Thomas B. Horvath

Positive and negative symptoms in schizophrenia

Negative and positive symptoms were determined for 46 drug-free patients who met Research Diagnostic Criteria (RDC) and/or Feighner criteria for schizophrenia. A modified version of the Scale for the Assessment of Negative Symptoms (SANS) was completed for each patient based on items from the Schedule for Affective Disorders and Schizophrenia (SADS) and other scales. Positive symptoms were scored from the SADS as well as from the following four diagnostic systems: RDC, Schneiders first-rank symptoms, the 12-point Flexible system, and Langfeldts criteria for poor prognosis schizophrenia. For all patients, there was no correlation of negative symptoms and positive symptoms defined by any diagnostic system. Within the paranoid and undifferentiated subtypes, there was a positive correlation of positive and negative symptoms. Patients moving from stable to exacerbated states had an increase in both positive and negative symptoms, and patients with a poor history of treatment response had both more positive and more negative symptoms than responsive patients in a stable state. These results do not support the view that subgroups of patients have predominantly either negative or positive symptoms.

Event-related potentials in schizophrenics ☆

Fifteen schizophrenics and 15 age-matched controls were compared on 3 auditory event-related potential (ERP) paradigms that elicited a variety of components. In one paradigm, tones were given at 0.75, 2.25 and 6.75 sec interstimulus intervals; in another, infrequently occurring targets in a reaction-time task were interspersed with frequent background stimuli; and, in a third, noise bursts or tones were delivered in a random sequence at either 70 or 100 dB SPL. The sensitivity of some of the ERP components in distinguishing schizophrenics from controls depended on the conditions under which the component was elicited. N1 amplitude was smaller in the schizophrenics than in the controls after longer interstimulus intervals. P2 amplitude was smaller in the schizophrenics than in the controls after longer interstimulus intervals. P2 amplitude was smaller in the schizophrenics only at higher stimulus intensities. P2 latency was shorter in schizophrenics except in the paradigm that varied interstimulus intervals. P3 amplitude, however, was much smaller in schizophrenics than controls ragardless of whether P3 was elicited by targets in a task or was elicited by 100 dB SPL stimuli. The loud stimuli also elicited blink reflexes that coincided with N1, but these reflexes did not vary by clinical group. Neither the amplitude of the slow wave following targets nor the sustained potential that accompanies prolonged auditory stimuli differed between schizophrenics and controls.

P3 reduction in auditory evoked potentials of schizophrenics

Fifteen schizophrenics and 15 age-matched controls performed a reaction time (RT) task. A Bernoulli sequence of 85 dB SPL, 50 msec, 800 c/sec (P = 0.85) and 1200 c/sec (P = 0.15) tones was presented with an interstimulus interval of 1 sec. Subjects were instructed to press a button quickly upon hearing the 1200 c/sec tone. If a subject failed to respond within 650 msec, a 50 msec white noise burst occurred. In averages synchronized with target tones and computed without respect to RT, P3 was maximal at PZ with a mean latency of 330 msec for both schizophrenics and controls. P3 amplitude at PZ, however, averaged 6 muV in schizophrenics and 14 muV in controls (P < 0.001). Both mean RT and mean within-subject variance were greater in schizophrenices than controls. Other kinds of averages were computed to investigate the possibility that the amplitude differences were associated with different RTs or with differences in P3 latency variability in underlying trails. Averages of trials associated with short RTs (100--286 msec) had larger P3s than averages associated with long RTs (287--600 msec) (P < 0.01). Within each RT range, however, schizophrenic P3s were smaller than control P3s. Neither response-synchronized averaging nor adaptive filtering eliminated P3 amplitude differences between groups, indicating that P3 latency variability cannot account for these differences. We hypothesize that the smaller P3s in schizophrenics represent a deficit in reactivity to unexpected stimuli that is compatible with normal RT performance.

Event-related potential changes in chronic alcoholics ☆

Ten chronic alcoholics (10+ year alcoholic drinking history) and ten age and sex matched controls were tested on an ERP paradigm which elicited a large P3 component. The N1 and P2 sensory evoked potential components did not differ in amplitude or latency between the two groups. The latency of the P3 was significantly longer for the alcoholics than the controls for both a response and non-response stimulus. This finding is consistent with the results seen in a variety of dementias and is offered as evidence of the dementing effects of prolonged alcoholism in this group of subjects. While the P3 latencies were prolonged for the alcoholics, their reaction times were not different from the controls. Single trial analysis using Woodys adaptive filter also demonstrated that the single trial estimates for the 3 latency were significantly prolonged for the alcoholics. The single trial correlation between the P3 latency and each trials corresponding reaction time was significantly greater for the alcoholics than for the controls.

4-Aminopyridine in the treatment of Alzheimer's disease.

The cognitive and behavioral effect of 4-aminopyridine (4-AP) was examined in Alzheimers disease (AD) using a dose finding/replication study design. Fourteen inpatients, aged 54-89 years (mean 66.1 +/- 10.6 SD), meeting NINCDS criteria for probable AD, were studied. Three doses of 4-AP--2.5 mg b.i.d., 5 mg b.i.d., and 10 mg b.i.d.--or placebo were administered for 4 consecutive days in random order. Symptomatic assessment was performed on the fourth day of each condition using the Alzheimer Disease Assessment Scale (ADAS). Thereafter, the dose on which the best performance occurred was readministered, as was placebo. Of the 13 patients who completed the dose-finding phase, 7 patients had at least one dose of 4-AP that was associated with less severe symptoms than was placebo, and those patients were included in the replication phase. Results indicated no significant difference in total ADAS scores (p greater than 0.05). Examination of the ADAS subscales revealed no significant 4-AP effect on any particular symptom. Possible explanations of the lack of a drug effect in this study include the unselective release of neurotransmitters by 4-AP, poor penetration into the central nervous system (CNS), and the presenile onset of the disease in these patients.

Clinical Studies of the Cholinergic Deficit in Alzheimer’s Disease

Autopsy studies indicating that cholinergic neurons are selectively lost in patients with Alzheimers disease (AD) and senile dementia of the Alzheimer type (SDAT) suggest that peripheral markers for central cholinergic activity would be useful in diagnosis. The present studies found that cerebrospinal fluid (CSF) concentrations of acetylcholine (ACh) correlated with the degree of cognitive impairment (r = .70) in a sample of carefully diagnosed patients with AD/SDAT, but metabolites of other neurotransmitters were not related to cognitive state; this suggests that CSF ACh may be a valid measure of cholinergic degeneration. cortisol and growth hormone were measured in plasma samples drawn from patients and controls every 30 minutes from 2100 to 1100 hours the next day. Mean plasma cortisol concentrations were higher in patients with AD/SDAT than in controls and correlated inversely with CSF methoxy‐hydroxyphenylglycol (MHPG) (r = .61) and positively with degree of cognitive impairment (r = +.53); as anticholinergic drugs suppress cortisol this finding indicates that cortisol dysregulation may be a marker for abnormalities in other neurotransmitter systems, particularly the noradrenergic system. Growth hormone secretion was not different in patients and controls but was positively correlated with CSF MHPG (r = + .63).

Clinical studies of the cholinergic deficit in Alzheimer's disease. I. Neurochemical and neuroendocrine studies.

Autopsy studies indicating that cholinergic neurons are selectively lost in patients with Alzheimers disease (AD) and senile dementia of the Alzheimer type (SDAT) suggest that peripheral markers for central cholinergic activity would be useful in diagnosis. The present studies found that cerebrospinal fluid (CSF) concentrations of acetylcholine (ACh) correlated with the degree of cognitive impairment (r = .70) in a sample of carefully diagnosed patients with AD/SDAT, but metabolites of other neurotransmitters were not related to cognitive state; this suggests that CSF ACh may be a valid measure of cholinergic degeneration. cortisol and growth hormone were measured in plasma samples drawn from patients and controls every 30 minutes from 2100 to 1100 hours the next day. Mean plasma cortisol concentrations were higher in patients with AD/SDAT than in controls and correlated inversely with CSF methoxy‐hydroxyphenylglycol (MHPG) (r = .61) and positively with degree of cognitive impairment (r = +.53); as anticholinergic drugs suppress cortisol this finding indicates that cortisol dysregulation may be a marker for abnormalities in other neurotransmitter systems, particularly the noradrenergic system. Growth hormone secretion was not different in patients and controls but was positively correlated with CSF MHPG (r = + .63).

Late Event-related Potentials and Schizophrenia

Event-related potential (ERP) correlates of schizophrenia have recently been reviewed in a series of articles in the Schizophrenia Builetin [Buchsbaum, 1977; Roth, 1977; Shagass, 1977]. Differences between patients and controls have been found for ERP components of various latencies and topographic distribution although generally only single ERP paradigms have been applied at one time. This paper reports the results of a pilot study designed to investigate schizo phrenic patients in a multiple ERP paradigm design. We tested subjects on three paradigms, each of which emphasized different late ERPs. Components with latencies over 50 msec are generally more sensitive than earlier components to psychological variables, such as attention and expectancy, and for that reason might be more sensitive to psychological alterations commonly reported in schizophrenia. By eliciting different ERP components in the same subjects we hoped to get an idea of the relative sensitivity of these components to schizophrenic illness.

Acute and Chronic Effects of Ethanol on Event-Related Potentials

Evoked potentials (EPs) have been widely used to elucidate some of the effects of the acute administration of ethanol on the human central nervous system. Ethanol reduces the amplitude of evoked potential components in the 30–400 msec range regardless of the stimulation modality: somatosensory (Lewis et al., 1970; Porjesz and Begleiter, 1973; Salamy, 1973; Salamy and Williams, 1973; Seales et al., in press), visual (Lewis et al., 1970; Porjesz and Begleiter, 1975; Rhodes et al., 1975; Taghavy et al., 1976) and auditory (Fruhstorfer and Soveri, 1968; Gross et al., 1966; Kopell et al., 1978; Pfefferbaum et al., in press; Roth et al., 1977). This amplitude reduction differs for different components and electrode locations. For example, Porjesz and Begleiter (1975) found that visual EP components in the earlier part of the 50 to 250 msec latency range were less sensitive to ethanol than peaks in the later part of this range. Similar results were also reported by Rhodes et al. (1975) for visual EPs and by Salamy and Williams (1973) for the somatosensory modality. Lewis et al. (1970) and Porjesz and Begleiter (1975) found that EPs recorded from central leads were more sensitive to ethanol than EPs from occipital leads.

Cortisol responses to mental arithmetic in acute and remitted depression

The present study utilizes a mental arithmetic task (MAT) to test the hypothesis that the response of plasma cortisol to a voluntary effortful task would be state-independent in depression and would be decreased in both acute and remitted depressed patients