Neurovascular coupling during nociceptive processing in the primary somatosensory cortex of the rat

Abstract

Neuroimaging methods such as functional magnetic resonance imaging (fMRI) have been used extensively to investigate pain-related cerebral mechanisms. However, these methods rely on a tight coupling of neuronal activity to hemodynamic changes. Because pain may be associated with hemodynamic changes unrelated to local neuronal activity (eg, increased mean arterial pressure [MAP]), it is essential to determine whether the neurovascular coupling is maintained during nociceptive processing. In this study, local field potentials (LFP) and cortical blood flow (CBF) changes evoked by electrical stimulation of the left hind paw were recorded concomitantly in the right primary somatosensory cortex (SI) in 15 rats. LFP, CBF, and MAP changes were examined in response to stimulus intensities ranging from 3 to 30 mA. In addition, LFP, CBF, and MAP changes evoked by a 10-mA stimulation were examined during immersion of the tail in non-nociceptive or nociceptive hot water (counter-stimulation). SI neurovascular coupling was altered for stimuli of nociceptive intensities (P<0.001). This alteration was intensity-dependent and was strongly associated with MAP changes (r=0.98, P<0.001). However, when the stimulus intensity was kept constant, SI neurovascular coupling was not significantly affected by nociceptive counter-stimulation (P=0.4), which similarly affected the amplitude of shock-evoked LFP and CBF changes. It remains to be determined whether such neurovascular uncoupling occurs in humans, and whether it also affects other regions usually activated by painful stimuli. These results should be taken into account for accurate interpretation of fMRI studies that involve nociceptive stimuli associated with MAP changes.

Functional Neuroimaging of Nociceptive and Pain‐Related Activity in the Spinal Cord and Brain: Insights From Neurovascular Coupling Studies

“…Generally, this study suggests that for nociceptive stimulation, cerebral and spinal neurovascular coupling are different and are affected differently by BP fluctuations, which further emphasizes the need for more research. Indeed, SCBF responses were proportional to LFP amplitude and large BP fluctuations evoked by nociceptive electrical stimuli did not affect either measure or their coupling, in contrast to previous cerebral studies (Jeffrey‐Gauthier et al, ; Uchida et al, ). However, an important factor to consider for the extrapolation of neurovascular coupling studies from animals to human is anesthesia.…”

“…In light of the present review, we report that only two studies using nociceptive stimuli were conducted on cerebral neurovascular coupling (Jeffrey‐Gauthier et al, ; Uchida et al, ) and two on spinal neurovasculare coupling (Piché et al, ; Paquette et al, 2018). Although these studies provide evidence showing neurovascular coupling alteration at nociceptive intensities, the number of studies is limited and further studies are needed.…”

“…Similarly to results from the barrel cortex studies, the relationship between neuronal and vascular responses to paw stimulation was linear for middle‐range durations (Matsuura and Kanno, ; Ureshi et al, ), intensities and frequencies (Ngai et al, ; Nemoto et al, ). As for the barrel cortex, nonlinearities were observed for parameter values below or above the middle range, for durations (Ances et al, ), intensities (Jeffrey‐Gauthier et al, ; Shih et al, ) and frequencies (Ngai et al, ; Nemoto et al, ; Huttunen et al, ). Although these findings were reported for non‐nociceptive stimulation, most of the nonlinearities between neuronal activity and vascular responses are relevant for neuroimaging studies of pain.…”

“…Although one study suggested that the BP rise has minimal influence on the CBF response to nociceptive stimulation (Adachi et al, ), it may not be the case for all experimental conditions and for the neurovascular coupling. We previously investigated this relationship in SI of rats under urethane anesthesia during nociceptive electrical stimulation of the hind paw (Jeffrey‐Gauthier et al, ) and in rats under isoflurane anesthesia during electrical stimulation of the forepaw (Uchida et al, ). We observed a linear coupling of LFP and regional CBF response amplitude to stimuli of 10 mA intensity or below.…”

Neuroimaging Chronic Pain: What Have We Learned and Where Are We Going?

“…These techniques have been used to study several chronic pain states, including, most commonly, chronic low back pain (cLBP) [6], fibromyalgia (FM) [7], osteoarthritis [8], complex regional pain syndrome (CRPS) [9,10], phantom-limb pain, chronic migraine [11], chronic pelvic pain (CPP) [12,13] and peripheral neuropathy [14], among others [15]. Experiments have evaluated acute pain processing mechanisms in healthy volunteers [16–18] and in animals [19] and in animal models of chronic pain [20]. Neuroimaging has helped elucidate many of the neural correlates regarding factors well known to modulate the experience of pain, including attention [21], anticipation [22], empathy [23,24], placebo [25], meditation [26], fear/anxiety [18] and reward [15].…”