Imaging the neuromodulation of pain

Chronic pain is a major health problem that affects approximately 20% of the adult population, but only 60% of its patients find success in managing their condition. As an alternative therapeutic tool, transcranial direct current stimulation (tDCS) has appeared promising in recent literature, with several papers using the left dorsolateral prefrontal cortex (L-DLPFC) as the stimulation target due to its inherent role in pain modulation. However, the underlying mechanisms of this treatment have never been directly investigated. The thesis intends to explore this question through the application of a combination of tDCS, functional and structural imaging, and an ongoing pain model.
The first study investigated the task-free effects of L-DLPFC tDCS by using concurrent arterial spin labeling (ASL) perfusion imaging. Anodal (excitatory) tDCS was associated with an increase in regional cerebral blood flow (rCBF) of L-DLPFC, while cathodal (inhibitory) tDCS was related to a relative decrease. Regions connected to L-DLPFC, such as thalamus and primary somatosensory cortex, also experienced significant perfusion changes. Further analyses found modulations of L-DLPFC–thalamic functional correlations, which was particularly relevant due to the importance of the thalamus in antinociceptive processing.
To understand pain neuromodulation, a robust ongoing pain model was required to serve as a platform for the investigation. Thus, electrical, thermal, and capsaicin stimuli were tested in a series of studies. The former two did not produce an ongoing pain sensation, thus failing to replicate a chronic pain experience on healthy volunteers. However, topical application of capsaicin appeared to induce such a response, which entailed a pain intensity rating between 5 and 7 on a 0-10 visual analogue scale for at least 30 minutes. Careful screening ensued to select capsaicin responders from the cohort, who served as the research volunteers for the remainder of the thesis.
Combining these two studies, rCBF changes associated with tDCS-induced pain neuromodulation were then directly investigated with concurrent ASL and the above capsaicin model. Behavioral measurements suggested a significant reduction in pain intensity for the anodal tDCS condition over the sham tDCS condition, which corroborated the results from previous pain-tDCS studies. Modulations of L-DLPFC and thalamic rCBF continued to be observed with anodal tDCS. In addition, the activity of the posterior insula, an indicator of ongoing pain intensity, was higher for the sham tDCS condition than for the anodal tDCS condition.
The final study explored the importance of L-DLPFC–thalamic connection in pain modulation with diffusion tensor imaging (DTI). Probability tractography and tract-based spatial statistics (TBSS) were used to extract the mean fractional anisotropy (FA) of the tract. As hypothesized, the mean FA values within this tract positively correlated with the pain intensity changes, which indicated that individuals with stronger structural connection enjoyed greater alleviation from L-DLPFC tDCS.
As a whole, the above studies suggest that the clinical efficacy of L-DLPFC tDCS in pain treatment may arise from the resulting top-down modulation of the thalamus. Further studies on chronic pain patients may offer further verification of the mechanism that has been proposed in this thesis.

Keywords: transcranial direct current stimulation
functional MRI
pain
neuroscience
Advisor: Tracey, I
Stagg, C