Review
The likelihood of cognitive enhancement

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Abstract

Whether drugs that enhance cognition in healthy individuals will appear in the near future has become a topic of considerable interest. We address this possibility using a three variable system (psychological effect, neurobiological mechanism, and efficiency vs. capabilities) for classifying candidates. Ritalin and modafinil, two currently available compounds, operate on primary psychological states that in turn affect cognitive operations (attention and memory), but there is little evidence that these effects translate into improvements in complex cognitive processing. A second category of potential enhancers includes agents that improve memory encoding, generally without large changes in primary psychological states. Unfortunately, there is little information on how these compounds affect cognitive performance in standard psychological tests. Recent experiments have identified a number of sites at which memory drugs could, in principle, manipulate the cell biological systems underlying the learning-related long-term potentiation (LTP) effect; this may explain the remarkable diversity of memory promoting compounds. Indeed, many of these agents are known to have positive effects on LTP. A possible third category of enhancement drugs directed specifically at integrated cognitive operations is nearly empty. From a neurobiological perspective, two plausible candidate classes have emerged that both target the fast excitatory transmission responsible for communication within cortical networks. One acts on nicotinic receptors (alpha7 and alpha4) that regulate release of the neurotransmitter glutamate while the other (‘ampakines’) allosterically modulates the glutamate receptors mediating the post-synaptic response (EPSCs). Brain imaging in primates has shown that ampakines expand cortical networks engaged by a complex task; coupled with behavioral data, these findings provide evidence for the possibility of generating new cognitive capabilities. Finally, we suggest that continuing advances in behavioral sciences provide new opportunities for translational work, and that discussions of the social impact of cognitive enhancers have failed to consider the distinction between effects on efficiency vs. new capabilities.

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.

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