frontiers in REVIEW ARTICLE SYSTEMS NEUROSCIENCE published:20 May 2014 dot10.3389/fnsys.2014.00090 Pharmacological enhancement of memory or cognition in normal subjects Gary Lynch12*,Conor D.Cox2 and Christine M.Gall2 Department of Psychiatry and Human Behavior,University of Califomia,Irvine,CA.USA Department of Anatomy and Neurobiology.University of California,Irvine,CA.USA Edited by: The possibility of expanding memory or cognitive capabilities above the levels in high Mikhail Lebedev,Duke University, functioning individuals is a topic of intense discussion among scientists and in society USA at large.The majority of animal studies use behavioral endpoint measures;this has Reviewed by: loan Opris,Wake Forest University, produced valuable information but limited predictability for human outcomes.Accordingly. USA several groups are pursuing a complementary strategy with treatments targeting synaptic Rafael Roesler,Federal University of events associated with memory encoding or forebrain network operations.Transcription Rio Grande do Sul,Brazil and translation figure prominently in substrate work directed at enhancement.Notably. Sam Deadwyler,Wake Forest University Health Sciences,USA the question of why new proteins would be needed for a now-forming memory given Maryam Farahmandfar,Tehran that learning-driven synthesis presumably occurred throughout the immediate past has University of Medical Sciences,Iran been largely ignored.Despite this conceptual problem,and some controversy,recent *Correspondence studies have reinvigorated the idea that selective gene manipulation is a plausible Gary Lynch,Department of route to enhancement.Efforts to improve memory by facilitating synaptic encoding Psychiatry and Human Behavior, Gillespie Neuroscience Research of information have also progressed,in part due of breakthroughs on mechanisms Facility,University of California,837 that stabilize learning-related,long-term potentiation (LTP).These advances point to a Health Science Road,Irvine,CA, reductionistic hypothesis for a diversity of experimental results on enhancement,and 92697.1275,US4 identify under-explored possibilities.Cognitive enhancement remains an elusive goal,in e-mail:glynch@uci.edu part due to the difficulty of defining the target.The popular view of cognition as a collection of definable computations seems to miss the fluid,integrative process experienced by high functioning individuals.The neurobiological approach obviates these psychological issues to directly test the consequences of improving throughput in networks underlying higher order behaviors.The few relevant studies testing drugs that selectively promote excitatory transmission indicate that it is possible to expand cortical networks engaged by complex tasks and that this is accompanied by capabilities not found in normal animals. Keywords:cognitive enhancement,learning,long term potentiation,ampakine,synaptic plasticity,BDNF,F-actin, positive AMPA receptor modulators INTRODUCTION of a system that,while capable of periodically focusing on spe- The present review concerns three topics,two of which involve cific tasks,usually works by integrating a vast amount of disparate terms-enhancement and cognition-that are not sharply material into a product accessible to consciousness.A true cogni- defined.Usage of the former seems straightforward when applied tive enhancer might therefore take the form of a treatment that to memory,although it is often unclear whether accelerated increases the speed or capacity of this assembly process. acquisition or an increase in encoding strength is intended.But Memory enhancement,as suggested,appears to be a much applied to cognition,claims for enhancement face the great prob- more tractable problem.Retention is easily measured as is the lem of how to quantify something for which there is no consensus amount of training needed to produce a given score in a test sub- measurement system.The difficulty can be reduced by focusing sequent to learning.But a curious problem emerges here:few of on cognitive activities of a type that can be described in compu- the many pharmacological agents that produce robust enhance- tational terms.This,however,raises questions about the extent ment of memory in animals are found to have positive effects in to which the sampled process is representative,or a major com- humans.This observation has become the subject of intense pub- ponent,of cognition as the term is typically used.In response,it lic discussion,perhaps with growing skepticism about the utility could reasonably be argued that cognition is a collection of semi- of animal studies on memory enhancement.Some neuroscien- independent operations (e.g.,categorization,value assignment) tists have argued that the"failure to predict"problem reflects the (Sugrue et al.,2005;Tsunada and Sawaguchi,2012)but this seems widespread use of paradigms that have little relevance to human unsatisfactory because the phenomenon is experienced as being, learning.These workers have devised ingenious protocols that can if not unitary,then at least strongly coherent.Electrophysiological be used in rodents and with minor modifications in humans(e.g., and brain imaging results showing coordinated activity across Bari et al.,2008;Demeter et al.,2008;Eichenbaum and Robitsek, broad stretches of neocortex provide some support for the idea 2009;Zeeb et al.,2009;Demeter and Sarter,2013).There is every Frontiers in Systems Neuroscience www.frontiersin.org May 2014 Volume 8 Article 90 1REVIEW ARTICLE published: 20 May 2014 doi: 10.3389/fnsys.2014.00090 Pharmacological enhancement of memory or cognition in normal subjects Gary Lynch1,2*, Conor D. Cox2 and Christine M. Gall 2 1 Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA 2 Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA Edited by: Mikhail Lebedev, Duke University, USA Reviewed by: Ioan Opris, Wake Forest University, USA Rafael Roesler, Federal University of Rio Grande do Sul, Brazil Sam Deadwyler, Wake Forest University Health Sciences, USA Maryam Farahmandfar, Tehran University of Medical Sciences, Iran *Correspondence: Gary Lynch, Department of Psychiatry and Human Behavior, Gillespie Neuroscience Research Facility, University of California, 837 Health Science Road, Irvine, CA, 92697-1275, USA e-mail: glynch@uci.edu The possibility of expanding memory or cognitive capabilities above the levels in high functioning individuals is a topic of intense discussion among scientists and in society at large. The majority of animal studies use behavioral endpoint measures; this has produced valuable information but limited predictability for human outcomes. Accordingly, several groups are pursuing a complementary strategy with treatments targeting synaptic events associated with memory encoding or forebrain network operations. Transcription and translation figure prominently in substrate work directed at enhancement. Notably, the question of why new proteins would be needed for a now-forming memory given that learning-driven synthesis presumably occurred throughout the immediate past has been largely ignored. Despite this conceptual problem, and some controversy, recent studies have reinvigorated the idea that selective gene manipulation is a plausible route to enhancement. Efforts to improve memory by facilitating synaptic encoding of information have also progressed, in part due of breakthroughs on mechanisms that stabilize learning-related, long-term potentiation (LTP). These advances point to a reductionistic hypothesis for a diversity of experimental results on enhancement, and identify under-explored possibilities. Cognitive enhancement remains an elusive goal, in part due to the difficulty of defining the target. The popular view of cognition as a collection of definable computations seems to miss the fluid, integrative process experienced by high functioning individuals. The neurobiological approach obviates these psychological issues to directly test the consequences of improving throughput in networks underlying higher order behaviors. The few relevant studies testing drugs that selectively promote excitatory transmission indicate that it is possible to expand cortical networks engaged by complex tasks and that this is accompanied by capabilities not found in normal animals. Keywords: cognitive enhancement, learning, long term potentiation, ampakine, synaptic plasticity, BDNF, F-actin, positive AMPA receptor modulators INTRODUCTION The present review concerns three topics, two of which involve terms—enhancement and cognition—that are not sharply defined. Usage of the former seems straightforward when applied to memory, although it is often unclear whether accelerated acquisition or an increase in encoding strength is intended. But applied to cognition, claims for enhancement face the great prob￾lem of how to quantify something for which there is no consensus measurement system. The difficulty can be reduced by focusing on cognitive activities of a type that can be described in compu￾tational terms. This, however, raises questions about the extent to which the sampled process is representative, or a major com￾ponent, of cognition as the term is typically used. In response, it could reasonably be argued that cognition is a collection of semi￾independent operations (e.g., categorization, value assignment) (Sugrue et al., 2005; Tsunada and Sawaguchi, 2012) but this seems unsatisfactory because the phenomenon is experienced as being, if not unitary, then at least strongly coherent. Electrophysiological and brain imaging results showing coordinated activity across broad stretches of neocortex provide some support for the idea of a system that, while capable of periodically focusing on spe￾cific tasks, usually works by integrating a vast amount of disparate material into a product accessible to consciousness. A true cogni￾tive enhancer might therefore take the form of a treatment that increases the speed or capacity of this assembly process. Memory enhancement, as suggested, appears to be a much more tractable problem. Retention is easily measured as is the amount of training needed to produce a given score in a test sub￾sequent to learning. But a curious problem emerges here: few of the many pharmacological agents that produce robust enhance￾ment of memory in animals are found to have positive effects in humans. This observation has become the subject of intense pub￾lic discussion, perhaps with growing skepticism about the utility of animal studies on memory enhancement. Some neuroscien￾tists have argued that the “failure to predict” problem reflects the widespread use of paradigms that have little relevance to human learning. These workers have devised ingenious protocols that can be used in rodents and with minor modifications in humans (e.g., Bari et al., 2008; Demeter et al., 2008; Eichenbaum and Robitsek, 2009; Zeeb et al., 2009; Demeter and Sarter, 2013). There is every Frontiers in Systems Neuroscience www.frontiersin.org May 2014 | Volume 8 | Article 90 | 1 SYSTEMS NEUROSCIENCE