Meditation Practice, Mindfulness, and Pain-Related Outcomes in Mindfulness-Based Treatment for Episodic Migraine.

Objectives: Mindfulness-based interventions (MBIs) have emerged as promising prophylactic episodic migraine treatments. The present study investigated biopsychosocial predictors and outcomes associated with formal, daily-life meditation practice in migraine patients undergoing MBI, and whether augmented mindfulness mechanistically underlies change. Methods: Secondary analyses of clinical trial data comparing a 12-week enhanced mindfulness-based stress reduction course (MBSR + ; n = 50) to stress management for headache (SMH; n = 48) were conducted. Results: Pre-treatment mesocorticolimbic system functioning (i.e., greater resting state ventromedial prefrontal cortex-right nucleus accumbens [vmPFC-rNAC] functional connectivity) predicted greater meditation practice duration over MBSR + (r = 0.58, p = 0.001), as well as the change in headache frequency from pre- to post-treatment (B = -12.60, p = 0.02) such that MBSR + participants with greater vmPFC-rNAC connectivity showed greater reductions in headache frequency. MBSR + participants who meditated more showed greater increases in mindfulness (B = 0.52, p = 0.02) and reductions in the helplessness facet of pain catastrophizing (B = -0.13, p = 0.01), but not headache frequency, severity, or impact. Augmented mindfulness mediated reductions in headache impact resulting from MBSR + , but not headache frequency. Conclusions: Mesocorticolimbic system function is implicated in motivated behavior, and thus, motivation-enhancing interventions might be delivered alongside mindfulness-based training to enhance meditation practice engagement. Formal, daily-life meditation practice duration appears to benefit pain-related cognitions, but not clinical pain, while mindfulness emerges as a mechanism of MBIs on headache impact, but not frequency. Further research is needed to investigate the day-to-day effects of formal, daily-life meditation practice on pain, and continue to characterize the specific mechanisms of MBIs on headache outcomes. Preregistration: This study is not preregistered.

Is Mindfulness Associated With Lower Pain Reactivity and Connectivity of the Default Mode Network? A Replication and Extension Study in Healthy and Episodic Migraine Participants.

Formal training in mindfulness-based practices promotes reduced experimental and clinical pain, which may be driven by reduced emotional pain reactivity and undergirded by alterations in the default mode network, implicated in mind-wandering and self-referential processing. Recent results published in this journal suggest that mindfulness, defined here as the day-to-day tendency to maintain a non-reactive mental state in the absence of training, associates with lower pain reactivity, greater heat-pain thresholds, and resting-state default mode network functional connectivity in healthy adults in a similar manner to trained mindfulness. The extent to which these findings extend to chronic pain samples and replicate in healthy samples is unknown. Using data from healthy adults (n = 36) and episodic migraine patients (n = 98) and replicating previously published methods, we observed no significant association between mindfulness and heat-pain threshold, pain intensity or unpleasantness, or pain catastrophizing in healthy controls, or between mindfulness and headache frequency, severity, impactor pain catastrophizing in patients. There was no association between default mode network connectivity and mindfulness in either sample when probed via seed-based functional connectivity analyses. In post-hoc whole brain exploratory analyses, a meta-analytically derived default mode network node (ie, posterior cingulate cortex) showed connectivity with regions unassociated with pain processing as a function of mindfulness, such that healthy adults higher in mindfulness showed greater functional connectivity between the posterior cingulate cortex-and cerebellum. Collectively, these findings suggest that the relationship between mindfulness and default mode network functional connectivity may be nuanced or non-robust, and encourage further investigation of how mindfulness relates to pain. PERSPECTIVE: This study found few significant associations between dispositional mindfulness and pain, pain reactivity and default mode connectivity in healthy adults and migraine patients. The relationship between mindfulness and default mode network connectivity may be nuanced or non-robust.

Three Dimensions of Association Link Migraine Symptoms and Functional Connectivity.

Migraine is a heterogeneous disorder with variable symptoms and responsiveness to therapy. Because of previous analytic shortcomings, variance in migraine symptoms has been inconsistently related to brain function. In the current analysis, we used data from two sites (n = 143, male and female humans), and performed canonical correlation analysis, relating resting-state functional connectivity (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. The first dimension 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 postintervention, were associated with 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. In addition to performing canonical correlation analysis, 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.SIGNIFICANCE STATEMENT Using a large multisite dataset of migraine patients, we identified three dimensions of multivariate association between symptoms and functional connectivity. This analysis revealed neural networks that relate to all measured symptoms, but also to specific symptom ensembles, such as patient propensity to catastrophize painful events. Using these three dimensions, we found four biotypes of migraine informed by clinical and neural variation together. Such findings pave the way for precision medicine therapy for migraine.

Migraine disability, pain catastrophizing, and headache severity are associated with evoked pain and targeted by mind-body therapy.

ABSTRACT: Meta-analysis suggests that migraine patients are no more sensitive to experimentally evoked pain than healthy control subjects. At the same time, studies have linked some migraine symptoms to quantitative sensory testing (QST) profiles. Unfortunately, previous studies associating migraine symptoms and QST have important methodological shortcomings, stemming from small sample sizes, and frequent use of univariate statistics for multivariate research questions. In the current study, we seek to address these limitations by using a large sample of episodic migraine patients (n = 103) and a multivariate analysis that associates pain ratings from many thermal intensities simultaneously with 12 clinical measures ranging from headache frequency to sleep abnormalities. We identified a single dimension of association between thermal QST and migraine symptoms that relates to pain ratings for all stimulus intensities and a subset of migraine symptoms relating to disability (Headache Impact Test 6 and Brief Pain Inventory interference), catastrophizing (Pain Catastrophizing Scale), and pain severity (average headache pain, Brief Pain Inventory severity, and Short-Form McGill Pain Questionnaire 2). Headache frequency, allodynia, affect, and sleep disturbances were unrelated to this dimension. Consistent with previous research, we did not observe any difference in QST ratings between migraine patients and healthy control subjects. Additionally, we found that the linear combination of symptoms related to QST was modified by the mind-body therapy enhanced mindfulness-based stress reduction (MBSR+). These results suggest that QST has a selective relationship with pain symptoms even in the absence of between-subjects differences between chronic pain patients and healthy control subjects.

Enhanced mindfulness-based stress reduction in episodic migraine: a randomized clinical trial with magnetic resonance imaging outcomes.

We aimed to evaluate the efficacy of an enhanced mindfulness-based stress reduction (MBSR+) vs stress management for headache (SMH). We performed a randomized, assessor-blind, clinical trial of 98 adults with episodic migraine recruited at a single academic center comparing MBSR+ (n = 50) with SMH (n = 48). MBSR+ and SMH were delivered weekly by group for 8 weeks, then biweekly for another 8 weeks. The primary clinical outcome was reduction in headache days from baseline to 20 weeks. Magnetic resonance imaging (MRI) outcomes included activity of left dorsolateral prefrontal cortex (DLPFC) and cognitive task network during cognitive challenge, resting state connectivity of right dorsal anterior insula to DLPFC and cognitive task network, and gray matter volume of DLPFC, dorsal anterior insula, and anterior midcingulate. Secondary outcomes were headache-related disability, pain severity, response to treatment, migraine days, and MRI whole-brain analyses. Reduction in headache days from baseline to 20 weeks was greater for MBSR+ (7.8 [95% CI, 6.9-8.8] to 4.6 [95% CI, 3.7-5.6]) than for SMH (7.7 [95% CI 6.7-8.7] to 6.0 [95% CI, 4.9-7.0]) (P = 0.04). Fifty-two percent of the MBSR+ group showed a response to treatment (50% reduction in headache days) compared with 23% in the SMH group (P = 0.004). Reduction in headache-related disability was greater for MBSR+ (59.6 [95% CI, 57.9-61.3] to 54.6 [95% CI, 52.9-56.4]) than SMH (59.6 [95% CI, 57.7-61.5] to 57.5 [95% CI, 55.5-59.4]) (P = 0.02). There were no differences in clinical outcomes at 52 weeks or MRI outcomes at 20 weeks, although changes related to cognitive networks with MBSR+ were observed. Enhanced mindfulness-based stress reduction is an effective treatment option for episodic migraine.

Pain-related nucleus accumbens function: modulation by reward and sleep disruption.

The nucleus accumbens (NAc) has been implicated in sleep, reward, and pain modulation, but the relationship between these functional roles is unclear. This study aimed to determine whether NAc function at the onset and offset of a noxious thermal stimulus is enhanced by rewarding music, and whether that effect is reversed by experimental sleep disruption. Twenty-one healthy subjects underwent functional magnetic resonance imaging scans on 2 separate days after both uninterrupted sleep and experimental sleep disruption. During functional magnetic resonance imaging scans, participants experienced noxious stimulation while listening to individualized rewarding or neutral music. Behavioral results revealed that rewarding music significantly reduced pain intensity compared with neutral music, and disrupted sleep was associated with decreased pain intensity in the context of listening to music. In whole-brain family-wise error cluster-corrected analysis, the NAc was activated at pain onset, but not during tonic pain or at pain offset. Sleep disruption attenuated NAc activation at pain onset and during tonic pain. Rewarding music altered NAc connectivity with key nodes of the corticostriatal circuits during pain onset. Sleep disruption increased reward-related connectivity between the NAc and the anterior midcingulate cortex at pain onset. This study thus indicates that experimental sleep disruption modulates NAc function during the onset of pain in a manner that may be conditional on the presence of competing reward-related stimuli. These findings point to potential mechanisms for the interaction between sleep, reward, and pain, and suggest that sleep disruption affects both the detection and processing of aversive stimuli that may have important implications for chronic pain.

A Negative Allosteric Modulator for α5 Subunit-Containing GABA Receptors Exerts a Rapid and Persistent Antidepressant-Like Action without the Side Effects of the NMDA Receptor Antagonist Ketamine in Mice.

New antidepressant pharmacotherapies that provide rapid relief of depressive symptoms are needed. The NMDA receptor antagonist ketamine exerts rapid antidepressant actions in depressed patients but also side effects that complicate its clinical utility. Ketamine promotes excitatory synaptic strength, likely by producing high-frequency correlated activity in mood-relevant regions of the forebrain. Negative allosteric modulators of GABA-A receptors containing α5 subunits (α5 GABA-NAMs) should also promote high-frequency correlated electroencephalogram (EEG) activity and should therefore exert rapid antidepressant responses. Because α5 subunits display a restricted expression in the forebrain, we predicted that α5 GABA-NAMs would produce activation of principle neurons but exert fewer side effects than ketamine. We tested this hypothesis in male mice and observed that the α5 GABA-NAM MRK-016 exerted an antidepressant-like response in the forced swim test at 1 and 24 h after administration and an anti-anhedonic response after chronic stress in the female urine sniffing test (FUST). Like ketamine, MRK-016 produced a transient increase in EEG γ power, and both the increase in γ power and its antidepressant effects in the forced swim test were blocked by prior administration of the AMPA-type glutamate receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX). Unlike ketamine, however, MRK-016 produced no impairment of rota-rod performance, no reduction of prepulse inhibition (PPI), no conditioned-place preference (CPP), and no change in locomotion. α5 GABA-NAMs, thus reproduce the rapid antidepressant-like actions of ketamine, perhaps via an AMPA receptor (AMPAR)-dependent increase in coherent neuronal activity, but display fewer potential negative side effects. These compounds thus demonstrate promise as clinically useful fast-acting antidepressants.