Chronic pain – Wile E. Cyote style


Chronic pain disrupts the reward circuitry in multiple sclerosis

Daniela Seixas, Jacqueline Palace and Irene Tracey. European Journal of Neuroscience.
DOI: 10.1111/ejn.13272.


Pain commonly affects multiple sclerosis (MS) patients, and has the potential to become chronic and burden an already damaged central nervous system. Imaging studies are providing insights into brain restructuring associated with chronic pain and different chronic pain conditions seem to evoke distinct plasticity patterns. Our objective was to study the structural and functional brain changes of chronic neuropathic pain of MS. Employing structural and resting functional magnetic resonance imaging we compared MS patients with chronic central pain with MS patients without pain matched with respect to age, gender, subtype and duration of MS and disability. Mean duration of pain was 7.6 years. Comparing the pain and no-pain groups, brain functional default-mode network differences were found. There was decreased coactivation in the caudate nucleus and nucleus accumbens bilaterally. Also, for the relapsing-remitting subgroup of patients, grey matter thickness changes predominated in the pain group in the mesial region of the temporal lobes, caudate, putamen, thalami and the fronto-parietal cortex; in the group without pain, changes predominated in the frontopolar and orbitofrontal cortices and in the occipital areas. A dysfunction in the reward system in chronic pain of MS was found, particularly in the brain areas involved in its motivational aspects, as such probably reflecting the maladaptive physiology of chronic pain, and possibly the signature of pain in MS, in a disease where reward impairment seems to be already one of its features.

Wile E. Cyote’s antics to capture the road runner also end in pain.

Is pain one of nature’s cruel jokes, a fail safe against stupidity, or is it a sign of frailty of an organic system? I’ll let you decide. Our untimely departure from the blogosphere has caused our readers significant pain, and I would like to sincerely apologise for this. Having read through your comments, I see now that the blog is greater than the sum of its parts.

For those who suffer from MS related pain (whether it be caused by stiffness/spasticity or nerve pain/neuropathic pain), the findings from this commentary should interest you.

Pain control is multibillion dollar franchise, and yet our understanding of it is small. Firstly, it is important to understand that the hardwiring of you brain changes with pain over time, and this varies based on the nature of the pain. Part of this change is visible in the brain resting-state networks (RSNs); the brain regions that are working during wakefulness when the brain is resting (similar to your computer CPU which is churning away in the background even though you’re not using it!). Secondly, changes here may also affect the function of the brain region concerned.

Here, the authors studied MS patients with pain for 7.6y on average. Using imaging, they studied the restructuring of the brain in MS in those with pain and without pain. They found changes between the two groups in the RSN network called the default-mode network (DMN). The DMN is usually silent during demanding tasks (for example, running), but is involved in cognition (memory, intelligence, planning for the future, and social interactions). In the DMN, in those experiencing chronic pain, there was reduced activation of brain regions (the caudate nucleus and nucleus accumbens; see Figure 1) that are linked to motivational (‘wanting’) aspects of behaviour, including reward, suggesting that this is impaired.

Figure 1: Default-mode network (DMN) comparison between pain and no pain groups revealed decreased activation in the caudate nucleus and nucleus accumbens bilaterally.

Therefore, even if different types of chronic pain are associated with distinct anatomical ‘brain signatures’, in MS at least both pain and reward seem to share the same neuroanatomical pathways. The question remains whether being on the receiving end of a reward can ameliorate pain?

About the author

Neuro Doc Gnanapavan


  • Thanks for the post, I found it interesting. How does seeing a neuropsychiatrist help in this context and what does the neuropsychiatrist do?

  • A neuropsychologist is likely to be more usefulness, especially one who is trained at mindfulness to modify pain behaviours at a cortical level.

  • Pain has been my only symptom since i was dx. Seems like a very uncommon presentation and course but i understand everyone is different. I mainly experience burning and aching pain in my legs. Lately, ive begun to expereince pain from spasticity, mainly in my calves.

    Is there a specific pathway that is damaged that is causes central nerve pain in MS? Can you point to a specific lesion on a standard mri and say it could be the cause of pain. Or is pain caused by some other mechanism that is not seen on standard mri? Is pain more common in a particular subtype of MS or is does it occur evenly throughout?

    • Pain, in particular neuropathic pain which you're describing is quite common and pain as a whole affects 50% of patients (A.B. O'Connor, S.R. Schwid, D.N. Herrmann, J.D. Markman, R.H. Dworkin
      Pain associated with multiple sclerosis: systematic review and proposed classification). Most studies in pain have reported a positive association between location of lesions and type of pain (you can read more about this in this review But in short, what they describe is the following:
      1) Upper limb pain – Posterior columns from C2 to C4
      2) Painful dysaesthesia at thoracic level and/or below – Posterior upper thoracic spinal cord; cord lesions at the level of C1, C4/5, Th3
      3) Back, leg, flank or abdominal pain – Spinal cord location of the lesions assumed.

      Hope this is useful.

  • Interesting article. Makes me think of my pain and how much of it I ignore being used to it; yet when tired/fatigued boy does it increase. Common?

    • Most things increase when tired, migraine is the commonest example which most people can relate to. Having said this, in this study they did not find a difference between the two groups (pain and no pain group)with regard to anxiety, fatigue or cognitive impairment. The chronic pain group, however, were more depressed (chicken or egg kind of scenario), and depression has been linked to stimulus induced heightened activity in the brain.

  • I have noticed a link between damp weather, colder weather and MS pain. The pain makes me anxious and I tense my body, leading to more pain. When my calf muscles/lower legs are cold they are painful.
    Bring on the dry and warmer weather (but not too hot).

    • Extreme temperature, in particular cold weather can worsen pain in distal extremities as blood vessels constrict in the skin and blood flow is diverted. Also spasticity/stiffness can worsen in cold temperatures adding to this.

    • Thanks NDG. Legs have been cold and painful over last few days, it's 1st June today and I'm wearing very thick socks to keep warm.

  • NDG intriguing as well.
    I soon had at the beginning of the outbreak lot of neuropathic pain in the calf and right foot.

    Lesions between C1 and C3 can cause neuropathic pain in the legs, then?

    At least for me Gabapentin greatly improves neuropathic pain.
    After I went back to working out regularly, even practicing the weight, neuropathic pain became sparser.

    • The evidence is pointing to disruption of the spinal cord neurones having an impact on pain when limbs are affected. In the case of legs the lesions appear to be higher up in the cervical cord.

  • Chronic pain is trying to disrupt most of my days, but I try to not let it get to me. It's hard though because of trigeminal neuralgia and other nerve pain. Was on Gabapentin until the highest dosage was not working anymore. On Lyrica and Amitriptyline now as well as on Trileptal but still getting so much pain I feel like I want to die and never wake up again.



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