Importance of temporal cues for tactile spatial- frequency discrimination.

While scanning a textured surface with fingers, tactile information is encoded both spatially, by differential activation of adjacent receptors, and temporally, by changes in receptor activation during movements of the fingers across the surface. We used a tactile discrimination task to examine the dependence of human tactile perception on the availability of spatial and temporal cues. Subjects discriminated between spatial frequencies of metal gratings presented simultaneously to both hands. Tactile temporal cues were eliminated by preventing lateral hand movements; tactile spatial cues were eliminated by using gloves with an attached rubber pin. Analysis revealed separation of the subjects into two groups: "spatiotemporal" (ST) and "latent-temporal" (LT). Under normal conditions, the performance of ST subjects was significantly better than that of the LT subjects. Prevention of lateral movements impaired performance of both ST and LT subjects. However, when only temporal cues were available, the performance of ST subjects was significantly impaired, whereas that of the LT subjects either improved or did not change. Under the latter condition, LT subjects changed strategy to scanning with alternating hands, at velocities similar to the velocities normally used by ST subjects. These velocities generated temporal frequencies between 15 and 30 Hz. The LT subjects were unaware of their improved performance. Nine of ten LT subjects significantly improved their performance under normal conditions when trained to scan gratings using alternating hands and velocities similar to those used by ST subjects. We conclude that (1) temporal cues are essential for spatial-frequency discrimination, (2) human subjects vary in the tactile strategies they use for texture exploration, and (3) poor tactile performers can significantly improve by using strategies that emphasize temporal cues.

Pharmacological effects of the non-competitive NMDA antagonist CNS 1102 in normal volunteers.

1. Non-competitive antagonists at the glutamatergic N-methyl D-aspartate receptor significantly reduce the volume of ischaemic cerebral infarction in animals and are potential agents for the treatment of acute stroke in humans. 2. CNS 1102, a novel non-competitive NMDA antagonist, was administered as a 15 min intravenous infusion to healthy male volunteers in a double-blind, placebo-controlled, dose-ranging study. This was the first administration to man. 3. Clinically significant sedation, increased mean arterial pressure and pulse rate were seen at doses of 30 micrograms kg-1 and above. Symptoms of sedation and central nervous excitation became unacceptable for conscious individuals at doses of 45 micrograms kg-1 and above. 4. Rapid onset of central nervous system effects after administration is in keeping with rapid distribution of CNS 1102 to brain. Steady state volume of distribution was large (444 l) and terminal elimination half-life from plasma was approximately 4 h. 5. Pharmacokinetic properties are favourable for a potential neuroprotective therapy. The maximum tolerated dose for conscious individuals was 30 micrograms kg-1 given intravenously over 15 min. Further assessment of CNS 1102 should seek methods of drug administration which maximise administered dose with minimal side effects.

A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disease. The Tacrine Collaborative Study Group.

BACKGROUND: In Alzheimer's disease, there is a marked decline in the function of cholinergic neurons in the brain. However, studies of treatment with cholinesterase inhibitors have produced conflicting results. We conducted a multicenter trial to evaluate whether the cholinesterase inhibitor tacrine (1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate) could improve cognition in patients with Alzheimer's disease. METHODS: Of 632 eligible patients with probable Alzheimer's disease, 215 improved while receiving tacrine during a preliminary crossover phase to determine responsiveness and the best dose. The 215 patients were randomly assigned to receive either placebo or their best dose of tacrine (10 or 20 mg four times a day) in a six-week, double-blind trial. The primary measures of efficacy were the cognitive subscale of the Alzheimer's Disease Assessment Scale and the Clinical Global Impression of Change scale; the secondary measures included the Mini-Mental State Examination and the assessment of the activities of daily living. RESULTS: At the end of the six-week trial, the patients receiving tacrine had a mean adjusted cognitive-subscale score of 30.3 (Alzheimer's Disease Assessment Scale) as compared with 32.7 in patients receiving placebo. This represents a smaller decline (by 2.4 points) in cognitive performance in the tacrine group (P < 0.001). There were no differences between the groups in their global-rating scores. The tacrine group had a significantly smaller decline in the activities of daily living. The results of the Mini-Mental State Examination favored tacrine, but the differences were small and not statistically significant (a score of 16.0 with tacrine vs. 15.3 with placebo; P = 0.08). Gastrointestinal symptoms, elevation of aminotransferase levels, and headache were the most frequent side effects; all could be reversed by reducing the dose or discontinuing treatment. CONCLUSIONS: In this short-term study in patients with Alzheimer's disease who were selected for apparent responsiveness to tacrine, treatment with tacrine resulted in a statistically significant reduction in the decline of cognitive function, although this reduction was not large enough to be detected by the study physicians' global assessments of the patients.

Pharmacological treatment of the cognitive side effects of ECT: a review.

Electroconvulsive therapy (ECT) is an extremely effective treatment for a variety of psychiatric syndromes. However, it is frequently associated with transient cognitive side effects. Recent research has shown that these effects are sensitive to a number of treatment parameters, such as electrode placement and stimulus dosage, that the clinician may manipulate. However there have been relatively few efforts to determine if these cognitive side effects may be reduced or prevented by psychopharmacological intervention. In animals electroconvulsive shock (ECS) has been used frequently to screen for compounds which may improve cognition and memory. This paper reviews basic research studies on such compounds, as well as clinical trials in the treatment of various cognitive disorders. Studies using such compounds to reduce the cognitive side effects of ECT are exhaustively reviewed. The compounds that have been examined include: opioids, vasopressin, adrenocorticotropic hormone, other neuropeptides, cholinergic agents, nootropic agents, ergoloid mesylates, calcium-channel blockers, dexamethasone, thyroid hormone, and stimulants.

TRH protection against memory retrieval deficits is independent of endocrine effects.

An electrobrainshock (EBS)-induced memory retrieval deficit was produced in normal and hypophysectomized mice. In normal mice, thyrotropin-releasing hormone (TRH) (0.1 to 30 mg/kg) protected against this EBS disruption of memory after intraperitoneal but not oral (1.0 to 100 mg/kg) administration. In hypophysectomized mice, TRH (0.3 and 3.0 mg/kg) also protected against the retrieval deficit induced by EBS. The memory protection afforded by TRH was unrelated to its ability to elevate plasma levels of triiodothyronine (T3) and thyroxine (T4), nor was TRH's memory protection mediated through an anticonvulsive mechanism. These results support the notion that TRH may play an important role in memory modulation and may have therapeutic value in certain disease states in humans.

Placebo-controlled study of pramiracetam in young males with memory and cognitive problems resulting from head injury and anoxia.

The current study evaluated under double-blind placebo-controlled conditions, the safety and efficacy of 400 mg pramiracetam sulphate TID in treating memory and other cognitive problems of males who have sustained brain injuries. The results of the study indicate that subject performance in measures of memory, especially delayed recall, evidenced clinically significant improvements after the administration of pramiracetam sulphate as compared to placebo. This improvement was maintained during an 18-month open-trial period on the medication as well as during a 1-month follow-up period after the pramiracetam was discontinued.

Neuropsychological deficits in adults with dyslexia.

Adults with severe dyslexia were compared with age-, sex-, IQ- and SES-matched controls on a neuropsychological and neuromotor test battery, and a contrast group who had recovered from dyslexia was also included. The severely dyslexic group was substantially impaired on tests of verbal fluency and learning, as well as on non-verbal temporal order judgements. These test scores were strong predictors of the degree of reading impairment, as was the rate of repetitive movement of the right hand and foot. The results suggest that adult dyslexia is not 'isolated', but is one expression of a widespread left-hemisphere dysfunction.

Early human trials in the assessment of cognition activators.

The assessment of cognition enhancers in the clinic is a broad topic that can be addressed from both academic/theoretical and therapeutic/drug development perspectives. The most important first step is to decide which perspective one is employing and to clearly specify, a priori, the goal of any intended study. Since the therapeutic benefit of cognition enhancers is not apparent until after many weeks of exposure, it is virtually impossible to demonstrate efficacy in early, short-duration Phase 2 trials. It is possible, however, to gain some knowledge of the doses that effect CNS, rCBF, PET etc. in either normal volunteers or the population of interest. However, these results should not be interpreted as evidence for, or lack of, efficacy. Recently, there has been growing interest in the reversal of scopolamine- or benzodiazepine-induced memory deficits in humans. A major problem is the potential for overinterpretation of the results of such studies. From a drug development approach, it is necessary to utilize larger numbers of subjects and longer-term studies. Specification of the indication should be as precise as possible and the outcome measures should accurately reflect both the current state of the patient and the course of the disease. The absence of normative and longitudinal data on such measures is a hurdle that is only now being overcome. Such data provide a scientific basis for the determination of the types of design and sample sizes that give adequate power to thoroughly assess new cognition enhancers.

Early clinical testing of cognition enhancers: prediction of efficacy.

The major problem in predicting clinical efficacy from animal experimental results and phase I data is the lack of resemblance between the models used and the clinical condition. This problem is complicated by the diversity of the potential mechanisms of action of new compounds. A further question is whether Phase I studies should be used as predictors of clinical efficacy at all. Should they be used simply for determining pharmacologically active dose ranges and tolerance? If used as predictors should drug development stop if negative results are obtained? These questions were not resolved. It was nonetheless suggested that some human models (e.g. scopolamine-induced amnesia, hypoxia-induced performance deficits) were indeed potential predictors of clinical response and, in addition, were analogous to similar models in animals. On the other hand characterisation of quantified EEG (QEEG) profiles remained controversial.

Steady-state pharmacokinetics of tacrine in patients with Alzheimer's disease.

Neurochemical studies of Alzheimer's disease (AD) suggest deficiencies in the cholinergic system. We evaluated the steady-state pharmacokinetics of tacrine (Cognex), an oral cholinesterase inhibitor, in 12 patients with AD. Patients sequentially received nine doses of 10 mg, 20 mg, and 30 mg of tacrine every 6 hours. Blood samples were collected until 24 hours after the final dose. Plasma tacrine concentrations were measured using a validated high-performance liquid chromatographic method. Mean maximum plasma concentrations (Cmax) were 5.1 ng/ml, 20.7 ng/ml, and 33.9 ng/ml following administration of 10 mg, 20 mg, and 30 mg doses, respectively. Corresponding mean values for steady-state area under the curve (AUC) were 19.7 ng/ml, 82.9 ng/ml, and 139 ng/ml.hr. Dose-normalized Cmax and AUC values after administration of the 20 mg and 30 mg doses of tacrine were comparable to each other but were significantly greater (p less than .05) than those after the 10 mg doses. The apparent elimination half-life was approximately 3.4 hours for all dosing regimens. Dose-dependent increases in Cmax and AUC values in patients with AD were similar to those previously reported in normal volunteers. The mechanism of the nonlinearity in tacrine pharmacokinetics is unknown.

Therapeutic trials using tacrine and other cholinesterase inhibitors.

At this time, the data available on tacrine are inconclusive with respect to efficacy. Preliminary data are often overinterpreted, and it seems prudent to wait for the results of the ongoing multicenter double-blind studies before reaching a definite conclusion about efficacy.

Animal model studies of benzodiazepine-induced amnesia.

The development of a mouse passive avoidance test as a model for amnesia produced by benzodiazepines is described. The model appropriately classifies the amnesic potential of a wide range of psychoactive drugs as validated by clinical findings. Control experiments indicate that the effect is best described as anterograde amnesia resulting from a failure of consolidation. gamma-Aminobutyric acid (GABA) antagonists had almost no effect on benzodiazepine-induced amnesia, whereas the benzodiazepine-receptor antagonist Ro 15-1788 completely and specifically reversed it. This clinically confirmed finding suggests that benzodiazepine-induced amnesia is mediated through the benzodiazepine-receptor. However, in vivo inhibition of benzodiazepine binding does not correlate well with amnesia in the mouse, and some benzodiazepine-receptor agonists with potent CNS effects in other in vitro models do not produce amnesia. Additional work is needed to clarify what aspects of benzodiazepine receptor occupancy mediate amnesia.

Cortical cholinergic impairment and behavioral deficits produced by kainic acid lesions of rat magnocellular basal forebrain.

The magnocellular basal forebrain (MNBF) provides extensive cholinergic innervation to frontoparietal cortex. In the rat, the MNBF is homologous to the human nucleus basalis of Meynert, a structure implicated in the cholinergic hypothesis of cognitive impairment in Alzheimer's disease (AD). Kainic acid (KA) was used to make lesions in the MNBF of rats which were compared with unoperated controls, sham-operated controls, and control rats injected with KA in the cortical area directly above the MNBF. The MNBF lesions depleted choline acetyltransferase in cortex but not in striatum or hippocampus. Cortical dopamine levels were unchanged; serotonin levels were unchanged in hippocampus and parietal cortex but decreased in frontal cortex. The metabolite levels of these neurotransmitters were unchanged in all brain regions examined. Compared with controls, rats with MNBF lesions were impaired in 24-hr retention, but not acquisition, of a passive avoidance task with escapable footshock. There were no differences between groups in mean number of daily avoidances on a bar-press active avoidance task, although the data suggested a slower rate of learning in MNBF rats. In a serial spatial discrimination reversal test with a snout-poke response, the MNBF rats performed significantly worse than controls, although all groups learned the task. This rodent model is useful for studying the role of the cholinergic system in memory and possibly for developing treatment strategies to alleviate the cognitive dysfunction of AD.

Benzodiazepine antagonist Ro 15-1788: neurological and behavioral effects.

In neurological and behavioral studies in mice, rats, dogs and squirrel monkeys, the imidazobenzodiazepinone Ro 15-1788 acted as a potent benzodiazepine antagonist. The antagonistic activity was both preventive and curative and seen at doses at which no intrinsic effects were detected. It was highly selective in that it acted against CNS effects induced by benzodiazepines but not against those produced by other depressants, such as phenobarbitone, meprobamate, ethanol, and valproate. The onset of action was rapid even after oral administration. Depending on the animal species studied, the antagonistic effects lasted from a few hours to 1 day. The acute and subacute toxicity of Ro 15-1788 was found to be very low. Benzodiazepine-like effects were not seen.

Effects of the novel compound aniracetam (Ro 13-5057) upon impaired learning and memory in rodents.

The effect of aniracetam (Ro 13-5057, 1-anisoyl-2-pyrrolidinone) was studied on various forms of experimentally impaired cognitive functions (learning and memory) in rodents and produced the following effects: (1) almost complete prevention of the incapacity to learn a discrete escape response in rats exposed to sublethal hypercapnia immediately before the acquisition session; (2) partial (rats) or complete (mice) prevention of the scopolamine-induced short-term amnesia for a passive avoidance task; (3) complete protection against amnesia for a passive avoidance task in rats submitted to electroconvulsive shock immediately after avoidance acquisition; (4) prevention of the long-term retention- or retrieval-deficit for a passive avoidance task induced in rats and mice by chloramphenicol or cycloheximide administered immediately after acquisition; (5) reversal, when administered as late as 1 h before the retention test, of the deficit in retention or retrieval of a passive avoidance task induced by cycloheximide injected 2 days previously; (6) prevention of the deficit in the retrieval of an active avoidance task induced in mice by subconvulsant electroshock or hypercapnia applied immediately before retrieval testing (24 h after acquisition). These improvements or normalizations of impaired cognitive functions were seen at oral aniracetam doses of 10-100 mg/kg. Generally, the dose-response curves were bell-shaped. The mechanisms underlying the activity of aniracetam and its 'therapeutic window' are unknown. Piracetam, another pyrrolidinone derivative was used for comparison. It was active only in six of nine tests and had about one-tenth the potency of aniracetam. The results indicate that aniracetam improves cognitive functions which are impaired by different procedure and in different phases of the learning and memory process.