Biology subjects

Moayedi, M.

Publications and source records attributed to Moayedi, M..

14 recordsLinked to original sources

bioRxiv2026

LENS: a transferable neuromuscular signature of musculoskeletal pain intensity

Self-reported pain remains the clinical standard for assessing musculoskeletal pain severity, but its subjectivity limits objective diagnosis, monitoring, and therapeutic development. We present LENS (Latent sEMG Neuromuscular Signature), which decodes exertion-evoked musculoskeletal pain intensity from surface electromyography (sEMG) alone. LENS was pre-trained via a cross-modal self-supervised objective that reconstructs muscle oxygenation from sEMG in 183 adults. LENS was trained exclusively on healthy muscle physiology and generalized to an independent healthy cohort (Spearman's {rho}=0.52) and discriminated moderate-to-severe pain (AUROC=0.83). Using a label-free test-time adaptation, LENS generalized to an unseen chronic musculoskeletal pain cohort--myogenous temporomandibular disorder (mTMD)--with comparable performance ({rho}=0.61; AUROC=0.86). Reverse transfer, from mTMD to controls, was substantially weaker, an asymmetry attributable to elevated motor variability in chronic pain; excluding highly variable mTMD participants recovered performance, indicating a conserved pain signature masked by pathology-specific motor noise. LENS offers a scalable, physiological correlate of musculoskeletal pain from a single sEMG channel.

neuroscience↗

bioRxiv2026

The Endocannabinoid System's Contribution to Placebo Analgesia

Placebo analgesia--pain reduction from inert treatments--varies widely across individuals, yet its neurochemical basis remains poorly understood. While endogenous opioids, specifically {beta}-endorphin, contribute to placebo effects, mu-opioid receptor blockade does not fully abolish analgesia, implicating additional systems. Here, we investigate the endogenous cannabinoid (eCB) systems contribution to placebo analgesia in 48 healthy adults using a validated placebo paradigm with blood sampling. We quantified circulating levels of eCB ligands and {beta}-endorphin at baseline, as well as before and after placebo and control conditions to determine condition-related changes. Individual differences in placebo analgesia were associated with increases in fatty acid amide hydrolase (FAAH) substrates--a composite of anandamide, palmitoylethanolamide, and oleoylethanolamide--but not 2-arachidonoylglycerol or {beta}-endorphin alone. Critically, {beta}-endorphin moderated this relationship: FAAH substrates were strongly associated with pain reduction only when {beta}-endorphin levels were low. These findings provide evidence that eCB and opioid systems interact in a state-dependent manner during placebo analgesia in humans, with implications for understanding individual variability in treatment responses.

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bioRxiv2025

Exploring the Neural Correlates of Body Perception Disturbance with a Visual Hand Morph Illusion in Complex Regional Pain Syndrome: An fMRI study

Complex regional pain syndrome (CRPS) is a debilitating chronic pain condition whose causal mechanisms remain poorly understood. Individuals with CRPS often experience distorted perceptions of their affected limb in terms of size and shape, accompanied by feelings of dislike and disownership-- collectively referred to as body perception disturbances (BPD). Evidence that both BPD and pain can rapidly reduce following a visual hand morph illusion suggests modulation of central body representations. To elucidate the neural correlates underlying these rapid perceptual changes, we investigated brain activity during the hand morph illusion using functional magnetic resonance imaging (fMRI). Forty-four participants (22 with upper limb CRPS, 22 pain-free controls) completed the hand morph illusion task during fMRI and provided trial-by-trial ratings of ownership, likeability, and pain of their affected hand. People with CRPS showed greater activation of the left premotor cortex (PMC) during the illusion compared with controls. Functional connectivity between the left PMC and right extrastriate body area (EBA) was also revealed in CRPS during the illusion. No main effects of the illusion, relative to a sham condition, were found on pain intensity, limb ownership, or likeability ratings. These findings provide the first identification of neural correlates of body perception disturbance in CRPS, implicating PMC-EBA networks in altered body representation. Further neuroimaging research is required to define the neural signature underlying this disturbance.

neuroscience↗

bioRxiv2025

The Contribution of Circulating Endocannabinoid Tone to Individual Differences in Human Pain Sensitivity: A Quantitative Sensory Testing Study

The endocannabinoid (eCB) system--comprising cannabinoid receptors, eCBs (anandamide-- AEA, 2-arachidonoylglycerol--2-AG) and related N-acylethanolamines (NAEs; N-palmitoylethanolamide--PEA, and N-oleoylethanolamide--OEA), and metabolizing enzymes (e.g., fatty acid amide hydrolase; FAAH)--modulates nociceptive circuits in rodents. In humans, the FAAH C385A polymorphism is associated with reduced pain sensitivity, suggesting eCB tone influences individual pain differences, but this has yet to be tested. Here, we determined whether the eCB system is associated with somatosensory and pain sensitivity measured with quantitative sensory testing (QST) in 91 healthy participants (39 males, 52 females). We tested three hypotheses: (1) FAAH C385A polymorphism, cannabis use, and sex affect serum eCB/NAE concentrations; (2) FAAH C385A carriers show altered pain sensitivity versus non-carriers; and (3) baseline serum eCB/NAE concentrations are associated with QST measures. eCB/NAE concentrations were not statistically different based on sex (p > .05), based on FAAH genotype (p > .05), and based on cannabis use (p > .05). To address collinearity of AEA, OEA and PEA, we performed a principal components analysis, which identified a single component of FAAH substrates. Linear regressions found that FAAH genotype did not affect QST measures and that baseline 2-AG and FAAH substrate concentrations were not associated with QST measures, except pressure pain thresholds (PPT; p = 0.003), which were associated with AEA and OEA. Baseline eCB/NAE levels and FAAH genotype are not associated with the outcome measures of standard QST tests that rely on point estimates in healthy adult humans; nonetheless, circulating FAAH substrate levels were associated with PPT.

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bioRxiv2025

Functional connectivity differences in adult's ADHD - a MEG study

The neurobiology of adult Attention-Deficit/Hyperactivity Disorder (ADHD), particularly functional brain network connectivity, remain poorly understood. Magnetoencephalography (MEG) can reveal frequency-specific network dynamics given its high temporal resolution. Here, we investigated intrinsic functional connectivity differences between adults with ADHD (n = 24) and healthy controls (n = 44) using MEG data from the Open MEG Archive (OMEGA) dataset. We employed source reconstruction (Destrieux atlas), weighted phase-lag index (wPLI) connectivity across six frequency bands, graph theory metrics (Characteristic Path Length (CPL), node strength, clustering coefficient), and network-based statistics (NBS). We observed widespread hypo-connectivity in the high-gamma band (50-150 Hz) in adults with ADHD compared to controls. NBS identified a significant high-gamma sub-network, predominantly involving dorsal and ventral attention networks (DAN/VAN) and default mode network (DMN) nodes centered around a left fusiform gyrus hub, where all constituent connections exhibited consistently lower connectivity in the ADHD group. Globally, this was reflected in reduced gamma network integration (longer CPL) within the DAN and VAN. Locally, reduced high-gamma clustering was observed in VAN nodes (e.g., insula) and reduced node strength in a DAN region (postcentral sulcus). Predictive modeling using ElasticNet regression confirmed the importance of high-gamma metrics, with CPL measures yielding moderate classification accuracy (AUC {approx} 0.70-0.73). In contrast to high-gamma findings, the alpha band showed increased integration (shorter CPL) within the DMN and between the VAN and DAN in the ADHD group, alongside differences in alpha and beta band node properties in cingulate and somatomotor regions. Our findings reveal robust, frequency-dependent functional network alterations in adult ADHD, particularly highlighting disrupted high-frequency communication within and between key cognitive networks.

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bioRxiv2025

The human claustrum initiates networks for externally and internally driven task demands.

Cognitive control is believed to arise from interactions among multiple brain networks depending on task demands. Although several debilitating neuropsychiatric disorders are characterized by cognitive network dysfunction, the neural circuit mechanisms supporting task-dependent network activation are largely unknown. Because the claustrum possesses widespread connections with cortex and can synchronize distant cortical regions, we tested whether the claustrum activates task-dependent network states using fMRI during working memory (n = 420) and autobiographical memory (n = 35), tasks which elicit opposing responses from key cognitive control networks. In both tasks, the claustrum exhibited increased activity and excitatory influence on task-associated cognitive control network nodes, with corroborating underlying structural connectivity. The claustrum also displayed stronger excitatory effective connectivity during task performance and greater structural connectivity with task-related network nodes than regions prominently implicated in directing network states--the anterior insula and pulvinar. These findings establish a role for the claustrum in initiating network states for cognitive control. SignificanceCognitive functioning is supported by large-scale networks across the brain. Yet, the neural circuit mechanisms supporting task-dependent network activation are largely unknown. Circuit analyses using human functional and structural neuroimaging in this study found that the claustrum, a subcortical nucleus, activates during multiple cognitive tasks eliciting a wide range of network states, possesses strong anatomical connections with cognitive control network nodes, and exerts excitatory influence on task-associated network regions. These results establish the claustrum as a network activator subserving cognitive control.

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bioRxiv2025

The Thermal Grill Elicits Central Sensitization

The thermal grill, in which innocuous warm and cool stimuli are interlaced, can produce a paradoxical burning pain sensation--the thermal grill illusion (TGI). While the mechanisms underlying TGI remain unclear, prominent theories point to spinal dorsal horn integration of innocuous thermal inputs to elicit pain. It remains unknown whether the TGI activates peripheral nociceptors, or solely thermosensitive afferents integrated within the spinal cord. Different types of sensitization have established mechanisms and can inform TGI mechanisms: if the TGI elicits (1) primary hyperalgesia, peripheral nociceptors are likely be activated; (2) secondary hyperalgesia without primary hyperalgesia, spinal integration is likely required; and (3) brush allodynia, wide-dynamic range neurons could be involved in mediating the TGI. Here, we determine whether the TGI elicits primary hyperalgesia, secondary hyperalgesia or brush allodynia. Fifty-two participants underwent individually calibrated phasic thermal grill stimulation. We found that the calibrated TGI elicited primary hyperalgesia, but only in participants with component temperatures in the noxious range (<19{degrees}C and >41{degrees}C). The TGI also elicited secondary hyperalgesia, even in participants with strictly innocuous thermal inputs. No participants developed brush allodynia. We observed sex differences in primary hyperalgesia: only males exhibited thermal grill-induced primary hyperalgesia. These findings suggest that the TGI is integrated in the spinal dorsal horn, potentially mediated by heat-pinch-cold (HPC) neurons, and, to some degree, by primary nociceptive afferents in males. This study shows that the calibrated TGI may have sex-dependent mechanisms and determines that HPC cells are involved in the illusory sensation of pain from innocuous thermal inputs.

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bioRxiv2024

It's the Sound not the Pulse: Peripheral Magnetic Stimulation Reduces Central Sensitization through Auditory Modulatory Effects

Repetitive peripheral magnetic stimulation (rPMS) is a non-pharmacological, non-invasive analgesic modality with limited side effects. However, there is a paucity of controlled studies demonstrating its efficacy compared to existing pain management tools. Here, in an initial sample of 100 healthy participants (age 18-40), we compared the analgesic efficacy of two rPMS stimulation protocols--continuous theta burst stimulation (ctbPMS) and intermittent TBS (itbPMS)--against transcutaneous electric nerve stimulation (TENS), a peripheral stimulation technique that is commonly used for pain management. We also included a sham rPMS protocol where participants heard the sound of rPMS stimulation while the coil was placed over their arm, but received no peripheral stimulation. We hypothesized that itbPMS and ctbPMS--but not sham--would reduce pain intensity, pain unpleasantness, and secondary hyperalgesia evoked by a phasic heat pain (PHP) paradigm on the volar forearm with similar efficacy to TENS. Neither rPMS nor TENS reduced reported pain intensity or unpleasantness (p>0.25). However, ctbPMS and itbPMS significantly reduced the area of secondary hyperalgesia, whereas TENS did not (F3,96= 4.828, p= 0.004). Unexpectedly, sham rPMS, which involved auditory but no peripheral nerve stimulation, also significantly reduced secondary hyperalgesia compared to TENS. We performed a second study (n=32) to investigate auditory contributions to rPMS analgesia. Masking the rPMS stimulation sound with pink noise eliminated its analgesic effect on secondary hyperalgesia (p=0.5). This is the first study to show that the analgesic properties of rPMS in acute experimental pain may be largely attributed to its auditory component rather than peripheral nerve stimulation.

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bioRxiv2024

Subjective salience ratings are a reliable proxy for physiological measures of arousal

Pain is an inherently salient multidimensional experience that signals potential bodily threats and promotes nocifensive behaviours. Any stimulus can be salient depending on its features and context. This poses a challenge in delineating pain-specific processes in the brain, rather than salience-driven activity. It is thus essential to salience match control (innocuous) stimuli and noxious stimuli, to remove salience effects, when aiming to delineate pain-specific mechanisms. Previous studies have salience-matched either through subjective salience ratings or the skin conductance response (SCR). The construct of salience is not intuitive, and thus matching through self-report poses challenges. SCR is used as a proxy measure that captures physiological arousal, which overcomes the nebulous construct of salience. However, SCR cannot be used to salience-match in real-time (i.e., during an experiment) and assumes an association between salience and physiological arousal elicited by painful and non-painful stimuli, but this has not been explicitly tested. To determine whether salience and physiological arousal are associated, thirty-five healthy adults experienced 30 heat pain and 30 non-painful electric stimuli of varying intensities. Stimuli were subjectively matched for salience and SCR was measured to each presentation. A linear mixed model found no differences in SCR between salience-matched heat and electric stimuli. A mediation analysis showed that salience fully mediated the relationship between stimulus intensity and SCR (proportion mediated=83%). In conclusion, salience and physiological arousal are associated, and subjective salience ratings are a suitable for salience-matching pain with non-painful stimuli. Future work can thus use subjective salience ratings to delineate pain-specific processes.

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bioRxiv2023

Pathological claustrum activity drives aberrant cognitive network processing in human chronic pain

Aberrant cognitive network activity and cognitive deficits are established features of chronic pain. However, the nature of cognitive network alterations associated with chronic pain and their underlying mechanisms require elucidation. Here, we report that the claustrum, a subcortical nucleus implicated in cognitive network modulation, is activated by acute painful stimulation and pain-predictive cues in healthy participants. Moreover, we discover pathological activity of the claustrum and a lateral aspect of the right dorsolateral prefrontal cortex (latDLPFC) in migraine patients. Dynamic causal modeling suggests a directional influence of the claustrum on activity in this latDLPFC region, and diffusion weighted imaging (DWI) verifies their structural connectivity. These findings advance understanding of claustrum function during acute pain and provide evidence of a possible circuit mechanism driving cognitive impairments in chronic pain.

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bioRxiv2023

Delineation of the Trigeminal-Lateral Parabrachial-Central Amygdala Tract in Humans: An Ultra-High Field Diffusion MRI Study

Orofacial pain is thought to be more unpleasant than pain elsewhere in the body due to the importance of the face in social, feeding, and exploratory behaviors. Nociceptive information from the orofacial region is carried to the brain via the trigeminal nerve (CNV) via the trigeminal brainstem sensory nuclear complex (VBSNC). Pre-clinical evidence revealed a monosynaptic circuit from CNV to the lateral parabrachial nucleus (latPB), which underlies the greater unpleasantness elicited by orofacial pain. The latPB further projects to the central amygdala (CeA), which contributes to the affective component of pain in rodents. However, this circuit has yet to be delineated in humans. Here, we aimed to resolve this circuit using 7T diffusion-weighted imaging from the Human Connectome Project (HCP). We performed probabilistic tractography in 80 participants to resolve the CNV-latPB-CeA circuit. The basolateral amygdala (BLAT) was used as a negative control, given that we did not anticipate CNV-latPB-BLAT connectivity. Connectivity strengths were compared using a repeated-measures ANOVA with factors hemisphere (left; right), and target (CeA; BLAT), with sex included in the model for both pilot and validation samples. Only the target factor was significant in both samples (FPilot = 11.4804, p = 0.005; FValidation = 69.113, p < .001). Post hoc tests showed that the CeA had significantly stronger connectivity strength than the BLAT (pTukey-Pilot = 0.005; pTukey-Validation < 0.001). {square}This study delineates the human CNV-latPB-CeA circuit for the first time in vivo. This circuit may provide a neuroanatomical substrate for the affective dimensions of orofacial pain. SUMMARYThis study delineates the human trigeminal-parabrachio-amygdalar circuit in vivo. This circuit may provide a neuroanatomical substrate for the affective dimension of orofacial pain.

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bioRxiv2020

The structural and functional connectivity neural underpinnings of body image

How we perceive our bodies is fundamental to our self-consciousness and our experience in the world. There are two types interrelated internal body representations--a subjective experience of the position of a limb in space (body schema) and the subjective experience of the shape and size of the limb (body image). Body schema has been extensively studied, but there is no evidence of the brain structure and network dynamics underpinning body image. Here, we provide the first evidence for the extrastriate body area (EBA), a multisensory brain area, as the structural and functional neural substrate for body shape and size. We performed a multisensory finger-stretch illusion that elongated the index finger. EBA volume and functional connectivity to the posterior parietal cortex are both related to the participants susceptibility to the illusion. Taken together, these data suggest that EBA structure and connectivity encode body representation and body perception disturbances.

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bioRxiv2020

Resting-State Functional Connectivity Predicts Individual Pain Ratings to a Tonic Orofacial Pain Stimulus

Pain is a subjective experience with significant individual differences. Laboratory studies investigating pain thresholds and experimental acute pain have identified structural and functional neural correlates. However, these types of pain stimuli have limited ecological validity to real-life pain experiences. Here, we use an orthodontic procedure--the insertion of an elastomeric separator between teeth--which typically induces mild to moderate pain that peaks within 2 days and lasts several days. We aimed to determine whether the baseline structure and resting-state functional connectivity (rsFC) of key regions along the trigeminal nociceptive and pain modulatory pathways correlate with subsequent peak pain ratings. Twenty-six healthy individuals underwent structural and resting-state functional (rs-fMRI) scanning prior to the placement of a separator between the first and second molars, which was kept in place for five days. Participants recorded pain ratings three times daily on a 100-mm visual analogue scale. Peak pain was not significantly correlated with diffusion metrics of the trigeminal nerve, or grey matter volume of any brain region. Peak pain did, however, positively correlate with baseline rsFC between the thalamus contralateral to the separator and bilateral insula, and negatively correlated with connectivity between the periaqueductal gray (PAG) and core nodes of the default mode network (medial prefrontal and posterior cingulate cortices). The ascending (thalamic) nociceptive and the descending (PAG) pain modulatory pathways at baseline each explained unique variation in peak pain intensity ratings. In sum, pre-interventional functional neural architecture of both systems determined the individual pain experience to a subsequent ecologically valid pain stimulus.

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bioRxiv2019

Ultra-low frequency neural entrainment to pain

Nervous systems exploit regularities in the sensory environment to predict sensory input and adjust behavior, and thereby maximize fitness. Entrainment of neural oscillations allows retaining temporal regularities of sensory information, a prerequisite for prediction. Entrainment has been extensively described at the frequencies of periodic inputs most commonly present in visual and auditory landscapes (e.g. >1 Hz). An open question is whether neural entrainment also occurs for regularities at much longer timescales. Here we exploited the fact that the temporal dynamics of thermal stimuli in natural environment can unfold very slowly. We show that ultra-low frequency neural oscillations preserved a long-lasting trace of sensory information through neural entrainment to periodic thermo-nociceptive input as low as 0.1 Hz. Importantly, revealing the functional significance of this phenomenon, both power and phase of the entrainment predicted individual pain sensitivity. In contrast, periodic auditory input at the same ultra-low frequency did not entrain ultra-low frequency oscillations. These results demonstrate that a functionally-significant neural entrainment can occur at temporal scales far longer than those commonly explored. The non-supramodal nature of our results suggests that ultra-low frequency entrainment might be tuned to the temporal scale of the statistical regularities characteristic of different sensory modalities.

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