The cerebellum and premenstrual dysphoric disorder

Feb 21 2011 Published by under Behavioral Neuro, Neuroscience, Uncategorized

Today's post is actually a TANDEM post. I'm sharing posting on this piece today with the brilliant and totally cool Kate Clancy of Context and Variation. So once you've finished here, head over THERE for her half of the take on this paper.

Kate showed me this paper, and I was immediately interested by the title and by the concept. And then she showed me the media coverage.

Is it that time of the month? These are the words no man should ever utter. How about this for a diplomatic alternative: "Are your GABA receptors playing up?"

You may be spot on. It seems that these brain cells are to blame for some women's monthly mood swings.

Heh. You watch out. Those GABA receptor...brain cells...are about to make your mood swing. I generally expect better from New Scientist, but it was pretty clear that this was based on the press release, and if so (I don't have the press release), the press release seems more than a little misleading. My "orly" cells are pinging.


(Source)

On the other hand, I would like to note that I LOVE that New Scientist includes journal references to what papers they are talking about at the bottom of their articles. SEE?!?! It's not so hard!!!

It's time to look at this paper.

Rapkin et al. "Neuroimaging Evidence of Cerebellar Involvement in Premenstrual Dysphoric Disorder" Biological Psychiatry, 2011.


Let's start with Premenstrual Dysphoric Disorder, or PMDD. This disorder, affecting 5-8% of women who are of reproductive age, is the perennial laughing stock of people who do not suffer from it, and has had a lot of trouble getting recognition, except for mean spirited jokes and inappropriate questions about "that time of the month" (see above). PMDD is a definite disorder, and severely disrupts the quality of life of the women who suffer from it, causing panic attacks, feelings of severe depression, mood swings, and physical symptoms like bloating and muscle pain. And this is not just for a day or two, it's often for the entire luteal phase of the menstrual cycle, which is, on average (with lots of variability, mind) 14 days. That's 14 days out of every 28 that women who suffer from PMDD have interference with their daily lives. That's a LOT of time (basically 50% of your time), a lot of potential lost work, and a lot of no fun at all.

PMDD has also had a tough time in the medical community. No one is sure what CAUSES PMDD. There have been hypotheses about different brain areas, including the amygdala, the prefrontal cortext, the orbitofrontal cortex, etc, etc.

And, now enter the...cerebellum?

The cerebellum seems like an odd brain area to look at for mood disorders. Most people know that the cerebellum is important for movement, and it is definitely involved in motor coordination. But it's ALSO starting to be looked at for mood disorders. When scientists examine different parts of the brain for differences in psychiatric disorders like schizophrenia or bipolar, they usually look for differences in places like the hippocampus, cortex, or amygdala, but they ALSO have found changes in the cerebellum. In particular, they are interested in the cerebellar vermis, which is the part of the cerebellum that lies on the midline, right in the back of your head. Feel the back of your head. As you move down towards your neck, feel that kind of dip in as your head becomes your neck? Just above there. This is an area that's important for motion, but also in sensory processing for things like pain...and in mood.

So they took 12 women with PMDD and 12 women without. They took blood samples in the follicular phase of the cycle and in the luteal phase. They also took PET and MRI studies at these two stages. The PET data looked at glucose utilization in the brain, showing which areas used more glucose than others, while the MRI data was just to localize the anatomy so you knew what areas you were looking at. Here's what they got:

What you can see here is the increase in glucose utilization in women with PMDD in the luteal phase, as compared to women without PMDD. It's all localized to the cerebellum (which comes out lovely in MRI data, see how you can see all the striations and how fluffy it looks from the side?), and they found that, while glucose utilization here was the same in both sets of women during the follicular phase, the women with PMDD had an INCREASE in utilization in the cerebellum during the luteal phase, while women without PMDD did not.

The conclusion here is pretty clear: there may be a role for the cerebellum in PMDD, right? Right.

And here's where I have a problem with this paper, and with the press release, and with the reporting. Because ALL you can say here is that women with PMDD had higher cerebellar glucose utilization during the luteal phase than women without PMDD. and the increase in activity correlated with a worsening of mood. This study shows NOTHING ELSE. NOTHING. But in the introduction, and the discussion, and the press coverage, I started seeing all this stuff about GABA-A receptors and 5-HT1A receptors, and anxiety. In fact, the authors hypothesize in the discussion that it must be the GABA-A receptors in the cerebellum (which I dunno, there's significant differences in 5-HT1A receptor localization in the cerebellum too, and I bet that merits a look). Sure, it might. There are other studies showing GABA-A receptor issues in other brain areas (but not in the cerebellum). But to go from "we see differences in glucose utilization in the cerebellum" to "GABA-A receptors are probably it" is to draw a lot out of a little. I don't blame the authors for hypothesizing, but I feel like the GABA receptors here got a lot of focus.

GABA is a relatively new player in PMDD. For a while scientists thought that people with PMDD had higher levels of progesterone during the luteal phase. During the luteal phase of your menstrual cycle (that's the part that comes AFTER ovulation), estrogen and progesterone both rise. The idea that scientists had was that maybe women with PMDD secreted more or less hormone (possibly estrogen, progesterone, leutenizing hormone, follicle-stimulating hormone, or any one of a number of hormones linked with the menstrual cycle), and that this was why they exhibited symptoms. Unfortunately, it's not that easy. Women with PMDD show no differences compared to other women in the amount of hormones or timing of hormone changes.

However, just because you have no differences in hormone levels doesn't mean you can't REACT differently to the hormone levels. The current hypothesis for PMDD is that women react differently to increases in progesterone during the luteal phase. A couple of studies have looked into this, and there appear to be two big players so far: GABA-A and 5-HT1A receptors.

GABA-A receptors are one of the two main types of GABA receptors in your brain (it's also in muscles, but brain is what I'm after right now). GABA stands for gamma-Aminobutyric acid, and it's known as the biggest inhibitory neurotransmitter in your brain. VERY basically, it tends to turn certain cells down a notch. When GABA binds to receptors in a brain cell (A neurotransmitter is NEVER any good without its receptor! In this case, GABA-A or GABA-B receptors), it causes an influx of ions in and out of the cell, making it more difficult for the cell to fire. Of course, the "shutting down" of different cells can result in different effects depending on where the cells are situated and what they are connected to (and the complexity of that will blow your mind if you think about it too hard).

Anyway, in women who do not suffer from PMDD, GABA-A receptors all over the brain decrease as the menstrual cycle goes on (don't worry, they come back every month). In women who DO suffer from PMDD, the GABA-A receptors actually INCREASE, and this may contribute to the symptoms. This is a good candidate for PMDD because GABA is a neurotransmitter that is implicated in anxiety disorders, and so changes here could play a part in the panic attacks seen in PMDD.

And there's another player, 5-HT1A. This is a receptor for serotonin, another neurotransmitter that is highly connected with mood. Most antidepressants in use today target the serotonin system, and the 5-HT1A receptor in particular may be important in depression and in antidepressant therapies. And 5-HT1A receptors have been shown to be lower in women with PMDD.

All this is some cool findings, and shows that PMDD is a definitely disorder with some very clear changes in neural responses. But all this DOESN’T show that GABA receptors in the cerebellum are specifically responsible for anxiety in PMDD. In fact, the results of this paper have nothing to say about GABA receptors AT ALL. I’m really not sure where the New Scientist article got that bit.

And more: why anxiety? There is far more to PMDD than anxiety, and while GABA receptors are implicated in anxiety disorders, the cerebellum ISN'T (though there are possible links with the formation of fear related memories, but that's not the same thing). To go from "we see differences in glucose utilization in the cerebelum" to "GABA-A receptors are it, and the GABA-A receptors in the cerebellum are responsible for anxiety in PMDD" is...more than a bit of a leap. It's a LOT of a leap. Not only did this study not measure GABA-A receptors, it also didn't measure anxiety specifically (just “worsening of mood), and did not correlate cerebellar activity in the luteal phase with anxiety in women with PMDD (which would have been a lovely finding if they'd done it).

And there’s more than just brain issues here.  Kate Clancy, who is far more skilled in endocrine measures than I, found some issues with the blood samples taken, as well as the POWER of the study itself.  Make you check out her post on the topic.

In the end, I wonder why they spent so much time on GABA and 5-HT1A, rather than talking about other things. For example, they didn't find any differences in activity in the orbiotfrontal cortex or amygdala. Other studies have shown some differences, and I wonder why they didn't find any here. The previous study did use a task that they didn't use in this study, which could have accounted for the differences.

And I wonder why they spent time talking about GABA and 5-HT1A at all. I think the finding that the cerebellum shows differences in activity in PMDD is plenty cool enough. The cerebellum is a new area in psychiatric disorders, and this shows that changes there may be detectable at baseline in women with PMDD. That’s PLENTY interesting, and brings a whole new focus to the cerebellum.

I do feel like I’m being a bit overly picky here. We’re all allowed to hypothesize and speculate on what our findings might mean. But considering that the media picked up on the GABA and anxiety and left the cerebellum behind, it seems to me that the speculation may have gone too far.

References!

1) My own Basics set: the Female Reproductive System: the menstural cycle.

2) Rubinow DR, Hoban MC, Grover GN, Galloway DS, Roy-Byrne P, Andersen R, & Merriam GR (1988). Changes in plasma hormones across the menstrual cycle in patients with menstrually related mood disorder and in control subjects. American journal of obstetrics and gynecology, 158 (1), 5-11 PMID: 2962499

3) Epperson CN, Haga K, Mason GF, Sellers E, Gueorguieva R, Zhang W, Weiss E, Rothman DL, & Krystal JH (2002). Cortical gamma-aminobutyric acid levels across the menstrual cycle in healthy women and those with premenstrual dysphoric disorder: a proton magnetic resonance spectroscopy study. Archives of general psychiatry, 59 (9), 851-8 PMID: 12215085

4) Albert PR, & François BL (2010). Modifying 5-HT1A Receptor Gene Expression as a New Target for Antidepressant Therapy. Frontiers in neuroscience, 4 PMID: 20661455

5) Jovanovic H, Cerin A, Karlsson P, Lundberg J, Halldin C, & Nordström AL (2006). A PET study of 5-HT1A receptors at different phases of the menstrual cycle in women with premenstrual dysphoria. Psychiatry research, 148 (2-3), 185-93 PMID: 17085022

6) Parsey RV, Arango V, Olvet DM, Oquendo MA, Van Heertum RL, & John Mann J (2005). Regional heterogeneity of 5-HT1A receptors in human cerebellum as assessed by positron emission tomography. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 25 (7), 785-93 PMID: 15716853

7) Protopopescu X, Tuescher O, Pan H, Epstein J, Root J, Chang L, Altemus M, Polanecsky M, McEwen B, Stern E, & Silbersweig D (2008). Toward a functional neuroanatomy of premenstrual dysphoric disorder. Journal of affective disorders, 108 (1-2), 87-94 PMID: 18031826

8) Rapkin, A., Berman, S., Mandelkern, M., Silverman, D., Morgan, M., & London, E. (2011). Neuroimaging Evidence of Cerebellar Involvement in Premenstrual Dysphoric Disorder Biological Psychiatry, 69 (4), 374-380 DOI: 10.1016/j.biopsych.2010.09.029

12 responses so far

  • Ed Yong says:

    (comment continued from Kate's blog) ...commonplace. Last year's arsenic story was a great example of a complex paper that required expertise from lots of different fields to dissect. I'm sure that these criticisms will arise naturally, but the extra step of coordinating your efforts and highlighting other takes to readers is a great addition

  • KBHC says:

    Finishing my response to Ed here :). I think the coordinated efforts thing turned out well, and I like the parallels you make to the arsenic story. I hope more collaborative science writing happens, since we all have so many important perspectives and kinds of expertise to bring to the table.

    Plus, who can resist tag-team blogging with someone who writes about BRAINZ?

    • scicurious says:

      OM NOM NOM, yer BRIANZ.

      I also had a lot of fun with this, and I thought it was great how we both picked out different parts of the paper to focus on, and brought different comments and expertise to the article, creating two entirely different posts and sets of criticisms.

      And I'm not gonna break it up, I'm just gonna cross post the comment cause I'm lazy...

  • AK says:

    The GABA-A receptor is arguably the smartest receptor in the CNS. This may be why it was promptly targeted.

    While searching for something else relevant to this subject, I found The role of progesterone and GABA in PMS/PMDD by Torbjörn Bäckström, Lotta Andréen, Inger Björn, Inga-Maj Johansson, and Magnus Löfgren, which appears to be chapter 13 of the book The Premenstrual Syndromes: PMS and PMDD edited by Shaughn O'Brien, Andrea J Rapkin, and Peter J Schmidt. (Note the second editor.)

    Two points stood out for me:

    To understand progesterone-induced adverse mood effects, it is important to note that progesterone is to high degree [sic] metabolized to allopregnanolone (3α-OH-5α-pregnan-20-one) and pregnanolone (3α-OH-5β-pregnan-20-one), both of which act as agonists on the γ-aminobutyric acid A (GABA-A) receptor complex in the brain.(9) [...] Allopregnanolone is a GABAA receptor positive modulator and enhances the effect of GABA on the receptor. The behavioral and pharmacological characteristics are similar to ethanol, barbiturates, and benzodiazepines.

    That is, it appears the effects of progesterone metabolites (including PMDD) can be simulated by appropriate doses of certain drugs.

    Besides the neuroactive progesterone metabolites[allopregnanolone and pregnanolone], benzodiazepines, barbiturates, and alcohol also act as positive modulators of the GABA-A receptor. Recent reports from human and animal studies indicate that in certain individuals all GABA-A receptor agonists can induce negative symptoms with anxiety and irritability/aggression. Strong irritability/aggression is induced in 3–6% of individuals; moderate symptoms are induced in 20–30%. Interestingly, the frequency parallels the 3–8% prevalence of PMDD among women in reproductive age and the 25–35% prevalence of milder symptoms, as in PMS.(20–22)

    That is, the same chemicals seem to have one effect in high doses, and another in low doses in a subset of individuals.

    What I'd like to see is research comparing the effects of PMDD with low doses of the drugs named, as well as higher doses. What do PET scans show here, and do the drugs affect the same subsets as PMDD (as well as one another)?

  • Renata says:

    Does this mean we should just eat more chocolate ??

  • Pinky says:

    PMDD sufferer here: As you mentioned, it's not a fun disorder to have. It's weird, having suicidal thoughts when one doesn't actually want to die. Hard to relate to unless one has experienced it.

    I found your site after I googled PMDD+GABA because I'm trying to figure out why pharmaceutical-grade GABA chewables have (apparently) cured me. This, after years of Zoloft, Wellbutrin, and vodka martinis (not necessarily at the same time or in that order, all of which I eventually gave up, since obvs they weren't working).

    I discovered it by accident, trying to solve a different problem. Since then, I've figured out that if I take several GABA at ovulation, I don't get PMDD symptoms. I don't need to continue it through the luteal phase, interestingly enough.

    I'm not a scientist and don't know what, if anything, this means. I'm a n=1 so it could be a fluke. But this recent study on GABA and PMDD is very interesting. Thanks for posting about it!

    • Jodi says:

      Could u please please tell me the type of GABA chewables ur referring to that have given u some relief. I too suffer from pmdd and take an anti depressant w lil relief.
      I also believe there is a connection here w GABA . Please if u could send me the name of the product u use.
      Thank u-
      Jodi

      • Sally says:

        Another apparent sufferer of PMDD as I get my panic attacks 7-10 days out from my period almost monthly. I also started taking GABA chewables after some research and recommendation of a psychologist and have noticed a HUGE improvement in my anxiety levels. I believe I take: Source Naturals GABA Calm, Orange

  • […] it on to me, and recommended that we do a tag-team on the paper, as we have done in the past on PMDD. Sci covers some important sociological aspects to the […]

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