“Working memory” refers to the cognitive processes involved in temporarily storing & manipulating information. Unsurprisingly, this capacity is correlated with many measures of intelligence, but (somewhat more surprisingly) is also impaired in a variety of neurological disorders, including schizophrenia.
In a recent Psychopharmacology article, Deanna Barch reviewed studies demonstrating drug-induced improvements in working memory with a focus on possible applications for future schizophrenia treatments. What follows is a summary of this excellent article.
To a large extent, the effects of WM-targeted drugs depend on how WM is being measured. Barch identifies four general varieties of WM assessment:
- Span tasks (e.g., reading span or operation span, in which subjects must remember some information while simultaneously processing other information)
- Delayed Match/NonMatch to Sample tasks (in which subjects must remember an item over a delay and then pick an item that matches or mismatches in a particular way)
- N-back tasks (in which a subject must remember items presented n trials ago, where n is 1, 2, or more; note that 1-back seems to differ from >1-back tasks more than >1-back tasks differ from each other)
- Self-ordered pointing tasks (in which subjects must select each of n randomized items without selecting any item twice)
Barch suggests that the most prominent theory of WM impairment implicates dopamine malfunction in in WM deficits. For example, dopamine antagonists tend to impair WM function and dopamine agonists (such as L-Dopa) tend to improve WM function in primates. But the reverse pattern has also been observed – suggesting that there is an optimal level of dopamine function, above or below which WM becomes impaired.
Consistent with this view, only subjects with impaired baseline WM performance seem to benefit from amphetamine, methylphenidate (Ritalin), and other nonselective dopamine agonists; among those with above average WM, these drugs can actually hurt performance. A similar pattern of drug-related change in WM performance is observed among individuals with variants of the COMT gene, such that those with the val/val allele (who break down dopamine more quickly) benefit from these drugs, and those with the met/met allele (who break down dopamine more slowly) are impaired by these drugs.
These effects on WM might result from the dopamine-specific action of amphetamines. For example, selective “D2” agonists (drugs targeting only D2 receptors, which are generally inhibitory and subcortical) improve some but not all WM measures (e.g., improvements in spatial but not object WM, or improvements on WCST but not n-back tasks). Drugs that also target D1 receptors (primarily excitatory and neocortical) enhance performance on yet other tasks – such as DMS – on which D2-specific agonists have no effect. Barch notes that more research is needed to determine whether D1-specific agonists might be sufficient for broad improvements in WM.
Drugs that target the adrenaline system also show promise for enhancing WM. Noradrenergic Alpha-2 drugs may improve WM by decreasing distractibility, but the evidence is mixed. For example, practiced adults improve on self-ordered tasks after high doses of alpha-2 agonists, but the same drugs have also been associated with decreases in performance on this and other WM tasks. (Note that self-ordered pointing tasks are one of the few WM tasks that do not seem to be affected by dopamine.) Barch suggests that adrenergic agonists may only “repair” age-related decrements in WM function, or impairments related to ADHD, rather than enhancing WM function in the general population.
Drugs that inhibit the breakdown of acetylcholine, another neurotransmitter, may also benefit WM performance. Barch reviews studies that have demonstrated improved reaction time, lower prefrontal activations (thought to reflect increased processing efficiency), and improved DMS accuracy on physostigmine. Other work suggests that acetylcholine drugs may work by increasing the “selectivity” of processing; acetylcholine has been negatively correlated with right prefrontal activity, again suggesting that this region (thought by some to implement “inhibition”) may actually be involved in monitoring and selection.
According to Barch, drugs targeting serotonin and glutamate seem to have less promise for improving WM performance. Unfortunately, Barch does not review the evidence related to ampakines (e.g., modafinil and the “CX” drugs including CX717) which have their effects primarily via glutamate receptors. Lynch reviews evidnce suggesting that ampakines improve DMS performance and may have even more pronounced effects on long-term memory, as a result of their relatively lower thalamic as opposed to hippocampal selectivity, their association with upregulated neuronal growth factors, and their tendency to lower the “threshold” of activity normally required for long term potentiation. Interestingly, ampakines are not receptor agonists – Lynch suggests that they directly modify receptor biophysics, with the end result of “enhanced” and “prolonged” synaptic transmission.
It is clear that many drugs used to alleviate WM dysfunction in disordered populations (ADHD and schizophrenia being just a few) may also improve WM in the general population. What remains unclear is exactly how, and under what circumstances, some of these drugs will be more effective than others. An additional complication is that working memory tasks seem heterogenous: some drugs impair certain WM tasks but not others. The development of more targeted drugs for working memory enhancement therefore needs to be accompanied by the parallel development of more targeted measurements of working memory and its subfunctions.
Attention: The Selection Problem
Selection and Updating Efficiency in the Attentional Blink
Selection Efficiency and Inhibition
Selection Efficiency in Updating Working Memory
Enhancing Peripheral Vision with TMS
Manipulating Memory Specificity with Acetylcholine
Enhancing Memory with Visual Flicker
Molecular Basis of Memory
Intelligent Adaptive Toys
Other Recommended Journal Articles:
‘Smart drugs’: do they work? Are they ethical? Will they be legal?
Facilitation of task performance and removal of the effects of sleep deprivation by an ampakine (CX717) in nonhuman primates.
Memory enhancement: the search for mechanism-based drugs.
Sensorimotor effects of pergolide, a dopamine agonist, in healthy subjects: a lateralized readiness potential study.