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.

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.

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.

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.

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.

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).

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.

Dopaminergic Regulation of Reward System Connectivity Underpins Pain and Emotional Suffering in Migraine.

PURPOSE: It has been suggested that reward system dysfunction may account for emotion and pain suffering in migraine. However, there is a lack of evidence whether the altered reward system connectivity is directly associated with clinical manifestations, including negative affect and ictal pain severity and, at the molecular level, the dopamine (DA) D2/D3 receptors (D2/3Rs) signaling implicated in encoding motivational and emotional cues. PATIENTS AND METHODS: We acquired resting-state functional MRI from interictal episodic migraine (EM) patients and age-matched healthy controls, as well as positron emission tomography (PET) with [11C]raclopride, a selective radiotracer for DA D2/3Rs, from a subset of these participants. The nucleus accumbens (NAc) was seeded to measure functional connectivity (FC) and DA D2/3Rs availability based on its essential involvement in pain-related aversive/reward functions. Associations of the brain measures with positive/negative affect and ictal pain severity were also assessed. RESULTS: Compared with controls, the EM group showed weaker right NAc connectivity with areas implicated in pain and emotional regulation, such as the amygdala, rostral anterior cingulate cortex, hippocampus, and thalamus; but showed stronger left NAc connectivity with the dorsolateral prefrontal cortex and lingual gyrus. Moreover, among the altered NAc connectivities, only right NAc-amygdala connectivity was inversely correlated with DA D2/3Rs availability in migraine patients (diagnostic group-by-D2/3Rs interaction p < 0.007). At a clinical level, such weaker NAc-amygdala connectivity was associated with lower interictal positive affect and greater ictal pain severity over the head and facial extension area (pain area and intensity number summation, PAINS). CONCLUSION: Together, our findings suggest that altered reward system connectivity, specifically between the NAc and amygdala, might be affected by endogenous DA D2/3Rs signaling, and such process might be a neural mechanism that underlies emotional and pain suffering in episodic migraineurs.

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.

Impact of chronic migraine attacks and their severity on the endogenous µ-opioid neurotransmission in the limbic system.

OBJECTIVE: To evaluate, in vivo, the impact of ongoing chronic migraine (CM) attacks on the endogenous µ-opioid neurotransmission. BACKGROUND: CM is associated with cognitive-emotional dysfunction. CM is commonly associated with frequent acute medication use, including opioids. METHODS: We scanned 15 migraine patients during the spontaneous headache attack (ictal phase): 7 individuals with CM and 8 with episodic migraine (EM), as well as 7 healthy controls (HC), using positron emission tomography (PET) with the selective µ-opioid receptor (µOR) radiotracer [11C]carfentanil. Migraineurs were scanned in two paradigms, one with thermal pain threshold challenge applied to the site of the headache, and one without thermal challenge. Multivariable analysis was performed between the µ-opioid receptor availability and the clinical data. RESULTS: µOR availability, measured with [11C]carfentanil nondisplaceable binding potential (BPND), in the left thalamus (P-value = 0.005) and left caudate (P-value = 0.003) were decreased in CM patients with thermal pain threshold during the ictal phase relative to HC. Lower µOR BPND in the right parahippocampal region (P-value = 0.001) and right amygdala (P-value = 0.002) were seen in CM relative to EM patients. Lower µOR BPND values indicate either a decrease in µOR concentration or an increase in endogenous µ-opioid release in CM patients. In the right amygdala, 71% of the overall variance in µOR BPND levels was explained by the type of migraine (CM vs. EM: partial-R2 = 0.47, P-value<0.001, Cohen's effect size d = 2.6SD), the severity of the attack (pain area and intensity number summation [P.A.I.N.S.]: partial-R2 = 0.16, P-value = 0.031), and the thermal pain threshold (allodynia: partial-R2 = 0.08). CONCLUSIONS: Increased endogenous µ-opioid receptor-mediated neurotransmission is seen in the limbic system of CM patients, especially in right amygdala, which is highly modulated by the attack frequency, pain severity, and sensitivity. This study demonstrates for the first time the negative impact of chronification and exacerbation of headache attacks on the endogenous µ-opioid mechanisms of migraine patients. ClinicalTrials.gov identifier: NCT03004313.

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.

Dopamine D2/D3 imbalance during migraine attack and allodynia in vivo.

OBJECTIVE: To evaluate in vivo the dynamics of endogenous dopamine (DA) neurotransmission during migraine ictus with allodynia. METHODS: We examined 8 episodic migraineurs and 8 healthy controls (HC) using PET with [11C]raclopride. The uptake measure of [11C]raclopride, nondisplaceable binding potential (BPND), would increase when there was a reduction in endogenous DA release. The opposite is true for a decrease in [11C]raclopride BPND. Patients were scanned twice: one PET session was during a spontaneous migraine ictus at rest, followed by a sustained thermal pain threshold (STPT) challenge on the trigeminal region, eliciting an allodynia experience; another was during interictal phase. RESULTS: Striatal BPND of [11C]raclopride in migraineurs did not differ from HC. We found a significant increase in [11C]raclopride BPND in the striatum region of migraineurs during both headache attack and allodynia relative to interictal phase. However, when compared to the migraine attack at rest, migraineurs during the STPT challenge had a significant sudden reduction in [11C]raclopride BPND in the insula. Such directional change was also observed in the caudate of HC relative to the interictal phase during challenge. Furthermore, ictal changes in [11C]raclopride BPND in migraineurs at rest were positively correlated with the chronicity of migraine attacks, and negatively correlated with the frequency during challenge. CONCLUSIONS: Our findings demonstrate that there is an imbalanced uptake of [11C]raclopride during the headache attack and ictal allodynia, which indicates reduction and fluctuation in ictal endogenous DA release in migraineurs. Moreover, the longer the history and recurrence of migraine attacks, the lower the ictal endogenous DA release.

Feasibility of Non-invasive Brain Modulation for Management of Pain Related to Chemoradiotherapy in Patients with Advanced Head and Neck Cancer.

Patients with head and neck cancer often experience a significant decrease in their quality of life during chemoradiotherapy (CRT) due to treatment-related pain, which is frequently classified as severe. Transcranial direct current stimulation (tDCS) is a method of non-invasive brain stimulation that has been frequently used in experimental and clinical pain studies. In this pilot study, we investigated the clinical impact and central mechanisms of twenty primary motor cortex (M1) stimulation sessions with tDCS during 7 weeks of CRT for head and neck cancer. From 48 patients screened, seven met the inclusion criteria and were enrolled. Electroencephalography (EEG) data were recorded before and after tDCS stimulation as well as across the trial to monitor short and long-term impact on brain function. The compliance rate during the long trial was extremely high (98.4%), and patients mostly reported mild side effects in line with the literature (e.g., tingling). Compared to a large standard of care study from our institution, our initial results indicate that M1-tDCS stimulation has a pain relief effect during the CRT that resulted in a significant attenuation of weight reduction and dysphagia normally observed in these patients. These results translated to our patient cohort not needing feeding tubes or IV fluids. Power spectra analysis of EEG data indicated significant changes in α, ß, and γ bands immediately after tDCS stimulation and, in addition, α, δ, and θ bands over the long term in the seventh stimulation week (p < 0.05). The independent component EEG clustering analysis showed estimated functional brain regions including precuneus and superior frontal gyrus (SFG) in the seventh week of tDCS stimulation. These areas colocalize with our previous positron emission tomography (PET) study where there was activation in the endogenous µ-opioid system during M1-tDCS. This study provides preliminary evidence demonstrating the feasibility and safety of M1-tDCS as a potential adjuvant neuromechanism-driven analgesic therapy for head and neck cancer patients receiving CRT, inducing immediate and long-term changes in the cortical activity and clinical measures, with minimal side-effects.

Changes in resting state functional connectivity after repetitive transcranial direct current stimulation applied to motor cortex in fibromyalgia patients.

BACKGROUND: Fibromyalgia (FM) is a chronic, centralized pain condition characterized by alterations in the functional, chemical, and structural brain networks responsible for sensory and mood processing. Transcranial direct current stimulation (tDCS) has emerged as a potential treatment for FM. tDCS can alter functional connectivity (FC) in brain regions underneath and distant to the stimulating electrode, although the analgesic mechanisms of repetitive tDCS remain unknown. The aim of this study was to investigate how a clinically relevant schedule of tDCS sessions alters resting state FC and how these changes might relate to clinical pain. METHODS: Resting state functional magnetic resonance imaging data were collected from 12 patients with FM at baseline, after 5 days of sham treatment, and after 5 days of real tDCS with the anode over the left primary motor cortex (M1) and the cathode over the right supraorbital cortex. Seed to whole-brain FC analyses were performed with seed regions placed in bilateral M1, primary somatosensory cortices (S1), ventral lateral (VL) and ventral posterolateral (VPL) thalami, and periaqueductal gray (PAG). RESULTS: Stronger baseline FC between M1-VL thalamus, S1-anterior insula, and VL thalamus-PAG predicted greater analgesia after sham and real tDCS. Sham treatment (compared with baseline) reduced FC between the VPL thalamus, S1, and the amygdala. Real tDCS (compared with sham treatment) reduced FC between the VL thalamus, medial prefrontal, and supplementary motor cortices. Interestingly, decreased FC between the VL/VPL thalamus and posterior insula, M1, and S1 correlated with reductions in clinical pain after both sham and active treatments. CONCLUSIONS: These results suggest that while there may be a placebo response common to both sham and real tDCS, repetitive M1 tDCS causes distinct changes in FC that last beyond the stimulation period and may produce analgesia by altering thalamic connectivity.

Excitatory and inhibitory brain metabolites as targets of motor cortex transcranial direct current stimulation therapy and predictors of its efficacy in fibromyalgia.

OBJECTIVE: Transcranial direct current stimulation (tDCS) has been shown to improve pain symptoms in fibromyalgia (FM), a central pain syndrome whose underlying mechanisms are not well understood. This study was undertaken to explore the neurochemical action of tDCS in the brain of patients with FM, using proton magnetic resonance spectroscopy (1H-MRS). METHODS: Twelve patients with FM underwent sham tDCS over the left motor cortex (anode placement) and contralateral supraorbital cortex (cathode placement) for 5 consecutive days, followed by a 7-day washout period and then active tDCS for 5 consecutive days. Clinical pain assessment and 1H-MRS testing were performed at baseline, the week following the sham tDCS trial, and the week following the active tDCS trial. RESULTS: Clinical pain scores decreased significantly between the baseline and active tDCS time points (P = 0.04). Levels of glutamate + glutamine (Glx) in the anterior cingulate were significantly lower at the post­active tDCS assessment compared with the post­sham tDCS assessment (P = 0.013), and the decrease in Glx levels in the thalami between these time points approached significance (P = 0.056). From baseline to the post­sham tDCS assessment, levels of N-acetylaspartate (NAA) in the posterior insula increased significantly (P = 0.015). There was a trend toward increased levels of γ-aminobutyric acid (GABA) in the anterior insula after active tDCS, compared with baseline (P = 0.064). Baseline anterior cingulate Glx levels correlated significantly with changes in pain score, both for the time period from baseline to sham tDCS (ß1 = 1.31, P < 0.001) and for the time period from baseline to active tDCS (ß1= 1.87, P < 0.001). CONCLUSION: The present findings suggest that GABA, Glx, and NAA play an important role in the pathophysiology of FM and its modulation by tDCS.

µ-Opioid activation in the midbrain during migraine allodynia - brief report II.

We investigated in vivo the allodynic response of the central µ-opioid system during spontaneous migraine headaches, following a sustained pain threshold challenge on the trigeminal ophthalmic region. Six migraineurs were scanned during the ictal and interictal phases using positron emission tomography (PET) with the selective µ-opioid receptor (µOR) radiotracer [11C]carfentanil. Females were scanned during the mid-late follicular phase of two separate cycles. Patients showed ictal trigeminal allodynia during the thermal challenge that was concurrent and positively correlated with µOR activation in the midbrain, extending from red nucleus to ventrolateral periaqueductal gray matter. These findings demonstrate for the first time in vivo the high µOR activation in the migraineurs' brains in response to their allodynic experience.

Building up analgesia in humans via the endogenous µ-opioid system by combining placebo and active tDCS: a preliminary report.

Transcranial Direct Current Stimulation (tDCS) is a method of non-invasive brain stimulation that has been frequently used in experimental and clinical pain studies. However, the molecular mechanisms underlying tDCS-mediated pain control, and most important its placebo component, are not completely established. In this pilot study, we investigated in vivo the involvement of the endogenous µ-opioid system in the global tDCS-analgesia experience. Nine healthy volunteers went through positron emission tomography (PET) scans with [11C]carfentanil, a selective µ-opioid receptor (MOR) radiotracer, to measure the central MOR activity during tDCS in vivo (non-displaceable binding potential, BPND)--one of the main analgesic mechanisms in the brain. Placebo and real anodal primary motor cortex (M1/2mA) tDCS were delivered sequentially for 20 minutes each during the PET scan. The initial placebo tDCS phase induced a decrease in MOR BPND in the periaqueductal gray matter (PAG), precuneus, and thalamus, indicating activation of endogenous µ-opioid neurotransmission, even before the active tDCS. The subsequent real tDCS also induced MOR activation in the PAG and precuneus, which were positively correlated to the changes observed with placebo tDCS. Nonetheless, real tDCS had an additional MOR activation in the left prefrontal cortex. Although significant changes in the MOR BPND occurred with both placebo and real tDCS, significant analgesic effects, measured by improvements in the heat and cold pain thresholds, were only observed after real tDCS, not the placebo tDCS. This study gives preliminary evidence that the analgesic effects reported with M1-tDCS, can be in part related to the recruitment of the same endogenous MOR mechanisms induced by placebo, and that such effects can be purposely optimized by real tDCS.

Association of µ-Opioid Activation in the Prefrontal Cortex with Spontaneous Migraine Attacks - Brief Report I.

We evaluated in vivo the µ-opioid system during spontaneous episodic migraine headaches. Seven patients were scanned at different phases of their migraine using Positron Emission Tomography with the selective µ-opioid receptor (µOR) radiotracer [11C]carfentanil. In the ictal phase, there was µOR activation in the medial prefrontal cortex, which was strongly associated with the µOR availability level during the interictal phase. Furthermore, µ-opioid binding changes showed moderate negative correlation with the combined extension and severity of the attacks. These results indicate for the first time that there is high µOR activation in the migraineurs' brains during headache attacks in response to their pain.

3D-neuronavigation in vivo through a patient's brain during a spontaneous migraine headache.

A growing body of research, generated primarily from MRI-based studies, shows that migraine appears to occur, and possibly endure, due to the alteration of specific neural processes in the central nervous system. However, information is lacking on the molecular impact of these changes, especially on the endogenous opioid system during migraine headaches, and neuronavigation through these changes has never been done. This study aimed to investigate, using a novel 3D immersive and interactive neuronavigation (3D-IIN) approach, the endogenous µ-opioid transmission in the brain during a migraine headache attack in vivo. This is arguably one of the most central neuromechanisms associated with pain regulation, affecting multiple elements of the pain experience and analgesia. A 36 year-old female, who has been suffering with migraine for 10 years, was scanned in the typical headache (ictal) and nonheadache (interictal) migraine phases using Positron Emission Tomography (PET) with the selective radiotracer [(11)C]carfentanil, which allowed us to measure µ-opioid receptor availability in the brain (non-displaceable binding potential - µOR BPND). The short-life radiotracer was produced by a cyclotron and chemical synthesis apparatus on campus located in close proximity to the imaging facility. Both PET scans, interictal and ictal, were scheduled during separate mid-late follicular phases of the patient's menstrual cycle. During the ictal PET session her spontaneous headache attack reached severe intensity levels; progressing to nausea and vomiting at the end of the scan session. There were reductions in µOR BPND in the pain-modulatory regions of the endogenous µ-opioid system during the ictal phase, including the cingulate cortex, nucleus accumbens (NAcc), thalamus (Thal), and periaqueductal gray matter (PAG); indicating that µORs were already occupied by endogenous opioids released in response to the ongoing pain. To our knowledge, this is the first time that changes in µOR BPND during a migraine headache attack have been neuronavigated using a novel 3D approach. This method allows for interactive research and educational exploration of a migraine attack in an actual patient's neuroimaging dataset.