Dextroamphetamine: cognitive and behavioral effects in normal prepubertal boys.

The behavioral, cognitive, and electrophysiological effect of a single dose of dextroamphetamine (0.5 milligram per kilogram of body weight) or placebo was examined in 14 normal prepubertal boys (mean age, 10 years 11 months) in a double-blind study. When amphetamine was given, the group showed a marked decrease in motor activity and reaction time and improved performance on cognitive tests. The similarity of the response observed in normal children to that reported in children with "hyperactivity" or minimal brain dysfunction casts doubt on pathophysiological models of minimal brain dysfunction which assume that children with this syndrome have a clinically specific or "paradoxical" response to stimulants.

Electrodermal activity in young adults at genetic risk for affective disorder.

Low electrodermal activity has been proposed as a trait marker for affective disorder. We attempted to determine if low electrodermal activity could be a genetic marker by testing subjects at genetic risk for affective disorder. High-risk subjects, 22 offspring of a parent with bipolar affective disorder, and 27 low-risk controls 15 to 25 years old had skin conductance recorded bilaterally during rest periods, presentation of 10 nonsignal tones, and performance of reaction-time and mental arithmetic tasks. There were no significant differences in skin conductance levels under any condition or in the frequency or amplitude of orienting responses to nonsignal tones. During task periods high-risk subjects showed significantly greater electrodermal activity that was lateralized to the left hand. Self-rated depression was higher in the high-risk group during task periods. The results show that low electrodermal activity is not a likely genetic marker for affective disorder but suggest that autonomic hyperresponsivity, atypically lateralized information processing, and depressive affect occur during mild stress in persons at risk for the development of affective disorder.

Minimal brain dysfunction, stimulant drugs, and autonomic nervous system activity.

Autonomic base levels and responsivity to stimuli were investigated in normal and minimally brain dysfunctioned (MBD) children. Continuous recordings of skin conductance, heart rate, skin temperature, and respiration rate were made during rest, at presentation of tones, and when performing a reaction time task. No significant differences in base levels were obtained between normal and MBD children when not taking drugs, but stimulant medication increased skin conductance and heart rate and decreased skin temperature and reaction time. The MBD children were less reactive, autonomically, to all types of stimuli. Stimulant drugs decreased electrodermal responsivity, which was predictable from concurrent changes in base line skin conductance and skintemperature. The MBD performance deficits are not related to lower autonomic responsivity or lower absolute base levels of arousal, but MBD children may perform better at relatively high autonomic base levels.

Autonomic nervous system activity in acute schizophrenia: I. method and comparison with normal controls.

Many reports of autonomic dysfunction in schizophrenia may have been influenced by the chronicity or medication status of patients, or both. This study eliminates these sources of variation. Skin conductance (SC) and heart rate (HR) base levels and activity were compared in 118 controls and 46 recently admitted, drug-free, acute schizophrenic patients during rest, 20 mild-tone stimuli, and reaction time (RT) and mental arithmetic tasks. Patients showed higher than normal HR and spontaneous SC responses but lower SC base levels. Schizophrenics showed less SC and HR reactivity to tones and RT stimuli, slow habituation of the SC orienting response, an attenuated tonic response to stress, and disproportionately more spontaneous than elicited SC activity. The findings are similar to previous results for unmedicated, chronic schizophrenics and suggest that autonomic activity in schizophrenics is determined relatively more by endogenous factors than by external stimuli.

Autonomic nervous system activity in acute schizophrenia: II. relationships to short-term prognosis and clinical state.

Autonomic nervous system (ANS) activity in acute schizophrenic patients was assessed to examine predictive relationships to clinical course. Unmedicated patients were rated on global psychopathology and tested on skin conductance, heart rate, and skin temperature during rest, a series of tones, and reaction time and mental arithmetic tasks three weeks after admission and again about three months later. On the admission tests, a pattern of ANS activity found in schizophrenics in general (high resting "arousal," slow habituation, and attenuated ANS reactivity, particularly to demanding stimuli and situations) was found in patients who were to remain clinically ill but not in patients whose recovery was more complete, especially in males. Thus, ANS activity is predictive of short-term outcome in acute schizophrenia. Minimal ANS changes accompanied clinical improvement, which suggests a "'trait" interpretation, but "state" effects cannot be completely ruled out.

Autonomic nervous system markers of psychopathology in childhood-onset schizophrenia.

BACKGROUND: Consistent abnormalities in peripheral indicators of autonomic activity, ie, skin conductance (SC) and heart rate (HR), have been reported in adult-onset schizophrenia. Herein, we use these markers to test the hypothesis of continuity between childhood-onset schizophrenia and adult-onset schizophrenia. METHODS: Skin conductance and HR were recorded from 21 severely ill children and adolescents (mean age, 14.1 years) with childhood-onset (< or = 12 years) schizophrenia (patient group) and from 54 age-matched controls (control group) during a rest period, a series of innocuous tones, reaction time instructions, and a simple warned reaction time task. RESULTS: During rest, patients had higher rates of spontaneous SC responses (SCRs) and HRs than controls, but their SC level was marginally lower and declined more slowly over time. Half of the patients, compared with 4% of the controls, failed to give SC-orienting responses to the first 2 tones. Patients who responded had impaired SCR magnitudes, and their habituation was more erratic than that of controls. The increase in SC level and SCR frequency at the onset of the task period was greatly attenuated in the patients, so that both variables were higher in controls. Patients had smaller SCRs and anticipatory HR responses to the reaction time stimuli. Skin conductance nonresponding was associated with negative and total symptoms, and spontaneous SCR frequency was associated with positive symptoms. CONCLUSIONS: The findings show similar abnormalities in autonomic nervous system activity in childhood-onset schizophrenia to those found in adult chronic schizophrenia, thus supporting the hypothesis of continuity of the childhood and adult forms of the illness. Comparisons with data from other childhood disorders suggest that the combination of low-elicited SC activity with high levels of spontaneous SC activity may be specific to schizophrenia.

Behavioral effects of caffeine in children. Relationship between dietary choice and effects of caffeine challenge.

From a survey of 24-hour caffeine intake of 798 grade-school children (mean age, 10.3 years), 19 "high consumers" (reported intake of 500 mg/day or more) and a matched group of 19 "low consumers" were recruited for a double-blind, placebo-controlled, caffeine challenge study. Children received 5 mg/kg of caffeine twice a day or placebo for two weeks each, using a crossover design. While not receiving caffeine, high consumers had higher scores on an anxiety questionnaire and tended to have lower autonomic arousal (less frequent spontaneous skin conductance response and lower skin conductance level). While receiving caffeine, low consumers were perceived by their parents as more emotional, inattentive, and restless, while high consumers were not rated as changed. These differences cannot be attributed to tolerance, withdrawal, or subject selection, and suggest a possible physiological basis in children for dietary caffeine preference.

Dextroamphetamine. Its cognitive and behavioral effects in normal and hyperactive boys and normal men.

The effects of a single oral dose of dextroamphetamine sulfate on motor activity, vigilance, learning, and mood were compared for normal and hyperactive prepubertal boys and normal college-aged men using a double-blind crossover design. Both groups of boys and men showed decreased motor activity increased vigilance, and improvement on a learning task after taking the stimulant drug. The men reported euphoria, while the boys reported only feeling "tired# or "different# after taking the stimulant. It is not clear whether this difference in effect on mood between adults and children is due to differing experience with drugs, ability to report affect, or a true pharmacologic age-related effect. While there were some quantitative differences in drug effects on motor activity and vigilance between these different groups, stimulants appear to act similarly on normal and hyperactive children and adults.

Attention dysfunction and psychopathology in college men.

Four hundred college men were screened on a measure of vigilance, the Continuous Performance Test (CPT). The individuals with good and poor attention (the upper and lower 5% of the CPT score distribution) were compared on multiple measures of psychiatric disturbance, cognition, and psycho-physiologic function. The attention dysfunction group (lower 5%) had a higher incidence of symptoms of hyperactivity both in childhood and as adults, but had no higher incidence of other psychopathology as assessed with either the Research Diagnostic Criteria or the Minnesota Multiphasic Personality Inventory. Cognitive differences between the lower and upper CPT groups, including differences on Wechsler Adult Intelligence Scale subtests, the Stroop test, reaction time, and evoked potentials, substantiated an attention dysfunction syndrome. Thus, attentional dysfunction in young adults seems more closely linked to hyperactivity than to current psychopathology.

A 2-year prospective follow-up study of children and adolescents with disruptive behavior disorders. Prediction by cerebrospinal fluid 5-hydroxyindoleacetic acid, homovanillic acid, and autonomic measures?

A 2-year prospective follow-up study of 100% (N = 29) of a sample of children and adolescents with disruptive behavior disorders found that the baseline lumbar cerebrospinal fluid monoamine metabolite concentration and autonomic nervous system activity predicted some subsequent outcomes. The 5-hydroxyindoleacetic acid concentration significantly predicted severity of physical aggression during follow-up. The skin conductance level significantly predicted institutionalization. Correlations were in predicted directions with lower cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations and autonomic activity correlated with poor outcome. Moreover, in multivariate analyses, which included nonlaboratory measures as predictors, cerebrospinal fluid and autonomic measures still contributed significantly to the prediction. However, hypothesized predictions of cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations for suicide attempts and of low autonomic nervous system activity for arrests were not supported thus far. Patients are still at risk; consequently, these results must be considered preliminary. Nonetheless, the results suggest that further investigation of relationships between biological factors and outcome of children with disruptive behavior disorders is warranted.

Autonomic effects of clozapine in schizophrenia: comparison with placebo and fluphenazine.

Peripheral indicators of autonomic nervous system activity, including electrodermal activity and heart rate, were studied in 25 chronic schizophrenic patients given clinical trials of clozapine, a standard neuroleptic (fluphenazine), and placebo. The protocol included a rest period, presentation of nonsignal tones, and a reaction time task. Clozapine markedly attenuated electrodermal base levels and both phasic and tonic electrodermal responsivity compared to placebo, and somewhat less consistently compared to fluphenazine. Both electrodermal and vasoconstrictive orienting responses to tones were reduced. Elevated heart rate and reduced heart rate variability were also observed in patients taking clozapine. Many of these effects can be accounted for by clozapine's anticholinergic and antihistaminic properties. There was evidence that a smaller autonomic response to the mild stress of task performance and larger heart rate responses to nonsignal tones on the alternate treatments were predictive of a good clinical response to clozapine. These results suggest that when on alternate treatments good clozapine responders show more psychophysiological signs of pathology than clinical nonresponders.

Controllable and uncontrollable stress in humans: alterations in mood and neuroendocrine and psychophysiological function.

The authors exposed 10 healthy human volunteers to the stress of loud (100 dB) noise under controllable and uncontrollable conditions on two separate days. Subjects reported higher self-ratings of helplessness, lack of control, tension, stress, unhappiness, anxiety, and depression; had greater hypothalamic-pituitary-adrenal axis function as measured by elevations in plasma adrenocorticotropic hormone; and had higher levels of sympathetic nervous system and electrodermal activity after the uncontrollable stress condition than after exposure to controllable stress. Thus, lack of control over even a mildly aversive stimulus can produce alterations in mood as well as neuroendocrine and autonomic nervous system changes in healthy subjects.

Acute effects of caffeine in normal prepubertal boys.

A recent study demonstrated that dextroamphetamine has an effect in normal prepubertal boys similar to that seen in hyperactive children. The purpose of the present study was to see whether the effects of caffeine are similar to those of amphetamine in normal children. The authors observed 19 prepubertal boys following administration of a single dose of placebo, 3 mg/kg of caffeine, and 10 mg/kg of caffeine in a double-blind, crossover design. Caffeine produced increased vigilance and decreased reaction time, as does amphetamine. Unlike amphetamine, however, the higher dose of caffeine did not have a motor calming effect but increased motor activity. Separate biological systems, therefore, may be differentially affected by the two substances.

Childhood obsessive-compulsive disorder.

The authors collected clinical diagnostic, neurophysiological, electrophysiological, and biochemical data on 9 adolescents who had primary obsessive-compulsive disorder. The results indicate considerable descriptive validity of the syndrome in childhood and its independence from obsessional traits; however, all of the children had a history of major depressive disorder, and their sleep EEG measures resembled those of young adults with primary depressive disorder. The patients' families did not have a more consistent pattern of anxiety disorder or any other psychiatric disorder than do families of adult obsessive patients. Psycholinguistic test results showed a lack of normal laterality, which has been reported for other psychiatric illness.

Frontal lobe lesions and electrodermal activity: effects of significance.

Several studies have shown that cortical damage, especially to the right hemisphere and to frontal lobes, may attenuate skin conductance responses selectively to psychologically significant stimuli. We tested this hypothesis in 32 patients with frontal lesions, verified by computer assisted tomography and magnetic resonance imaging, and 45 healthy controls. Patients and controls were given a protocol which included a rest period, a series of innocuous tones, and a reaction time task. Patients were given a second protocol in which they viewed slides with positive and negative emotional content and neutral slides. Results showed attenuated electrodermal activity (EDA) during task instructions and smaller skin conductance responses to reaction-time stimuli in patients compared to controls but few differences under passive conditions or in orienting responses to simple tones. Patients with lateral prefrontal and paraventricular lesions were especially low in EDA in the reaction time task, and those with right and bilateral lesions in the cingulate gyrus and/or frontal operculum had attenuated EDA in both protocols. We conclude that the effects of certain frontal lesions are on the psychological response to significance which is indexed by EDA rather than directly on EDA per se.

Acute autonomic nervous system effects of caffeine in prepubertal boys.

The effects of caffeine on autonomic activity were tested in 19 normal prepubertal boys. Subjects received placebo, 3 mg/kg, and 10 mg/kg caffeine in a random order (double blind) before three test sessions 48 h apart. Skin conductance (SC), heart rate (HR), and skin temperature (ST) were recorded during a rest period, a series of nonsignal tones, and a simple reaction time (RT) task. Caffeine increased the frequency of both spontaneous and elicited SC responses (SCR) under all conditions. Resting SC base level (SCL) was increased, and shorter SCR half recovery time also occurred in some periods. In contrast, caffeine decreased HR and motor activity at 3 mg/kg. Evidence of improved attention on caffeine was also obtained. The physiological effects are partially similar to the effects seen in clinical anxiety states, and they are also consistent with the physiological concomitants of good sustained attention. The profile of effects did not resemble those of dextroamphetamine in a similar population.

Effects of clozapine, fluphenazine, and placebo on reaction time measures of attention and sensory dominance in schizophrenia.

Two reaction time (RT) paradigms were used to study clozapine's effects on sustained and selective attention compared to fluphenazine and placebo in 25 chronic schizophrenic patients. Sensory dominance was studied via simple and choice RTs to lights and tones, and on double-stimulus trials in which the two stimuli were presented simultaneously. Although 8 of the 25 patients could not perform the RT tasks when taking placebo, there were no effects of clozapine on simple or choice RT compared to placebo or fluphenazine. Subjects on all 3 treatments showed visual dominance: faster RT to lights than to tones on choice and double-stimulus trials. However, clozapine reduced this by means of a selective increase in RT to lights. Clozapine reduced failures to respond to the tone on double-stimulus trials. This was shown to be due to reductions in hallucinations. Clozapine does not generally improve attention, but it may increase the ability of schizophrenic persons to process nondominant or unattended stimuli possibly by increasing the efficiency of resource allocation. This may be partially mediated by a reduction in hallucinations.

"Multidimensionally impaired disorder": is it a variant of very early-onset schizophrenia?

OBJECTIVE: To examine the validity of diagnostic criteria for a subgroup of children with atypical psychosis (n = 19), designated here as "multidimensionally impaired." These children are characterized by poor attention and impulse control, psychotic symptoms, and poor affective control. METHOD: Children and adolescents (n = 19) meeting our criteria for multidimensionally impaired syndrome with onset of psychotic symptoms at or before age 12 years were identified from a total of 150 in-person screenings for very early-onset schizophrenia between 1990 and 1996. We compared the premorbid adjustment, family history, follow-up status, and laboratory measures for a subgroup of these children with those of (1) a rigorously defined group of 29 children with DSM-III-R schizophrenia and (2) 19 children with attention-deficit hyperactivity disorder. RESULTS: Patients with multidimensionally impaired syndrome and patients with very early-onset schizophrenia shared a similar pattern of early transient autistic features, postpsychotic cognitive decline, and an elevated risk of schizophrenic-spectrum disorders among their first-degree relatives. This pattern was not seen in the attention-deficit hyperactivity disorder group. In contrast to very early-onset schizophrenia, the multidimensionally impaired group had significantly poorer scores on the Freedom From Distractibility factor on the WISC-R, a less deviant pattern of autonomic reactivity, and no progression to schizophrenia. CONCLUSIONS: The findings support the distinction of the multidimensionally impaired cases as separate from those with other psychiatric disorders, and there is somewhat greater evidence to suggest that this disorder belongs in the schizophrenia spectrum.

Studies of autonomic psychophysiology and attention in schizophrenia.

Research from this laboratory over the years has found a rather consistent pattern of high baseline levels of many (but not all) indices of autonomic activity, slow adaptation, and attenuated autonomic reactivity to significant stimuli and situations in schizophrenia and that this pattern may be related to prognosis. Our studies have also shown that qualitatively similar changes occur in healthy subjects after a dose of dextroamphetamine and that certain aspects of the pattern are exaggerated in schizophrenic patients with cortical atrophy. It is hypothesized that there are specific autonomic markers for the two syndromes of schizophrenia defined by positive and negative symptoms which reflect distinct biological mechanisms. Current research seeks to determine the biological and symptomatic correlates of autonomic activity, to establish the specificity of certain autonomic markers to schizophrenia versus other major diagnoses, and to study the mechanisms and improve the assessment of attentional deficits in schizophrenia.

Neuroleptic effects on autonomic activity in schizophrenia: between-group and within-subject paradigms and comparisons with controls.

Effects of fluphenazine on electrodermal activity (EDA) and heart rate (HR) were studied in patients with schizophrenia and normal control subjects during rest periods, presentation of innocuous tones, and a reaction time (RT) task. Two types of analyses were used: (1) between-group analyses-patients taking placebo were compared with patients taking fluphenazine and with control subjects using only data from the first test session; and (2) within-subject analyses-the same patients were tested when taking fluphenazine and when taking placebo. Results showed higher resting EDA and HR and smaller increments to task performance in placebo patients than in control subjects. Fluphenazine attenuated EDA levels but not the tonic response. Fluphenazine attenuated the HR response but did not affect HR level. Placebo patients were electrodermally hyporesponsive to the RT stimuli but not to simple tones. Fluphenazine markedly attenuated responsivity to simple tones but it attenuated responsivity less for RT stimuli. Testing medicated patients may thus produce misleading results with respect to many, but not all, purported autonomic markers of diagnosis in schizophrenia studies.