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.

Reduced tactile acuity in chronic low back pain is linked with structural neuroplasticity in primary somatosensory cortex and is modulated by acupuncture therapy.

Prior studies have shown that patients suffering from chronic Low Back Pain (cLBP) have impaired somatosensory processing including reduced tactile acuity, i.e. reduced ability to resolve fine spatial details with the perception of touch. The central mechanism(s) underlying reduced tactile acuity are unknown but may include changes in specific brain circuitries (e.g. neuroplasticity in the primary somatosensory cortex, S1). Furthermore, little is known about the linkage between changes in tactile acuity and the amelioration of cLBP by somatically-directed therapeutic interventions, such as acupuncture. In this longitudinal neuroimaging study, we evaluated healthy control adults (HC, N â€‹= â€‹50) and a large sample of cLBP patients (N â€‹= â€‹102) with structural brain imaging (T1-weighted MRI for Voxel-Based Morphometry, VBM; Diffusion Tensor Imaging, DTI) and tactile acuity testing using two-point discrimination threshold (2PDT) over the lower back (site of pain) and finger (control) locations. Patients were evaluated at baseline and following a 4-week course of acupuncture, with patients randomized to either verum acupuncture, two different forms of sham acupuncture (designed with or without somatosensory afference), or no-intervention usual care control. At baseline, cLBP patients demonstrated reduced acuity (greater 2PDT, P â€‹= â€‹0.01) over the low back, but not finger (P â€‹= â€‹0.29) locations compared to HC, suggesting that chronic pain affects tactile acuity specifically at body regions encoding the experience of clinical pain. At baseline, Gray Matter Volume (GMV) was elevated and Fractional Anisotropy (FA) was reduced, respectively, in the S1-back region of cLBP patients compared to controls (P â€‹< â€‹0.05). GMV in cLBP correlated with greater 2PDT-back scores (ρ â€‹= â€‹0.27, P â€‹= â€‹0.02). Following verum acupuncture, tactile acuity over the back was improved (reduced 2PDT) and greater improvements were associated with reduced S1-back GMV (ρ â€‹= â€‹0.52, P â€‹= â€‹0.03) and increased S1-back adjacent white matter FA (ρ â€‹= â€‹-0.56, P â€‹= â€‹0.01). These associations were not seen for non-verum control interventions. Thus, S1 neuroplasticity in cLBP is linked with deficits in tactile acuity and, following acupuncture therapy, may represent early mechanistic changes in somatosensory processing that track with improved tactile acuity.

Impaired mesocorticolimbic connectivity underlies increased pain sensitivity in chronic low back pain.

Chronic low back pain (cLBP) is a prevalent disorder. A growing body of evidence linking the pathology of the reward network to chronic pain suggests that pain sensitization may contribute to cLBP chronification via disruptions of mesocortical and mesolimbic circuits in the reward system. Resting-state (RS) functional magnetic resonance imaging (fMRI) data was acquired from 90 patients with cLBP and 74 matched pain-free controls (HCs) at baseline and after a manipulation for back pain intensification. The ventral tegmental area (VTA) was chosen as a seed region to perform RS functional connectivity (FC) analysis. Baseline rsFC of both the mesocortical (between the VTA and bilateral rostral anterior cingulate cortex (rACC)/and medial prefrontal cortex (mPFC)) and mesolimbic (between the VTA and bilateral hippocampus/parahippocampus) pathways was reduced in patients with cLBP (vs. HCs). In addition, patients exhibiting higher back pain intensity (compared to the relatively lower back pain intensity condition) also showed increases in both mesocortical and mesolimbic connectivity, implicating these pathways in pain downregulation in cLBP. Mediation analysis further isolated the mesolimbic (VTA-hippocampus/parahippocampus) dysconnectivity as a neural mechanism mediating the association between mechanical pain sensitivity (indexed by P40 pressure) and cLBP severity. In sum, the current study demonstrates deficient mesocorticolimbic connectivity in cLBP, with mesolimbic dysconnectivity potentially mediating the contribution of pain sensitization to pain chronification. These reward network dysfunctions and purportedly, dopaminergic dysregulations, may help us to identify key brain targets of neuromodulation in the treatment of cLBP.

Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease.

BACKGROUND: Prion disease is neurodegenerative disease that is typically fatal within months of first symptoms. Clinical trials in this rapidly declining symptomatic patient population have proven challenging. Individuals at high lifetime risk for genetic prion disease can be identified decades before symptom onset and provide an opportunity for early therapeutic intervention. However, randomizing pre-symptomatic carriers to a clinical endpoint is not numerically feasible. We therefore launched a cohort study in pre-symptomatic genetic prion disease mutation carriers and controls with the goal of evaluating biomarker endpoints that may enable informative trials in this population. METHODS: We collected cerebrospinal fluid (CSF) and blood from pre-symptomatic individuals with prion protein gene (PRNP) mutations (N = 27) and matched controls (N = 16), in a cohort study at Massachusetts General Hospital. We quantified total prion protein (PrP) and real-time quaking-induced conversion (RT-QuIC) prion seeding activity in CSF and neuronal damage markers total tau (T-tau) and neurofilament light chain (NfL) in CSF and plasma. We compared these markers cross-sectionally, evaluated short-term test-retest reliability over 2-4 months, and conducted a pilot longitudinal study over 10-20 months. RESULTS: CSF PrP levels were stable on test-retest with a mean coefficient of variation of 7% for both over 2-4 months in N = 29 participants and over 10-20 months in N = 10 participants. RT-QuIC was negative in 22/23 mutation carriers. The sole individual with positive RT-QuIC seeding activity at two study visits had steady CSF PrP levels and slightly increased tau and NfL concentrations compared with the others, though still within the normal range, and remained asymptomatic 1 year later. T-tau and NfL showed no significant differences between mutation carriers and controls in either CSF or plasma. CONCLUSIONS: CSF PrP will be interpretable as a pharmacodynamic readout for PrP-lowering therapeutics in pre-symptomatic individuals and may serve as an informative surrogate biomarker in this population. In contrast, markers of prion seeding activity and neuronal damage do not reliably cross-sectionally distinguish mutation carriers from controls. Thus, as PrP-lowering therapeutics for prion disease advance, "secondary prevention" based on prodromal pathology may prove challenging; instead, "primary prevention" trials appear to offer a tractable paradigm for trials in pre-symptomatic individuals.

Clinical Trials and Tribulations in the COVID-19 Era.

Advances in treating and preventing Alzheimer disease and other neurocognitive disorders of aging arise from rigorous preclinical and clinical research, with randomized controlled treatment trials as the last and definitive test. The COVID-19 pandemic has greatly disrupted ongoing interventional studies and researchers are scrambling to find ways to safely continue this critical work amidst rapidly shifting guidelines from sponsors, institutions, and state and federal guidelines. Here the authors describe novel approaches and work-flow adaptations to study visits, drug delivery and interim and endpoint safety and outcomes assessments to avoid sacrificing years of preparation and substantial financial investments, to work in the best interest of participants and their caregivers, and to continue on the path toward discovering disease-modifying treatments for the millions of individuals impacted by major neurocognitive disorders.

Identifying brain regions associated with the neuropathology of chronic low back pain: a resting-state amplitude of low-frequency fluctuation study.

BACKGROUND: Previous studies have found widespread pain processing alterations in the brain in chronic low back pain (cLBP) patients. We aimed to (1) identify brain regions showing altered amplitude of low-frequency fluctuations (ALFF) using MRI and use these regions to discriminate cLBP patients from healthy controls (HCs) and (2) identify brain regions that are sensitive to cLBP pain intensity changes. METHODS: We compared ALFF differences by MRI between cLBP subjects (90) and HCs (74), conducted a discriminative analysis to validate the results, and explored structural changes in key brain regions of cLBP. We also compared ALFF changes in cLBP patients after pain-exacerbating manoeuvres. RESULTS: ALFF was increased in the post-/precentral gyrus (PoG/PrG), paracentral lobule (PCL)/supplementary motor area (SMA), and anterior cingulate cortex (ACC), and grey matter volume was increased in the left ACC in cLBP patients. PCL/SMA ALFF reliably discriminated cLBP patients from HCs in an independent cohort. cLBP patients showed increased ALFF in the insula, amygdala, hippocampal/parahippocampal gyrus, and thalamus and decreased ALFF in the default mode network (DMN) when their spontaneous low back pain intensity increased after the pain-exacerbating manoeuvre. CONCLUSIONS: Brain low-frequency oscillations in the PCL, SMA, PoG, PrG, and ACC may be associated with the neuropathology of cLBP. Low-frequency oscillations in the insula, amygdala, hippocampal/parahippocampal gyrus, thalamus, and DMN are sensitive to manoeuvre-induced spontaneous back pain intensity changes.

Rewiring the primary somatosensory cortex in carpal tunnel syndrome with acupuncture.

Carpal tunnel syndrome is the most common entrapment neuropathy, affecting the median nerve at the wrist. Acupuncture is a minimally-invasive and conservative therapeutic option, and while rooted in a complex practice ritual, acupuncture overlaps significantly with many conventional peripherally-focused neuromodulatory therapies. However, the neurophysiological mechanisms by which acupuncture impacts accepted subjective/psychological and objective/physiological outcomes are not well understood. Eligible patients (n = 80, 65 female, age: 49.3 ± 8.6 years) were enrolled and randomized into three intervention arms: (i) verum electro-acupuncture 'local' to the more affected hand; (ii) verum electro-acupuncture at 'distal' body sites, near the ankle contralesional to the more affected hand; and (iii) local sham electro-acupuncture using non-penetrating placebo needles. Acupuncture therapy was provided for 16 sessions over 8 weeks. Boston Carpal Tunnel Syndrome Questionnaire assessed pain and paraesthesia symptoms at baseline, following therapy and at 3-month follow-up. Nerve conduction studies assessing median nerve sensory latency and brain imaging data were acquired at baseline and following therapy. Functional magnetic resonance imaging assessed somatotopy in the primary somatosensory cortex using vibrotactile stimulation over three digits (2, 3 and 5). While all three acupuncture interventions reduced symptom severity, verum (local and distal) acupuncture was superior to sham in producing improvements in neurophysiological outcomes, both local to the wrist (i.e. median sensory nerve conduction latency) and in the brain (i.e. digit 2/3 cortical separation distance). Moreover, greater improvement in second/third interdigit cortical separation distance following verum acupuncture predicted sustained improvements in symptom severity at 3-month follow-up. We further explored potential differential mechanisms of local versus distal acupuncture using diffusion tensor imaging of white matter microstructure adjacent to the primary somatosensory cortex. Compared to healthy adults (n = 34, 28 female, 49.7 ± 9.9 years old), patients with carpal tunnel syndrome demonstrated increased fractional anisotropy in several regions and, for these regions we found that improvement in median nerve latency was associated with reduction of fractional anisotropy near (i) contralesional hand area following verum, but not sham, acupuncture; (ii) ipsilesional hand area following local, but not distal or sham, acupuncture; and (iii) ipsilesional leg area following distal, but not local or sham, acupuncture. As these primary somatosensory cortex subregions are distinctly targeted by local versus distal acupuncture electrostimulation, acupuncture at local versus distal sites may improve median nerve function at the wrist by somatotopically distinct neuroplasticity in the primary somatosensory cortex following therapy. Our study further suggests that improvements in primary somatosensory cortex somatotopy can predict long-term clinical outcomes for carpal tunnel syndrome.

Influence of the patient-practitioner interaction context on acupuncture outcomes in functional dyspepsia: study protocol for a multicenter randomized controlled trial.

BACKGROUND: In the treatment of functional dyspepsia, the placebo effect has been reported to be high, and the influence of the patient-practitioner relationship may be a major component of this effect. The specific and non-specific effects of acupuncture cannot be easily distinguished, and the patient-practitioner relationship may influence the total therapeutic effect in clinical practice. There have been no studies that investigate the influence of patient-practitioner relationship on acupuncture treatment for patients with functional dyspepsia. METHODS: Patients with postprandial distress syndrome, a functional dyspepsia subtype, will be recruited at three hospitals (two in Korea and one in USA) for an international, multi-center, randomized, patient/assessor-blinded, clinical trial. The total anticipated sample size is 88. The participants will be randomly allocated into two groups: an augmented interaction group and a limited interaction group. Acupuncture, with total 12 acupoints, will be performed twice weekly for 4 weeks in both groups. Trained practitioners will provide an "augmented" or "limited" interaction context, as determined by random allocation. The primary outcome measure is the proportion of responders, the proportion of participants who answer "yes" to more than half of the adequate relief questions during the study. Secondary outcome measures include questionnaires for quality of life and symptoms of dyspepsia, and maximum tolerable volume of nutrient drink test. Data will be collected at baseline and following 4 weeks of acupuncture. DISCUSSION: This study will evaluate the influence of the patient-practitioner interaction on clinical effects of acupuncture in patients with functional dyspepsia. TRIAL REGISTRATION: CRIS Identifier: ( KCT0002229 ).

Functional deficits in carpal tunnel syndrome reflect reorganization of primary somatosensory cortex.

Carpal tunnel syndrome, a median nerve entrapment neuropathy, is characterized by sensorimotor deficits. Recent reports have shown that this syndrome is also characterized by functional and structural neuroplasticity in the primary somatosensory cortex of the brain. However, the linkage between this neuroplasticity and the functional deficits in carpal tunnel syndrome is unknown. Sixty-three subjects with carpal tunnel syndrome aged 20-60 years and 28 age- and sex-matched healthy control subjects were evaluated with event-related functional magnetic resonance imaging at 3 T while vibrotactile stimulation was delivered to median nerve innervated (second and third) and ulnar nerve innervated (fifth) digits. For each subject, the interdigit cortical separation distance for each digit's contralateral primary somatosensory cortex representation was assessed. We also evaluated fine motor skill performance using a previously validated psychomotor performance test (maximum voluntary contraction and visuomotor pinch/release testing) and tactile discrimination capacity using a four-finger forced choice response test. These biobehavioural and clinical metrics were evaluated and correlated with the second/third interdigit cortical separation distance. Compared with healthy control subjects, subjects with carpal tunnel syndrome demonstrated reduced second/third interdigit cortical separation distance (P < 0.05) in contralateral primary somatosensory cortex, corroborating our previous preliminary multi-modal neuroimaging findings. For psychomotor performance testing, subjects with carpal tunnel syndrome demonstrated reduced maximum voluntary contraction pinch strength (P < 0.01) and a reduced number of pinch/release cycles per second (P < 0.05). Additionally, for four-finger forced-choice testing, subjects with carpal tunnel syndrome demonstrated greater response time (P < 0.05), and reduced sensory discrimination accuracy (P < 0.001) for median nerve, but not ulnar nerve, innervated digits. Moreover, the second/third interdigit cortical separation distance was negatively correlated with paraesthesia severity (r = -0.31, P < 0.05), and number of pinch/release cycles (r = -0.31, P < 0.05), and positively correlated with the second and third digit sensory discrimination accuracy (r = 0.50, P < 0.05). Therefore, reduced second/third interdigit cortical separation distance in contralateral primary somatosensory cortex was associated with worse symptomatology (particularly paraesthesia), reduced fine motor skill performance, and worse sensory discrimination accuracy for median nerve innervated digits. In conclusion, primary somatosensory cortex neuroplasticity for median nerve innervated digits in carpal tunnel syndrome is indeed maladaptive and underlies the functional deficits seen in these patients.

Influence of patient-clinician relationship style on acupuncture outcomes in functional dyspepsia: A multi-site randomized controlled trial in Korea.

INTRODUCTION: Research suggests that a warm and empathic "patient-centered" patient-clinician relationship produces better clinical outcomes when compared with a more neutral "disease-centered" relationship. Acupuncturists performed both styles of therapy for patients with functional dyspepsia in Korea. METHODS: The present randomized controlled trial assigned patients (n = 73) to identical acupuncture treatment with either patient-centered augmented care or disease-centered limited care. The Korean version of the Nepean Dyspepsia Index (NDI-K) was the primary outcome measure. Secondary outcome measures included Consultation And Relational Empathy (CARE) scale. RESULTS: Both groups showed improvement in NDI-K. Patient-centered augmented acupuncture produced less effective symptom improvement compared to disease-centered limited acupuncture (NDI-K sum score and frequency; P = 0.008 and P = 0.037 respectively). CARE scores were higher for the augmented versus limited group (P = 0.001), supporting the fidelity of the experimentally controlled patient/clinician relationship. There were no significant differences between the groups in any of other secondary outcomes. CONCLUSION: Patients demonstrated greater improvement following acupuncture conducted with a more neutral, "disease-centered" style of relationship. This result is counter to similar research conducted in Western countries and suggests that cultural factors can significantly shape optimum styles of acupuncture therapy. PRACTICE IMPLICATIONS: Clinicians should consider cultural differences when applying acupuncture therapy.

Fluid Biomarkers in Individuals at Risk for Genetic Prion Disease up to Disease Conversion.

OBJECTIVES: To longitudinally characterize disease-relevant CSF and plasma biomarkers in individuals at risk for genetic prion disease up to disease conversion. METHODS: This single-center longitudinal cohort study has followed known carriers of PRNP pathogenic variants at risk for prion disease, individuals with a close relative who died of genetic prion disease but who have not undergone predictive genetic testing, and controls. All participants were asymptomatic at first visit and returned roughly annually. We determined PRNP genotypes, measured NfL and GFAP in plasma, and RT-QuIC, total PrP, NfL, T-tau, and beta-synuclein in CSF. RESULTS: Among 41 carriers and 21 controls enrolled, 28 (68%) and 15 (71%) were female, and mean ages were 47.5 and 46.1. At baseline, all individuals were asymptomatic. We observed RT-QuIC seeding activity in the CSF of 3 asymptomatic E200K carriers who subsequently converted to symptomatic and died of prion disease. 1 P102L carrier remained RT-QuIC negative through symptom conversion. No other individuals developed symptoms. The prodromal window from detection of RT-QuIC positivity to disease onset was 1 year long in an E200K individual homozygous (V/V) at PRNP codon 129 and 2.5 and 3.1 years in 2 codon 129 heterozygotes (M/V). Changes in neurodegenerative and neuroinflammatory markers were variably observed prior to onset, with increases observed for plasma NfL in 4/4 converters, and plasma GFAP, CSF NfL, CSF T-tau, and CSF beta-synuclein each in 2/4 converters, although values relative to age and fold changes relative to individual baseline were not remarkable for any of these markers. CSF PrP was longitudinally stable with mean coefficient of variation 9.0% across all individuals over up to 6 years, including data from converting individuals at RT-QuIC-positive timepoints. DISCUSSION: CSF prion seeding activity may represent the earliest detectable prodromal sign in E200K carriers. Neuronal damage and neuroinflammation markers show limited sensitivity in the prodromal phase. CSF PrP levels remain stable even in the presence of RT-QuIC seeding activity. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT05124392 posted 2017-12-01, updated 2023-01-27.

Feasibility of common, enjoyable game play for assessing daily cognitive functioning in older adults.

Background: Frequent digital monitoring of cognition is a promising approach for assessing endpoints in prevention and treatment trials of Alzheimer's disease and related dementias (ADRD). This study evaluated the feasibility of the MIND GamePack© for recurrent semi-passive assessment of cognition across a longitudinal interval. Methods: The MIND GamePack consists of four iPad-based games selected to be both familiar and enjoyable: Word Scramble, Block Drop, FreeCell, and Memory Match. Participants were asked to play 20 min/day for 5 days (100 min) for 4 months. Feasibility of use by older adults was assessed by measuring gameplay time and game performance. We also evaluated compliance through semi-structured surveys. A linear generalized estimating equation (GEE) model was used to analyze changes in gameplay time, and a regression tree model was employed to estimate the days it took for game performance to plateau. Subjective and environmental factors associated with gameplay time and performance were examined, including daily self-reported questions of memory and thinking ability, mood, sleep, energy, current location, and distractions prior to gameplay. Results: Twenty-six cognitively-unimpaired older adults participated (mean age ± SD = 71.9 ± 8.6; 73% female). Gameplay time remained stable throughout the 4-months, with an average compliance rate of 91% ± 11% (1946 days of data across all participants) and weekly average playtime of 210 ± 132 min per participant. We observed an initial learning curve of improving game performance which on average, plateaued after 22-39 days, depending on the game. Higher levels of self-reported memory and thinking ability were associated with more gameplay time and sessions. Conclusion: MIND GamePack is a feasible and well-designed semi-passive cognitive assessment platform which may provide complementary data to traditional neuropsychological testing in research on aging and dementia.

Biomarker changes preceding symptom onset in genetic prion disease.

Importance: Genetic prion disease is a universally fatal and rapidly progressive neurodegenerative disease for which genetically targeted therapies are currently under development. Preclinical proofs of concept indicate that treatment before symptoms will offer outsize benefit. Though early treatment paradigms will be informed by the longitudinal biomarker trajectory of mutation carriers, to date limited cases have been molecularly tracked from the presymptomatic phase through symptomatic onset. Objective: To longitudinally characterize disease-relevant cerebrospinal fluid (CSF) and plasma biomarkers in individuals at risk for genetic prion disease up to disease conversion, alongside non-converters and healthy controls. Design setting and participants: This single-center longitudinal cohort study has followed 41 PRNP mutation carriers and 21 controls for up to 6 years. Participants spanned a range of known pathogenic PRNP variants; all subjects were asymptomatic at first visit and returned roughly annually. Four at-risk individuals experienced prion disease onset during the study. Main outcomes and measures: RT-QuIC prion seeding activity, prion protein (PrP), neurofilament light chain (NfL) total tau (t-tau), and beta synuclein were measured in CSF. Glial fibrillary acidic protein (GFAP) and NfL were measured in plasma. Results: We observed RT-QuIC seeding activity in the CSF of three E200K carriers prior to symptom onset and death, while the CSF of one P102L carrier remained RT-QuIC negative through symptom conversion. The prodromal window of RT-QuIC positivity was one year long in an E200K individual homozygous (V/V) at PRNP codon 129 and was longer than two years in two codon 129 heterozygotes (M/V). Other neurodegenerative and neuroinflammatory markers gave less consistent signal prior to symptom onset, whether analyzed relative to age or individual baseline. CSF PrP was longitudinally stable (mean CV 10%) across all individuals over up to 6 years, including at RT-QuIC positive timepoints. Conclusion and relevance: In this study, we demonstrate that at least for the E200K mutation, CSF prion seeding activity may represent the earliest detectable prodromal sign, and that its prognostic value may be modified by codon 129 genotype. Neuronal damage and neuroinflammation markers show limited sensitivity in the prodromal phase. CSF PrP levels remain stable even in the presence of RT-QuIC seeding activity.

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.

S1 Brain Connectivity in Carpal Tunnel Syndrome Underlies Median Nerve and Functional Improvement Following Electro-Acupuncture.

Carpal Tunnel Syndrome (CTS) is a median nerve entrapment neuropathy that alters primary somatosensory cortex (S1) organization. While electro-acupuncture (EA), a form of peripheral neuromodulation, has been shown to improve clinical and neurophysiological CTS outcomes, the role of EA-evoked brain response during therapy (within and beyond S1) for improved outcomes is unknown. We investigated S1-associated whole brain fMRI connectivity during both a resting and sustained EA stimulation state in age-matched healthy controls (N = 28) and CTS patients (N = 64), at baseline and after 8 weeks of acupuncture therapy (local, distal, or sham EA). Compared to healthy controls, CTS patients at baseline showed decreased resting state functional connectivity between S1 and thalamic pulvinar nucleus. Increases in S1/pulvinar connectivity strength following verum EA therapy (combined local and distal) were correlated with improvements in median nerve velocity (r = 0.38, p = 0.035). During sustained local EA, compared to healthy controls, CTS patients demonstrated increased functional connectivity between S1 and anterior hippocampus (aHipp). Following 8 weeks of local EA therapy, S1/aHipp connectivity significantly decreased and greater decrease was associated with improvement in patients' functional status (r = 0.64, p = 0.01) and increased median nerve velocity (r = -0.62, p = 0.013). Thus, connectivity between S1 and other brain areas is also disrupted in CTS patients and may be improved following EA therapy. Furthermore, stimulus-evoked fMRI connectivity adds therapy-specific, mechanistic insight to more common resting state connectivity approaches. Specifically, local EA modulates S1 connectivity to sensory and affective processing regions, linked to patient function and median nerve health.

A pilot protocol to assess the feasibility of a virtual multiple crossover, randomized controlled trial design using methylphenidate in mild cognitive impairment.

BACKGROUND: The conventional clinical trial design in Alzheimer's disease (AD) and AD-related disorders (ADRDs) is the parallel-group randomized controlled trial. However, in heterogeneous disorders like AD/ADRDs, this design requires large sample sizes to detect meaningful effects in an "average" patient. They are very costly and, despite many attempts, have not yielded new treatments for many years. An alternative, the multi-crossover, randomized control trial (MCRCT) is a design in which each patient serves as their own control across successive, randomized blocks of active treatment and placebo. This design overcomes many limitations of parallel-group trials, yielding an unbiased assessment of treatment effect at the individual level ("N-of-1") regardless of unique patient characteristics. The goal of the present study is to pilot a MCRCT of a potential symptomatic treatment, methylphenidate, for mild-stage AD/ADRDs, testing feasibility and compliance of participants in this design and efficacy of the drug using both standard and novel outcome measures suited for this design. METHODS: Ten participants with mild cognitive impairment or mild-stage dementia due to AD/ADRDs will undergo a 4-week lead-in period followed by three, month-long treatment blocks (2 weeks of treatment with methylphenidate, 2 weeks placebo in random order). This trial will be conducted entirely virtually with an optional in-person screening visit. The primary outcome of interest is feasibility as measured by compliance and retention, with secondary and exploratory outcomes including cognition as measured by neuropsychological assessment at the end of each treatment period and daily brain games played throughout the study, actigraphy, and neuropsychiatric and functional assessments. DISCUSSION: This pilot study will gauge the feasibility of conducting a virtual MCRCT for symptomatic treatment in early AD/ADRD. It will also compare home-based daily brain games with standard neuropsychological measures within a clinical trial for AD/ADRD. Particular attention will be paid to compliance, tolerability of drug and participation, learning effects, trends and stability of daily measures across blocks, medication carryover effects, and correlations between standard and brief daily assessments. These data will provide guidance for more efficient trial design and the use of potentially more robust, ecological outcome measures in AD/ADRD research. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03811847 . Registered on 21 January 2019.

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.

Author Correction: Distinct thalamocortical network dynamics are associated with the pathophysiology of chronic low back pain.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Distinct thalamocortical network dynamics are associated with the pathophysiology of chronic low back pain.

Thalamocortical dysrhythmia is a key pathology of chronic neuropathic pain, but few studies have investigated thalamocortical networks in chronic low back pain (cLBP) given its non-specific etiology and complexity. Using fMRI, we propose an analytical pipeline to identify abnormal thalamocortical network dynamics in cLBP patients and validate the findings in two independent cohorts. We first identify two reoccurring dynamic connectivity states and their associations with chronic and temporary pain. Further analyses show that cLBP patients have abnormal connectivity between the ventral lateral/posterolateral nucleus (VL/VPL) and postcentral gyrus (PoCG) and between the dorsal/ventral medial nucleus and insula in the less frequent connectivity state, and temporary pain exacerbation alters connectivity between the VL/VPL and PoCG and the default mode network in the more frequent connectivity state. These results extend current findings on thalamocortical dysfunction and dysrhythmia in chronic pain and demonstrate that cLBP pathophysiology and clinical pain intensity are associated with distinct thalamocortical network dynamics.

Acupuncture Treatment Modulates the Connectivity of Key Regions of the Descending Pain Modulation and Reward Systems in Patients with Chronic Low Back Pain.

Chronic low back pain (cLBP) is a common disorder with unsatisfactory treatment options. Acupuncture has emerged as a promising method for treating cLBP. However, the mechanism underlying acupuncture remains unclear. In this study, we investigated the modulation effects of acupuncture on resting state functional connectivity (rsFC) of the periaqueductal gray (PAG) and ventral tegmental area (VTA) in patients with cLBP. Seventy-nine cLBP patients were recruited and assigned to four weeks of real or sham acupuncture. Resting state functional magnetic resonance imaging data were collected before the first and after the last treatment. Fifty patients completed the study. We found remission of pain bothersomeness in all treatment groups after four weeks, with greater pain relief after real acupuncture compared to sham acupuncture. We also found that real acupuncture can increase VTA/PAG rsFC with the amygdala, and the increased rsFC was associated with decreased pain bothersomeness scores. Baseline PAG-amygdala rsFC could predict four-week treatment response. Our results suggest that acupuncture may simultaneously modulate the rsFC of key regions in the descending pain modulation (PAG) and reward systems (VTA), and the amygdala may be a key node linking the two systems to produce antinociceptive effects. Our findings highlight the potential of acupuncture for chronic low back pain management.