NIMH Non-Invasive Brain Stimulation E-Field Modeling Workshop

Sponsor(s): NIMH Division of Translational Research

The NIMH Division of Translational Research sponsored a workshop to provide an overview of the use of electric-field (e-field) modeling in noninvasive brain stimulation studies. Experts provided theoretical background information on e-field modeling as well as practical hands-on experience with a variety of available software packages.

A transcribed video of the meeting can be found here: NIMH Non-Invasive Brain Stimulation E-Field Modeling Workshop . The meeting agenda can be found here.

Workshop Overview

An overview of the importance of E-field modeling was presented to provide context for the workshop. The essential nature of target engagement as part of the experimental therapeutics approach to clinical trials was explained. The critical elements of target engagement include:

• (i) the ability to reach the target,
• (ii) the ability to modulate the target (mechanism of action); and
• (iii) dose-dependence.

Lacking these vital aspects of target engagement, when conventional clinical trials fail, we may not know what lead to the failure (e.g. the dose may have been too low, or failed to reach the therapeutic target). By requiring measures of target engagement in the NIMH Clinical Trials RFAs, NIMH seeks to ensure that the results of clinical trials are informative scientifically, whether the intervention demonstrated efficacy.
In the case of devices, E-field modeling can play an important role in demonstrating that the device can deliver an E-field above the threshold for neuronal depolarization to the intended target, and can be part of demonstrating dose-response relationships between delivered E-field and physiological or clinical effect. The simulated E-field can help to explain inter-individual differences in effect, and as such, may be an important aspect of understanding heterogeneity of response.

E-field modeling is also important in addressing the requirement in the R61/33 RFA  requiring that all aspects of the spatial and temporal aspects of the stimulation be reported. Specifically, the RFA states “Characterization of the spatial aspects of delivered dose for electromagnetic devices should use realistic head modeling to simulate the amplitude of the electric field induced across the brain, and should evaluate degree of target to non-target stimulation.”

Introduction to E-field Modeling

An introduction to the physics behind E-field modeling was given to provide participants with a theoretical understanding of E-field models and brain stimulation. Electrical and magnetic stimulation were discussed, including the spatial and temporal characteristics of delivered doses. The advantages and disadvantages of a variety of different types of head models were explained. The various steps necessary to compute a head model were demonstrated. The benefits of using individual scans and incorporating cortical folds was discussed. E-field models across a variety of tools were shown to demonstrate similarity and differences. Model validation and important reportable metrics were highlighted. Validation included animal and human intra-cranial recording studies. The uses of E-field models and future directions were reviewed.

Application of E-field Models to Clinical Research

The applied use of E-fields in clinical research was highlighted. The issue of variability of delivered dose was discussed and the advantage of individual head models was highlighted. The difference between simulated and actual results was discussed. The importance of exploring the stimulation parameter space was discussed as well. Examples of E-field models contributing to the fundamental understanding of stimulation effects was demonstrated across a variety of clinical trials using various brain stimulation tools. E-field models can also be used to compare localization approaches. The possibility of future clinical studies to assess the prospective use of E-field modeling was discussed. Current research questions surrounding which parameter (spatial, connectivity-based, etc..) to optimize were highlighted for future studies. The relative strength of e-fields from various brain stimulation tools was shown. Participants were provided a deeper understanding of E-field models and their appropriate usage.

Review of E-field Modeling Software Packages

Experts from several E-field modeling software packages presented their programs and provided practical hands-on demonstrations. They provided a brief overview of their toolsets highlighting the uses and limitations of each approach. Some toolsets focused on transcranial magnetic stimulation (TMS) while some focused on transcranial electric stimulation (tES/tDCS/tACS). Some were open source while some were proprietary or linked to certain navigation systems. The user interface and pre-requisite knowledge required for each package varied as well. Experts brought participants through a practical, hands on, demonstration creating and modifying E-field models from template MRI brain scans. Time was provided at the end of the workshop for participants online or in person to ask questions. Presented packages included (in order of presentation): SimNIBS, SciRUN, ROAST/HD-Explore, Nextstim, and StarStim.

Grant Application Guidance

Guidance relevant to brain stimulation grant applications was provided. An overview of the NIH device development pathway and traditional NIMH Clinical Trial funding opportunities was given to provide additional context for applicants and to guide them to the appropriate funding choice for their stage of clinical research. The experimental therapeutics approach was explained, highlighting the importance of E-field modeling to demonstrating the capability of reaching and manipulating the proposed target. Relevant grant language was highlighted to reinforce the importance of key components of the application. The importance of including an E-field model demonstrating the potential of target engagement at proposed sites in the original grant application was highlighted as well as the importance of including individual E-field modeling in clinical studies. Good and poor examples of E-field models were provided for participants. Practical guidance was provided, such as:

• Include a clearly labeled figured demonstrating the effect of stimulation on the specific brain region
  • If multiple targets are proposed, use multiple e-field models
    • Can be combined in one figure
    • If individualizing target for each patient, include representative brain targets
• Labeled color bar
  • Include values, ranges
  • If intending to reach a threshold level of neural activation, indicate on color bar
• Quantify amplitude of field at target brain structure, relative to threshold for neuronal depolarization
• Quantify ratio of target to nontarget activation
  • i.e. is your target being selectively stimulated and not neighboring areas?
  • Especially important for deep brain targets
• Novel tool
  • Include supporting literature to demonstrate that the model is accurate
    • Peer-review publications preferable
• Apply for FIH U01 or device development R01 if research base not present
  • Can do clinical trial research in FIH U01 or seek funding for tool development in R01
• Individual subjects
  • Use modeling for individual subjects
  • Ok to use generic brain for application figure, but grant itself should scan and model each subject’s brain for optimal stimulation

Specific guidance was given regarding meeting the requirements to specify the spatial, temporal, and contextual aspects of dosing for devices. All aspects of delivered dose should be thoroughly defined, modeled, and where appropriate, measured. This includes:

• Spatial aspects
  • Realistic head modeling simulates electric field induced
    • Amplitude, and spatial distribution
  • Evaluate degree of target to non-target stimulation
  • Demarcate threshold for neuronal activation, show reached at target and not at non-tergets
  • Toolsets
    • SimNIBS, SCIRun, HD-Explore/HD-Targets, Nextstim neuronavigation etc…
• Temporal elements
  • Pulse shape
  • Pulse direction
  • Frequency
  • Train duration
  • Inter-train interval, etc.
• Context
  • Temporal correspondence to underlying neural oscillations in open or closed-loop fashion,
  • Brain state at time of administration,
  • On-line or off-line cognitive/behavioral therapies
  • Social context of device delivery
  • Concomitant pharmacological intervention, etc. 
  • Interest in multi-modal strategies

Further requirements to improve the rigor and reproducibility of research with noninvasive brain stimulation include:

• Evaluation of target engagement should use brain measures, such as
  • on-line (e.g., TMS/fMRI interleaving, TCS-EEG, TMS-PET, DBS-EEG) or
  • off-line (PET, fMRI/rsfcMRI, MRS, etc) approaches,
  • depending on the nature of the spatial anatomical and/or neural oscillatory targets.
• Focus on identifying stimulation paradigm (spatial, temporal, and contextual features) that most effectively results in a CNS modification, based on the proposed mechanism of action
• Sham/control should be included
  • Demonstrate adequate masking procedures and
  • Lack of biological action that would exert CNS effects
• Deep penetrating devices
  • Must demonstrate deep targets are effectively and selectively reached, with a clinically acceptable target-to-nontarget ratio.
  • Claims of deep targeting using noninvasive devices must be accompanied with rigorous pre-clinical and modeling data supporting the claims

The impact of the implementation of the revised clinical trial definition was discussed and guidance provided to prospective applicants. A majority of brain stimulation applications that were previously exempted from clinical trials will now be placed under the umbrella of 'mechanistic' clinical trial R01/R21s. A question and answer session concluded the meeting.

For more information

David McMullen, M.D., Program Officer, Neuromodulation and Neurostimulation, NIMH, David.mcmullen@nih.gov
Sarah H. Lisanby, M.D., Director, Division of Translational Research, NIMH, Sarah.Lisanby@nih.gov.

Additional Event Information

NIMH Non-Invasive Brain Stimulation E-Field Modeling Workshop

Agenda: NIMH Non-Invasive Brain Stimulation E-Field Modeling Workshop