Functional Magnetic Resonance Imaging Signal Variability Is Associated With Neuromodulation in Fibromyalgia.

OBJECTIVES: Although primary motor cortex (M1) transcranial direct current stimulation (tDCS) has an analgesic effect in fibromyalgia (FM), its neural mechanism remains elusive. We investigated whether M1-tDCS modulates a regional temporal variability of blood-oxygenation-level-dependent (BOLD) signals, an indicator of the brain's flexibility and efficiency and if this change is associated with pain improvement. MATERIALS AND METHODS: In a within-subjects cross-over design, 12 female FM patients underwent sham and active tDCS on five consecutive days, respectively. Each session was performed with an anode placed on the left M1 and a cathode on the contralateral supraorbital region. The subjects also participated in resting-state functional magnetic resonance imaging (fMRI) at baseline and after sham and active tDCS. We compared the BOLD signal variability (SDBOLD), defined as the standard deviation of the BOLD time-series, between the tDCS conditions. Baseline SDBOLD was compared to 15 healthy female controls. RESULTS: At baseline, FM patients showed reduced SDBOLD in the ventromedial prefrontal cortex (vmPFC), lateral PFC, and anterior insula and increased SDBOLD in the posterior insula compared to healthy controls. After active tDCS, compared to sham, we found an increased SDBOLD in the left rostral anterior cingulate cortex (rACC), lateral PFC, and thalamus. After sham tDCS, compared to baseline, we found a decreased SDBOLD in the dorsomedial PFC and posterior cingulate cortex/precuneus. Interestingly, after active tDCS compared to sham, pain reduction was correlated with an increased SDBOLD in the rACC/vmPFC but with a decreased SDBOLD in the posterior insula. CONCLUSION: Our findings suggest that M1-tDCS might revert temporal variability of fMRI signals in the rACC/vmPFC and posterior insula linked to FM pain. Changes in neural variability would be part of the mechanisms underlying repetitive M1-tDCS analgesia in FM.

Brain Mechanisms of Virtual Reality Breathing Versus Traditional Mindful Breathing in Pain Modulation: Observational Functional Near-infrared Spectroscopy Study.

BACKGROUND: Pain is a complex experience that involves sensory-discriminative and cognitive-emotional neuronal processes. It has long been known across cultures that pain can be relieved by mindful breathing (MB). There is a common assumption that MB exerts its analgesic effect through interoception. Interoception refers to consciously refocusing the mind's attention to the physical sensation of internal organ function. OBJECTIVE: In this study, we dissect the cortical analgesic processes by imaging the brains of healthy subjects exposed to traditional MB (TMB) and compare them with another group for which we augmented MB to an outside sensory experience via virtual reality breathing (VRB). METHODS: The VRB protocol involved in-house-developed virtual reality 3D lungs that synchronized with the participants' breathing cycles in real time, providing them with an immersive visual-auditory exteroception of their breathing. RESULTS: We found that both breathing interventions led to a significant increase in pain thresholds after week-long practices, as measured by a thermal quantitative sensory test. However, the underlying analgesic brain mechanisms were opposite, as revealed by functional near-infrared spectroscopy data. In the TMB practice, the anterior prefrontal cortex uniquely modulated the premotor cortex. This increased its functional connection with the primary somatosensory cortex (S1), thereby facilitating the S1-based sensory-interoceptive processing of breathing but inhibiting its other role in sensory-discriminative pain processing. In contrast, virtual reality induced an immersive 3D exteroception with augmented visual-auditory cortical activations, which diminished the functional connection with the S1 and consequently weakened the pain processing function of the S1. CONCLUSIONS: In summary, our study suggested two analgesic neuromechanisms of VRB and TMB practices-exteroception and interoception-that distinctively modulated the S1 processing of the ascending noxious inputs. This is in line with the concept of dualism (Yin and Yang).

Differential alteration of fMRI signal variability in the ascending trigeminal somatosensory and pain modulatory pathways in migraine.

BACKGROUND: The moment-to-moment variability of resting-state brain activity has been suggested to play an active role in chronic pain. Here, we investigated the regional blood-oxygen-level-dependent signal variability (BOLDSV) and inter-regional dynamic functional connectivity (dFC) in the interictal phase of migraine and its relationship with the attack severity. METHODS: We acquired resting-state functional magnetic resonance imaging from 20 migraine patients and 26 healthy controls (HC). We calculated the standard deviation (SD) of the BOLD time-series at each voxel as a measure of the BOLD signal variability (BOLDSV) and performed a whole-brain voxel-wise group comparison. The brain regions showing significant group differences in BOLDSV were used to define the regions of interest (ROIs). The SD and mean of the dynamic conditional correlation between those ROIs were calculated to measure the variability and strength of the dFC. Furthermore, patients' experimental pain thresholds and headache pain area/intensity levels during the migraine ictal-phase were assessed for clinical correlations. RESULTS: We found that migraineurs, compared to HCs, displayed greater BOLDSV in the ascending trigeminal spinal-thalamo-cortical pathways, including the spinal trigeminal nucleus, pulvinar/ventral posteromedial (VPM) nuclei of the thalamus, primary somatosensory cortex (S1), and posterior insula. Conversely, migraine patients exhibited lower BOLDSV in the top-down modulatory pathways, including the dorsolateral prefrontal (dlPFC) and inferior parietal (IPC) cortices compared to HCs. Importantly, abnormal interictal BOLDSV in the ascending trigeminal spinal-thalamo-cortical and frontoparietal pathways were associated with the patient's headache severity and thermal pain sensitivity during the migraine attack. Migraineurs also had significantly lower variability and greater strength of dFC within the thalamo-cortical pathway (VPM-S1) than HCs. In contrast, migraine patients showed greater variability and lower strength of dFC within the frontoparietal pathway (dlPFC-IPC). CONCLUSIONS: Migraine is associated with alterations in temporal signal variability in the ascending trigeminal somatosensory and top-down modulatory pathways, which may explain migraine-related pain and allodynia. Contrasting patterns of time-varying connectivity within the thalamo-cortical and frontoparietal pathways could be linked to abnormal network integrity and instability for pain transmission and modulation.

Feasibility of a Real-Time Clinical Augmented Reality and Artificial Intelligence Framework for Pain Detection and Localization From the Brain.

BACKGROUND: For many years, clinicians have been seeking for objective pain assessment solutions via neuroimaging techniques, focusing on the brain to detect human pain. Unfortunately, most of those techniques are not applicable in the clinical environment or lack accuracy. OBJECTIVE: This study aimed to test the feasibility of a mobile neuroimaging-based clinical augmented reality (AR) and artificial intelligence (AI) framework, CLARAi, for objective pain detection and also localization direct from the patient's brain in real time. METHODS: Clinical dental pain was triggered in 21 patients by hypersensitive tooth stimulation with 20 consecutive descending cold stimulations (32°C-0°C). We used a portable optical neuroimaging technology, functional near-infrared spectroscopy, to gauge their cortical activity during evoked acute clinical pain. The data were decoded using a neural network (NN)-based AI algorithm to classify hemodynamic response data into pain and no-pain brain states in real time. We tested the performance of several networks (NN with 7 layers, 6 layers, 5 layers, 3 layers, recurrent NN, and long short-term memory network) upon reorganized data features on pain diction and localization in a simulated real-time environment. In addition, we also tested the feasibility of transmitting the neuroimaging data to an AR device, HoloLens, in the same simulated environment, allowing visualization of the ongoing cortical activity on a 3-dimensional brain template virtually plotted on the patients' head during clinical consult. RESULTS: The artificial neutral network (3-layer NN) achieved an optimal classification accuracy at 80.37% (126,000/156,680) for pain and no pain discrimination, with positive likelihood ratio (PLR) at 2.35. We further explored a 3-class localization task of left/right side pain and no-pain states, and convolutional NN-6 (6-layer NN) achieved highest classification accuracy at 74.23% (1040/1401) with PLR at 2.02. CONCLUSIONS: Additional studies are needed to optimize and validate our prototype CLARAi framework for other pains and neurologic disorders. However, we presented an innovative and feasible neuroimaging-based AR/AI concept that can potentially transform the human brain into an objective target to visualize and precisely measure and localize pain in real time where it is most needed: in the doctor's office. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/13594.

An updated synthesis of [11 C]carfentanil for positron emission tomography (PET) imaging of the µ-opioid receptor.

[11 C]Carfentanil ([11 C]CFN) is a selective radiotracer for in vivo positron emission tomography imaging studies of the µ-opioid system that, in our laboratories, is synthesized by methylation of the corresponding carboxylate precursor with [11 C]MeOTf, and purified using a C2 solid-phase extraction cartridge. Changes in the commercial availability of common C2 cartridges have necessitated future proofing the synthesis of [11 C]CFN to maintain reliable delivery of the radiotracer for clinical imaging studies. An updated synthesis of [11 C]CFN is reported that replaces a now obsolete purification cartridge with a new commercially available version and also substitutes the organic solvents used in traditional production methods with ethanol.

Migraine and the Mu-opioidergic system-Can we directly modulate it? Evidence from neuroimaging studies.

Migraine is a chronic trigeminal pain condition that affects the daily lives of a large part of our population. Its debilitating headache attacks, with increased sensitivity to multiple forms of stimuli, force many patients to rely on over the counter analgesics and resort to abuse of prescription medications, particularly opioid agonists. In the latter case, the indiscriminate medication-driven activation of the opioid system can lead to undesired side effects, such as the augmentation of hyperalgesia and allodynia, as well as the chronification of the attacks. However, we still lack information regarding the impact of migraine attacks and their relief on the function of µ-opioid receptor (µOR) mediated neurotransmission, the primary target of opioid medications. This line of inquiry is of particular importance as this neurotransmitter system is arguably the brain's most important endogenous mechanism involved in pain regulation, and understanding this endogenous mechanism is crucial in determining the effectiveness of opioid medications. Recently, new advances in molecular neuroimaging and neuromodulation have provided important information that can elucidate, in vivo, the role of the endogenous opioid system in migraine suffering and relief.

Real-time sharing and expression of migraine headache suffering on Twitter: a cross-sectional infodemiology study.

BACKGROUND: Although population studies have greatly improved our understanding of migraine, they have relied on retrospective self-reports that are subject to memory error and experimenter-induced bias. Furthermore, these studies also lack specifics from the actual time that attacks were occurring, and how patients express and share their ongoing suffering. OBJECTIVE: As technology and language constantly evolve, so does the way we share our suffering. We sought to evaluate the infodemiology of self-reported migraine headache suffering on Twitter. METHODS: Trained observers in an academic setting categorized the meaning of every single "migraine" tweet posted during seven consecutive days. The main outcome measures were prevalence, life-style impact, linguistic, and timeline of actual self-reported migraine headache suffering on Twitter. RESULTS: From a total of 21,741 migraine tweets collected, only 64.52% (14,028/21,741 collected tweets) were from users reporting their migraine headache attacks in real-time. The remainder of the posts were commercial, re-tweets, general discussion or third person's migraine, and metaphor. The gender distribution available for the actual migraine posts was 73.47% female (10,306/14,028), 17.40% males (2441/14,028), and 0.01% transgendered (2/14,028). The personal impact of migraine headache was immediate on mood (43.91%, 6159/14,028), productivity at work (3.46%, 486/14,028), social life (3.45%, 484/14,028), and school (2.78%, 390/14,028). The most common migraine descriptor was "Worst" (14.59%, 201/1378) and profanity, the "F-word" (5.3%, 73/1378). The majority of postings occurred in the United States (58.28%, 3413/5856), peaking on weekdays at 10:00h and then gradually again at 22:00h; the weekend had a later morning peak. CONCLUSIONS: Twitter proved to be a powerful source of knowledge for migraine research. The data in this study overlap large-scale epidemiological studies, avoiding memory bias and experimenter-induced error. Furthermore, linguistics of ongoing migraine reports on social media proved to be highly heterogeneous and colloquial in our study, suggesting that current pain questionnaires should undergo constant reformulations to keep up with modernization in the expression of pain suffering in our society. In summary, this study reveals the modern characteristics and broad impact of migraine headache suffering on patients' lives as it is spontaneously shared via social media.

High-definition tDCS over primary motor cortex modulates brain signal variability and functional connectivity in episodic migraine.

OBJECTIVE: This study investigated how high-definition transcranial direct current stimulation (HD-tDCS) over the primary motor cortex (M1) affects brain signal variability and functional connectivity in the trigeminal pain pathway, and their association with changes in migraine attacks. METHODS: Twenty-five episodic migraine patients were randomized for ten daily sessions of active or sham M1 HD-tDCS. Resting-state blood-oxygenation-level-dependent (BOLD) signal variability and seed-based functional connectivity were assessed pre- and post-treatment. A mediation analysis was performed to test whether BOLD signal variability mediates the relationship between treatment group and moderate-to-severe headache days. RESULTS: The active M1 HD-tDCS group showed reduced BOLD variability in the spinal trigeminal nucleus (SpV) and thalamus, but increased variability in the rostral anterior cingulate cortex (rACC) compared to the sham group. Connectivity decreased between medial pulvinar-temporal pole, medial dorsal-precuneus, and the ventral posterior medial nucleus-SpV, but increased between the rACC-amygdala, and the periaqueductal gray-parahippocampal gyrus. Changes in medial pulvinar variability mediated the reduction in moderate-to-severe headache days at one-month post-treatment. CONCLUSIONS: M1 HD-tDCS alters BOLD signal variability and connectivity in the trigeminal somatosensory and modulatory pain system, potentially alleviating migraine headache attacks. SIGNIFICANCE: M1 HD-tDCS realigns brain signal variability and connectivity in migraineurs closer to healthy control levels.

Exploring HD-tDCS Effect on µ-opioid Receptor and Pain Sensitivity in Temporomandibular Disorder: A Pilot Randomized Clinical Trial Study.

This study explored the association between experimentally-induced pain sensitivity and µ-opioid receptor (µOR) availability in patients with temporomandibular disorder (TMD) and further investigated any changes in the pain and µOR availability following high-definition transcranial direct current stimulation (HD-tDCS) over the primary motor cortex (M1) with pilot randomized clinical trials. Seven patients with TMD completed either active (n = 3) or sham treatment (n = 4) for 10 daily sessions and underwent positron emission tomography (PET) scans with [11C]carfentanil, a selective µOR agonist, a week before and after treatment. PET imaging consisted of an early resting and late phase with the sustained masseteric pain challenge by computer-controlled injection of 5% hypertonic saline. We also included 12 patients with TMD, obtained from our previous study, for baseline PET analysis. We observed that patients with more sensitivity to pain, indicated by lower infusion rate, had less µOR availability in the right amygdala during the late phase. Moreover, active M1 HD-tDCS, compared to sham, increased µOR availability post-treatment in the thalamus during the early resting phase and the amygdala, hippocampus, and parahippocampal gyrus during the late pain challenge phase. Importantly, increased µOR availability post-treatment in limbic structures including the amygdala and hippocampus was associated with decreased pain sensitivity. The findings underscore the role of the µOR system in pain regulation and the therapeutic potential of HD-tDCS for TMD. Nonetheless, large-scale studies are necessary to establish the clinical significance of these results. TRIAL REGISTRATION: ClinicalTrial.gov (NCT03724032) PERSPECTIVE: This study links pain sensitivity and µ-opioid receptors in patients with TMD. HD-tDCS over M1 improved µOR availability, which was associated with reduced pain sensitivity. Implications for TMD pain management are promising, but larger clinical trials are essential for validation.

Management of Episodic Migraine with Neuromodulation: A Case Report.

Migraine is a highly prevalent neurovascular disorder that affects approximately 15% of the global population. Migraine attacks are a complex cascade of neurologic events that lead to debilitating symptoms and are often associated with inhibitory behavior. The constellation of severe signs and symptoms during the ictal phase (headache attack) makes migraine the third most common cause of disability globally in both sexes under the age of 50. Misuse of pharmaceuticals, such as opiates, can lead to devastating outcomes and exacerbation of pain and headache attacks. A safe and well-tolerated non-pharmacological research approach is high-definition transcranial direct current stimulation over the M1.

Classifying migraine using PET compressive big data analytics of brain's µ-opioid and D2/D3 dopamine neurotransmission.

Introduction: Migraine is a common and debilitating pain disorder associated with dysfunction of the central nervous system. Advanced magnetic resonance imaging (MRI) studies have reported relevant pathophysiologic states in migraine. However, its molecular mechanistic processes are still poorly understood in vivo. This study examined migraine patients with a novel machine learning (ML) method based on their central µ-opioid and dopamine D2/D3 profiles, the most critical neurotransmitters in the brain for pain perception and its cognitive-motivational interface. Methods: We employed compressive Big Data Analytics (CBDA) to identify migraineurs and healthy controls (HC) in a large positron emission tomography (PET) dataset. 198 PET volumes were obtained from 38 migraineurs and 23 HC during rest and thermal pain challenge. 61 subjects were scanned with the selective µ-opioid receptor (µOR) radiotracer [11C]Carfentanil, and 22 with the selective dopamine D2/D3 receptor (DOR) radiotracer [11C]Raclopride. PET scans were recast into a 1D array of 510,340 voxels with spatial and intensity filtering of non-displaceable binding potential (BPND), representing the receptor availability level. We then performed data reduction and CBDA to power rank the predictive brain voxels. Results: CBDA classified migraineurs from HC with accuracy, sensitivity, and specificity above 90% for whole-brain and region-of-interest (ROI) analyses. The most predictive ROIs for µOR were the insula (anterior), thalamus (pulvinar, medial-dorsal, and ventral lateral/posterior nuclei), and the putamen. The latter, putamen (anterior), was also the most predictive for migraine regarding DOR D2/D3 BPND levels. Discussion: CBDA of endogenous µ-opioid and D2/D3 dopamine dysfunctions in the brain can accurately identify a migraine patient based on their receptor availability across key sensory, motor, and motivational processing regions. Our ML-based findings in the migraineur's brain neurotransmission partly explain the severe impact of migraine suffering and associated neuropsychiatric comorbidities.

Strategies for the Production of [11C]LY2795050 for Clinical Use.

This report describes a comparison of four different routes for the clinical-scale radiosynthesis of the κ-opioid receptor antagonist [11C]LY2795050. Palladium-mediated radiocyanation and radiocarbonylation of an aryl iodide precursor as well as copper-mediated radiocyanation of an aryl iodide and an aryl boronate ester have been investigated. Full automation of all four methods is reported, each of which provides [11C]LY2795050 in sufficient radiochemical yield, molar activity, and radiochemical purity for clinical use. The advantages and disadvantages of each radiosynthesis method are compared and contrasted.

Tolerability and blinding of high-definition transcranial direct current stimulation among older adults at intensities of up to 4 mA per electrode.

BACKGROUND: Few studies have investigated tolerability, blinding, and double-blinding of High-Definition transcranial Direct Current Stimulation (HD-tDCS) at amplitudes above 2 milliamps (mA). OBJECTIVE: We examined a) tolerability of HD-tDCS during stimulation sessions and b) blinding and double blinding of participants and study team members. METHODS: Data from a mixed neurologic sample of 292 older adults were pooled from 3046 HD-tDCS sessions (2329 active; 717 sham). Per electrode amplitudes ranged from 1 mA to 4 mA with total currents up to 10 mA. Participants completed a standardized sensation (tolerability) questionnaire after each session. Participants and study team members stated whether the participant received active or sham stimulation at the end of various sessions. Data were collapsed into the presence/absence of a symptom due to low rates of positive responding and were analyzed for both differences and bioequivalency. RESULTS: There were no safety-related adverse events. HD-tDCS was well tolerated with mostly no ("none") or "mild" sensations reported across sessions, regardless of active or sham condition and in both stimulation naïve and experienced participants. There were no significant differences in side effects between active and sham, with some achieving bioequivalence. Tingling and itching were significantly more common after lower (<2 mA) than higher (≥3 mA) amplitude active sessions, while skin redness was significantly more common after higher amplitudes. Blinding was effective at the participant and study team levels. CONCLUSIONS: HD-tDCS was well tolerated with center electrode amplitudes up to 4 mA. The bimodal ramp-up/down format of the sham was effective for blinding. These results support higher scalp-based amplitudes that enable greater brain-based current intensities in older adults.

Effect of High-Definition Transcranial Direct Current Stimulation on Headache Severity and Central µ-Opioid Receptor Availability in Episodic Migraine.

Objective: The current understanding of utilizing HD-tDCS as a targeted approach to improve headache attacks and modulate endogenous opioid systems in episodic migraine is relatively limited. This study aimed to determine whether high-definition transcranial direct current stimulation (HD-tDCS) over the primary motor cortex (M1) can improve clinical outcomes and endogenous µ-opioid receptor (µOR) availability for episodic migraineurs. Methods: In a randomized, double-blind, and sham-controlled trial, 25 patients completed 10-daily 20-min M1 HD-tDCS, repeated Positron Emission Tomography (PET) scans with a selective agonist for µOR. Twelve age- and sex-matched healthy controls participated in the baseline PET/MRI scan without neuromodulation. The primary endpoints were moderate-to-severe (M/S) headache days and responder rate (≥50% reduction on M/S headache days from baseline), and secondary endpoints included the presence of M/S headache intensity and the use of rescue medication over 1-month after treatment. Results: In a one-month follow-up, at initial analysis, both the active and sham groups exhibited no significant differences in their primary outcomes (M/S headache days and responder rates). Similarly, secondary outcomes (M/S headache intensity and the usage of rescue medication) also revealed no significant differences between the two groups. However, subsequent analyses showed that active M1 HD-tDCS, compared to sham, resulted in a more beneficial response predominantly in higher-frequency individuals (>3 attacks/month), as demonstrated by the interaction between treatment indicator and baseline frequency of migraine attacks on the primary outcomes. These favorable outcomes were also confirmed for the secondary endpoints in higher-frequency patients. Active treatment also resulted in increased µOR concentration compared to sham in the limbic and descending pain modulatory pathway. Our exploratory mediation analysis suggests that the observed clinical efficacy of HD-tDCS in patients with higher-frequency conditions might be potentially mediated through an increase in µOR availability. Conclusion: The 10-daily M1 HD-tDCS can improve clinical outcomes in episodic migraineurs with a higher baseline frequency of migraine attacks (>3 attacks/month). This improvement may be, in part, facilitated by the increase in the endogenous µOR availability. Clinical Trial Registration: www.ClinicalTrials.gov, identifier - NCT02964741.

Reduced basal ganglia µ-opioid receptor availability in trigeminal neuropathic pain: a pilot study.

BACKGROUND: Although neuroimaging techniques have provided insights into the function of brain regions involved in Trigeminal Neuropathic Pain (TNP) in humans, there is little understanding of the molecular mechanisms affected during the course of this disorder. Understanding these processes is crucial to determine the systems involved in the development and persistence of TNP. FINDINGS: In this study, we examined the regional µ-opioid receptor (µOR) availability in vivo (non-displaceable binding potential BPND) of TNP patients with positron emission tomography (PET) using the µOR selective radioligand [11C]carfentanil. Four TNP patients and eight gender and age-matched healthy controls were examined with PET. Patients with TNP showed reduced µOR BPND in the left nucleus accumbens (NAc), an area known to be involved in pain modulation and reward/aversive behaviors. In addition, the µOR BPND in the NAc was negatively correlated with the McGill sensory and total pain ratings in the TNP patients. CONCLUSIONS: Our findings give preliminary evidence that the clinical pain in TNP patients can be related to alterations in the endogenous µ-opioid system, rather than only to the peripheral pathology. The decreased availability of µORs found in TNP patients, and its inverse relationship to clinical pain levels, provide insights into the central mechanisms related to this condition. The results also expand our understanding about the impact of chronic pain on the limbic system.

tDCS-induced analgesia and electrical fields in pain-related neural networks in chronic migraine.

OBJECTIVE: We investigated in a sham-controlled trial the analgesic effects of a 4-week treatment of transcranial direct current stimulation (tDCS) over the primary motor cortex in chronic migraine. In addition, using a high-resolution tDCS computational model, we analyzed the current flow (electric field) through brain regions associated with pain perception and modulation. METHODS: Thirteen patients with chronic migraine were randomized to receive 10 sessions of active or sham tDCS for 20 minutes with 2 mA over 4 weeks. Data were collected during baseline, treatment and follow-up. For the tDCS computational analysis, we adapted a high-resolution individualized model incorporating accurate segmentation of cortical and subcortical structures of interest. RESULTS: There was a significant interaction term (time vs group) for the main outcome (pain intensity) and for the length of migraine episodes (ANOVA, P < .05 for both analyses). Post-hoc analysis showed a significant improvement in the follow-up period for the active tDCS group only. Our computational modeling studies predicted electric current flow in multiple cortical and subcortical regions associated with migraine pathophysiology. Significant electric fields were generated, not only in targeted cortical regions but also in the insula, cingulate cortex, thalamus, and brainstem regions. CONCLUSIONS: Our findings give preliminary evidence that patients with chronic migraine have a positive, but delayed, response to anodal tDCS of the primary motor cortex. These effects may be related to electrical currents induced in pain-related cortical and subcortical regions.

Explosive Synchronization-Based Brain Modulation Reduces Hypersensitivity in the Brain Network: A Computational Model Study.

Fibromyalgia (FM) is a chronic pain condition that is characterized by hypersensitivity to multimodal sensory stimuli, widespread pain, and fatigue. We have previously proposed explosive synchronization (ES), a phenomenon wherein a small perturbation to a network can lead to an abrupt state transition, as a potential mechanism of the hypersensitive FM brain. Therefore, we hypothesized that converting a brain network from ES to general synchronization (GS) may reduce the hypersensitivity of FM brain. To find an effective brain network modulation to convert ES into GS, we constructed a large-scale brain network model near criticality (i.e., an optimally balanced state between order and disorders), which reflects brain dynamics in conscious wakefulness, and adjusted two parameters: local structural connectivity and signal randomness of target brain regions. The network sensitivity to global stimuli was compared between the brain networks before and after the modulation. We found that only increasing the local connectivity of hubs (nodes with intense connections) changes ES to GS, reducing the sensitivity, whereas other types of modulation such as decreasing local connectivity, increasing and decreasing signal randomness are not effective. This study would help to develop a network mechanism-based brain modulation method to reduce the hypersensitivity in FM.

Study Protocol of tDCS Based Pain Modulation in Head and Neck Cancer Patients Under Chemoradiation Therapy Condition: An fNIRS-EEG Study.

Background: Multiple therapeutic strategies have been adopted to reduce pain, odynophagia, and oral mucositis in head and neck cancer patients. Among them, transcranial direct current stimulation (tDCS) represents a unique analgesic modality. However, the details of tDCS mechanisms in pain treatment are still unclear. Aims: (1) to study the analgesic effects of a protocol that encompassed supervised-remote and in-clinic tDCS sessions applied in head and neck patients undergoing chemoradiation therapy; (2) to explore the underlining brain mechanisms of such modulation process, using a novel protocol that combined functional near-infrared spectroscopy (fNIRS), and electroencephalograph (EEG), two distinct neuroimaging methods that bring information regarding changes in the hemodynamic as well as in the electrical activity of the brain, respectively. Methods: This proof-of-concept study was performed on two subjects. The study protocol included a 7-week-long tDCS stimulation procedure, a pre-tDCS baseline session, and two post-tDCS follow-up sessions. Two types of tDCS devices were used. One was used in the clinical setting and the other remotely. Brain imaging was obtained in weeks 1, 2, 5, 7, 8, and after 1 month. Results: The protocol implemented was safe and reliable. Preliminary results of the fNIRS analysis in weeks 2 and 7 showed a decrease in functional connections between the bilateral prefrontal cortex (PFC) and the primary sensory cortex (S1) (p < 0.05, FDR corrected). Changes in EEG power spectra were found in the PFC when comparing the seventh with the first week of tDCS. Conclusion: The protocol combining remote and in-clinic administered tDCS and integrated fNIRS and EEG to evaluate the brain activity is feasible. The preliminary results suggest that the mechanisms of tDCS in reducing the pain of head and neck cancer patients may be related to its effects on the connections between the S1 and the PFC.

The Concept, Development, and Application of a Home-Based High-Definition tDCS for Bilateral Motor Cortex Modulation in Migraine and Pain.

Whereas, many debilitating chronic pain disorders are dominantly bilateral (e.g., fibromyalgia, chronic migraine), non-invasive and invasive cortical neuromodulation therapies predominantly apply unilateral stimulation. The development of excitatory stimulation targeting bilateral primary motor (M1) cortices could potentially expand its therapeutic effect to more global pain relief. However, this is hampered by increased procedural and technical complexity. For example, repetitive transcranial magnetic stimulation (rTMS) and 4 × 1/2 × 2 high-definition transcranial direct current stimulation (4 × 1/2 × 2 HD-tDCS) are largely center-based, with unilateral-target focus-bilateral excitation would require two rTMS/4 × 1 HD-tDCS systems. We developed a system that allows for focal, non-invasive, self-applied, and simultaneous bilateral excitatory M1 stimulation, supporting long-term home-based treatment with a well-tolerated wearable battery-powered device. Here, we overviewed the most employed M1 neuromodulation methods, from invasive techniques to non-invasive TMS and tDCS. The evaluation extended from non-invasive diffuse asymmetric bilateral (M1-supraorbital [SO] tDCS), non-invasive and invasive unilateral focal (4 × 1/2 × 2 HD-tDCS, rTMS, MCS), to non-invasive and invasive bilateral bipolar (M1-M1 tDCS, MCS), before outlining our proposal for a neuromodulatory system with unique features. Computational models were applied to compare brain current flow for current laboratory-based unilateral M11 and bilateral M12 HD-tDCS models with a functional home-based M11-2 HD-tDCS prototype. We concluded the study by discussing the promising concept of bilateral excitatory M1 stimulation for more global pain relief, which is also non-invasive, focal, and home-based.

Shedding light on pain for the clinic: a comprehensive review of using functional near-infrared spectroscopy to monitor its process in the brain.

ABSTRACT: Pain is a complex experience that involves sensation, emotion, and cognition. The subjectivity of the traditional pain measurement tools has expedited the interest in developing neuroimaging techniques to monitor pain objectively. Among noninvasive neuroimaging techniques, functional near-infrared spectroscopy (fNIRS) has balanced spatial and temporal resolution; yet, it is portable, quiet, and cost-effective. These features enable fNIRS to image the cortical mechanisms of pain in a clinical environment. In this article, we evaluated pain neuroimaging studies that used the fNIRS technique in the past decade. Starting from the experimental design, we reviewed the regions of interest, probe localization, data processing, and primary findings of these existing fNIRS studies. We also discussed the fNIRS imaging's potential as a brain surveillance technique for pain, in combination with artificial intelligence and extended reality techniques. We concluded that fNIRS is a brain imaging technique with great potential for objective pain assessment in the clinical environment.