| Summary: | A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. === There is central pain complaint of burning cold pain common to patients with multiple
sclerosis. Approximately 30‐40% of patients with multiple sclerosis (MS) suffer from central
neuropathic pain, usually focused symmetrically in both feet and legs and often accompanied by
cold allodynia and deep hyperesthesia [Osterberg et al 2005]. This condition resembles thalamic
central pain, which also presents with dysfunctional pain and temperature sensations; however,
thalamic pain is strictly contralateral [Craig 2007]. A distinct explanation for bilateral MS central
pain likely involves a spinal lesion, yet a correlation has not been found [Svendson et al 2011].
We hypothesized that ascending projections from lumbosacral lamina I neurons to bilateral midthoracic
autonomic nuclei are mirrored by descending projections [Craig 2002]; thus, a midthoracic
lesion that damaged bilateral autonomic descending projections to lumbosacral lamina
I neurons might underlie bilateral central pain in MS. Sympathetic interneurons in the midthoracic
IMM/IML project to the brainstem but not the thalamus, implying they could be involved
in homeostatic sensory integration at both brainstem and spinal levels. The lower extremity pain
could be due to a lesion in the upper thoracic cord, interrupting the homeostatic integration
pathway between the parabrachial nucleus in the brainstem, the (intermediomedial) and
intermediolateral (IMM/IML) region of T2‐6 segments of the spinal cord, and lumbar lamina 1.
To prove the existence of bilateral propriospinal projections between upper thoracic sympathetic
interneurons and lumbosacral sensory (“pain”) neurons, anterograde and retrograde labeling
with CTb and fluorescent tracers were performed in three animal species. In parallel, MRI
analysis of MS patients with bilateral burning cold pain in the lower extremities tested the theory
by examining for spinal lesions in the upper thoracic level. We tested this hypothesis with
parallel clinical and neuroanatomical studies and identified a striking correspondence; MS
patients with central neuropathic pain are distinguished by the presence of a lesion focused in
the center of the mid‐thoracic spinal cord, and in three mammalian species neurons with bilateral
descending projections to the lumbosacral superficial dorsal horn are concentrated in the
autonomic intermediomedial nucleus surrounding the mid‐thoracic central canal. These findings
will allow us to devise future treatments based on the newly understood neuroanatomical
mechanisms.
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