Cognitive psychology has provided clinicians with specific tools for analyzing the processes of cognition memory, language and executive functions attention-concentration, abstract reasoning, planning. The prevalence of cognitive and attention disorders is high in adults because all the diseases implicating the central nervous system are associated with cognitive correlates of variable intensity depending on the disease process and the age of the patient. Data from adult human beings, mainly concerning memory, language, and attention processes, will be reported. In human beings, cognitive functions correspond schematically to the brain processes of acquisition and exploitation of knowledge. Research in cognitive psychology and neurosciences is devoted to unraveling these complex processes that underlie several mental functions.
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Cognitive psychology has provided clinicians with specific tools for analyzing the processes of cognition memory, language and executive functions attention-concentration, abstract reasoning, planning. The prevalence of cognitive and attention disorders is high in adults because all the diseases implicating the central nervous system are associated with cognitive correlates of variable intensity depending on the disease process and the age of the patient.
Data from adult human beings, mainly concerning memory, language, and attention processes, will be reported. In human beings, cognitive functions correspond schematically to the brain processes of acquisition and exploitation of knowledge. Research in cognitive psychology and neurosciences is devoted to unraveling these complex processes that underlie several mental functions. The high prevalence of cognitive complaints has prompted neuropsychologists to elaborate tools necessary for the objective measurement and understanding of cognitive alterations, thereby allowing the establishment of a diagnosis.
Each nosographic entity is described by a set of criteria defining alterations in memory Tulving ; De Deyn et al ; Lieury , language Damasio and Damasio ; Damasio et al ; Damasio ; Frederici ; Fries et al , and executive functions, which also include concentration, or more precisely attention Berger and Posner ; Cowan et al necessary for planning, organization, and synchronization of complex actions Stuss et al ; Stuss and Alexander ; Royall et al Cognitive impairment, explicitly demonstrated by altered performance in specific tasks, is of high prevalence as it is associated with advanced age Raz and most 1neurological and psychiatric disorders.
As a rule, the impairment affects several domains of cognition memories, executive functions, attention, etc simultaneously or consecutively eg, isolated memory impairment converting into AD. It can develop progressively neurodegenerative diseases or occur suddenly after an acute event stroke, head trauma. Cognitive impairment thus occurs in very different contexts involving the central nervous system CNS and resulting from very different pathogenic processes neurodegeneration, inflammation, toxic reaction, ischemia, trauma, neurochemical deficiency Budson and Price The purpose of this review is to highlight potential drugs, and therefore therapeutic drug strategies for improving cognitive impairment in adults.
Arguments are also put forward favoring more extensive indications for pharmacological management of a wider range of pathological conditions involving cognitive dysfunction; this will broaden the scope of patients benefiting from advances in cognitive pharmacology and neurosciences, as strongly suggested by the 2nd Canadian Conference on Antidementia Drugs Feldman et al Although the biological and neurochemical basis of human cognition is undeniable Ichols and Newsome , human thought is something more than the result of a chemical secretion of the brain.
Cognition is a complex phenomenon involving multiple levels of neurobiological processes. Very schematically, studies are thus designed to search for a correlation between a given task requiring cognitive work and an observable elementary change within the CNS.
Access to specific modules of cognition, particularly memory Lynch ; Arshavsky ; Drapeau et al ; Nader and attention Coull ; Filley ; Russell et al , can be facilitated with animal models, mainly in rodents and primates, whereas language and linguistics are strictly limited to human research Perani et al ; Pulvermuller Functional neuroimaging using positron emission tomography PET , functional nuclear magnetic resonance f MRI , magnetoencephalography MEG or magnetic resonance spectroscopy Ross and Sachdev has greatly contributed to our knowledge of the anatomic substrate of the principal cognitive functions.
The hippocampus is involved in detecting and encoding new information and the striato-frontal circuits in decision making processes while the frontal lobe is involved the contextual retrieval and in the shift from one idea or one task to another. Long-term memory and its storage are scattered over different areas of the cerebral cortex Woolf ; this notion of distributed anatomic localizations contrasts with the localized areas described by phrenology. A bilingual person, for example, has distinct and separate temporal cortical areas handling each separate language, passage from one to the other activating the Broca area and spelling and phonology activating the supramarginalis gyrus Price et al Attentional processes also involve a substratum of complex networks regulating and maintaining alertness and orienting sensorial information and executive control Fan and Posner ; Filley ; Fernandez-Duque and Posner Knowledge of the functional substratum in the human brain is particularly important in neuropsychology.
Zhang and Feng reported particularly illustrative work demonstrating that analysis of Chinese characters with their fundamental attributes pictographic similarity, homophony, synonymia involves close collaboration between the two cerebral hemispheres, probably via the corpus callosum. Histological modifications eg, change in synaptic density associated with cognitive performance or learning have been indirectly demonstrated with MEG in elite cello players compared to music lovers or to controls without music training Pantev et al This very partial list offers a few arguments favoring a distributed anatomy of cognition cross-talks between these structures.
Neurochemistry, although difficult to measure in humans, provides clear proof of the organic nature of cognition, offering attractive targets for designing new compounds. Technological advances, eg, specific ligands with PET-scan, experimental models in rodents or primates, in vivo access to neurotransmitters, cerebral metabolism etc, are crucial for targeting drugs to correct for neurochemical anomalies.
All of these techniques have their specific limitations and uncertainties explaining why only a few cognitive functions memory, orientation, attention, decision making, speed of data processing, learning and rare neurotransmission systems acetylcholine [ACh], dopamine [DA], GABA, glutamate and their respective receptors are accessible in humans.
Consequently, cognitive pharmacology is limited at the present time to drugs affecting the aminergic antipsychotics, antiparkinsonians, psychostimulants, drugs such as cocaine , GABAergic anxiolytics , and cholinergic cholinesterase inhibitors, nicotine agonists systems and substances activating neuronal metabolism nootropic agents, vasodilators and brain oxygenators Lynch ; Lockhart and Lestage ; Higgins et al ; Lynch ; Mehlman ; Newhouse et al Collected pharmacological data have nevertheless greatly improved our knowledge of fundamental neurobiology and thus have provided supplementary proof in favor of the biological basis of cognitive mechanisms.
Steroid hormones clearly modify CNS function as demonstrated by the analysis of the neuropsychiatric correlations observed during the perimenopause period Feld et al Cholesterol has recently been at the forefront line of potential cognition-modifiers, any modification of its metabolism, for instance by the statins, having an impact on membrane integrity and intra-neuronal signaling and hence cognitive performance Xiong et al When considering the neurobiological targets which, in the near future, could be accessible for drugs Vakalopoulos ; Nichols and Newsome , glutamate and its different receptors, notably NMDA, AMPA or metabotropic glutamate 5 mGluR5 receptors, appear as excellent candidates Robbins and Murphy more precisely in the domain of learning and retrieval Riedel et al ; the role of glutamate in cytotoxicity amplifies the interest of the pharmacology of this system in the neurodegenerative diseases where cognitive impairment is at the forefront.
Although at the present time out of the scope of human therapeutics, the genetic basis of cognition and of general cognitive ability appears to be a fascinating approach Flint ; Plomin for the teams involved in drug discovery.
Different genes have been pointed out in different situations from AD presenilins, apolipoprotein E , dyslexia chromosome 6 to schizophrenia associated with a pronounced learning deficit Sanderson et al Williams syndrome, which is a rare neurogenetic developmental disorder, is a paradigm linking a profound cognitive impairment to a deletion on chromosome band 7q According to Payton potential pharmacological advantages may be procured from the study of cognitive genetics.
Despite the high prevalence of cognitive disorders and the disastrous consequences in terms of individual independence and social and familial relations, health authorities in almost all countries of the world have failed to officially recognize the beneficial effects of cognitive drug therapy outside the realm of symptomatic treatment for AD.
Cognitive and concentration-attention disorders thus remain orphan symptoms even when they occur as part of an identified condition parkinsonism, non-AD dementia, depression, post-traumatic stress disorder, schizophrenia or are the sole expression of an identified cerebral dysfunction post-ischemia sequela, head trauma, neurogenetic disease.
In addition to these problems, there is the question, perhaps more psychological than regulatory, of priorities. Inversely, the risk of deleterious effects on cognition may become the unique consideration when examining certain drugs or drug classes. The example of psychotropics, particularly benzodiazepines, is particularly illustrative since this class of drugs has been associated with memory impairment. The same type of thinking leads to the idea that use of a given compound should be restricted to a given disease and not for pathological conditions occurring within different diseases cholinesterase inhibitors for example have proven efficacy for cognitive disorders in several diseases such as AD or PD or even attention disorders in children.
This type of discordance between regulatory guidelines and proven efficacy necessarily leads to prescriptions outside officially approved indications. Faced with this dominant attitude of international regulatory authorities, the pharmaceutical industry appears to be gradually slipping away from the objective of developing products which could provide purely symptomatic improvement for the different components of cognition.
The fear is that such symptomatic drugs could be sidetracked from their intended use, as has been observed with psychostimulants ie, amphetamines , producing a negative impact on the drug development project.
The current orientation in the pharmaceutical industry is to direct research towards products with more pathophysiological actions, contributing to progress in the concepts of neurocytoprotection and neuroregeneration, at least within the framework of the main neurodegenerative diseases such as AD Akwa et al or PD.
In spite of the long-term efforts and initiative of the Nationale Institute of Heath NIH in the USA to develop cognitive pharmacology Cutler et al , the National Institute for Health and Clinical Excellence NICE in UK, recently reappraised the cost-effectiveness ratio of anti-dementia drugs in a rather critical, controversial and negative way; the debate again cast some shadow over this category of compounds.
Several test batteries are available and commonly used in clinical pharmacology; the comparative advantages or caveats of those procedures are beyond the scope of the review; the question will be either to cover the main cognitive functions performances Table 2 or rather to deeply analyze the different components of a specific function, such as the different types of memory.
Tests are comparative using different doses, with the initial objective of determining the relative safety of the compound under study.
Note: From Hindmarch and Shamsi Beyond this standard approach, the current objectives of laboratory studies have been broadened to try to demonstrate the real beneficial effect of drugs on cognition. This is a new approach to clinical pharmacology with the goal of developing new treatments for a wide range of indications accompanied by cognitive disturbances: pathological brain aging, dementia neurodegenerative disease, vascular or HIV-related dementia , the major psychiatric syndromes and the consequences of head trauma.
In order to ascertain the specific effects of a given drug psychotropics, psychostimulants, anti-hypertensives, anti-histaminics on brain processes, early phase trials must comply with standard controlled and validated methodologies. Trials must be conducted in certified laboratories using double-blind experimental protocols versus placebo and a reference product substances with well-known effects: caffeine, benzodiazepine, amphetamine, clonidine , in young or older healthy volunteers for certain tasks, it may be useful to have volunteers with a diminished baseline performance in order to facilitate demonstration of the pharmacological activity and avoid the floor or ceiling effects.
The different evaluation criteria require experienced observers to produce valid information. Results must be interpreted with due precautions. Measurements of a given parameter, for example, depend on the degree of motivation or on changes in strategy as well as test-induced fatigue. For each compound evaluated, the risk-benefit ratio can be expressed by the formula I: NI, where I is the number of tests with a significant change in performance score and NI the number of tests with result scores not different from placebo Hindmarch and Shamsi The results obtained in a small number of healthy volunteers are reliable the disease effect is absent as are cotherapies usually observed in patients and can be extrapolated to patients in a therapeutic situation; here the exercise will consist in comparing those laboratory studies with the results obtained, with the same drugs, either in the large scale phase III studies or in Pharmacovigilance surveys.
The cognitive map thus obtained enables a surmise of more overall and behavioral effects, in patients. For clinical research, ligands specific for certain CNS receptors enable assigning a specific or selective role to certain receptors or neurotransmission circuits during a specific phase of data processing in the CNS.
As mentioned above, this enables linking data collected from animal models to those observed in human volunteers. The example of the dopaminergic systems is instructive here, since relatively specific agonist and antagonist agents are identified for each of the five subtypes of receptors.
In their work with quinpirole, a specific dopaminergic D 2 agonist, Arnsten et al demonstrated in the monkey that these receptors are implicated in higher cognitive functions such as memory tasks with delayed recall. This observation demonstrated in particular the importance of dosage. It was also instructive to use older monkeys which demonstrated an age-related alteration in the dopaminergic systems with a prefrontal projection and also explained that the deleterious effect of small doses was attenuated or absent, demonstrating probably altered presynaptic structures in these older animals.
Other experimental work supported the hypothesis of a role of DA in the function of the prefrontal cerebral cortex cortical D 1 receptors for example determining the performance on a working memory task Nieoullon Similar results were obtained in healthy volunteers. Servan-Schreiber et al a , b provided an elegant demonstration that administration of d -amphetamine 0.
Similarly, recent work by Volkow et al in healthy volunteers demonstrated a correlation between age-related dopaminergic activity and performance on different neuropsychological tests. These results provide supplementary proof of the role of the dopaminergic system in cognitive disorders in the elderly subject.
These data demonstrate a pro-cognitive and awakening effect of these dopamine agonists increased beta activity on the EEG, improved delayed recall. These results opened an interesting discussion concerning the attribution of narcolepsy attacks in traffic accident victims Frucht et al to ropinirole D 2 agonist similar to quinpirole mentioned above and pramipexole D 2 , D 3 , D 4 agonist.
Several pharmacological classes have been analyzed using the cognitive mapping method mentioned above. This should contribute to better definition of their risk-benefit ratio and their potential indications: nicotine, caffeine, antihistaminics, hypnotics, anxiolytics, antipsychotics Allain et al a ; Gandon and Allain ; Patat et al ; Patat ; Stip et al In all likelihood, the list of the drugs to be tested according to such a procedure will continue to lengthen for three reasons: 1 sudden increase in the number of drugs available in neurology, 2 overt policy to treat several orphan conditions of the CNS most of which are dominated by cognitive disorders , 3 worries about drug safety for cognition Cognitive Pharmacovigilance.
Several cholinesterase inhibitors donepezil, rivastigmine, galantamine and one glutamatergic neurotransmission modulator memantine are officially recognized as beneficial for patients with AD. These compounds were awarded marketing approval on the basis of improved scores on global scales measuring overall cognitive decline and its impact on daily living, and not because of a positive effect on specific memory tests Lane et al Such targeted tests would have to exhibit a clear effect before these drugs could be used for MCI at least for amnestic-MCI, as still controversially considered to be an isolated memory disorder probably announcing AD.
Recent studies of cholinesterase inhibitors in MCI have been unable to demonstrate any beneficial effects in terms of symptomatic improvement on memory tests Allain et al , nor any preventive effect on conversion to AD Petersen et al These negative results, although partially explainable for instance upregulation of cholinergic systems at the early phase of the disease continue to discredit the cholinesterase inhibitor class of drugs Kaduszkiewicz et al At very high doses, vitamin E tocopherol does not have any direct effect on memory but it appears to retard by a few months progression to AD and might be helpful for the prevention of other forms of dementia in healthy subjects.
Similar results have been obtained with selegiline, a MAO-B monoamine oxidase type B inhibitor whose impact on DA concentrations could also have a symptomatic effect by stimulating dopaminergic tone.
Antioxidants, which counteract the deleterious effect of free radicals, cannot be considered as pro-memory drugs per se. They have however opened new avenues of very active research in the field of neuroprotective agents, reflecting the fragile nature of human memory and its vulnerability to aggression age, depression, anxiety, ischemia-hypoxia, addiction, HIV-related dementia.
In many countries, a variety of medications are marketed and prescribed for age-related cognitive decline. These old drugs vasodilators, brain oxygenators, nootropics, cognitive enhancers Riedel and Jolles have been used for years without either formal proof of efficacy in dementia or showing a small effect-size. Aging being a normal physiological process, there is no clear indication for their use.
These drugs do however have pharmacological properties quite in line with the multifactorial disseminated nature of memory disorders: membrane fluidification, activation of neuronal energy metabolism, arousal. A few old studies highlight a facilitating effect on memory which might be worth evaluating with modern methodology.
Much work has demonstrated that menopausal women taking synthetic estrogens in hormone substitutive therapy exhibit better results on memory tests than those not on replacement therapy Matthews et al ; Steffens et al The debate remains open regarding the beneficial effect of natural or synthetic oestrogens, respectively, on memory in menopausal women Henderson et al ; Sherwin A short list of natural substances with a recognized effect on memory performance is presented in Table 3.
These compounds, often found in foodstuffs caffeine, glucose, nicotine , cannot be proposed without the necessary precautions but can greatly contribute to targeted research on the possible impact of future promnestic drugs. This opens new perspectives for a more mechanistic approach to the cellular signaling pathways of memory, for example with the use of phosphodiesterase IV inhibitors increasing CREB phosphorylation Nagakura et al ; Tully et al
Impaired cognition and attention in adults: pharmacological management strategies.
Caparos, S. Emotional Stroop interference in trauma-exposed individuals: A contrast between two accounts. Garon, M. Influence of music-induced mood on the detection of angry faces.
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My research focuses on various issues related to the cognitive processing of complex documents and human-machine interaction:. Colliot, T. In press. Can tablet apps support the learning of handwriting? An investigation of learning outcomes in kindergarten classroom. Jamet, E.
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