Biology subjects

Keaser, M. L.

Publications and source records attributed to Keaser, M. L..

8 recordsLinked to original sources

bioRxiv2026

Sex-dependent changes in insular cortex connectivity in a rat model of comorbid pain

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 Freunds 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.

neuroscience↗

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.

neuroscience↗

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.

neuroscience↗

bioRxiv2021

Prolonged tonic pain in healthy humans enhances functional connectivity of descending pain modulation networks involving the amygdala, periaqueductal gray and parabrachial nucleus to cortical sensory-discriminative areas

IntroductionResting state functional connectivity (FC) is widely used to assess functional brain alterations in patients with chronic pain. However, reports of FC changes accompanying tonic pain in pain-free persons is rare. A brain network disrupted during chronic pain is a network we term the Descending Pain Modulatory Network (DPMN). Here, we evaluate the effect of tonic pain on FC of this network: anterior cingulate cortex (ACC), amygdala (AMYG), periaqueductal gray (PAG), and parabrachial nuclei (PBN). MethodsIn 50 pain-free participants (30F), we induced tonic pain using a capsaicin-heat pain model. We used functional MRI to measure resting BOLD signal during pain-free rest where participants experienced warmth and tonic pain where participants experienced the same temperature thermode combined with capsaicin. We evaluated FC from ACC, AMYG, PAG, and PBN with correlation of self-report pain intensity with FC during both states. We hypothesized tonic pain would disrupt FC dyads within the DPMN. We used partial correlation to determine FC correlated with pain intensity and BOLD signal. ResultsOf hypothesized FC dyads, PAG and subgenual ACC was weakly disrupted during tonic pain (F=3.34; p=0.074; pain-free>pain d=0.25). sgACC-PAG FC became positively related to pain intensity (R=0.38; t=2.81; p=0.007). Right PBN-PAG FC during pain-free rest positively correlated with subsequently experienced pain (R=0.44; t=3.43; p=0.001). During tonic pain, FC of this connection was abolished (paired t=-3.17; p=0.0026). During pain-free rest, FC between left AMYG and right superior parietal lobule and caudate nucleus were positively correlated with subsequent pain. During tonic pain, FC between left AMYG and right inferior temporal and superior frontal gyri negatively correlated with pain. Subsequent pain positively correlated with right AMYG FC and right claustrum; left and right primary visual cortex; right middle temporal gyrus and right temporo-occipitoparietal junction. Finally, subsequent pain positively correlated with PAG FC and left cerebellum, left dorsolateral prefrontal, right posterior cingulate cortex and paracentral lobule, inferior parietal lobule, medial precuneus and PBN. ConclusionWe demonstrate 1) tonic pain weakly disrupts of sgACC-PAG FC; 2) sgACC-PAG tonic pain FC positively correlates with pain; 3) right PBN-PAG FC predicts subsequent pain and is abolished during tonic pain. Finally, we reveal PAG- and right AMYG-anchored networks which predict intensity of tonic pain. Our findings suggest specific connectivity patterns within the DPMN at rest predict experienced pain and are modulated by tonic pain. These nodes and their functional modulation may reveal new therapeutic targets for neuromodulation and biomarkers to guide interventions. HighlightsO_LIParabrachial-periaqueductal gray (PAG) functional connectivity (FC) predicts pain C_LIO_LISubgenual anterior cingulate cortex-PAG FC correlates with pain during tonic pain C_LIO_LIPAG- and amydalocortical networks at rest predict tonic pain intensity C_LIO_LIResting FC of PAG supports cortical targets of neuromodulation to control pain C_LI

neuroscience↗

bioRxiv2021

Prolonged Pain Reliably Slows Peak Alpha Frequency by Reducing Fast Alpha Power

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.

neuroscience↗

bioRxiv2021

Three Dimensions of Association Link Migraine Symptoms and Functional Connectivity

Migraine is a heterogeneous disorder with variable symptoms and responsiveness to therapy. Due to previous analytic shortcomings, variance in migraine symptoms has been weakly and inconsistently related to brain function. Taking advantage of neural network organization measured through resting-state functional connectivity (RSFC) and advanced statistical analysis, sophisticated symptom-brain mapping can now be performed. In the current analysis we used data from two sites (n=102 and 41), and performed Canonical Correlation Analysis (CCA), relating RSFC with a broad range of migraine symptoms ranging from headache characteristics to sleep abnormalities. This identified three dimensions of covariance between symptoms and RSFC. Importantly, none of these dimensions bore any relationship with subject motion. The first dimension was related to headache intensity, headache frequency, pain catastrophizing, affect, sleep disturbances, and somatic abnormalities, and was associated with frontoparietal and dorsal attention network connectivity, both of which are major cognitive networks. Additionally, RSFC scores from this dimension - both the baseline value and the change from baseline to post-intervention - were associated with clinical responsiveness to mind-body therapy. The second dimension was related to an inverse association between pain and anxiety, and to default mode network connectivity. The final dimension was related to pain catastrophizing, and salience, sensorimotor and default mode network connectivity. These unique symptom/brain-mappings over three dimensions provide novel network targets to modify specific ensembles of symptoms. In addition to performing CCA, we evaluated the current clustering of migraine patients into episodic and chronic subtypes, and found no evidence to support this clustering. However, when using RSFC scores from the three significant dimensions, we identified a novel clustering of migraine patients into four biotypes with unique functional connectivity patterns. These findings provide new insight into individual variability in migraine, and could serve as the foundation for novel therapies that take advantage of migraine heterogeneity.

neuroscience↗

bioRxiv2019

Prolonged tonic pain in healthy humans disrupts intrinsic brain networks implicated in pain modulation

Neural mechanisms of ongoing nociceptive processing in the human brain remain largely obscured by the dual challenge of accessing neural dynamics and safely applying sustained painful stimuli. Recently, pain-related neural processing has been measured using fMRI resting state functional connectivity (FC) in chronic pain patients. However, ongoing pain-related processing in normally pain-free humans remains incompletely understood. Therefore, differences between chronic pain patients and controls may be due to comorbidities with chronic pain. Decreased FC among regions of the descending pain modulation network (DPMN) are associated with presence and severity of chronic pain disorders. We aimed to determine if the presence of prolonged tonic pain would lead to disruption of the DPMN. High (10%) concentration topical capsaicin was combined with a warm thermode applied to the leg to create a flexible, prolonged tonic pain model to study the FC of brain networks in otherwise healthy, pain-free subjects in two separate cohorts (n=18; n=32). We contrasted seed-based FC during prolonged tonic pain with a pain-free passive task. In seed-based FC analysis prolonged tonic pain led to enhanced FC between the anterior middle cingulate cortex (aMCC) and the somatosensory leg representation. Additionally, FC was enhanced between the pregenual anterior cingulate cortex (pACC), right mediodorsal thalamus and the posterior parietal cortex bilaterally. Further, in the seed-driven PAG network, positive FC with the left DLPFC became negative FC during prolonged tonic pain. These data suggest that some altered DPMN FC findings in chronic pain could partially be explained by the presence of ongoing pain.

neuroscience↗

bioRxiv2019

Sensorimotor peak alpha frequency is a reliable biomarker of pain sensitivity

Previous research has observed that individuals with chronic pain demonstrate slower alpha band oscillations (8-12 Hz range) during resting electroencephalography (EEG) than do age-matched, healthy controls. While this slowing may reflect pathological changes within the brain that occur during the chronification of pain, an alternative explanation is that healthy individuals with slower alpha frequencies are more sensitive to prolonged pain, and by extension, more susceptible to developing chronic pain. To formally test this hypothesis, we examined the relationship between the pain-free, resting alpha frequency of healthy individuals and their subsequent sensitivity to two experimental models of prolonged pain, Phasic Heat Pain and Capsaicin Heat Pain, at two testing visits separated by 8 weeks on average (n = 61 Visit 1, n = 46 Visit 2). We observed that the speed of an individuals pain-free alpha oscillations was negatively correlated with sensitivity to both prolonged pain tests and that this relationship was reliable across short (minutes) and long (weeks) timescales. Furthermore, we used the speed of pain-free alpha oscillations to successfully identify those individuals most sensitive to prolonged pain, which we also validated on data from a separate, independent study. These results suggest that alpha oscillation speed is a reliable biomarker of prolonged pain sensitivity with the potential to become a tool for prospectively identifying pain sensitivity in the clinic.

neuroscience↗