The impact of depressive symptoms on supraspinal pain neuromodulatory functional connectivity and therapeutic...

Background: Both depressive and pain symptoms are highly prevalent and relevant comorbid conditions in Veterans with Gulf War Illness (GWI). This study assessed how the severity of depressive symptoms may affect supraspinal pain modulatory functional connectivity (FC) in Veterans with GWI-related chronic Headache And body, muscle, and joint Pain conditions (GWI-HAP) and how depressive symptoms alone or paired with pain symptomology or other neuropsychological and functional assessments were able to predict supraspinal functional connectivity (FC) relevant to pain modulation. Methods: Resting state functional MRI (rs-fMRI) conducted in Veterans with GWI-HAP and moderate to severe depressive symptoms reflected by the Hamilton Rating Scale for Depression (HRSD) score <14(GWI ≥ 14) and their counterparts with no or mild depressive symptoms (GWI<14) were compared along with pain symptomology, functional, quality of life, and Post-Traumatic Stress Disorder assessments. Results: Region of interest (ROI)-to-ROI rs-fMRI FC analyses indicated the GWI ≥ 14 group (N=33) showed significantly enhanced FC of the left dorsolateral prefrontal cortex (DLPFC) with the contralateral Insula (BA 13; P < 0.001; T= 7.14), visuomotor cortex (BA7, P<0.01, T=4.82) and two regions of contralateral thalamus (P < 0.01, P < 0.001; T= 5.32, T= 5.25, respectively); and decreased FC with the ipsilateral premotor cortex (BA 6; P < 0.01; t = -3.34) and contralateral anterior cingulate cortex (BA 32; P < 0.001; T= -3.64) than the GWI<14 group (N=33). Independent T-tests also indicated that the GWI ≥ 14 group demonstrated a significantly (P<0.05) higher level of pain severity, functional, and quality of life impairments, and PTSD symptomology in comparison with the GWI<14 group. Stepwise regression analyses of the combined group indicated that despite the detected significant between-group difference in supraspinal FC of the left DLPFC to other pain-relevant supraspinal regions, either the degree of depressive symptoms or any other study assessment was able to reliably predict the FC of the left DLPFC to the right ACC. In addition, other assessments alone did not reliably predict the left DLPFC to other pain relevant ROI. However, adding other pain symptomology, neuropsychological, and functional assessments to depressive symptom severity assessment can enhance the prediction of the supraspinal FC relevant to pain modulation. Conclusions: While significant between-group differences in supraspinal modulatory FC were found based on the severity of depressive symptoms, pain symptomology, functional, and quality of life impairments, these assessments alone did not predict the FC correlation of left the DLPFC in most detected ROI differences. However, individually pairing mood with other pain and functional assessments can enhance the prediction of the underlying supraspinal pain modulatory FC. Potential non-invasive brain stimulation interventions such as TMS with various treatment targeting options, which are applicable for addressing these highly prevalent co-morbid conditions and functional impairments, may incorporate this mechanistic correlation and prediction in formulating a corresponding therapeutic strategy.