Noninvasive Brain Stimulation to Evaluate Neural Plasticity After Stroke
Phase: NA
Conditions: Cerebrovascular Stroke
Sponsor: Emory University

Noninvasive brain stimulation to evaluate neural 
  Dr. Michael R. Borich, DPT, PhD 
plasticity after stroke    
 
 
    
 
1
 
 
Noninvasive brain stimulation to evaluate neural plasticity 
after stroke 
 
Principal Investigator: Dr. Michael R. Borich, DPT, PhD 
Protocol version 3, dated October 28, 2021 
NCT02465034 
 
 
 

Noninvasive brain stimulation to evaluate neural 
  Dr. Michael R. Borich, DPT, PhD 
plasticity after stroke    
 
 
    
 
2
Research Plan: 
This pilot project will recruit a sample of 30 individuals with subcortical stroke aged 18-85 in the 
chronic phase of recovery with mild-moderate impairment of arm function (Fugl-Meyer upper 
extremity motor score1 of less than 61) and 30 healthy controls. In testing sessions at the Neural 
Plasticity Research Laboratory (NPRL), participants will undergo: 1) noninvasive targeting of 
cortical locations by stereotactic neuronavigation using TMS, 2) a paired associative stimulation 
(PAS) protocol using noninvasive stimulation 3) EEG recording during TMS and, 4) arm motor 
function assessments. Participants may also be asked to complete a single magnetic resonance 
imaging (MRI) session prior to testing in the NPRL. Up to 5 testing sessions will be performed. 
The duration of each session will be less than 3 hours. 
Inclusion Criteria. Individuals aged 18-85 with a middle cerebral artery stroke will be recruited. 
Individuals will have a first time stroke that affects the corona radiata and/or internal capsule. 
Stroke in these regions is common, comprising 34% of the total population2. Individuals in the 
healthy control group will be matched for handedness, gender, age (within 5 years) and 
education (within 2 years) to each participant in the stroke group. 
Exclusion Criteria. Any participant will be excluded if they: 1) are outside the age range of 18-
85; 2) show signs of dementia (score < 24 on the Montreal Cognitive Assessment);3 3) have 
aphasia (score < 13 on the Frenchay Aphasia Screen);4 4) have a history of head trauma, a major 
psychiatric diagnosis, neurodegenerative disorder or substance abuse; or 5) report 
contraindications to TMS. 
 
TMS procedures:  
During TMS assessment, stereotactic neuronavigation will be conducted in real-time using the 
BrainSight system to localize stimulation over the motor representation of the hand bilaterally 
using a standard brain template (Figure 1). Subjects will be seated comfortably in a reclining 
chair during the TMS-
EEG assessment. The 
target muscle for 
stimulation will be the 
abductor pollicis brevis 
(APB). Active motor 
threshold (% of 
maximum stimulator 
output) for the APB 
representation in M1 
will be determined 
bilaterally using standard 
protocols5. All 
stimulation parameters 
fall within published 
safety guidelines6.  
 
Median nerve stimulation 
TMS-evoked responses can be modulated when paired with a preceding peripheral nerve 
stimulus. When peripheral stimulation is applied 20-25ms prior to cortical stimulation, a 
Figure 1. Real-time integration of EEG, TMS, EMG and MRI template 
information using BrainSight system.  

Noninvasive brain stimulation to evaluate neural 
  Dr. Michael R. Borich, DPT, PhD 
plasticity after stroke    
 
 
    
 
3
reduction in cortical excitability is observed, termed short-afferent inhibition (SAI)7,8. 
Stimulation of the median nerve will be performed using a bipolar bar electrode affixed to 
palmar aspect of the forearm proximal to the crease of the wrist bilaterally. Stimuli will be 
delivered 23ms prior to the TMS pulse with 0.1ms rectangular pulses at an intensity to evoke a 
1mV response in the APB.   
 
Paired associative stimulation (PAS) protocols to induce transient shifts in cortical excitability: 
TMS pulses can be paired with another stimulation pulse at a particular interstimulus interval 
(ISI) in order to elicit transient changes in synaptic plasticity in humans. For example, long-term 
potentiation (LTP, a feature of synaptic plasticity) can be measured in humans using a technique 
termed PAS, which combines TMS and electrical stimulation of the median nerve, to excite the 
motor cortex (M1).8 TMS pulses over M1 can also be combined with TMS pulses delivered over 
other cortical regions in a ‘cortico-cortical’ (cc)PAS paradigm to also induce local LTP-like 
effects.9 For each PAS session, individuals will either receive traditional PAS, ccPAS or a sham 
stimulation intervention. Regardless of PAS group, each participant will receive 180 paired 
stimuli delivered at 0.25Hz for a total PAS duration of 12min. The ISI will depend on PAS 
condition. For traditional PAS, median nerve stimuli at 300% of the perceptual threshold will be 
applied 25ms prior to TMS delivery over the ipsilesional (stroke) or non-dominant (control) 
cortex. For ccPAS, the interstimulus interval will range from 5-15ms depending on site of 
stimulation9-11.  
 
EEG recording of TMS-evoked cortical responses:  
EEG data will be recorded using a 64-channel TMS-compatible electrode cap (Easy Cap)12. 
Signals will be collected at 2000Hz (impedance: <5kΩ, low-pass filter: 0.1-500Hz) during pre- 
and post-TMS stimulation epochs (-100ms to 200ms) (Figure 3). Fifty suprathreshold (120% 
AMT) TMS pulses will be applied to M1 while the subject is seated quietly with eyes open13,14. 
This procedure will be conducted bilaterally at each assessment timepoint (Pre-PAS, Post-PAS 
0’, Post-PAS 30’, Post-PAS 60’). Peripheral auditory and somatosensory stimulation  
effects will be minimized to avoid EEG artifact15. Data epochs (−1000 to 4000 ms with respect 
to TMS delivery) will be extracted for subsequent imaginary phase coherence analysis (IPC). 
Post-TMS coherence values between electrodes overlying M1 bilaterally (C3 and C4) will be 
calculated within the beta frequency range (15 to 30 Hz)16.  These IPC values will be used to 
index local M1 excitability and connectivity with the contralateral homotopic region17,18. 
Differences in single-channel evoked potentials in the TMS alone will be calculated to consider 
the effect of afferent peripheral input on TMS-elicited cortical responses.  
 
 
 
 
 
 
 
 
 
 
Figure 2. Example of TMS-evoked EEG data recorded from stimulated (iM1) and non-stimulated 
(cM1) cortical regions. 

Noninvasive brain stimulation to evaluate neural 
  Dr. Michael R. Borich, DPT, PhD 
plasticity after stroke    
 
 
    
 
4
Motor function assessment:  
In the stroke group, arm function will be evaluated by the Wolf Motor Function Test (WMFT), 
shown to be a valid and reliable test of arm function in stroke19. In both groups, hand-held 
dynamometry will be used to measure grip strength and manual dexterity will be indexed by the 
Nine-hole Peg Test (9HPT)20. These assessments will be carried out by a licensed physical 
therapist (M.R.B) prior to completing the PAS protocol. The serial reaction time task (SRTT) 
will be performed at each assessment time point to evaluate motor skill performance. The SRTT 
involves pressing a key that corresponds to a target square positioned on a screen in front of the 
participant as quickly and accurately as possible. The response time for repeated and random 
sequences will evaluate SRTT performance.  
 
MRI acquisition: Scanning will be conducted at Emory University at the Center for Systems 
Imaging on a Siemens 3T Trio whole-body MRI scanner. A high-resolution T1 scan (TR = 
7.4ms, TE = 3.7ms, flip angle θ = 6°, FOV = 256mm, 160 slices, 1 mm thickness, scan 
time=3.2min) will be performed without contrast. The study team will have direct and immediate 
access to the data using Emory University’s secure network server. 
Statistical Plan:  
To address the hypothesis that PAS induces LTP-like plasticity in both individuals with stroke 
and healthy controls, a three-way group (stroke, control) x condition (real PAS, sham PAS) x 
time (Pre-PAS, Post-PAS 0’, Post-PAS 30’, Post-PAS 60’) analysis of variance (ANOVA) will 
be performed for the primary dependent measures (IPC and WMFT time). 
For the analysis, an alpha = .05 will be used and simple effects analyses will be performed for 
significant interaction effects.  
 
Power analysis: 
To ensure we have sufficient statistical power for our proposed aims, we used a combination of 
our standalone TMS data collected in participants with chronic stroke and TMS-EEG data 
collected to evaluate interhemispheric connectivity in young, healthy individuals16. To detect a 
hemispheric difference in iSP ratio of 0.06 with a common σ=0.11, b=0.8, a sample size of 27 
subjects is required. In order to measure differences in TMS-evoked EEG responses in the 
hemisphere opposite the site of stimulation with a mean difference: 430µV.msec, common 
σ=288µV.msec, b=0.8, a sample size of 4 subjects is required. Due to the increased measurement 
variability in stroke, we chose a necessary sample size of n=30/group. 
 
 
References: 
 
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plasticity after stroke    
 
 
    
 
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Noninvasive brain stimulation to evaluate neural 
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plasticity after stroke    
 
 
    
 
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