"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.
Wynn and Coolidge have a couple of interesting papers on working memory in an archaeological/evolutionary context:
These look really interesting - thanks for the recommendation! Always interesting to see familiar concepts from an unfamiliar perspective.
Very interesting. I wonder why she didn't discuss ampakines? Your extension of the topic coverage with links is extremely helpful. Thanks Chris.
No problem. There is a wide range of very interesting literature looking at cognition from an palaeo perspective. Thomas Wynn has done a lot of interesting work in this regard (although there are plenty of other researchers out there) and the following provides a good overview. Its also worth reading as it contains a discussion/response at the end that highlights some of the limitations in this regard.
I'd also flag up this paper, mainly because it has data from my PhD site! It isn't groundbreaking or earth shattering, but its a nice bit of work that cleverly shows that our evolutionary forbears were maybe a little more "advanced" than we once gave them credit for.
Its amazing what you can infer from a few bits of flint!
Al fin - I would suggest that Barch didn't cover ampakines because they're not used in the context of schizophrenia, but it looks like CX-516 is already in phase II clinical trials for possibly enhancing the action of typical antipsychotics. So I'm really not sure.
"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."
This year in CHADD (main conference for ADD/ ADHD-related practitioners) there was a lot of talk about 1) the role of dopamine, 2) the "re-framing" of ADHD-Combined type as an executive function deficit, 3) the role of computer-based cognitive training as a complement to drugs.
Now, when we talk about a healthy "general population", I would suggest that we are many many years away from a safe and effective Working Memory pill. We are much closer to computer-based working memory training programs that everyone could use in the same way we go (or could go) to the gym and regularly spend 30-40 minutes on a treadmill.
How does this play out in other syndromes, like Asperger's? I note that Aspies (well, at least the one I know and love) often have trouble dealing with a task that is multidimensional.
My family member has an apparent severe working memory deficit to the point where despite a genius level IQ, he has trouble just completing basic daily tasks like cooking or even comprehending multiple sentence paragraphs or understanding simple conversation if it extends too long as he will literally not be able to hold information in mind long enough before forgetting it to do most productive mental work. He managed through sheer grit and determination and his incredibly high IQ to excel academically and gain entry to one of the top 5 ranked US News Undergrad Colleges before being forced to suspend his education due to discovering this severe difficulty at that point. He has tried the herb Centella Asiatica (aka Gotu Kola) with tremendous success in enhancing working memory with no apparent side effects, but says that tolerance to the herb develops very quickly within a 2-4 days; he then needs a holiday period of 1-2 weeks after this usage before he can repeat the cycle. He says even with its limited duration of effectiveness, this is a miracle therapy for him because for even those few days, it opens a whole new world to him with enhanced WM that nothing else, including prescription stimulants could assist with/improve. This mild improvement in his WM when experiencing the optimal herb effect, as it is still obviously impaired compared to others without any WM deficits, does wonders for his ability to engage in virtually any and all tasks from reading comprehension to learning to organizing and planning, and practically all higher order, more complex activities.
However, I was wondering if anyone could discuss any and all other treatments for WM they've found, or if they could just discuss more research about Centella Asiatica itself, as all this information has come out merely through painstaking trial and error without any clearcut, proven research on proper dosages of Centella, or other relevant information as Centella side effects with long-term use, etc. The research on this method of using Centella - just for a few days before taking a 1-2 weeks off to avoid tolerance - is also something we haven't been able to find any information about and were wondering if there were other drugs/therapies out there that might work in a similar, short-term fashion, as we could then try rotating to those during the off time with Centella? Thanks so much, you don't understand what a difference you'll be making in his life, he is torn about his academic/professional future which is very much up in the air at this point, as the extent of his WM difficulties are rarely seen, and the combination of his incredibly high intelligence that makes him all too aware of his shortcomings is acutely painful to him.
A Concerned Family Member
Concerned Family Member,
I really shouldn't make any clinical recommendations, and in this case I can't anyway, b/c what you've described is thoroughly puzzling to me. WM is highly correlated with fluid intelligence, and so if that's the form of IQ you're referring to, I can't fathom why there should be such a large discrepancy here. Does your kid have a clinical diagnosis?