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Contextual Conditioning: How the Brain May Change with Chronic Pain

Chronic pain conditions come in many forms.  Chronic pain can have a well-known ongoing cause, such as osteoarthritis or rheumatoid arthritis.  Other cases consist of pain that lasts long after the initial injury has healed, or can even occur when there has been no injury or illness at all.  An inappropriately functioning sensory system has often been blamed as the cause of this type of unexplainable pain (Cervero 2009).  Pain is an enormously complex process which has been analyzed and studied for decades.  The involvement of numerous pathways in both the peripheral and central nervous systems as well as emotional responses have made it a very difficult area to pin down.  Recently, a relatively new hypothesis involving the emotional experience of pain and how it could relate to the persistence of chronic pain has added to the debate.

The study authors (Mutso et al., 2012) suggest that chronic pain can be redefined as a state of continual aversive learning, where pain and other aversive associations are continually made in otherwise benign contexts.  For example, for a chronic pain patient, a negative association is made with a familiar space once their pain is felt in that space.  Whenever the person enters the space again, the negative association is reinforced.  When a patient becomes thus conditioned, the extinction of the emotional effects of pain becomes impossible: pain is ever-present, even at re-exposure to the same context.  There is never a chance for extinction of the conditioned aversion, because re-exposure cannot be achieved in the absence of pain, and aversive associations can be made in myriad spaces throughout a patient’s normal day (Apkarian 2008).

In such terms, chronic pain can be regarded as a continual presence of an unconditioned stimulus, with an inability to dissociate the stimulus from random events (Apkarian 2008).  Over time, results in the potential for cortical reorganization concurrent with chronic pain, with cortical changes becoming significant factors in the persistence of pain states.

Based on this hypothesis, the current study zeroes in on the hippocampus, necessary for contextual fear extinction, and other forms of learning and memory, as well as anxiety and depression.  Using a spared nerve injury model of neuropathic pain, Mutso et al. showed that neuropathic animals and control animals could learn fear conditioning for both context and cue, but neuropathic animals could not extinguish contextual fear conditioning, which is a hippocampus-dependent task.  This finding points to a clear deficit in hippocampal functioning, supporting the hypothesis that emotional learning and cognitive function are indeed affected under conditions of persistent pain.  Several other hippocampal changes were noted in neuropathic animals as compared to controls, including higher anxiety behaviors, a decrease in phosphorylation of ERK2 (previously shown to be critical in contextual fear extinction), decreased neurogenesis, and altered short-term plasticity.  The authors also examined the brains of chronic pain patients, including those suffering from osteoarthritis, chronic back pain, and complex regional pain syndrome using fMRI techniques.  They found that patients with both chronic back pain and complex regional pain syndrome had reduced hippocampal volumes, which may result from similar mechanisms found in animal studies that show reduced hippocampal functioning.

This publication brings up some interesting questions about the way we think of pain and the numerous neuronal systems it affects, and suggests that hippocampal dysfunction may have the capability to perpetuate chronic pain states.

What do you think?

Do you agree that altered fear extinction mechanisms could be an important aspect of the pain experience?  If so, how do you think intact fear extinction mechanisms would change the pain experience?

Further Reading:

Apkarian AV. 2008.  Pain perception in relation to emotional learning.  Curr Opin Neurobiol. 2008 Aug;18(4):464-8.

Cervero F. 2009. Pain: friend or foe?  A Neurobiologic perspective: the 2008 Bonica Award Lecture.  Reg Anesth Pain Med. Nov-Dec;34(6):569-74.

Mutso AA, Radzicki D, Baliki MN, Huang L, Banisadr G, Centeno MV, Radulovic J, Martina M, Miller RJ, Apkarian AV.  2012.  Abnormalities in hippocampal functioning with persistent pain. J Neurosci. Apr 25;32(17):5747-56.

For more information on chronic pain:


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