Spatiotemporal alterations of thalamocortical circuitry functioning underlie pain

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SUMMARY Pain is a highly debilitating condition that is complex and difficult to manage. The neural basis of pain involves alterations in thalamocortical (TC) circuitry functioning, which can manifest as TC dysconnectivity and dysrhythmia (especially, impaired alpha oscillations). While likely reflecting inherently coupled (spatial and temporal) aspects of TC circuitry dysfunction, to date, TC dysconnectivity and dysrhythmia have only been examined independently, precluding fundamental understanding and effective intervention of this important pathology of pain. Capitalizing on our fully developed multimodal neuroimaging methodology (simultaneous EEG-fMRI and combined EEG-MEG-fMRI) and transcranial alternating current stimulation (tACS), the current R01 aims to address this critical gap. Aim 1 (Expt. 1) will directly link the spatial (via fMRI TC connectivity) and temporal (via EEG/MEG alpha oscillations) aspects to demonstrate coupled spatiotemporal alterations in TC circuitry functioning in experimental (tonic) and clinical (chronic low back) pain. Aims 2 & 3 will causally unify and upregulate the coupled spatiotemporal TC circuitry functioning in experimental and clinical pain, as causal manipulation of one aspect (TC dysrhythmia) via tACS of alpha oscillations (α-tACS) induces TC-circuit-wide functional restoration. Implementing a rigorously controlled experiment with a double-blind, double-controlled (active and passive control), crossover tACS design (Expt. 2), Aim 2 will establish an experimental model of this hitherto unexplored mechanism of pain. Through four weeks of α-tACS among patients with chronic low back pain (Expt. 3), Aim 3 will ascertain this unified TC circuitry pathology of pain (and reveal potential therapeutic effects of neuromodulation of alpha oscillations). Leveraging special but complementary expertise and facilities of our two labs, the three Aims pursue a broad and in-depth investigation, translating basic experimental insights into mechanistic understanding of acute and chronic pain. The project also emphasizes rigor and reproducibility through parallel recruitment of large and diverse samples (200 healthy participants and 140 patients) and multi-point cross/within-site validation and integration. Findings from this project will cast a “new look”—a unified spatiotemporal account—on TC pathology of pain and hence inspire novel pain treatments.