Ladies: why Ritalin may not always be helpful. (Hint: sex, genes and dem hormones)

For a while now I’ve been mulling over why Ritalin/Adderall doesn’t affect cognitive performance of healthy volunteers. Several reasons come to mind. I wasn’t reading the “right” literature (ie studies with positive results - any suggestions?). Stimulants may only influence brain activation patterns, but not performance. In this case, we can only detect differences by fMRI or other direct imagining techniques. Or individual differences confounded the results – especially differences in basal dopamine levels and how dopamine is processed after its release. I’m going to focus on the last bit here. Image: http://www.livewellwinona.org/ 

As a fellow XX member of society, I know very well how much ladies are controlled by their monthly cycle. Thinking appetite and mood? That’s just the beginning. The rise and fall of estrogen and progesterone also influence sound processing, neurogenesis and vulnerability to drug addiction. And that’s not all.

Estrogen directly impacts how well you think.

Jabobs E and D’Esposito MD. 2011. Estrogen Shapes Dopamine-Dependent Cognitive Processes: Implications for Women’s Health. The Journal of Neuroscience. 31(14): 5286-5293.

Ok, I was being overdramatic. But based on results from this study, estrogen seems to impact one important aspect of cognition: working memory. Working memory is a fundamental cognitive ability to hold information in mind while manipulating it towards a goal. It supports a massive array of complex thinking, such as problem analyzing and updating your ideas/strategies when new information comes in. To some, working memory is a good surrogate marker (albeit not the only one) for intelligence.

The part of the brain supporting working memory is called the prefrontal cortex (PFC). For the PFC to function optimally, it needs to be in the Goldilocks’ zone of dopamine concentration: too low or too high, and PFC function deteriorates. Think of an inverted “U” (see the graph below).

This is where estrogen and genes come into play. Estrogen (or estradiol, to be more precise) enhances dopamine. Simple. Genes are slightly less straightforward. The concentration of PFC dopamine in the synaptic cleft (where it is released) is mostly determined by an enzyme called COMT. COMT comes in two flavors: the met/met variant, which has low activity and consequently higher dopamine, and it’s opposite, the val/val variant, which results in less dopamine. As of now, we think met/met individuals have near-optimal dopamine concentrations at baseline, while val/val carriers are a little short from optimum PFC function. Since estrogen enhances dopamine, the authors in this study asked: how will estrogen fluctuations influence a women’s working memory based on her genotype?

The authors recruited 24 healthy young women, rigorously tracked their cycles, and genotyped them for val/val or met/met alleles. The women were then invited back on two occasions – with estrogen levels at its highest and lowest – and performed a grueling task called the N-back while in an fMRI scanner.

Here’s how N-back works: for example, in the 2-back, subjects see a string of letters one-by-one, and need to pick out a letter that matched the one they saw 2 letters ago ("B"). To make things harder, researchers set up “lures”, where a letter matched a previously seen one, just not 2 letters ago ("R"). Although both 2 and 3-back trials depend on working memory, lure trails are exquisitely sensitive in differences in PFC function.

Not surprisingly, all women, regardless of cycle and genotype, performed worse as the load increased (needing to remember more letters), especially for lure trials. However, as seen below, in the 2-back, val/val women (less basal dopamine) performed much better when their estrogen was high (B) compared to low (A). Met/met women showed the opposite trend, with performance declining as estrogen went up. Dopamine levels seem to account for these observations: under high estrogen conditions (which boosts dopamine), increasing COMT enzyme activity (which degrades more dopamine) correlated with better accuracy. However, low estrogen (less dopamine) requires low COMT activity (slow degradation) for good performance.

A to C is significant. No info on anything else. Sad face.

These results suggest that estrogen is controlling working memory performance through dopamine. For met/met women, who already function well at baseline(C), increasing estrogen pushes them past the optimal dopamine peak, resulting in poorer function (D). For val/val women, who are slightly deficient in dopamine, estrogen is essentially a “smart drug”, boosting their performance by raising their dopamine levels to near optimum (A to B). Unfortunately, the authors only showed a significant difference between low dopamine (val/val, low estrogen, A) and high dopamine (met/met, low estrogen, C) conditions. I would love to know whether estrogen can boost val/val women’s performance to that comparable or above that of met/met women’s (C), and vice-versa, if the decreased met/met women’s performance is like that of val/val women’s at low estrogren (A) (confusing, I know).

Looking at the fRMI, the authors showed that the more the PFC (specifically, a part of the PFC called the middle frontal gyrus) activates, the better the women performs on lure trials, regardless of estrogen levels or gentotype. The activity level of PFC tightly correlated with COMT activity, with lower COMT activity (more dopamine) leading to higher PFC activation during the lure trials. Finally, the researchers found that women who had near-optimal dopamine levels (val/val high estrogen and met/met low estrogen) had the largest increase in PFC activity, and hence performed more accurately.

These results suggest that working memory, a key component of cognition, is dependent on the interplay between genes, neurotransmitters and hormones. If you’re a val/val, it may be beneficial to perform cognitively challenging tasks during the late follicular phase, when estrogen levels are high. If you’re a met/met, maybe save those tasks for the beginning of your cycle, when estrogen levels are low. Of course, this is heavy extrapolation, as the study only focused on dopamine and estrogen, without looking at the myriad of other neurotransmitter (especially norepinephrine, which also greatly influences PFC function) and sex hormones.

The study also hints that not every woman at every time will benefit from taking stimulants, such as Adderall or Ritalin. Stimulants enhance PFC function in ADHD individuals by increasing levels of dopamine. Hence, if you’re a val/val, stimulants may help improve working memory when estrogen levels are low (and possibly when high – we don’t have data to analyze this). On the other hand, if you’re a met/met already functioning at optimal dopamine concentrations, taking stimulants may instead decrease working memory performance, especially when your estrogen levels are high.

Linking back to the "smart drugs" post, since most studies didn't screen for genotype and estrus cycle, could it be that different individual responses masked a net positive gain from stimulants? I'd love to know your thoughts.

Jacobs E, & D'Esposito M (2011). Estrogen shapes dopamine-dependent cognitive processes: implications for women's health. The Journal of neuroscience : the official journal of the Society for Neuroscience, 31 (14), 5286-93 PMID: 21471363