Pre-operative Limbic System Functional Connectivity Distinguishes Responders From Non-responders to Surgical Treatment for Trigeminal Neuralgia

Background: Trigeminal neuralgia (TN) is a severe facial pain condition often requiring surgical treatment. Unfortunately, even technically successful surgery fails to achieve durable pain relief in many patients. The purpose of this study was to use resting-state functional magnetic resonance imaging (fMRI) to: (1) compare functional connectivity between limbic and accessory sensory networks in TN patients vs. healthy controls; and (2) determine if pre-operative variability in these networks can distinguish responders and non-responders to surgery for TN. Methods: We prospectively recruited 22 medically refractory classic or idiopathic TN patients undergoing surgical treatment over a 3-year period, and 19 age- and sex-matched healthy control subjects. fMRI was acquired within the month prior to surgery for all TN patients and at any time during the study period for controls. Functional connectivity analysis was restricted to six pain-relevant brain regions selected a priori: anterior cingulate cortex (ACC), posterior cingulate cortex, hippocampus, amygdala, thalamus, and insula. Two comparisons were performed: (1) TN vs. controls; and (2) responders vs. non-responders to surgical treatment for TN. Functional connectivity was assessed with a two-sample t-test, using a statistical significance threshold of p < 0.050 with false discovery rate (FDR) correction for multiple comparisons. Results: Pre-operative functional connectivity was increased in TN patients compared to controls between the right insular cortex and both the left thalamus [t((39)) = 3.67, p = 0.0007] and right thalamus [t((39)) = 3.22, p = 0.0026]. TN patients who were non-responders to surgery displayed increased functional connectivity between limbic structures, including between the left and right hippocampus [t((18)) = 2.85, p = 0.0106], and decreased functional connectivity between the ACC and both the left amygdala [t((18)) = 2.94, p = 0.0087] and right hippocampus [t((18)) = 3.20, p = 0.0049]. Across all TN patients, duration of illness was negatively correlated with connectivity between the ACC and left amygdala (r(2) = 0.34, p = 0.00437) as well as the ACC and right hippocampus (r(2) = 0.21, p = 0.0318). Conclusions: TN patients show significant functional connectivity abnormalities in sensory-salience regions. However, variations in the strength of functional connectivity in limbic networks may explain why some TN patients fail to respond adequately to surgery.