of 24 patients with DWI-positive lesions, 17 (71%) had embolic sources in the heart; 9 were classified in the UD group because they had embolic sources both in the heart and large artery. CONCLUSION: Ischemic DWI lesions in TIAs are most likely caused by a cardioembolic mechanism. In TIA patients showing lesions on DWI, heart disease should be surveyed as the possible embolic source.

Early CT findings in unknown-onset and wake-up strokes.

BACKGROUND: Approximately one quarter of the acute ischemic stroke patients notice the event at awakening. Such patients with stroke at awakening are usually excluded from thrombolysis, since the time of stroke onset cannot be definitely identified. We compared the hyperacute CT findings of awakening stroke patients with those of stroke patients with known onset to assess whether the time of stroke onset is shortly before awakening. METHODS: Subjects were cardioembolic stroke patients who were consecutively admitted to our department within 3 h after the recognition of stroke during the period between January 2000 and March 2003. The patients were classified into three groups: group A with stroke of known onset, group B with stroke at awakening, and group C with stroke of unknown onset due to lack of a witness. The clinical and CT findings in each group were compared. RESULTS: A total of 81 patients fulfilled the study criteria. There were 46 patients in group A, 17 patients in group B, and 18 patients in group C. There was no significant difference in CT findings between groups A and B. In group C, however, definite hypodense areas were more commonly found than in group A (56 vs. 0%; p<0.001) or in group B (56 vs. 11%; p=0.012). CONCLUSION: Based on our CT findings, stroke at awakening seems to be developing shortly before in a large subset of patients, making them potential candidates for acute stroke therapies.

Moderate atheroma of the aortic arch and the risk of stroke.

BACKGROUND AND PURPOSE: Severe atheroma >or=4 or 5 mm of the aortic arch is a risk factor for stroke. We investigated the most predictive characteristics of arch atheroma, including maximal plaque thickness, for subsequent cardiovascular events, and also examined whether moderate atheroma<4 mm is a risk of cerebral emboli. METHODS: The maximal plaque thickness (MPT) and plaque morphologies of the aortic arch were evaluated by transesophageal echocardiography in 236 patients with ischemic stroke. We assessed the relationship between the incidence of cardiovascular events, recurrent stroke or myocardial infarction, and the characteristics of the atheroma. We also investigated the thickness of atheroma in patients with known causes of stroke (n=148) and in patients with undetermined causes (n=19). RESULTS: Cardiovascular events occurred in 47 patients in the follow-up period with a mean of 3.5 years. MPT was a significant risk factor of the cardiovascular events, although plaque morphologies were not. For the receiver operator characteristics curve analysis, the suitable cutoff point of MPT associated with the cardiovascular events was 3.5 mm. Patients with MPT >or=3.5 mm had a higher risk of cardiovascular events than did those with MPT<3.5 mm. In addition, aortic atheroma with MPT >or=3.5 mm was more frequently observed in patients with undetermined causes of stroke than those with known causes at 68 vs. 39% (p=0.024). CONCLUSIONS: MPT >or=3.5 mm is the best predictor of subsequent cardiovascular events and a possible cause of embolic stroke.

Is stroke a paradoxical embolism in patients with patent foramen ovale?

OBJECTIVE: Purpose was to assess the stroke mechanism in patients with patent foramen ovale (PFO). METHODS: We reviewed the medical records of 111 stroke patients with PFO and sinus rhythm (PFO-S group), 25 with PFO and atrial fibrillation (AF) (PFO-AF group) and 67 with AF but not PFO (AF group), who had received contrast transesophageal echocardiography. The clinical and neuroradiological findings were then compared among the three groups. Deep vein thrombosis was investigated in 93 patients with PFO. We determined the number of patients with definite paradoxical embolism who met three criteria: deep vein thrombosis, neuroradiological features indicating embolic stroke, and the absence of other sources of emboli. We also evaluated those with probable paradoxical embolism who met two of the three criteria. RESULTS: The PFO-S group more frequently exhibited hypercholesterolemia (p<0.0001) and lesions limited to the posterior circulation (p<0.0004), and less frequently exhibited large or cortical lesions in the anterior circulation (p=0.0008, p<0.0001, respectively), than the PFO-AF and AF groups. In the PFO-S and PFO-AF groups, other sources of emboli such as a cardiac source of emboli, cerebral artery stenosis > or =50%, or complicated atheroma in the aortic arch were identified in 72 cases (52.9%). In the 93 patients with examination for deep vein thrombosis, the definite and probable criteria of paradoxical embolism were fulfilled only in three (3.2%) and 33 cases (35.5%), respectively. CONCLUSION: In stroke patients with PFO, not only paradoxical brain embolism through the PFO but also other causes of stroke may contribute to the development of stroke.

Mechanisms of bihemispheric brain infarctions in the anterior circulation on diffusion-weighted images.

BACKGROUND AND PURPOSE: Multiple acute brain infarctions in both cerebral hemispheres usually suggest an embolic mechanism, particularly one of aortic or cardiac origin. The purpose of this study was to clarify the etiologic mechanisms and topographic features of bihemispheric infarctions depicted on diffusion-weighted imaging (DWI). METHODS: Among 411 consecutive patients with ischemic stroke who underwent MR imaging in the acute phase, DWI showed bilateral infarctions in 19 (4.6%). In these patients, we analyzed the presence of carotid, aortic or cardiac embolic sources by using ultrasonography, cerebral angiography, and/or transesophageal echocardiography and evaluated the size and topographic distribution of the lesions. We assessed intracranial cross-flow through the anterior communicating artery, mainly on the basis of the anatomic information obtained from angiography or MR angiography. RESULTS: Bilateral lesions were derived from cardiac and/or aortic embolic sources in 16 (84%) of 19 patients and appeared to originate from unilateral carotid diseases in three (16%). In nine (82%) of 11 patients with cardiac embolic sources, at least one large territorial or subcortical lesion was found in either hemisphere, whereas in all eight patients without a cardiac embolic source, the lesions were small and disseminated bilaterally. CONCLUSION: Unilateral carotid lesions can cause bihemispheric infarctions through cross-flow in the anterior communicating artery. On DWI, small bihemispheric, disseminated lesions strongly suggest an artery-to-artery embolism. In such cases, aortic and carotid lesions should be assessed as potential embolic sources.

Right-to-left shunt evaluated at the aortic arch by contrast-enhanced transesophageal echocardiography.

OBJECTIVE: The right-to-left shunt (RLS) is diagnosed by contrast-enhanced transesophageal echocardiographic monitoring of the bilateral atria (cTEE-BA). However, the procedure is often disturbed by nonsmoke spontaneous individual contrast (NSSIC) with fast motion, which appears in the left atrium after respiratory maneuvers without administration of a contrast medium and moves past in several seconds. We attempted to perform cTEE monitoring of the aortic arch (cTEE-AA) for evaluation of the RLS and compared the findings with those of cTEE-BA. METHODS: Both cTEE-BA and cTEE-AA were performed in 168 patients with ischemic stroke (133 men and 35 women; mean age +/- SD, 62.0 +/- 14.4 years). The frequency of NSSIC in the left atrium was compared with that in the aortic arch during the respiratory maneuver. When contrast much brighter than the NSSIC was visualized in the left atrium and the aortic arch during the respiratory maneuver with administration of the contrast medium, we considered the RLS to be positive in the cTEE-BA and cTEE-AA, respectively. Findings were then compared between the 2 examinations. RESULTS: Nonsmoke spontaneous individual contrast was more frequently observed in the left atrium than the aortic arch (61.3% versus 14.9%; chi2 test, P < .0001). The RLS was positive in 34 patients in the cTEE-BA and in 39 patients in the cTEE-AA. The sensitivity and specificity of the cTEE-AA for the cTEE-BA were 100% and 96.3%, respectively. CONCLUSIONS: The cTEE-AA may be an alternative method for detection of an RLS, especially in patients with a large amount of NSSIC in the left atrium.

[Multiple brain infarctions in a young patient with Buerger's disease. A case report of cerebral thromboangiitis obliterans].

We report a 46-year-old woman with Buerger's disease who presented vascular dementia. In her early thirties, she began to feel cold sensation and pain in the lower extremities and later developed Raynaud's phenomenon in the upper extremities. The diagnosis of Buerger's disease was established on the basis of angiographic findings which showed the obstruction of peripheral vessels in both anterior tibial arteries. She was admitted to our hospital because of a transient attack of left brachial monoparesis and two episodes of epileptic seizure with progressive cognitive impairment for preceding five years. Neurological examination revealed acalculia, constructional apraxia, recent memory disturbance, and hyperreflexia of the left limbs without motor disturbance. Brain MRI revealed multiple infarctions mainly located in the border zone territories of the major cerebral arteries. Conventional angiography failed to detect abnormalities of cerebral vessels. She had no cardiovascular abnormality or coagulopathy. Cerebrovascular complications, so-called cerebral thoromboangiitis obliterans (CTAO), occur approximately in 2% of patients with Buerger's disease. CTAO has two types. Type 1 is associated with large artery changes and type 2 is associated with medium and small artery changes. Patients with type 2 CTAO usually have multiple infarcts in the cerebral arterial border zones and may develop progressive cognitive decline without motor deficit. Her clinical features are compatible with type 2 CTAO. While CTAO is a relatively rare manifestation of Buerger's disease, it should be suspected in cases of Buerger's disease in association with cognitive impairment of unknown onset.

Link between linear hyperintensity objects in cerebral white matter and hypertensive intracerebral hemorrhage.

BACKGROUND: We retrospectively studied the relationship between linear hyperintensity objects (LHOs) on T(2)-weighted magnetic resonance images (MRI) in the cerebral white matter and the occurrence of hypertensive intracerebral hemorrhage (HIH). METHODS: Forty-nine hypertensive patients with a fixed imaging condition MRI were classified into three groups: HIH (n = 17), ischemic stroke due to hypertensive vasculopathy (n = 19), and hypertension only (n = 13). After assessing clinical and radiological background information among these groups and the reliability of LHO measurements, polynomial logistic regression analysis was used to identify the factors relating to HIH. RESULTS: HIH had a significantly higher LHO number (p = 0.002) and larger diameter (p = 0.007). The LHO number showed an excellent interrater (kappa = 0.91, 95% CI = 0.87-0.94, SEM = 6.2%) and intrarater reliability (kappa = 0.95, 95% CI= 0.92-0.97, SEM = 4.8%), and was the most significant independent indicator of HIH (OR = 1.29, 95% CI = 1.05-1.60, p = 0.017). The number of microbleeds was an additional indicator (OR = 3.73, 95% CI = 1.10-12.65, p = 0.034). CONCLUSIONS: LHOs are closely linked to HIH. A prospective, longitudinal study is needed to clarify whether LHOs can predict HIH.

[Stroke recurrence in patients with brain embolism and patent foramen ovale--association with deep vein thrombosis detected by ultrasonography].

Paradoxical embolism through a patent foramen ovale (PFO) is a recognized cause of stroke, but its prognosis is not well known. The aim of our study is to evaluate differences in risk factors, recurrent stroke subtypes and effects of various preventive therapies between PFO associated stroke patients with and without deep vein thrombosis (DVT). A total of 63 patients who had an embolic stroke with a PFO within 3 months from stroke onset were enrolled. Venous ultrasonography, which was performed in all the patients, revealed DVT in 26 patients (41%). Venous thrombosis was confined to the isolated calf veins in 24 of 26 cases (92%). For prevention of stroke recurrence, warfarin was administrated in 32 patients, antiplatelet therapy was given in 21 patients, and combination of warfarin and antiplatelet therapy was chosen in 10 patients. Three patients with DVT and three other patients without DVT had recurrent ischemic events during a mean follow-up period of 14.6 months. In all the 3 patients without DVT, complicated aortic arch lesions were also observed, and 2 of them had lacunar infarcts. In all the three patients with DVT recurrent embolic stroke or TIA occurred in spite of anticoagulant therapy. Their INR values at the time of recurrence were all below 1.7, and 2 of them were associated with atrial septal aneurysm (ASA). Association with PFO, ASA, and DVT may be a substantial risk factor for recurrent stroke. Higher INR value in anticoagulation may be recommended for such patients to prevent stroke recurrence.

Quantitative magnetic detection of finger movements in patients with Parkinson's disease.

To develop a new measurement tool for quantitatively detecting the finger movement of a patient with Parkinson's disease (PD), we designed a magnetic sensing system consisting of a magnetic induction coil, a sensing coil, and a circuit unit. The sensing coil detects the inducted magnetic field that varies with the distance between the two coils, and the detected signals are demodulated in the circuit unit in order to obtain the variation voltage from the oscillation frequency. To obtain a coefficient for converting voltage to distance, we measured the output voltages for seven fixed finger positions of 12 normal volunteers. The voltage differences corresponding to the finger movement in 20 PD patients, six age-matched controls, and 12 normal volunteers were then recorded for 30s. To investigate the velocity and acceleration of the finger movement, we calculated their waveforms from the measured displacement waveform. We also detected the main frequency of the tapping rhythm by using a fast Fourier transform (FFT). The averaged amplitude of each waveform decreased with the disorder in the Hoehn-Yahr (HY) stage, while the averaged tapping frequency of PD patients did not have any correlation with this stage. It can be concluded that this magnetic sensing system can assess finger movement quantitatively.

Aortic arch atherosclerotic lesions and the recurrence of ischemic stroke.

BACKGROUND AND PURPOSE: Aortic arch atherosclerotic lesions are often associated with embolic brain infarction. We investigated the relationship between stroke recurrence and the characteristics of aortic arch atherosclerotic lesions. METHODS: Among 487 stroke patients who underwent transesophageal echocardiography, 283 patients with brain embolism diagnosed without significant occlusive lesions (> or =50%) in their cerebral arteries were included in this study. We measured the intima-media thickness (IMT) and evaluated the extension and mobility of the aortic arch atherosclerotic lesions. During a mean follow-up period of 3.4 years, we investigated the relationship between stroke recurrence and the various characteristics of the aortic arch atherosclerotic lesions. RESULTS: An IMT > or =4.0 mm was found in 67 patients (25.3%). In 51 of these patients, the aortic lesions extended to the origin of the branches of the arch. Recurrences of cerebral ischemic events were found in 32 patients (recurrence group) and not in the other 251 (nonrecurrence group). Aortic atheroma > or =4.0 mm (41% versus 22%), aortic atheroma extending to the branches (63% versus 39%), and both (38% versus 16%) were more frequently seen in the recurrence group than in the nonrecurrence group (P<0.05, P<0.1, P<0.01, respectively). After adjustment for age and the presence of hypertension, an aortic atheroma that was > or =4.0 mm as well as extending to the branches was found to be an independent predictor of ischemic stroke recurrence (hazard ratio=2.42, P<0.05). CONCLUSIONS: Stroke recurrence is associated with the severity of the atheroma (IMT > or =4.0 mm) and plaque extension to the branches.

Magneto-encephalographic measurement of neural activity during period of vertigo induced by cold caloric stimulation.

The aim of this study was to investigate neural activity during period of vertiginous sensation, induced by caloric stimulation. After caloric vestibular stimulation (CVS) by cold water of five volunteers (n=5, age: 30+/-10), auditory evoked magnetic fields (AEFs) during the subsequent period of vertiginous sensations were measured by magnetoencephalography (MEG). Current-arrow maps (CAMs) were produced to estimate the spatial current distribution of the AEF responses, and a rotation value (dI(rot)) was calculated from the CAM. The worth of the dI(rot) values as indicators of vertigo was evaluated by comparing them with earlier reported values for elderly control (n=11, age: 67+/-5) and chronic dizziness (CD) (n=27, age: 68+/-8) groups (obtained from AEF responses with no the CVS). Although all volunteers felt vertigo during the AEF measurements, the AEF waveforms and CAM pattern only showed slight changes. While the dI(rot) values (1.43+/-0.73) just after CVS were not significantly different from those (1.59+/-0.46) for the elderly controls, they were significantly different from those (3.54+/-1.34) for the CD patients. These findings suggest that (i) the new parameter (dI(rot)) is more sensitively indicates dizziness (non-rotatory sensation) than vertigo (ii) the auditory cortical region may play an important role in body-balance perception of floating sensations.

Abnormal auditory neural networks in patients with right hemispheric infarction, chronic dizziness, and moyamoya disease: a magnetoencephalogram study.

The purpose of this study was to determine whether the auditory cortex is sensitive to cortical insults and to determine the specificity of the insults in three clinical situations with different cortical involvement. Auditory-evoked magnetic fields of ten normal subjects, 8 patients with right hemispheric infarction, 11 with chronic dizziness, and 2 with moyamoya disease were measured. To analyze the abnormality of auditory neural networks, the magnitude ratio and the angle difference (Deltatheta) between response vectors, which were determined from maximum current arrows corresponding to the N100m peak for contralateral and ipsilateral stimuli were used. A normal range of the parameters was defined so that abnormal values could be determined. Of the three parameters, Deltatheta was the most sensitive: 4 patients with right hemispheric infarction, 4 with chronic dizziness, and 1 with moyamoya disease had abnormal Deltatheta. The electrical activity in the patients with such abnormal Deltathetas had a circular current pattern. These findings suggest that right infarction lesions sometime affect the left auditory neural network, dizziness is caused by abnormal neural networks between the vestibular cortical area and the auditory cortex or by an imbalance between left and right auditory-cortex activities, and moyamoya-disease patients have almost normal auditory-electrical activity.