Herbert Weingartner

NMDA receptor function and human cognition: the effects of ketamine in healthy volunteers.

A rapidly growing body of preclinical data has implicated the glutamatergic N-methyl-d-aspartate (NMDA) receptor in memory and other cognitive processes. There is comparatively less information about this receptor system in human cognition. We examined the effects of subanesthetic doses of ketamine, a noncompetitive NMDA receptor antagonist, on two forms of memory, free recall and recognition, as well as attention and behavior in a double-blind, placebo-controlled, 1-hour infusion in 15 healthy volunteers. Ketamine produced decrements in free recall, recognition memory, and attention. In addition, ketamine induced a brief psychosis in our healthy volunteers marked by thought disorder and withdrawal-retardation. Ketamine-induced memory impairments were not accounted for by changes in subjects attention and were not significantly related to psychosis ratings. These data suggest that the NMDA receptor plays a direct role in two types of explicit memory. The implications of these data for the pathophysiology of schizophremia are discussed.

Hemispheric lateralization of functions related to emotion

We have reviewed the evidence that processes and functions related to perception and expression of emotions are represented asymmetrically in the cerebral hemispheres. The literature describes three possible aspects of emotional lateralization: that emotions are better recognized by the right hemisphere; that control of emotional expression and related behaviors takes place principally in the right hemisphere; and that the right hemisphere is specialized for dealing with negative emotions, while the left is specialized for dealing with positive emotions. Evidence for the three hypotheses derives from methodologically diverse studies in unimpaired, brain-lesioned, and mood-disordered populations. Relatively little of the work has been precisely replicated, and conclusions rest on parallel lines of evidence from diverse sources. The present level of knowledge suggests a model of emotional control based on interactive inhibition between a right negatively biased and left positively biased hemisphere. However, the details of such a model, including the precise conditions under which emotion-related functions are lateralized, and the mechanisms of such lateralization have yet to be elucidated.

Dehydroepiandrosterone (DHEA) treatment of depression

Dehydroepiandrosterone (DHEA) and its sulfate, DHEA-S, are plentiful adrenal steroid hormones that decrease with aging and may have significant neuropsychiatric effects. In this study, six middle-aged and elderly patients with major depression and low basal plasma DHEA f1p4or DHEA-S levels were openly administered DHEA (30-90 mg/d x 4 weeks) in doses sufficient to achieve circulating plasma levels observed in younger healthy individuals. Depression ratings, as well as aspects of memory performance significantly improved. One treatment-resistant patient received extended treatment with DHEA for 6 months: her depression ratings improved 48-72% and her semantic memory performance improved 63%. These measures returned to baseline after treatment ended. In both studies, improvements in depression ratings and memory performance were directly related to increases in plasma levels of DHEA and DHEA-S and to increases in their ratios with plasma cortisol levels. These preliminary data suggest DHEA may have antidepressant and promemory effects and should encourage double-blind trials in depressed patients.

Intravenous nicotine in Alzheimer's disease: a pilot study

In the first study to examine direct nicotinic augmentation of central cholinergic functioning in Alzheimers disease, six patients were studied in an intensive pilot study with three doses (0.125, 0.25, and 0.5 μg/kg/min) of intravenous nicotine and placebo. Cognitive tests showed a decrease in intrusion errors on the middle (0.25 μg) dose. Prominent behavioral effects were noted, with significant dose-related increases in anxiety and depressive affect. These results suggest that central nicotinic cholinergic stimulation deserves further investigation as a treatment in Alzheimers disease and that nicotine may also be a useful investigative tool in other populations as a probe of central cholinergic function, especially in regard to the modulation of affect.

Qualitative analysis of scopolamine-induced amnesia.

The neurochemistry of memory remains to be determined. Acetylcholine may be one of the neuotransmitters which mediates memory function, since the anticholinergic drug scopolamine produces amnesia in man. This study of scopolamine-induced memory deficits further defines those cognitive processes which are disrupted. The drug does not diminish attention, as assessed with an auditory vigilance task, or initial signal detection. More complex auditory decoding is affected, however. Scopolamine impairs aspects of initial memory acquisition (e. g., encoding and consolidation) and spontaneous memory retrieval. Retention is unaffected. Precise delineation of the neurochemistry of human memory will require comparative studies of amnesia-producing compounds, systematically examining the neuropsychological processes impaired by each.

Increased cognitive sensitivity to scopolamine with age and a perspective on the scopolamine model

18 older normal volunteers (mean age = 66.5 +/- 7.9 years) and 46 younger volunteers (mean age = 27.0 +/- 6.1 years) were administered the anticholinergic drug scopolamine (0.5 mg i.v.) followed by a battery of cognitive tests evaluating attention, learning and memory. The older subjects were significantly more impaired than the younger by scopolamine on some tests of learning and memory. This increased sensitivity of the older group to scopolamine is consistent with studies in animals and humans showing decreased cholinergic system function with age. The findings also indicate that age is an important variable to consider in using the scopolamine model of memory impairment. The cognitive impairment caused by scopolamine in younger subjects in this and prior studies is similar to some, but not all aspects of the impairment which occurs in normal aging. Scopolamine also caused impairments on digit span and word fluency tasks, which are not consistent with normal aging changes. In the older group of subjects, scopolamine produced aspects of the cognitive impairment which occurs in AD on tests of episodic memory and learning, vigilance-attention, category retrieval, digit span, and number of intrusions. Other areas of cognition that are of relevance to aging and AD such as psychomotor speed, praxis, concept formation and remote memory were not evaluated in this study. Some of these are being evaluated in ongoing studies, along with additional and more specific tests of retrieval from knowledge memory, implicit memory and attention. The scopolamine model has provided a fruitful pharmacologic starting point for the study of a number of cognitive operations. The idea of dissecting apart aspects of memory systems pharmacologically depends on the availability of neurochemically specific drugs and on the specificity and sensitivity of neuropsychological tests for distinct cognitive operations or domains. Further studies using such tools will aid not only in the understanding of the impairments which occur in aging and in AD, but also of the conceptualization of memory and other cognitive operations and ultimately the physiological mechanisms involved in memory and learning.

An outline for the analysis of dementia. The memory disorder of Huntingtons disease.

Methods have been developed for assessing the cognitive parameters contributing to a memory disorder. Our findings suggest that individuals with Huntington disease have impairments in the encoding of new information and the consistent retrieval from storage of learned material. Their difficulties lie particularly in the realm of episodic memory.

Dementia of the Alzheimer type Clinical and family study of 22 twin pairs

We studied 22 twin pairs in which one or both twins had dementia of the Alzheimer type (DAT). In four twins, diagnosis was confirmed by autopsy. Seven monozygotic (MZ) pairs were concordant for DAT; 10 MZ pairs were discordant. Two dizygotic (DZ) pairs were concordant for DAT, and 3 DZ pairs were discordant. The current concordance rate was 41% for MZ twins and 40% for DZ twins. The study supports the belief that, etiologically, DAT cannot be entirely accounted for by a single autosomal dominant gene. The data also suggest that in certain genetic circumstances, disease expression may be delayed in females.

State-Dependent Accessibility of Retrieval Cues in the Retention of a Categorized List.

A state-dependent learning paradigm was used in which subjects encoded and recalled equivalent lists of conceptually categorized words in each of the following conditions: (a) encode following administration of a marijuana placebo—recall placebo, (b) encode placebo—recall following administration of a marijuana placebo—recall placebo, (b) encode placebo—recall following administration of active marijuana, (c) encode marijuana—recall marijuana, and (d) encode marijuana—recall placebo. Free recall of both words and categories was more complete in the encode marijuana—recall marijuana condition than in the encode marijuana—recall placebo condition, a finding indicative of asymmetric state-dependent learning. However, these differences were not apparent when recall was prompted with appropriate extralist retrieval cues. It was concluded that the accessibility of retrieval cues which provide access to higher-order memory units which have been encoded in the dissociated state depends on restoration of that state at the time of attempted recall. Several implications of this reasoning for future studies of the cognitive mechanism underlying human state-dependence were considered.

Cognitive effects of l-deprenyl in Alzheimer's disease

Monoamine neurotransmitter systems, along with cholinergic systems, are known to play important roles in cognition, and are disrupted in at least some patients with dementia of the Alzheimer type (DAT). This suggests that monoamine-enhancing drugs might ameliorate cognitive symptoms in certain patients with DAT. l-Deprenyl is a monoamine oxidase (MAO) inhibitor which may selectively inhibit MAO-B at low doses, while at high doses it nonselectively inhibits MAO-A as well as MAO-B. We studied its effects on several types of cognitive function in 17 patients with DAT. Two doses of l-deprenyl (10 mg/day and 40 mg/day) and placebo were compared in a double-blind, serial treatment design. Episodic learning and memory, knowledge memory, attention, recognition, and performance on a continuous performance task were assessed at baseline and under these drug and placebo conditions. Statistically significant improvement was noted in performance on an episodic memory and learning task requiring complex information processing and sustained conscious effort during treatment with l-deprenyl 10 mg/day. Knowledge memory, intrusions, and other cognitive functions relevant to DAT were not altered by l-deprenyl at either dose.