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.

Cognitive and affective interaction with somatosensory afference in acupuncture-a specific brain response to compound stimulus.

Introduction: Acupuncture is a clinical intervention consisting of multiple stimulus components, including somatosensory stimulation and manipulation of therapeutic context. Existing findings in neuroscience consolidated cognitive modulation to somatosensory afferent process, which could differ from placebo mechanism in brain. Here, we aimed to identify intrinsic process of brain interactions induced by compound stimulus of acupuncture treatment. Methods: To separately and comprehensively investigate somatosensory afferent and cognitive/affective processes in brain, we implemented a novel experimental protocol of contextual manipulation with somatosensory stimulation (real acupuncture: REAL) and only contextual manipulation (phantom acupuncture: PHNT) for fMRI scan, and conducted independent component (IC)-wise assessment with the concatenated fMRI data. Results: By our double (experimentally and analytically) dissociation, two ICs (CA1: executive control, CA2: goal-directed sensory process) for cognitive/affective modulation (associated with both REAL and PHNT) and other two ICs (SA1: interoceptive attention and motor-reaction, SA2: somatosensory representation) for somatosensory afference (associated with only REAL) were identified. Moreover, coupling between SA1 and SA2 was associated with a decreased heart rate during stimulation, whereas CA1 was associated with a delayed heart rate decrease post-stimulation. Furthermore, partial correlation network for these components demonstrated a bi-directional interaction between CA1 and SA1/SA2, suggesting the cognitive modulation to somatosensory process. The expectation for the treatment negatively affected CA1 but positively affected SA1 in REAL, whereas the expectation positively affected CA1 in PHNT. Discussion: These specific cognitive-somatosensory interaction in REAL were differed from vicarious sensation mechanism in PHNT; and might be associated with a characteristic of acupuncture, which induces voluntary attention for interoception. Our findings on brain interactions in acupuncture treatment elucidated the underlying brain mechanisms for compound stimulus of somatosensory afferent and therapeutic contextual manipulation, which might be a specific response to acupuncture.

Attenuated facial movement in depressed women is associated with symptom severity, and nucleus accumbens functional connectivity.

It is assumed that mood can be inferred from one's facial expression. While this association may prove to be an objective marker for mood disorders, few studies have explicitly evaluated this linkage. The facial movement responses of women with major depressive disorder (n = 66) and healthy controls (n = 46) under emotional stimuli were recorded using webcam. To boost facial movements, the naturalistic audio-visual stimuli were presented. To assess consistent global patterns across facial movements, scores for facial action units were extracted and projected onto principal component using principal component analysis. The associations of component for facial movements with functional brain circuitry was also investigated. Clusters of mouth movements, such as lip press and stretch, identified by principal component analysis, were attenuated in depressive patients compared to those in healthy controls. This component of facial movements was associated with depressive symptoms, and the strengths of resting brain functional connectivity between nucleus accumbens and both posterior insular cortex and thalamus. The evaluation of facial movements may prove to be a promising quantitative marker for assessing depressive symptoms and their underlying brain circuitry.

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.

The Evaluation of Efficacy and Safety of A Radiofrequency Hydro-Injector Device for the Skin around the Eye Area.

In recent years, variable rejuvenation techniques, such as hyaluronic acid (HA) fillers and radiofrequency (RF) devices, have become popular. We evaluated the RF hydro-injector (RFHI) device that simultaneously delivers both a microneedle intradermal RF treatment and a HA filler injection to overcome the disadvantages of HA filler and RF devices alone. This study aimed to assess the efficacy and safety of the RFHI device for the rejuvenation of the periorbital area, including the lateral canthal lines (LCLs) and the infraorbital area. A total of 24 subjects were enrolled in this study and underwent 2 to 3 treatments using the RFHI device. The investigator's global assessment of the lateral canthal line (IGA-LCL) and the global esthetic improvement scale (GAIS) were used to evaluate the improvement in the LCL. Cutometer® was used to evaluate the skin's elasticity, and the Antera 3D image capture system® was used to evaluate the degree of wrinkles, roughness, and pore volume. At the 8 week follow-up after the first treatment session, both the IGA-LCL and GAIS showed significant improvement. The improvement in the wrinkles, roughness, and pore volume, measured by the Antera 3D image capture system®, was statistically significant. No serious adverse event was reported. This RFHI device, which delivers both microneedle intradermal RF treatment and HA filler injection, is effective and safe for periorbital rejuvenation.

Investigation of combined treatment of acupuncture and neurofeedback for improving cognitive function in mild neurocognitive disorder: A randomized, assessor-blind, pilot study.

BACKGROUND: Mild neurocognitive disorder (MND) is an intermediate state that can progress to dementia, and the cognitive reserve of MND is an important task in preventing dementia. Acupuncture and neurofeedback (NF) training have been used to improve cognitive function and treat MND or dementia, but their effectiveness remains controversial. In this trial, we will evaluate the efficacy and safety of combined NF-acupuncture treatment in comparison with single acupuncture treatment. METHODS AND DESIGN: This study is a randomized, assessor-blind, pilot trial. It is designed in accordance with the Standards for Reporting Interventions in Controlled Trials of Acupuncture. A total of 44 MND participants who meet the inclusion and exclusion criteria will be enrolled, and each will be randomly assigned to 1 of 2 groups of 22 subjects. Each subject will visit 24 times over 12 weeks and receive either acupuncture or NF-acupuncture combined treatment. At visit 25 (week 13), a follow-up evaluation will be performed, and then the investigator will analyze the results. The primary outcome is defined by the Korean version of the Montreal Cognitive Assessment score from screening to visit 25. The secondary outcome includes the following: change in Alzheimer Disease Assessment Scale-Cognitive, the Korean version of the Beck Depression Inventory, Body Awareness Questionnaire, delayed matching to sample task scores, and functional near-infrared spectroscopy values, from visit 1 to visit 25; heart rate variability values from visit 1 to visit 5, visit 9, visit 13, visit 21, visit 25; breath per minute values from visit 1 to visit 1 to 25. DISCUSSION: We will evaluate the effectiveness and safety of combined NF-acupuncture therapy, and expect that it will serve as the basis for the use of NF together with acupuncture in the clinical setting. TRIAL REGISTRATION NUMBER: KCT0004972 (registered in Clinical Research Information Service of the Republic of Korea, https://cris.nih.go.kr/cris/search/detailSearch.do/16239).

Clinicoprognostic and Histopathological Features of Guttate and Plaque Psoriasis Based on PD-1 Expression.

Several studies have determined the correlation between programmed cell death protein-1 (PD-1) and chronic plaque psoriasis (CPP). However, limited studies have assessed the association between PD-1 expression and the clinicoprognostic and distinct clinicopathological characteristics of CPP and guttate psoriasis (GP). Twenty-nine patients with skin biopsy-confirmed CPP were recruited at the Asan Medical Center between January 2018 and June 2020, and 33 patients with biopsy-confirmed GP were enrolled between January 2002 and June 2020. The clinicoprognostic and histopathological characteristics were analyzed according to immunohistochemical PD-1 expression in the epidermal or dermal inflammatory infiltrates. The CPP and GP lesions were divided into PD-1-low and PD-1-high groups. The CPP epidermal PD-1-high group had typical histopathological changes and significantly higher psoriasis area and severity index scores (p = 0.014) and disease duration (p = 0.009) than the epidermal PD-1-low group. In patients with GP, compared with the dermal PD-1-high group, the dermal PD-1-low group exhibited significantly higher disease duration (p = 0.002) and relapse rate of plaque psoriasis (p = 0.005) and significantly lower relapse-free survival (p = 0.016). Upregulated epidermal PD-1 expression was correlated with the chronicity and severity of CPP, while downregulated dermal PD-1 expression was correlated with poor prognosis of GP.

Magnetic resonance imaging of neuroinflammation in chronic pain: a role for astrogliosis?

Noninvasive measures of neuroinflammatory processes in humans could substantially aid diagnosis and therapeutic development for many disorders, including chronic pain. Several proton magnetic resonance spectroscopy (H-MRS) metabolites have been linked with glial activity (ie, choline and myo-inositol) and found to be altered in chronic pain patients, but their role in the neuroinflammatory cascade is not well known. Our multimodal study evaluated resting functional magnetic resonance imaging connectivity and H-MRS metabolite concentration in insula cortex in 43 patients suffering from fibromyalgia, a chronic centralized pain disorder previously demonstrated to include a neuroinflammatory component, and 16 healthy controls. Patients demonstrated elevated choline (but not myo-inositol) in anterior insula (aIns) (P = 0.03), with greater choline levels linked with worse pain interference (r = 0.41, P = 0.01). In addition, reduced resting functional connectivity between aIns and putamen was associated with both pain interference (whole brain analysis, pcorrected < 0.01) and elevated aIns choline (r = -0.37, P = 0.03). In fact, aIns/putamen connectivity statistically mediated the link between aIns choline and pain interference (P < 0.01), highlighting the pathway by which neuroinflammation can impact clinical pain dysfunction. To further elucidate the molecular substrates of the effects observed, we investigated how putative neuroinflammatory H-MRS metabolites are linked with ex vivo tissue inflammatory markers in a nonhuman primate model of neuroinflammation. Results demonstrated that cortical choline levels were correlated with glial fibrillary acidic protein, a known marker for astrogliosis (Spearman r = 0.49, P = 0.03). Choline, a putative neuroinflammatory H-MRS-assessed metabolite elevated in fibromyalgia and associated with pain interference, may be linked with astrogliosis in these patients.

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.

Machine learning-based prediction of clinical pain using multimodal neuroimaging and autonomic metrics.

Although self-report pain ratings are the gold standard in clinical pain assessment, they are inherently subjective in nature and significantly influenced by multidimensional contextual variables. Although objective biomarkers for pain could substantially aid pain diagnosis and development of novel therapies, reliable markers for clinical pain have been elusive. In this study, individualized physical maneuvers were used to exacerbate clinical pain in patients with chronic low back pain (N = 53), thereby experimentally producing lower and higher pain states. Multivariate machine-learning models were then built from brain imaging (resting-state blood-oxygenation-level-dependent and arterial spin labeling functional imaging) and autonomic activity (heart rate variability) features to predict within-patient clinical pain intensity states (ie, lower vs higher pain) and were then applied to predict between-patient clinical pain ratings with independent training and testing data sets. Within-patient classification between lower and higher clinical pain intensity states showed best performance (accuracy = 92.45%, area under the curve = 0.97) when all 3 multimodal parameters were combined. Between-patient prediction of clinical pain intensity using independent training and testing data sets also demonstrated significant prediction across pain ratings using the combined model (Pearson's r = 0.63). Classification of increased pain was weighted by elevated cerebral blood flow in the thalamus, and prefrontal and posterior cingulate cortices, and increased primary somatosensory connectivity to frontoinsular cortex. Our machine-learning approach introduces a model with putative biomarkers for clinical pain and multiple clinical applications alongside self-report, from pain assessment in noncommunicative patients to identification of objective pain endophenotypes that can be used in future longitudinal research aimed at discovery of new approaches to combat chronic pain.