To estimate and to prevent the developmental brain damage caused by maternal environmental agents, the results were compared between epidemiological and experimental studies. I. Ethanol. The features of CNS involvement in human FAS (fetal alcohol syndrome) and FAE (fetal alcohol effects) were developmental delay and intellectual impairment. In rat FAS or FAE, a beneficial effect of supplementary zinc on the fetal cerebrum was observed, but was limited. The consistent dysformation of synapses during early brain development may be associated with the functional impairment of CNS in FAS and FAE. II. Caffeine. A reduction in the fetal cerebral weight was observed with caffeine ingestion during pregnancy at levels of 1.5-3.0μg caffeine/ml or g wet wt. in dams and fetuses. Maternal caffeine disturbs the neonatal cerebrum and produces behavioral abnormalities in developing rats. III. X-irradiation. Our study provides evidence of the protection by vitamin E of neuronal development in X-irradiated rat fetuses, through its antioxidant properties, against attacks by free radicals and/or lipid peroxide. IV. Low copper level in brain. A teratogenic effect of triethylene tetramine dihydrochloride, a chelating drug for copper, on the mouse brain was noted, both grossly and microscopically, with a dose of higher than 6, 000 mg/l, which is twenty times as high as the clinical treatment dose. V. Tobacco. Thirty- three percent of human FTS (fetal tobacco syndrome) cases had CNS involvement, which was characterized by developmental delay. Fifty percent or more of FTS children of women who smoked more than 20 cigarettes per day had CNS involvement. In conclusion, the concomitant effects of maternal enviromental agents on human brain development should be studied.

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The basal ganglia modulate voluntary movements involving the neural circuit of the cortex-basal ganglia-thalamus-cortex.
The basal ganglia receive all of the afferents at the striatum and project the efferents from two output structures, the medial segment of the globus pallidus and pars reticulata of the substantia nigra. Besides the cortex, the basal ganglia receive imputs from pars compacta of the substantia nigra (SNc) and centromedian nuclei of the thalamus.
The afferent from the SNc is the nigrostriatal (NS) dopamine (DA) neuron and has important roles in functional modulation of the basal ganglia. As for efferents, the basal ganglid also have output projections to the superior colliculus and pedunculo- pontine nuclei. In the basal ganglia, the striatum has two efferent pathways; one is the direct projection which projects directly to the output structure and the other is the indirect pathway which projects to the output structures via the lateral segment of the globus pallidus and the subthalaniic nuclei, changing synapses at these nuclei.
The lesions in the basal ganglia show various movement disorders or involuntary movements depending on their foci. Basal ganglia lesions also develop symptoms age dependently; a certain lesion develops dys-tonia in younger brains, while revealing parkinsonism in adult or older brains. This age dependency depends on the difference in the course of the functional maturation of each component and pathway of the basal ganglia.
At this symposium we tried to show the basic pathophysiologies of age dependency by discussing basal ganglia disorders in children compared to those in adults and referring to the basic science of the basal ganglia.

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Inhibitory control of basal ganglia output to thalamocortical projection plays an important role in normal cortical activity in the current model of the basal ganglia motor circuit. Hypokinetic and hyperkinetic movement disorders of basal ganglia origin can be explained by excess or collapse of the basal ganglia output. An abundance of evidence indicates that parkinsonian akinesia results from hyperactivity of the basal ganglia output. Reversal of akinesia by lesions of the internal division of the globus pallidus GPi or its excitatory source, the subthalamic nucleus, agrees with this pathological schema. Ballism associated with subthalamic lesions, and dopa-induced dyskinesia are regarded as hyperkinetic disorders resulting from suppressed subthalamopallidal projection. Decreased firing rate in GPi was reported in both disorders. However, pallidotomy has recently been postulated to abolish both ballism and dopa- induced dyskinesia. A possible mechanism for the effect of GPi destruction in these hyperkinetic disorders may be blockade of the generation or conduction of phasic neuronal activities driving choreic movements. Symptomatologically, dystonia has aspects of both hypokinetic and hyperkinetic disorders. Overactivity of the premotor cortices, which receive projections from the basal ganglia via the ventral thalamus, was found both at rest and on movement in idiopathic dystonia. This abnormal cortical activity may arise from underactivity of basal ganglia output; however, the amelioration of dystonia with pallidotomy suggests a complex pathomechanism of the pallidothalamic system in dystonia.

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The basal ganglia play important roles in the pathophysiology of various types of involuntary movement disorders, such as chorea, ballism, athetosis, dystonia, tremor and tics.
These involuntary movements when occur in the childhood show the specific ages of onset and the courses. For example, postural dystonia occurs in childhood but action dystonia tend to occur in later ages. Postural tremor occurs after the second decades but resting tremor does not occur in childhood. Furthermore drug induced dystonia but not levodopa induced dyskinesia occurs in childhood.
The age dependent clinical features observed in these involuntary movements are thought to be due to the specific developmental processes of the pathway in the basal ganglia and its efferent projections, which are involved in the pathophysiology in the each disorder. For example, the dopamine activity is known to be increased in the striatum before ten years of age which decreases rapidly during the first decade and further decreases in the next decade with the moderate degree till adult level. The direct pathway, which is predominant in the ventral area in the basal ganglia, matures earlier than the indirect pathway, which is predominant in the dorsal area.
In this paper the pathophysiologies of the hereditary progressive dystonia with marked diurnal fluctuation, juvenile parkinsonism, idiopathic torsion dystonia, chorea, ballismus and tics, all of which occur in the childhood, are discussed from the view point of the age dependent specificities of the involved pathways in the basal ganglia and their projections during development.

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Ventrolateral (VL)-thalamotomy and posteroventral pallidotomy were carried out in 37 patients with idiopathic dystonia, including 23 with dystonia musculorum deformans, 12 with Meige syndrome and 2 with focal dystonia. There were 11 patients with the onset age of dystonia below 10 years and 26 with the age above 11 years. Dystonia tended to generalize in the pediatric patients and to localize to the palmo-mental region in the adult patients. VL-thalamotomy in 30 patients improved the upper body dystonia especially in the adult patients, but, often failed to benefit the pediatric patients. Posteroventral pallidotomy in 18 patients dramatically alleviated the generalized dystonia especially in the pediatric patients. In one adult patient, pallidotomy caused hemiparesis due to intracerebral hemorrhage. The internal pallidum projects the efferents to the thalamic motor nuclei and also to the brainstem reticular formation that connects to the spinal motoneurons. The present findings implicate the descending pallido- reticular pathway in the mechanism of dystonia of pediatric patients, and the ascending pallido-thalamic pathway in that of adult patients.

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We examined age-dependent changes in voluntary eye movements in normal subjects (age: 5-76) using a visually guided saccade (V-saccade) task and a memory guided saccade (M-saccade) task. Changes were more evident in M-saccades. The latencies were long in children (<12y.o.) and elderly people (>50y.o.). Both young children and elderly people tended to break fixation by making a saccade to the cue stimulus that indicated the future target position. On the other hand, both young children and elderly people tended to be slow in making M-saccade promptly after the central fixation point went off. Thus, they had difficulties both in suppressing unnecessary saccades and in initiating saccades based on memory.
Interestingly, similar difficulties were observed, in exaggerated forms, in patients in basal ganglia disorders, such as Parkinson's disease, juvenile parkinsonism, dopa- responsive dystonia, and hereditary progressive dystonia with marked diurnal fluctuation.
These findings were consistent with the known functions of the basal ganglia which have been revealed by physiological studies using trained monkeys. The substantia nigra pars reticulata exerts tonic inhibitory influences over the superior colliculus, thereby preventing excitatory inputs from triggering unnecessary saccades. The tonic inhibition, however, is removed by a phasic inhibition largely originating in the caudate nucleus. Thus, inhibition and disinhibition are key mechanisms of the basal ganglia. In fact, experimental manipulations of these serial inhibitory pathway in the basal ganglia led either to the difficulty in initiation of saccades, especially M-saccades, or to the difficulty in suppressing unnecessary saccades.
These comparisons suggest that the functions of the basal ganglia are immature in young children while they become deteriorated in elderly people.

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Asphyxia may play an important role in the pathogenesis of cerebral palsy (CP) in a subpopulation of patients, although this has recently been questioned by some investigators. Here I describe the resluts of our analyses into the involuntary movements of children with CP, which resulted from perinatal hypoxic brain damages.
Based on cranial CT or MRI findings, the patients were divided into five groups: A, those showing high density on CT in the basal nuclei (bilateral thalami in particular); B, those showing destruction of bilateral putamina; C, those with diffuse low-density areas in the cerebral white matter on CT during the neonatal period that evolved later into polycystic leukomalacia; D, those with similar low-density areas which subsequently resolved; and E, those without any pathological findings.
Using video records, I demonstrated the motor development of six cases with CP. Patients of Group A showed pure athetosis with hypotonia. A patient of Group B had severe athetoid CP with spasticity, being unable to right his trunk and neck. A case of Group C developed severe spastic quadriplegia with athetosis. His mental ability was retained to some extent. In Group D, there was moderate spasticity and mild athetosis. A patient with transient anxia had disturbance in the coordinated finger movements. Cases with choreic movements had no particular CT or MRI findings. Even in the severest of these cases, distinction from normal infants was difficult in the very early infancy. After four to five months, locomotive prognoses were well predicted by the patients' ability to control their trunk.
To know more about the pathogenesis and CP and to elucidate the significance of involuntary movements, further data should be accumulated by clinical observations on motor development, and by imaging studies.

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Forty-nine patients with cerebral palsy, mental retardation, or other congenital neurological disorders who had experienced febrile convulsions and had no previous nonfebrile seizures were presented. They were followed for 1.6 years to 15 years (mean: 6.8 years) after the initial febrile convulsion.
The incidence of subsequent epilepsy (two or more afebrile seizures) was 39%, and 80% of them developed epilepsy within 2 years after the first febrile convulsion. The paroxysmal discharges on EEG recorded prior to or after the first febrile convulsion did not predict the occurrence of later epilepsy. Also under 3 years of age, EEG findings led to the same result. There was no definite evidence that administration of anticonvulsive drugs prevented later epilepsy. Pre-existing neurological abnormality was identified as a risk factor for epilepsy, and was an indication of persistent medication. There is no clear prophylactic procedure against long-lasting attacks. Accordingly, medical therapy can be started when epilepsy has developed.
Patients with very severe brain damage who could not move except lying comprised only 6% of all cases, and 69% of the epilepsy patients were well controlled. They showed a good prognosis as compared with children with brain-damage in general with epilepsy.

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Prevalence rate and etiology were studied in severely handicapped children of school age in Nagano prefecture as of July, 1994. Severely retarded children were defined as those whose IQ's were lower than 35 and who were unable to walk. The total number of severely retarded children was 165. The prevalence rate was 0.71/1000, 90% of them being in class 1 or 2 of Oshima's classification (bedridden or unable to sit alone and with IQ less than 20), and 26% being cared for at home. Their average gestational age was 38.5 weeks, and the average birthweight 2, 772g. At birth none of them had extremely low birth weight. Etiology of the handicaps was classified as follows: congenital 26.1%; maternal infection 3.0%; prenatal 3.6%; perinata 27.3%; postnatal 13.9% and unknown 26.1%. Asphyxia decreased gradually but the number of low birth weight premature infants increased. When postnatal etiologies were excluded, the patients with unknown etiology occupied 30.3%, 23.3% of them being light-for-dates baby. The examination of the case histories revealed that causes of unknown etiology are prenatal. If we add unknown etiology to congenital, maternal infection, and prenatal etiology, the prenatal origin is 68%.

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Rhythmic alpha/theta bursts were studied on forty-nine electroencephalographic records of early premature infants, ranging from 25 to 30 weeks of conceptional ages. Frontal alpha bursts and occipital theta bursts were prominant at 25-26 weeks, and temporal theta bursts prominant at 27-28 weeks. Frontal, temporal and occipital alpha/theta bursts were observed unilaterally, when all rhythmic bursts were seen frequently. Frontal and temporal bursts appeared often on the left side and occipital bursts on the right side.

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Rhythmic alpha/theta bursts were studied on ninty-five electroencephalographic records of early prema-ture infants, ranging from 25 to 30 weeks of conceptional ages in relation with background EEG activity. When background EEG showed normal, frontal alpha bursts and occipital theta bursts were prominent at 25-26 weeks, and temporal theta bursts at 27-28 weeks. A significant decrease in all rhythmic bursts on the frontal, temporal and occipital areas, was seen in early premature infants showing severe background EEG depression. Incidence of rhythmic alpha/theta bursts varies inversely with depression of background EEG activity.

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We reported a 7-year-old, right-handed boy whose reading and writing of kana and kanji were impaired. He also showed a severe deficit in visuo-spatial perception skills. Nevertheless, his ability to read and write kana characters was facilitated by means of the Japanese Syllabaries. It is generally considered that the Syllabary involve two kinds of language modalities: auditory-verbal and visuo-verbal language systems. In spite of his intact auditory-verbal language system, his visuo-verbal language skills involved in writing kanji were severely impaired. It was suggested that a severe deficit of visuo-spatial perception skills influenced performance of visuo-verbal language systems. Accordingly, we inferred that the patient recalled a kana character by use of the Japanese Syllabaries based on his good auditory-verbal language system, and supposed that his reading and writing disorders were similar to alexia with agraphia in adult patients with angular lesions.

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A fourteen-month-old girl, who had shown remittent fever frequently from the neonatal period, hypohidrosis, frequent change of face color and self-mutilation of the 1st and 2nd fingers of both hands and tongue in the first months of her life, developed an acute encephalopathy with generalized tonic convulsion outdoors on a sunny hot day. Generalized tonic convulsion subsided within two days, but doll's eye phenomenon, loss of pupillary reaction to light, palpebral myoclonus, and ballismus of arms and legs followed. L-dopa showed some effect on the ballismus 1 month after the attack. During the hospital stay, biopsy of sural nerve was performed. Morphometric and ultrastructural studies of the sural nerve demonstrated decreased numbers of unmyelinated and small myelinated fibers. Skin biopsy of the leg revealed sweat glands with no nerve terminals, axons and Schwann cells around them. She was diagnosed as having hereditary sensory and autonomic neuropathy type IV based on the histological and clinical findings. After discharge, bone fracture was found three times without any evidence of trauma.
Acute encephalopathy, probably produced in relation to the underlying neuropathy, was considered to be due to heat stroke.

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[in Japanese]

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