The likelihood of cognitive enhancement

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.

Figure 1. A provisional classification scheme for candidate cognitive enhancers

The ‘x’ axis (dimension “I”) lists possible psychological processes affected by the compound. The other two axes indicate neurobiological mechanisms (y; dimension II), and the question of whether the compound affects the efficiency of cognition or allows the subject to exceed normal boundaries (z; dimension III). The axes are collections of associated variables [e.g., brain mechanisms] that have no quantitative relationship with each other.

Fig. 2. Summary of the events responsible for the consolidation of LTP and their relationship to sites of action for candidate enhancers

Experimental work shows that the learning-related theta bursting pattern of afferent activity is particularly well suited for inducing stable LTP. Drugs acting on the ascending biogenic amine systems, including methylphenidrate, potently affect the generation of this rhythm [circled ‘1’]. Theta causes enhanced release of the neurotransmitter glutamate, a process that is increased by other types of possible cognitive enhancers [circled ‘2’]; a compound of this type is discussed in the text. The post-synaptic responses of AMPARs to theta can be pharmacologically amplified with ampakines [circled ‘3’], thereby promoting the post-synaptic (NMDA receptor triggered) signaling pathways that lead to stable LTP. Theta also causes the release of compounds that act on ‘modifier’ receptors that regulate the post-synaptic events that stabilize LTP; various candidate enhancers act at this level [circled ‘4’]. The glutamate transmitter receptors engage two co-localized classes of receptors: the above mentioned modifier receptors and a group of synaptic adhesion receptors; these two groups then combine to initiate and regulate two actin signaling pathways that respectively initiate the assembly and then the stabilization of a new subsynaptic cytoskeleton (Rex et al., 2009). This last event consolidates the synaptic changes that constitute LTP. Potential enhancers, directed at the actin signaling pathways [circled ‘4’], are beyond the scope of this review.

Fig. 3. An ampakine causes well trained rats to exceed asymptotic performance levels in a complex, delayed non-match to sample problem

(Top panels) Rats were trained over several weeks to press one extended bar, then move to a nose poke location where they activate a light, and wait (for varying intervals) for the light to go out (left side). They then returned to the test location where two bars were extended. Pressing the bar not previously extended resulted in a water reward. (Bottom panel) Baseline performance over weeks of testing was about 77%. The graph summarizes changes in this performance level over 3 additional weeks for two groups that received daily vehicle injections (controls: open circles) or every other day injections of the ampakine CX516 (see fig. 5 below). The drug (“ampakine days”, filled circles) caused a gradual increase in performance that carried over into vehicle treated days and persisted after the treatments were terminated (gray circles) (Hampson et al., 1998a).

Fig. 4. Performance scores and correlated imaging results for rhesus monkeys in a complex match-to-sample problem in the absence and presence of an ampakine

(A). Correct scores by the monkeys when they were required to select, after a variable delay, a previously seen object from a group of 2–6 similar objects. Note that the ampakine caused a marked improvement in scores that was most pronounced for the most difficult part of the problem (6 choices) and with the longest delays. (B) Coronal PET images of glucose metabolism during performance of the match to sample problem. Images at left show the difference between vehicle-treated monkeys before and during performance; note the behaviorally linked increases in activity in the dorsal prefrontal cortex (DPFC), medial temporal lobe (MTL), and primary sensorimotor cortex (SI). Images in the right column summarize the increase above the vehicle-learning effect produced by ampakine injection. The DPFC and MTL were enhanced above the vehicle level but the SI was not. The precuneus, which was not activated during performance in the vehicle condition, is engaged by the task following drug treatment (modified from Porrino et al., 2005).

Fig 5. Effects of ampakines at three levels of analysis

(A) Shown to the left are chemical structures for two functionally different types of ampakines (A-type: CX516; B-type: CX614). The middle schematic illustrates the binding pocket for the drugs as deduced from work using site directed mutagenesis (Partin, 2001) and X-Ray crystallography (Jin et al., 2005). The two structures represent two of the four subunits (GluR1,2, etc.) that comprise the tetrameric receptor. The glutamate binding site is located in the extracellular domains (circled ‘1’ and ‘2’) of each subunit. The subunits pair up to form two dimers; the ampakine pocket (orange circle) lies in the dimer interface. The traces to the right show representative effects of ampakines on the inward current flux produced by applying a one millesecond pulse of glutamate to a patch excised from a hippocampal pyramidal cell. Note that the drug slows deactivation of the AMPAR gated current (Arai et al., 1996). Synaptic responses from hippocampus are shown in the lower two records. A-Type ampakines increase the amplitude of the response while B-Types produce this effect along with a broadening of the EPSP (Arai et al., 2002). (B) Two neurons receiving different numbers of contacts from an activated (2 axon) input are illustrated (control). The density of the afferent connections is sufficient to spike the cell to the left but not that to the right. An ampakine increases AMPAR mediated EPSCs at each activated synapse, thereby increasing the spike output form the one cell and causing the other to cross spike threshold (+ampakine). The non-linear nature of spiking thus amplifies the functional effect of a drug causing relatively modest increases in transmission at individual synapses. (C) Four separate cortical regions that form a serial network are schematized in these panels. A strong input activates a set of neurons (solid dots) in the first network and brings several others (yellow dots) close to firing threshold. This causes a slightly weaker response (number of activated cells) in the next stage of the network, which then produces a still weaker response in the next stage. This gradual weakening of throughput results in a failure to engage the fourth potential component of the circuit. An ampakine, by increasing EPSCs at individual synapses, causes near threshold cells to fire (blue dots). This causes greater throughput, thus allowing the original input to activate an additional cortical region (Porrino et al., 2005).

Fig 6. Studying unsupervised learning (USL) in matched, complex environments by rats and humans

Shown are the novel environments faced by a rat leaving a darkened ‘refuge’ (left) and a human subject entering a total immersion virtual reality ‘village’ (right; the simulation includes additional streets and distant buildings). In both cases, the subjects are allowed unrestricted exploration through the real (rats) and simulated environments. The experimental questions are the same for both cases: Does a candidate enhancer increase the amount of information encoded during a single exploration session in a novel, non-threatening commonplace world and to what extent is this accompanied by changes in baseline behaviors (selectivity)?