Cognitive control is believed to arise from task-dependent interactions among networks of brain regions. Although several debilitating neuropsychiatric disorders are characterized by cognitive network dysfunction, the neural circuit mechanisms supporting task-dependent network activity are largely unknown. External and internal task demands elicit opposing responses from key cognitive networks, and claustrum projections target regions associated with both network states. We tested if claustrum supports task-dependent network activity in humans using fMRI during tasks with externally and internally driven demands: working memory ( n = 420) and autobiographical memory ( n = 35). Claustrum activity increased in both tasks. Claustrum exhibited anatomical connectivity with regions representing all implicated networks, and claustrum effective connectivity suggested an excitatory influence on regions in multiple task-associated networks. Task response and connectivity measures differed between the claustrum and regions prominently implicated in directing network states—the anterior insula and pulvinar. These findings establish a role for the claustrum in supporting task-dependent network states subserving cognitive control.

ABSTRACT:Chronic pain is associated with maladaptive reorganization of brain networks, particularly in the anterior cingulate cortex (ACC), contributing to the affective dimension of pain. Although peripheral capsaicin administration relieves neuropathic pain in clinics, its effects on central pain networks remain unclear. In this study, we determined the resting-state functional connectivity of ACC (ACC FC) rearrangement after infraorbital nerve chronic constriction injury (ION-CCI) and subsequent peripheral administration of capsaicin through longitudinal resting-state functional magnetic resonance imaging (fMRI) in male rats. We also conducted functional silencing of the ACC using inhibitory chemogenetic receptors to determine ACC networks commonly reversed by peripheral capsaicin and chemogenetic silencing. Infraorbital nerve chronic constriction injury produced orofacial mechanical allodynia accompanied by ACC FC changes compared to sham. A single injection of capsaicin into the maxillary skin decreased mechanical allodynia. Five days after capsaicin injection, CCI-enhanced ACC FC was significantly reduced compared to the time point before the injection in the same rats or to the rats with vehicle injection. Subsequent chemogenetic silencing of ACC in the previously vehicle-treated CCI rats reduced mechanical allodynia and suppressed CCI-enhanced ACC FC. Peripheral capsaicin and chemogenetic inhibition of ACC commonly reversed approximately one-third of the CCI-enhanced ACC FC. Affected regions included the bilateral cingulate areas, primary and secondary somatosensory cortex, primary and secondary auditory areas, hippocampus, and temporal association cortex. We conclude that peripheral capsaicin administration reverses maladaptive ACC networks in male rats with nerve injury and that peripheral nociceptors contribute to the maintenance chronic pain and peripherally targeted treatment can produce long-lasting analgesia.

Temporomandibular disorder (TMD) and irritable bowel syndrome (IBS) are two highly comorbid, nociplastic pain conditions that belong to a broader group of commonly co-occurring chronic pain conditions. Most of these chronic overlapping pain conditions (COPCs), including TMD and IBS, disproportionately affect females and are highly stress sensitive. Our previous study illustrated sex differences in brain activity during colorectal distension specific to our model of comorbid pain hypersensitivity (CPH), in which masseter muscle inflammation followed by restraint stress elicits IBS-like visceral hypersensitivity. Since insular cortex (Ins) activity increased in female CPH rats only and abnormal Ins activity has been identified in TMD and IBS patients, we sought to characterize patterns of Ins-based functional connectivity (FC) by performing functional MRI (fMRI) scans at baseline, 1 week, and 7 weeks post-injury/stress in groups of male and female Sprague-Dawley rats randomized to the following conditions: CPH, stress-induced hypersensitivity (SIH), Complete Freund's Adjuvant (CFA)-induced masseter muscle inflammation, and naive. CPH females displayed extensive Ins FC with brain regions in the cortex and limbic system, including the thalamus. Compared to CPH males, CPH females showed robust insular-thalamo connectivity at week seven, a time point where visceral hypersensitivity and referred pain-like behavior persists in CPH females but not males. This trend is also apparent in CPH females' week seven versus week one Ins FC, whereas CPH males tend to decrease Ins FC broadly. These findings potentially suggest sensitization within the insular-thalamo and -cortical networks in CPH females, warranting future investigation of Ins circuit involvement in comorbid pain.

ImportanceBiomarkers would greatly assist decision-making in the diagnosis, prevention, and treatment of chronic pain.ObjectiveTo undertake analytical validation of a sensorimotor cortical biomarker signature for pain consisting of 2 measures: sensorimotor peak alpha frequency (PAF) and corticomotor excitability (CME).Design, Setting, and ParticipantsThis cohort study at a single center (Neuroscience Research Australia) recruited participants from November 2020 to October 2022 through notices placed online and at universities across Australia. Participants were healthy adults aged 18 to 44 years with no history of chronic pain or a neurological or psychiatric condition. Participants experienced a model of prolonged temporomandibular pain with outcomes collected over 30 days. Electroencephalography to assess PAF and transcranial magnetic stimulation (TMS) to assess CME were recorded on days 0, 2, and 5. Pain was assessed twice daily from days 1 through 30.ExposureParticipants received an injection of nerve growth factor (NGF) to the right masseter muscle on days 0 and 2 to induce prolonged temporomandibular pain lasting up to 4 weeks.Main Outcomes and MeasuresThe predictive accuracy of the PAF/CME biomarker signature was determined using a nested control-test scheme: machine learning models were run on a training set (n = 100), where PAF and CME were predictors and pain sensitivity was the outcome. The winning classifier was assessed on a test set (n = 50) comparing the predicted pain labels against the true labels.ResultsAmong the final sample of 150 participants, 66 were female and 84 were male; the mean (SD) age was 25.1 (6.2) years. The winning classifier was logistic regression, with an outstanding area under the curve (AUC = 1.00). The locked model assessed on the test set had excellent performance (AUC = 0.88; 95% CI, 0.78-0.99). Results were reproduced across a range of methodological parameters. Moreover, inclusion of sex and pain catastrophizing as covariates did not improve model performance, suggesting the model including biomarkers only was more robust. PAF and CME biomarkers showed good to excellent test-retest reliability.Conclusions and RelevanceThis study provides evidence for a sensorimotor cortical biomarker signature for pain sensitivity. The combination of accuracy, reproducibility, and reliability suggests the PAF/CME biomarker signature has substantial potential for clinical translation, including predicting the transition from acute to chronic pain.

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.

Chronic pain is associated with reduced cognitive function, potentially due to a diversion of cognitive resources to processing pain. However, reduced cognitive function during pain is not always consistently evidenced, perhaps due to individual differences in the attentional cost of pain processing. In the current electroencephalography investigation, we therefore examined differences in the top-down modulation of oscillatory activity in a cognitive task, between participants who performed better, and worse, during experimentally induced neuropathic-like pain. We employed a cross-modal attention task in which visual cues indicated whether participants needed to judge the visual orientation or discriminate the auditory pitch of an upcoming target. The visual and auditory targets were presented either simultaneously or individually, enabling us to assess the "cost" of having a distractor present in each modality. Participants engaged in the task under two conditions: prolonged pain via the capsaicin-heat pain model, and pain-free. Participants less "costed" by visual distraction during pain demonstrated a greater increase in alpha power (8-12 Hz) over frontal/central electrodes during pain. This may reflect inhibition of regions related to the processing of painful stimuli (somatosensory cortex), which could increase availability of resources to meet task-demands - a possible task-favouring pattern. In conclusion, our results support the notion that better cognitive function during pain is associated with a behavioral strategy.

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 region near the posterior inferior frontal sulcus of the right dorsolateral prefrontal cortex (piDLPFC) in migraine patients during acute pain and cognitive task performance. Dynamic causal modeling suggests a directional influence of the claustrum on activity in this piDLPFC region, and diffusion weighted imaging 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.

Abstract. Introduction:. Previous studies have demonstrated associations between sex and racialized group on pain sensitivity and tolerance. We analyzed the association of sex and racialized group on heat pain sensitivity, sensibility to painful suprathreshold mechanical pain (STMP), and pain sensitivity questionnaire (PSQ). We hypothesized that anxiety and pain catastrophizing reported by racialized minority groups and women would mediate enhanced pain sensitivity. Our secondary aim was to evaluate validity of the PSQ in a diverse population. Methods:. Using quantitative sensory testing for painful heat, STMP (forces: 64, 128, 256, and 512 mN), and PSQ, we evaluated pain sensitivity in 134 healthy participants [34 (18 women) Asian, 25 (13 women) Black, and 75 (41 women) White]. We used general linear and linear mixed models to analyze outcomes. We assessed mediation of state and trait anxiety and pain catastrophizing on pain sensitivity. Results:. Racialized minority status was associated with greater heat pain sensitivity (F = 7.63; P = 0.00074) and PSQ scores (F = 15.45; P = 9.84 × 10−7) but not associated with STMP (F = 1.50; P = 0.23). Female sex was associated with greater heat pain sensitivity (F = 4.9; P = 0.029) and lower PSQ (F = 9.50; P = 0.0025) but not associated with STMP (F = 0.0018; P = 0.97). Neither anxiety nor pain catastrophizing mediated associations between sex or racialized group with heat pain threshold or PSQ. Differential experience of individual items (F = 19.87; P = 3.28 × 10−8) limited PSQ face validity in racialized minorities. Conclusion:. Consistent with previous research, sensitivity to painful heat was associated with racialized minority status and female sex. By contrast, there was no significant effect of racialized minority status or female sex on STMP. Some PSQ items are inapplicable to participants from racialized minority groups.

Knee osteoarthritis (OA) often causes chronic pain that disproportionately affects females. Proinflammatory cytokines TNF-α, IL-1β, and IL-6 are key effectors of OA pathological changes. Green light shows potential as an alternative intervention for various pain conditions. However, no studies have investigated green light′s analgesic effects in both sexes in chronic knee OA. We induced unilateral knee OA with intra-articular injection of monoiodoacetate (MIA) in male and female Sprague-Dawley rats. Two days post-injection, the rats were exposed to green-light-emitting diodes (GLED) or ambient room light eight hours daily for 24 days. Knee mechanical sensitivity was assessed using a small animal algometer. Blood serum concentrations of TNF-α, IL-1β, IL-6, and IL-10 were quantified at baseline and 23 days post-injection. MIA injection decreased the knee mechanical thresholds of the male and female rats. GLED exposure attenuated mechanical hypersensitivity in both sexes compared to the controls; however, GLED-induced analgesia occurred sooner and with greater magnitude in males than in females. In both sexes, the analgesic effects of green light lasted 5 days after the final GLED session. Finally, GLED exposure reversed the elevation of serum proinflammatory cytokines. These findings suggest that GLED exposure reduces primary hyperalgesia in OA, potentially by lowering proinflammatory cytokines, and indicate sex differences in GLED-induced analgesia.

Environmental Enrichment (EE) has been shown to reduce pain- and anxiety-like behaviors, enhance learning and memory, and induce neural plasticity. We have developed a mouse model of comorbid pain hypersensitivity (CPH: stress during preexisting orofacial pain, Complete Freund's Adjuvant (CFA) induced masseter muscle inflammation) and examined the effects of EE on behavioral and brain connectivity changes induced by this model. Eighteen female mice underwent resting-state fMRI scans and were divided into 3 groups: 6 CPH + EE, 6 CPH only, and 6 naive mice. Referred pain (visceral pain correlate) was measured as the increase in responsiveness to von Frey stimulation of the lower abdomen above baseline mechanosensitivity following inflammation and stress. CPH increased referred pain in female mice for at least 4 weeks. EE blocked the referred pain development. Mice placed in an enriched environment exhibited significantly lower insula functional connectivity to the following regions compared to CPH mice without EE: Claustrum, Caudoputamen, Central medial nucleus of the thalamus, Central amygdalar nucleus, medial part (Allen Brain Atlas nomenclature). Additionally, CPH mice with EE show a trend of increased connectivity between insula and periaqueductal gray, which is similarly seen in naive mice compared to CPH group. These results demonstrate that EE can reduce referred pain and functional connectivity of areas involved in pain and stress processing, and may be strengthening the impaired endogenous pain inhibitory system seen in comorbid pain conditions. Funding: We acknowledge the support of the Department of Neural and Pain Sciences, University of Maryland School of Dentistry.

Osteoarthritis (OA) is a leading cause of chronic pain, with more women reporting knee OA-related pain and disability than men. Proinflammatory cytokines—namely tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6)—are key effectors of knee OA pathogenesis. Standard pain interventions for knee OA remain suboptimal. Green light therapy has recently emerged as a safe and accessible nonpharmacological pain intervention, reducing pain in fibromyalgia patients and headache frequency in chronic migraine patients. However, the effects of green light emitting diode (GLED) exposure on a chronic inflammatory condition such as knee OA, especially considering sex as a biological variable, are still unknown. Here, we examined the effects of GLED exposure on pain-like behavior using the small animal algometer (Bioseb) and blood cytokine levels with ELISA in the monoiodoacetate model of knee OA. A single injection of monoiodoacetate (3mg/15µL) into the left knee joint significantly reduced mechanical thresholds of the ipsilateral knee in both male and female Sprague Dawley rats starting one day after injection, consistent with previous findings in this model. GLED exposure attenuated mechanical hyperalgesia in both sexes compared to ambient room light controls; however, this hypoalgesic effect occurred sooner (6 GLED sessions) and with greater magnitude in males than in females. Moreover, GLED exposure prevented the expected increase in pro-inflammatory cytokines TNF-α, IL-1β, and IL-6. These findings suggest that GLED may reduce knee hyperalgesia partly by decreasing circulating pro-inflammatory cytokine levels and that these effects may differ based on sex. Funding: School of Dentistry, UMB.

Positive emotions are a promising target for intervention in chronic pain, but mixed findings across trials to date suggest that existing interventions may not be optimized to efficiently engage the target. The aim of the current mechanistic randomized controlled trial was to test the effects of a single skill positive emotion-enhancing intervention called Savoring Meditation on pain-related neural and behavioral targets in patients with rheumatoid arthritis (RA). Participants included 44 patients with a physician-confirmed diagnosis of RA (n=29 included in fMRI analyses), who were randomized to either Savoring Meditation or a Slow Breathing control. Both meditation interventions were brief (four 20-minute sessions). Self-report measures were collected pre- and post-intervention. An fMRI task was conducted at post-intervention, during which participants practiced the meditation technique on which they had been trained while exposed to non-painful and painful thermal stimuli. Relative to Slow Breathing, Savoring significantly reduced experimental pain intensity ratings relative to rest (p<.001), increased cerebral blood flow in the ventromedial prefrontal cortex (vmPFC) and increased connectivity between the vmPFC and caudate during noxious thermal stimulation (z=2.3 voxelwise, FDR cluster corrected p=0.05). Participants in the Savoring condition also reported significantly increased positive emotions (ps<.05) and reduced anhedonic symptoms (p<.01) from pre- to post-intervention. These findings suggest that that Savoring recruits reward-enhancing corticostriatal circuits in the face of pain, and future work should extend these findings to evaluate if these mechanisms of Savoring are associated with improved clinical pain outcomes in diverse patient populations.

The relationship between the 8-12 Hz “alpha: rhythm, the predominant oscillatory activity of the brain, and pain remains unclear. In healthy individuals, acute, noxious stimuli suppress alpha power while patients with chronic pain demonstrate both enhanced alpha power and slowing of the peak alpha frequency (PAF). To investigate these apparent differences, EEG was recorded from healthy individuals while they completed two models of prolonged pain, Phasic Heat Pain and Capsaicin Heat Pain, at two testing visits occurring roughly 8 weeks apart. We report that PAF is reliably slowed and that alpha power is reliably decreased in response to prolonged pain. Furthermore, we show that alpha power changes, but not PAF changes, are fully reversed with stimulus removal suggesting that PAF slowing reflects pain associated states such as sensitization rather than the presence of ongoing pain. Finally, we provide evidence that changes to alpha power and PAF are due to power decreases in the “fast” (10-12 Hz) range of the alpha rhythm. This frequency dependent pain response aligns with the hypothesis that the alpha rhythm is composed of multiple, independent oscillators, and suggest that modulation of a putative “fast” oscillator may represent a promising therapeutic target for treating ongoing pain. In sum, we provide strong evidence that PAF is reliably slowed during prolonged pain and additionally identify a mechanism, “fast” alpha Power, which is responsible for these PAF changes.