Attention to breath sensations does not engage endogenous opioids to reduce pain.

The endogenous opioidergic system is critically involved in the cognitive modulation of pain. Slow-breathing-based techniques are widely used nonpharmacological approaches to reduce pain. Yet, the active mechanisms of actions supporting these practices are poorly characterized. Growing evidence suggest that mindfulness-meditation, a slow-breathing technique practiced by nonreactively attending to breathing sensations, engages multiple unique neural mechanisms that bypass opioidergically mediated descending pathways to reduce pain. However, it is unknown whether endogenous opioids contribute to pain reductions produced by slow breathing. The present double-blind, placebo-controlled crossover study examined behavioral pain responses during mindfulness-meditation (n = 19), sham-mindfulness meditation (n = 20), and slow-paced breathing (n = 20) in response to noxious heat (49°C) and intravenous administration (0.15 mg/kg bolus + 0.1 mg/kg/hour maintenance infusion) of the opioid antagonist, naloxone, and placebo saline. Mindfulness significantly reduced pain unpleasantness ratings across both infusion sessions when compared to rest, but not pain intensity. Slow-paced breathing significantly reduced pain intensity and unpleasantness ratings during naloxone but not saline infusion. Pain reductions produced by mindfulness-meditation and slow-paced breathing were insensitive to naloxone when compared to saline administration. By contrast, sham-mindfulness meditation produced pain unpleasantness reductions during saline infusion but this effect was reversed by opioidergic antagonism. Sham-mindfulness did not lower pain intensity ratings. Self-reported "focusing on the breath" was identified as the operational feature particularly unique to the mindfulness-meditation and slow paced-breathing, but not sham-mindfulness meditation. Across all individuals, attending to the breath was associated with naloxone insensitive pain-relief. These findings provide evidence that slow breathing combined with attention to breath reduces pain independent of endogenous opioids.

Mindfulness-Meditation-Based Pain Relief Is Not Mediated by Endogenous Opioids.

Mindfulness meditation, a cognitive practice premised on sustaining nonjudgmental awareness of arising sensory events, reliably attenuates pain. Mindfulness meditation activates multiple brain regions that contain a high expression of opioid receptors. However, it is unknown whether mindfulness-meditation-based analgesia is mediated by endogenous opioids. The present double-blind, randomized study examined behavioral pain responses in healthy human volunteers during mindfulness meditation and a nonmanipulation control condition in response to noxious heat and intravenous administration of the opioid antagonist naloxone (0.15 mg/kg bolus + 0.1 mg/kg/h infusion) or saline placebo. Meditation during saline infusion significantly reduced pain intensity and unpleasantness ratings when compared to the control + saline group. However, naloxone infusion failed to reverse meditation-induced analgesia. There were no significant differences in pain intensity or pain unpleasantness reductions between the meditation + naloxone and the meditation + saline groups. Furthermore, mindfulness meditation during naloxone produced significantly greater reductions in pain intensity and unpleasantness than the control groups. These findings demonstrate that mindfulness meditation does not rely on endogenous opioidergic mechanisms to reduce pain. SIGNIFICANCE STATEMENT: Endogenous opioids have been repeatedly shown to be involved in the cognitive inhibition of pain. Mindfulness meditation, a practice premised on directing nonjudgmental attention to arising sensory events, reduces pain by engaging mechanisms supporting the cognitive control of pain. However, it remains unknown if mindfulness-meditation-based analgesia is mediated by opioids, an important consideration for using meditation to treat chronic pain. To address this question, the present study examined pain reports during meditation in response to noxious heat and administration of the opioid antagonist naloxone and placebo saline. The results demonstrate that meditation-based pain relief does not require endogenous opioids. Therefore, the treatment of chronic pain may be more effective with meditation due to a lack of cross-tolerance with opiate-based medications.

Mindfulness Meditation-Based Pain Relief Employs Different Neural Mechanisms Than Placebo and Sham Mindfulness Meditation-Induced Analgesia.

Mindfulness meditation reduces pain in experimental and clinical settings. However, it remains unknown whether mindfulness meditation engages pain-relieving mechanisms other than those associated with the placebo effect (e.g., conditioning, psychosocial context, beliefs). To determine whether the analgesic mechanisms of mindfulness meditation are different from placebo, we randomly assigned 75 healthy, human volunteers to 4 d of the following: (1) mindfulness meditation, (2) placebo conditioning, (3) sham mindfulness meditation, or (4) book-listening control intervention. We assessed intervention efficacy using psychophysical evaluation of experimental pain and functional neuroimaging. Importantly, all cognitive manipulations (i.e., mindfulness meditation, placebo conditioning, sham mindfulness meditation) significantly attenuated pain intensity and unpleasantness ratings when compared to rest and the control condition (p < 0.05). Mindfulness meditation reduced pain intensity (p = 0.032) and pain unpleasantness (p < 0.001) ratings more than placebo analgesia. Mindfulness meditation also reduced pain intensity (p = 0.030) and pain unpleasantness (p = 0.043) ratings more than sham mindfulness meditation. Mindfulness-meditation-related pain relief was associated with greater activation in brain regions associated with the cognitive modulation of pain, including the orbitofrontal, subgenual anterior cingulate, and anterior insular cortex. In contrast, placebo analgesia was associated with activation of the dorsolateral prefrontal cortex and deactivation of sensory processing regions (secondary somatosensory cortex). Sham mindfulness meditation-induced analgesia was not correlated with significant neural activity, but rather by greater reductions in respiration rate. This study is the first to demonstrate that mindfulness-related pain relief is mechanistically distinct from placebo analgesia. The elucidation of this distinction confirms the existence of multiple, cognitively driven, supraspinal mechanisms for pain modulation. SIGNIFICANCE STATEMENT: Recent findings have demonstrated that mindfulness meditation significantly reduces pain. Given that the "gold standard" for evaluating the efficacy of behavioral interventions is based on appropriate placebo comparisons, it is imperative that we establish whether there is an effect supporting meditation-related pain relief above and beyond the effects of placebo. Here, we provide novel evidence demonstrating that mindfulness meditation produces greater pain relief and employs distinct neural mechanisms than placebo cream and sham mindfulness meditation. Specifically, mindfulness meditation-induced pain relief activated higher-order brain regions, including the orbitofrontal and cingulate cortices. In contrast, placebo analgesia was associated with decreased pain-related brain activation. These findings demonstrate that mindfulness meditation reduces pain through unique mechanisms and may foster greater acceptance of meditation as an adjunct pain therapy.

Neural correlates of mindfulness meditation-related anxiety relief.

Anxiety is the cognitive state related to the inability to control emotional responses to perceived threats. Anxiety is inversely related to brain activity associated with the cognitive regulation of emotions. Mindfulness meditation has been found to regulate anxiety. However, the brain mechanisms involved in meditation-related anxiety relief are largely unknown. We employed pulsed arterial spin labeling MRI to compare the effects of distraction in the form of attending to the breath (ATB; before meditation training) to mindfulness meditation (after meditation training) on state anxiety across the same subjects. Fifteen healthy subjects, with no prior meditation experience, participated in 4 d of mindfulness meditation training. ATB did not reduce state anxiety, but state anxiety was significantly reduced in every session that subjects meditated. Meditation-related anxiety relief was associated with activation of the anterior cingulate cortex, ventromedial prefrontal cortex and anterior insula. Meditation-related activation in these regions exhibited a strong relationship to anxiety relief when compared to ATB. During meditation, those who exhibited greater default-related activity (i.e. posterior cingulate cortex) reported greater anxiety, possibly reflecting an inability to control self-referential thoughts. These findings provide evidence that mindfulness meditation attenuates anxiety through mechanisms involved in the regulation of self-referential thought processes.

Brain mechanisms supporting the modulation of pain by mindfulness meditation.

The subjective experience of one's environment is constructed by interactions among sensory, cognitive, and affective processes. For centuries, meditation has been thought to influence such processes by enabling a nonevaluative representation of sensory events. To better understand how meditation influences the sensory experience, we used arterial spin labeling functional magnetic resonance imaging to assess the neural mechanisms by which mindfulness meditation influences pain in healthy human participants. After 4 d of mindfulness meditation training, meditating in the presence of noxious stimulation significantly reduced pain unpleasantness by 57% and pain intensity ratings by 40% when compared to rest. A two-factor repeated-measures ANOVA was used to identify interactions between meditation and pain-related brain activation. Meditation reduced pain-related activation of the contralateral primary somatosensory cortex. Multiple regression analysis was used to identify brain regions associated with individual differences in the magnitude of meditation-related pain reductions. Meditation-induced reductions in pain intensity ratings were associated with increased activity in the anterior cingulate cortex and anterior insula, areas involved in the cognitive regulation of nociceptive processing. Reductions in pain unpleasantness ratings were associated with orbitofrontal cortex activation, an area implicated in reframing the contextual evaluation of sensory events. Moreover, reductions in pain unpleasantness also were associated with thalamic deactivation, which may reflect a limbic gating mechanism involved in modifying interactions between afferent input and executive-order brain areas. Together, these data indicate that meditation engages multiple brain mechanisms that alter the construction of the subjectively available pain experience from afferent information.

Early segregation of layered projections from the lateral superior olivary nucleus to the central nucleus of the inferior colliculus in the neonatal cat.

The central nucleus of the inferior colliculus (IC) is a laminated structure that receives multiple converging afferent projections. These projections terminate in a layered arrangement and are aligned with dendritic arbors of the predominant disc-shaped neurons, forming fibrodendritic laminae. Within this structural framework, inputs terminate in a precise manner, establishing a mosaic of partially overlapping domains that likely define functional compartments. Although several of these patterned inputs have been described in the adult, relatively little is known about their organization prior to hearing onset. The present study used the lipophilic carbocyanine dyes DiI and DiD to examine the ipsilateral and contralateral projections from the lateral superior olivary (LSO) nucleus to the IC in a developmental series of paraformaldehyde-fixed kitten tissue. By birth, the crossed and uncrossed projections had reached the IC and were distributed across the frequency axis of the central nucleus. At this earliest postnatal stage, projections already exhibited a characteristic banded arrangement similar to that described in the adult. The heaviest terminal fields of the two inputs were always complementary in nature, with the ipsilateral input appearing slightly denser. This early arrangement of interdigitating ipsilateral and contralateral LSO axonal bands that occupy adjacent sublayers supports the idea that the initial establishment of this highly organized mosaic of inputs that defines distinct synaptic domains within the IC occurs largely in the absence of auditory experience. Potential developmental mechanisms that may shape these highly ordered inputs prior to hearing onset are discussed.

Brain mechanisms supporting spatial discrimination of pain.

Pain is a uniquely individual experience that is heavily shaped by evaluation and judgments about afferent sensory information. In visual, auditory, and tactile sensory modalities, evaluation of afferent information engages brain regions outside of the primary sensory cortices. In contrast, evaluation of sensory features of noxious information has long been thought to be accomplished by the primary somatosensory cortex and other structures associated with the lateral pain system. Using functional magnetic resonance imaging and a delayed match-to-sample task, we show that the prefrontal cortex, anterior cingulate cortex, posterior parietal cortex, thalamus, and caudate are engaged during evaluation of the spatial locations of noxious stimuli. Thus, brain mechanisms supporting discrimination of sensory features of pain extend far beyond the somatosensory cortices and involve frontal regions traditionally associated with affective processing and the medial pain system. These frontoparietal interactions are similar to those involved in the processing of innocuous information and may be critically involved in placing afferent sensory information into a personal historical context.

Opposing basal ganglia processes shape midbrain visuomotor activity bilaterally.

The manner in which the nervous system allocates limited motor resources when confronted with conflicting behavioural demands is a crucial issue in understanding how sensory information is transformed into adaptive motor responses. Understanding this selection process is of particular concern in current models of functions of the basal ganglia. Here we report that the basal ganglia use simultaneous enhancing and suppressing processes synergistically to modulate sensory activity in the superior colliculi, which are bilaterally paired midbrain structures involved in the control of visual orientation behaviours. These complementary processes presumably ensure accurate gaze shifts mediated by the superior colliculi despite the presence of potential distractors.