Publications

2017
Lo M-C, Widge AS. Closed-loop neuromodulation systems: next-generation treatments for psychiatric illness. International Review of Psychiatry [Internet]. 2017;29 (2) :191–204. Publisher's Version lo_and_widge_-_2017_-_closed-loop_neuromodulation_systems_next-generati.pdf
Chakrabarty P, Negi S, Andrés RM, Favaro B, Singh B, Hilleary R, Arthur PK, Street IH, Cheung MK, Parsons M, et al. Facilitating conservation. Science [Internet]. 2017;356 (6335) :242–244. Publisher's VersionAbstract
We asked young scientists from a variety of fields to address this issue: The changes required to preserve Earth's ecosystems and biodiversity (and human population) depend on human behavior and values, yet often conflict with current lifestyles. Describe one way that your field can improve
chakrabarty_et_al._-_2017_-_facilitating_conservation.pdf
LaPlante R, Tang W, Peled N, Vallejo DI, Borzello M, Dougherty DD, Eskandar EN, Widge AS, Cash SS, Stufflebeam SM. The interactive electrode localization utility: software for automatic sorting and labeling of intracranial subdural electrodes. International Journal of Computer Assisted Radiology and Surgery. 2017;12 (10) :1829–37.Abstract
Existing methods for sorting, labeling, registering, and across-subject localization of electrodes in intracranial encephalography (iEEG) often take hours of laborious work requiring manual inspection of radiological images. Methods We describe a method to automatically sort and label electrodes from subdural grids of known geometry. We also describe a new software package, the Interactive Electrode Localization Utility (IELU) which implements our sorting/labeling algorithm and presents a full pipeline for the registration, localization, and labeling of iEEG electrodes from CT and MR images. Results We validated our software against well established manual inspection methods in sixth subjects undergoing iEEG for medically intractable epilepsy. Our algorithm for sorting and labeling correctly identified 98% of the electrodes. Conclusions The sorting and labeling algorithm we describe offers nearly perfect performance and the software package we have distributed may lessen the onerous burden of registering sorting, labeling, and localizing iEEG electrodes by manual inspection.
10.1007_2fs11548-016-1504-2.pdf
Philip NS, Nelson BG, Frohlich F, Lim KO, Widge AS, Carpenter LL. Low-intensity transcranial current stimulation in psychiatry. American Journal of Psychiatry [Internet]. 2017;174 (7) :628–639. Publisher's VersionAbstract
Neurostimulation is rapidly emerging as an important treatment modality for psychiatric disorders. One of the fastest-growing and least-regulated approaches to noninvasive therapeutic stimulation involves the application of weak electrical currents. Widespread enthusiasm for low-intensity transcranial electrical current stimulation (tCS) is reflected by the recent surge in direct-to-consumer device marketing, do-it-yourself enthusiasm, and an escalating number of clinical trials. In the wake of this rapid growth, clinicians may lack sufficient information about tCS to inform their clinical practices. Interpretation of tCS clinical trial data is aided by familiarity with basic neurophysiological principles, potential mechanisms of action of tCS, and the complicated regulatory history governing tCS devices. A growing literature includes randomized controlled trials of tCS for major depression, schizophrenia, cognitive disorders, and substance use disorders. The relative ease of use and abundant access to tCS may represent a broad-reaching and important advance for future mental health care. Evidence supports application of one type of tCS, transcranial direct current stimulation (tDCS), for major depression. However, tDCS devices do not have regulatory approval for treating medical disorders, evidence is largely inconclusive for other therapeutic areas, and their use is associated with some physical and psychiatric risks. One unexpected finding to arise from this review is that the use of cranial electrotherapy stimulation devices—the only category of tCS devices cleared for use in psychiatric disorders—is supported by low-quality evidence.
philip_et_al_2017_low-intensity_transcranial_current_stimulation_in_psychiatry.pdf
Dougherty DD, Widge AS. Neurotherapeutic interventions for psychiatric illness. Harvard Review of Psychiatry [Internet]. 2017;25 (6) :253–255. Publisher's VersionAbstract
An abstract is unavailable.
neurotherapeutic_interventions_for_psychiatric.1.pdf
Gonzalez SD, Williams AJ, Blacker CJ, Voort JLV, Schak KM, Nemeroff CB, Widge AS, Tohen M. Putative biological predictors of treatment response in bipolar disorders. Personalized Medicine in Psychiatry. 2017;1 :39–58. gonzalez_et_al._-_2017_-_putative_biological_predictors_of_treatment_respon.pdf
Goering S, Klein E, Dougherty DD, Widge AS. Staying in the loop: relational agency and identity in next-generation DBS for psychiatry. AJOB Neuroscience. 2017;8 (2) :59–70. goering_et_al_-_staying_in_the_loop_relational_agency_and_identity_in_next_generation_dbs_for_psychiatry_-_ajob-neuro_2017.pdf
Freeman DK, O'Brien JM, Kumar P, Daniels B, Irion RA, Shraytah L, Ingersoll BK, Magyar AP, Czarnecki A, Wheeler J, et al. A sub-millimeter, inductively powered neural stimulator. Frontiers in Neuroscience [Internet]. 2017;11. Publisher's VersionAbstract
Wireless neural stimulators are being developed to address problems associated with traditional lead-based implants. However, designing wireless stimulators on the sub-millimeter scale (\textless1mm3) is challenging. As device size shrinks, it becomes difficult to deliver sufficient wireless power to operate the device. Here, we present a sub-millimeter, inductively powered neural stimulator consisting only of a coil to receive power, a capacitor to tune the resonant frequency of the receiver, and a diode to rectify the radio-frequency signal to produce neural excitation. By replacing any complex receiver circuitry with a simple rectifier, we have reduced the required voltage levels that are needed to operate the device from – 0.5 - 1V (e.g. for CMOS) to approximately 0.25 – 0.5V. This reduced voltage allows the use of smaller receive antennas for power, resulting in a device volume of 0.3 – 0.5mm3. The device was encapsulated in epoxy, and successfully passed accelerated lifetime tests in 80°C saline for two weeks. We demonstrate a basic proof-of-concept using stimulation with tens of microamps of current delivered to the sciatic nerve in rat to produce a motor response. The device is designed to operate in tissue up to approximately 5cm depth.
fnins-11-00659.pdf
Widge AS, Ellard KK, Paulk AC, Basu I, Yousefi A, Zorowitz S, Gilmour A, Afzal A, Deckersbach T, Cash SS, et al. Treating refractory mental illness with closed-loop brain stimulation: progress towards a patient-specific transdiagnostic approach. Experimental Neurology. 2017;287 (4) :361–472.Abstract
Mental disorders are a leading cause of disability, morbidity, and mortality among civilian and military populations. Most available treatments have limited efficacy, particularly in disorders where symptoms vary over relatively short time scales. Targeted modulation of neural circuits, particularly through open-loop deep brain stimulation (DBS), showed initial promise but has failed in blinded clinical trials. We propose a new approach, based on targeting neural circuits linked to functional domains that cut across diagnoses. Through that framework, which includes measurement of patients using six psychophysical tasks, we seek to develop a closed-loop DBS system that corrects dysfunctional activity in brain circuits underlying those domains. We present convergent preliminary evidence from functional neuroimaging, invasive human electrophysiology, and human brain stimulation experiments suggesting that this approach is feasible. Using the Emotional Conflict Resolution (ECR) task as an example, we show that emotion-related networks can be identified and modulated in individual patients. Invasive and non-invasive methodologies both identify a network between prefrontal cortex, cingulate cortex, insula, and amygdala. Further, stimulation in cingulate and amygdala changes patients' performance in ways that are linked to the task's emotional content. We present preliminary statistical models that predict this change and allow us to track it at a single-trial level. As these diagnostic and modeling strategies are refined and embodied in an implantable device, they offer the prospect of a new approach to psychiatric treatment and its accompanying neuroscience.
widge_et_al_2016_treating_refractory_mental_illness_with_closed-loop_brain_stimulation.pdf
2016
Dougherty DD, Chou T, Corse AK, Arulpragasam AA, Widge AS, Cusin C, Evans KC, Greenberg BD, Haber SN, Deckersbach T. Acute deep brain stimulation changes in regional cerebral blood flow in obsessive-compulsive disorder. Journal of Neurosurgery. 2016;125 (5) :1087–1093. dougherty_et_al_2016_acute_deep_brain_stimulation_changes_in_regional_cerebral_blood_flow_in.pdf
Widge AS, Zorowitz S, Link K, Miller EK, Deckersbach T, Eskandar EN, Dougherty DD. Ventral capsule/ventral striatum deep brain stimulation does not consistently diminish occipital cross-frequency coupling. Biological Psychiatry. 2016;80 (7) :e59–e60. 1-s2.0-s0006322315010562-main.pdf
Kim L, Harer J, Rangamani A, Moran J, Parks P, Widge AS, Eskandar EN, Dougherty DD, Chin S. Predicting local field potentials with recurrent neural networks, in Proceedings of the 2016 IEEE Engineering in Medicine & Biology Conference. Orlando, Florida ; 2016 :808–811. 07590824.pdf
Widge AS, Moritz CT. Closed-loop stimulation in emotional circuits for neuro-psychiatric disorders. In: El Hady A Closed Loop Neuroscience. San Diego, CA: Elsevier ; 2016.
Taylor JQ, Kovacik P, Traer J, Zakahi P, Oslowski C, Widge AS, Glorioso CA. Avoiding a lost generation of scientists. eLife [Internet]. 2016;5 :e17393. Publisher's VersionAbstract

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taylor_et_al_2016_avoiding.pdf
Klein E, Goering S, Gagne J, Shea CV, Franklin R, Zorowitz S, Dougherty DD, Widge AS. Brain-computer interface-based control of closed-loop brain stimulation: attitudes and ethical considerations. Brain-Computer Interfaces [Internet]. 2016;3 (3) :140–148. Publisher's VersionAbstract

Patients who have undergone deep brain stimulation (DBS) for emerging indications have unique perspectives on ethical challenges that may shape trial design and identify key design features for BCI-driven DBS systems. DBS research in cognitive and emotional disorders has generated significant ethical interest. Much of this work has focused on developing ethical guidelines and recommendations for open-loop DBS systems. While early trials of open-loop DBS for depression gave disappointing results, research is moving toward clinical trials with closed-loop or patient-controllable DBS systems that may modulate aspects of personality and emotion. Though user-centered design is an increasingly important principle in neurotechnology, the perspectives of implanted individuals on ethical issues raised by DBS are poorly understood. We solicited those perspectives through a focus group and set of qualitative interviews of participants in trials of DBS for depression and obsessive-compulsive disorder. We identified four major themes: control over device function, authentic self, relationship effects, and meaningful consent. Each has implications for the design of closed-loop systems for non-motor disorders.

brain_computer_interface_2016.pdf
Lizano P, Popat-Jain A, Scharf JM, Berman NC, Widge A, Dougherty DD, Eskandar E. Challenges in managing treatment-refractory obsessive-compulsive disorder and Touretteʼs syndrome:. Harvard Review of Psychiatry [Internet]. 2016;24 (4) :294–301. Publisher's Version lizano_et_al_2016_challenges.pdf
Widge AS, Deckersbach T, Eskandar EN, Dougherty DD. Deep brain stimulation for treatment-resistant psychiatric illnesses: what has gone wrong and what should we do next?. Biological Psychiatry [Internet]. 2016;79 (4) :e9–e10. Publisher's VersionAbstract

None

widge_et_al_deep_brain_stimulation_01.pdf
Bjune CK, Marinis TF, Sriram TS, Brady JM, Moran J, Parks PD, Widge AS, Dougherty DD, Eskandar EN. Packaging architecture for an implanted system that monitors brain activity and applies therapeutic stimulation. Journal of Microelectronics and Electronics Packaging. 2016;13 (2) :64–70.Abstract

Deep brain stimulation therapies for Parkinson's disease utilize hardware, which from a packaging perspective, resembles that used in cardiac pacemakers. A hermetic package that contains stimulation electronics and a primary battery supply is implanted under the scalp in a recess cut into the skull. Stimulation probes, each with up to four electrodes, are inserted into the brain and connected to the electronics package via a plug and cable system. By contrast, the closed loop neural stimulator being developed under the DARPA SUBNETS program utilizes probes, which each carry up to 64 electrodes that can be switched between recording and stimulation functions. This capability necessitates locating low noise amplifiers, switching and communication electronics in close proximity to each probe. Each of these satellite electronics packages requires ten electrical connections to the hub package, which significantly increases the complexity of the interconnect system relative to current practice. The power requirements of this system preclude the use of a primary battery supply so instead, a large lithium ion battery is used with a recharging coil and electronics. The hub system is fabricated as a separate connector header, electronics package and battery pack that are interconnected by a flex circuit to allow it to conform to the skull for implanting. In this paper, we will describe the various packaging components of the system and the design considerations that drove our technology choices.

bjune_et_al_2015.pdf
Widge AS, Sahay A. Closing the loop in deep-brain stimulation for psychiatric disorders: lessons from motor neural prosthetics. Neuropsychopharmacology ReviewsNeuropsychopharmacology Reviews. 2016;41 (1) :379-380. npp2015241a.pdf
2015
Makris N, Rathi Y, Mouradian P, Bonmassar G, Papadimitriou G, Ing WI, Yeterian EH, Kubicki M, Eskandar EN, Wald LL, et al. Variability and anatomical specificity of the orbitofrontothalamic fibers of passage in the ventral capsule/ventral striatum (VC/VS): precision care for patient-specific tractography-guided targeting of deep brain stimulation (DBS) in obsessive compulsive. Brain Imaging and Behavior [Internet]. 2015 :1–14. Publisher's VersionAbstract
Deep Brain Stimulation (DBS) is a neurosurgical procedure that can reduce symptoms in medically intractable obsessive-compulsive disorder (OCD). Conceptually, DBS of the ventral capsule/ventral striatum (VC/VS) region targets reciprocal excitatory connections between the orbitofrontal cortex (OFC) and thalamus, decreasing abnormal reverberant activity within the OFC-caudate-pallidal-thalamic circuit. In this study, we investigated these connections using diffusion magnetic resonance imaging (dMRI) on human connectome datasets of twenty-nine healthy young-adult volunteers with two-tensor unscented Kalman filter based tractography. We studied the morphology of the lateral and medial orbitofrontothalamic connections and estimated their topographic variability within the VC/VS region. Our results showed that the morphology of the individual orbitofrontothalamic fibers of passage in the VC/VS region is complex and inter-individual variability in their topography is high. We applied this method to an example OCD patient case who underwent DBS surgery, formulating an initial proof of concept for a tractography-guided patient-specific approach in DBS for medically intractable OCD. This may improve on current surgical practice, which involves implanting all patients at identical stereotactic coordinates within the VC/VS region.

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