Disrupted Brain Circuitry for Pain‐Related Reward/Punishment in Fibromyalgia

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102040/1/art38191.pd

Effects of the glial modulator palmitoylethanolamide on chronic pain intensity and brain function.

Background: Chronic neuropathic pain (NP) is a complex disease that results from damage or presumed damage to the somatosensory nervous system. Current treatment regimens are often ineffective. The major impediment in developing effective treatments is our limited understanding of the underlying mechanisms. Preclinical evidence suggests that glial changes are crucial for the development of NP and a recent study reported oscillatory activity differences within the ascending pain pathway at frequencies similar to that of cyclic gliotransmission in NP. Furthermore, there is evidence that glial modifying medications may be effective in treating NP. The aim of this Phase I open-label clinical trial is to determine whether glial modifying medication palmitoylethanolamide (PEA) will reduce NP and whether this is associated with reductions in oscillatory activity within the pain pathway. Methods: We investigated whether 6 weeks of PEA treatment would reduce pain and infra-slow oscillatory activity within the ascending trigeminal pathway in 22 individuals (17 females) with chronic orofacial NP. Results: PEA reduced pain in 16 (73%) of the 22 subjects, 11 subjects showed pain reduction of over 20%. Whilst both the responders and non-responders showed reductions in infra-slow oscillatory activity where orofacial nociceptor afferents terminate in the brainstem, only responders displayed reductions in the thalamus. Furthermore, functional connections between the brainstem and thalamus were altered only in responders. Conclusion: PEA is effective at relieving NP. This reduction is coupled to a reduction in resting oscillations along the ascending pain pathway that are likely driven by rhythmic astrocytic gliotransmission

A preliminary fMRI study of analgesic treatment in chronic back pain and knee osteoarthritis

The effects of an analgesic treatment (lidocaine patches) on brain activity in chronic low back pain (CBP) and in knee osteoarthritis (OA) were investigated using serial fMRI (contrasting fMRI between before and after two weeks of treatment). Prior to treatment brain activity was distinct between the two groups: CBP spontaneous pain was associated mainly with activity in medial prefrontal cortex, while OA painful mechanical knee stimulation was associated with bilateral activity in the thalamus, secondary somatosensory, insular, and cingulate cortices, and unilateral activity in the putamen and amygdala. After 5% lidocaine patches were applied to the painful body part for two weeks, CBP patients exhibited a significant decrease in clinical pain measures, while in OA clinical questionnaire based outcomes showed no treatment effect but stimulus evoked pain showed a borderline decrease. The lidocaine treatment resulted in significantly decreased brain activity in both patient groups with distinct brain regions responding in each group, and sub-regions within these areas were correlated with pain ratings specifically for each group (medial prefrontal cortex in CBP and thalamus in OA). We conclude that the two chronic pain conditions involve distinct brain regions, with OA pain engaging many brain regions commonly observed in acute pain. Moreover, lidocaine patch treatment modulates distinct brain circuitry in each condition, yet in OA we observe divergent results with fMRI and with questionnaire based instruments

Developing and characterising imaging biomarkers for pain and analgesia

There is a need to improve translation of novel pain treatments from pre-clinical to clinical research, and the development of objective standardised biomarkers to verify target engagement is a vital step towards this goal. Features of chronic pain conditions, such as central sensitisation, can be experimentally induced in healthy humans. Functional magnetic resonance imaging (fMRI) is a highly valuable method to explore the neural basis for pain and also analgesic activity. This thesis combines these two research tools to develop and characterise neuroimaging biomarkers for pain and analgesia. The first chapter consists of a systematic literature review, evidencing that this combination of techniques has provided a wealth of information about brain activity during pain states and analgesia. Co-ordinate based meta-analysis conducted to summarise results for a simple comparison between the neural responses during experimental hyperalgesia compared to control showed activation clusters in the insula cortex and thalamus. Next, exploratory analysis of early 7 Tesla MRI data was conducted to investigate the neural changes that occur during the onset of central sensitisation. Conclusions were limited due to a low sample size, but there were interesting results showing increased blood oxygen-level dependent (BOLD) response in the insula and in the nucleus cuneiformis, a brainstem region shown to be specific to maintenance of central sensitisation. The remaining three chapters comprise primary results and exploratory analysis from the IMI- PainCare BioPain RCT4 trial. The trial utilises the high frequency stimulation (HFS) model to induce central sensitisation, the neural basis for which had not previously been studied using fMRI. Comparison between pre-HFS and post-HFS data showed that the neural basis for HFS-induced central sensitisation was aligned to that seen with the well-characterised capsaicin model in imaging studies. Subsequently, analysis of the main trial endpoints was conducted, to investigate the effects of lacosamide, pregabalin and tapentadol on biomarkers of pain processing observed by fMRI. Pregabalin reduced the punctate-evoked BOLD response in the posterior insula cortex. Lacosamide modulated resting state functional connectivity between the thalamus and secondary somatosensory cortex. In whole-brain analyses, tapentadol modulated responses in areas relevant to pain processing such as the anterior insula cortex. Finally, exploratory analysis was conducted to characterise the placebo effect in the trial, showing that during placebo analgesia changes in brain activity were observed in regions associated with pain perception, including the insula and anterior cingulate cortices, and regions involved in affective and cognitive aspects of pain processing, such as the amygdala and dorsolateral prefrontal cortex. Overall, this work comprises a valuable contribution to increase the utility and standardisation of applying experimental models in conjunction with fMRI in the assessment of novel analgesics prior to large scale clinical trials. As evidenced in the systematic review, individual fMRI studies are highly informative, but lack of standardisation makes comparison between studies difficult. The BioPain work addresses this challenge, providing a standardised assessment of multiple drugs across many pain biomarkers, demonstrating how these biomarkers can be valuably employed in drug development

A comparative fMRI meta-analysis of altruistic and strategic decisions to give

The decision to share resources is fundamental for cohesive societies. Humans can be motivated to give for many reasons. Some generosity incurs a definite cost, with no extrinsic reward to the act, but instead provides intrinsic satisfaction (labelled here as 'altruistic' giving). Other giving behaviours are done with the prospect of improving one's own situation via reciprocity, reputation, or public good (labelled here as 'strategic' giving). These contexts differ in the source, certainty, and timing of rewards as well as the inferences made about others' mental states. We executed a combined statistical map and coordinate-based fMRI meta-analysis of decisions to give (36 studies, 1150 participants). Methods included a novel approach for accommodating variable signal dropout between studies in meta-analysis. Results reveal consistent, cross-paradigm neural correlates of each decision type, commonalities, and informative differences. Relative to being selfish, altruistic and strategic giving activate overlapping reward networks. However, strategic decisions showed greater activity in striatal regions than altruistic choices. Altruistic giving, more than strategic, activated subgenual anterior cingulate cortex (sgACC). Ventromedial prefrontal cortex (vmPFC) is consistently involved during generous decisions and processing across a posterior to anterior axis differentiates the altruistic/strategic context. Posterior vmPFC was preferentially recruited during altruistic decisions. Regions of the 'social brain' showed distinct patterns of activity between choice types, reflecting the different use of theory of mind in the two contexts. We provide the consistent neural correlates of decisions to give, and show that many will depend on the source of incentives

Author response

Previously we observed differential activation in individual columns of the periaqueductal grey (PAG) during breathlessness and its conditioned anticipation (Faull et al., 2016). Here, we have extended this work by determining how the individual columns of the PAG interact with higher cortical centres, both at rest and in the context of breathlessness threat. Activation was observed in ventrolateral PAG (vlPAG) and lateral PAG (lPAG), where activity scaled with breathlessness intensity ratings, revealing a potential interface between sensation and cognition during breathlessness. At rest the lPAG was functionally correlated with cortical sensorimotor areas, conducive to facilitating fight/flight responses, and demonstrated increased synchronicity with the amygdala during breathlessness. The vlPAG showed fronto-limbic correlations at rest, whereas during breathlessness anticipation, reduced functional synchronicity was seen to both lPAG and motor structures, conducive to freezing behaviours. These results move us towards understanding how the PAG might be intricately involved in human responses to threat