ABOUT

Directed by Dr. Alexandre F. DaSilva, H.O.P.E. (Headache & Orofacial Pain Effort) is a multidisciplinary collaborative effort to investigate the brain as a research and therapeutic target for chronic trigeminal pain disorders, including primary headaches (e.g. migraine), TMJD and trigeminal neuropathic pain.

The fact that many therapeutic modalities for chronic pain, which focus on peripheral mechanisms, do not provide relief for treatment-resistant patients raises the possibility that the cause for the chronicity of these debilitating disorders may lie in the brain itself. One hypothesis is that functional and structural dysfunction of specific cortical areas (e.g. SI, DLPFC), even at molecular level (e.g. opioidergic and gabanergic mechanisms), may be responsible for the persistence and intensification of the pain suffering.

Together with collaborators from University of Michigan and other academic institutions, we use state-of-the-art neuroimaging techniques (fMRI, PET, MRS, DTI, and MRI-based morphometry) to study neuroplasticity, and to investigate novel therapeutic approaches and mechanisms (e.g. non-invasive brain stimulation) in chronic trigeminal pain disorders.

DIRECTOR

Alexandre F. DaSilva, DDS, DMedSc

Director and Founder, Headache & Orofacial Pain Effort (H.O.P.E.) Lab
Co-Director, fNIRS Laboratory, Center for Human Growth & Development
Assistant Professor, Biologic & Materials Sciences, School of Dentistry

Dr. Alexandre DaSilva is an Assistant Professor at the Biologic & Materials Sciences Department at the University of Michigan Dental School. He has received his Doctorate in Medical Science (DMSc) degree in Oral Biology with clinical training in trigeminal pain at Harvard University. His thesis subject was on somatotopic (fMRI) activation in the human trigeminal pain pathway. This training was followed by a post-doctoral fellowship on migraine neuroimaging at the Martinos Center for Biomedical Imaging, Massachusetts General Hospital, to investigate subcortical and cortical neuroplasticity in migraine patients. He was also an Instructor in the Psychiatric Department at Harvard University/McLean Hospital, as well as, an Assistant Clinical Investigator at the Forsyth Institute in Boston. During his training, he collaborated with his colleagues on innovative neuroimaging and non-invasive brain stimulation projects for chronic TMJD, trigeminal neuropathic pain and migraine.

He is currently the Director of H.O.P.E. (Headache & Orofacial Pain Effort), which is a multidisciplinary collaborative effort to investigate the brain as a research and therapeutic target for chronic trigeminal pain disorders. The fact that many therapeutic modalities for chronic pain, which focus on peripheral mechanisms, do not provide relief for treatment-resistant patients raises the possibility that the cause for the chronicity of these debilitating disorders may lie in the brain itself. One hypothesis is that functional and structural dysfunction of specific cortical areas (e.g. SI, DLPFC), even at a molecular level (e.g. opioidergic and gabanergic mechanisms), may be responsible for the persistence and intensification of the pain suffering. Together with collaborators from the University of Michigan and other academic institutions, we use state-of-the-art neuroimaging techniques (fMRI, PET, MRS, DTI, and MRI-based morphometry) to study neuroplasticity, and to investigate novel therapeutic approaches and mechanisms in chronic trigeminal pain disorders, including TMD the main focus.

PUBLICATIONS

The most recent publications are reported below via PubMed search.

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

Related Articles

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

Front Hum Neurosci. 2016;10:466

Authors: Hu XS, Fisher CA, Munz SM, Toback RL, Nascimento TD, Bellile EL, Rozek L, Eisbruch A, Worden FP, Danciu TE, DaSilva AF

Abstract
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.

PMID: 27729853 [PubMed - in process]

Digital Version

Potential Mechanisms Supporting the Value of Motor Cortex Stimulation to Treat Chronic Pain Syndromes.

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Potential Mechanisms Supporting the Value of Motor Cortex Stimulation to Treat Chronic Pain Syndromes.

Front Neurosci. 2016;10:18

Authors: DosSantos MF, Ferreira N, Toback RL, Carvalho AC, DaSilva AF

Abstract
Throughout the first years of the twenty-first century, neurotechnologies such as motor cortex stimulation (MCS), transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS) have attracted scientific attention and been considered as potential tools to centrally modulate chronic pain, especially for those conditions more difficult to manage and refractory to all types of available pharmacological therapies. Interestingly, although the role of the motor cortex in pain has not been fully clarified, it is one of the cortical areas most commonly targeted by invasive and non-invasive neuromodulation technologies. Recent studies have provided significant advances concerning the establishment of the clinical effectiveness of primary MCS to treat different chronic pain syndromes. Concurrently, the neuromechanisms related to each method of primary motor cortex (M1) modulation have been unveiled. In this respect, the most consistent scientific evidence originates from MCS studies, which indicate the activation of top-down controls driven by M1 stimulation. This concept has also been applied to explain M1-TMS mechanisms. Nevertheless, activation of remote areas in the brain, including cortical and subcortical structures, has been reported with both invasive and non-invasive methods and the participation of major neurotransmitters (e.g., glutamate, GABA, and serotonin) as well as the release of endogenous opioids has been demonstrated. In this critical review, the putative mechanisms underlying the use of MCS to provide relief from chronic migraine and other types of chronic pain are discussed. Emphasis is placed on the most recent scientific evidence obtained from chronic pain research studies involving MCS and non-invasive neuromodulation methods (e.g., tDCS and TMS), which are analyzed comparatively.

PMID: 26903788 [PubMed]

Digital Version

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

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

Arthritis Res Ther. 2016 Feb 03;18:40

Authors: Cummiford CM, Nascimento TD, Foerster BR, Clauw DJ, Zubieta JK, Harris RE, DaSilva AF

Abstract
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.

PMID: 26842987 [PubMed - indexed for MEDLINE]

Digital Version

Comparison of motion correction techniques applied to functional near-infrared spectroscopy data from children.

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Comparison of motion correction techniques applied to functional near-infrared spectroscopy data from children.

J Biomed Opt. 2015;20(12):126003

Authors: Hu XS, Arredondo MM, Gomba M, Confer N, DaSilva AF, Johnson TD, Shalinsky M, Kovelman I

Abstract
Motion artifacts are the most significant sources of noise in the context of pediatric brain imaging designs and data analyses, especially in applications of functional near-infrared spectroscopy (fNIRS), in which it can completely affect the quality of the data acquired. Different methods have been developed to correct motion artifacts in fNIRS data, but the relative effectiveness of these methods for data from child and infant subjects (which is often found to be significantly noisier than adult data) remains largely unexplored. The issue is further complicated by the heterogeneity of fNIRS data artifacts. We compared the efficacy of the six most prevalent motion artifact correction techniques with fNIRS data acquired from children participating in a language acquisition task, including wavelet, spline interpolation, principal component analysis, moving average (MA), correlation-based signal improvement, and combination of wavelet and MA. The evaluation of five predefined metrics suggests that the MA and wavelet methods yield the best outcomes. These findings elucidate the varied nature of fNIRS data artifacts and the efficacy of artifact correction methods with pediatric populations, as well as help inform both the theory and practice of optical brain imaging analysis.

PMID: 26662300 [PubMed - indexed for MEDLINE]

Digital Version

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

Related Articles

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

Front Neuroanat. 2015;9:89

Authors: DaSilva AF, Truong DQ, DosSantos MF, Toback RL, Datta A, Bikson M

Abstract
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.

PMID: 26236199 [PubMed]

Digital Version

High-Definition and Non-invasive Brain Modulation of Pain and Motor Dysfunction in Chronic TMD.

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High-Definition and Non-invasive Brain Modulation of Pain and Motor Dysfunction in Chronic TMD.

Brain Stimul. 2015 Nov-Dec;8(6):1085-92

Authors: Donnell A, D Nascimento T, Lawrence M, Gupta V, Zieba T, Truong DQ, Bikson M, Datta A, Bellile E, DaSilva AF

Abstract
BACKGROUND: Temporomandibular disorders (TMD) have a high prevalence and in many patients pain and masticatory dysfunction persist despite a range of treatments. Non-invasive brain neuromodulatory methods, namely transcranial direct current stimulation (tDCS), can provide relatively long-lasting pain relief in chronic pain patients.
OBJECTIVE: To define the neuromodulatory effect of five daily 2x2 motor cortex high-definition tDCS (HD-tDCS) sessions on clinical pain and motor measures in chronic TMD patients. It is predicted that M1 HD-tDCS will selectively modulate clinical measures, by showing greater analgesic after-effects compared to placebo, and active treatment will increase pain free jaw movement more than placebo.
METHODS: Twenty-four females with chronic myofascial TMD pain underwent five daily, 20-min sessions of active or sham 2 milliamps (mA) HD-tDCS. Measurable outcomes included pain-free mouth opening, visual analog scale (VAS), sectional sensory-discriminative pain measures tracked by a mobile application, short form of the McGill Pain Questionnaire, and the Positive and Negative Affect Schedule. Follow-up occurred at one-week and four-weeks post-treatment.
RESULTS: There were significant improvements for clinical pain and motor measurements in the active HD-tDCS group compared to the placebo group for: responders with pain relief above 50% in the VAS at four-week follow-up (P = 0.04); pain-free mouth opening at one-week follow-up (P < 0.01); and sectional pain area, intensity and their sum measures contralateral to putative M1 stimulation during the treatment week (P < 0.01). No changes in emotional values were shown between groups.
CONCLUSION: Putative M1 stimulation by HD-tDCS selectively improved meaningful clinical sensory-discriminative pain and motor measures during stimulation, and up to four-weeks post-treatment in chronic myofascial TMD pain patients.

PMID: 26226938 [PubMed - indexed for MEDLINE]

Digital Version

Different Brain Responses to Pain and Its Expectation in the Dental Chair.

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Different Brain Responses to Pain and Its Expectation in the Dental Chair.

J Dent Res. 2015 Jul;94(7):998-1003

Authors: Racek AJ, Hu X, Nascimento TD, Bender MC, Khatib L, Chiego D, Holland GR, Bauer P, McDonald N, Ellwood RP, DaSilva AF

Abstract
A dental appointment commonly prompts fear of a painful experience, yet we have never fully understood how our brains react to the expectation of imminent tooth pain once in a dental chair. In our study, 21 patients with hypersensitive teeth were tested using nonpainful and painful stimuli in a clinical setting. Subjects were tested in a dental chair using functional near-infrared spectroscopy to measure cortical activity during a stepwise cold stimulation of a hypersensitive tooth, as well as nonpainful control stimulation on the same tooth. Patients' sensory-discriminative and emotional-cognitive cortical regions were studied through the transition of a neutral to a painful stimulation. In the putative somatosensory cortex contralateral to the stimulus, 2 well-defined hemodynamic peaks were detected in the homuncular orofacial region: the first peak during the nonpainful phase and a second peak after the pain threshold was reached. Moreover, in the upper-left and lower-right prefrontal cortices, there was a significant active hemodynamic response in only the first phase, before the pain. Subsequently, the same prefrontal cortical areas deactivated after a painful experience had been reached. Our study indicates for the first time that pain perception and expectation elicit different hemodynamic cortical responses in a dental clinical setting.

PMID: 25904140 [PubMed - indexed for MEDLINE]

Digital Version

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

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

Arthritis Rheumatol. 2015 Feb;67(2):576-81

Authors: Foerster BR, Nascimento TD, DeBoer M, Bender MA, Rice IC, Truong DQ, Bikson M, Clauw DJ, Zubieta JK, Harris RE, DaSilva AF

Abstract
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 post–active tDCS assessment compared with the post–sham 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 post–sham 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 (β1 = 1.31, P < 0.001) and for the time period from baseline to active tDCS (β1= 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.

PMID: 25371383 [PubMed - indexed for MEDLINE]

Digital Version

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

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

Front Cell Neurosci. 2014;8:302

Authors: DosSantos MF, Holanda-Afonso RC, Lima RL, DaSilva AF, Moura-Neto V

Abstract
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.

PMID: 25339863 [PubMed]

Digital Version

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

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

Ann Clin Transl Neurol. 2014 Jun;1(6):445-50

Authors: Nascimento TD, DosSantos MF, Lucas S, van Holsbeeck H, DeBoer M, Maslowski E, Love T, Martikainen IK, Koeppe RA, Smith YR, Zubieta JK, DaSilva AF

Abstract
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.

PMID: 25328905 [PubMed]

Digital Version

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

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

Ann Clin Transl Neurol. 2014 Jun 1;1(6):439-444

Authors: DaSilva AF, Nascimento TD, DosSantos MF, Lucas S, van HolsbeecK H, DeBoer M, Maslowski E, Love T, Martikainen IK, Koeppe RA, Smith YR, Zubieta JK

Abstract
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.

PMID: 25072055 [PubMed - as supplied by publisher]

Digital Version

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

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

PLoS One. 2014;9(7):e102350

Authors: DosSantos MF, Martikainen IK, Nascimento TD, Love TM, DeBoer MD, Schambra HM, Bikson M, Zubieta JK, DaSilva AF

Abstract
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.

PMID: 25029273 [PubMed - indexed for MEDLINE]

Digital Version

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

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

J Vis Exp. 2014 Jun 02;(88):

Authors: DaSilva AF, Nascimento TD, Love T, DosSantos MF, Martikainen IK, Cummiford CM, DeBoer M, Lucas SR, Bender MA, Koeppe RA, Hall T, Petty S, Maslowski E, Smith YR, Zubieta JK

Abstract
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.

PMID: 24962460 [PubMed - indexed for MEDLINE]

Digital Version

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

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

Curr Pain Headache Rep. 2014 Jul;18(7):429

Authors: DaSilva AF, Nascimento TD, DosSantos MF, Zubieta JK

Abstract
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.

PMID: 24842566 [PubMed - indexed for MEDLINE]

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

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

Brain Stimul. 2014 Jul-Aug;7(4):623-4

Authors: Schambra HM, Bikson M, Wager TD, DosSantos MF, DaSilva AF

PMID: 24810955 [PubMed - indexed for MEDLINE]

Digital Version

BOOKS, CHAPTER, AND ESSAYS

DaSilva AFM and Hadjikhani N. Contributing author – essay: “Human Thalamic Response to Experimental Pain (Neuroimaging)” in the section “Nociceptive Processing in the Thalamus “ by Dr. Vania Apkarian, Encyclopedic Reference of Pain. Editor Schmidt RF and Willis WD, Springer-Verlag – October 2006.
DaSilva AFM and Acquadro MA. Chapter: “Orofacial Pain” in the handbook The Massachusetts General Hospital Handbook of Pain Management – Third Edition. Editor Dr. Jane Ballantyne, Linppincott Williams & Wilkins – 2005.
Borsook D, Moulton E, Scrivani S, DaSilva AFM, Becerra L. Chapter: “Imaging the Trigeminal System in Health and Disease”. Textbook: Head, Face and Neck Pain: Science, Evaluation, and Management. Mehta N, Maloney G, Bana D, Scrivani SJ. WJ Wiley. Accepted for publication.
DaSilva AFM, Bivins D, Acquadro MA. Chapter: “Neuropathic Facial Pain”. Textbook: Head, Face and Neck Pain: Science, Evaluation, and Management. Mehta N, Maloney G, Bana D, Scrivani SJ. WJ Wiley – Accepted for publication.

TEAM

ALEXANDRE F. DaSILVA, DDS, DMSc

Director and Founder, H.O.P.E. Lab
adasilva@umich.edu

THEODORA DANCIU, DMD, DMSc

Oral Pathologist
tdanciu@umich.edu

Cancer Pain and Pathology, H.O.P.E. Lab

THIAGO NASCIMENTO, MSc, DDS

Orofacial Pain Research Investigator, H.O.P.E. Lab
nasci@umich.edu

Project: Brain as a Research and Therapeutic Target in Chronic TMD

XIAOSU (FRANK) HU, MSc, PhD

Bioengineer, H.O.P.E. Lab
Research Investigator, Center for Human Growth & Development

xiaosuhu@umich.edu

Project: Neuroimaging of Dentin Hypersensitivity: An fNIRS Study

REBECCA TOBACK, BS

Research Coordinator, H.O.P.E. Lab
rtoback@umich.edu

EMILY BELLILE, MS

Cancer and Pain Biostatistician, H.O.P.E. Lab
lighte@umich.edu

DINA SALMAN, DDS

Orthodontic Resident, Class of 2016
dosalman@umich.edu

Project: Brain as a Research and Therapeutic Target in Chronic TMD

NATALIE YANG, DDS

Orthodontic Resident, Class of 2017
natyang@umich.edu

Project: Predicting NSAID Response in TMD Using Patient Phenotype and Genotypes

RYAN MCMAHAN, MS, DDS

Endodontic Resident, Class of 2017
rbmcmaha@umich.edu

Project: Neuroimaging and Neuromodulation of Dental Pain in a Clinical Setting

LEEN KHATIB, BS

Dental Student, Class of 2017
lkhatib@umich.edu

Project: Brain as a Research and Therapeutic Target in Chronic TMD

NATHAN WIGINGTON, BA

Dental Student, Class of 2018
nwig@umich.edu

Project: Visual and Auditory Neuromodulation of Pain Perception


H.O.P.E. Lab Alumni

ALUMNI

Recent Graduates

DREW RACEK, MS, DDS

Endodontic Resident, 2015

Project: Neuroimaging of Dentin Hypersensitivity: An fNIRS Study

CLAYTON FISHER, MS, DDS

Oral and Maxillofacial Pathology Resident, 2015

Project: Neuroimaging and Neuromodulation of Orofacial Cancer Pain

ADAM DONNEL, MS, DDS

Orthodontic Resident, 2014

Project: Neuromodulation in Chronic TMD Pain

Currently at Harvard University Part-Time Faculty in Orthodontics & Private Practice


Alumni: Postdoctoral Trainees & Residents

2011 - 2012 Ilkka Martikaninen MD, PhD
Project: Neuroimaging in Trigeminal pain
2009 - 2012 Marcos DosSantos MSc, DDS, PhD
Project: Neuroimaging and Neurostimulation in Orofacial Pain
Currently: Tenured Faculty Member, Universidade Federal do Rio de Janeiro

Alumni: Research Assistants & Dental Students

2013 - 2014 Mary-Catherine Bender
Currently: DDS Program, University of Michigan
2013 - 2014 Sarah Lucas
Currently: Optometry Program, Indiana University
2012 - 2013 Hendrik Van Holsbeck
Currently: DDS Program, University of Michigan
2012 - 2013 JJ Ubonwan Sae-Ung, DDS
Currently: Lecturer Oral Surgery Clinic, University of Michigan
2012 - 2013 Misty DeBoer
Currently: Communications Coordinator, Institute for Central American Development Studies (ICADS), Costa Rica
2010 - 2011 Nellie Kippley
Currently: Nephrology Physician Assistant, CentraCare Health System, MN
2009 - 2010 Alexandra Martella, DDS
Currently: Endodontic Resident at University of Illinois Chicago

Current Lab Team

MEDIA

Public Media and Editorials

UNIVERSITY OF MICHIGAN NEWS SERVICE COVERAGE

Hologram-like 3-D brain helps researchers decode migraine brain


Full article on PAIN NEUROIMAGING / NEURONAVIGATION


Migraine patients find pain relief in electrical brain stimulation

The animation above shows where on the skull scientists placed the non-invasive electrodes, and where the current flowed through the brain. The areas in blue show low current. The areas in red show high current, and they found that this high current reached key pain processing structures deeper within the brain

Full article on PAIN NEUROMODULATION

PAIN MOBILE TECHNOLOGY

PAIN (MIGRAINE) INFODEMIOLOGY

3D-ANATOMY DISSECTION

SELECTED MEDIA COVERAGE OF OUR WORK

CBS News: Migraines prompt colorful tweets.

Plus coverage in: Metro, Slate, Financial Express, NBC, CBS, BBC, Scientific American Mind Magazine, Reuters, Forbes, Washington Post, The Guardian, The Telegraph, CBC, Medical News Today, Delhi Daily News, Free Press Journal, The News International, RedOrbit, Detroit Free Press, UPI, and others.

SELECTED INTERVIEWS

CONTACT

H.O.P.E. Lab
Office: Biologic & Materials Sciences
School of Dentistry
1011 N. University Ave., Room 1014A
Ann Arbor, MI 48109-1078

H.O.P.E. Lab: The Molecular & Behavioral Neuroscience Institute (MBNI)
205 Zina Pitcher Pl, Room 1026
Ann Arbor, MI 48109-5720
Tel: 734 615-3807
Fax: 734 763-3453
Email: adasilva@umich.edu