[Hemodynamic activities in children with autism while imitating emotional facial expressions: a near-infrared spectroscopy study].

OBJECTIVE: To examine the hemodynamic activities in the frontal lobe, children with autistic disorder and matched controls underwent near-infrared spectroscopy (NIRS) while imitating emotional facial expressions. METHODS: The subjects consisted of 10 boys with autistic disorder without mental retardation (9 - 14 years) and 10 normally developing boys (9 - 14 years). The concentrations of oxyhemoglobin (oxy-Hb) were measured with frontal probes using a 34-channel NIRS machine while the subjects imitated emotional facial expressions. RESULTS: The increments in the concentration of oxy-Hb in the pars opercularis of the inferior frontal gyrus in autistic subjects were significantly lower than those in the controls. However, the concentrations of oxy-Hb in this area were significantly elevated in autistic subjects after they were trained to imitate emotional facial expressions. The increments in the concentration of oxy-Hb in this area in autistic subjects were positively correlated with the scores on a test of labeling emotional facial expressions. CONCLUSIONS: The pars opercularis of the inferior frontal gyrus is an important component of the mirror neuron system. The present results suggest that mirror neurons could be activated by repeated imitation in children with autistic disorder.

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.

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.

Evaluation of the GABAergic nervous system in autistic brain: (123)I-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 Asperger's 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).

Function of the frontal lobe in autistic individuals: a proton magnetic resonance spectroscopic study.

PURPOSE: In this investigation, we studied differences in chemical metabolites in certain brain regions between autistic patients and normal control subjects. METHODS: Proton magnetic resonance spectroscopy ((1)H-MRS) was used to evaluate functional activity in these regions. Specific regions studied were right and left dorsolateral prefrontal cortex(DLPFC) and the anterior cingulated cortex(ACC). RESULTS: In the ACC, the N-acetylaspartate(NAA)/creatine/phosphocreatine(Cr) ratio in autistic patients (n=31) was significantly lower than that in control subjects (n=28). The decrease in the NAA/Cr ratio for the ACC was much greater in the group with worst social ability. NAA/Cr for the left DLPFC and social ability of autistic patients also correlated well. Furthermore, NAA/Cr for the left DLPFC in the group with intelligence quotient (IQ) below 50 was significantly less than in controls. NAA/Cr for the right DLPFC in autistic patients was not decreased compared to controls, and did not correlate with IQ or social ability. CONCLUSIONS: These findings suggest neuronal dysfunction in the ACC and left DLPFC in autism, and also a relationship between social disability and metabolic dysfunction in these regions. Dysfunction in the ACC and the left DLPFC may contribute to the pathogenesis of autism.

[A study of cognitive and behavioral development in pre-school and school children with high functioning pervasive developmental disorder].

It has been reported that school-aged children with high functioning pervasive developmental disorder (HFPDD) have numerous difficulties in their school class. We used three psychological tests to investigate whether there is a relationship between intelligence and cognitive, behavioral development in children with HFPDD. The three tests used were an intelligence test (WIPPSI, WISC-lll), the P-F (Picture Frustration) study, and behavioral assessment by their parents. In the P-F study, 60% of 23 children with HFPDD showed a GCR% (Group Conformity Rating) above or below the standard. There was no relationship between GCR% and IQ. In the behavioral assessment by their parents, over 50% of 40 children with HFPDD showed maladaptive behaviors. The high VIQ group showed more maladaptive behaviors than the low VIQ group. These findings suggest that school-aged children with H-FPDD need educational treatment for social deficits and maladaptive behaviors.

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

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.

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.

A novel mutation at the N-terminal of SMN Tudor domain inhibits its interaction with target proteins.

Although most patients with spinal muscular atrophy (SMA) are homozygous for deletion of the SMN1 gene, some patients bear one SMN1 copy with a subtle mutation. Detection of such an intragenic mutation may be helpful not only in confirming diagnosis but also in elucidating functional domains of the SMN protein. In this study, we identified a novel mutation in SMN1 of two Japanese patients with type I SMA. DHPLC and sequencing analysis revealed that they harbored a point mutation in SMN1 exon 3, 275G > C, leading to tryptophan-to-serine substitution at amino acid 92 (W92S) at the Nterminal of SMN Tudor domain. In-vitro protein binding assays showed that the mutation severely reduced interaction of the domain with SmB protein and fibrillarin, suggesting that it impairs the critical function of SMN. In conclusion, we reported here that a novel mutation, W92S, in the Tudor domain affects the interaction of SMN with the target proteins.

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.

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.

Effect of heat stress on lipopolysaccharide-induced vascular permeability change in mice.

The effect of heat shock protein (hsp) induction on lipopolysaccharide (LPS)-induced increase in vascular permeability was studied in mice as a model of inflammatory mediator-induced inflammatory response. Mice were exposed to an ambient temperature of 43 degrees C for 1 h and then returned to 23 degrees C to recover up to 24 h. Dermal contents of hsp70 and hsp90 but not heat shock cognate protein (hsc)70 increased at 6 h after heat exposure and returned to the basal level at 24 h. LPS was injected subcutaneously at 0, 2, 4, 6, or 24 h after heat exposure. Two hours after LPS injection, vascular permeability was assessed by dermal accumulation of intravenously injected dye. LPS-induced dye leakage was reduced by 42 and 49% in heat-exposed mice after recovery for 4 and 6 h, respectively. Increases in dermal tumor necrosis factor-alpha (TNF-alpha) and prostaglandin E(2) (PGE(2)) contents induced by LPS were significantly reduced in the heat-stressed mice recovered for 6 h. LPS-induced increase in cyclooxygenase-2 but not TNF-alpha mRNA was attenuated in heat-stressed mice. Deoxyspergualin, an inhibitor of hsc70 and hsp90, and geldanamycin, a specific hsp90 inhibitor, dose dependently reversed the inhibitory effect of heat stress on LPS-induced dye leakage and dermal TNF-alpha content but not PGE(2) content. These results suggest that heat stress attenuated LPS-induced vascular permeability change by inducing hsp90, leading to inhibition of TNF-alpha production.

[The preventive effect of allopurinol spray on stomatitis induced by anti-cancer drugs].

The present study was conducted to evaluate the effect of allopurinol spray on stomatitis induced by chemotherapy for esophageal cancer. The chemotherapeutics used consisted of 5-FU + CDDP (FC) given to 40 patients and 5-FU + ND (FN) given to 9 patients. Allopurinol solution for spray was prepared using a gelatin agent as base. The allopurinol spray was used 3-5 times daily before and after chemotherapy. The Japan Society for Cancer Therapy's criteria for stomatitis were used. With FN-therapy, no stomatitis was observed. With FC-therapy, 9 of 40 patients developed stomatitis of grade 1 (8 patients) or grade 2 (1). The incidence of stomatitis was 18.4% with all therapies and 22.5% with FC-therapy. The average graded toxicity was 0.20 for all therapies and 0.25 for FC-therapy. These results suggest that allopurinol spray is markedly effective for the prevention of stomatitis induced by chemotherapy. In addition, allopurinol spray is portable and convenient, and resulted in less nausea or vomiting than mouthwash.