ReviewThe likelihood of cognitive enhancement
Research Highlights
► A classification scheme for cognitive enhancers based on their effects on psychological state, neurobiological mechanisms of action, and influences on efficiency vs. limits of cognitive function. ► Ritalin and Modafinil influence learning through effects on psychological state. ► A broad range of compounds selectively facilitate neurobiological mechanisms of memory encoding. ► New generation drugs may expand cortical networks, and thus computational resources, available for dealing with complex problems. ► Evaluation of the societal impact of cognitive enhancers should include the possibility of compounds that produce entirely new capabilities.
Introduction
Debates about the feasibility of cognitive enhancement rarely begin with what seems to be a pertinent question: How effective are cortical networks in performing the complex steps underlying serial thought, planning, memory retrieval, and other operations that go into cognition? If the substrates are not particularly efficient, then there should be numerous opportunities for improvement. Conversely, networks that are finely tuned with regard to cognition would presumably not be amenable to selective enhancement, at least with current technologies. Another natural question is whether improvements in one dimension of performance (e.g. speed, or accuracy) will necessarily lead to improvements in others (e.g. creativity, or judgment). The reason that these points are not generally discussed is, of course, that, despite enormous advances in neuroscience over the past few years, we still know very little about the neurobiology and operating characteristics of cognition-related networks. But perhaps the ‘room for improvement’ issue can be recast in terms of brain evolution by asking whether comparative anatomical evidence points to strong adaptive pressures for designs that are logically related to improved cognitive performance.
Anatomists often resort to allometry when dealing with questions of selective pressures on brain regions. Applied to brain proportions, this involves collecting measurements for the region of interest—e.g., frontal cortex—for a series of animals within a given taxonomic group and then relating it to the volume or weight of the brains of those animals. This can establish with a relatively small degree of error whether a brain component in a particular species is larger than would be predicted from that species’ brain size. While there is not a great deal of evidence, studies of this type point to the conclusion that cortical subdivisions in humans, including association regions, are about as large as expected for an anthropoid primate with a 1350 cm3 brain. The volume of area 10 of human frontal cortex, for example, fits on the regression line (area 10 vs. whole brain) calculated from published data (Semendeferi et al., 2001) for a series composed of gibbons, apes and humans (Lynch and Granger, 2008). Given that this region is widely assumed to play a central role in executive functions and working memory, these observations do not encourage the idea that selective pressures for cognition have differentially shaped the proportions of human cortex. Importantly, this does not mean that those proportions are in any sense typical. The allometric equations involve different exponents for different regions, meaning that absolute proportions (e.g., primary sensory cortex vs. association cortex) change as brains grow larger. The balance of parts in the cortex of the enormous human brain is dramatically different than found in the much smaller monkey brain: area 10, for instance, occupies a much greater percentage of the cortex in man. But these effects seem to reflect expansion according to rules embedded in a conserved brain plan rather than selection for the specific pattern found in humans (Finlay et al., 2001).
In all, the explosive expansion of brain over the last 2 million years of hominid evolution resulted in a cortex with proportions that are greatly different than those found in laboratory animals. We can assume that this is responsible for the emergence of the unique capabilities incorporated into human mentation. But our argument here is that these expanded cortical areas are likely to use generic network designs shared by most primates; if so, then it appears unlikely that the designs are in any sense ‘optimized’ for cognition. We take this as a starting position for the assumption that the designs are far from being maximally effective for specialized human functions, and therefore that it is realistic to expect that cognition-related operations can be significantly enhanced.
But what is the likelihood that current lines of research will succeed in exploiting the assumed room for improvement over the next several years? The present review addresses this question beginning with a provisional scheme for classifying candidate cognitive enhancers, an exercise that we think will be useful in discussing what enhancement means. We will use the scheme to classify a restricted sample of compounds, and then employ the results as a starting point for asking if their effects constitute cognitive enhancement. The last two segments of the paper take up various problems surrounding translation, some of which relate directly to the above introductory material, and social issues that could arise if new generation drugs do in fact reach clinical application.
Section snippets
A classification scheme for cognitive enhancers
What constitutes a cognitive enhancer? Would this include agents that only secondarily affect cognition via actions on broader psychological variables? Should distinctions be made between drugs influencing psychological processes (e.g., short-term memory) that feed into cognition vs. those acting on higher, integrative activities? Rather than trying to reach agreement on such questions, it may be more useful to classify potential enhancers according to multiple dimensions of action as
Functional categories of candidate enhancers
This section uses specific instances to consider the problem of classifying putative enhancers, and thus to deal with the intertwined question of what enhancement means. It is organized along the dimension of psychological action (dimension I in Fig 1), but also includes information about neurobiological mechanism of action and efficiency vs. capability (dimensions II and III).
Translation issues
It is striking that the many compounds found to improve retention scores in rodents or monkeys have yet to translate into a drug with clear-cut enhancing effects in healthy humans operating in real world environments. Of course, the absence of potent memory enhancers could simply reflect the fact that many of the most promising candidates are still winding their way through the multiple stages of clinical development. But the point remains that older agents multiply reported to produce positive
Social issues
The introduction of cognitive enhancers would have profound and unpredictable consequences for society, as usefully discussed in recent reviews (Greely et al., 2008, Farah et al., 2009, Sahakian and Morein-Zamir, 2010). Greely et al. (2008) take a generally positive stance towards the potential for such drugs to enhance human life, arguing they should be generally classed with “education, good health habits, and information technology” as means of cognitive enhancement, but warn that their
Funding
Research from the authors' laboratories was supported, in part, by grants from the National Institutes of Health (NS045260 to GL and CMG; NS051823 to GL), an Office of Naval Research Multidisciplinary University Research Initiative Award N00014-10-1-0072 to G.L., and reagents provided by Cortex Pharmaceuticals (Irvine, CA).
Acknowledgements
The authors thank Cheryl Cotman for the preparation of Fig. 6 and to Drs. Linda Porrino and Sam Deadwyler for permission to use material in Fig. 4.
References (111)
What are the cognitive effects of stimulant medications? Emphasis on adults with attention-deficit/hyperactivity disorder (ADHD)
Neurosci Biobehav Rev
(2010)- et al.
Effects of a centrally active benzoylpyrrolidine drug on AMPA receptor kinetics
Neuroscience
(1996) - et al.
Improvement of learning processes following chronic systemic administration of modafinil in mice
Pharmacol Biochem Behav
(2002) - et al.
Enhancement of learning processes following an acute modafinil injection in mice
Pharmacol Biochem Behav
(2003) - et al.
Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation
Cell
(1999) - et al.
Treatment with the noradrenergic alpha-2 agonist clonidine, but not diazepam, improves spatial working memory in normal young rhesus monkeys
Neuropsychopharmacology
(1999) - et al.
Estrogen treatment alleviates NMDA-antagonist induced hippocampal LTP blockade and cognitive deficits in ovariectomized mice
Neurobiol Learn Mem
(2003) - et al.
Olfactory cortex: model circuit for study of associative memory?
Trends Neurosci
(1989) - et al.
Enhancement by an ampakine of memory encoding in humans
Exp Neurol
(1997) - et al.
Modafinil increases histamine release in the anterior hypothalamus of rats
Neurosci Lett
(2003)
Developmental and regional differences in the consolidation of long-term potentiation
Neuroscience
Enhancement of place and object recognition memory in young adult and old rats by RS 67333, a partial agonist of 5-HT4 receptors
Neuropharmacology
Effect of I.C.V. injection of AT4 receptor ligands, NLE1-angiotensin IV and LVV-hemorphin 7, on spatial learning in rats
Neuroscience
Effects of the alpha4beta2 partial agonist varenicline on brain activity and working memory in abstinent smokers
Biol Psychiatry
AMPA receptor modulators as cognitive enhancers
Curr Opin Pharmacol
Glutamate-based therapeutic approaches: ampakines
Curr Opin Pharmacol
Ampakines and the threefold path to cognitive enhancement
Trends Neurosci
The substrates of memory: defects, treatments, and enhancement
Eur J Pharmacol
Linking brain, mind and behavior
Int J Psychophysiol
Memory-enhancing effects of DHEAS in aged mice on a win-shift water escape task
Physiol Behav
Modafinil improves attention, inhibitory control, and reaction time in healthy, middle-aged rats
Pharmacol Biochem Behav
Evidence for synaptic potentiation in a cortical network during learning
Brain Res
nAChR agonist-induced cognition enhancement: integration of cognitive and neuronal mechanisms
Biochem Pharmacol
ROC in animals: uncovering the neural substrates of recollection and familiarity in episodic recognition memory
Conscious Cogn
Comparative studies of various amphetamine analogues demonstrating different interactions with the metabolism of the catecholamines in the brain
Eur J Psychopharmacol
Methylphenidate affects strategic choice behavior in normal adult humans
Pharmacol Biochem Behav
Non-amphetaminic mechanism of stimulant locomotor effect of modafinil in mice
Eur Neuropsychopharmacol
Effects of pharmacologically facilitating glutamatergic transmission in the trisynaptic intrahippocampal circuit
Neuroscience
Studies on retrograde and anterograde amnesia of olfactory memory after denervation of the hippocampus by entorhinal cortex lesions
Behav Neural Biol
Dose-dependent effect of CDPPB, the mGluR5 positive allosteric modulator, on recognition memory is associated with GluR1 and CREB phosphorylation in the prefrontal cortex and hippocampus
Neuropharm
Non-specific effects of methylphenidate (Ritalin) on cognitive ability and decision-making of ADHD and healthy adults
Psychopharmacology (Berl)
Simulation of paleocortex performs hierarchical clustering
Science
Dopamine transporter-related effects of modafinil in rhesus monkeys
Psychopharmacology (Berl)
Pharmacology of ampakine modulators: from AMPA receptors to synapses and behavior
Curr Drug Targets
Benzamide-type AMPA receptor modulators form two subfamilies with distinct modes of action
J Pharmacol Exp Ther
Effects of modafinil on cognitive and meta-cognitive performance
Hum Psychopharmacol
DRUG FOCUS: S 18986: a positive allosteric modulator of AMPA-Type glutamate receptors pharmacological profile of a novel cognitive enhancer
CNS Neurosci Ther
A synaptic model of memory: long-term potentiation in the hippocampus
Nature
Cognitive enhancing properties and tolerability of cholinergic agents in mice: a comparative study of nicotine, donepezil, and SIB-1553A, a subtype-selective ligand for nicotinic acetylcholine receptors
Neuropsychopharmacology
Cognitive effects of milacemide and methylphenidate in healthy young adults
Psychopharmacology (Berl)
The precuneus: a review of its functional anatomy and behavioural correlates
Brain
Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice
Nat Neurosci
Rats and humans paying attention: cross-species task development for translational research
Neuropsychology
Effect of ispronicline, a neuronal nicotinic acetylcholine receptor partial agonist, in subjects with age associated memory impairment (AAMI)
J Psychopharmacol
Modafinil induces wakefulness without intensifying motor activity or subsequent rebound hypersomnolence in the rat
J Pharmacol Exp Ther
Effects of methylphenidate on spatial working memory and planning in healthy young adults
Psychopharmacology (Berl)
Effects of ethanol and GABAB drugs on working memory in C57BL/6J and DBA/2J mice
Psychopharmacology (Berl)
When we enhance cognition with Adderall, do we sacrifice creativity? A preliminary study
Psychopharmacology (Berl)
Evidence that long-term potentiation occurs within individual hippocampal synapses during learning
J Neurosci
Developmental structure in brain evolution
Behav Brain Sci
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