OEF/OIF Pain Research Summit

Imaging

-   Dr. Cook presented data discussing his parallel work in fibromyalgia
    (FM) and Gulf War veterans (GVs) with chronic musculoskeletal pain
    (CMP).

-   Dr. Cook's work and the work of others suggest that FM pain may be
    maintained by central nervous system mechanisms. These mechanisms
    may involve abnormal central processing of sensory stimuli, abnormal
    central regulation of sensory stimuli or a combination of augmented
    processing and diminished regulation.

-   It was proposed that functional neuroimaging methods such as
    functional magnetic resonance imaging (fMRI) can provide information
    regarding the extent and location along the neruoaxis of central
    dysregulation, as well as, provide information concerning what
    regions are involved in abnormal pain processing in OEF/OIF
    veterans.

-   Dr. Cook presented data showing augmented processing of both painful
    and non-painful stimuli in GVs with CMP similar to that seen in FM.
    His data demonstrated pain-relevant responses in the brain to warm
    stimuli that were not moderated by the delivery of several painful
    stimuli in GVs with CMP compared with controls. Controls showed less
    activity to warm stimuli that was further diminished by the delivery
    of several painful stimuli. He further showed augmented responses to
    mild, moderate and strong pain stimuli in GVs with CMP. A dose
    response to graded pain stimuli was evident in healthy GVs, but not
    GVs with CMP providing further evidence of augmented central
    processing of pain.

-   Dr. Cook presented preliminary data from his recent work in FM
    demonstrating augmented brain responses to warm stimuli that were
    influenced by anticipation. These results suggest greater
    anticipation of painful events for FM patients and support one
    potential mechanism of chronic pain maintenance in CMP. Healthy
    women showed top-down regulation of pain responses during pain and
    distraction with increased activity in cingulo-frontal regions and
    decreased activity in the anterior insular cortex. This response was
    not evident in FM suggesting a failure to cognitively modulate pain.

-   Discussion focused on the future of neuroimaging methods to study
    CMP, particularly as it relates to OEF/OIF veterans. Many questions
    were posed as to the meaning of a particular neural response and the
    specificity of neuroimaging to provide neural maps of 'pain'.

-   Proponents of functional imaging methods as pathophysiological
    indices of pain pointed out the potential to further understand
    brain mechanisms of pain in CMP and the ability to test processing
    and regulatory aspects of pain that cannot be obtained by measures
    that solely rely on self-report. Skeptics questioned whether brain
    imaging provided anything unique beyond that of the self-report.
    This was a good discussion.

-   There was general consensus that brain imaging was not a surrogate
    for self-report and that the subjective nature of pain required that
    pain always be measured at the person level in addition to any
    "objective" correlate of the experience. Additionally, brain imaging
    methods were recognized as providing support for the subjective
    experience.

-   Discussion was also focused on the potential of neuroimaging methods
    to track brain and pain responses in treatment trials perhaps as a
    means to look at responders and non-responders. Brain imaging
    methods may be useful to look for the most reliable neural response
    for treatment and to look at the relationship between neural
    responses to pan and CMP symptoms.

-   The second speaker, Dr. Eva Widerström-Noga, gave an overview of the
    problem of SCI-related pain and her new study using MR spectroscopy
    in individuals who have suffered a spinal cord injury (SCI) and who
    experience chronic neuropathic pain. Chronic pain is common
    following SCI and recent studies from the US, Germany, Denmark and
    the Netherlands indicate that at least 2/3 of persons who have
    sustained a SCI will develop chronic pain. Furthermore, most
    neuropathic pains are refractory to treatment and several studies
    show that few of these pains completely resolve spontaneously or due
    to treatment. SCI-related pain is superimposed upon the physical
    impairments and disability caused by other consequences of SCI and
    one of the major reasons for decreased quality of life after a SCI.

-   Because pain after SCI is heterogeneous including both nociceptive
    and neuropathic pain types, an individual often have several types
    of pain simultaneously. This fact complicates the treatment since it
    is likely that several pathophysiological and psychosocial
    mechanisms are responsible for causing and maintaining a person's
    pain. While basic research studies have identified several possible
    pathophysiological pain generating mechanisms, it is difficult in
    the clinical treatment situation to determine the exact mechanism
    for as specific pain.

-   Although peripheral mechanisms are involved in the generation of
    pain, central mechanisms may play a larger role in SCI and other
    traumatic injuries and diseases involving the central nervous
    system. For example, pain has been shown to activate large areas of
    the brain, and a network consisting of both cortical and subcortical
    structures has been suggested. For psychological factors involved in
    the experience of pain (i.e., anticipation of pain, attention,
    hypnotic reduction of pain, anxiety and placebo responses), the
    prefrontal, anterior cingulate and insular cortices have been
    implicated. In neuropathic pain conditions, increased activity has
    been found in the somatosensory cortices I and II, prefrontal
    cortex, thalamus, anterior cingulate cortex and insular cortex.

-   Magnetic Resonance spectroscopy (MRS) is a non-invasive method to
    measure metabolites in the human brain, which is based on that
    different chemicals vibrate at different frequencies when stimulated
    by a magnet. MRS produces a signature of the nature and amounts of
    chemicals that are present in the brain. The stability of these
    signals is thought to be reflective of long-term plasticity and may
    therefore be particularly useful in longitudinal studies or clinical
    trials.

-   Dr. Widerström-Noga and her colleagues have previously used MRS to
    study metabolic changes in the thalamus related to neuropathic pain
    in persons with SCI and chronic neuropathic pain. In this study they
    found that there are changes in thalamic metabolites specific to
    neuropathic pain. In their new study they focus on two
    metabolites: (1) N-acetyl aspartate, which is a free aminoacid
    thought to be localized in neurons in the brain and commonly
    considered a neuronal marker and an indicator of neuronal
    dysfunction; and (2) Myo-inositol, which is an organic osmolyte,
    with a major role in the volume and osmoregulation of astrocytes and
    is considered a glial marker. In this new study, brain areas
    important for both the sensory and affective processing of pain are
    examined. This research aims to further our understanding of the
    role of metabolic processes in the thalamus and anterior cingulate
    cortex and their relationships with psychosocial factors and
    neuropathic pain in SCI.

-   In conclusion, chronic pain associated with SCI is both
    heterogeneous and refractory. Multiple pathophysiological and
    psychological mechanisms are responsible for the origin and
    maintenance. With the goal of tailored mechanism-based treatments,
    specific pain generating mechanisms need to be identified in each
    person and treatment targeted to these.