Mapping STN DBS Effects in PD: Optogenetics and fMRI Analysis of Pulse Rate-Dependent Modulation
Poster No:
242
Submission Type:
Abstract Submission
Authors:
Sung-Ho Lee1,2,3, Yuhui Li4, Chunxiu Yu4,5, LiMing Hsu1,2,3, Tzu-Wen Wang1,2, Khoa Do4, Hyeon-Joong Kim1,2,3, Yen-Yu Shih1,2,3, Warren Grill4,6,7,8
Institutions:
1Center for Animal MRI, University of North Carolina, Chapel Hill, NC, 2Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC, 3Department of Neurology, University of North Carolina, Chapel Hill, NC, 4Department of Biomedical Engineering, Duke University, Durham, NC, 5Department of Biomedical Engineering, Michigan Technology University, Houghton, MI, 6Department of Electrical and Computer Engineering, Duke University, Durham, NC, 7Department of Neurobiology, Duke University, Durham, NC, 8Department of Neurosurgery, Duke University School of Medicine, Durham, NC
First Author:
Sung-Ho Lee
Center for Animal MRI, University of North Carolina|Biomedical Research Imaging Center, University of North Carolina|Department of Neurology, University of North Carolina
Chapel Hill, NC|Chapel Hill, NC|Chapel Hill, NC
Center for Animal MRI, University of North Carolina|Biomedical Research Imaging Center, University of North Carolina|Department of Neurology, University of North Carolina
Chapel Hill, NC|Chapel Hill, NC|Chapel Hill, NC
Co-Author(s):
Chunxiu Yu
Department of Biomedical Engineering, Duke University|Department of Biomedical Engineering, Michigan Technology University
Durham, NC|Houghton, MI
Department of Biomedical Engineering, Duke University|Department of Biomedical Engineering, Michigan Technology University
Durham, NC|Houghton, MI
LiMing Hsu
Center for Animal MRI, University of North Carolina|Biomedical Research Imaging Center, University of North Carolina|Department of Neurology, University of North Carolina
Chapel Hill, NC|Chapel Hill, NC|Chapel Hill, NC
Center for Animal MRI, University of North Carolina|Biomedical Research Imaging Center, University of North Carolina|Department of Neurology, University of North Carolina
Chapel Hill, NC|Chapel Hill, NC|Chapel Hill, NC
Tzu-Wen Wang
Center for Animal MRI, University of North Carolina|Biomedical Research Imaging Center, University of North Carolina
Chapel Hill, NC|Chapel Hill, NC
Center for Animal MRI, University of North Carolina|Biomedical Research Imaging Center, University of North Carolina
Chapel Hill, NC|Chapel Hill, NC
Hyeon-Joong Kim
Center for Animal MRI, University of North Carolina|Biomedical Research Imaging Center, University of North Carolina|Department of Neurology, University of North Carolina
Chapel Hill, NC|Chapel Hill, NC|Chapel Hill, NC
Center for Animal MRI, University of North Carolina|Biomedical Research Imaging Center, University of North Carolina|Department of Neurology, University of North Carolina
Chapel Hill, NC|Chapel Hill, NC|Chapel Hill, NC
Yen-Yu Shih
Center for Animal MRI, University of North Carolina|Biomedical Research Imaging Center, University of North Carolina|Department of Neurology, University of North Carolina
Chapel Hill, NC|Chapel Hill, NC|Chapel Hill, NC
Center for Animal MRI, University of North Carolina|Biomedical Research Imaging Center, University of North Carolina|Department of Neurology, University of North Carolina
Chapel Hill, NC|Chapel Hill, NC|Chapel Hill, NC
Warren Grill
Department of Biomedical Engineering, Duke University|Department of Electrical and Computer Engineering, Duke University|Department of Neurobiology, Duke University|Department of Neurosurgery, Duke University School of Medicine
Durham, NC|Durham, NC|Durham, NC|Durham, NC
Department of Biomedical Engineering, Duke University|Department of Electrical and Computer Engineering, Duke University|Department of Neurobiology, Duke University|Department of Neurosurgery, Duke University School of Medicine
Durham, NC|Durham, NC|Durham, NC|Durham, NC
Introduction:
Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) marks a significant advancement in managing Parkinson's disease (PD), especially beneficial for patients unresponsive to dopaminergic medication or those experiencing levodopa-induced motor complications (Schuepbach et al., 2013; Hacker et al., 2018). Pioneering studies employing ChannelRhodopsin-2 (ChR2) have highlighted that STN DBS achieves therapeutic effects, in part, by antidromic activation of motor cortical neurons via the hyper-direct pathway (Gradinaru et al., 2009; Sanders et al., 2016). This has shifted the focus of DBS research towards this pathway. In our study, we utilize optogenetics and functional MRI (fMRI) to investigate the neural circuitry influenced by STN DBS, with particular attention to the differential therapeutic effects of various pulse repetition rates (PRR) (Bruet et al., 2001, Gale et al., 2013). Addressing the limitations of ChR2 observed in prior research, we examine the downstream circuits of the STN using the ultrafast opsin Chronos (Klapoetke et al., 2014). This approach builds upon our previous findings (Yu et al., 2020), which validated the efficacy of high-PRR STN-DBS in PD rat models, thereby enriching our understanding of how neural pathways contribute to high-PRR stimulation in PD treatment.
Methods:
Female Sprague Dawley rats were used to model STN DBS effects via optogenetics. The process involved two stages: viral opsin expression and Parkinsonian model induction. Rats received STN injections of AAV vector viruses carrying Chronos or ChR2. After expression, a hemi-parkinsonian state was induced with 6-OHDA in the medial forebrain bundle, categorizing them into Chronos (n=5) and ChR2 (n=4) groups.
Testing Circling Behavior: We investigated various STN stimulation PRRs (0, 5, 20, 75, 100, and 130 Hz) to confirm abnormal circling behavior in the PD model and assess the optogenetic intervention's efficacy in mitigating this behavior before fMRI measurements under anesthesia.
fMRI Mapping: Using a BOLD-fMRI approach as described in Lee et al., 2021, we examined neural responses to optogenetic STN DBS in a Bruker 9.4T preclinical scanner. This allowed identification of network changes essential for the therapeutic efficacy of DBS. The same animals from the behavioral analysis were assessed to align behavioral responses with fMRI data across various DBS PRRs.
Testing Circling Behavior: We investigated various STN stimulation PRRs (0, 5, 20, 75, 100, and 130 Hz) to confirm abnormal circling behavior in the PD model and assess the optogenetic intervention's efficacy in mitigating this behavior before fMRI measurements under anesthesia.
fMRI Mapping: Using a BOLD-fMRI approach as described in Lee et al., 2021, we examined neural responses to optogenetic STN DBS in a Bruker 9.4T preclinical scanner. This allowed identification of network changes essential for the therapeutic efficacy of DBS. The same animals from the behavioral analysis were assessed to align behavioral responses with fMRI data across various DBS PRRs.
Results:
High PRR STN DBS (above 100Hz) in the Chronos group significantly reduced pathological circling behavior, a notable effect not seen in the ChR2 group. fMRI mapping using General Linear Model approaches revealed marked PRR-dependent effects in the substantia nigra (SN), globus pallidus (GP), caudate-putamen (CPu), lateral geniculate nucleus (LGN), and superior colliculus (SC). In the Chronos group, SN, GP, and CPu responses were PRR-dependent and correlated with behavioral changes. The ChR2 group showed significant responses primarily in LGN and SC, associated with visual sensory regions. The mediation analysis sought to identify brain regions mitigating pathological circling behavior, with a focus on those showing PRR-dependent responses in the Chronos group. Changes in GP and CPu activities significantly mediated the therapeutic effects of high pulse repetition rate DBS, underlining their pivotal roles in the treatment's success.
Conclusions:
This study reevaluates the role of STN DBS in PD, focusing on the regions downstream of STN. Our findings suggest that, alongside the hyper-direct pathway, the roles of the GP and CPu are also crucial in comprehending the full spectrum of STN DBS effects.
Brain Stimulation:
Deep Brain Stimulation 2
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Modeling and Analysis Methods:
Activation (eg. BOLD task-fMRI)
Novel Imaging Acquisition Methods:
BOLD fMRI
Multi-Modal Imaging
Keywords:
ANIMAL STUDIES
Basal Ganglia
Degenerative Disease
FUNCTIONAL MRI
Other - Optogenetics
1|2Indicates the priority used for review
Provide references using author date format
Gale, J.T. et al. (2013), ‘Electrical Stimulation-Evoked Dopamine Release in the Primate Striatum.’, Stereotactic and Functional Neurosurgery, 91(6), 355-363.
Gradinaru, V. et al. (2009), ‘Optical deconstruction of parkinsonian neural circuitry.’, Science, 324(5925), 354-359.
Hacker, M.L. et al. (2018), ‘Effects of deep brain stimulation on rest tremor progression in early stage Parkinson disease.’, Neurology, 91(5), e463-e471.
Klapoetke, N.C. et al. (2014), ‘Independent optical excitation of distinct neural populations.’, Nature Methods, 11, 338-346.
Lee, S. et al. (2021), ‘An isotropic EPI database and analytical pipelines for rat brain resting-state fMRI.’, NeuroImage, 243, 118541.
Sanders, T.H. et al. (2016), ‘Optogenetic stimulation of cortico-subthalamic projections is sufficient to ameliorate bradykinesia in 6-OHDA lesioned mice.’, Neurobiology of Disease, 95, 225-237.
Schuepbach, W.M.M. et al. (2013), ‘Neurostimulation for Parkinson's disease with early motor complications.’, New England Journal of Medicine, 368(7), 610-622.
Yu, C. et al. (2020), ‘Frequency-Specific Optogenetic Deep Brain Stimulation of Subthalamic Nucleus Improves Parkinsonian Motor Behaviors.’, Journal of Neuroscience, 40(22): 4323-4334.