Deep Brain Stimulation treatment effectiveness may be enhanced by using imaging to guide electrode placement

Localization of Deep Brain Stimulation Targets Using Diffusion MRI Fiber Tracking Validated Against CLARITY 3D Histology

Jennifer McNab, Ph.D.

Stanford University School of Medicine

Funded in November, 2016: $200000 for 3 years


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Deep Brain Stimulation treatment effectiveness may be enhanced by using imaging to guide electrode placement

This laboratory study in human tissues will determine whether a new imaging technique called “CLARITY” can enhance image-guided neurosurgery such that surgeons can optimally place deep brain stimulation (DBS) electrodes to treat depression, obsessive compulsive disorder and obesity.

In DBS treatment, surgeons implant electrodes in specific locations deep within the brain to affect the transmission of electrical signals from brain cells in one region to cells in another region along nerve fiber pathways that connect the regions. DBS is currently approved by the Federal Food and Drug Administration for treating involuntary movements in Parkinson’s disease, essential tremor, and dystonia. In addition, researchers are testing DBS for treating depression, obsessive compulsive disorder (OCD), and obesity, as well as several other conditions. 

A single area in the brain, called the nucleus accumbens, is a potential site for implanting DBS electrodes to treat depression, OCD, and obesity. This area has two sub-regions, a core and a shell. The shell is where aspects of limbic system and emotional processing take place and is therefore the target area for DBS implantation in treating depression, OCD and obesity. In patients, though, imaging currently cannot differentiate the shell from the core.

The investigators contend that the accuracy of diffusion MRI fiber tracking can be improved enough to make this differentiation, though, by correlating its measures with those produced by a newly developed optical imaging technique, called CLARITY. This technique provides a 3D view of intact nerve fiber pathways in human tissue samples in the laboratory.

The investigators hypothesize that: 1) diffusion MRI fiber tracking can be made more precise by comparing its results to those produced by CLARITY; 2) improved diffusion MRI fiber tracking will differentiate the shell from the core of the nucleus accumbens; and 3) diffusion MRI fiber tracking results will guide surgical placement of DBS electrodes in the nucleus accumbens shell and result in improved outcomes in treating depression, OCT and obesity. Their laboratory studies of human tissue samples using diffusion MRI and CLARITY will optimize methods for imaging the nucleus accumbens, determine neural inputs and outputs for this area, and differentiate the shell from the core based on connectivity patterns and other features.

Significance : The study is anticipated to lead to the establishment of guidelines for using diffusion MRI fiber tracking to guide neurosurgeons in the optimal placement of DBS electrodes to treat depression, OCD and obesity.


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Localization of Deep Brain Stimulation Targets Using Diffusion MRI Fiber Tracking Validated Against CLARITY 3D Histology

Deep brain stimulation (DBS) is a neurosurgical procedure in which electrodes are placed in precise locations within the brain to modulate signal transmission along fiber tracts. This procedure is recognized as an effective treatment for a variety of neurological conditions including Parkinson’s disease, essential tremor, and dystonia. More recently, DBS is being explored as a possible treatment for a number of other neurological and psychiatric disorders. The nucleus accumbens (NAc) is an important DBS target for the potential treatment of depression, obsessive compulsive disorder and obesity. Histological studies in animals and humans indicate that the NAc has two functionally distinct subregions: a core involved in motor function and a shell that mediates aspects of limbic and emotional processing. This segmentation strongly suggests that targeting the appropriate subregion (i.e. the shell) is critical for an effective intervention; however, a rigorous procedure for determining precise NAc target location does not yet exist due to the inability to resolve subregions using conventional imaging protocols. Hypothesis: We hypothesize that the shell of the NAc can be localized and differentiated from the core of the NAc based on differences in the connectivity between the core and shell subregions and that diffusion MRI fiber tracking may be used to identify these connectivity differences and therefore improve DBS targeting of the shell of the NAc. Aims: 1. Develop technology to quantitatively compare dMRI fiber tracking and CLARITY optical imaging in the same intact human brain tissue specimens of the nucleus accumbens (NAc). 1.1) Optimize dMRI and CLARITY imaging methods on fixed human tissue blocks of the NAc. 1.2) Develop a novel landmark strategy to accurately align dMRI and CLARITY in the region of the NAc. 1.3) Develop analysis tools to extract quantitative measurements of: 3D orientational structure and axon/dendrite density, size and myelination, from CLARITY images of the NAc. 2. Map the inputs and outputs of the human nucleus accumbens using dMRI fiber tracking (whole brain and local region) and CLARITY (local region only) in human brain tissue specimens. 2.1) Determine the specific cortical and subcortical inputs to and outputs from the NAc in the human brain using dMRI fiber tracking in whole-brain, ex vivo human tissue. 2.2) Map the local inputs and outputs of the NAc using dMRI fiber tracking and CLARITY in a human tissue sample containing just the immediate NAc region. 2.3) Optimize segmentation of the core and shell of the NAc based on differences in connectivity. 3. Establish guidelines for using dMRI fiber tracking to localize the shell of the nucleus accumbens for placement of deep brain stimulation electrodes. 3.1) Determine how much the gold-standard dMRI (ex vivo and in vivo human connectome project) data quality can be degraded before fiber pathways become undetectable. 3.2) Determine the optimal: a) regions of interest to track between, b) threshold for probabilistic streamlines and c) use of anatomical priors; for localizing common deep brain stimulation targets. Methods: Diffusion MRI (dMRI) fiber tracking is the only imaging method with clinical potential to map fiber pathways, in the in vivo human brain. Unfortunately, clinical application of dMRI fiber tracking is impeded many false positives and negatives. Therefore, our approach is to map the NAc inputs and outputs using dMRI fiber tracking and CLARITY 3D histology in the same post-mortem tissue specimens, such that the dMRI fiber tracking methods may be optimized and validated against direct optical observation of neuronal projections. CLARITY was invented by members of our team and uses a highly innovative process, by which a hydrogel is built within a brain tissue specimen and the tissue lipids are subsequently removed. The result is brain tissue that is physically stable with fine structures, proteins and nucleic acids preserved, yet permeable to both visible-spectrum photons (for optical imaging) and exogenous macromolecules (such as antibodies for staining). Unlike conventional 2D histology, which fails to capture the 3D projections of neurons (axons and dendrites), CLARITY offers an unprecedented view of 3D intact fiber pathways. To translate the benefits of the high-resolution, high-specificity postmortem CLARITY images back to clinical neuroimaging, we will compare the postmortem dMRI fiber tracking and CLARITY results to in vivo dMRI fiber tracking in data from the NIH Human Connectome Project (HCP). We have strong preliminary work supporting the acquisition of high-quality postmortem dMRI, co-registration of dMRI and CLARITY images, and the ability to quantitatively assess biological features using CLARITY of human tissue. This uniquely positions us to address the inherent technological challenges and perform the proposed work.


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Jennifer McNab, Ph.D.

Jennifer McNab is an Assistant Professor of Radiology at Stanford University. Her research focuses on developing new Magnetic Resonance Imaging (MRI) technology to help guide the treatment of neurological injuries and diseases. She has developed numerous MRI acquisition methods, with her primary contributions being in the field of diffusion MRI; a type of MRI that measures water diffusion to infer on tissue microstructure. She has extensive experience with the most cutting-edge MRI technology including the world’s strongest human-MRI gradients (300 mT/m), highly-parallelized phased-array radio-frequency coils (64-channels) and ultra-high-magnetic field (7T). Her lab has a strong focus on validating and better understanding the biological sources of MRI contrast through rigorous comparisons with the most advanced histology methods such as CLARITY. She received her Ph.D. from Oxford University and was a postdoctoral fellow at Harvard University and Massachusetts General Hospital’s Martinos Center for Biomedical Imaging before starting her current faculty position at Stanford University.



Anatomy: Axons
White matter
Conditions: Depression
Obsessive-compulsive disorder
Function: Brain and behavior
Technology: Diffusion tensor imaging