Effect of Deafferentation from Spinal Anesthesia on Pain Sensitivity and Resting-State Functional Brain Connectivity in Healthy Male Volunteers

Abstract

Patients may perceive paradoxical heat sensation during spinal anesthesia. This could be due to deafferentation-related functional changes at cortical, subcortical, or spinal levels. In the current study, the effect of spinal deafferentation on sensory (pain) sensitivity was studied and linked to whole-brain functional connectivity as assessed by resting-state functional magnetic resonance imaging (RS-fMRI) imaging. Deafferentation was induced by sham or spinal anesthesia (15 mg bupivacaine injected at L3-4) in 12 male volunteers. RS-fMRI brain connectivity was determined in relation to eight predefined and seven thalamic resting-state networks (RSNs) and measured before, and 1 and 2 h after spinal/sham injection. To measure the effect of deafferentation on pain sensitivity, responses to heat pain were measured at 15-min intervals on nondeafferented skin and correlated to RS-fMRI connectivity data. Spinal anesthesia altered functional brain connectivity within brain regions involved in the sensory discriminative (i.e., pain intensity related) and affective dimensions of pain perception in relation to somatosensory and thalamic RSNs. A significant enhancement of pain sensitivity on nondeafferented skin was observed after spinal anesthesia compared to sham (area-under-the-curve [mean (SEM)]: 190.4 [33.8] versus 13.7 [7.2]; p<0.001), which significantly correlated to functional connectivity changes observed within the thalamus in relation to the thalamo-prefrontal network, and in the anterior cingulate cortex and insula in relation to the thalamo-parietal network. Enhanced pain sensitivity from spinal deafferentation correlated with functional connectivity changes within brain regions involved in affective and sensory pain processing and areas involved in descending control of pain.

Thalamic Functional Connectivity in Mild Traumatic Brain Injury: Longitudinal Associations With Patient-Reported Outcomes and Neuropsychological Tests

“…65–67 Studies using acute pain models have found decreased thalamic FC to multiple pain-related brain regions that were associated with reductions in clinical pain. 66, 67 Additional studies in chronic pain conditions such as fibromyalgia have implicated thalamic FC changes as a potential underlying feature of chronic pain. 68–70 Ichesco et al 68 noted increased THAL-DMN FC was associated with increased pain in patients with chronic pain.…”

Biomarkers, designs, and interpretations of resting‐state fMRI in translational pharmacological research: A review of state‐of‐the‐Art, challenges, and opportunities for studying brain chemistry

“…Cole et al have illustrated that three non‐overlapping seeds, all taken from the posterior part of the default mode network (DMN), produce extensive non‐overlapping cortical connectivity maps [Cole et al, ]. On the plus side, these anatomical variations in network topography help explore the regional specificity of the response of specific brain regions, for example sub‐nuclei of the thalamus [Niesters et al, ], or subsections of the hippocampus [Khalili‐Mahani et al, ], to drugs that are expected to target these regions.…”

“…Using the putamen as a seed, Upadhyay et al showed a dose‐dependent decreases in functional connectivity of the somatosensory and sensorimotor networks [Upadhyay et al, ] under buprenorphine, with a topography that closely resembled an NOI‐based analysis of the morphine effect on these networks in an independent study [Khalili‐Mahani et al, ] prominent effects in the hippocampus and sensorimotor networks. A dose‐dependent increase in functional connectivity of the frontoparietal and thalamocortical regions has been shown to correlate with pain perception in spinal anesthesia using bupivacaine [Niesters et al, ]. A dose‐dependent ketamine‐induced increase in the functional connectivity of the corticohippocampal subnetworks has also been reported concurrent with reduced alertness states [Khalili‐Mahani et al, ].…”

“…GICA/DR and NOI/DR approaches are very common, and they are vastly used in pharma-RSfMRI studies [Boveroux et al, 2010;Cole et al, 2013;Esposito et al, 2013b;Greicius et al, 2008;Guldenmund et al, 2013;Jordan et al, 2013;Khalili-Mahani et al, 2012;Klaassens et al, 2015;Klumpers et al, 2012;Licata et al, 2013;Mueller et al, 2014;Niesters et al, 2012Niesters et al, , 2014Roseman et al, 2014;Tanabe et al, 2011]. Similar to seed-based analysis, NOI/DR-based analyses are easy to standardize and accommodates replication studies, however issues related to nonstationarity of functional networks needs to be further explored (see "Challenges and Limitations").…”

“…A similar analytical approach has been used to explore the effects of psilocybin versus MDMA [Roseman et al, 2014]. The NOI/DR method has been used to study the effects of a single compound on the topography of resting-state networks under PKcontrolled administration of THC [Klumpers et al, 2012;Van Hell et al, 2011], ketamine [Niesters et al, 2012] and bupivacaine [Niesters et al, 2014]. ASL has proven to be a sensitive method for FP studies of alcohol [Khalili-Mahani et al, 2011;Marxen et al, 2014;Strang et al, 2015], opioids [Khalili-Mahani et al, 2011;Kofke et al, 2007;MacIntosh et al, 2008] and THC [Van Hell et al, 2011].…”