A Randomized Controlled Neuroimaging Trial of Cognitive Behavioral Therapy for Fibromyalgia Pain.

OBJECTIVE: Fibromyalgia (FM) is characterized by pervasive pain-related symptomatology and high levels of negative affect. Mind-body treatments such as cognitive behavioral therapy (CBT) appear to foster improvement in FM via reductions in pain-related catastrophizing, a set of negative, pain-amplifying cognitive and emotional processes. However, the neural underpinnings of CBT's catastrophizing-reducing effects remain uncertain. This randomized controlled mechanistic trial was designed to assess CBT's effects on pain catastrophizing and its underlying brain circuitry. METHODS: Of 114 enrolled participants, 98 underwent a baseline neuroimaging assessment and were randomized to 8 weeks of individual CBT or a matched FM education control (EDU) condition. RESULTS: Compared with EDU, CBT produced larger decreases in pain catastrophizing post treatment (P < 0.05) and larger reductions in pain interference and symptom impact. Decreases in pain catastrophizing played a significant role in mediating those functional improvements in the CBT group. At baseline, brain functional connectivity between the ventral posterior cingulate cortex (vPCC), a key node of the default mode network (DMN), and somatomotor and salience network regions was increased during catastrophizing thoughts. Following CBT, vPCC connectivity to somatomotor and salience network areas was reduced. CONCLUSION: Our results suggest clinically important and CBT-specific associations between somatosensory/motor- and salience-processing brain regions and the DMN in chronic pain. These patterns of connectivity may contribute to individual differences (and treatment-related changes) in somatic self-awareness. CBT appears to provide clinical benefits at least partially by reducing pain-related catastrophizing and producing adaptive alterations in DMN functional connectivity.

Brain-to-brain mechanisms underlying pain empathy and social modulation of pain in the patient-clinician interaction.

Social interactions such as the patient-clinician encounter can influence pain, but the underlying dynamic interbrain processes are unclear. Here, we investigated the dynamic brain processes supporting social modulation of pain by assessing simultaneous brain activity (fMRI hyperscanning) from chronic pain patients and clinicians during video-based live interaction. Patients received painful and nonpainful pressure stimuli either with a supportive clinician present (Dyadic) or in isolation (Solo). In half of the dyads, clinicians performed a clinical consultation and intake with the patient prior to hyperscanning (Clinical Interaction), which increased self-reported therapeutic alliance. For the other half, patient-clinician hyperscanning was completed without prior clinical interaction (No Interaction). Patients reported lower pain intensity in the Dyadic, relative to the Solo, condition. In Clinical Interaction dyads relative to No Interaction, patients evaluated their clinicians as better able to understand their pain, and clinicians were more accurate when estimating patients' pain levels. In Clinical Interaction dyads, compared to No Interaction, patients showed stronger activation of the dorsolateral and ventrolateral prefrontal cortex (dlPFC and vlPFC) and primary (S1) and secondary (S2) somatosensory areas (Dyadic-Solo contrast), and clinicians showed increased dynamic dlPFC concordance with patients' S2 activity during pain. Furthermore, the strength of S2-dlPFC concordance was positively correlated with self-reported therapeutic alliance. These findings support that empathy and supportive care can reduce pain intensity and shed light on the brain processes underpinning social modulation of pain in patient-clinician interactions. Our findings further suggest that clinicians' dlPFC concordance with patients' somatosensory processing during pain can be boosted by increasing therapeutic alliance.

Functional network reconfiguration supporting memory-guided attention.

Studies have identified several brain regions whose activations facilitate attentional deployment via long-term memories. We analyzed task-based functional connectivity at the network and node-specific level to characterize large-scale communication between brain regions underlying long-term memory guided attention. We predicted default mode, cognitive control, and dorsal attention subnetworks would contribute differentially to long-term memory guided attention, such that network-level connectivity would shift based on attentional demands, requiring contribution of memory-specific nodes within default mode and cognitive control subnetworks. We expected that these nodes would increase connectivity with one another and with dorsal attention subnetworks during long-term memory guided attention. Additionally, we hypothesized connectivity between cognitive control and dorsal attention subnetworks facilitating external attentional demands. Our results identified both network-based and node-specific interactions that facilitate different components of LTM-guided attention, suggesting a crucial role across the posterior precuneus and restrosplenial cortex, acting independently from the divisions of default mode and cognitive control subnetworks. We found a gradient of precuneus connectivity, with dorsal precuneus connecting to cognitive control and dorsal attention regions, and ventral precuneus connecting across all subnetworks. Additionally, retrosplenial cortex showed increased connectivity across subnetworks. We suggest that connectivity from dorsal posterior midline regions is critical for the integration of external information with internal memory that facilitates long-term memory guided attention.

Functional reconfiguration of task-active frontoparietal control network facilitates abstract reasoning.

While the brain's functional network architecture is largely conserved between resting and task states, small but significant changes in functional connectivity support complex cognition. In this study, we used a modified Raven's Progressive Matrices Task to examine symbolic and perceptual reasoning in human participants undergoing fMRI scanning. Previously, studies have focused predominantly on discrete symbolic versions of matrix reasoning, even though the first few trials of the Raven's Advanced Progressive Matrices task consist of continuous perceptual stimuli. Our analysis examined the activation patterns and functional reconfiguration of brain networks associated with resting state and both symbolic and perceptual reasoning. We found that frontoparietal networks, including the cognitive control and dorsal attention networks, were significantly activated during abstract reasoning. We determined that these same task-active regions exhibited flexibly-reconfigured functional connectivity when transitioning from resting state to the abstract reasoning task. Conversely, we showed that a stable network core of regions in default and somatomotor networks was maintained across both resting and task states. We propose that these regionally-specific changes in the functional connectivity of frontoparietal networks puts the brain in a "task-ready" state, facilitating efficient task-based activation.

Patient-clinician brain concordance underlies causal dynamics in nonverbal communication and negative affective expressivity.

Patient-clinician concordance in behavior and brain activity has been proposed as a potential key mediator of mutual empathy and clinical rapport in the therapeutic encounter. However, the specific elements of patient-clinician communication that may support brain-to-brain concordance and therapeutic alliance are unknown. Here, we investigated how pain-related, directional facial communication between patients and clinicians is associated with brain-to-brain concordance. Patient-clinician dyads interacted in a pain-treatment context, during synchronous assessment of brain activity (fMRI hyperscanning) and online video transfer, enabling face-to-face social interaction. In-scanner videos were used for automated individual facial action unit (AU) time-series extraction. First, an interpretable machine-learning classifier of patients' facial expressions, from an independent fMRI experiment, significantly distinguished moderately painful leg pressure from innocuous pressure stimuli. Next, we estimated neural-network causality of patient-to-clinician directional information flow of facial expressions during clinician-initiated treatment of patients' evoked pain. We identified a leader-follower relationship in which patients predominantly led the facial communication while clinicians responded to patients' expressions. Finally, analyses of dynamic brain-to-brain concordance showed that patients' mid/posterior insular concordance with the clinicians' anterior insula cortex, a region identified in previously published data from this study1, was associated with therapeutic alliance, and self-reported and objective (patient-to-clinician-directed causal influence) markers of negative-affect expressivity. These results suggest a role of patient-clinician concordance of the insula, a social-mirroring and salience-processing brain node, in mediating directional dynamics of pain-directed facial communication during therapeutic encounters.

Increased Salience Network Connectivity Following Manual Therapy is Associated with Reduced Pain in Chronic Low Back Pain Patients.

Chronic low back pain (cLBP) has been associated with changes in brain plasticity. Nonpharmacological therapies such as Manual Therapy (MT) have shown promise for relieving cLBP. However, translational neuroimaging research is needed to understand potential central mechanisms supporting MT. We investigated the effect of MT on resting-state salience network (SLN) connectivity, and whether this was associated with changes in clinical pain. Fifteen cLBP patients, and 16 matched healthy controls (HC) were scanned with resting functional Magnetic Resonance Imaging (fMRI), before and immediately after a MT intervention (cross-over design with two separate visits, pseudorandomized, grades V 'Manipulation' and III 'Mobilization' of the Maitland Joint Mobilization Grading Scale). Patients rated clinical pain (0-100) pre- and post-therapy. SLN connectivity was assessed using dual regression probabilistic independent component analysis. Both manipulation (Pre: 39.43 ± 16.5, Post: 28.43 ± 16.5) and mobilization (Pre: 38.83 ± 17.7, Post: 31.76 ± 19.4) reduced clinical back pain (P < .05). Manipulation (but not mobilization) significantly increased SLN connectivity to thalamus and primary motor cortex. Additionally, a voxelwise regression indicated that greater MT-induced increase in SLN connectivity to the lateral prefrontal cortex was associated with greater clinical back pain reduction immediately after intervention, for both manipulation (r = -0.8) and mobilization (r = -0.54). Our results suggest that MT is successful in reducing clinical low back pain by both spinal manipulation and spinal mobilization. Furthermore, this reduction post-manipulation occurs via modulation of SLN connectivity to sensorimotor, affective, and cognitive processing regions. PERSPECTIVE: MT both reduces clinical low back pain and modulates brain activity important for the processing of pain. This modulation was shown by increased functional brain connectivity between the salience network and brain regions involved in cognitive, affective, and sensorimotor processing of pain.

Dynamic brain-to-brain concordance and behavioral mirroring as a mechanism of the patient-clinician interaction.

The patient-clinician interaction can powerfully shape treatment outcomes such as pain but is often considered an intangible "art of medicine" and has largely eluded scientific inquiry. Although brain correlates of social processes such as empathy and theory of mind have been studied using single-subject designs, specific behavioral and neural mechanisms underpinning the patient-clinician interaction are unknown. Using a two-person interactive design, we simultaneously recorded functional magnetic resonance imaging (hyperscanning) in patient-clinician dyads, who interacted via live video, while clinicians treated evoked pain in patients with chronic pain. Our results show that patient analgesia is mediated by patient-clinician nonverbal behavioral mirroring and brain-to-brain concordance in circuitry implicated in theory of mind and social mirroring. Dyad-based analyses showed extensive dynamic coupling of these brain nodes with the partners' brain activity, yet only in dyads with pre-established clinical rapport. These findings introduce a putatively key brain-behavioral mechanism for therapeutic alliance and psychosocial analgesia.

Stimulus frequency modulates brainstem response to respiratory-gated transcutaneous auricular vagus nerve stimulation.

BACKGROUND: The therapeutic potential of transcutaneous auricular VNS (taVNS) is currently being explored for numerous clinical applications. However, optimized response for different clinical indications may depend on specific neuromodulation parameters, and systematic assessments of their influence are still needed to optimize this promising approach. HYPOTHESIS: We proposed that stimulation frequency would have a significant effect on nucleus tractus solitarii (NTS) functional MRI (fMRI) response to respiratory-gated taVNS (RAVANS). METHODS: Brainstem fMRI response to auricular RAVANS (cymba conchae) was assessed for four different stimulation frequencies (2, 10, 25, 100 Hz). Sham (no current) stimulation was used to control for respiration effects on fMRI signal. RESULTS: Our findings demonstrated that RAVANS delivered at 100 Hz evoked the strongest brainstem response, localized to a cluster in the left (ipsilateral) medulla and consistent with purported NTS. A co-localized, although weaker, response was found for 2 Hz RAVANS. Furthermore, RAVANS delivered at 100 Hz also evoked stronger fMRI responses for important monoamine neurotransmitter source nuclei (LC, noradrenergic; MR, DR, serotonergic) and pain/homeostatic regulation nuclei (i.e. PAG). CONCLUSION: Our fMRI results support previous localization of taVNS afference to pontomedullary aspect of NTS in the human brainstem, and demonstrate the significant influence of the stimulation frequency on brainstem fMRI response.

The influence of respiration on brainstem and cardiovagal response to auricular vagus nerve stimulation: A multimodal ultrahigh-field (7T) fMRI study.

BACKGROUND: Brainstem-focused mechanisms supporting transcutaneous auricular VNS (taVNS) effects are not well understood, particularly in humans. We employed ultrahigh field (7T) fMRI and evaluated the influence of respiratory phase for optimal targeting, applying our respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) technique. HYPOTHESIS: We proposed that targeting of nucleus tractus solitarii (NTS) and cardiovagal modulation in response to taVNS stimuli would be enhanced when stimulation is delivered during a more receptive state, i.e. exhalation. METHODS: Brainstem fMRI response to auricular taVNS (cymba conchae) was assessed for stimulation delivered during exhalation (eRAVANS) or inhalation (iRAVANS), while exhalation-gated stimulation over the greater auricular nerve (GANctrl, i.e. earlobe) was included as control. Furthermore, we evaluated cardiovagal response to stimulation by calculating instantaneous HF-HRV from cardiac data recorded during fMRI. RESULTS: Our findings demonstrated that eRAVANS evoked fMRI signal increase in ipsilateral pontomedullary junction in a cluster including purported NTS. Brainstem response to GANctrl localized a partially-overlapping cluster, more ventrolateral, consistent with spinal trigeminal nucleus. A region-of-interest analysis also found eRAVANS activation in monoaminergic source nuclei including locus coeruleus (LC, noradrenergic) and both dorsal and median raphe (serotonergic) nuclei. Response to eRAVANS was significantly greater than iRAVANS for all nuclei, and greater than GANctrl in LC and raphe nuclei. Furthermore, eRAVANS, but not iRAVANS, enhanced cardiovagal modulation, confirming enhanced eRAVANS response on both central and peripheral neurophysiological levels. CONCLUSION: 7T fMRI localized brainstem response to taVNS, linked such response with autonomic outflow, and demonstrated that taVNS applied during exhalation enhanced NTS targeting.

Encoding of Self-Referential Pain Catastrophizing in the Posterior Cingulate Cortex in Fibromyalgia.

OBJECTIVE: Pain catastrophizing is a common feature of chronic pain, including fibromyalgia (FM), and is strongly associated with amplified pain severity and disability. While previous neuroimaging studies have focused on evoked pain response modulation by catastrophizing, the brain mechanisms supporting pain catastrophizing itself are unknown. We designed a functional magnetic resonance imaging (fMRI)-based pain catastrophizing task whereby patients with chronic pain engaged in catastrophizing-related cognitions. We undertook this study to test our hypothesis that catastrophizing about clinical pain would be associated with amplified activation in nodes of the default mode network (DMN), which encode self-referential cognition and show altered functioning in chronic pain. METHODS: During fMRI, 31 FM patients reflected on how catastrophizing (CAT) statements (drawn from the Pain Catastrophizing Scale) impact their typical FM pain experience. Response to CAT statements was compared to response to matched neutral (NEU) statements. RESULTS: During statement reflection, higher fMRI signal during CAT statements than during NEU statements was found in several DMN brain areas, including the ventral (posterior) and dorsal (anterior) posterior cingulate cortex (vPCC and dPCC, respectively). Patients' ratings of CAT statement applicability were correlated solely with activity in the vPCC, a main DMN hub supporting self-referential cognition (r = 0.38, P < 0.05). Clinical pain severity was correlated solely with activity in the dPCC, a PCC subregion associated with cognitive control and sensorimotor processing (r = 0.38, P < 0.05). CONCLUSION: These findings provide evidence that the PCC encodes pain catastrophizing in FM and suggest distinct roles for different PCC subregions. Understanding the brain circuitry encoding pain catastrophizing in FM will prove to be important in identifying and evaluating the success of interventions targeting negative affect in chronic pain management.