Human Studies

The purpose of this study is to assess the efficacy of transcranial direct current stimulation (tDCS) in patients with treatment-refractory trigeminal neuralgia (TN) and examine the utility of neuroimaging methods in identifying markers of such efficacy. Six patients with classical TN refractory to maximal medical treatment, underwent tDCS (three cases inhibitory/cathodic and three cases excitatory/anodic stimulation). All patients underwent pre- and posttreatment functional magnetic resonance imaging (fMRI) during block-design tasks (i.e., Pain, Pain + tDCS, tDCS) as well as single-shell diffusion MRI (dMRI) acquisition. The precise locations of tDCS electrodes were identified by neuronavigation. Five therapeutic tDCS sessions were carried out for each patient with either anodic or cathodic applications. The Numeric Rating Scale of pain (NRS) and the Headache Disability Index (HDI) were used to score the subjective efficacy of treatment. Altered activity of regional sites was identified by fMRI and associated changes in the spinothalamocortical sensory tract (STCT) were measured by the dMRI indices of fractional anisotropy (FA) and mean diffusivity (MD). Fiber counts of the bilateral trigeminal root entry zone (REZ) were performed as an added measure of fiber loss or recovery. All patients experienced a significant reduction in pain scores with a substantial decline in HDI ( value < 0.01). Following a course of anodic tDCS, the ipsilateral caudate, globus pallidus, somatosensory cortex, and the contralateral globus pallidus showed a significantly attenuated activation whereas cathodic tDCS treatment resulted in attenuation of the thalamus and globus pallidus bilaterally, and the somatosensory cortex and anterior cingulate gyrus contralaterally. dMRI analysis identified a substantial increase (>50%) in the number of contralateral sensory fibers in the STCT with either anodic or cathodic tDCS treatment in four of the six patients. A significant reduction in FA (>40%) was observed in the ipsilateral REZ in the posttreatment phase in five of the six patients. Preliminary evidence suggests that navigated tDCS presents a promising method for alleviating the pain of TN. Different patterns of activation manifested by anodic and cathodic stimulation require further elaboration to understand their implication. Activation and attenuation of responses at various sites may provide further avenues for condition treatment.

Pain is an experience of a subjective nature, interpreted in a personal way and according to an extensive palette of factors unique to each individual. Orofacial pain can be acute or chronic and it is usually the main reason for the patient to seek dental care. Pain perception varies widely among individuals. This variability is considered a mosaic of factors, which include biopsychosocial factors and genetic factors. Understanding these differences can be extremely beneficial for pain management in a personalized and more efficient way. We performed association studies to investigate phenotypes associated with genetic markers in pain-related genes in two groups of patients who received more or less anesthesia during dental treatment. The study group was comprised of 1289 individuals participating in the Dental Registry and DNA Repository Project (DRDR) of the University of Pittsburgh, with 900 participants in the group that received the most anesthesia and 389 constituting the comparison group that received less anesthesia. We tested 58 phenotypes and genotypic data of seven SNPs in genes that are associated with pain perception, pain modulation and response to drugs used in pain treatment: COMT (rs4818 and rs6269), GCH1 (rs3783641), DRD2 (rs6276), OPRM1 (rs1799971), SCN9A (rs6746030) and SCN10A (rs6795970). The analysis revealed a protective effect of rs1799971 on asthma in the total sample. rs3783641 was associated with salivary secretion disorders in females who received more anesthesia. rs1799971 was also associated with periodontitis in Whites who received less anesthesia. rs4818 was associated with disease and other tongue conditions in the group composed of Blacks who received less anesthesia. In conclusion, our study implicated variants in pain-related genes in asthma and oral phenotypes.

Neuropathic pain is a debilitating disease caused by damage or diseases of the somatosensory nervous system. Previous research has indicated potential associations between neuropathic pain and aging. However, the mechanisms by which they are interconnected remain unclear. In this study, we aim to identify the common differentially expressed genes (co-DEGs) between neuropathic pain and aging through integrated bioinformatics methods and further explore the underlying molecular mechanisms.

Temporomandibular disorders (TMD) involve chronic pain in the masticatory muscles and jaw joints, but the mechanisms underlying the pain are heterogenous and vary across individuals. In some cases, structural, functional, and metabolic changes in the brain may underlie the condition. In the present study, we evaluated the functional connectivity between 86 regions of interest (ROIs), which were chosen based on previously reported neuroimaging studies of pain and differences in brain morphology identified in an initial surface-based morphometry analysis. Our main objectives were to investigate the topology of the network formed by these ROIs and how it differs between individuals with TMD and chronic pain ( = 16) and pain-free control participants ( = 12). In addition to a true resting state functional connectivity scan, we also measured functional connectivity during a 6-min application of a noxious cuff stimulus applied to the left leg. Our principal finding is individuals with TMD exhibit more suprathreshold correlations (higher nodal degree) among all ROIs but fewer "hub" nodes (i.e., decreased betweenness centrality) across conditions and across all pain pathways. These results suggest is this pain-related network of nodes may be "over-wired" in individuals with TMD and chronic pain compared to controls, both at rest and during experimental pain.

Pain is a common non-motor symptom of Parkinson`s disease (PD), however, its pathomechanism remains elusive.

Herpes zoster (HZ) is a localized, painful cutaneous eruption that occurs upon reactivation of the herpes virus. Postherpetic neuralgia (PHN) is the most common chronic complication of HZ. In this study, we examined the metabolomic and proteomic signatures of disease progression in patients with HZ and PHN. We identified differentially expressed metabolites (DEMs), differentially expressed proteins (DEPs), and key signaling pathways that transition from healthy volunteers to the acute or/and chronic phases of herpetic neuralgia. Moreover, some specific metabolites correlated with pain scores, disease duration, age, and pain in sex dimorphism. In addition, we developed and validated three optimal predictive models (AUC > 0.9) for classifying HZ and PHN from healthy individuals based on metabolic patterns and machine learning. These findings may reveal the overall metabolomics and proteomics landscapes and proposed the optimal machine learning predictive models, which provide insights into the mechanisms of HZ and PHN.