Beyond biopsychosocial: The keystone mechanism theory of pain.

Pain is a deeply personal experience, with interindividual differences in its chronification and treatment presenting a formidable healthcare challenge. The biopsychosocial model (BPSm) has been hugely influential within nascent attempts at precision pain medicine, steering the field away from a reductionist biomechanical viewpoint and emphasising complex interactions of biological, psychological, and social factors which shape the individuality of pain. However, despite offering a strong theoretical foundation and holistic perspective, we contend that the BPSm remains limited in its capacity to deliver truly mechanistically informed treatment of pain. We therefore propose the keystone model of pain which offers a pragmatic balance between the dimensionality expansive BPSm and overly reductive approaches, providing both theoretical and practical advantages for the transition from treating populations to individual people.

Harnessing the power of endogenous pain control mechanisms for novel therapeutics: how might innovations in neuroimaging help?

PURPOSE OF REVIEW: This review explores the potential of using novel imaging approaches to deepen our understanding of descending modulatory mechanisms in pain, focussing on functional magnetic resonance imaging (fMRI) of the spinal cord and novel approaches to combining molecular and fMRI data. This review sheds light on the neural processes involved in pain modulation, paving the way for the development of targeted treatments. RECENT FINDINGS: The reviewed literature demonstrates significant advancements in pain research. Recent studies show the potential of using fMRI to investigate the spinal cord's role in pain modulation. Furthermore, novel analytical approaches integrating molecular and fMRI data show promise in elucidating the complex neurobiological processes underlying pain regulation. The main themes explored here include the identification of neurochemical markers associated with pain modulation and the characterisation of neural circuits involved in descending pain control. SUMMARY: A comprehensive understanding of descending modulatory mechanisms in pain can inform the development of novel treatments, targeting dysfunction of these key pathways. By leveraging spinal fMRI and integrating molecular data into brain fMRI, researchers can identify potential therapeutic targets throughout the neuraxis. These advances may contribute to the development of personalised medicine approaches, allowing for tailored interventions based on individual pain profiles.

From neurotransmitters to networks: Transcending organisational hierarchies with molecular-informed functional imaging.

The human brain exhibits complex interactions across micro, meso-, and macro-scale organisational principles. Recent synergistic multi-modal approaches have begun to link micro-scale information to systems level dynamics, transcending organisational hierarchies and offering novel perspectives into the brain's function and dysfunction. Specifically, the distribution of micro-scale properties (such as receptor density or gene expression) can be mapped onto macro-scale measures from functional MRI to provide novel neurobiological insights. Methodological approaches to enrich functional imaging analyses with molecular information are rapidly evolving, with several streams of research having developed relatively independently, each offering unique potential to explore the trans-hierarchical functioning of the brain. Here, we address the three principal streams of research - spatial correlation, molecular-enriched network, and in-silico whole brain modelling analyses - to provide a critical overview of the different sources of molecular information, how this information can be utilised within analyses of fMRI data, the merits and pitfalls of each methodology, and, through the use of key examples, highlight their promise to shed new light on key domains of neuroscientific inquiry.

The effects of propofol anaesthesia on molecular-enriched networks during resting-state and naturalistic listening.

Placing a patient in a state of anaesthesia is crucial for modern surgical practice. However, the mechanisms by which anaesthetic drugs, such as propofol, impart their effects on consciousness remain poorly understood. Propofol potentiates GABAergic transmission, which purportedly has direct actions on cortex as well as indirect actions via ascending neuromodulatory systems. Functional imaging studies to date have been limited in their ability to unravel how these effects on neurotransmission impact the system-level dynamics of the brain. Here, we leveraged advances in multi-modal imaging, Receptor-Enriched Analysis of functional Connectivity by Targets (REACT), to investigate how different levels of propofol-induced sedation alter neurotransmission-related functional connectivity (FC), both at rest and when individuals are exposed to naturalistic auditory stimulation. Propofol increased GABA-A- and noradrenaline transporter-enriched FC within occipital and somatosensory regions respectively. Additionally, during auditory stimulation, the network related to the dopamine transporter showed reduced FC within bilateral regions of temporal and mid/posterior cingulate cortices, with the right temporal cluster showing an interaction between auditory stimulation and level of consciousness. In bringing together these micro- and macro-scale systems, we provide support for both direct GABAergic and indirect noradrenergic and dopaminergic-related network changes under propofol sedation. Further, we delineate a cognition-related reconfiguration of the dopaminergic network, highlighting the utility of REACT to explore the molecular substrates of consciousness and cognition.

Improving neuropathic pain treatment - by rigorous stratification from bench to bedside.

Chronic pain is a constantly recurring and persistent illness, presenting a formidable healthcare challenge for patients and physicians alike. Current first-line analgesics offer only low-modest efficacy when averaged across populations, further contributing to this debilitating disease burden. Moreover, many recent trials for novel analgesics have not met primary efficacy endpoints, which is particularly striking considering the pharmacological advances have provided a range of highly relevant new drug targets. Heterogeneity within chronic pain cohorts is increasingly understood to play a critical role in these failures of treatment and drug discovery, with some patients deriving substantial benefits from a given intervention while it has little-to-no effect on others. As such, current treatment failures may not result from a true lack of efficacy, but rather a failure to target individuals whose pain is driven by mechanisms which it therapeutically modulates. This necessitates a move towards phenotypical stratification of patients to delineate responders and non-responders in a mechanistically driven manner. In this article, we outline a bench-to-bedside roadmap for this transition to mechanistically informed personalised pain medicine. We emphasise how the successful identification of novel analgesics is dependent on rigorous experimental design as well as the validity of models and translatability of outcome measures between the animal model and patients. Subsequently, we discuss general and specific aspects of human trial design to address heterogeneity in patient populations to increase the chance of identifying effective analgesics. Finally, we show how stratification approaches can be brought into clinical routine to the benefit of patients.

Neurotransmitter receptor densities are associated with changes in regional Cerebral blood flow during clinical ongoing pain.

Arterial spin labelling (ASL) plays an increasingly important role in neuroimaging pain research but does not provide molecular insights regarding how regional cerebral blood flow (rCBF) relates to underlying neurotransmission. Here, we integrate ASL with positron emission tomography (PET) and brain transcriptome data to investigate the molecular substrates of rCBF underlying clinically relevant pain states. Two data sets, representing acute and chronic ongoing pain respectively, were utilised to quantify changes in rCBF; one examining pre-surgical versus post-surgical pain, and the second comparing patients with painful hand Osteoarthritis to a group of matched controls. We implemented a whole-brain spatial correlation analysis to explore associations between change in rCBF (ΔCBF) and neurotransmitter receptor distributions derived from normative PET templates. Additionally, we utilised transcriptomic data from the Allen Brain Atlas to inform distributions of receptor expression. Both datasets presented significant correlations of ΔCBF with the µ-opioid and dopamine-D2 receptor expressions, which play fundamental roles in brain activity associated with pain experiences. ΔCBF also correlated with the gene expression distributions of several receptors involved in pain processing. Overall, this is the first study illustrating the molecular basis of ongoing pain ASL indices and emphasises the potential of rCBF as a biomarker in pain research.

Differential contributions of serotonergic and dopaminergic functional connectivity to the phenomenology of LSD.

RATIONALE: LSD is the prototypical psychedelic. Despite a clear central role of the 5HT2a receptor in its mechanism of action, the contributions of additional receptors for which it shows affinity and agonist activity remain unclear. OBJECTIVES: We employed receptor-enriched analysis of functional connectivity by targets (REACT) to explore differences in functional connectivity (FC) associated with the distributions of the primary targets of LSD-the 5HT1a, 5HT1b, 5HT2a, D1 and D2 receptors. METHODS: We performed secondary analyses of an openly available dataset (N = 15) to estimate the LSD-induced alterations in receptor-enriched FC maps associated with these systems. Principal component analysis (PCA) was employed as a dimension reduction strategy for subjective experiences associated with LSD captured by the Altered States of Consciousness (ASC) questionnaire. Correlations between these principal components as well as VAS ratings of subjective effects with receptor-enriched FC were explored. RESULTS: Compared to placebo, LSD produced differences in FC when the analysis was enriched with each of the primary serotonergic and dopaminergic receptors. Altered receptor-enriched FC showed relationships with the subjective effects of LSD on conscious experience, with serotonergic and dopaminergic systems being predominantly associated with perceptual effects and perceived selfhood as well as cognition respectively. These relationships were dissociable, with different receptors showing the same relationships within, but not between, the serotonergic and dopaminergic systems. CONCLUSIONS: These exploratory findings provide new insights into the pharmacology of LSD and highlight the need for additional investigation of non-5HT2a-mediated mechanisms.

Cerebellar involvement in hallucinations may transcend clinical conditions and perceptual modalities.

Our recent neuroimaging study identified structural differences in cerebellar subfields linked to cortical attentional networks in patients with eye disease or Parkinson's disease who experience visual hallucinations and a commentary on the study by Zorzi et al. provided additional evidence of functional cerebellar changes in Dementia with Lewy bodies. Here, we review evidence for cerebellar involvement in hallucinations across multiple clinical conditions and sensory modalities as well as examine its wider clinical and mechanistic implications. The combined structural and functional evidence is consistent with two models of cerebellar contribution to hallucination which differ in their implied direction of cause, effect and temporal sequence. Additionally, we contend that the relatively neuroanatomically localised nature of the cerebellum makes it particularly suited to identifying changes affecting distributed cortical networks using imaging techniques. As such, cerebellar subfield differences may offer value as candidate prognostic and predictive biomarkers as well as targets for neuromodulatory treatment across a range of clinical conditions.

Cerebellar correlates of visual hallucinations in Parkinson's disease and Charles Bonnet Syndrome.

Hallucinations, percepts in the absence of external stimuli, are a shared feature of eye-disease (Charles Bonnet Syndrome, CBS) and Parkinson's disease (PD) thought to arise through pathophysiologically distinct mechanisms: deafferentation and attentional network dysfunction respectively. Recent studies have found an association between visual hallucinations and structural changes in the cerebellum without obvious link to either mechanism. Here, we employed Voxel Based Morphometry (VBM), optimised for the cerebellum using the Spatially Unbiased Infratentorial Template (SUIT), to characterise similarities and differences in cerebellar structure associated with visual hallucinations in PD and CBS. Grey and white matter volume (GMV & WMV) from patients with eye-disease (n = 12 hallucinators; n = 9 non-hallucinators) and PD (n = 7 hallucinators; n = 9 non-hallucinators) was examined in a 2-way ANOVA controlling for age, sex, and intracranial volume. Comparing hallucinators to controls across both groups, lower GMV was found bilaterally within cerebellar lobule VIII extending to IX/VII. GMV reductions were also found in Crus 1, greater in PD than eye-disease. Predominantly within PD, hallucination-related lower WMV was found in the medulla. No regions of increased GMV or WMV were found. A correlation was observed between brainstem WMV and lobule VIIIb GMV suggesting a functional association. Lobule VIII comprises a functional node within the Dorsal Attention Network (DAN), linking these findings to current attentional theories of hallucinations, while Crus 1 is linked to cortical visual processing. These findings provide preliminary evidence of a cerebellar contribution to hallucinations that transcends clinical conditions.

Pain in neurodegenerative diseases with atypical parkinsonism: a systematic review on prevalence, clinical presentation, and findings from experimental studies.

Parkinson's disease-related pain has increasingly been investigated in research studies. Still, only a few studies have addressed the prevalence and clinical characteristics of pain in neurodegenerative disorders with atypical parkinsonism. The existing evidence, although scarce, suggests that, similarly as in Parkinson's disease, individuals with neurodegenerative diseases with atypical parkinsonism might be predisposed to the development of persistent pain. Today, as the global population is aging and we face an epidemic of neurodegenerative disorders, under-treated pain is taking a great toll on an ever-rising number of people. Here, we provide an up-to-date review of the current knowledge on the prevalence of pain, its clinical features, and findings from experimental studies that might signpost altered pain processing in the most prevalent neurodegenerative disorders with atypical parkinsonism: multiple system atrophy, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, and dementia with Lewy bodies. Finally, we point out the current gaps and unmet needs that future research studies should focus on. Large-scale, high-quality clinical trials, coupled with pre-clinical research, are urgently needed to reveal the exact pathophysiological mechanisms underpinning heightened pain and pave the path for mechanistically-driven analgesic interventions to be developed, ultimately leading to an improvement in the quality of life of individuals with neurodegenerative disorders.