It’s really all about the brain

Neuroscience is such a geeky area to study. And I have to say I didn’t really study the brain all that well in my undergraduate training all those years ago – but oh, how the worm has turned! It’s so exciting to see how basic science directly influences treatments that we can use for people who don’t have many pharmacologic options for their pain.

While I don’t have really up-to-date papers today, I think the 2008 paper by Herta Flor presages some of the approaches we’re starting to use in clinical settings now, a scant three years later. Flor’s work has always been impressive – she has often looked at what happens when brains are deprived of their normal feedback because of trauma or amputation, and (really exciting!) she is coming to Australia for NOI’s Conference 2012.
I came across this 2008 paper while compiling some readings for students enrolling in the Postgraduate papers in Musculoskeletal Medicine through University of Otago (distance taught papers for health professionals interested in pain and pain management).

BTW it’s not too late to enrol for MSMX 704 (Pain) and MSMX 708 (Pain Management) – papers suitable for medics, nurses, occupational therapists, physiotherapists, psychologists, social workers – anyone working in the area of pain.

In this paper, Flor summarises some of the changes that occur along the neuraxis following amputation, and spends time expanding on the mechanisms of maladaptive neuroplasticity and from this, discusses therapies that might directly influence this plasticity.  She notes that the majority of current therapies (particularly pharmacological) don’t address this at all.  Sadly, most of these therapies have limited effect on people, and a large number of unpleasant side effects.

Let’s take a look at some of the mechanisms thought to play a role in phantom limb (and note the similarities between phantom limb, complex regional pain syndrome and post-spinal cord injury pain).  Also please note that I’ve simply abridged notes from Flor’s paper – no reinventing the wheel!

Peripheral mechanisms

  • Structural changes in neurons and axons – terminal swelling and regenerative sprouting of the injured axon end occurs and neuromas form, giving rise to abnormal afferent input to the spinal cord with upregulation, and altered trafficking, of voltage-sensitive sodium channels and decreased potassium channel expression, as well as altered transduction molecules for mechano-, heat and cold sensitivity in the neuromas.
  • Ectopic impulses – these occur in the DRG and can summate with ectopic activity from neuromas in the stump, which can lead to the depolarization and activation of neighbouring neurons, significantly amplifying the overall ectopic barrage.
  • Ephaptic transmission – this refers to transmission of nerve impulses without the need for a neurotransmitter, developing from non-functional connections between axons.
  • Sympathetic–afferent coupling – in some patients sympathetic dysregulation in the residual limb is apparent, and spontaneous as well as triggered sympathetic discharge can elicit and exacerbate ectopic neuronal activity from neuromas as well as at the level of the DRG
  • Down- and upregulation of transmitters – novel receptors in the neuroma that are sensitive to cytokines, amines and so on, may enhance nociceptive processing, while ‘setpoints’ at which the nerve may fire are lowered, requiring less input for the nerve to respond
  • Selective loss of unmyelinated fibres – following trauma, axotomized afferent neurons show retrograde degeneration and shrinking, primarily involving unmyelinated neurons

Central changes

  • Unmasking – Inhibitory GABA(γ-aminobutyric acid)-containing and glycinergic interneurons in the spinal cord could be destroyed by rapid ectopic discharge or other effects of axotomy, or might change from having an inhibitory to an excitatory effect under the influence of brain-derived neurotrophicfactor (BDNF) released from microglia at the spinal cord level, leading to a loss of the normal inhibitory responses.  Downregulation of opioid receptors, on both primary afferent endings and intrinsic spinal neurons can add to this disinhibition due to reducing the normal inhibitory GABA and glycine activity.
  • Sprouting – nerve growth factors can be released in part because of activation of previously quiescent pathways that become functionally strengthened.
  • General disinhibition – previously quiescent, or low-threshold afferents can become functionally connected to ascending spinal projection neurons that carry nociceptive information to supraspinal centres, leading to an increase in the amount of information flowing upwards to higher centres.
  • Map remodelling – reorganization of the spinal map of the limb,could be due to the unmasking of previously silent connections, is also reflected in brainstem and cortical remapping – this is experienced as increased sensitivity in areas adjacent to the original area of damage.
  • Loss of neurons and neuronal function
  • Denervation
  • Alterations in neuronal and glial activity
  • Sensory–motor and sensory–sensory incongruence – the effect of illusions, such as the perception of body ownership of a rubber hand originally demonstrate the speed at which the SI cortex and also frontal and parietal areas respond to visual and sensory incongruence.  It’s this aspect of brain function that is particularly targeted when we start to incorporate mirrorbox or other visual feedback into treatments for phantom limb pain.

I get all excited when I read about this kind of research.  It opens up a whole range of treatment strategies that, for some clinicians, has previously been thought of as ‘purely psychological’, as if there was no ‘real’ (ie ‘organic’, ‘we can image/detect it’) effect.  As we go further into how the neuromatrix works, it starts to provide us with both new ways for treating this kind of pain – but it also goes to explain why some of our treatments work the way they do.

Let’s take, for instance, hypnosis.  One of the effects of hypnosis in chronic pain management can be to provide a person with post-hypnotic analgesia.  An interesting factoid to consider is that hypnosis can also produce post-hypnotic pain, with the right kind of  suggestion.  How can that be?

We didn’t really know how hypnosis worked until fMRI started being used in research.  When someone is given a hypnotic suggestion of analgesia, the cerebellum, anterior midcingulate cortex, anterior and posterior insula and the inferior parietal cortex are all activated to a greater extent than when a suggestion of analgesia is given without hypnosis.

Another form of so-called psychological treatment, cognitive behavioural therapy including biofeedback (EMG and temperature modalities), also activates ‘higher centres’, providing people with structured feedback on what their bodies do in response to their own coping efforts.  When these approaches are monitored with fMRI, lo and behold, once again those same areas of the cerebellum, anterior midcingulate cortex, anterior and posterior insula and the inferior parietal cortex are affected.  This applies when people use ‘coping self statements’ like “I can manage”, “I’ll be OK”, and diaphragmatic breathing as well.

Where this leads me to is that over the next 5 – 10 years, I predict that there will be increasing recognition for pain management strategies that have been demonstrated to be effective for some people, in that the neurobiological basis for this treatment response will be imaged.  It’s a shame that “seeing is believing” rather than looking at longitudinal outcome results within RCT ‘s for treatments that are not biomedical to be accepted, but there you have it.

Tomorrow – some more approaches that have been found useful for phantom limb, post spinal cord injury pain, and CRPS pain.   Not just mirrorbox!

Flor, H. (2008). Maladaptive plasticity, memory for pain and phantom limb pain: review and suggestions for new therapies Expert Review of Neurotherapeutics, 8 (5), 809-818 DOI: 10.1586/14737175.8.5.809

Flor, H., Nikolajsen, L., & Staehelin Jensen, T. (2006). Phantom limb pain: a case of maladaptive CNS plasticity? Nature Reviews Neuroscience, 7 (11), 873-881 DOI: 10.1038/nrn1991

Derbeyshire, S., Whalley, M., Oakley, D. (2009). Fibromyalgia pain and its modulation by hypnotic and non-hypnotic suggestion: An fMRI analysis. European Journal of Pain, 13(5), Pages 542-550 doi:10.1016/j.ejpain.2008.06.010


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