Cognitive enhancement by drugs in health and disease

Abstract

Attempts to improve cognitive function in patients with brain disorders have become the focus of intensive research efforts. A recent emerging trend is the use of so-called cognitive enhancers by healthy individuals. Here, we consider some of the effects - positive and negative - that current drugs have in neurological conditions and healthy people. We conclude that, to date, experimental and clinical studies have demonstrated relatively modest overall effects, most probably because of substantial variability in response both across and within individuals. We discuss biological factors that might account for such variability and highlight the need to improve testing methods and to extend our understanding of how drugs modulate specific cognitive processes at the systems or network level.

Figure 1

Network effects of reboxetine in visuomotor control. (a) The noradrenaline reuptake inhibitor reboxetine improved visuomotor control in healthy volunteers and increased cortical activity in the right intraparietal sulcus (IPS), frontal eye field (FEF) and primary visual cortex (V1). (b) Dynamic causal modelling demonstrated enhanced coupling between these regions when participants were on reboxetine (adapted from with permission from [50]).

Figure 2

Effect sizes of cognitive enhancers in clinical studies. (a) Overall change in ADAS-Cog scores over 6 months on an AChE inhibitor in probable vascular dementia and Alzheimer disease patients (black circles) compared to patients on placebo (white circles) (adapted from with permission from [89]). (b) Improvements in ADHD Rating Scale IV with guanfacine at different doses versus placebo over 9 weeks in children and adolescents with ADHD (adapted from with permission from [90]).

Figure 3

Drug concentrations modulate cognition across and within individuals. (a) Evidence from animal studies suggests that modulation of a cognitive process, such as spatial working memory, by a neurotransmitter such as dopamine might be described by an inverted U-shaped function. Too low or too high a concentration of dopamine in prefrontal cortex might not produce optimal functional effects. If an individual has low baseline concentrations of dopamine, small increases in concentration might help to improve performance (red circle). However, individuals with a higher baseline concentration of dopamine (green circle) might actually suffer an impairment of function on introduction of a drug. (b) Two cognitive processes within the same individual might have differential drug sensitivity (compare functions F1 and F2). In this case, this individual performed nearly optimally on cognitive function F1 but relatively poorly on function F2 (green circles) before drug administration. Administration of the drug led to an increase in neurotransmitter concentration from baseline levels. At the new drug level (dashed vertical line) performance on function 1 might theoretically decrease, whereas cognitive function 2 might now be optimized (yellow circles).