Laboratory of Albert Fenoy, M.D.
The Deep Brain Stimulation (DBS) surgery program led by Dr. Albert Fenoy focuses on delivering optimal treatment to patients suffering from movement disorders such as Parkinson’s disease, tremor, and dystonia, as well as refining treatments for patients with refractory psychiatric disease states, such as treatment resistant depression. In the majority of these surgeries, we record from the subcortical structures of the awake patient in an effort to better understand the disease process, refine the targeting, and together with new brain imaging techniques provide exemplar outcomes. Thus, the operating room is our chief laboratory space, to both learn from each patient and optimize treatment strategies.
Outside the operating room, the use of imaging to illustrate both the structural and functional connectivity of the networks involved in various pathophysiologies treated by deep brain stimulation can improve our understanding of the disease process and potentially lead to more strategic treatment paradigms.
Simultaneously with learning intraoperatively from human research subjects, animal models of disease enable us to understand the biochemical mediators of such pathological cortical states and how the intervention of deep brain stimulation improves aberrant subcortical firing to improve symptomatology.
Albert J. Fenoy, MD, is Associate Professor and Director of Deep Brain Stimulation at the University of Texas Health Science Center at Houston. He completed his residency in neurosurgery at the University of Iowa and completed a fellowship in functional neurosurgery at the Centre Hospitalier Universitaire de Grenoble, France.
Elucidating the temporality of structural and functional connectivity changes in essential tremor after successful deep brain stimulation of the dentato-rubro-thalalmic tract
Supported by: NIH Grant Number 1R01NS113893
Principal Investigator: Albert J. Fenoy, MD
Project Period: 09/15/2020 – 08/31/2025
Total Cost support: $2.1 M
The symptoms of Essential Tremor (ET), the most common movement disorder in adults, are seriously disabling and are only marginally improved by medication alone. Tremor control has improved greatly with the use of deep brain stimulation (DBS) to the ventrointermediate nucleus (Vim) of the thalamus, a node along a circuit of abnormal rhythmic output in ET that travels from the cerebellar dentate nucleus to the contralateral red nucleus and cortex via the dentato-rubro-thalamic tract (DRTt).
Recent advances in diffusion imaging have led to the development of tractography techniques where the structural connectivity of fiber tracts such as the DRTt can be illustrated and then, as we have shown, directly targeted during DBS surgery for excellent clinical effect. Despite such novel targeting methodology and initial tremor improvement, however, the development of side effects such as progressive gait ataxia and waning efficacy after years of chronic stimulation points to the fact that the pathology of essential tremor is poorly understood.
Such incomplete knowledge of the network effects of chronic stimulation in ET is a major barrier that needs to be overcome through understanding the dysfunction and modulation of the connectivity of the cerebellar-thalamic-cortical (CTC) network over time.
Resting state functional MRI (rsfMRI) has emerged as a powerful tool to explore the functional connectivity between different brain regions and has improved the idea of ET as a network-based disease not confined to the motor circuit, including parietal visuomotor processing cortices; however, comparisons pre- and post- DBS have not been performed.
The use of positron emission tomography (PET) has correlated ataxic side effect with cerebellar metabolic changes after chronic DBS; however, associated changes seen with rsfMRI are unknown. Our long-term goal is to understand how stimulation of the DRTt causes network-level effects over time. Our central hypothesis is that structural and functional connectivity of the DRTt correlates with clinical response to DBS in a time-dependent fashion. In pursuit of this hypothesis, we will recruit new ET patients already undergoing DBS and additionally perform imaging analysis to elucidate the effects of stimulation and define DRTt connectivity. First, we will seek to define the structural connectivity of the DRTt by using tractography methods and compare over time diffusivity changes correlated with clinical response and/or ataxic side effect. Second, we seek to detect functional network changes due to DBS by using rsfMRI obtained serially in ON/OFF states, where we will track the evolution of altered connectivity changes over time. Third, we seek to confirm the cortical mediators of tremor identified by tractography and rsfMRI through the use of intraoperative electrocorticography during DBS. This innovative combination of using a novel targeting technique and serial imaging across DBS states will advance our understanding of the larger network response to DBS, which is essential to develop more specific stimulation of fibers to improve response and avoid side effects in ET.
Deep Brain Stimulation for Treatment Resistant Depression: Clinical Trial
Performed in conjunction with the UT Center of Excellence on Mood Disorders, led by chairman Jair C. Soares, MD, PhD, this is an FDA-approved clinical trial for patients suffering from treatment resistant depression. This study is aimed to determine feasibility, safety and efficacy of DBS applied to the supero-lateral branch of the medial forebrain bundle (slMFB). UT is the only site in the US to perform such surgery at this target, and the second in the world.
View the Houston Chronicle article here.
Deep Brain Stimulation for Treatment Resistant Depression: Animal models
Performed in collaboration with the UT Translational Psychiatry Program at the Behavioral and Biomedical Sciences Building (BBSB), led by Joao Quevedo, MD, PhD., this project aims to evaluate the mechanisms by which MFB DBS improves depression. In the rodent, once a depression model is created using chronic unpredictable stress, MFB DBS is applied to observe behavioral improvement. Afterward, histological analysis is performed on subcortical/cortical structures investigating the involvement or modulation of the dopamine-reward pathway, which is hypothesized to be a key factor in how MFB DBS can incur a reversal of anhedonia.
See Translational Psychiatry Program and rodent behavior core facility where animal experimentation occurs.
Diffusion Tensor Brain Imaging in Deep Brain Stimulation
Many of the disease states treated by DBS involve placement of an electrode into to an anatomical area of the brain that has historically been seen to be part of a neuronal circuit subserving some function, such as the motor system. These anatomical nodes within this network are visible on standard imaging, but the circuits connecting them are not. Use of diffusion tensor imaging to identify tracts linking subcortical/cortical structures has elucidated novel and more refined targeting protocols for certain disease states, such as tremor. Evolution of imaging acquisitioning, stereotactic analysis and targeting schemes is underway to optimize outcomes.
Chris Conner, MD, PhD, PGY6 neurosurgery
Animal Protocol Team:
Manoj Dandekar, PhD, post-doc fellow
Vija Giriharan, PhD, post-doc fellow
Agata Migut BS, Medical Student
Jenny Shin BS, Medical Student
Department of Neurosurgery
The University of Texas Medical School-Houston
Fenoy AJ, Schulz P, Selvaraj S, Burrows C, Spiker D, Cao B, Zunta-Soares G, Gajwani P, Quevedo J, Soares J. Deep brain stimulation of the medial forebrain bundle: Distinctive responses in resistant depression. J Affect Disord. 203:143- 151, 2016
Fenoy AJ, McHenry MA, Schiess MC. Speech changes induced by deep brain stimulation of the subthalamic nucleus in Parkinson disease: involvement of the dentato-rubro-thalamic tract. J Neurosurg. 2016 Sep 9:1-11.
Fenoy AJ, Schiess MC. Deep Brain Stimulation of the Dentato-Rubro-Thalamic tract: Outcomes of Direct Targeting for Tremor. Neuromodulation. 2017. DOI: 10.1111/ner.12585.
Dandekar MP, Luse D, Hoffmann C, Cotton P, Peery T, Ruiz C, Hussey C, Giridharan VV, Soares JC, Quevedo J, Fenoy AJ. Increased dopamine receptor expression and anti-depressant response following deep brain stimulation of the medial forebrain bundle. J Affect Disord. 2017 Apr 5;217:80-88. DOI: 10.1016/j.jad.2017.03.074.
Fenoy AJ, Schulz P, Selvaraj S, Burrows C, Zunta-Soares G, Durkin K, Zanotti-Fregonara P, Quevedo J, Soares J. A longitudinal study on deep brain stimulation of the medial forebrain bundle for treatment-resistant depression. Transl Psychiatry. 2018 Jun 4; 8(1):111. doi: 10.1038/s41398-018-0160-4.
Fenoy AJ, Schiess MC. Comparison of Tractography-Assisted to Atlas-Based Targeting for Deep Brain Stimulation in Essential Tremor. Mov Disord. 2018; 33(12):1895-1901. DOI: 10.1002/mds.27463.
Dandekar MP, Saxena A, Scaini G, Shin JH, Migut A, Giridharan VV, Zhou Y, Barichello T, Soares JC, Quevedo J, Fenoy AJ. Medial Forebrain Bundle Deep Brain Stimulation Reverses Anhedonic-Like Behavior in a Chronic Model of Depression: Importance of BDNF and Inflammatory Cytokines. Molecular Neurobiology. 2019; 56(6): 4364-4380.