William J. McEntee

Cognitive enhancement in Korsakoff's psychosis by clonidine: a comparison with L-dopa and ephedrine.

Each of three catecholamine agonsit medications (clonidine, l-dopa, and ephedrine) and placebo were administered for 2-week trials to a group of amnesics with Korsakoffs psychosis following a double-blind, counterbalanced design. During the last 3 days of each treatment, patients were given a battery of neuropsychological tests to determine the effects of the drugs on memory and related cognitive processes. Only clonidine had a significant effect on measures of anterograde amnesia, and this response was restricted to the same psychometric measures that improved with clonidine in an earlier study (McEntee and Mair 1980). Each of the medications affected performance on some measures of attention. None of the treatments had any effect on measures of retrograde amnesia or digit-symbol substitution. There appears to be a significant negative correlation between the mnestic effects of clonidine and the concentration of the primary noradrenergic metabolite in lumbar CSF (as measured prior to the initial drug trial).

Thiamine deficiency depletes cortical norepinephrine and impairs learning processes in the rat.

Several lines of evidence indicate that thiamine deficiency causes the Wernicke-Korsakoff syndrome, a human memory disorder. The present study examined behavioral deficits in rats after recovery from a bout of thiamine deficiency. Following behavioral testing, the brains were dissected into regions and assayed biochemically for levels of dopamine, norepinephrine, serotonin and the primary metabolites of these monoamines. Based on previous findings in this laboratory, we predicted that thiamine deficiency not only produces behavioral deficits but loss in catecholamines as well. Impairments were observed for a spatial delayed alternation task that had been learned prior to experimental treatment. In addition, experimental animals were impaired in their ability to acquire two novel tasks, active and passive shock avoidance, after recovery from the acute effects of thiamine deficiency. Comparable deficits were not observed for a number of reflex responses that were measured to assess the general neurological state of the animals. Biochemical analyses revealed that the concentration of norepinephrine was reduced significantly in cortex-hippocampus and olfactory bulb but not in other regions, while dopamine and serotonin levels were not altered in any brain region examined. These data demonstrate that a bout of thiamine deficiency can produce persistent deficits in brain norepinephrine and concomitant decrements in behavioral measures of learning and memory. These results are consistent with our hypothesis and evidence that noradrenergic deficits contribute to the amnesic symptoms of Korsakoffs psychosis.

Behavioral impairments, brain lesions and monoaminergic activity in the rat following recovery from a bout of thiamine deficiency

Learning impairments were measured in rats following recovery from a subacute bout of thiamine deficiency. Behavioral training was carried out in an automated T-maze, beginning with paired run spatial delayed non-matching to sample (PR-1), then light-dark discrimination (LD), light-dark discrimination reversal (LD-R), spatial discrimination (SD), spatial discrimination-reversal (SD-R), and finally retraining on the original paired run task (PR-2). Comparable deficits were observed for PR-1 and PR-2, thus demonstrating long-lasting impairment on delayed non-matching to sample. Experimentals performed as well as controls on LD and LD-R. Two experimental animals were unable to perform above chance on the simple SD task. The remaining 15 experimental animals were equivalent to controls on several measures of SD and SD-R performance (errors to criterion, number of animals reaching criterion, correct responses in last 60 trials) although they were significantly worse than controls on both PR-1 and PR-2. Taken together, these results indicate an impairment of representational memory (PR-1, PR-2) with a spared capacity for dispositional memory (LD, LD-R, SD, SD-R) as defined by Thomas and Spafford (Behav. Neurosci., 1984, 98: 394-404). Histological analyses of left hemispheres revealed a high incidence (94%) of thalamic lesions, specifically within the intralaminar nuclei and ventral parts of the mediodorsal nucleus; and an absence of detectable changes in other structures, including the mammillary bodies, hippocampus, cortex, and locus coeruleus. In the right hemispheres, assays of monoamines and metabolites in 17 brain regions showed significant reduction only for norepinephrine in entorhinal cortex. All animals that were selectively impaired on the paired-run task had both the medial thalamic lesions and reduction in entorhinal norepinephrine.

Korsakoff's psychosis: noradrenergic systems and cognitive impairment.

Recent studies of patients with Korsakoffs amnesia suggest that central noradrenergic (NE) activity is diminished by the brainstem and diencephalic lesions associated with this disease. Similarly, there is a body of evidence that experimental manipulations of central NE activity affect the ability of animals to learn and remember some conditioned behaviors. The relationship between brain NE activity and human amnesia is underscored by evidence of comparable behavioral deficits in animals with NE depleting lesions and in humans with Korsakoffs psychosis. We argue that diminished NE activity impairs cognitive activation and that this limits processes related to attention and to the information processing capacity of patients with Korsakoffs psychosis.

Odor discrimination and memory in Korsakoff's psychosis.

Korsakoffs syndrome is an organic brain disease, characterized by severe amnesia, that has been associated with olfactory perceptual deficits. Two experiments utilized normal observers to describe the effect of similarity on odor recognition memory and to develop methodology to measure odor discrimination and memory in patients with Korsakoffs disease. The results demonstrate an impaired capacity to discriminate between odors among patients with this disease that is not attributable to impaired sensitivity or to rapid decay of memory stores. These results are compared with results from animals with lesions affecting the medial layer of the mediodorsal thalamic nucleus and its neocortical projections. This structure is consistently damaged in Korsakoffs disease and receives a major input from primary olfactory cortex.

Monoamines and metabolites in cortex and subcortical structures: normal regional distribution and the effects of thiamine deficiency in the rat.

The present study measured the concentration of monoamines, metabolites and estimates of turnover rate in eighteen separate brain regions from controls and a rat model of Korsakoffs disease induced by a two week bout of pyrithiamine and thiamine deficient diet (PTD). A behaviorally tested control (n = 12) and PTD (n = 17) group, and a non-behaviorally tested PTD group (n = 8) were sacrificed 7 months after recovery from treatment. The brains were dissected into nine cortical areas and nine subcortical regions. In behaviorally tested PTD animals, a significant reduction of NE was observed in entorhinal cortex. Diminished norepinephrine (NE) concentration was also observed in entorhinal, hippocampal, septal and olfactory areas of the non-behaviorally tested PTD group. Serotonin and 5-hydroxyindoleacetic acid (5-HIAA) levels were increased in several brain areas, particularly midbrain-thalamus, striatum, of both groups of recovered PTD animals. These findings are discussed with respect to results and hypotheses presented in our previous study of this animal model. Significant differences in monoamine, metabolite and turnover estimates were also observed among cortical areas of the control animals. Entorhinal cortex contained the highest concentration of NE and 5-hydroxytryptamine (5-HT), while DA was highest in somatosensory cortex. The distribution of 5-HT and 5-HIAA were more homogeneous and displayed a rostral-caudal decline in concentration.

Long-Lasting Changes in Regional Brain Amino Acids and Monoamines in Recovered Pyrithiamine Treated Rats

Rats were subjected to a severe bout of thiamine deficiency induced by daily pyrithiamine +a thiamine deficient diet, reversed by thiamine administration and allowed to recover. Pyrithiamine treated animals demonstrated impaired retention of a 24 h recall of passive avoidance. Regional brain concentration of norepinephrine, dopamine, serotonin, 3,4-dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid, GABA, glutamate, aspartate, glutamine, and glycine were determined after 2 and 9 weeks of nutritional recovery. A significant increase in NE content of cerebellum from the pyrithiamine treated animals was observed at both 2 and 9 week recovery periods. The concentrations of serotonin and its metabolite were signifciantly elevated in midbrain-thalamus and striatum. Significant reductions of GABA and glutamate were also observed in midbrain-thalamus. Amino acid levels in all other brain areas were unchanged from pair-fed controls. These results suggest regionally specific, chronic alterations in GABA, glutamate, serotonin, and norepinephrine activity following recovery from an acute bout of pyrithiamine-induced thiamine deficiency. The absence of a permanent reduction of cortical norepinephrine similar to that observed in an earlier study is discussed.

Monoamine activity correlates with psychometric deficits in Korsakoff's disease

Korsakoffs psychosis is associated with impairments of memory and perception but not global dementia. We have previously reported diminished concentrations of catecholamine metabolites in the CSF of patients with Korsakoffs psychosis. In this study, we compared CSF monoamine metabolite data with performance on psychometric tests for 26 patients with this disease. We report that patients with more severe neurobehavioral deficits have lower concentrations of monoamine metabolites. Our data also provide evidence that diminished brain noradrenergic and dopaminergic activities are related to impairments on different psychometric tasks.

Learning impairments after 6-OHDA treatment: A comparison with the effects of thiamine deficiency

Cortical norepinephrine, dopamine and 3,4-dihydroxyphenylacetic acid were reduced by injection of 6-hydroxydopamine (6-OHDA) jointly into the cisterna magna and the dorsal noradrenergic bundle. On subsequent behavioral testing, deficits were observed for spatial delayed alternation learning, but not for active or passive avoidance. Treatment with clonidine resulted in a significant improvement in spatial delayed alteration for experimental as compared to control animals. Injections of 6-OHDA into the cisterna magna alone had no significant effect on brain chemistry or behavioral measures. These results are similar to previous observations following a bout of thiamine deficiency, in which cortical catecholamines were depleted in animals that had exhibited deficits for spatial delayed alternation learning. We argue that the cortical catecholamine deficits observed in post-thiamine-deficient animals are sufficient to account for the delayed alternation deficits observed in this animal model of Korsakoffs psychosis.

Semantic encoding deficits in a case of traumatic amnesia

A 33-year-old patient was studied neuropsychologically 19 years after sustaining severe head trauma. A recent CT scan showed lesions in the left frontal and right temporal regions. Performance on standard memory tests, both verbal and visuospatial, was extremely poor, although other intellectual functioning was relatively spared. The patient showed some interesting deficits in semantic processing. In a depth of processing task there was no advantage for words where semantic encoding had been induced. Neither was there any release from proactive interference after shifts in semantic categories. Deficits were also observed in short-term memory distractor tasks as well as in cueing tasks. These findings suggest that the cognitive deficits commonly observed in Korsakoffs disease can also be present in other amnesic disorders and may in part be related to cortical and especially frontal lobe atrophy.