Thiago D. Nascimento

Immediate Effects of tDCS on the μ-Opioid System of a Chronic Pain Patient

We developed a unique protocol where transcranial direct current stimulation (tDCS) of the motor cortex is performed during positron emission tomography (PET) scan using a μ-opioid receptor (μOR) selective radiotracer, [11C]carfentanil. This is one of the most important central neuromechanisms associated with pain perception and regulation. We measured μOR non-displaceable binding potential (μOR BPND) in a trigeminal neuropathic pain patient (TNP) without creating artifacts, or posing risks to the patient (e.g., monitoring of resistance). The active session directly improved in 36.2% the threshold for experimental cold pain in the trigeminal allodynic area, mandibular branch, but not the TNP patient’s clinical pain. Interestingly, the single active tDCS application considerably decreased μORBPND levels in (sub)cortical pain-matrix structures compared to sham tDCS, especially in the posterior thalamus. Suggesting that the μ-opioidergic effects of a single tDCS session are subclinical at immediate level, and repetitive sessions are necessary to revert ingrained neuroplastic changes related to the chronic pain. To our knowledge, we provide data for the first time in vivo that there is possibly an instant increase of endogenous μ-opioid release during acute motor cortex neuromodulation with tDCS.

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.

Brief Report: Excitatory and Inhibitory Brain Metabolites as Targets of Motor Cortex Transcranial Direct Current Stimulation Therapy and Predictors of Its Efficacy in Fibromyalgia†

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).

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.

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

BackgroundAlthough 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.FindingsIn 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.ConclusionsOur 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.

Excitatory and Inhibitory Brain Metabolites as Targets and Predictors of Effective Motor Cortex tDCS Therapy in Fibromyalgia

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).

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, β, 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.

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 [11C]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 patients 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 patients neuroimaging dataset.

Brain Functional Changes before, during, and after Clinical Pain:

This study used an emerging brain imaging technique, functional near-infrared spectroscopy (fNIRS), to investigate functional brain activation and connectivity that modulates sometimes traumatic pain experience in a clinical setting. Hemodynamic responses were recorded at bilateral somatosensory (S1) and prefrontal cortices (PFCs) from 12 patients with dentin hypersensitivity in a dental chair before, during, and after clinical pain. Clinical dental pain was triggered with 20 consecutive descending cold stimulations (32° to 0°C) to the affected teeth. We used a partial least squares path modeling framework to link patients’ clinical pain experience with recorded hemodynamic responses at sequential stages and baseline resting-state functional connectivity (RSFC). Hemodynamic responses at PFC/S1 were sequentially elicited by expectation, cold detection, and pain perception at a high-level coefficient (coefficients: 0.92, 0.98, and 0.99, P < 0.05). We found that the pain ratings were positively affected only at a moderate level of coefficients by such sequence of functional activation (coefficient: 0.52, P < 0.05) and the baseline PFC-S1 RSFC (coefficient: 0.59, P < 0.05). Furthermore, when the dental pain had finally subsided, the PFC increased its functional connection with the affected S1 orofacial region contralateral to the pain stimulus and, in contrast, decreased with the ipsilateral homuncular S1 regions (P < 0.05). Our study indicated for the first time that patients’ clinical pain experience in the dental chair can be predicted concomitantly by their baseline functional connectivity between S1 and PFC, as well as their sequence of ongoing hemodynamic responses. In addition, this linked cascade of events had immediate after-effects on the patients’ brain connectivity, even when clinical pain had already ceased. Our findings offer a better understating of the ongoing impact of affective and sensory experience in the brain before, during, and after clinical dental pain.