The Brain in Pain Cortical contributions to Complex Regional Pain Syndrome Dr Janet Bultitude This is not a talk about central sensitisation, but about how changes in the cognitive and cortical representations of the body may contribute to clinical symptoms of CRPS, with implications for other pain syndromes.

Overview Cognitive and cortical changes in CRPS Possible role in clinical symptoms Implications for treatment Proposed mechanisms

Complex Regional Pain Syndrome Complex Regional Pain Syndrome is a disorder of chronic pain that can follow injury to a limb. It is characterised by pain, swelling and other symptoms that are disproportionate to the original injury, and persist long after the injury has healed.

Complex Regional Pain Syndrome “As the pain increases, the general sympathy becomes more marked. The temper changes and grows irritable, the face becomes anxious, and has a look of weariness and suffering. The sleep is restless, and the constitutional condition, reacting on the wounded limb, exasperates the hyperaesthetic state, so that the rattling of a newspaper, a breath of air…the vibrations caused by a military band, or the shock of the feet in walking, gives rise to increase of pain.” CRPS was first described by Weir Mitchel during the American Civil war. His account gives an example of the extreme suffering and disability experienced by patients with CRPS. Silas Weir Mitchel, 1864

Distorted body representation Body representation is the cognitive representation of the size, shape and location of the affected limb Lewis et al., 2010, Pain

Distorted body representation “I feel disgust, I know it sounds a very strong word to use but I’m disgusted that my arm is this way.” “It was just like this foreign body you were carrying around with you cause it didn’t feel like it was part of you.” In addition to the changes in perceived size and shape of the limb, body representation distortions can be present in the form of negative emotions about the limb or a sense that it doesn’t belong to the person. Lewis et al., 2007, Pain

Distorted body representation Difficulty locating / moving the limb unless directly looking at it Difficulty identifying fingers from touch Referred pain, or pain when viewing an object approaching the limb Movement-induced pain greater when viewing hand through magnifying lens, less when viewing hand through minimising lens. These cognitive changes suggest a reorganization of neural representations of the limb and its location relative to the body and other objects in the environment.

Cortical reorganisation Consistent with this hypothesis, research has shown that the representation of the affected hand in somatosensory cortex is reduced. Somatosensory changes correlate with changes in tactile detection and sustained pain. Maihöfner et al., 2004, Neurology

Cortical reorganisation Normally when we imagine moving our hand a similar motor network is recruited as when we actually move our hand. Compared with controls, imagined movement of the affected hand in patients showed reduced activation of the motor network. Gieteling et al., 2008, Pain

Mechanisms of CRPS The idea of a cortical contribution to CRPS is not new. For many years CRPS has been thought of as a systemic disease involving immune responses and local changes to the nerves, skin, muscles, blood vessels, tendons and bones as well as changes to the spinal cord and central nervous system.

“When our senses present us with discordant information, such as when our eyes give our brain information that does not agree with our senses of body position, balance, and equilibrium, we feel nausea. Less familiar is the notion that discordance between awareness of motor intention, muscle and joint proprioception, and vision may result in our feeling pain.” However it has recently been suggested that the changes in the representation of the limb in motor and sensory cortex may lead to clinical symptoms. Harris first proposed this explanation for repetitive strain injury and carpel tunnel syndrome, and McCabe and Blake have since applied the idea to CRPS. 1999, The Lancet

Poke your eye When we poke our eye we perceive that the world jumps, but this is not what we see when we deliberately make an eye movement. Why? When we plan a movement a predictive signal called an “efference copy” is also generated. This predicts the sensory outcome of the movement. In the case of eye movements, this predictive signal cancels out the effects of the image moving on the back of the retina so that we perceive a stable world that we are looking around. But if no predictive signal is generated because no eye movement is programmed, the interpretation of our visual system is that the world must have jumped.

Predictive signal True sensory outcome These predictive signals are made for all types of movements. When we want to reach for a desired object a movement sequence is programmed and a predictive signal is generated about the sensory outcomes of that movement. Once we have made the movement the true sensory consequences of the movement is compared to the predictive signal. Normally these match up with each other

? ? ? Predictive signal True sensory outcome The predictive signal is calculated based on the representation of the joints of the limb and where they are located relative to each other and to other objects in the environment. In patients with CRPS the body representation is distorted, therefore the predictive signal is incorrect. This leads to a mismatch between the predictive signal and the true sensory outcome of the movement. Harris proposed that this mismatch leads to the generation of pain signaling, swelling and other autonomic responses.

Implications for treatment The implications of this theory are that it may be possible to treat CRPS by targeting the cognitive and cortical representations of the affected limb. This is already done in current practice, for example, there is some evidence that daily use of mirror box therapy can reduce pain over some time.

? ? ? Healthy hand representation Predictive signal True sensory outcome There is evidence that mirror box therapy works by recruiting the intact representation of the healthy hand from the other side of the brain to be used in the movement planning. This could enable an accurate predictive signal to be generated, resolving the mismatch between the predicted and true sensory outcome of the movement.

Healthy hand representation Predictive signal True sensory outcome

? ? ? Predictive signal True sensory outcome So mirror box therapy is thought to work by recruiting the intact representation of the unaffected hand to be used in place of the missing or distorted representation of the affected hand. But in my research we are studying two treatment techniques that may help to restore an accurate representation of the affected hand itself.

Prism adaptation If prisms shift the visual scene to the right (first panel) then pointing movements will initially err in the direction of the visual shift (second panel). Upon repeated pointing, a realignment of the spatial representation of the limb gradually occurs, and the pointing errors gradually decrease, disappearing entirely within only a few trials (third panel). If the prism goggles are then removed the participants will show an adaptation after-effect in the form of a reaching bias in the opposite direction to the visual shift (fourth panel).

Prism adaptation Sumitani et al., 2007, Neurology Sumitani and colleagues found that one session of prism adaptation did not reduce CRPS symptoms, but two weeks of daily treatment resulted in a significant reduction in pain from approx. 6 to approx 2. Sumitani et al., 2007, Neurology

Prism adaptation My colleagues and I performed a case study of a patient with CRPS for whom mirror therapy was ineffective, however prism adaptation reduced her symptoms from about 4-5 to zero in 11 days. Pain remained at zero or negligible with ongoing daily use of prism adaptation It is not clear how prism adaptation reduces CRPS symptoms, but one hypothesis is that the technique artificially induces a large discrepancy between the predicted and true sensory outcomes of movement, and this provides a signal that leads to the re-calibration of the cognitive representation of the limb.

Transcranial Direct Current Stimulation Another possible way to treat the CRPS by targeting the cortical changes is to use a type of low-level electrical brain stimulation called transcranial direct current stimulation. This is thought to enhance neuroplasticity, and has been used to treat several different cognitive and psychological disorders, as well as in cognitive neuroscience research.

Transcranial Direct Current Stimulation Patients who received tDCS for twenty minutes per day for five days (“anodal” group) reported lower pain levels than those who received placebo tDCS (“sham” group). This difference was still present at 28 days post-treatment. Antal et al., 2010; The Clinical Journal of Pain

Proposed mechanisms

Immobilization-driven reorganisation? Immobilized IF Healthy IF A few weeks of hand and arm immobilization by cast wearing significantly impaired tactile acuity, associated with reduced activation of the respecitve somatosensory cortex (SI), measured by fMRI. Two to three weeks after cast removal and cortical changes recovered, whereas tactile acuity on healthy side remained superior. Lissek et al., 2004, Current Biology

Direct immune mechanisms? In the last years, several studies have used functional MRI to investigate how systemic inflammation influences brain function. We view this evidence, although not obtained in CRPS patients, as a potential overlapping mechanism: As illustrated in Fig. 1, there is substantial overlap in the brain regions that have been linked to both CRPS and to systemic inflammation independently: notably the middle cingulate, posterior insula, dorsolateral prefrontal cortex and the parietal lobule.

Overview Cognitive and cortical changes in CRPS Possible role in clinical symptoms Implications for treatment Proposed mechanisms

≠ Take-home messages Cortical origins to pain It’s all just in your head In fact, the evidence of changes in the brain tend to reassure patients who have difficulty convincing clinicians and family members that their pain is ‘real’

Take-home messages Importance of: Early recognition Aggressive intervention Multiple simultaneous approaches Cognitively- and cortically-targeted treatments

The reorganisation that is observed in CRPS has been reported in other syndromes of chronic pain, so CRPS may provide a model population with which to understand the cortical contributions to pain in other conditions.

Now recruiting We are looking for volunteers with CRPS for a study investigating two potential treatments that target cognitive and cortical changes. Interested patients can contact me at crps@fmrib.ox.ac.uk or jbultitude@fmrib.ox.ac.uk