New semantic learning in patients with large medial temporal lobe lesions.

Two patients with large lesions of the medial temporal lobe were given four tests of semantic knowledge that could only have been acquired after the onset of their amnesia. In contrast to previous studies of postmorbid semantic learning, correct answers could be based on a simple, nonspecific sense of familiarity about single words, faces, or objects. According to recent computational models (for example, Norman and O'Reilly (2003) Psychol Rev 110:611-646), this characteristic should be optimal for detecting the kind of semantic learning that might be supported directly by the neocortex. Both patients exhibited some capacity for new learning, albeit at a level substantially below control performances. Notably, the correct answers appeared to reflect declarative memory. It was not the case that the correct answers simply popped out in some automatic way in the absence of any additional knowledge about the items. Rather, the few correct choices made by the patients tended to be accompanied by additional information about the chosen items, and the available knowledge appeared to be similar qualitatively to the kind of factual knowledge that healthy individuals gradually acquire over the years. The results are consistent with the idea that neocortical structures outside the medial temporal lobe are able to support some semantic learning, albeit to a very limited extent. Alternatively, the small amount of learning detected in the present study could depend on tissue within the posterior medial temporal lobe that remains intact in both patients.

Yes/no recognition, forced-choice recognition, and the human hippocampus.

Two recent studies reported that yes/no recognition can be more impaired by hippocampal lesions than forced-choice recognition when the targets and foils are highly similar. This finding has been taken in support of two fundamental proposals: (1) yes/no recognition tests depend more on recollection than do forced-choice tests; and (2) the hippocampus selectively supports the recollection process. Using the same stimulus materials as in the earlier studies, we tested five memory-impaired patients with circumscribed hippocampal lesions and 15 controls. As in the earlier studies, participants studied 12 pictures of objects and then took either a 12-item forced-choice test with four alternatives or a 60-item yes/no test. Patients were impaired on both tests but did more poorly on the yes/no test. However, a yes/no test based on 12 study items would conventionally involve only 24 test items (i.e., 12 study items and 12 foil items). When we scored only the first 24 test items, the patients performed identically on the yes/no and forced-choice tests. Examination of the data in blocks of 12 trials indicated that the scores of the patients declined as testing continued. We suggest that a yes/no test of 60 items is difficult relative to a 12-item forced-choice test due to the increased study-test delay and due to increased interference, not because of any fundamental difference between the yes/no and forced-choice formats. We conclude that hippocampal lesions impair yes/no and forced-choice recognition to the same extent.

The anatomy of semantic knowledge: medial vs. lateral temporal lobe.

Semantic knowledge (e.g., long-established knowledge about objects, facts, and word meanings) is known to be severely impaired by damage to the anterolateral temporal lobe. For example, patients with semantic dementia have prominent atrophy in anterolateral temporal cortex and also have significant damage within the medial aspect of the temporal lobe. However, there is uncertainty about the contribution of medial temporal lobe damage, including perirhinal cortex damage, to impaired semantic knowledge. Drawing largely on published material from multiple sources, we compared the performance of severely amnesic patients with large medial temporal lobe lesions and patients with semantic dementia on nine tests of semantic knowledge and two tests of new learning ability. On the tests of semantic knowledge, the amnesic patients performed markedly better than the patients with semantic dementia. By contrast, on the tests of new learning, the patients with semantic dementia performed markedly better than the amnesic patients. We conclude that medial temporal lobe damage impairs the formation of declarative memory, and that semantic knowledge is impaired to the extent that damage extends laterally in the temporal lobe. Reports that the extent of atrophy in perirhinal cortex correlated with the severity of impaired semantic knowledge may be understood by supposing that the extent of damage in many temporal lobe areas is intercorrelated in this progressive disease, and that the extent of atrophy in perirhinal cortex is a proxy for the overall severity of dementia.

Anticonvulsant and adverse effects of avermectin analogs in mice are mediated through the gamma-aminobutyric acid(A) receptor.

Twenty-five avermectin analogs were assessed in a mouse seizure model. The ED(50) against pentylenetetrazole-induced tonic seizures ranged from 0.48 mg/kg (L-676,893) to >160 mg/kg (L-685,869) cf. 0. 26 mg/kg for diazepam. Although avermectins are without acute toxic effects, they have been historically shown to have relative low LD(50) values in mammals. The mechanisms involved in the anticonvulsant effect and the toxicity were investigated. A series of avermectin analogs displaced [(3)H]ivermectin binding to rat brain membranes and recombinant GABA(A) receptors (alpha1beta3gamma2-subtype) with the same affinities, strongly suggesting that [(3)H]ivermectin labels the GABA(A) receptor in rodent brain. Avermectins, which were anticonvulsant, were also potent inhibitors of [(3)H]ivermectin binding in rat brain. However, the rank order for anticonvulsant activity did not parallel the rank order for affinity at the [(3)H]ivermectin site and it was reasoned that avermectins may have differential affinity or efficacy at subtypes of the GABA(A) receptor. All the active compounds tested potentiated the effects of GABA at recombinant GABA(A) receptors in oocytes and at native cortical GABA(A) receptors and the efficacy of avermectins at the GABA(A) receptor correlated best with their anticonvulsant potency. Although avermectins weakly inhibited [(3)H]strychnine binding in rat spinal cord, and inhibited glycine responses on primary cultured cortical neurons, activity at glycine receptors did not correlate with either anticonvulsant activity or toxicity. Because both anticonvulsant activity and toxicity correlated best with activity at GABA(A) receptors, it is unlikely that these effects can be separated, which may contraindicate the potential use of avermectins as anticonvulsants.

Choline acetyltransferase activity and cognitive domain scores of Alzheimer's patients.

Choline acetyltransferase activity and cognitive domain scores of Alzheimer's patients. Item scores from the Mattis Dementia Rating Scale (MDRS) and the Mini-Mental State Examination (MMSE) from 389 patients with probable Alzheimer's disease were submitted to principal component analysis with orthogonal rotation. The optimal solution identified four factors that reflected the cognitive domains of attention/registration, verbal fluency/reasoning, graphomotor/praxis and recent memory. A subgroup of patients was identified for whom both the MDRS and the MMSE had been administered within the 12 months before death. Scores were assigned to these patients for the four factors. These cognitive-domain scores were then correlated with postmortem choline acetyltransferase (ChAT) activity in the medial frontal cortex, inferior parietal cortex, and hippocampus. ChAT activity in both the medial frontal and the inferior parietal cortex significantly correlated with scores on the graphomotor/praxis factor. Medial frontal ChAT also correlated significantly with the attention/registration scores. Hippocampal ChAT correlated significantly only with recent memory scores. These results are consistent with current animal research regarding the effect of selective cholinergic lesions on behavior.

Comparison of the serial position effect in very mild Alzheimer's disease, mild Alzheimer's disease, and amnesia associated with electroconvulsive therapy.

Individuals given a series of words to memorize normally show better immediate recall for items from the beginning and end of the list than for mid-list items. This phenomenon, known as the serial position effect, is thought to reflect the concurrent contributions of secondary and primary memory, respectively, to recall performance. The present study compared the serial position effects produced on Trial 1 of the California Verbal Learning Test (CVLT) in mildly demented (N = 25; M MMSE = 20.0) and very mildly demented (N = 25; M MMSE = 25.5) patients with Alzheimer's disease (AD), and age- and education-matched normal control (NC) participants (N = 50). In addition, the serial position effects of the very mildly demented AD patients were compared to those of patients with a transient, circumscribed amnesia arising from a prescribed series of electroconvulsive therapy (ECT) treatments for the relief of depressive illness (N = 11). While the NC group exhibited the typical serial position effect, AD patients recalled significantly fewer words than NC participants overall, and exhibited a significantly reduced primacy effect (i.e., recall of the first 2 list items) with a normal recency effect (i.e., recall of the last 2 list items). Patients with circumscribed amnesia due to ECT were as impaired as the very mildly demented AD patients on most standard CVLT measures of learning and memory, but exhibited primacy and recency effects, which were within normal limits. These results suggest that a reduction in the primacy effect, but not the recency effect, is an early and ubiquitous feature of the memory impairment of AD. It is not, however, a necessary feature of all causes of memory impairment.

The effects of selected antidepressant drugs on timing behaviour in rats.

It has been suggested that the increased reinforcement rate on a differential-reinforcement-of-low-rate of responding (DRL) schedule observed following acute antidepressant administration in the rat is due to an improvement in timing accuracy. The aim of the present work was to evaluate the effects of antidepressants in another schedule that requires accurate estimation of time intervals, the peak procedure. Three antidepressant drugs were tested, the tricyclic antidepressant imipramine (1.0-10.0 mg/kg, i.p.) and the 5-HT reuptake inhibitors, zimelidine (10.0-40.0 mg/kg, i.p.) and clomipramine (1.0-10.0 mg/kg, i.p.). For reference, the full benzodiazepine receptor agonist, diazepam (1.0-5.0 mg/kg, i.p.) and the psychomotor stimulant, d-amphetamine (0.5-1.5 mg/kg, s.c.) were also tested. All doses of d-amphetamine tested significantly increased lever-pressing rates, whereas all the other compounds induced significant decreases in lever-pressing rates. Overall, the time at which the maximal lever-pressing rate occurred was not altered by any of the compounds, suggesting that timing accuracy was not significantly affected by any of the compounds administered. The only exception was zimelidine (40.0 mg/kg), which reduced the time at which the maximal lever-pressing rate occurred, although lever-pressing rates were also significantly reduced at this dose. These data suggest that previously reported antidepressant-induced improvement in performance on the DRL schedule may not have been due to improved timing accuracy per se but may have been due to a decrease in lever-pressing rates.

Comparison of benzodiazepine (BZ) receptor agonists in two rodent activity tests.

The effects of four BZ receptor ligands in an operant test were compared with a rotarod test. In the operant test, rats were trained to pull a chain on a schedule that regulates the probability of delivery of food pellets to maintain a steady chain-pulling rate across a 1 h test session. For the rotarod test, mice were trained to remain on a rotarod for 2 min. Diazepam (0.1-3.0 mg/kg, i.p.), FG 8205 (0.1-3.0 mg/kg, i.p.), quazepam (3.0-60.0 mg/kg, i.p.) and zolpidem (0.3-10.0 mg/kg, i.p.) each produced dose-related impairments of performance in both the chain- pulling test and the mouse rotarod test. Furthermore, the impairment in performance induced by FG 8205 (10.0 mg/kg, p.o.) was dose-dependently reversed by the BZ receptor antagonist, flumazenil (1.0-10.0 mg/kg, i.p.), indicating that the chain-pulling deficit was mediated via BZ receptor activation. Diazepam, FG 8205 and quazepam all had comparable potencies in both the rotarod assay and the chain-pulling test. However, zolpidem suppressed the chain-pulling rates at a dose 30-fold lower than that required to induce a significant deficit in the rotarod performance. As zolpidem is a preferentially sedative compound, this pattern of results is consistent with the hypothesis that the chain-pulling test is sensitive to sedation induced by BZ receptor agonists.