Correlation between PainDETECT Questionnaire and Quantitative Sensory Testing for the Detection of Neuropathic Pain in Hidradenitis Suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that is often severely painful due to nociceptive mechanisms (i.e., stimulation of cutaneous nociceptors). However, patient-reported pain character suggests that neuropathy may also drive HS pain in a subset of patients. Quantitative sensory testing (QST) can help identify neuropathic pain by testing for heightened and paradoxical pain responses in patients, but it is less feasible for routine clinical use compared with brief questionnaires. We therefore tested the suitability of a standardized neuropathic questionnaire (PainDETECT; PD-Q) for use as a surrogate clinical measure by directly comparing it with QST-identified neuropathic pain in HS. METHODS: This observational, cross-sectional study included 22 adults with painful HS lesions who completed the PD-Q and underwent QST. A receiver operating characteristic curve was generated and Cohen's Kappa, sensitivity, and specificity were examined at three scoring thresholds. RESULTS: Of the 22 participants, 14 (64%) exhibited dynamic mechanical allodynia and/or paradoxical thermal sensations in QST, which are characteristically found in neuropathic pain. According to the PD-Q, 8 participants (36%) were unlikely, 8 (36%) were possible, and 6 (27%) were likely to have neuropathic pain. A PD-Q Score indicating possible or likely neuropathic pain (i.e., ≥13) demonstrated 82% agreement with QST-determined neuropathic pain (Cohen's Kappa = 0.61 [p = 0.004]; sensitivity = 86%; specificity = 75%). CONCLUSION: The PD-Q demonstrates moderate agreement with QST in screening for neuropathic pain in HS and may be a helpful clinical tool.

Computational Scaling Relationships Predict Experimental Activity and Rate-Limiting Behavior in Homogeneous Water Oxidation.

While computational screening with first-principles density functional theory (DFT) is essential for evaluating candidate catalysts, limitations in accuracy typically prevent the prediction of experimentally relevant activities. Exemplary of these challenges are homogeneous water oxidation catalysts (WOCs) where differences in experimental conditions or small changes in ligand structure can alter rate constants by over an order of magnitude. Here, we compute mechanistically relevant electronic and energetic properties for 19 mononuclear Ru transition-metal complexes (TMCs) from three experimental water oxidation catalysis studies. We discover that 15 of these TMCs have experimental activities that correlate with a single property, the ionization potential of the Ru(II)-O2 catalytic intermediate. This scaling parameter allows the quantitative understanding of activity trends and provides insight into the rate-limiting behavior. We use this approach to rationalize differences in activity with different experimental conditions, and we qualitatively analyze the source of distinct behavior for different electronic states in the other four catalysts. Comparison to closely related single-atom catalysts and modified WOCs enables rationalization of the source of rate enhancement in these WOCs.

Representations and strategies for transferable machine learning improve model performance in chemical discovery.

Strategies for machine-learning (ML)-accelerated discovery that are general across material composition spaces are essential, but demonstrations of ML have been primarily limited to narrow composition variations. By addressing the scarcity of data in promising regions of chemical space for challenging targets such as open-shell transition-metal complexes, general representations and transferable ML models that leverage known relationships in existing data will accelerate discovery. Over a large set (∼1000) of isovalent transition-metal complexes, we quantify evident relationships for different properties (i.e., spin-splitting and ligand dissociation) between rows of the Periodic Table (i.e., 3d/4d metals and 2p/3p ligands). We demonstrate an extension to the graph-based revised autocorrelation (RAC) representation (i.e., eRAC) that incorporates the group number alongside the nuclear charge heuristic that otherwise overestimates dissimilarity of isovalent complexes. To address the common challenge of discovery in a new space where data are limited, we introduce a transfer learning approach in which we seed models trained on a large amount of data from one row of the Periodic Table with a small number of data points from the additional row. We demonstrate the synergistic value of the eRACs alongside this transfer learning strategy to consistently improve model performance. Analysis of these models highlights how the approach succeeds by reordering the distances between complexes to be more consistent with the Periodic Table, a property we expect to be broadly useful for other material domains.

Are Outcomes of Temporomandibular Joint Arthroscopy Influenced by Central Sensitization?

PURPOSE: A proportion of subjects with internal derangements of the temporomandibular joint (TMJ) may have a central sensitization disorder that may affect pain perception after surgery. This study aims to estimate the association between fibromyalgianess (FMness) score, a summed score of the Widespread Pain Index (WPI) and Symptom Severity Sore (SSS), and outcomes following TMJ arthroscopy. METHODS: A retrospective cohort study including individuals who received arthroscopy for TMJ internal derangement at Michigan Medicine between 2011 and 2020 was performed. A predictor variable, FMness score, was assigned via the sum of WPI and SSS. Univariate and bivariate analyses were performed. Linear-mixed effects models were used to analyze 6 different outcomes, each in their own model: pain, jaw functional limitation scale (JFLS), JFLS-mobility domain, pain-related disability, comfortable maximum interincisal opening, and active maximum interincisal opening. Covariance structure was selected based on null model fit separately for each outcome. RESULTS: Thirty-one subjects were included in the study sample. Twenty-eight subjects were female. Average age was 45.9 years. Bivariate analysis demonstrated that subject's FMness score was not correlated with pain (b = 0.03 [-0.10, 0.17] P = .59) or JFLS score (b = 1.00 [-.80, 2.81] P = .27). However, subject's FMness score was significant for predicting JFLS-mobility domain score (b = .61, [0.05, 1.18] P = .04). CONCLUSION: A greater extent of central sensitization was associated with lower comfortable mouth opening after surgery, greater limitations in opening wide enough to eat various foods (higher JFLS-mobility scores), and higher pain-related disability. Future studies with larger sample sizes and reconstructive TMJ operations such as total TMJ arthroplasty may help clarify the impact of SSS and WPI scores on outcomes of TMJ surgery.

Impact of Fibromyalgia Phenotype in Temporomandibular Disorders.

BACKGROUND: Mounting evidence suggests that central nervous system amplification, similar to that seen in fibromyalgia (FM), contributes to the pain experience in a subset of patients with temporomandibular disorders (TMD). METHODS: In this prospective observational study, patients with TMD completed the 2011 FM survey questionnaire, a surrogate measure of "centralized" pain. The influence of centralized pain on TMD pain, dysfunction, and disability was assessed dichotomously by determining the incidence of FM-positive cases in the sample and by using FM survey scores as a continuous measure of "fibromyalgia-ness" ("FM-ness"). RESULTS: The patients meeting criteria for FM diagnosis (17 of 89) had significantly more disease burden on numerous measures. FM-ness was positively associated with pain at rest, negative mood, tenderness to palpation, perceived jaw functional limitation, and pain-related disability, and it was negatively associated with comfortable pain-free jaw opening. The impact of FM-ness on perceived jaw functional limitation and disability was mediated by levels of spontaneous, ongoing pain in the orofacial region. Importantly, this pattern of findings was still present even in those not meeting the criteria for FM diagnosis. CONCLUSION: Together, these results imply that higher FM-ness increases TMD patient burden by amplifying spontaneous pain and further hampering painless jaw function, even in patients who do not meet criteria for FM diagnosis. These results are highly relevant for the clinical management of TMD, as they imply that targeting the central nervous system in the treatment of patients with TMD with evidence of pain centralization may help ameliorate both pain and jaw dysfunction.

Large-scale comparison of 3d and 4d transition metal complexes illuminates the reduced effect of exchange on second-row spin-state energetics.

Density functional theory (DFT) is widely used in transition-metal chemistry, yet essential properties such as spin-state energetics in transition-metal complexes (TMCs) are well known to be sensitive to the choice of the exchange-correlation functional. Increasing the amount of exchange in a functional typically shifts the preferred ground state in first-row TMCs from low-spin to high-spin by penalizing delocalization error, but the effect on properties of second-row complexes is less well known. We compare the exchange sensitivity of adiabatic spin-splitting energies in pairs of mononuclear 3d and 4d mid-row octahedral transition-metal complexes. We analyze hundreds of complexes assembled from four metals in two oxidation states with ten small monodentate ligands that span a wide range of field strengths expected to favor a variety of ground states. We observe consistently lower but proportional sensitivity to exchange fraction among 4d TMCs with respect to their isovalent 3d TMC counterparts, leading to the largest difference in sensitivities for the strongest field ligands. The combined effect of reduced exchange sensitivities and the greater low-spin bias of most 4d TMCs means that while over one-third of 3d TMCs change ground states over a modest variation (ca. 0.0-0.3) in exchange fraction, almost no 4d TMCs do. Differences in delocalization, as judged through changes in the metal-ligand bond lengths between spin states, do not explain the distinct behavior of 4d TMCs. Instead, evaluation of potential energy curves in 3d and 4d TMCs reveals that higher exchange sensitivities in 3d TMCs are likely due to the opposing effect of exchange on the low-spin and high-spin states, whereas the effect on both spin states is more comparable in 4d TMCs.

The role of thoracic epidural anesthesia in severe acute pancreatitis.

In animal studies of severe acute pancreatitis, thoracic epidural anesthesia appears to enhance the splanchnic circulation, improve end-organ perfusion, and favorably influence mortality. The application of thoracic epidurals in the critically ill human patient is less clear. Methodological difficulties in reliably assessing mesenteric flow have hampered progress, and clinical concerns surrounding this potentially attractive therapeutic modality remain unanswered. Future research needs to focus on the impact of epidural anesthesia on basic human physiological parameters to help direct further randomized studies in human disease.

Development of a rapid knee cartilage damage quantification method using magnetic resonance images.

BACKGROUND: Cartilage morphometry based on magnetic resonance images (MRIs) is an emerging outcome measure for clinical trials among patients with knee osteoarthritis (KOA). However, current methods for cartilage morphometry take many hours per knee and require extensive training on the use of the associated software. In this study we tested the feasibility, reliability, and construct validity of a novel osteoarthritis cartilage damage quantification method (Cartilage Damage Index [CDI]) that utilizes informative locations on knee MRIs. METHODS: We selected 102 knee MRIs from the Osteoarthritis Initiative that represented a range of KOA structural severity (Kellgren Lawrence [KL] Grade 0 - 4). We tested the intra- and inter-tester reliability of the CDI and compared the CDI scores against different measures of severity (radiographic joint space narrowing [JSN] grade, KL score, joint space width [JSW]) and static knee alignment, both cross-sectionally and longitudinally. RESULTS: Determination of the CDI took on average14.4 minutes (s.d. 2.1) per knee pair (baseline and follow-up of one knee). Repeatability was good (intra- and inter-tester reliability: intraclass correlation coefficient >0.86). The mean CDI scores related to all four measures of osteoarthritis severity (JSN grade, KL score, JSW, and knee alignment; all p values < 0.05). Baseline JSN grade and knee alignment also predicted subsequent 24-month longitudinal change in the CDI (p trends <0.05). During 24 months, knees with worsening in JSN or KL grade (i.e. progressors) had greater change in CDI score. CONCLUSIONS: The CDI is a novel knee cartilage quantification method that is rapid, reliable, and has construct validity for assessment of medial tibiofemoral osteoarthritis structural severity and its progression. It has the potential to addresses the barriers inherent to studies requiring assessment of cartilage damage on large numbers of knees, and as a biomarker for knee osteoarthritis progression.

Validation of quantitative magnetic resonance imaging-based apparent bone volume fraction in peri-articular tibial bone of cadaveric knees.

BACKGROUND: In the knee, high-resolution magnetic resonance (MR) imaging has demonstrated that increased apparent bone volume fraction (trabecular bone volume per total volume; BV/TV) in the peri-articular proximal medial tibia is associated with joint space narrowing and the presence of bone marrow lesions. However, despite evidence of construct validity, MR-based apparent BV/TV has not yet been cross-validated in the proximal medial tibia by comparison with a gold standard (e.g., micro-computed tomography [microCT]). In this cadaveric validation study we explored the association between MR-based apparent BV/TV and microCT-based BV/TV in the proximal peri-articular medial tibia. METHODS: Fresh cadaveric whole knee specimens were obtained from individuals 51 to 80 years of age with no knee pathology other than osteoarthritis. Ten knees were collected from five cadavers within 10 hours of death and underwent a 3-Tesla MR exam including a coronal-oblique 3-dimensional fast imaging with steady state precession (3D FISP) sequence within 36 hours of death. The specimens were placed in a 4% paraformaldehyde in phosphate buffer within 58 hours of death. After preservation, a subchondral region from the tibial plateau was collected and underwent microCT imaging with a voxel size of 9 µm x 9 µm x 9 µm. A single reader analyzed the microCT images in a similar volume of interest as selected in the MR measures. A different reader analyzed the MR-based trabecular morphometry using a custom analysis tool. To analyze the MR-based trabecular morphometry, a rectangular region of interest (ROI) was positioned on the 20 central images in the proximal medial tibial subchondral bone. The primary outcome measures were MR-based and microCT-based trabecular BV/TV in the proximal medial tibia. RESULTS: The MR-based apparent BV/TV was strongly correlated with microCT-based BV/TV (r=0.83, confidence interval=0.42 to 0.96), despite the MR-based apparent BV/TV being systematically lower than measured using microCT. CONCLUSIONS: MR-based apparent BV/TV in the proximal peri-articular medial tibia has good construct validity and may represent an alternative for CT-based BV/TV.

Quantitative sensory testing in notalgia paresthetica reveals small fiber-type-specific differences in non-pruritic sensitivity: a pilot study.

Introduction: Notalgia paresthetica (NP) is a chronic condition characterized by pruritus and other unpleasant dysesthetic sensations unilaterally on the subscapular back. Its specific underlying mechanisms are largely unknown, though hypothesized to be neuropathic. Determination of possible somatosensory contributors to the condition could pave the way for novel treatments. Objectives: Given the potential involvement of non-pruritic mechanisms in NP, our objective was to broadly characterize the somatosensory function in NP-affected and unaffected skin using methods that have been standardized in pain-free controls and painful neuropathic disorders. We hypothesized that if NP is caused by neuropathic mechanisms not targeted directly to pruritoceptors in the skin, somatosensory abnormalities would not be itchspecific. Second, given the lack of symptoms on the contralateral side of the back, we hypothesized that this region would be normally sensitive. Methods: In this study, quantitative sensory testing (QST) was used to comprehensively assess the somatosensory function in 15 adult patients with NP. Standardized QST metrics were performed in the NP-affected region and compared with the contralateral asymptomatic skin and itch-free individuals using an age, gender, and site-matched reference data set. Results: There were no significant differences in sensitivity between symptomatic and asymptomatic skin, except for increased mechanical-evoked itch on the itchy side. However, reference data set comparisons revealed bilateral hyposensitivity to innocuous cold and noxious pinprick and higher temporal summation of pain in patients with NP. In addition, compared with reference data, patients with NP demonstrated decreased sensitivity to cold and pinprick, presence of paradoxical heat sensations, and increased wind-up of pain. Conclusion: These results suggest a role for Aδ fiber pathways and central sensitization in NP-associated itch. More research is needed to determine whether sensory differences extend beyond the NP-affected dermatomal level and what might cause neuropathy specifically targeting Aδ fibers.

Relational Work Is the Work: Virtual Healthcare Transformation for Rural, Remote and First Nations Communities in British Columbia.

The healthcare crisis across unceded First Nations' territories in rural, remote and Indigenous communities in British Columbia (BC) is marked by persistent barriers to accessing care and support close to home. This commentary describes an exceptional story of how technology, trusted partnerships and relationships came together to create an innovative suite of virtual care programs called "Real-Time Virtual Support" (RTVS). We describe key approaches, learnings and future considerations to improve the equity of healthcare delivery for rural, remote and First Nations communities. The key lessons include the following: (1) moving beyond a biomedical model - the collaboration framework for health service design incorporated First Nations' perspective on health and wellness; (2) relational work is the work - the RTVS collaboration was grounded in building connections and relationships to prioritize cultivating trust in the partnership over specific outputs; and (3) aligning to the core values of co-creation - working from a commitment to do things differently and applying an inclusive approach of engagement to integrate perspectives across different sectors and interest groups.

Quantitative Sensory Testing to Characterize Sensory Changes in Hidradenitis Suppurativa Skin Lesions.

Importance: Pain is the most impactful symptom in patients with hidradenitis suppurativa (HS). Characterization of sensory profiles may improve understanding of pain mechanisms in HS and facilitate identification of effective pain management strategies. Objective: To characterize somatosensory profiles in patients with HS at clinically affected and nonaffected sites compared with pain-free reference data. Design, Setting, and Participants: This cross-sectional study was conducted at the Emory University Dermatology Clinic. It was hypothesized (1) that patients with HS would demonstrate hypersensitivity to pain in HS lesions and (2) that some patients would have sensory profiles consistent with complex pain mechanisms. Therefore, adults with dermatologist-diagnosed HS and at least 1 painful HS lesion at the time of testing were enrolled between September 10, 2020, and March 21, 2022. Patients with other diagnoses contributing to pain or neuropathy were excluded. Data analysis was conducted between March and April 2022. Exposure: Quantitative sensory testing was performed on HS lesions and control skin according to a standardized protocol. Main Outcomes and Measures: Quantitative sensory testing outcomes included innocuous thermal and mechanical sensitivity (cold, warmth, and light touch detection thresholds), noxious thermal and mechanical sensitivity (cold, heat, pinprick, and deep pressure pain thresholds and suprathreshold pinprick sensitivity), temporal summation of pinprick, paradoxical thermal sensations, and dynamic mechanical allodynia (pain upon light stroking of the skin). Sensitivity in HS lesions was compared with sensitivity in a control location (the hand) and in pain-free controls using t tests. Results: This study included 20 participants with a median age of 35.5 (IQR, 30.0-46.5) years, the majority of whom were women (15 [75%]). In terms of race and ethnicity, 2 participants (10%) self-identified as Asian, 11 (55%) as Black, 6 (30%) as White, and 1 (5%) as more than 1 race or ethnicity. Compared with site-specific reference values from healthy, pain-free control participants, HS lesions were insensitive to innocuous cold and warmth, noxious heat, and light touch (t = -5.69, -10.20, -3.84, and 4.46, respectively; all P < .001). In contrast, HS lesions also demonstrated significant hypersensitivity to deep pressure pain (t = 8.36; P < .001) and cutaneous pinprick (t = 2.07; P = .046). Hypersensitivity to deep pressure pain was also observed in the control site (t = 5.85; P < .001). A subset of patients with HS displayed changes in pain processing that are often seen in neuropathic and nociplastic pain conditions, including hypersensitivity to repetitive pinprick (5 [26%]), paradoxical thermal sensations (3 [15%]), and pain upon light stroking of the skin (10 [50%]). Conclusions and Relevance: The findings of this cross-sectional study suggest that HS involves local changes in the skin or its free nerve endings, possibly leading to peripheral neuropathy and alterations in the transduction of innocuous and noxious thermal and mechanical stimuli. For some patients, central nervous system changes in somatosensory processing may also occur, but confirmatory evidence is needed. Better understanding of neuropathic and nociplastic mechanisms in HS pain could lead to individually tailored treatments.

Characterization of visual processing in temporomandibular disorders using functional magnetic resonance imaging.

BACKGROUND AND PURPOSE: Many patients with chronic pain report hypersensitivity not only to noxious stimuli, but also to other modalities including innocuous touch, sound, and light, possibly due to differences in the processing of these stimuli. The goal of this study was to characterize functional connectivity (FC) differences between subjects with temporomandibular disorders (TMD) and pain-free controls during a visual functional magnetic resonance imaging (fMRI) task that included an unpleasant, strobing visual stimulus. We hypothesized the TMD cohort would exhibit maladaptations in brain networks consistent with multisensory hypersensitivities observed in TMD patients. METHODS: This pilot study included 16 subjects, 10 with TMD and 6 pain-free controls. Clinical pain was characterized using self-reported questionnaires. Visual task-based fMRI data were collected on a 3T MR scanner and used to determine differences in FC via group independent component analysis. RESULTS: Compared to controls, subjects with TMD exhibited abnormally increased FC between the default mode network and lateral prefrontal areas involved in attention and executive function, and impaired FC between the frontoparietal network and higher order visual processing areas. CONCLUSIONS: The results indicate maladaptation of brain functional networks, likely due to deficits in multisensory integration, default mode network function, and visual attention and engendered by chronic pain mechanisms.

A Primer and Literature Review on Internal and External Retention Mechanisms for Catheter Fixation.

Although catheters are commonplace in hospital settings, there is scarce literature discussing the internal and external retention mechanisms used to aid in catheter fixation. Additionally, exact definitions and detailed information on internal and external retention mechanisms are almost non-existent in the literature. This article serves three primary purposes. The first purpose is to define internal and external catheter retention mechanisms, describe how they work, and provide examples of each that are routinely used in healthcare settings. The second goal of this paper is to provide a literature review comparing various aspects of the different types of internal and external catheter retention mechanisms discussed in the paper, including performance variance and the advantages and disadvantages of each. The third aim of this article is to provide a brief overview of catheter dislodgment, including the rates at which this occurs, the problems that can arise, and the best treatment option when this does occur.

Preoperative Embolization of a Delayed Femoral Metastasis of Renal Cell Carcinoma: A Case Report.

Preoperative embolization of hypervascular bone metastasis is an effective measure for reducing blood loss during open orthopedic surgery. When the clinician is experienced with the procedure, the risks of the procedure are minimal and final outcomes are typically good. In this study, we report a case of a 50-year-old female patient who presented with a delayed metastatic renal cell tumor in the left proximal femur one year after radical nephrectomy. The patient underwent an effective preoperative embolization, which resulted in a remarkable absence of bleeding and a successful response subsequent to surgical fixation.

A Sleeve-Sheath With a Coaxial Exchangeable Catheter for Palliative Evacuation of Recurrent Thoracic and Abdominal Effusions.

Herein we describe an outer cannula sleeve-sheath with a coaxially inserted exchangeable drainage catheter (SCDC) for effective evacuation of recurrent symptomatic fluid collections in the thorax and abdomen on patients in lieu of, or failed, current evacuation catheters and methods. The design is an alternative to existing commercially available devices and adds distinct enhancements with the possibility of intrathoracic or intrabdominal trans outer sleeve-sheath diagnostic or therapeutic interventions. This device aims at requiring a single invasive procedure (thoracentesis and paracentesis) while offering catheter exchange and repositioning if malfunction or malposition occurs during the patient's lifetime. The SCDC outer sheath in the subcutaneous tissues of the thorax or abdomen has built-in two antibacterial cuffs to prevent infection. At the same time, the exchangeable coaxially inserted drainage catheter is deployed over a guidewire within the thoracic or abdominal cavities. The drainage catheter has a fluid dynamic proven efficient design to facilitate drainage and can recanalize its lumen if occluded by fibrin or tissue.

Topology of pain networks in patients with temporomandibular disorder and pain-free controls with and without concurrent experimental pain: A pilot study.

Temporomandibular disorders (TMD) involve chronic pain in the masticatory muscles and jaw joints, but the mechanisms underlying the pain are heterogenous and vary across individuals. In some cases, structural, functional, and metabolic changes in the brain may underlie the condition. In the present study, we evaluated the functional connectivity between 86 regions of interest (ROIs), which were chosen based on previously reported neuroimaging studies of pain and differences in brain morphology identified in an initial surface-based morphometry analysis. Our main objectives were to investigate the topology of the network formed by these ROIs and how it differs between individuals with TMD and chronic pain (n = 16) and pain-free control participants (n = 12). In addition to a true resting state functional connectivity scan, we also measured functional connectivity during a 6-min application of a noxious cuff stimulus applied to the left leg. Our principal finding is individuals with TMD exhibit more suprathreshold correlations (higher nodal degree) among all ROIs but fewer "hub" nodes (i.e., decreased betweenness centrality) across conditions and across all pain pathways. These results suggest is this pain-related network of nodes may be "over-wired" in individuals with TMD and chronic pain compared to controls, both at rest and during experimental pain.

Percutaneous electric nerve field stimulation alters cortical thickness in a pilot study of veterans with fibromyalgia.

Objective: To evaluate changes in cortical thickness and right posterior insula (r-pIns) gamma-aminobutyric acid (GABA) concentrations in veterans with fibromyalgia treated with auricular percutaneous electric nerve field stimulation (PENFS). Materials & methods: This was a randomized, controlled, open label investigation conducted in a government hospital. Twenty-one veterans with fibromyalgia were randomized to receive either standard therapy (ST; i.e., 4 weekly visits with a pain practitioner) or ST with auricular PENFS (ST + PENFS). Neuroimaging data was collected at baseline (i.e. before the first treatment session) and again within 2 weeks post-treatment.​ Clinical pain and physical function were also assessed at these timepoints. Single-voxel magnetic resonance spectroscopy was carried out in r-pIns to assess changes in r-pIns GABA concentrations and high-resolution T1-weighted images were collected to assess changes in regional gray matter volume using cortical thickness. Results: Both the ST + PENFS and ST groups reported a decrease in pain with treatment. Volumetric: Cortical thickness significantly decreased in the left middle posterior cingulate (p = 0.018) and increased in the left cuneus (p = 0.014) following ST + PENFS treatment. These findings were significant following FDR correction for multiple comparisons. ST group right hemisphere insula cortical thickness increased post-treatment and was significantly (p = 0.02) inversely correlated with pain scores. ST + PENFS group right hemisphere posterior dorsal cingulate size significantly (p = 0.044) positively correlated with pain scores. GABA: There were no significant correlations with GABA, though a trend was noted towards increased GABA following treatment in both groups (p = 0.083) using a linear mixed effects model. Conclusions: Results suggest a novel effect of PENFS reflected by differential volumetric changes compared to ST. The changes in GABA that occur in both groups are more likely related to ST. Insular GABA and cortical thickness in key regions of interest may be developed as potential biomarkers for evaluating chronic pain pathology and treatment outcomes.

Prediction of Differential Pharmacologic Response in Chronic Pain Using Functional Neuroimaging Biomarkers and a Support Vector Machine Algorithm: An Exploratory Study.

OBJECTIVE: There is increasing demand for prediction of chronic pain treatment outcomes using machine-learning models, in order to improve suboptimal pain management. In this exploratory study, we used baseline brain functional connectivity patterns from chronic pain patients with fibromyalgia (FM) to predict whether a patient would respond differentially to either milnacipran or pregabalin, 2 drugs approved by the US Food and Drug Administration for the treatment of FM. METHODS: FM patients participated in 2 separate double-blind, placebo-controlled crossover studies, one evaluating milnacipran (n = 15) and one evaluating pregabalin (n = 13). Functional magnetic resonance imaging during rest was performed before treatment to measure intrinsic functional brain connectivity in several brain regions involved in pain processing. A support vector machine algorithm was used to classify FM patients as responders, defined as those with a ≥20% improvement in clinical pain, to either milnacipran or pregabalin. RESULTS: Connectivity patterns involving the posterior cingulate cortex (PCC) and dorsolateral prefrontal cortex (DLPFC) individually classified pregabalin responders versus milnacipran responders with 77% accuracy. Performance of this classification improved when both PCC and DLPFC connectivity patterns were combined, resulting in a 92% classification accuracy. These results were not related to confounding factors, including head motion, scanner sequence, or hardware status. Connectivity patterns failed to differentiate drug nonresponders across the 2 studies. CONCLUSION: Our findings indicate that brain functional connectivity patterns used in a machine-learning framework differentially predict clinical response to pregabalin and milnacipran in patients with chronic pain. These findings highlight the promise of machine learning in pain prognosis and treatment prediction.

Stimulation of zona incerta selectively modulates pain in humans.

Stimulation of zona incerta in rodent models has been shown to modulate behavioral reactions to noxious stimuli. Sensory changes observed in Parkinsonian patients with subthalamic deep brain stimulation suggest that this effect is translatable to humans. Here, we utilized the serendipitous placement of subthalamic deep brain stimulation leads in 6 + 5 Parkinsonian patients to directly investigate the effects of zona incerta stimulation on human pain perception. We found that stimulation at 20 Hz, the physiological firing frequency of zona incerta, reduces experimental heat pain by a modest but significant amount, achieving a 30% reduction in one fifth of implants. Stimulation at higher frequencies did not modulate heat pain. Modulation was selective for heat pain and was not observed for warmth perception or pressure pain. These findings provide a mechanistic explanation of sensory changes seen in subthalamic deep brain stimulation patients and identify zona incerta as a potential target for neuromodulation of pain.