Emiko Fujii

DEVELOPMENTAL BRAIN CHANGES INVESTIGATED WITH PROTON MAGNETIC RESONANCE SPECTROSCOPY

Volume‐selective proton magnetic resonance spectroscopy (1H‐MRS) of the brain was performed with a 1.5 Tesla magnet in 47 healthy children and in six healthy adults. Peaks of N‐acetylaspartate (NAA), choline (Clio) and creatine (Cr) were observed in all cases, but a lactate peak was not observed. In the right parietal region, I H‐MRS revealed increases in the rations of NAAJCho and NAA/Cr and a decrease in Cho/Cr with advancing age. The most rapid changes were noted between one and three years of age. 1H‐MRS of the right frontal region also was performed in 21 cases (20 children and one adult). In the right frontal region, there was an increase in the ratio of NAA/Cho and a decrease in Cho/Cr with advancing age, while a developmental change was not observed in the ratio of NAA/Cr. The ratios of both NAA/Cho and NAA/Cr were lower in the right frontal region than in the right parietal region. These results show that developmental changes and regional variation of metabolites are observed in 1 H‐MRS of the brain, and need to be considered in its application.

Evaluation of the GABAergic nervous system in autistic brain : 123I-iomazenil SPECT study

PURPOSE To evaluate the GABA(A) receptor in the autistic brain, we performed (123)I-IMZ SPECT in patients with ASD. We compared (123)I-IMZ SPECT abnormalities in patients who showed intellectual disturbance or focal epileptic discharge on EEG to those in patients without such findings. SUBJECTS AND METHODS The subjects consisted of 24 patients with ASD (mean age, 7.3±3.5 years), including 9 with autistic disorder (mean age, 7.0±3.7 years) and 15 with Aspergers disorder (mean age, 7.5±3.2 years). We used 10 non-symptomatic partial epilepsy patients (mean age, 7.8±3.6 years) without intellectual delay as a control group. For an objective evaluation of the (123)I-IMZ SPECT results, we performed an SEE (Stereotactic Extraction Estimation) analysis to describe the decrease in accumulation in each brain lobule numerically. RESULTS In the comparison of the ASD group and the control group, there was a dramatic decrease in the accumulation of (123)I-IMZ in the superior and medial frontal cortex. In the group with intellectual impairment and focal epileptic discharge on EEG, the decrease in accumulation in the superior and medial frontal cortex was greater than that in the group without these findings. CONCLUSION The present results suggest that disturbance of the GABAergic nervous system may contribute to the pathophysiology and aggravation of ASD, since the accumulation of (123)I-IMZ was decreased in the superior and medial frontal cortex, which is considered to be associated with inference of the thoughts, feelings, and intentions of others (Theory of Mind).

Short‐latency somatosensory evoked potentials in infantile autism: evidence of hyperactivity in the right primary somatosensory area

Children with infantile autism sometimes show hyperesthesia or hypoesthesia to touch, pain, and/or temperature. To clarify the pathophysiology, we examined short‐latency somatosensory evoked potentials (S‐SEPs), elicited by median nerve stimulation, in 24 children with infantile autism (17 males, seven females; age range 2y 2mo–9y; mean age 4y 2mo [SD 1y 7mo]). We also evaluated relationships between S‐SEP findings and clinical manifestations. Of the 24 children, 10 showed abnormal S‐SEPs as follows: prolonged peak latency of N20 (n=2), extended interpeak latency of P13/14–N20 (n=7), appearance of a giant SEP (n=1), and a more than twofold right hemispheric peak‐to‐peak amplitude predominance of N20–P25 (n=5). In addition, a peak‐to‐peak amplitude of N20–P25 elicited by left median nerve stimuli was significantly higher than that obtained with right median nerve stimuli, which indicated right hemispheric hyperactivity relative to the left (p=0.008). Infantile autism is frequently associated with somatosensory abnormalities and right hemispheric hyperactivity relative to the left, especially in the primary somatosensory area. This is believed to contribute to the pathophysiology of infantile autism, especially the idiopathic form.

Infantile spasms: localized cerebral lesions on SPECT.

Summary: Ten infantile spasms (IS) patients had single photon emission computed tomography (SPECT) with [99mTc]HMPAO, EEG, and magnetic resonance imaging (MRI) studies. SPECT showed localized cerebral hypo‐perfusion in 7 infants (4 unifocal; 3 multifocal) always involving the temporal regions either unilaterally or bilaterally. EEGs obtained in near time of the SPECT studies showed focal abnormalities in all 7 infants with hypoper‐fusion on SPECT, with complete correspondence of the abnormalities in 5. MRI showed localized cerebral lesionsin only 3 of the 10 infants, all of whom had corresponding areas of hypoperfusion on SPECT. Our study indicates that localized cerebral abnormalities (especially of the temporal lobes) may often be associated with IS and that such patients may have localized cerebral hypoperfusion on SPECT even when the MRI is normal.

A proton magnetic resonance spectroscopic study in autism spectrum disorders: amygdala and orbito-frontal cortex.

We previously reported neural dysfunction in the anterior cingulate cortex and dorsolateral prefrontal cortex in autistic patients using proton magnetic resonance spectroscopy ((1)H-MRS). In this investigation, we measured chemical metabolites in the left amygdala and the bilateral orbito-frontal cortex (OFC), which are the main components of the social brain. We also examined the association between these metabolic findings and social abilities in subjects with autism. The study group included 77 autistic patients (3-6years old; mean age 4.1; 57 boys and 20 girls). The control subjects were 31 children (3-6years old; mean age 4.0; 23 boys and 8 girls). Conventional proton MR spectra were obtained using the STEAM sequence with parameters of TR=5 sec and TE=15 msec by a 1.5-tesla clinical MRI system. We analyzed the concentrations of N-acetylaspartate (NAA), creatine/phosphocreatine (Cr), and choline-containing compounds (Cho) using LCModel (Ver. 6.1). The concentrations of NAA in the left amygdala and the bilateral OFC in autistic patients were significantly decreased compared to those in the control group. In the autistic patients, the NAA concentrations in these regions correlated with their social quotient. These findings suggest the presence of neuronal dysfunction in the amygdala and OFC in autism. Dysfunction in the amygdala and OFC may contribute to the pathogenesis of autism.

Successful allogeneic unrelated bone marrow transplantation using reduced-intensity conditioning for the treatment of X-linked adrenoleukodystrophy in a one-yr-old boy

Abstract:  The childhood cerebral form of X‐linked ALD is a demyelinating disorder of the central nervous system, which rapidly leads to total disability and death. Allogeneic stem cell transplantation benefits patients who show early evidence of the demyelination. We report here a one‐yr‐old boy with ALD who received HLA‐matched unrelated BMT in an early stage of the disease after careful planning and observation since his birth. BMT was performed when MRI began to show slight signal intensity changes in the white matter of the brain. Pretransplant conditioning consisted of fludarabine, l‐PAM and TBI (2 Gy). GVHD prophylaxis consisted of cyclosporine A and short‐course methotrexate. The patient showed an uneventful BMT course with fast and stable engraftment. Following BMT, the plasma levels of VLCFA decreased gradually and MRI changes improved. The patient did not have any evidence of further neurological deterioration 22 months following the transplant. Although this is still a short follow‐up, it has been shown that BMT should be considered when a child has a biochemical diagnosis and MRI findings of ALD without any neurological signs. RIST should be considered as a pretransplant conditioning for ALD.

Decreased benzodiazepine receptor and increased GABA level in cortical tubers in tuberous sclerosis complex

PURPOSE To elucidate the functional characteristics of cortical tubers that might be responsible for epilepsy in tuberous sclerosis complex (TSC), proton magnetic resonance spectroscopy ((1)H-MRS) and [123I] iomazenil (123I-IMZ) single photon emission computed tomography (SPECT) were performed. METHODS (1)H-MRS using a clinical 3-tesla magnetic resonance imager was performed in four children with TSC and 10 age-and sex-matched healthy control subjects. A single voxel was set on the right parietal lobe in control subjects. In patients with TSC, a single voxel was set on the epileptogenic tuber in the parietal or temporal lobe, and another voxel was set on the contralateral normal-appearing brain region. N-Acetylaspartate (NAA), myo-Inositol (mIns) and Glutamate (Glu) were analyzed using a conventional STEAM (Stimulated Echo Acquisition Mode) method. The concentration of gamma-aminobutyric acid (GABA) was quantified using MEGA-Point Resolved Spectroscopy (PRESS). Interictal 123I-IMZ SPECT was examined in all four patients with TSC. RESULTS A significant decrease in the NAA concentration and significant increases in the mIns and GABA concentrations were detected in the cortical tubers of all 4 patients. No significant difference was observed in Glu concentrations. In all of the cortical tubers detected by magnetic resonance imaging, 123I-IMZ binding was significantly decreased. CONCLUSION Epileptogenesis in TSC might be caused by decreased inhibition secondary to the decrease in GABA receptors in dysplastic neurons of cortical tubers. An increase in the GABA concentration may compensate for decreased inhibition.

Patients with West syndrome whose ictal SPECT showed focal cortical hyperperfusion

To clarify the mechanism of clustered spasms in West syndrome (WS), we examined ictal SPECT and EEG, as well as those during the interictal period, in three patients with symptomatic WS who had apparent focal cerebral lesions. For ictal SPECT and EEG, we monitored the patients with EEG, and as soon as we noticed the occurrence of clustered spasms clinically and electroencephalographically, [(99m)Tc]ECD was injected intravenously and flushed thoroughly with saline. In these three patients, regional cerebral blood flow (rCBF) increased during ictus and decreased during the interictal period in the area that coincided with the focal cerebral lesion recognized by CT/MRI. The ictal hyperperfusion of bilateral basal ganglia was also detected in two of the three patients. The ictal EEG showed a diffuse slow wave complex corresponding to a clinical spasm. The sharp waves that preceded the diffuse slow wave complex and the spasm appeared in the same area in which rCBF increased during ictus. None of the patients showed partial seizure before or after clustered spasms clinically or electroencephalographically during the ictal SPECT study. Secondary generalization from a cerebral focus may explain the mechanism of spasms in these patients with WS: focal cortical discharge may primarily generate clustered spasms and trigger the brainstem and basal ganglia structures to produce spasms.

Somatosensory evoked potentials in attention deficit/hyperactivity disorder and tic disorder

OBJECTIVE Both attention deficit/hyperactivity disorder (ADHD) and chronic tic disorder (TD) are hyperkinetic disorders. These disorders often coexist with each other and frequently have sensory components. Therefore, we hypothesized that they might have a common pathophysiology involving the somatosensory system, especially hyper-excitabilities of primary somatosensory area. METHODS To evaluate sensory system excitability, we examined somatosensory evoked potentials (SEP) elicited by median nerve stimulation in 18 children with ADHD and 18 children with TD. RESULTS Three children with ADHD and 8 children with TD showed giant SEP and the peak-to-peak amplitude for N20-P25 was also significantly greater than that obtained from normally developing children (P<0.05 for ADHD and P<0.01 for TD). Children with TD had significant left-ward asymmetry of N20-P25 (P<0.01) and higher left-hemispheric N20-P25 than children with ADHD (P<0.05). CONCLUSIONS Although hyper-excitability of the primary somatosensory area is a common characteristic for ADHD and TD, its severity, especially in the left-hemisphere, differs (i.e. TD has left-ward hyper-excitability). SIGNIFICANCE The possibility remains that hyper-excitability of the primary somatosensory area is a reason why these disorders often coexist with each other and left-ward hyper-excitability of the primary somatosensory area is a unique feature of TD described for the first time.

Neuroradiological and neurofunctional examinations for patients with 22q11.2 deletion.

Since the neuroradiological features of patients with 22q11.2 deletion syndrome are not well-understood, examinations using functional imaging were performed in this study. Brain magnetic resonance imaging (MRI) and 1H-magnetic resonance spectroscopy (MRS) were performed using a clinical 3-Tesla MR imager in 4 patients with 22q11.2 deletion syndrome (2 boys and 2 girls; aged 2-6 years.) and 20 age- and sex-matched healthy control subjects. Furthermore, interictal 123I-iomazenil (IMZ) single photon emission computed tomography (SPECT) was examined in 2 of the 4 patients. Among the 4 patients with 22q11.2 deletion syndrome, 2 patients showed polymicrogyria and 1 patient showed agyria. Those patients with brain malformations also showed abnormal brain artery patterns and decreased accumulation of IMZ in 123I-IMZ SPECT. Although all 4 patients showed epileptic discharges in their electroencephalograms (EEG), one patient with polymicrogyria had no seizure episodes. Decreases in γ-aminobutyric acid (GABA) corresponding to the areas of polymicrogyria and/or epileptic discharges in EEG were shown in all patients except for the patient with agyria. Although consistent evidence was not seen in patients with 22q11.2 deletion syndrome in this study, brain malformations and disturbances of the GABAergic nervous system would be underlying mechanisms of the neurodevelopmental abnormalities in this syndrome.