Distinct BOLD fMRI Responses of Capsaicin-Induced Thermal Sensation Reveal Pain-Related Brain Activation in Nonhuman Primates

Abstract

BackgroundApproximately 20% of the adult population suffer from chronic pain that is not adequately treated by current therapies, highlighting a great need for improved treatment options. To develop effective analgesics, experimental human and animal models of pain are critical. Topically/intra-dermally applied capsaicin induces hyperalgesia and allodynia to thermal and tactile stimuli that mimics chronic pain and is a useful translation from preclinical research to clinical investigation. Many behavioral and self-report studies of pain have exploited the use of the capsaicin pain model, but objective biomarker correlates of the capsaicin augmented nociceptive response in nonhuman primates remains to be explored.MethodologyHere we establish an aversive capsaicin-induced fMRI model using non-noxious heat stimuli in Cynomolgus monkeys (n = 8). BOLD fMRI data were collected during thermal challenge (ON:20 s/42°C; OFF:40 s/35°C, 4-cycle) at baseline and 30 min post-capsaicin (0.1 mg, topical, forearm) application. Tail withdrawal behavioral studies were also conducted in the same animals using 42°C or 48°C water bath pre- and post- capsaicin application (0.1 mg, subcutaneous, tail).Principal FindingsGroup comparisons between pre- and post-capsaicin application revealed significant BOLD signal increases in brain regions associated with the ‘pain matrix’, including somatosensory, frontal, and cingulate cortices, as well as the cerebellum (paired t-test, p<0.02, n = 8), while no significant change was found after the vehicle application. The tail withdrawal behavioral study demonstrated a significant main effect of temperature and a trend towards capsaicin induced reduction of latency at both temperatures.ConclusionsThese findings provide insights into the specific brain regions involved with aversive, ‘pain-like’, responses in a nonhuman primate model. Future studies may employ both behavioral and fMRI measures as translational biomarkers to gain deeper understanding of pain processing and evaluate the preclinical efficacy of novel analgesics.

Neuroimaging of pain in animal models: a review of recent literature

“…The most commonly used brain imaging method in animals is MRI, which includes fMRI 1–3,9,17,22,35,37,40,46,56,61,64,75,84,85,88,89 and MEMRI 16,25,41,42,74 in the current literature of pain. Functional MRI usually uses the blood oxygenation level–dependent (BOLD) method as an indirect measure of neuronal activity associated with a task or stimulus, or using temporal interdependence of fMRI time series across regions to infer brain connectivity (see Refs.…”

“…Spatial resolution refers to how accurately the measured activity is localized within the brain, and temporal resolution refers to how closely the measured activity corresponds to the timing of the actual neural activity. 45 Functional MRI has a good spatial resolution (mm) that can be further improved using high magnetic field and scan duration (small animal scanners were 7 to over 11.7 Tesla (T) in recent studies, 1–3,17,22,35,40,46,56,61,64,75,84,85,88,89 except 2 studies using 4.7 T 9,37 ). However, some methods that increase signal-to-noise ratio can also come at a cost of greater distortion.…”

“…36 The spatial resolution for in-plane resolution and slice thickness, respectively, in the reviewed fMRI articles ranged from 0.2 to 0.4 mm and 0.5 to 5 mm for mice studies, 0.2 to 0.8 mm and 0.5 to 2 mm for rat studies and 1 to 2 mm and 1 to 2.4 mm for monkey studies. 1–3,9,17,22,35,37,40,46,56,61,64,75,84,85,88,89 By contrast, the temporal resolution of neuronal events is limited through the hemodynamic delay: typically, the BOLD response has a peak occurring ∼4–6 seconds after the onset of a brief neuronal event. 32 One of the reviewed studies improved the temporal resolution by capturing more points of the hemodynamic response and interpolating those linearly (multishot EPI), which can also reduce the repetition time (TR) of magnetic pulses (500 ms).…”

“…9,17 Although animals are habituated to the scanning environment, awake rodent fMRI protocols can cause long-lasting changes in physiological and brain responses to pain stimuli that are stress-related. 50 Isoflurane has been the most common anesthetic source for fMRI, 1,3,22,37,40,56,61,75,84,85,89 MEMRI, 25,41,42 and PET. 19,44 Halothane and sevoflurane are also inhalational anesthetics, but few studies have been used them because of the associated higher rate of liver injury and the decreased cerebral blood flow compared with isoflurane.…”

“…Exclusion criteria for this review were studies that did not include brain imaging and did not assess pain. In that period, 18 animal neuroimaging studies have used fMRI, 1–3,9,17,22,35,37,40,46,56,61,64,75,84,85,88,89 whereas 10 other studies have used less commonly used techniques including 5 with MEMRI, 16,25,41,42,74 3 with PET, 19,44,78 and 2 with EEG. 48,72 There were no studies using diffusion tensor imaging or structural MRI in that period.…”