Probable metachromatic leukodystrophy/pseudodeficiency compound heterozygote at the arylsulfatase A locus with neurological and psychiatric symptomatology.

Metachromatic leukodystrophy (MLD) is an autosomal recessive progressive demyelination disorder caused by the deficiency of arylsulfatase A (ASA). However, there exist individuals with low ASA activity without clinical symptoms. This state is described as ASA pseudodeficiency (PD). A number of patients with low ASA activity and various neuropsychiatric symptoms have been observed. It is controversial to what extent low ASA activity predisposes for neurological and/or psychiatric symptomatology. Therefore, persons with low ASA activity who were collected from a large-scale screening among neuropsychiatric patients and healthy controls are presently being extensively evaluated using biochemical, genetic, and clinical methods. Here we present a female patient, who had been first hospitalized with the diagnosis encephalomyelitis disseminata. Her ASA activity determined in fibroblast extracts is intermediate between adult MLD and PD. Sulfatide degradation in cultured fibroblasts is diminished. The subunit pattern obtained after SDS-polyacrylamide gel electrophoresis and immunoblotting was determined in the index patient and 2 sibs. It is compatible with a compound genotype ASA-/ASAp in the index case. It appears probable that in this patient low ASA activity leads to the accumulation of sulfatide and either causes the appearance of neuropsychiatric symptoms or at least contributes to the demyelination process.

The influence of low arylsulfatase A activity on neuropsychiatric morbidity: a large-scale screening in patients.

A total of 1728 patients consecutively admitted to a neuropsychiatric hospital and 379 chronically ill inpatients were examined for activity of arylsulphatase A (ASA) in leucocytes. A further 519 healthy individuals served as controls. We did not find evidence for the involvement of low ASA activity in chronic patients. The consecutive admissions showed a slight preponderance in the lower ASA activity classes. This activity range covers persons heterozygous for ASA deficiency alleles. The data are compatible with the hypothesis that carriers of low ASA activity alleles are at a slightly higher risk for neuropsychiatric disorders.

Schizophrenia, psychoticism, neuroleptics, and auditory evoked potentials.

Auditory cortical evoked potentials of 20 schizophrenic patients with an acute exacerbation of the illness were investigated before neuroleptic medication and after remission of the acute symptoms, and compared with healthy controls matched for sex and age. Additionally, tests were conducted in 40 healthy volunteers to ascertain whether psychoticism or other personality factors were correlated with evoked potentials. The aim of the study was to test the overarousal hypothesis of schizophrenia and to control the effects of clinical state, neuroleptic medication and personality factors. Acutely ill schizophrenic patients had a shorter evoked potential N1 latency (Table 1). After remission of the symptoms under haloperidol N1 latency of the patients was no longer different from that of the controls. Patients after remission and on medication, however, had longer P2 and N2 latencies and a greater P2-N2 amplitude (Table 2). Psychoticism and extraversion were correlated negatively with amplitude data of components N1 and P2 in healthy volunteers. The results favor the overarousal hypothesis of schizophrenia. Haloperidol normalizes N1 latency in acutely ill patients. It's effect on later components of the evoked potentials seems comparable to a reduction in vigilance. Auditory evoked potentials might allow to follow up the effect of neuroleptics in acute schizophrenia. It seems necessary to consider personality factors when comparing patients with healthy controls in evoked potential studies.

Baroreceptor reflex during arousal induced by electrical stimulation of the amygdala or by natural stimuli.

Baroreceptor control of heart rate was studied in 14 unanaesthetized cats during rest and arousal induced by either electrical stimulation of the central nucleus of the amygdala or by natural stimuli. The baroreceptor reflex was elicited by i.v. injections of angiotensin II and the sensitivity of the vagal component of the reflex expressed as the regression coefficient of the relationship between the systolic blood pressures of successive arterial pulses and their pulse intervals. Baroreceptor reflex sensitivity was reduced by all types of arousing procedure studied; an effect assumed to be a part of integrated cardiovascular adjustments accompanying arousal. Further studies in slightly anaesthetized cats were performed in order to investigate the time-course of such changes in reflex sensitivity. Th inhibition of the vagal component of the reflex did not last for the entire period of the electrically elicited arousal and it is suggested, therefore, that this might reflect the activation of mechanisms which limit orienting behaviour. Overall, these results indicate that the central nucleus of the amygdala may be involved in a transient integration of cardiovascular and behavioural responses during arousal.

Cardiovascular changes during arousal elicited by stimulation of amygdala, hypothalamus and locus coeruleus.

Experiments were performed in chronically operated cats first awake and thereafter anesthetized with pentobarbitone, 16-20 mg/kg i.v. Stimulation of the central amygdala in awake cats elicited an arousal reaction seen in cortical and hippocampal EEG, and in muscle activity of dorsal neck muscles. Concomitantly therewith were autonomic system reactions resulting in a decrease in aortic blood flow distal to the renal arteries, an increase in arterial blood pressure, a tachycardia during, and a short-lasting bradycardia at the end of stimulation. In slightly anesthetized cats the cardiovascular reactions were found to be qualitatively similar. If the postero-lateral hypothalamus or the locus coeruleus complex were stimulated in cats first awake and thereafter anesthetized, similar arousal reactions and similar cardiovascular changes were obtained as with amygdaloid stimulations. However, the onset and magnitude of the response were more abrupt and more marked than those obtained by amygdaloid stimulations. Recordings of single unit activity within the central amygdala during spontaneously occurring changes in the level of arousal showed that amygdaloid units (n = 10) discharged at a rate of 7-14 impulses/sec during wakefulness whereas during slow wave sleep (n = 5) the discharge was only 2-9 impulses/sec. The hypothesis is put forward that the amygdala integrates behavioral and cardiovascular changes during arousal.

Enkephalin effects on blood pressure, heart rate, and baroreceptor reflex.

The cardiovascular effects of opioid peptides have been studied. Leucine-enkephalin (Leu-ENK) produced blood pressure (BP) increases following administration into the lateral brain ventricles (i.v.t.), into the cisterna magna (i.c.i.), and following intravenous (i.v.) administration. Heart rate (HR) increases were observed following all routes of administration (threshold for BP and HR effects at 0.3 nmole, maximum at 360 nmoles). The cardiovascular effects were independent of generalized seizures, which may occur at higher doses of enkephalins (ENK). D-alanine-enkephalin (D-Ala-ENK) attenuated the vagal component of the baroreceptor reflex in cats. This was indicated by the findings that HR did not decrease following D-Ala-ENK-induced BP increases and that the compensatory decreases in HR following i.v. pressor doses of angiotensin II (ANG II) were markedly attenuated in cats treated with i.v.t. D-Ala-ENK. Naloxone inhibited the BP and HR effects following i.c.i. and i.v., but not following i.v.t., administration of Leu-ENK. The i.v.t. Leu-ENK effect were inhibited by beta-adrenergic receptor blockade. Bratteboro rats homozygous for hereditary diabetes insipidus with total absence of antidiuretic hormone (ADH) synthesis responded with BP decreases following i.v.t. Leu-ENK, while BP increases were observed in control Long-Evans rats. Blood pressure increases to i.v.t. Leu-ENK were markedly greater in spontaneously hypertensive rats of the stroke-prone strain (SHR-sp) than in normotensive control rats; SHR-sp exhibit a humoral pattern of increased ADH, ACTH, and catecholamines, presumably due to central peptidergic stimulation. The known effects of opioid peptides on these hormones and the observed cardiovascular responses suggest a possible participation of this peptide system in the maintenance of high BP in the SHR-sp.

Absence of sympathetic cholinergic vasodilatation in cats during early stages of affective behaviour elicited by stimulation of central amygdala, postero-lateral hypothalamus and locus coeruleus.

1. Stimulation of the central amygdala, postero-lateral hypothalamus and locus coeruleus in cats resulted in a sustained increase in arterial pressure, an increase in heart rate, with a poststimulation bradycardia and an increase in peripheral resistance (vasoconstriction in the vessels of the hindlimbs). The behavioural pattern was characterized by an alerting reaction. Increased stimulus intensities resulted in rage reactions if the amygdala or the hypothalamus were stimulated. 2. Stimulation of the basal amygdala resulted in a cardiovascular pattern characterized by a sympathetic cholinergic vasodilatation. The concomitantly observed behaviour was characterized by alerting, anxious behaviour, eventually resulting in defence. 3. Alerting was not necessarily linked to sympathetic cholinergic vasodilatation. 4. The cardiovascular pattern including sustained vasoconstriction of the vessels of the hindlimbs was supposed to be of greater importance for the induction of hypertension than the cardiovascular pattern, including sympathetic cholinergic vasodilatation.

The influence of chronic deep brain stimulation on excitability and morphology of the stimulated tissue.

Bipolar electrical stimulations of the rostal hippocampus and of the amygdala were performed at irregular intervals in wakeful unrestrained cats via chronically implanted glass-insulated stainless steel electrodes. The excitability of the stimulated tissue remained unchanged during the whole investigation period of six months up to one and a half years, as was revealed by regularly performed comparisons of shape, latency, and amplitude of evoked potentials elicited by electrical stimulation of the rostral hippocampus and recorded within the ipsilateral mammillary body. The histological examination of the stimulated tissue revealed a fibrillary gliosis due to the trauma caused by the insertion of the electrodes, but no signs of additional tissue damage due to electrical stimulation or chronic mechanical irritation. The results indicate that it is possible to perform therapeutic stimulations of deep brain structures for long periods without inducing relevant changes in morphology or electrical responsiveness of the stimulated tissue. No kindling phenomena are to be expected, if the stimulations are performed at irregular intervals.

Effects of enkephalins on arterial blood pressure are reduced by propranolol.

1. The cardiovascular effects of enkephalins have been tested in normotensive Wistar-Kyoto rats. Methionine-enkephalin and leucine-enkephalin increased blood pressure and heart rate after infusion into the brain ventricles. 2. After intravenous injection, blood pressure was increased by methionine-enkephalin and leucine-enkephalin, but heart rate was increased by methionine-enkephalin only. 3. Propranolol treatment reduced the increases in blood pressure following intraventricular methionine-enkephalin and leucine-enkephalin, while only the methionine-enkephalin-induced increases in heart rate were reduced by propranolol. 4. Heart rate and blood pressure responses after intravenous administration of methionine-enkephalins and leucine-enkephalin were not affected by propranolol. 5. Since opioid peptides occur in the blood and in regions of the brain involved in blood pressure regulation, the demonstrated cardiovascular effects to intraventricular and intravenous enkephalins support a role of these peptides in central and peripheral mechanisms of blood pressure control.

Sleep patterns in cat induced by gammahydroxybutyric acid.

Intravenous injections of gammahydroxybutyric acid (GHBA) (150-200 mg/kg) induce desynchronized sleep (DS) in the cat. This was shown by recording the EEG, eye-movements, the neck EMG, heart-rate and arterial pressure. The decreases in arterial pressure were not different from those recorded during naturally occurring DS. GHBA, given at doses above 200 mg/kg induced anaesthesia, during which arterial pressure was elevated. At the end of GHBA-induced sleep or anaesthesia there was a stage during which the animals were ataxic. The EEG showed a hypersynchronous spike pattern and arterial pressure was markedly elevated.