2014 — 2019 |
Mcintyre, Cameron |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Crcns: Patient-Specfic Models of Local Field Potentials in Subcallosal Cingulate @ Case Western Reserve University
DESCRIPTION (provided by applicant): Early stage clinical trials of deep brain stimulation (DBS) of the subcallosal cingulate (SCC) region has demonstrated real potential to improve the lives of patients with treatment-resistant depression (TRD). However, the neurophysiological basis for TRD symptoms remains unknown and definition of electrophysiological biomarkers that could someday be useful in closed-loop DBS control systems remain to be defined. The goal of this project is to identify the key electrophysiological features of chronically recorded local field potentials (LFPs) in the SCC. We propose that recent advances in patient-specific modeling, coupled with novel clinical DBS devices that enable ongoing LFP recording, represent a unique opportunity to augment our understanding of SCC electrophysiology and TRD. Therefore, we will develop detailed computer models that simulate the SCC LFP and use them to help interpret the clinical longterm recordings acquired from TRD patients. We hypothesize that modulation of theta-band activity in SCC can be correlated with TRD symptom relief from DBS, and these LFP signals arise from the interaction of inhibitory and excitatory inputs on SCC pyramidal neurons. We will use patient-specific models of SCC LFPs to evaluate our hypotheses. The LFP models for this project will consist of volume conductor models of the DBS electrodes implanted in each patient's brain, coupled to biophysical models SCC pyramidal neurons generating the sources and sinks responsible for the experimentally recorded signals. We will analyze 10 patients enrolled in an investigator initiated clinical trial of SCC DBS for TRD (FDA IDE G130107). That trial will use the new Medtronic Activa PC+S experimental DBS system, which enables recording and telemetry of LFP signals from the implanted device. LFP measures of SCC oscillatory activity will also be accompanied by simultaneous acquisition of mood and clinical depression outcome measures. This unique collaborative research opportunity will integrate two DBS world experts, uniquely blending their specific skills and strengths, and apply cutting edge modeling methods to address real life clinical questions. The results of the project will expand our basic understanding of LFP signals in the human brain, and facilitate the evolution of closed-loop DBS technology for the treatment of depression. BROADER IMPACTS: This proposal takes advantage of an evolving paradigm shift in how depression is defined and treated. The concept that depression is a neurological disorder with a quantifiable neurophysiological signature (even though we do not yet know the exact details), may be accepted by learned scholars. However, the world at large is still lacking in basic education and elucidation on one of the most common afflictions in society. Specifically the work proposed in this project has great potential to provide a cellular-level understanding of mood regulatory circuits in human patients. This has important translational implications for future quantitative classification of mood disorders and brain-based criteria for recovery. Such paradigm shifts in the clinical documentation and classification of depression could represent a springboard for public education and enlightenment on depression, driven by scientific discovery. Dr. Mayberg is especially well positioned to facilitate this broader impact goal; however, the scientific data must be assembled. This 2-center collaboration will facilitate that process and provide a unique training opportunity for both graduate students and post-doctoral fellows in both computational neuroscience and systems neuroscience. This project will further provide important infrastructure for training the next generation of interdisciplinary team scientists that will be necessary to address the complex neuro-engineering demands of the burgeoning field of clinical neuromodulation.
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0.915 |
2014 — 2018 |
Mcintyre, Cameron |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Tractography-Activation Models For Neuropsychiatric Deep Stimulation @ Case Western Reserve University
DESCRIPTION (provided by applicant): Deep brain stimulation (DBS) is an established clinical therapy for movement disorders and is positioned to grow as a treatment for neuropsychiatric disorders. Subcallosal cingulate white matter (SCCWM) DBS has potential to improve the lives of patients with treatment-resistant depression (TRD); however, the specific white matter pathway(s) responsible for therapeutic benefit from stimulation remain unknown. The goal of this project is to identify the key axonal pathways directly stimulated by therapeutic SCCWM DBS. We will combine patient-specific diffusion-weighted imaging (DWI) based tractography with neurostimulation modeling to enable probabilistic identification of the axonal pathways whose direct activation is linked to changes in clinical outcome metrics measured in SCCWM DBS patients. We hypothesize that therapeutic benefit from SCCWM DBS is dependent upon activation of pathways associated with the ventromedial pre-frontal cortex (vmPFC) and its subcortical connections. We will use patient-specific tractography-activation models (TAMs) to evaluate our hypothesis by analyzing patients enrolled in investigator initiated clinical trials of SCCWM DBS (FDA IDE G060028 & FDA IDE G130107). Our specific aims call for the development of TAMs in a cohort of 35 total SCCWM DBS patients. Results from these models will enable us to evolve our hypothesis on the target pathways for stimulation and help us to differentiate between therapeutic and non-therapeutic pathways by creating a probabilistic stimulation atlas (PSA). We will also compare our SCCWM results with TAMs derived from ventral capsule (VC) DBS for TRD, as it may be possible that common target pathways exist between the different surgical targets. Finally, we will use our TAMs to investigate theoretically optimal methods for stimulating our PSA-identified target pathways. The results of this study have great potential to assist in the evolution of neuropsychiatric DBS technology and help guide future clinical protocols.
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0.915 |
2018 — 2020 |
Griswold, Mark Mcintyre, Cameron |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Augmented Reality Platform For Deep Brain Stimulation @ Case Western Reserve University
PROJECT SUMMARY Subthalamic deep brain stimulation (DBS) for the treatment of Parkinson's disease (PD) can be highly effective at improving motor symptoms and enhancing the patient's quality of life. However, the specific details of the anatomical target(s) for therapeutic stimulation remain unresolved. Recent DBS surgical targeting hypotheses have evolved to consider that direct stimulation of specific axonal pathways within the subthalamic region may be linked to the control of specific symptoms. Unfortunately, 3D anatomical characterization of the wide array of different axonal pathways in the human subthalamic region is very limited and techniques to visualize the complex neuroanatomy currently focus on 2D computer screens. These limitations hinder our ability to create accurate models and interpret the effects of DBS. Therefore, we propose that significant need exists for an anatomically driven model of subthalamic axonal pathways that can be interactively visualized with holographic 3D imaging and coupled to patient-specific DBS simulations. The goal of this Bioengineering Research Grant (PAR-16-242) is to create next generation visualization tools and surgical targeting models for clinical DBS. The first step of this study will rely on direct input from a collection of world experts in basal ganglia neuroanatomy to help us build a virtual 3D atlas model of 8 different axonal pathways in the subthalamic region. This development will occur within the HoloLens augmented reality (AR) environment, thereby enabling face-to-face discussion among the anatomy experts while visualizing the model hologram and its interactive adjustment. The second step of this study will evaluate the ability of various tractography algorithms to recreate the pathways described by the anatomy experts. We hypothesize that tractography will fail to accurately capture the anatomical trajectory of most subthalamic axonal pathways without extensive modeling constraints. Results from this analysis will have important implications for the rapid growth of tractography in DBS research, as well as clinical practice. Finally, we will translate our subthalamic axonal pathway model system into an interactive HoloLens AR application that works in concert with patient-specific MRI datasets and DBS pathway-activation modeling. We propose that such a tool will be especially useful for DBS surgical education and research investigation.
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0.915 |
2021 |
Mcintyre, Cameron |
R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
Application of Advanced Imaging and Visualization to Clinical Deep Brain Stimulation @ Case Western Reserve University
PROJECT SUMMARY Subthalamic deep brain stimulation (DBS) for the treatment of Parkinson?s disease (PD) can be highly effective at improving motor symptoms and enhancing the patient?s quality of life. However, DBS surgical targeting technology and post-operative programming practices have been relatively stagnant over the ~20 year history of the therapy. Nonetheless, substantial scientific advances have been made in MRI acquisition protocols, patient-specific DBS modeling methods, and 3D visualization technologies. Therefore, the goal of this Bioengineering Research Grant (PAR-19-159) is to apply the latest advances in MR imaging, DBS modeling, and holographic visualization to the clinical practice of subthalamic DBS for PD. The first step of this project is to apply the scientific advances of quantitative MRI to the clinical problem of subthalamic nucleus (STN) identification in patients with PD. Magnetic Resonance Fingerprinting (MRF) is a completely new approach to MR acquisition, reconstruction, and post processing. Our group has used MRF to simultaneously acquire quantitative maps of T1, T2, and T2* in a single, inherently co-registered, whole-brain 3D acquisition, with 0.6 mm3 image resolution, lasting only ~15 min. The key advantage of multi-dimensional MRF data is that provides the best possible information for performing volumetric segmentation of the STN. The second step of this project is to take the patient-specific MRF data, with our STN segmentations, and integrate them with the coordinate system of the stereotactic frame via holographic visualization for the neurosurgeon. Our group developed the first fully functional neurosurgical navigation system within the Microsoft HoloLens visualization platform and this system is directly compatible with the Leksell stereotactic frame. This study will apply that tool we call HoloDBS to the creation of the pre-operative surgical plan for our research subjects. The third step of this project is to take the patient-specific holographic model of DBS and put it into the hands of the programming neurologist. Modern DBS devices consist of electrodes with 8 contacts and a nearly infinite parameter space of stimulus amplitudes, pulse durations, and frequencies. This study will provide our patient-specific DBS models, which also run within the HoloLens platform, to the neurologist who can then use holographic visualization to help customize the treatment to patient.
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0.915 |
2021 |
Mcintyre, Cameron |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Biophysical Characterization of Subthalamic Local Field Potentials in Parkinson's Disease @ Case Western Reserve University
PROJECT SUMMARY Subthalamic deep brain stimulation (DBS) can significantly improve the motor symptoms and quality of life of patients with Parkinson?s disease (PD). Recent advances in DBS technology are providing new opportunities to interrogate and characterize the pathophysiology of PD using local field potential (LFP) recordings. Previous LFP investigations brought to light the important role of beta-band (12-30 Hz) activity in PD. However, we are still faced with a wide range of questions on the biophysics of subthalamic LFPs. For example, How many subthalamic nucleus (STN) neurons need to be synchronized to generate a clinically measurable LFP signal? What are the synaptic input characteristics responsible for that synchronization? Where are those neurons located in the STN? The McIntyre lab has spent the last decade developing the computational infrastructure to address these questions within the context of the human STN implanted with clinical DBS electrodes. Therefore, we propose the integration of those advanced modeling tools with ongoing human studies (directional STN LFP recordings ? Dr. Walker, and chronic STN LFP recordings ? Dr. Bronte- Stewart) that are defining the clinical cutting edge of DBS LFP studies. The goal of this Bioengineering Research Grant (PAR-19-158) is to apply the latest advances in patient- specific LFP modeling to the analysis of directional STN recordings and chronic STN recordings in PD patients. These analyses will allow us to address fundamental questions on the size and location of synchronous neural populations in the STN, which have important implications for understanding the pathophysiology of PD. In addition, our models will enable us to evaluate the variance in STN neural synchrony across populations of patients, and over long periods of time within the same patient, both of which have important implications for the engineering design of LFP-based DBS algorithms. The first step of this project will focus on evolving the patient-specific LFP modeling infrastructure to accommodate directional DBS electrodes and adapt to different electrode positions in each patient-specific STN volume. The second step of this project will use the patient- specific LFP model system to identify the size and location of beta synchrony in 10 PD patients using directional DBS recordings acquired during intra-operative experiments. Finally, we will quantify the modulation of the size and location of the beta synchrony in 5 PD patients using chronic LFP recordings and measurements taken at 4 different time points over a 1 year period.
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0.915 |