Friday, March 6, 2015

TNF alpha, your brain, inflammatory diseases, and mindfulness: Thoughts provoked by the new study in Pain


A recent study in the journal Pain (found here - if you don't have access & want full text, shoot me a message) provokes some  interesting questions on the relationship between the brain and inflammation, and perhaps what we can do about these things....

In sum, here's what the authors show:

(1) Thinning in somatosensory & motor cortex is associated with pain reduction,
(2) Thinning in insular cortex (a brain area associated with interoception, empathy, emotion regulation, etc) is associated with fatigue reduction 

....In a subject sample of ankylosing spondylitis patients (an autoimmune inflammatory disease) on TNF inhibitors (which block tumor necrosis factor alpha, an inflammatory cytokine with several roles in the body, including inducing inflammatory processes and regulating tumorigenesis - hence the name).

From Wu et al, 2015
This raises all sorts of questions about TNF alpha pathway effects on the brain. First, cortical thinning has generally been characterized as a bad thing (and associated with excess inflammation, not reduction of inflammation), but here, we see positive correlates with self-reported pain and fatigue reduction, which is interesting in and of itself. Keep in mind that this is a patient population, and the first thing I'd like to know is how cortical thickness in these regions compares to healthy control subjects at baseline - perhaps, due to chronic pain and fatigue, we already see thickening of somatosensory and insular cortices in AS patients (entirely plausible since processing these signals recruits these brain areas). So perhaps controlling disease symptoms with anti-TNF therapy is just bringing these people down to a more normal baseline in terms of brain anatomy, alongside the normalization of inflammatory markers (e.g. C-reactive protein, sed rate) that usually occurs with successful anti-TNF treatment. 

But the most interesting thoughts occur when you try and relate these findings to what we know about how we can alter (a) cortical thickness in these regions and (b) the immune system with cognitive training and stress reduction techniques such as mindfulness. 

In separate studies, mindfulness has been shown to (1) reduce the subjective experience of pain (see Zeidan et al, 2012 for a review - including how insula, prefrontal, and somatosensory cortex activity is modulated by meditation during pain), (2) increase cortical thickness in insula and somatosensory cortices, among other areas (Lazar 2005, Grant 2010), and (3) decrease markers of inflammation (including IL-6, TNF, and cortisol). The Grant et al. study even ties (1) and (2) together, associating decreased pain sensitivity in Zen meditators with thicker anterior insula, cingulate, and somatosensory cortex. So...back to the current study, anti-inflammatory treated patients show less pain/fatigue in conjunction with cortical thinning in insula and somatosensory cortices. But if we think we might get similar immunomodulation with mindfulness as we would on an anti-inflammatory drug (disclaimer: not advocating that anyone ditch their necessary meds to just meditate), why are the brain effects the opposite? 

Intriguing question - as I hinted at before, maybe the effects are different when you've already got aberrant neural circuitry and brain structure from chronic pain/inflammation. After all, your body is pretty good at self-correcting when given the tools to do so.

But what would happen if we combined mindfulness meditation and an anti-TNF in someone with an inflammatory condition? Based on the (self-report, non-controlled study) data out there, good things, in terms of symptom improvement. But again, opposite effects in terms of increased/decreased cortical thickness being beneficial are reported separately - which has to make you wonder, if I meditate while on an anti-TNF, am I shooting myself in the foot because the brain effects of one pain-reduction technique counteract the brain effects of another? I'm still guessing no - .we know that normal inflammatory pathways are dysregulated and brain structure is slightly different to begin with under conditions of chronic inflammation, so most likely the underlying neural mechanisms would work differently too. I'd love to see someone run a brain structure/anti-TNF/MBSR triple-arm randomized controlled trial of this. NIH, any takers? 

In sum, this is a perfect example of the simultaneously awesome and maddening thing about cognitive neuroscience - we constantly bump up against things we still don't know. For now, I suppose I'll keep mindfully swimming along and trust that any changes going on in my brain are in my best interest. 

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