My research focuses on the use of neuroimaging methods to understand brain structure and function and treatment-related plasticity in individuals with chronic pain. Current projects focus on basic mechanisms and biomarkers underlying chronic headache subtypes using multimodal brain imaging and deep phenotyping and repetitive transcranial magnetic stimulation to augment pain and hypnotizability. Additionally, I am interested in understanding the central mechanisms of chronic pain associated with Lyme disease.
Teaching roles include Co-Director for the Neuroscience, Behavior, and Cognition (NBC) Scholarly Concentration, part of a required structured program of study in the medical student curriculum that promotes in depth learning and scholarship, and Instructor for ANES 215, a required course in the Department of Anesthesia for medical students enrolled in the NBC Scholarly Concentration.
Instructor, Neurology & Neurological Sciences
Doctor of Philosophy, University of Toronto (2015)
Master of Science, University of Toronto (2009)
Bachelor of Science, University of Toronto (2006)
Functional MRI and sensory evaluation of central mechanisms of chronic pain associated with Lyme disease, Stanford University
Lyme disease is an emerging tick-borne infectious disease. It is a multisystem disorder associated with several symptoms including pain, fatigue, depression, and cognitive impairments. Importantly, there can be differences in clinical symptoms, particularly with regard to pain. For some patients, initial pain symptoms resolve early, but for others, chronic pain develops.
In order to understand why some patients develop chronic pain and others do not, we are currently recruiting adults with chronic Lyme disease to participate in a research study investigating the central mechanisms of pain using sensory testing and brain imaging (MRI). If you have been diagnosed with Lyme disease for at least one year, please complete a brief survey by clicking on the "Lyme Survey" link under the For More Information section below.
If you have trouble accessing the link, please email email@example.com or call 650-497-5704 and we will be happy to assist.
Stanford University, Palo Alto, CA.
For More Information:
Investigating the role of GABA and glutamate on anterior cingulate activity associated with hypnosis, Stanford University (1/2017 - 8/2018)
Hypnosis is a powerful evidence-based tool for the treatment of many disorders. Hypnotizability is a stable trait over time suggesting neurophysiological factors underlying hypnotic responsiveness. We have previously shown differential brain activity in the anterior cingulate cortex (ACC) in high vs. low hypnotizable individuals. For this study, we are assessing levels of inhibitory (GABA) and excitatory (glutamate) neurotransmitters in the ACC of healthy individuals to determine if these measures are also associated with level of hypnotizability.
Stanford University, Palo Alto, CA.
MCADNNet: Recognizing Stages of Cognitive Impairment Through Efficient Convolutional fMRI and MRI Neural Network Topology Models
2019; 7: 155584 - 155600
View details for DOI 10.1109/ACCESS.2019.2949577
Altered structural brain network topology in chronic migraine.
Brain structure & function
Despite its prevalence and high disease burden, the pathophysiological mechanisms underlying chronic migraine (CM) are not well understood. As CM is a complex disorder associated with a range of sensory, cognitive, and affective comorbidities, examining structural network disruption may provide additional insights into CM symptomology beyond studies of focal brain regions. Here, we compared structural interconnections in patients with CM (n = 52) and healthy controls (HC) (n = 48) using MRI measures of cortical thickness and subcortical volume combined with graph theoretical network analyses. The analysis focused on both local (nodal) and global measures of topology to examine network integration, efficiency, centrality, and segregation. Our results indicated that patients with CM had altered global network properties that were characterized as less integrated and efficient (lower global and local efficiency) and more highly segregated (higher transitivity). Patients also demonstrated aberrant local network topology that was less integrated (higher path length), less central (lower closeness centrality), less efficient (lower local efficiency) and less segregated (lower clustering). These network differences not only were most prominent in the limbic and insular cortices but also occurred in frontal, temporal, and brainstem regions, and occurred in the absence of group differences in focal brain regions. Taken together, examining structural correlations between brain areas may be a more sensitive means to detect altered brain structure and understand CM symptomology at the network level. These findings contribute to an increased understanding of structural connectivity in CM and provide a novel approach to potentially track and predict the progression of migraine disorders.This study is registered on ClinicalTrials.gov (Identifier: NCT03304886).
View details for DOI 10.1007/s00429-019-01994-7
View details for PubMedID 31792696
Imaging in CDH
Chronic Headache: A Comprehensive Guide to Evaluation and Management
Springer. 2019; 1st: 157–168
View details for DOI DOI: 10.1007/978-3-319-91491-6_11
High-dose spaced theta-burst TMS as a rapid-acting antidepressant in highly refractory depression.
Brain : a journal of neurology
View details for PubMedID 29415152
- Transcranial Magnetic Simulation for Disorders other than Depression Transcranial Magnetic Stimulation: Clinical Appllications for Psychiatric Practice American Psychiatric Association Publishing. 2018: 157–172
Structural Magnetic Resonance Imaging Can Identify Trigeminal System Abnormalities in Classical Trigeminal Neuralgia
FRONTIERS IN NEUROANATOMY
Classical trigeminal neuralgia (TN) is a chronic pain disorder that has been described as one of the most severe pains one can suffer. The most prevalent theory of TN etiology is that the trigeminal nerve is compressed at the root entry zone (REZ) by blood vessels. However, there is significant evidence showing a lack of neurovascular compression (NVC) for many cases of classical TN. Furthermore, a considerable number of patients who are asymptomatic have MR evidence of NVC. Since there is no validated animal model that reproduces the clinical features of TN, our understanding of TN pathology mainly comes from biopsy studies that have limitations. Sophisticated structural MRI techniques including diffusion tensor imaging provide new opportunities to assess the trigeminal nerves and CNS to provide insight into TN etiology and pathogenesis. Specifically, studies have used high-resolution structural MRI methods to visualize patterns of trigeminal nerve-vessel relationships and to detect subtle pathological features at the trigeminal REZ. Structural MRI has also identified CNS abnormalities in cortical and subcortical gray matter and white matter and demonstrated that effective neurosurgical treatment for TN is associated with a reversal of specific nerve and brain abnormalities. In conclusion, this review highlights the advanced structural neuroimaging methods that are valuable tools to assess the trigeminal system in TN and may inform our current understanding of TN pathology. These methods may in the future have clinical utility for the development of neuroimaging-based biomarkers of TN.
View details for DOI 10.3389/finana.2016.0095
View details for Web of Science ID 000385677500001
View details for PubMedID 27807409
View details for PubMedCentralID PMC5070392
Reversal of insular and microstructural nerve abnormalities following effective surgical treatment for trigeminal neuralgia.
2015; 156 (6): 1112–23
Classical trigeminal neuralgia (TN) is a severe neuropathic facial pain disorder commonly associated with neurovascular compression at the trigeminal nerve root entry zone (REZ). Neurosurgical interventions can relieve TN pain, but the mechanisms underlying these effects are unknown. We determined whether the abnormalities we previously reported at the REZ of TN patients using diffusion tensor imaging (DTI) and brain gray matter (GM) analyses resolve after effective neurosurgical treatment. Twenty-five patients who underwent either microvascular decompression surgery or Gamma Knife radiosurgery for right-sided TN had magnetic resonance imaging scans before and after treatment and were compared with age-matched controls. Cortical thickness and voxel-based morphometry examined specific brain GM we previously reported as abnormal in TN. White matter metrics of fractional anisotropy (FA), mean, radial, and axial diffusivities (MD, RD, and AD, respectively) were extracted bilaterally from each trigeminal REZ. Before treatment, patients had widespread GM abnormalities including thinner ventral anterior insula (vAI) cortex, and REZ microstructural abnormalities (lower FA, and higher MD, RD, and AD) compared with controls. We considered a 75% reduction in pain as effective treatment. The right vAI was the only GM region that normalized toward the level of healthy controls after effective treatment. At the REZ, effective treatment reversed FA, MD, RD, and AD abnormalities and was correlated with pain relief after treatment. These results demonstrate that treatment can effectively resolve pain by normalizing REZ abnormalities, which may influence vAI abnormalities. Future studies should consider DTI as an adjunct to assess the patient outcome and subtle microstructural changes after treatment.
View details for DOI 10.1097/j.pain.0000000000000156
View details for PubMedID 25782366
Individual Differences in Temporal Summation of Pain Reflect Pronociceptive and Antinociceptive Brain Structure and Function.
The Journal of neuroscience : the official journal of the Society for Neuroscience
2015; 35 (26): 9689–9700
Temporal summation of pain (TSP), the perception of increasingly greater pain evoked by repetitive noxious stimuli, is highly variable between individuals. Individuals with facilitated pain processing and/or reduced pain-modulatory capabilities are regarded as pronociceptive, whereas individuals with reduced pain processing capacity are characterized as antinociceptive. Brodmann area (BA) 3a of the primary somatosensory cortex is part of an ascending pathway from the sensory thalamus that mediates TSP. Descending pain modulation involves projections from the subgenual anterior cingulate cortex (sgACC) to the periaqueductal gray to the rostral ventromedial medulla (RVM). Here, we tested the hypothesis that pronociceptive individuals have an enhanced TSP response compared with antinociceptive individuals, marked by facilitated ascending nociceptive processing and/or reduced capacity for descending pain modulation. Eighty healthy humans were tested with a TSP protocol and underwent structural and resting-state functional magnetic resonance imaging. We found large interindividual differences in TSP responses, which were positively correlated with functional connectivity (FC) between individuals' right sensory thalamus with their BA 3a (thal-BA 3a), and with cortical thickness in their insula and medial prefrontal cortex. In contrast, TSP was negatively correlated with FC between individuals' RVM with their sgACC (RVM-sgACC). When subjects were grouped as pronociceptive or antinociceptive based on whether they had greater thal-BA 3a or RVM-sgACC FC respectively, pronociceptive subjects showed greater TSP responses. Furthermore, TSP was positively correlated with the extent of imbalance toward ascending nociceptive processing. Our study indicates that individuals with enhanced TSP have facilitated ascending nociceptive processing and reduced pain-modulatory capacities.This study provides novel evidence that an individual's propensity to experience amplified pain with repeated stimuli [i.e., temporal summation of pain (TSP)] reflects attributes of their "pain connectome," namely stronger ascending nociceptive and weaker descending pain-modulatory components. Understanding the individual neural mechanisms underlying TSP within individuals has implications for developing personalized pain-management strategies for chronic pain.
View details for DOI 10.1523/JNEUROSCI.5039-14.2015
View details for PubMedID 26134651
Diffusivity signatures characterize trigeminal neuralgia associated with multiple sclerosis.
Multiple sclerosis (Houndmills, Basingstoke, England)
Trigeminal neuralgia secondary to multiple sclerosis (MS-TN) is a facial neuropathic pain syndrome similar to classic trigeminal neuralgia (TN). While TN is caused by neurovascular compression of the fifth cranial nerve (CN V), how MS-related demyelination correlates with pain in MS-TN is not understood.We aim to examine diffusivities along CN V in MS-TN, TN, and controls in order to reveal differential neuroimaging correlates across groups.3T MR diffusion weighted, T1, T2 and FLAIR sequences were acquired for MS-TN, TN, and controls. Multi-tensor tractography was used to delineate CN V across cisternal, root entry zone (REZ), pontine and peri-lesional segments. Diffusion metrics including fractional anisotropy (FA), and radial (RD), axial (AD), and mean diffusivities (MD) were measured from each segment.CN V segments showed distinctive diffusivity patterns. The TN group showed higher FA in the cisternal segment ipsilateral to the side of pain, and lower FA in the ipsilateral REZ segment. The MS-TN group showed lower FA in the ipsilateral peri-lesional segments, suggesting differential microstructural changes along CN V in these conditions.The study demonstrates objective differences in CN V microstrucuture in TN and MS-TN using non-invasive neuroimaging. This represents a significant improvement in the methods currently available to study pain in MS.
View details for DOI 10.1177/1352458515579440
View details for PubMedID 25921052
Abnormal trigeminal nerve microstructure and brain white matter in idiopathic trigeminal neuralgia.
2014; 155 (1): 37-44
Idiopathic trigeminal neuralgia (TN) is classically associated with neurovascular compression (NVC) of the trigeminal nerve at the root entry zone (REZ), but NVC-induced structural alterations are not always apparent on conventional imaging. Previous studies report lower fractional anisotropy (FA) in the affected trigeminal nerves of TN patients using diffusion tensor imaging (DTI). However, it is not known if TN patients have trigeminal nerve abnormalities of mean, radial, or axial diffusivity (MD, RD, AD - metrics linked to neuroinflammation and edema) or brain white matter (WM) abnormalities. DTI scans in 18 right-sided TN patients and 18 healthy controls were retrospectively analyzed to extract FA, RD, AD, and MD from the trigeminal nerve REZ, and Tract-Based Spatial Statistics (TBSS) was used to assess brain WM. In patients, the affected trigeminal nerve had lower FA, and higher RD, AD, and MD was found bilaterally compared to controls. Group TBSS (P<0.05, corrected) showed patients had lower FA and increased RD, MD, and AD in brain WM connecting areas involved in the sensory and cognitive-affective dimensions of pain, attention, and motor functions, including the corpus callosum, cingulum, posterior corona radiata, and superior longitudinal fasciculus. These data indicate that TN patients have abnormal tissue microstructure in their affected trigeminal nerves, and as a possible consequence, WM microstructural alterations in the brain. These findings suggest that trigeminal nerve structural abnormalities occur in TN, even if not apparent on gross imaging. Furthermore, MD and RD findings suggest that neuroinflammation and edema may contribute to TN pathophysiology.
View details for DOI 10.1016/j.pain.2013.08.029
View details for PubMedID 23999058
Sensorimotor and Pain Modulation Brain Abnormalities in Trigeminal Neuralgia: A Paroxysmal, Sensory-Triggered Neuropathic Pain.
2013; 8 (6): e66340
Idiopathic trigeminal neuralgia (TN) is characterized by paroxysms of severe facial pain but without the major sensory loss that commonly accompanies neuropathic pain. Since neurovascular compression of the trigeminal nerve root entry zone does not fully explain the pathogenesis of TN, we determined whether there were brain gray matter abnormalities in a cohort of idiopathic TN patients. We used structural MRI to test the hypothesis that TN is associated with altered gray matter (GM) in brain areas involved in the sensory and affective aspects of pain, pain modulation, and motor function. We further determined the contribution of long-term TN on GM plasticity.Cortical thickness and subcortical GM volume were measured from high-resolution 3T T1-weighted MRI scans in 24 patients with right-sided TN and 24 healthy control participants.TN patients had increased GM volume in the sensory thalamus, amygdala, periaqueductal gray, and basal ganglia (putamen, caudate, nucleus accumbens) compared to healthy controls. The patients also had greater cortical thickness in the contralateral primary somatosensory cortex and frontal pole compared to controls. In contrast, patients had thinner cortex in the pregenual anterior cingulate cortex, the insula and the orbitofrontal cortex. No relationship was observed between GM abnormalities and TN pain duration.TN is associated with GM abnormalities in areas involved in pain perception, pain modulation and motor function. These findings may reflect increased nociceptive input to the brain, an impaired descending modulation system that does not adequately inhibit pain, and increased motor output to control facial movements to limit pain attacks.
View details for DOI 10.1371/journal.pone.0066340
View details for PubMedID 23823184
View details for PubMedCentralID PMC3688879
Aberrant Structural Network Architecture in Chronic Migraine
SAGE PUBLICATIONS LTD. 2019: 392
View details for Web of Science ID 000491167100058
High-Dose Spaced Theta-Burst Transcranial Magnetic Stimulation as a Rapid-Acting Anti- Depressant in Highly Refractory Depression
ELSEVIER SCIENCE INC. 2018: S191
View details for Web of Science ID 000432466300476
High-Dose Theta-Burst Transcranial Magnetic Stimulation Modulates Heart Rate Variability
ELSEVIER SCIENCE INC. 2018: S189
View details for Web of Science ID 000432466300472
Clinical Features Contributing to Cortical Thickness Changes in Chronic Migraine - A Pilot Study.
The objectives of this cross-sectional pilot study were threefold: to identify regions of cortical thickness that differentiate chronic migraine (CM) from controls, to assess group differences in interregional cortical thickness covariance, and to determine group differences in associations between clinical variables and cortical thickness.Cortical thickness alterations in relation to clinical features have not been adequately explored in CM. Assessment of this relationship can be useful to describe cortical substrates for disease progression in migraine and to identify clinical variables that warrant management emphasis.Thirty CM cases (mean age 40 years; male-to-female 1:4) and 30 sex-matched healthy controls (mean age 40 years) were enrolled. Participants completed self-administered and standardized questionnaires assessing headache-related clinical features and common psychological comorbidities. T1-weighted brain images were acquired on a 3T MRI. A whole-brain cortical thickness analysis was performed. Additionally, correlations between all brain regions were assessed to examine interregional cortical thickness covariance. Interactions were analyzed to identify clinical variables that were significantly associated with cortical thickness.The whole brain cortical thickness analysis revealed no significant differences between CM patients and controls. However, significant associations between clinical features and cortical thickness were observed for the patients only. These associations included the right superior temporal sulcus (R2 = 0.72, P = .001) and the right insula (R2 = 0.71, P = .002) with distinct clinical variables ie, longer history of CM, posttraumatic stress disorder (PTSD), sleep quality, pain self-efficacy, and somatic symptoms. Higher interregional cortical covariance was found in CM compared to controls (OR = 3.1, CI 2.10-4.56, P < .0001), such that cortical thickness between regions tended to be more correlated in patients, particularly in the temporal and frontal lobes.CM patients have significantly greater cortical covariance compared to controls. Cortical thickness in CM patients was predominantly accounted for by CM duration, PTSD, and poor sleep quality, while improved pain self-efficacy buffered cortical thickness. While it is important to address all CM features and comorbidities, it may be useful to emphasize optimizing the management of certain clinical features that contribute to cortical abnormalities including managing PTSD, early management to shorten duration of CM, and improving pain self-efficacy and sleep quality.
View details for PubMedID 30468246
Modulation of the Neural Circuitry Underlying Trait Hypnotizability With Spaced Continuous Theta-Burst Stimulation
NATURE PUBLISHING GROUP. 2017: S508–S509
View details for Web of Science ID 000416846303052
Comparison of Diffusion-Weighted MRI Reconstruction Methods for Visualization of Cranial Nerves in Posterior Fossa Surgery.
Frontiers in neuroscience
2017; 11: 554
Diffusion-weighted imaging (DWI)-based tractography has gained increasing popularity as a method for detailed visualization of white matter (WM) tracts. Different imaging techniques, and more novel, advanced imaging methods provide significant WM structural detail. While there has been greater focus on improving tract visualization for larger WM pathways, the relative value of each method for cranial nerve reconstruction and how this methodology can assist surgical decision-making is still understudied. Images from 10 patients with posterior fossa tumors (4 male, mean age: 63.5), affecting either the trigeminal nerve (CN V) or the facial/vestibular complex (CN VII/VIII), were employed. Three distinct reconstruction methods [two tensor-based methods: single diffusion tensor tractography (SDT) (3D Slicer), eXtended streamline tractography (XST), and one fiber orientation distribution (FOD)-based method: streamline tractography using constrained spherical deconvolution (CSD)-derived estimates (MRtrix3)], were compared to determine which of these was best suited for use in a neurosurgical setting in terms of processing speed, anatomical accuracy, and accurate depiction of the relationship between the tumor and affected CN. Computation of the tensor map was faster when compared to the implementation of CSD to provide estimates of FOD. Both XST and CSD-based reconstruction methods tended to give more detailed representations of the projections of CN V and CN VII/VIII compared to SDT. These reconstruction methods were able to more accurately delineate the course of CN V and CN VII/VIII, differentiate CN V from the cerebellar peduncle, and delineate compression of CN VII/VIII in situations where SDT could not. However, CSD-based reconstruction methods tended to generate more invalid streamlines. XST offers the best combination of anatomical accuracy and speed of reconstruction of cranial nerves within this patient population. Given the possible anatomical limitations of single tensor models, supplementation with more advanced tensor-based reconstruction methods might be beneficial.
View details for PubMedID 29062268
View details for PubMedCentralID PMC5640769
Journal Club: Exacerbation of headache during dihydroergotamine for chronic migraine does not alter outcome.
2016; 87 (16): e196-e198
Transient headache exacerbation during IV dihydroergotamine (DHE) therapy of migraine may prompt clinicians to prematurely discontinue DHE therapy, potentially depriving patients of the full benefit of DHE infusion. In a recent Neurology® article, Eller et al. evaluated whether or not worsening headache during DHE infusion was associated with suboptimal medium-term headache outcomes.
View details for PubMedID 27754915
Journal Club: Change in brain network connectivity during PACAP38-induced migraine attacks.
2016; 87 (16): e199-e202
View details for PubMedID 27754916
Discriminating neural representations of physical and social pains: how multivariate statistics challenge the 'shared representation' theory of pain.
Journal of neurophysiology
Overlapping functional magnetic resonance imaging (fMRI) activity elicited by physical pain and social rejection has posited a common neural representation between the two experiences. However, Woo and colleagues (Woo et al., 2014) recently used multivariate statistics to challenge the 'shared representation' theory of pain. This study has implications in the way results from fMRI studies are interpreted, and has the potential of broadening our understanding of different pain states and future development of personalized medicine.
View details for DOI 10.1152/jn.00075.2015
View details for PubMedID 25787949
- Diffusion imaging in trigeminal neuralgia reveals abnormal trigeminal nerve and brain white matter. Pain 2014; 155 (9): 1905-1906
- Making Sense of Gray Matter Abnormalities in Chronic Orofacial Pain-Synthesizing Divergent Findings JOURNAL OF NEUROSCIENCE 2011; 31 (35): 12396-12397
Use of Diffusion Tensor Imaging to Examine Subacute White Matter Injury Progression in Moderate to Severe Traumatic Brain Injury
ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION
2008; 89 (12): S45-S50
To demonstrate subacute progression of white matter (WM) injury (4.5mo-2.5y postinjury) in patients with traumatic brain injury using diffusion-tensor imaging.Prospective, repeated-measures, within-subjects design.Inpatient neurorehabilitation program and teaching hospital MRI department.Brain-injured adults (N=13) with a mean Glasgow Coma Scale score of 7.67+/-4.16.Not applicable.Fractional anisotropy (FA) values were measured at 4.5 and 29 months postinjury in right and left frontal and temporal deep WM tracts and the anterior and posterior corpus callosum.FA significantly decreased in frontal and temporal tracts: right frontal (.38+/-.06 to .30+/-.06; P<.005), left frontal (.37+/-.06 to .32+/-.06; P<.05), right temporal (.28+/-.05 to .22+/-.018; P<.005), and left temporal (.28+/-.05 to .24+/-.02; P<.05). No significant changes were in the corpus callosum.Preliminary results demonstrate progression of WM damage as evidenced by interval changes in diffusion anisotropy. Future research should examine the relationship between decreased FA and long-term clinical outcome.
View details for DOI 10.1016/j.apmr.2008.08.211
View details for Web of Science ID 000261999400006
View details for PubMedID 19081441