• Determining the Neural Correlates of Burning Mouth Syndrome

      Payano Sosa, Janell; Seminowicz, David A.; 0000-0003-1337-3749 (2020)
      In the United States, nearly 1 million people suffer from burning mouth syndrome (BMS), a chronic orofacial pain condition that is largely unrecognized by the medical community and predominantly affects post- and peri-menopausal women. Relatively little in-depth research is available on the condition, and patients often give up seeking treatment. The pain in BMS arises spontaneously (i.e. in the absence of stimuli), but the mechanisms of this spontaneous pain is unclear, and there is limited research on structural and functional brain changes that may occur in a BMS sufferer. The goal of this dissertation was to investigate the central nervous system mechanisms of pain experienced in BMS. We collected: 8-day diaries, morning and afternoon quantitative sensory testing of both orofacial and forearm regions; afternoon structural and functional MRIs, and questionnaires from 27 BMS patients and 33 healthy post-menopausal women. Our hypotheses that, compared to healthy participants BMS patients have: higher pain sensitivity, especially in orofacial regions during the afternoon; lower grey matter volume and higher functional connectivity in nociceptive pathways associated with noxious heat during rest and evoked thermal pain, even after accounting for anxiety, were not supported. Instead, we found a time-of-day-dependent effect during warm detection and cold detection of face and forearm; lower grey matter volume of the dorsolateral prefrontal cortex (DLPFC), and higher grey matter volume of the inferior temporal gyrus and parabrachial nucleus (PBN); lower PBN connectivity with the DLPFC and primary somatosensory cortex (S1); higher connectivity of the right lateral hypothalamus (LH) with posterior insula during warm condition; connectivity of right medial hypothalamus and LH to left DLPFC and right PBN to bilateral S1 not associated with anxiety in BMS compared to healthy participants. Altogether, BMS showed abnormal responses to innocuous stimuli. This was supported by fMRI data, where connectivity differences were mostly present during innocuous stimulation. These altered sensory and brain responses could reflect heightened anticipation of thermal stimuli (both pain-specific and non-pain specific) associated with disruption of communication between regions associated with negative affect of pain (insula), attention modulation of pain (left DLPFC), somatosensation (S1), and thermoregulation (LH and PBN).
    • Placebo Analgesia in Neuropathic Pain: A Translational Investigative Approach from Rodents to Humans

      Akintola, Titilola; Colloca, Luana (2020)
      Pain is a complex phenomenon which can be influenced by various factors. Placebo analgesia (PA) is the experience of pain relief after the administration of a physiologically inert intervention via the expectation of benefit. However, adequate animal models of PA in chronic neuropathic pain were unavailable to determine how PA occurs in neuropathic pain. Neuropathic pain (NP) is a chronic pain condition characterized by a dysfunction of the peripheral or central nervous system. There is still limited progress in translating the findings of preclinical studies to address the clinical burden of chronic pain. This is thought to partly reflect difficulties in reliably assessing pain in animals. Hence, we employ a translational approach in both rodents and humans to explore the occurrence of PA in chronic NP. First, I tested the hypothesis that the facial grimace scale is a useful metric of spontaneous pain in rodents. We performed a chronic constriction injury of the infraorbital nerve (CCI-ION) and tested for changes in mechanical hypersensitivity and grimace scores. Results showed rodents with CCI-ION had significantly higher grimace scores and lower mechanical withdrawal thresholds compared to controls. These changes were reversed by an opioid, indicating the grimace scale as a sensitive metric for assessing ongoing pain in CCI-ION. Secondly, I tested the hypothesis that pharmacological conditioning with fentanyl would produce PA in a rat model of CCI-ION. Rats were pharmacologically conditioned with or without contextual cues. We administered a placebo and found marginally significant PA effect via the grimace scale but not in mechanical sensitivity. These findings suggest that PA may be more challenging to induce in rodents. Finally, in humans, I investigated how NP-like symptoms in Temporomandibular Joint Disorder alter PA. The effect of NP on PA is yet to be fully understood. I tested the hypothesis that the presence of NP-like symptoms would decrease PA in TMD. NP assessment was carried out both in the orofacial region and across the whole body using validated screening tools. Our results showed that the presence of co-occurring NP-like symptoms increased PA in TMD. We also show that this effect is mediated by reinforced expectation.