Marcos F. DosSantos

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.

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.

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.

State-of-art neuroanatomical target analysis of high-definition and conventional tDCS montages used for migraine and pain control

Although transcranial direct current stimulation (tDCS) studies promise to modulate cortical regions associated with pain, the electric current produced usually spreads beyond the area of the electrodes’ placement. Using a forward-model analysis, this study compared the neuroanatomic location and strength of the predicted electric current peaks, at cortical and subcortical levels, induced by conventional and High-Definition-tDCS (HD-tDCS) montages developed for migraine and other chronic pain disorders. The electrodes were positioned in accordance with the 10–20 or 10–10 electroencephalogram (EEG) landmarks: motor cortex-supraorbital (M1-SO, anode and cathode over C3 and Fp2, respectively), dorsolateral prefrontal cortex (PFC) bilateral (DLPFC, anode over F3, cathode over F4), vertex-occipital cortex (anode over Cz and cathode over Oz), HD-tDCS 4 × 1 (one anode on C3, and four cathodes over Cz, F3, T7, and P3) and HD-tDCS 2 × 2 (two anodes over C3/C5 and two cathodes over FC3/FC5). M1-SO produced a large current flow in the PFC. Peaks of current flow also occurred in deeper brain structures, such as the cingulate cortex, insula, thalamus and brainstem. The same structures received significant amount of current with Cz-Oz and DLPFC tDCS. However, there were differences in the current flow to outer cortical regions. The visual cortex, cingulate and thalamus received the majority of the current flow with the Cz-Oz, while the anterior parts of the superior and middle frontal gyri displayed an intense amount of current with DLPFC montage. HD-tDCS montages enhanced the focality, producing peaks of current in subcortical areas at negligible levels. This study provides novel information regarding the neuroanatomical distribution and strength of the electric current using several tDCS montages applied for migraine and pain control. Such information may help clinicians and researchers in deciding the most appropriate tDCS montage to treat each pain disorder.

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.

The role of the blood-brain barrier in the development and treatment of migraine and other pain disorders.

The function of the blood–brain barrier (BBB) related to chronic pain has been explored for its classical role in regulating the transcellular and paracellular transport, thus controlling the flow of drugs that act at the central nervous system, such as opioid analgesics (e.g., morphine) and non-steroidal anti-inflammatory drugs. Nonetheless, recent studies have raised the possibility that changes in the BBB permeability might be associated with chronic pain. For instance, changes in the relative amounts of occludin isoforms, resulting in significant increases in the BBB permeability, have been demonstrated after inflammatory hyperalgesia. Furthermore, inflammatory pain produces structural changes in the P-glycoprotein, the major efflux transporter at the BBB. One possible explanation for these findings is the action of substances typically released at the site of peripheral injuries that could lead to changes in the brain endothelial permeability, including substance P, calcitonin gene-related peptide, and interleukin-1 beta. Interestingly, inflammatory pain also results in microglial activation, which potentiates the BBB damage. In fact, astrocytes and microglia play a critical role in maintaining the BBB integrity and the activation of those cells is considered a key mechanism underlying chronic pain. Despite the recent advances in the understanding of BBB function in pain development as well as its interference in the efficacy of analgesic drugs, there remain unknowns regarding the molecular mechanisms involved in this process. In this review, we explore the connection between the BBB as well as the blood–spinal cord barrier and blood–nerve barrier, and pain, focusing on cellular and molecular mechanisms of BBB permeabilization induced by inflammatory or neuropathic pain and migraine.

It's all in your head: reinforcing the placebo response with tDCS.

Themechanisms of action of tDCS for behavioral modification are not yet fully understood. However, one common observation is that its behavioral effects are most pronounced and long-lasting when tDCS is paired with endogenous, training-induced brain activity [1]. In humans, training produces modality-specific neural network activation and activity-dependent learning. A commonly-held notion is that tDCS encourages plasticity by exogenous priming and reinforcement of neural networks that are actively engaged in learning, although the neurophysiological mechanisms may eventually prove to be more complex [2]. Given that electrical fields induced by conventional tDCS montages are likely widespread and heterogenous, specificity of tDCS action is thought to result from concurrent activity in neural networks, i.e. through “functional targeting” rather than only anatomic localization [3]. We were thus curious about the source of functional specificity for tDCS in several recent double-blind, sham-controlled depression studies, inwhich concurrent training (e.g., cognitive behavioral therapy or interpersonal psychotherapy) is not given [4,5]. The beneficial effects of tDCS in depression have been attributed to its transient activation of a pathologically hypoactive left dorsolateral prefrontal cortex (DLPFC), attenuation of a hyperactive right DLPFC, and/or restoration of the interhemispheric balance between the two [4]. Even if aberrant network excitability is temporarily adjusted by tDCS, given that paired cognitive therapy is absent and that conventional tDCS montages produce diffuse current flow, how is the specificity of these behavioral outcomes achieved? We note that in these studies, depression scores in all shamstimulated groups improved in the first fewweeks relative to baseline. This change was even more pronounced when sham stimulation was combined with a placebo pill [5]. These improvements from baseline could reflect regression toward the mean, response bias, spontaneous disease remission, ordimportantlyda placebo response. In depression, the placebo response is a psychobiological phenomenon increasingly understood to be underpinned by various learning processes, both conscious and unconscious [6]. Undergoing a therapeutic ritual (e.g., receiving overt administration of a treatment in a clinical environment, experiencing a compassionate clinicianepatient relationship) creates the conscious expectation of therapeutic benefit, which may guide motivation, affective responses, and learning. In non-naïve patients, prior therapeutic exposures result in conditioned learning, where an inert clinical feature (e.g., pill color, medical equipment) is associated with an eventual behavioral improvement; these conditioned associations are carried forward into new clinical contexts. In pharmacological depression studies, these processes create a significant placebo response, resulting in short-term symptomatic improvements that can match those of the drug being studied [7,8]. Using Positron Emission Tomography imaging, Mayberg and colleagues proposed the functional neuroanatomy of the placebo response in depression [9]. In this small double-blind study, depressed patients were given fluoxetine or a placebo pill, and regional brain metabolism and clinical improvement were assayed at 1 and 6 weeks after therapy. Clinical responders e regardless of having received active or placebo medication e shared metabolic activation in lateral PFC, posterior cingulate, and insula, and decreases in subgenual anterior cingulate cortex. As this pattern was not seen in non-responders, preceded the clinical effect in responders, and dissipated by the time there was a clinical effect, it was inferred that this activation pattern reflected the expectation of therapeutic benefit [9]. The potential for active placebo responses suggest an alternative explanation for the effects of tDCS on depression: tDCS reinforces brain networks activated by the expectation of therapeutic benefit. In other words, tDCS fortifies the placebo response to which it may, in part, contribute [10]. When given with other sources of expected benefit, such as a placebo pill in a clinical context, tDCS may reinforce additional but distinct neural substrates [6]. Indeed, our modeling of the conventional cephalic tDCS montages used in depression trials suggests current flow across frontal cortices and deeper structures such as the cingulate and insula [11,12]. An interesting question recently put forth is whether the placebo response could be exploited for clinical benefit [13]. In its current practice, the safety profile of tDCS is very good. Combined with active medication, tDCS could reduce drug dosage and thus unwanted side effects. For example, in the recent SELECT trial, patients were given a daily sertraline or placebo pill, plus repeated sessions of real or sham bi-prefrontal tDCS [5]. At 6 weeks, the combination of real tDCS and sertraline resulted in the most pronounced reduction in depression, but there was no significant interaction effect between tDCS and active drug. This finding suggests that the additive benefit arises from independent mechanisms of action [5]. One could thus envision a complementary approach in depression that optimizes response to drugs on two levels: first, using medication to modulate the limbic system or other relevant networks, and second, using tDCS to reinforce placebo network activity arising from the expectation of medication benefit and associated affective learning. In future shamcontrolled depression trials, the addition of a no-stimulation arm may also help disambiguate the degree to which brain stimulation alone may contribute to the expectation of benefit [14]. Finally, the placebo response is not a single psychobiological entity, but is mediated by separate neural substrates in different diseases [6]. In pain studies, where tDCS given alone has produced only minor and transient effects [15], one may thus consider the value of heightening patient expectations, such as with a placebo pill. Analgesia induced by placebo medications is associated with activity in the insula, cingulate, and thalamus [16], which are regions believed to be polarized by tDCS montages commonly used in pain trials [17]. For other areas potentially involved in the placebo analgesic response, such as the midbrain periaqueductal gray and rostroventromedial medulla [18], tDCS effects may be more indirect: the current may polarize a more superficial portion of the active network, thereby altering functional connectivity to deeper, more inaccessible subcortical areas [19]. We know of no studies thus far that have combined placebo or active medication with tDCS in pain. Could placebo administration, given even explicitly in a clinical psychosocial context [20], be used to create a neural “training signal” to be reinforced by tDCS? We hypothesize that placeboactivated brain regions, particular to the pathopsychology being ameliorated, would be the physiologic substrate of tDCS neuromodulation. In clinical trials designed to enhance patient expectations through the therapeutic ritual, a behavioral prediction of this hypothesis would be an interaction of active tDCS and physiologic placebo effects. Simultaneously, it is incumbent for ongoing trials to carefully document patient expectations and blinding success.

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.

A novel method for intraoral access to the superior head of the human lateral pterygoid muscle.

Background. The uncoordinated activity of the superior and inferior parts of the lateral pterygoid muscle (LPM) has been suggested to be one of the causes of temporomandibular joint (TMJ) disc displacement. A therapy for this muscle disorder is the injection of botulinum toxin (BTX), of the LPM. However, there is a potential risk of side effects with the injection guide methods currently available. In addition, they do not permit appropriate differentiation between the two bellies of the muscle. Herein, a novel method is presented to provide intraoral access to the superior head of the human LPM with maximal control and minimal hazards. Methods. Computational tomography along with digital imaging software programs and rapid prototyping techniques were used to create a rapid prototyped guide to orient BTX injections in the superior LPM. Results. The method proved to be feasible and reliable. Furthermore, when tested in one volunteer it allowed precise access to the upper head of LPM, without producing side effects. Conclusions. The prototyped guide presented in this paper is a novel tool that provides intraoral access to the superior head of the LPM. Further studies will be necessary to test the efficacy and validate this method in a larger cohort of subjects.