Techniques Development

 

The techniques development grants are designed to perfect or develop or refine important brain stimulation for rehabilitation research methods or approaches. Often there are very important methods or developments needed that would not qualify for a stand-alone NIH grant. We have been carrying out the following over the years, with NM4R executive board advice and approval.

Example 1: Multimodal Integrated Approaches

MUSC has been a pioneer in combining different imaging and brain stimulation modalities. The NC NM4R grant has helped us continue to improve these combined methods. MUSC is currently funded through DARPA to build on several multimodal integrated approaches. Although the test case now is depression, this work is important for uses in rehabilitation. 

• George MS, Huffman S, Doose J, Sun X, Dancy M, Faller J, Li X, Yuan H, Goldman RI, Sajda P, Brown TR. EEG synchronized left prefrontal transcranial magnetic stimulation (TMS) for treatment resistant depression is feasible and produces an entrainment dependent clinical response: A randomized controlled double blind clinical trial. Brain Stimul. 2023;16:1753-1763.
• Egana-delSol P, Sun X, Sajda P. Neurophysiological markers of emotion regulation predict efficacy of entrepreneurship education. Sci Rep. 2023;13:7206.
• Faller J, Doose J, Sun X, McLntosh JR, Saber GT, Lin Y, Teves JB, Blankenship A, Huffman S, Goldman RI, George MS, Brown TR, Sajda P. Daily prefrontal closed-loop repetitive transcranial magnetic stimulation (rTMS) produces progressive EEG quasi-alpha phase entrainment in depressed adults. Brain Stimul. 2022;15:458-471.

The audacious goal is to create a TMS protocol that within a day eliminates suicidality, reducing what now takes about 6 weeks and 36 treatments into one day

The initiative is pushing the limit on:

• Where to target (within individual networks, defined both by functional connectivity and integrated task based networks, as well as advanced neuronavigation accounting for distance and coil orientation)
• What the brain is doing during stimulation (cognitive tasks, EEG phase)
• How to determine response (EEG entrainment, cortical excitability). We are using EEG, fMRI, and fNIRS to check response over time and adjust
• Closed loop adjustments in real time

DARPA wants this to benefit and supercharge the field. We are thus working with vendors to create plug-and-play systems that other researchers and clinicians can purchase and use. Thus, the full system of integrated TMS/EEG/fMRI as well as the clinical system for integrated TMS/EEG/fNIRS which is EEG phase matched, will be available to all researchers. Insights and knowledge will quickly cross-fertilize to other areas like stroke and rehabilitation.

Here are some of the advances within this grant:

TMS Targeting versus Therapeutic Targeting

Hypothesis: the level of neural activation induced by TMS in areas distal to direct TMS stimulation is dependent on the instantaneous brain state (e.g. alpha phase) when the pulse(s) is applied

Simultaneous fMRI-EEG-TMS (fET)

Why is TMS/fMRI Important for Rehab?

• To date TMS has not proven highly successful in stroke rehab clinical trials.
• The field lacks critical information about TMS locations and dosing that might translate therapeutically.
• Where do we position the coil (ipsilesional, contralesional, perilesional) with what intensity, to best engage circuits needed for recovery?
• Doing TMS in the scanner allows for direct testing of locations and TMS parameters that are then important for effective clinical trials.
• For example, TMS/fMRI was critical in developing TMS for treating depression, identifying prefrontal cortical locations that then interacted with subcortical nodes (Anterior Cingulate Gyrus) for effective treatment.
• Doing this for stroke rehab is important, and more challenging as each individual stroke patient has varying anatomy and connections.

fNIRS-EEG-TMS (fNET)

Doing TMS and EEG within the MRI scanner is expensive, time-consuming, and not widely available. We are also perfecting TMS and EEG with fNIRS to determine if fNIRS might be a more widely available substitute for determining where and when to stimulate with TMS. Some patients are being studied with both systems to see if there is cross-modal validity and whether and how fNIRS might be used instead of fMRI. 

Example 2: Development of E-Field Modeling

When NM4R began very few people were using e-field modeling to help guide or refine brain stimulation. A series of NC NM4R-funded studies have helped move this approach into the mainstream. Several studies have shown that e-field distance and dose adjustments can be applied post-hoc to tDCS studies where MRI scans are available and improve the ability to see a research effect. Prospective studies with e-field adjustment are underway. Target Engagement with e-field is now the standard!

Overarching Hypothesis: tDCS will not develop into a treatment until we understand how to individually adjust the dose.

Goal: To develop a personalized method of applying transcranial direct current stimulation (tDCS) and test whether it improves response

Electric field (E-field) modeling: Uses structural MRI scans and tissue conductivities to simulate tDCS (and TMS) stimulation

A reexamination of motor and prefrontal TMS in tobacco use disorder: Time for personalized dosing based on electric field modeling?
Article by Kevin A. Caulfield, Xingbao Li, and Mark S. George in Clinical Neurophysiology

E-field modeling is helping with all forms of brain stimulation, not just tDCS   

• E.g TMS e-field mattered in the recent TMS Sync depression trial
• All subjects were treated at 120% of MT, but post study analysis (Caulfield) found there were still large differences in distance, AND this Mattered
• Argues for need for individualized personalized dose

Example 3: Closed Loop Transauricular VNS (taVNS) in Constraint-Induced Movement Therapy (CIMT) for Treatment of Cerebral Palsy

An exciting new development in the neuroscience of rehabilitation has been the discovery that time-locked stimulation of the vagus nerve either in the neck or the ear (taVNS) can help sculpt plasticity and improve learning.

MUSC has helped refine these methods and test them in exciting new rehab applications.

Dr. Dorothea Jenkins and her colleagues have paired taVNS to enhance bottle feeding in newborns failing oral feeding (Jenkins, PI).

• P, Thompson S, George MS, Badran BW. Higher Dose Noninvasive Transcutaneous Auricular Vagus Nerve Stimulation Increases Feeding Volumes and White Matter Microstructural Complexity in Open-Label Study of Infants Slated for Gastrostomy Tube. J Pediatr. 2023;262:113563.
• Aljuhani T, Coker-Bolt P, Katikaneni L, Ramakrishnan V, Brennan A, George MS, Badran BW, Jenkins D. Use of non-invasive transcutaneous auricular vagus nerve stimulation: neurodevelopmental and sensory follow-up. Front Hum Neurosci. 2023;17:1297325.
• Cook DN, Thompson S, Stomberg-Firestein S, Bikson M, George MS, Jenkins DD, Badran BW. Design and validation of a closed-loop, motor-activated auricular vagus nerve stimulation (MAAVNS) system for neurorehabilitation. Brain Stimul. 2020;13:800-803.
• Badran BW, Jenkins DD, Cook D, Thompson S, Dancy M, DeVries WH, Mappin G, Summers P, Bikson M, George MS. Transcutaneous Auricular Vagus Nerve Stimulation-Paired Rehabilitation for Oromotor Feeding Problems in Newborns: An Open-Label Pilot Study. Front Hum Neurosci. 2020;14:77.

Ongoing study by Dr. Kelly McGloon, Dr. Patricia Coker-Bolt, and colleagues of taVNS during CIMT rehab for infants

Soterix device is strapped to the infant’s back. ’Functioning’ arm is splinted and wrapped. Therapist has button push to deliver taVNS during good performance, sculpt behavior.

 

EMG-triggered taVNS with CIMT

Can we unburden the therapist and have automatic EMG triggered taVNS during CIMT training?

Philip Summers
Julia Brennan
Elizabeth Humanitski
Kelly McGloon
Dorothea Jenkins
Patty Coker Bolt

Four (of 5 planned) participants have completed so far. The technology is promising.

 

Example 4: ERIK TMS Training and Testing Phantom

We developed a phantom dummy for teaching how to perform TMS and find the motor hotspot and determine the motor threshold. This has been used now in teaching workshops and as a way to make sure all sites are performing TMS in a similar manner in multisite TMS clinical trials.

ERIK was named after the ‘phantom’ in Gaston Leroux’s The Phantom of the Opera, and is also an acronym for ‘Evaluating Resting motor threshold and Insuring Kappa’. It consists of a 3D-printed head-shaped shell which encloses a cluster of 16 pairs of orthogonal sensing coils. Each sensing coil pair is oriented tangentially to the skull surface and can measure the intensity and direction of the magnetic pulse delivered by a TMS coil. One pair of sensing coils is active at any point in time, acting as the simulated hotspot. When a TMS pulse is detected at the hotspot, the phantom records the peak value of the induced electromotive force and converts it to a simulated EMG response.

Training and testing conditions can be varied between sessions and individuals, and Erik can be programmed in one location, shipped to a remote location for testing, and then returned following the assessment. Erik can be used to quantitatively assess participants’ proficiency with TMS, to track progress over time, or to potentially test and certify TMS researchers and clinicians at remote labs. Erik may be used as a standardized teaching and testing tool that allows for repeatable training and testing conditions across participants and sites. Further information about ERIK has been presented by Christian Finetto, Chloe Glusman, Jade Doolittle, and Mark S. George in a letter to Brain Stimulation.