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 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.
The most recent publications are reported below via PubMed search.
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
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]
Changes in resting state functional connectivity after repetitive transcranial direct current stimulation applied to motor cortex in fibromyalgia patients.
Arthritis Res Ther. 2016;18(1):40
Authors: Cummiford CM, Nascimento TD, Foerster BR, Clauw DJ, Zubieta JK, Harris RE, DaSilva AF
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 - in process]
Comparison of motion correction techniques applied to functional near-infrared spectroscopy data from children.
J Biomed Opt. 2015 Dec;20(12):126003
Authors: Hu XS, Arredondo MM, Gomba M, Confer N, DaSilva AF, Johnson TD, Shalinsky M, Kovelman I
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 - in process]
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
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]
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
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 - in process]
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
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]
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
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]
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
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]
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
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]
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
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]
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
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]
3D-neuronavigation in vivo through a patient's brain during a spontaneous migraine headache.
J Vis Exp. 2014;(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
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]
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
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]
Real-time sharing and expression of migraine headache suffering on Twitter: a cross-sectional infodemiology study.
J Med Internet Res. 2014;16(4):e96
Authors: Nascimento TD, DosSantos MF, Danciu T, DeBoer M, van Holsbeeck H, Lucas SR, Aiello C, Khatib L, Bender MA, UMSoD (Under)Graduate Class Of 2014, Zubieta JK, DaSilva AF
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.
PMID: 24698747 [PubMed - indexed for MEDLINE]
Technique and considerations in the use of 4x1 ring high-definition transcranial direct current stimulation (HD-tDCS).
J Vis Exp. 2013;(77):e50309
Authors: Villamar MF, Volz MS, Bikson M, Datta A, Dasilva AF, Fregni F
High-definition transcranial direct current stimulation (HD-tDCS) has recently been developed as a noninvasive brain stimulation approach that increases the accuracy of current delivery to the brain by using arrays of smaller "high-definition" electrodes, instead of the larger pad-electrodes of conventional tDCS. Targeting is achieved by energizing electrodes placed in predetermined configurations. One of these is the 4x1-ring configuration. In this approach, a center ring electrode (anode or cathode) overlying the target cortical region is surrounded by four return electrodes, which help circumscribe the area of stimulation. Delivery of 4x1-ring HD-tDCS is capable of inducing significant neurophysiological and clinical effects in both healthy subjects and patients. Furthermore, its tolerability is supported by studies using intensities as high as 2.0 milliamperes for up to twenty minutes. Even though 4x1 HD-tDCS is simple to perform, correct electrode positioning is important in order to accurately stimulate target cortical regions and exert its neuromodulatory effects. The use of electrodes and hardware that have specifically been tested for HD-tDCS is critical for safety and tolerability. Given that most published studies on 4x1 HD-tDCS have targeted the primary motor cortex (M1), particularly for pain-related outcomes, the purpose of this article is to systematically describe its use for M1 stimulation, as well as the considerations to be taken for safe and effective stimulation. However, the methods outlined here can be adapted for other HD-tDCS configurations and cortical targets.
PMID: 23893039 [PubMed - indexed for MEDLINE]
Immediate effects of tDCS on the μ-opioid system of a chronic pain patient.
Front Psychiatry. 2012;3:93
Authors: DosSantos MF, Love TM, Martikainen IK, Nascimento TD, Fregni F, Cummiford C, Deboer MD, Zubieta JK, Dasilva AF
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, [(11)C]carfentanil. This is one of the most important central neuromechanisms associated with pain perception and regulation. We measured μOR non-displaceable binding potential (μOR BP(ND)) 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 μORBP(ND) 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.
PMID: 23130002 [PubMed]
Reduced basal ganglia μ-opioid receptor availability in trigeminal neuropathic pain: a pilot study.
Mol Pain. 2012;8:74
Authors: DosSantos MF, Martikainen IK, Nascimento TD, Love TM, Deboer MD, Maslowski EC, Monteiro AA, Vincent MB, Zubieta JK, DaSilva AF
BACKGROUND: Although neuroimaging techniques have provided insights into the function of brain regions involved in Trigeminal Neuropathic Pain (TNP) in humans, there is little understanding of the molecular mechanisms affected during the course of this disorder. Understanding these processes is crucial to determine the systems involved in the development and persistence of TNP.
FINDINGS: In this study, we examined the regional μ-opioid receptor (μOR) availability in vivo (non-displaceable binding potential BPND) of TNP patients with positron emission tomography (PET) using the μOR selective radioligand [11C]carfentanil. Four TNP patients and eight gender and age-matched healthy controls were examined with PET. Patients with TNP showed reduced μOR BPND in the left nucleus accumbens (NAc), an area known to be involved in pain modulation and reward/aversive behaviors. In addition, the μOR BPND in the NAc was negatively correlated with the McGill sensory and total pain ratings in the TNP patients.
CONCLUSIONS: Our findings give preliminary evidence that the clinical pain in TNP patients can be related to alterations in the endogenous μ-opioid system, rather than only to the peripheral pathology. The decreased availability of μORs found in TNP patients, and its inverse relationship to clinical pain levels, provide insights into the central mechanisms related to this condition. The results also expand our understanding about the impact of chronic pain on the limbic system.
PMID: 23006894 [PubMed - indexed for MEDLINE]
tDCS-induced analgesia and electrical fields in pain-related neural networks in chronic migraine.
Headache. 2012 Sep;52(8):1283-95
Authors: Dasilva AF, Mendonca ME, Zaghi S, Lopes M, Dossantos MF, Spierings EL, Bajwa Z, Datta A, Bikson M, Fregni F
OBJECTIVE: We investigated in a sham-controlled trial the analgesic effects of a 4-week treatment of transcranial direct current stimulation (tDCS) over the primary motor cortex in chronic migraine. In addition, using a high-resolution tDCS computational model, we analyzed the current flow (electric field) through brain regions associated with pain perception and modulation.
METHODS: Thirteen patients with chronic migraine were randomized to receive 10 sessions of active or sham tDCS for 20 minutes with 2 mA over 4 weeks. Data were collected during baseline, treatment and follow-up. For the tDCS computational analysis, we adapted a high-resolution individualized model incorporating accurate segmentation of cortical and subcortical structures of interest.
RESULTS: There was a significant interaction term (time vs group) for the main outcome (pain intensity) and for the length of migraine episodes (ANOVA, P < .05 for both analyses). Post-hoc analysis showed a significant improvement in the follow-up period for the active tDCS group only. Our computational modeling studies predicted electric current flow in multiple cortical and subcortical regions associated with migraine pathophysiology. Significant electric fields were generated, not only in targeted cortical regions but also in the insula, cingulate cortex, thalamus, and brainstem regions.
CONCLUSIONS: Our findings give preliminary evidence that patients with chronic migraine have a positive, but delayed, response to anodal tDCS of the primary motor cortex. These effects may be related to electrical currents induced in pain-related cortical and subcortical regions.
PMID: 22512348 [PubMed - indexed for MEDLINE]
The role of sensory fiber demography in trigeminal and postherpetic neuralgias.
J Dent Res. 2012 Jan;91(1):17-24
Authors: DaSilva AF, DosSantos MF
In this study, we systematically investigated fiber demography, based on function and distribution, from the periphery to their destinations in the various central (sub) nuclei in the trigeminal brainstem nuclear sensory complex. Conventional and novel compelling information is provided, demonstrating that the ratio and somatotopy of types A and C sensory fibers at the site of a lesion can elucidate important puzzles in TNP disorders. For instance, we explain how of a major shift in the fibers' direction and ratio at the level of the trigeminal root entry zone (REZ) influences the pathophysiology of pre- and typical trigeminal neuralgia. As a result, there is a high A/C ratio of oral and peri-oral fibers in the supero-medial region of the REZ, which is mostly susceptible to vascular compression. However, this A/C ratio varies considerably at lower proportions in other areas along the peripheral trigeminal pathway, where an injury (viral, vessel compression, or trauma) can lead to a broader spectrum of fiber involvement and, consequently, pain outcome. In summary, we explain how fiber demography can influence pain quality, location, temporal features, progress, and treatment prognosis of TNP in those patients who develop it.
PMID: 21670221 [PubMed - indexed for MEDLINE]
Electrode positioning and montage in transcranial direct current stimulation.
J Vis Exp. 2011;(51)
Authors: DaSilva AF, Volz MS, Bikson M, Fregni F
Transcranial direct current stimulation (tDCS) is a technique that has been intensively investigated in the past decade as this method offers a non-invasive and safe alternative to change cortical excitability. The effects of one session of tDCS can last for several minutes, and its effects depend on polarity of stimulation, such as that cathodal stimulation induces a decrease in cortical excitability, and anodal stimulation induces an increase in cortical excitability that may last beyond the duration of stimulation. These effects have been explored in cognitive neuroscience and also clinically in a variety of neuropsychiatric disorders--especially when applied over several consecutive sessions. One area that has been attracting attention of neuroscientists and clinicians is the use of tDCS for modulation of pain-related neural networks. Modulation of two main cortical areas in pain research has been explored: primary motor cortex and dorsolateral prefrontal cortex. Due to the critical role of electrode montage, in this article, we show different alternatives for electrode placement for tDCS clinical trials on pain; discussing advantages and disadvantages of each method of stimulation.
PMID: 21654618 [PubMed - indexed for MEDLINE]
Colocalized structural and functional changes in the cortex of patients with trigeminal neuropathic pain.
PLoS One. 2008;3(10):e3396
Authors: DaSilva AF, Becerra L, Pendse G, Chizh B, Tully S, Borsook D
BACKGROUND: Recent data suggests that in chronic pain there are changes in gray matter consistent with decreased brain volume, indicating that the disease process may produce morphological changes in the brains of those affected. However, no study has evaluated cortical thickness in relation to specific functional changes in evoked pain. In this study we sought to investigate structural (gray matter thickness) and functional (blood oxygenation dependent level - BOLD) changes in cortical regions of precisely matched patients with chronic trigeminal neuropathic pain (TNP) affecting the right maxillary (V2) division of the trigeminal nerve. The model has a number of advantages including the evaluation of specific changes that can be mapped to known somatotopic anatomy.
METHODOLOGY/PRINCIPAL FINDINGS: Cortical regions were chosen based on sensory (Somatosensory cortex (SI and SII), motor (MI) and posterior insula), or emotional (DLPFC, Frontal, Anterior Insula, Cingulate) processing of pain. Both structural and functional (to brush-induced allodynia) scans were obtained and averaged from two different imaging sessions separated by 2-6 months in all patients. Age and gender-matched healthy controls were also scanned twice for cortical thickness measurement. Changes in cortical thickness of TNP patients were frequently colocalized and correlated with functional allodynic activations, and included both cortical thickening and thinning in sensorimotor regions, and predominantly thinning in emotional regions.
CONCLUSIONS: Overall, such patterns of cortical thickness suggest a dynamic functionally-driven plasticity of the brain. These structural changes, which correlated with the pain duration, age-at-onset, pain intensity and cortical activity, may be specific targets for evaluating therapeutic interventions.
PMID: 18923647 [PubMed - indexed for MEDLINE]
Thickening in the somatosensory cortex of patients with migraine.
Neurology. 2007 Nov 20;69(21):1990-5
Authors: DaSilva AF, Granziera C, Snyder J, Hadjikhani N
OBJECTIVE: To examine morphologic changes in the somatosensory cortex (SSC) of patients with migraine.
METHODS: Cortical thickness of the SSC of patients with migraine was measured in vivo and compared with age- and sex-matched healthy subjects. The cohort was composed of 24 patients with migraine, subdivided into 12 patients who had migraine with aura, 12 patients who had migraine without aura, and 12 controls. Group and individual analyses were performed in the SSC and shown as average maps of significant changes in cortical thickness.
RESULTS: Migraineurs had on average thicker SSCs than the control group. The most significant thickness changes were noticed in the caudal SSC, where the trigeminal area, including head and face, is somatotopically represented.
CONCLUSIONS: Our findings indicate the presence of interictal structural changes in the somatosensory cortex (SSC) of migraineurs. The SSC plays a crucial role in the noxious and nonnoxious somatosensory processing. Thickening in the SSC is in line with diffusional abnormalities observed in the subcortical trigeminal somatosensory pathway of the same migraine cohort in a previous study. Repetitive migraine attacks may lead to, or be the result of, neuroplastic changes in cortical and subcortical structures of the trigeminal somatosensory system.
PMID: 18025393 [PubMed - indexed for MEDLINE]
Interictal alterations of the trigeminal somatosensory pathway and periaqueductal gray matter in migraine.
Neuroreport. 2007 Mar 5;18(4):301-5
Authors: DaSilva AF, Granziera C, Tuch DS, Snyder J, Vincent M, Hadjikhani N
Migraine has been traditionally considered a nonprogressive, paroxysmal disorder with no brain abnormalities between attacks. We used diffusion tensor imaging to examine interictal diffusion properties of the brains of migraineurs with aura, migraineurs without aura and matched healthy controls. Areas of lower fractional anisotropy were present in migraineurs along the thalamocortical tract. In addition, migraineurs with aura had lower fractional anisotropy in the ventral trigeminothalamic tract, and migraineurs without aura had lower fractional anisotropy in the ventrolateral periaqueductal grey matter. Our results indicate the presence of permanent interictal changes in migraineurs, pointing to an effect of migraine on the trigeminal somatosensory and modulatory pain systems.
PMID: 17435592 [PubMed - indexed for MEDLINE]
Cluster headache: a review of neuroimaging findings.
Curr Pain Headache Rep. 2007 Apr;11(2):131-6
Authors: DaSilva AF, Goadsby PJ, Borsook D
Classified as a trigeminal autonomic cephalalgia, cluster headache is characterized by recurrent short-lived excruciating pain attacks, which are concurrent with autonomic signs. These clinical features have led to the assumption that cluster headache's pathophysiology involves central nervous system structures, including the hypothalamus. In the past decade, neuroimaging studies have confirmed such clinically derived theory by uncovering in vivo neuronal changes located in the inferior posterior hypothalamus. Using a variety of neuro-imaging techniques (functional , biochemical , and structural ) in patients with cluster headache, we are making improvements in our understanding of the role of the brain in this disorder. This article summarizes neuroimaging findings in cluster headache patients, describing neuronal changes that occur during attacks and remission, as well as during hypothalamic stimulation.
PMID: 17367592 [PubMed - indexed for MEDLINE]
Anatomical alterations of the visual motion processing network in migraine with and without aura.
PLoS Med. 2006 Oct;3(10):e402
Authors: Granziera C, DaSilva AF, Snyder J, Tuch DS, Hadjikhani N
BACKGROUND: Patients suffering from migraine with aura (MWA) and migraine without aura (MWoA) show abnormalities in visual motion perception during and between attacks. Whether this represents the consequences of structural changes in motion-processing networks in migraineurs is unknown. Moreover, the diagnosis of migraine relies on patient's history, and finding differences in the brain of migraineurs might help to contribute to basic research aimed at better understanding the pathophysiology of migraine.
METHODS AND FINDINGS: To investigate a common potential anatomical basis for these disturbances, we used high-resolution cortical thickness measurement and diffusion tensor imaging (DTI) to examine the motion-processing network in 24 migraine patients (12 with MWA and 12 MWoA) and 15 age-matched healthy controls (HCs). We found increased cortical thickness of motion-processing visual areas MT+ and V3A in migraineurs compared to HCs. Cortical thickness increases were accompanied by abnormalities of the subjacent white matter. In addition, DTI revealed that migraineurs have alterations in superior colliculus and the lateral geniculate nucleus, which are also involved in visual processing.
CONCLUSIONS: A structural abnormality in the network of motion-processing areas could account for, or be the result of, the cortical hyperexcitability observed in migraineurs. The finding in patients with both MWA and MWoA of thickness abnormalities in area V3A, previously described as a source in spreading changes involved in visual aura, raises the question as to whether a "silent" cortical spreading depression develops as well in MWoA. In addition, these experimental data may provide clinicians and researchers with a noninvasively acquirable migraine biomarker.
PMID: 17048979 [PubMed - indexed for MEDLINE]
A primer on diffusion tensor imaging of anatomical substructures.
Neurosurg Focus. 2003 Jul 15;15(1):E4
Authors: DaSilva AF, Tuch DS, Wiegell MR, Hadjikhani N
In this article, the authors review the application of diffusion tensor (DT) magnetic resonance (MR) imaging to demonstrate anatomical substructures that cannot be resolved by conventional structural imaging. They review the physical basis of DT imaging and provide illustrative anatomical examples. The DT imaging technique measures the self-diffusion, or random thermal motion, of the endogenous water in nerve tissue. Because of the preferred diffusion of water molecules along the nerve fiber direction, DT imaging can measure the orientation of the neural fiber structure within each voxel of the MR image. The fiber orientation information yielded by DT imaging provides a new contrast mechanism that can be used to resolve images of anatomical substructures that cannot otherwise be visualized using conventional structural imaging. The authors illustrate how DT imaging can resolve individual pathways in the brainstem as well as individual nuclei of the thalamus and conclude by describing potential applications in neurosurgery.
PMID: 15355006 [PubMed - indexed for MEDLINE]
The temporomandibular joint: clinical and surgical aspects.
Neuroimaging Clin N Am. 2003 Aug;13(3):573-82
Authors: DaSilva AF, Shaefer J, Keith DA
Advances in imaging techniques have greatly enhanced the ability to visualize the internal anatomy of the temporomandibular joint and have increased understanding of the etiology of many temporomandibular disorders. When used together with careful history and physical examination, this knowledge can contribute to better treatment outcomes.
PMID: 14631691 [PubMed - indexed for MEDLINE]
Specific and somatotopic functional magnetic resonance imaging activation in the trigeminal ganglion by brush and noxious heat.
J Neurosci. 2003 Aug 27;23(21):7897-903
Authors: Borsook D, DaSilva AF, Ploghaus A, Becerra L
We used functional magnetic resonance imaging (fMRI) to assess activation in the trigeminal ganglion during innocuous mechanical (brush) and noxious thermal (46 degrees C) stimulation of the face within the receptive fields of each of the three divisions of the trigeminal nerve in healthy volunteers. For both stimulus types, we observed signal changes only in the ipsilateral ganglion, and activation occurred somatotopically, as predicted by the known anatomical segregation of the neurons comprising the ophthalmic (V1), maxillary (V2), and mandibular (V3) divisions of the nerve. Signal decreased after brush stimuli and increased after the application of noxious heat. The abilities to detect somatotopic activation within the ganglion and to segregate non-noxious mechanical from noxious thermal stimuli suggest that fMRI will be valuable for measuring changes in the trigeminal ganglion in human models of neuropathic pain and in the clinical condition itself and may also be useful in the evaluation of pain therapies.
PMID: 12944520 [PubMed - indexed for MEDLINE]
Somatotopic activation in the human trigeminal pain pathway.
J Neurosci. 2002 Sep 15;22(18):8183-92
Authors: DaSilva AF, Becerra L, Makris N, Strassman AM, Gonzalez RG, Geatrakis N, Borsook D
Functional magnetic resonance imaging was used to image pain-associated activity in three levels of the neuraxis: the medullary dorsal horn, thalamus, and primary somatosensory cortex. In nine subjects, noxious thermal stimuli (46 degrees C) were applied to the facial skin at sites within the three divisions of the trigeminal nerve (V1, V2, and V3) and also to the ipsilateral thumb. Anatomical and functional data were acquired to capture activation across the spinothalamocortical pathway in each individual. Significant activation was observed in the ipsilateral spinal trigeminal nucleus within the medulla and lower pons in response to at least one of the three facial stimuli in all applicable data sets. Activation from the three facial stimulation sites exhibited a somatotopic organization along the longitudinal (rostrocaudal) axis of the brain stem that was consistent with the classically described "onion skin" pattern of sensory deficits observed in patients after trigeminal tractotomy. In the thalamus, activation was observed in the contralateral side involving the ventroposteromedial and dorsomedial nuclei after stimulation of the face and in the ventroposterolateral and dorsomedial nuclei after stimulation of the thumb. Activation in the primary somatosensory cortex displayed a laminar sequence that resembled the trigeminal nucleus, with V2 more rostral, V1 caudal, and V3 medial, abutting the region of cortical activation observed for the thumb. These results represent the first simultaneous imaging of pain-associated activation at three levels of the neuraxis in individual subjects. This approach will be useful for exploring central correlates of plasticity in models of experimental and clinical pain.
PMID: 12223572 [PubMed - indexed for MEDLINE]
Project: Neuroimaging of Dentin Hypersensitivity: An fNIRS Study
Project: Neuroimaging and Neuromodulation of Orofacial Cancer Pain
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
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
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.
2014 WWJ Newsradio CBS radio affiliated: “Migraine twitter” by Sean Lee
2001 Globo Reporter (Brazil): “The Brain with Pain.”
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