Neurotransmitters should fulfil the following main three criteria; 1) they should be localized in synaptic terminals, 2) they should have certain actions on neurons, 3) they should be released from the terminals after nerve stimulation. In addition to the above three, recent studies have revealed that neurotransmittersshould have their own receptors. Moreover, recent immunohistochemical studies have revealed certain neurons to have two or more neurotransmitter candidates; one classic and the other non-classic neurotransmitter candidate. These progresses in the field of neurotransmitter science were briefly reviewed.
As an extension of the basic studies mentioned above, clinical studies of measurements of neurotransmitter markers in brains of neurodegenerative disorders are now actively performed. Based on my own studies in the same line, it is possible to summarize the fundamental patterns of neurotransmitter alterations in neurodegenerative disorders as follows: 1) they decrease as a result of degeneration of neuron groups (the most popular pattern); 2) they decrease in spite of the morphologically normal appearance of neurons (“biochemical non-functioning”); 3) they increase in the projecting regions of certain neurons which escaped degeneration. This may be a result of simple condensation of normal nerve terminals or real increase based on the compensatory mechanisms.

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Recent rapid development of the MRI system has enabled us to diagnose pricisely the disorders of the central nervous system (CNS) also in neonates and young children. Because of a long studying time, the use of oral chloral hydrate or other alternative drugs for sedation, such as secobarbital and meperidine, is necessary for young children under 6 years of age. The advantages of MRI are the optional plane imaging, a high contrast resolution, and the artifact-free imaging from the surrounding bones and air. MRI can detect myelination disorders and the lesions in the posterior fossa, the middle fossa, and the spinal canal. These abnormalities are difficult to depict with conventional X-ray CT scanning. MRI is useful also for the survey of various congenital anomalies of the brain and the spine. Furthermore, it is sensitive enough to detect the CNS blood flow and the cerebrospinal fluid (CSF) flow. Arteriovenous malformation, moyamoya disease, and sinus thrombosis are diagnosed by MRI without using contrast media, CSF flow void phenomena in the aqueduct and the Monro's foramina are indexes of the CSF pathway obstruction and of normal pressure hydrocephalus.

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The aim of this symposium was to discuss recent advances of evoked potentials in child neurological disorders. Five topics, including visual evoked potentials, brainstem auditory evoked potentials, short latency somatosensory evoked potentials to median nerve and lower extremity peripheral nerve stimulation, and motor and somatosensory evoked potentials to magnetic stimulation were discussed. Each speaker reviewed the usefulness and limitations of each type of evoked potentials as it applies to pediatric cases.

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Under the pathological conditions, the VEP may show changes in amplitude, latency, or waveform in one or more of its components. The major advantage of the pattern reversal VEP over the flash VEP lies in smaller variability in the waveform and latency of its components in the healthy population.
The flash VEP is, however, particularly useful to infants and newborns. The variation in the waveform of the flash VEP was evaluated, and Type V (Fig. 1) was abnormal waveform.
Subsequently, patients with various CNS diseases were examined. Acute hemiplegic patients showed high amplitude or increased latency patterns.
In 45 percent of the West syndrome cases, VEP showed abnormal responses. The patients with asphyxia, respiratory distress syndrome and mental retardation showed increased latency. Latency was decreased in hypoglycemia and hypocalcemia of newborns, and it was increased or decreased in autism and epilepsy.
In our study, it was concluded that the rhythmic after-discharge is a true response. This assumption is supported by the following observations:(1) the of discharge of VEP appeared before the occurrence fo the alpha-wave in EEG (2) the frequency of the after-discharge was generally higher than that in EEG and (3) the frequency of the after-discharge did not change between the conditions of the resting state and hyperventilation. There was no after-dischage in VEP in patients with a history of encephalitis even when their IQs were normal, and the latency was increased in pattern reversal VEP.

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In 1967, Sohmer and Feinmesser recorded four negative peaks from extracochlear surface electrodes and they stated that the later components may be due to repetitive firing of auditory nerve fibers or may be due to the discharge of neurons in brain stem auditory nuclei. In 1970, Jewett, Romano and Williston presented the first full description of the scalp responses, postulated to be generated by brainstem nuclei. Since then, the auditory brainstem response (ABR) technique has attracted attention because it satisfied two previously unattainable needs; 1) a means of quantitative measurement of changes in auditory function in newborn babies or uncooperative patients, and 2) the detection of brainstem neurological abnormalities. Recording during wakefulness and in sleep or under drug intoxication has shown that ABRs are independent of the level of arousal or attention, and this feature is particularly useful for people unable to cooperate appropriately. Because of the close relationship to the anatomy of brainstem pathways, ABRs offer a neurophysiological index of neuronal function at the level of the brainstem. At present, these responses have become widely recognized as an important tool for the diagnosis of neurological diseases.
One specific feature of the ABR is its dependence on maturation. The ABR appears at around 26 weeks of gestation and thereafter undergoes systematic changes in latency, amplitude and threshold. By using a supramaximal intensity of more than 60 dBHL, it is possible to evoke in all newborn babies with sufficient hearing ability, waves I, III and V. The principal pathophysiological findings in neurologic diseases concern the absolute and interpeak latencies of each wave, the amplitude ratio (wave V /wave I), the response threshold, the response to changes in the rate of stimulation, and the elimination of specific components. The amplitude ratio for which there are sufficient data is wave V /wave I, which usually exceeds 1 in normal subjects. The younger the patient, the longer are all the component latencies, the smaller the amplitude ratios, and the larger the effect of changes in the rate of stimulation. Therefore, age specific norms must be determined. Besides absolute latencies, interwave latencies are clinically significant since they allow evaluation of the brainstem function even in the presence of a hearing disturbance. The application of the ABR technique to various auditory and neurological diseases was discussed. It is noteworthy that none of these abnormalities is specific for any disease, and normal ABRs do not guarantee that hearing is normal in the perceptual sense, because further transmission may be disturbed. MLPs may be useful in such a situation. Conversely, the absence of several brainstem components dose not necessarily mean structural damage to the brainstem neurons or hearing impairment. The diagnosis of an audiological or a neurological disorder must be made on the basis of the clinical status and other available examination.

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We investigated short latency somatosensory evoked potentials (SSEP) to median nerve stimulation in normal children and children with neurological disorders. The waveform of SSEP in normal children was almost the same as that in adults. The peak latency and interpeak latency in normal children changed during their development. Moreover, after 3 years of age, each peak latency was positively correlated with the body length and arm length. Each peak latency per 1m of body length decreased with age. We examined SSEP in children with various neurological disorders and found that SSEP was useful for evaluating sensory functions and somatosensory damages in children who were unable to cooperate in clinical examinations. Using SSEP, we could estimate the distal margin of the lesion in the somatosensory pathway, but it was difficult to determine the acurate range of the lesion.

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We have evaluated the short latency somatosensory evoked potentials (SSEPs) following peroneal and posterior tibial nerve stimulation in 27 normal children and adults, and then applied SSEPs examination following peroneal nerve stimulation to 6 children with neurological deficits. Features of the evoked potentials following peroneal nerve stimulation in normal children were almost similar to those in adults, but we found several points characteristic in children; a higher incidence of evoked potentials and a clearer appearance of “standing potential” at the lower thoracic vertebral level than in adults. Spinal afferent conduction velocity reached at a maximum at 3-4 years of age.
The SSEPs following peripheral nerve stimulation in lower extremities are useful in pediatric neurology to determine the level of the spinal lesion, to reveal the distribution and pathophysiology of the spinal dysfunction, and to analyze the prossess of the disease progression.

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Motor evoked potentials (MEP) by magnetic stimulation on the scalp and the spinous processes of the 7th cervical (C 7) and 5th lumbar (L 5) vertebrae were studied in 20 normal subjects and 10 patients with the pyramidal tract lesions. The magnetic stimulator composed of two flat helical coils with mean inner diameters of 12.0 and 2.2 cm. The evoked muscle action potentials were recorded from the thenar muscle in the hand and abductor hallucis muscle in the leg. The mean peak latencies of MEP recorded from the thenar muscle were 22.1±1.7 and 12.8±0.9 msec at the stimulations on the scalp and C 7, respectively. The central motor conduction time (CMCT) between the cortex and C 7 was 9.1±1.1 msec. On the other hand, the peak latencies of MEP were 41.0±3.2 and 21.6±2.3 msec at the stimulations on the scalp and L 5, respectively. CMCT between the cortex and L 5 was 19.3±2.3 msec. The patients with pyramidal tract involvements showed delayed peak latencies or absent MEP.
The cortical somatosensory evoked potentials (SEP) by the noninvasive magnetic stimulation on the levels of Th 10, Th 12 and L 5 spines, gluteus and ankle were studied in 20 normal subjects and 7 patients with neurological diseases. Cortical components P 2 and N 2 were recorded clearly in all normal subjects. The mean peak latencies of P 2 were 21.1±1.2, 23.5±1.4, 27.9±2.0 and 38.1±1.8 msec at the Th 12, L 5, gluteus and ankle stimulations, respectively. P 2 and N 2 evoked by Th 10 and Th 12 stimulations were normal in thepeak latencies and the morphology in the patients with polyneuropathy or polyradiculoneuropathy. The peak latencies of P 2 and N 2 evoked by Th 10 and Th 12 stimulations were significantly delayed in the patients with myelopathy. The patients with radiculopathy showed delayed peak latency and conduction time of P 2 evoked by L 5 stimulation. The magnetic stimulation at spinal roots could detect the lesions in the spinal cord levels noninvasively.

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This symposium was aimed to present recent advances of child neurological researches on infantile autism in Japan. Four topics were included: neuroendocrinological studies, neurophysiological investigations, neurological model, and a new drug (RTHBP) of infantile autism. These topics were also discussed by two discussants, a pediatrican and a child psychiatrist. Each speaker presented and discussed the problems of infantile autism on the basis of the findings of their own research.

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The cause of autism is unknown. Recently, it has been suggested that it involves metabolic disorders of serotonin and/or dopamine. On the other hand, there is a close relationship between hormone secretion and monoamines. The aim of this study was to analyze the secretion of GH, PRL, TSH, cortisol, LH and FSH.
The subjects were 30 children with autism, 25 males and 5 females, aged from 1 10/12 to 9 10/12 years. Their IQs (DQs) ranged from 34 to 123. Pituitary hormone secretion was measured during provocation with insulin (0.1 unit/kg), TRH (10μg/kg) and/or LH-RH (100μg/m²) in 26 of 30 cases. Control subjects included 16 age-matched children with attention dificit disorder (ADD) and 18 age-matched children with mental retardation (MR) without autistic and organic central nervous diseases.The 24-hour secretion rhythm of GH, PRL and cortisol for 14 cases with autism and of LH and FSH for 9 cases was also investigated.
In insulin provocation test, the peak values of GH and 4 GH (peak GH level minus baseline GH level) in ADD were significantly higher than those in MR (p<0.05). In TRH provocation test, the peak values of TSH and ΔTSH in autism were significantly lower than those in MR. Five cases of autistic children revealed borderline responses for TSH, while the only one each of ADDs and MRs revealed borderline responses for TSH. In a study of the 24-hour hormone secretion rhythm, eleven of the 14 autistic children showed an abnormal secretion rhythm.
It was concluded that there are various types of neuroendocrinological abnormalities in autism, ADD and MR, and that the hypothalamic lesion in autism was different from that in MR or ADD.

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Two different hypotheses have been proposed on the pathophysiology of infantile autism a caudally directed pathological influence originating in telencephalic structure, and a rostally directed pathological influence originating in brainstem and diencephalic structure. This paper described results of neurophysiologic research of infantile autism:(1) cortical evoked potentials, (2) autoregressive spectral analysis of EEG, (3) brainstem lesions on ABR and vestibular study by Ornitz E M (1985) and (4) cognitive functioning by Novick (1980) and Niwa (1983).
Those studies suggest that the brainstem, including the vestibular nuclei, and related nonspecific thalamic centers, can be the primary loci of the system dysfunction in autism.

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Based on the abnormalities in sleep-wakefulness cycle of early infantile autism, the author discussed its pathophysiology focusing on its main lesion in the raphe nuclei. These neurons, located in the midline portion of the brainstem send their axons to various neurons of the upper and lower nervous systems, including the locus coeruleus and the dopamine neurons of the tegmentum, the former having a broad innervation and the latter a restricted area in the central nervous system. These monoaminergic neurons modulate the functions of the involved neurons and regulate their functional and structural maturation in the early developmental course. The early lesion of the raphe nuclei causes poor adaptation to environment which develops as abnormal circadian oscillation and pervasive lack of responsivenss. Combined hypofunction of the locus ceruleus, particularly of its dorsal bundle, results in the failure of extinction of acquired memory in mice which relates clinically to the excellent memory and resistance to change peculiar interests and attachments in humans. From early childhood, the disturbance of dopaminergic neurons becomes apparent clinically, and causes hyperkinesia and stereotyped activities. With the other two monoaminergic neurons, dopaminergic neurons cause occasional aggressiveness or selfmutilation. The latter behaviors are like those of pampered children and are simulated to “muricide” and “friendliness” observed in rats with these monoaminergic lesions.
The particular language disturbance with echolalia is due to the right hemispheric dominancy, which might have been caused by a delayed functional lateralization of the hemisphere resulting also from the delayed development of the circadian oscillation in infancy. The motor disturbances consisting of hypotonia and impaired locomotion might be due to decreased tonic innervations of the locus ceruleus and the raphe nuclei the spinal locomotion center.
the spinal locomotion center. CT examination of symtomatic autism showed the amygdala as one of the causative nuclei for the autistic behavior.

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A new method for measurement, of the turnover rate of aromatic amino acids and related compounds in vivo using stable isotopes was developed. Deuterium-and carbon 13-labeled phenylalanine and deuteriumlabeled tryptophan were used as tracers. This method was applied for the analysis of amino acid and amine metabolism in infantile autism. Marked disturbances of uptake of deuterated phenylalanine and tryptophan from intestine into blood were found in a portion of autistic patients (group A). In another group of the patients a remarkable decrease of turnover of tyrosine in blood was found (group B). This phenomenon was confirmed by an experiment using carbon 13 labeled phenylalanine.
These findings might suggest that supply of tyrosine and free tryptophan to the brain (in group A) or supply of tyrosine (group B) to the brain might be decreased. We postulated that in some of autistic patients there might exist decreases in synthesis of catecholamine or serotonin. Based on the hypothesis, we started a new treatment with L-DOPA and 5 HTP in small doses, and found significant effects in some patients. However, in somes, the amino acids caused marked aggravation of the symptoms.
Recently, Hayaishi and his colleagues reported that R-tetrahydrobiopterin (R-THBP) could enhance biosynthesis of catecholamine and serotonin in the brain. Therefore, we started a clinical trial concerning effects of R-THBP. In the beginning, 17 cases were treated and patients younger than 5 years old showed marked improvement. Then, a double blind trial with inactive placebo was performed. A significant effect of RTHBP was proved in a group less than 5 years old, and the effect was most prominent to improve the abnormal behaviors which seemed to be the core symptoms of the disease.

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Biological studies on autism have become popular from the 1970s, and theories founded upon some forms of dysfunction of the CNS are coming to be accepted world wide. However, despite the voluminous studies undertaken to present, the biological markers of the disorder are as yet unknown, and there are many problems remaining in the present state wherein we are dependent upon diagnoses made on the behavior level. The behavior characteristics of autism and the problems in extracting its early signs, methods of evaluating behavior changes in pharmacotherapy and determination of its safety were discussed.

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Since Leo Kanner reported 11 cases of “early infantile autism” in 1943, various kinds of studies and researches have been made. At present, we generally understand the “autism” is a behavioral syndrome of multiple etiologies. I would like to stress that we pediatricians, meeting the patients first, must play the roles of the specialists in diagnosis, treatment, prophylaxis, and of the advisers in guiding mothers, teachers and the others. The purpose of medicine and education is to help the handicapped to draw as much satisfaction and enjoyment from life as possible.

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