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BackgroundThe occurrence of debilitating chronic persistent (24/7) headache after mild traumatic brain injury represents a central neuropathic pain state. Previous studies suggest that this chronic headache state can be attributed to altered supraspinal modulatory functional connectivity in both resting and evoked pain states. Abnormalities in the myelin sheaths along the supraspinal superior longitudinal fasciculus and anterior thalamic radiation are frequently associated with alteration in pain modulation related to functional connectivity deficit with the prefrontal cortex. This study assessed the correlated axonal injury-related white matter tract abnormality underlying these previously observed prefrontal functional connectivity deficits by comparing the fractional anisotropy, axial diffusivity, and radial diffusivity of brain white matter in patients with mild traumatic brain injury-related headache to healthy controls.ResultDiffusion tensor imaging data from patients (N = 12, average age ± SD = 35.0 ± 8.0 years old, 10 male) with mild traumatic brain injury-headache were compared with images acquired from healthy controls. The mild traumatic brain injury cohort demonstrated two areas of significant (P < 0.01, F value >16, cluster size >50 voxels) white matter tract abnormalities closely related to pain affective and modulatory functions in (1) the left superior longitudinal fasciculus which connects the prefrontal cortices with the parietal cortices and (2) the right anterior thalamic radiation connecting the prefrontal cortices with the anterior cingulate cortex. In addition, a significant (P < 0.01) decrease in axial diffusivity and increase in radial diffusivity at the superior longitudinal fasciculus cluster were noted in the mild traumatic brain injury cohort.ConclusionThe identified white matter tract abnormalities may represent a state of Wallerian degeneration which correlates with the functional connectivity deficit in pain modulation and can contribute to the development of the chronic persistent headache in the patients with mild traumatic brain injury.

Mild Traumatic Brain Injury (MTBI) patients with persistent headaches are known to have diminished supraspinal modulatory connectivity from their prefrontal cortices. Repetitive transcranial magnetic stimulation (rTMS) is able to alleviate MTBI-related headache (MTBI-HA). This functional magnetic resonance imaging (fMRI) study assessed supraspinal correlates associated with the headache analgesic effect of rTMS at left prefrontal cortex (LPFC), hypothesizing real rTMS would significantly increase modulatory functions at LPFC in comparison to sham treatment. Subjects with MTBI-HA were randomized to receive either real or sham rTMS treatments and subjected to pre- and post-treatment resting state and evoked heat-pain fMRI as described in a prior study. Real rTMS consisted of 2000 pulses delivered at 10 Hz and 80% of the resting motor threshold at left dorsolateral prefrontal cortex, whereas sham treatment was delivered with same figure-of-eight coil turned 180 degrees. Follow-up fMRI was performed one-week post-treatment. All fMRI data was processed using BrainVoyager QX Software. 14 subjects receiving real and 12 subjects receiving sham treatments completed the study. The REAL group demonstrated significant (P < 0.02) decreases in headache frequency and intensity at one week following treatment. fMRI scans in the REAL group showed increased evoked heat pain activity (P < 0.002) and resting functional connectivity (P < 0.0001) at the LPFC after rTMS. Neither this significant analgesic effect nor these fMRI findings were seen in the sham group. Sham treatment was, however, associated with a decrease in resting state activity at the LPFC (P < 0.0001). This study correlates the demonstrated analgesic effect of rTMS in the treatment of MTBI-HA with enhanced supraspinal functional connectivity in the left prefrontal cortex, which is known to be involved in “top-down” pain inhibition along the descending midbrain-thalamic-cingulate pathway. Trial Registration: This study was registered on September 24, 2013, on ClinicalTrials.gov with the identifier: NCT01948947. https://clinicaltrials.gov/ct2/show/NCT01948947.

Peripheral nerve injury diminishes fast conducting large myelinated afferent fibers transmission but enhances smaller pain transmitting fibers firing. This aberrant afferent neuronal behavior contributes to development of chronic post-traumatic peripheral neuropathic pain (PTP-NP). Non-invasive dynamic magnetic flux stimulation has been implicated in treating PTP-NP, a condition currently not adequately addressed by other therapies including transcutaneous electrical nerve stimulation (TENS). The current study assessed the effect of low frequency transcutaneous magnetic stimulation (LFTMS) on peripheral sensory thresholds, nerve conduction properties, and TENS induced fast afferent slowing effect as measured by motor and sensory conduction studies in the ulnar nerve. Results indicated sham LFTMS with TENS (Sham + TENS) significantly (P = 0.02 and 0.007, respectively) reduces sensory conduction velocity (CV) and increases sensory onset latency (OL), and motor peak latency (PL) whereas, real LFTMS with TENS (Real + TENS) reverses effects of TENS on sensory CV and OL, and significantly (P = 0.036) increases the sensory PL. LFTMS alone significantly (P < 0.05) elevates sensory PL and onset-to-peak latency. LFTMS appears to reverse TENS slowing effect on fast conducting fibers and casts a selective peripheral modulatory effect on slow conducting pain afferent fibers.