Preclinical research into cognition enhancers
Department of Psychology, University of Michigan, 4032 East Hall, 530 Church Street, Ann Arbor, MI 48109-1043, USA. Trends in Pharmacological Sciences
(Impact Factor: 11.54).
12/2006; 27(11):602-8. DOI: 10.1016/j.tips.2006.09.004
The preclinical development of drugs to treat the cognitive symptoms of neuropsychiatric and neurological disorders is a formidable challenge. Evidence from a wide range of preclinical behavioral and neuropharmacological tests has formed the basis for predicting drug-induced cognition enhancement in normal volunteers and in patients with cognitive impairments. However, the limited validity of preclinical predictions of this enhancement in humans indicates that conventional screening for "broadly active" compounds represents a below-optimal research strategy. This article conceptualizes the evidence needed to improve the predictive validity of preclinical research designed to discover and characterize cognition enhancers. We suggest that the investigation of reciprocal relationships among molecular, cellular, behavioral and cognitive processes modulated by candidate drugs represents the core of such research. By contrast, the usefulness of simple and high-throughput screening tests for the detection of cognition enhancers might be restricted to advanced drug-finding programs that are guided by evidence of the modulation of neurocognitive relationships by cognition enhancers and that are informed by iterative preclinical-clinical cross-validation of research approaches. We stress the need for basic biopsychological research approaches in preclinical programs to find and characterize drugs to treat cognitive disorders.
Available from: Stefano Cesinaro
- "Most CED candidates are evaluated in preclinical models, sets where standardized behavioral outcomes are easily assessed. Although the translation of preclinical data in valid clinical outputs poses several limitations (see Sarter, 2006), animal models remain extremely valuable to identify CED neurobiology (Roesler, 2011). "
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ABSTRACT: Brain aging and aging-related neurodegenerative disorders are major health challenges faced by modern societies. Brain aging is associated with cognitive and functional decline and represents the favourable background for the onset and development of dementia. Brain aging is associated with early and subtle anatomo-functional physiological changes that often precede the appearance of clinical signs of cognitive decline. Neuroimaging approaches unveiled the functional correlates of these alterations and helped in the identification of therapeutic targets that can be potentially useful in counteracting age-dependent cognitive decline. A growing body of evidence supports the notion that cognitive stimulation and aerobic training can preserve and enhance operational skills in elderly individuals as well as reduce the incidence of dementia. This review aims at providing an extensive and critical overview of the most recent data that support the efficacy of non-pharmacological and pharmacological interventions aimed at enhancing cognition and brain plasticity in healthy elderly individuals as well as delaying the cognitive decline associated with dementia.
Available from: Cindy Lustig
- "Increases in attentional effort are thought to be under the control of the " central executive " (Baddeley, 1986) and the anterior attention system (Posner, 1994; Posner and Dehaene, 1994), including frontal and parietal regions. Attentional effort is thought to engage top-down attentional control processes that are employed in order to carry out goal-directed behaviors (Sarter et al., 2006). The right MFG results in this study support the idea that this region is particularly sensitive to the attentional control demands of a given task and is engaged to a greater extent under more demanding conditions. "
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ABSTRACT: Maintaining attention and performance over time is an essential part of many activities, and effortful cognitive control is required to avoid vigilance decrements and interference from distraction. Regions at or near right middle frontal gyrus (Brodmann's area (BA) 9), as well as in other prefrontal and parietal areas, are often activated in studies of sustained attention (e.g., Cabeza and Nyberg, 2000; Kim et al., 2006; Lim et al., 2010). This activation has often been interpreted as representing the engagement of cognitive control processes. However, such studies are typically implemented at one level of task difficulty, without an experimental manipulation of control demands. The present study used the distractor condition sustained attention task (dSAT), which has been used extensively in animals to determine the role of neuromodulator systems in attentional performance, to test the hypotheses that BA 9 is sensitive to changes in the demand for cognitive control and that this sensitivity reflects an increased engagement of attentional effort. Continuous arterial spin labeling (ASL) was used to measure neural activity in sixteen healthy, young adults performing a sustained attention task under standard conditions and under a distraction condition that provided an experimental manipulation of demands on cognitive control. The distractor impaired behavioral performance and increased activation in right middle frontal gyrus. Larger increases in right middle frontal gyrus activity were associated with greater behavioral vulnerability to the distractor. These findings indicate that while right middle frontal gyrus regions are sensitive to demands for attentional effort and control, they may not be sufficient to maintain performance under challenge. In addition, they demonstrate the sensitivity of ASL methods to variations in task demands, and suggest that the dSAT may be a useful tool for translational cross-species and clinical research.
Available from: Romain Le Cozannet
- "One impediment to the identification and evaluation of potential new drug treatments is the lack of reliable animal models specifically designed to simulate episodic memory impairment in schizophrenia , as identified by recent research consortia, e.g. Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) (Sarter, 2006 ; Young et al. 2009). "
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ABSTRACT: Episodic memory is the capacity to recall an event in time and place (What? Where? When?). Impaired episodic memory is a debilitating cognitive symptom in schizophrenia but is poorly controlled by currently available antipsychotic drugs. Consistent with glutamatergic abnormality in schizophrenia, the NDMA receptor antagonist, phencyclidine (PCP), induces persistent 'schizophrenia-like' symptoms including memory deficits in humans and rodents and is widely used as an animal model of the disorder. However, in contrast to humans, PCP and PCP withdrawal-induced memory deficits in rodents are reversed by antipsychotic drugs such as clozapine. One possible explanation is that the memory tasks used in animal studies do not simultaneously test the What? Where? When? components that characterize episodic memory in human tasks. We investigated whether subchronic PCP withdrawal disrupts memory in rats in a task that requires simultaneous integration of memory for object, place and context. Rats learn to discriminate objects under specific spatial and contextual conditions analogous to the What? Where? When? components of human episodic memory. We found that PCP withdrawal impaired performance on this task and that the atypical antipsychotic drug clozapine did not reverse this impairment. However the acetylcholinesterase inhibitor (AChEI) donepezil, which has been shown to improve episodic memory in humans did reverse the effect of PCP. This suggests that PCP withdrawal disruption of object-place-context recognition in rats may prove to be a useful model to investigate episodic memory impairment in schizophrenia and supports the suggestion that AChEIs could prove to be a useful pharmacological strategy to specifically treat episodic memory problems in schizophrenia.
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