Functional MRI of the Reserpine-Induced Putative Rat Model of Fibromyalgia Reveals Discriminatory Patterns of Functional Augmentation to Acute Nociceptive Stimuli

Abstract

Functional neuroimaging, applied to pre-clinical models of chronic pain, offers unique advantages in the drive to discover new treatments for this prevalent and oppressive condition. The high spatial and temporal resolution of fMRI affords detailed mapping of regional pharmacodynamics that underlie mechanisms of pain suppression by new analgesics. Despite evidence supporting the translational relevance of this approach, relatively few studies have investigated fMRI abnormalities in rodent models of chronic pain. In this study, we used fMRI to map the BOLD response in a recently developed putative rat model of fibromyalgia to innocuous and acute nociceptive stimuli by applying a step-wise graded electrical forepaw stimulation paradigm, with comparison to healthy controls. We observed discriminatory functional signatures (p < 0.001) to 2 mA electrical forepaw stimulation, found to be innocuous in the control group. As such, this translational approach provides sensitive and quantitative neural correlates of the underlying chronic disease. The regional patterns of functional augmentation were found to be concordant with previous studies of nociception in the anaesthetised rat brain, supporting the specificity of this approach in the study of altered central pain processing in reserpine induced myalgia. The methodology introduced in this work represents a novel platform for emerging treatment evaluation in highly experimentally controlled conditions.

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).…”

“…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). 85 However, it is worth mentioning that those procedures cannot change the speed of the hemodynamic response. Manganese-enhanced MRI benefits from the use of T1-weighted images, providing better spatial resolution than fMRI, varying between 150 and 75 µm for rat studies, 16,25,41,42,74 but the temporal resolution is up to 8 hours to achieve a good signal-to-noise ratio.…”

“…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.…”