Trial Outcomes & Findings for Noninvasive Brain Stimulation to Evaluate Neural Plasticity After Stroke (NCT NCT02465034)

Last Updated: 2021-11-26

Results Overview

Long-term potentiation-like plasticity was measured using paired associative stimulation (PAS). PAS consists of repeated peripheral electric stimulation paired with Transcranial Magnetic Stimulation (TMS) applied to the motor cortex at varying interstimulus intervals. Participants received 180 paired stimuli at 0.25 hertz (Hz) for 12 minutes. Impaired long-term potentiation-like plasticity points towards reduced excitatory synaptic connectivity and deficits in sensorimotor integration. Decrease or no change in the amplitudes of motor-evoked potentials (MEPs) indicates impaired long-term potentiation-like plasticity.

Recruitment status

TERMINATED

Study phase

Target enrollment

45 participants

Primary outcome timeframe

Baseline, 1 Minute Post-Paired Associative Stimulation

Results posted on

2021-11-26

Participant Flow

Participant enrollment began in May 2015 and all study follow up was completed by July 24, 2019. Study activities took place at the Emory Wesley Woods Health Center in Atlanta, Georgia.

Forty-five individuals gave consent to participate in the study and were enrolled into the appropriate study arm based on health status. Four screen failed or withdrew resulting in 41 who participated in the study. Participants with subcortical stroke could take part in both the PAS and CC-PAS studies.

Participant milestones

Participant milestones
Measure	Participants With Subcortical Stroke Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function undergoing noninvasive targeting of cortical locations by stereotactic neuronavigation using Transcranial Magnetic Stimulation (TMS), median nerve stimulation and arm motor function assessments. A paired associative stimulation (PAS) protocol using noninvasive stimulation was used where participants received traditional PAS and sham PAS or a cortico-cortical paired associative stimulation (CC-PAS) and sham CC-PAS. Participants also underwent median nerve stimulation.	Healthy Controls Healthy individuals underwent noninvasive targeting of cortical locations by stereotactic neuronavigation using Transcranial Magnetic Stimulation (TMS), median nerve stimulation and arm motor function assessments. A paired associative stimulation (PAS) protocol using noninvasive stimulation was used where participants received traditional PAS and sham PAS.
Overall Study STARTED	19	26
Overall Study Started PAS	12	21
Overall Study Completed PAS	9	20
Overall Study Started CC-PAS	16	0
Overall Study Completed CC-PAS	16	0
Overall Study COMPLETED	16	20
Overall Study NOT COMPLETED	3	6

Reasons for withdrawal

Reasons for withdrawal
Measure	Participants With Subcortical Stroke Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function undergoing noninvasive targeting of cortical locations by stereotactic neuronavigation using Transcranial Magnetic Stimulation (TMS), median nerve stimulation and arm motor function assessments. A paired associative stimulation (PAS) protocol using noninvasive stimulation was used where participants received traditional PAS and sham PAS or a cortico-cortical paired associative stimulation (CC-PAS) and sham CC-PAS. Participants also underwent median nerve stimulation.	Healthy Controls Healthy individuals underwent noninvasive targeting of cortical locations by stereotactic neuronavigation using Transcranial Magnetic Stimulation (TMS), median nerve stimulation and arm motor function assessments. A paired associative stimulation (PAS) protocol using noninvasive stimulation was used where participants received traditional PAS and sham PAS.
Overall Study Withdrawal by Subject	1	1
Overall Study Screen fail	2	0
Overall Study Could not be scheduled for study visit	0	5

Baseline Characteristics

Noninvasive Brain Stimulation to Evaluate Neural Plasticity After Stroke

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Participants With Subcortical Stroke n=19 Participants Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function undergoing noninvasive targeting of cortical locations by stereotactic neuronavigation using Transcranial Magnetic Stimulation (TMS), median nerve stimulation and arm motor function assessments. A paired associative stimulation (PAS) protocol using noninvasive stimulation was used where participants received traditional PAS and sham PAS or a cortico-cortical paired associative stimulation (CC-PAS) and sham CC-PAS. Participants also underwent median nerve stimulation.	Healthy Controls n=26 Participants Healthy individuals underwent noninvasive targeting of cortical locations by stereotactic neuronavigation using Transcranial Magnetic Stimulation (TMS), median nerve stimulation and arm motor function assessments. A paired associative stimulation (PAS) protocol using noninvasive stimulation was used where participants received traditional PAS and sham PAS.	Total n=45 Participants Total of all reporting groups
Age, Continuous	58.9 years STANDARD_DEVIATION 12.1 • n=93 Participants	26.3 years STANDARD_DEVIATION 6.1 • n=4 Participants	39.9 years STANDARD_DEVIATION 18.0 • n=27 Participants
Sex: Female, Male Female	9 Participants n=93 Participants	13 Participants n=4 Participants	22 Participants n=27 Participants
Sex: Female, Male Male	10 Participants n=93 Participants	13 Participants n=4 Participants	23 Participants n=27 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=93 Participants	1 Participants n=4 Participants	1 Participants n=27 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	19 Participants n=93 Participants	25 Participants n=4 Participants	44 Participants n=27 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Asian	0 Participants n=93 Participants	4 Participants n=4 Participants	4 Participants n=27 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Black or African American	6 Participants n=93 Participants	6 Participants n=4 Participants	12 Participants n=27 Participants
Race (NIH/OMB) White	13 Participants n=93 Participants	16 Participants n=4 Participants	29 Participants n=27 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Region of Enrollment United States	19 Participants n=93 Participants	26 Participants n=4 Participants	45 Participants n=27 Participants

PRIMARY outcome

Timeframe: Baseline, 1 Minute Post-Paired Associative Stimulation

Population: This analysis includes participants with complete and usable data. Errors with data acquisition occurred with three participants in the stroke PAS assessment, two participants in the stroke CC-PAS assessment, and three healthy controls. Two additional control participants were not included in the analysis due to data quality issues.

Outcome measures

Outcome measures
Measure	Subcortical Stroke PAS n=6 Participants Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving paired associative stimulation (PAS). PAS is a combination of transcranial magnetic stimulation (TMS) and electrical stimulation of the median nerve. 180 paired stimuli are delivered at 0.25 Hz for 12 minutes. Median nerve stimuli at 300% of the perceptual threshold is applied 25ms prior to transcranial magnetic stimulation delivery over the ipsilesional (stroke) or non-dominant (control) cortex.	Subcortical Stroke PAS Sham n=6 Participants Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving sham paired associative stimulation (PAS).	Subcortical Stroke CC-PAS n=14 Participants Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving cortico-cortical paired associative stimulation (CC-PAS). CC-PAS is a combination of TMS and electrical stimulation of the median nerve. 180 paired stimuli are delivered at 0.25 Hz for 12 minutes. The interstimulus interval ranges from 5-15 ms depending on site of stimulation.	Subcortical Stroke CC-PAS Sham n=14 Participants Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving sham cortico-cortical paired associative stimulation (CC-PAS).	Healthy Control Group n=15 Participants Healthy participants received noninvasive targeting of cortical locations by stereotactic neuronavigation using Transcranial Magnetic Stimulation (TMS), median nerve stimulation and arm motor function assessments. A paired associative stimulation (PAS) protocol using noninvasive stimulation was also used.	Healthy Control Sham n=15 Participants Healthy participants receiving sham paired associative stimulation (PAS).
Change in Long-term Potentiation-like Plasticity 1 minute post-PAS	1455.77 microvolts (µV) Standard Deviation 1383.06	883.74 microvolts (µV) Standard Deviation 424.24	644.46 microvolts (µV) Standard Deviation 627.70	525.34 microvolts (µV) Standard Deviation 502.67	1777.57 microvolts (µV) Standard Deviation 1192.83	1121.38 microvolts (µV) Standard Deviation 641.96
Change in Long-term Potentiation-like Plasticity Baseline	813.86 microvolts (µV) Standard Deviation 619.81	819.47 microvolts (µV) Standard Deviation 387.37	665.14 microvolts (µV) Standard Deviation 645.05	427.80 microvolts (µV) Standard Deviation 360.45	1408.08 microvolts (µV) Standard Deviation 871.52	1025.60 microvolts (µV) Standard Deviation 451.76

PRIMARY outcome

Timeframe: Baseline, 5 Minutes Post-Paired Associative Stimulation

Population: Only participants receiving CC-PAS were studied for this outcome. Errors with data acquisition occurred with two participants. Data were not collected for one participant due to EEG equipment malfunction, and not collected for one participant due to time constraints.

Electroencephalography (EEG) data were recorded using a 64-channel TMS-compatible electrode cap (Easy Cap). Signals were collected at 2000 hertz (Hz) during pre- and post-transcranial magnetic stimulation epochs (-100ms to 200ms). Up to fifty suprathreshold (120% AMT) transcranial magnetic stimulation pulses were applied to motor cortex while the subject was seated quietly with eyes open. This procedure was conducted bilaterally. Data epochs (-1000 to 4000 ms with respect to TMS delivery) were extracted for subsequent imaginary phase coherence analysis. Post-TMS coherence values between electrodes overlying M1 bilaterally (C3 and C4) were calculated within the beta frequency range (15 to 30 Hz). EEG data values are unit-free that can range from 0 to 1. Higher values represent greater coherence which is thought to indicate stronger connectivity.

Outcome measures

Outcome measures
Measure	Subcortical Stroke PAS n=12 Participants Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving paired associative stimulation (PAS). PAS is a combination of transcranial magnetic stimulation (TMS) and electrical stimulation of the median nerve. 180 paired stimuli are delivered at 0.25 Hz for 12 minutes. Median nerve stimuli at 300% of the perceptual threshold is applied 25ms prior to transcranial magnetic stimulation delivery over the ipsilesional (stroke) or non-dominant (control) cortex.	Subcortical Stroke PAS Sham n=12 Participants Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving sham paired associative stimulation (PAS).	Subcortical Stroke CC-PAS Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving cortico-cortical paired associative stimulation (CC-PAS). CC-PAS is a combination of TMS and electrical stimulation of the median nerve. 180 paired stimuli are delivered at 0.25 Hz for 12 minutes. The interstimulus interval ranges from 5-15 ms depending on site of stimulation.	Subcortical Stroke CC-PAS Sham Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving sham cortico-cortical paired associative stimulation (CC-PAS).	Healthy Control Group Healthy participants received noninvasive targeting of cortical locations by stereotactic neuronavigation using Transcranial Magnetic Stimulation (TMS), median nerve stimulation and arm motor function assessments. A paired associative stimulation (PAS) protocol using noninvasive stimulation was also used.	Healthy Control Sham Healthy participants receiving sham paired associative stimulation (PAS).
Electroencephalography Recordings at Baseline and 5 MInutes Post-PAS Baseline	0.20 coefficient of coherence Standard Deviation 0.08	0.20 coefficient of coherence Standard Deviation 0.07	—	—	—	—
Electroencephalography Recordings at Baseline and 5 MInutes Post-PAS 5 minutes post-PAS	0.19 coefficient of coherence Standard Deviation 0.08	0.19 coefficient of coherence Standard Deviation 0.07	—	—	—	—

PRIMARY outcome

Timeframe: Baseline, 10 Minutes Post-Paired Associative Stimulation

Population: Only participants receiving CC-PAS were studied for this outcome. Errors with data acquisition occurred with two participants.

Three items of the Wolf Motor Function Test (WMFT) were used to evaluate functional motor performance. The 3 items were selected based on task difficulty ranging from easiest (hand to table) to most difficult (stack checkers) along with a task of moderate difficulty (lift can). Each task has different control demands and number of actions required to complete successfully. Task performance is timed in seconds, with a maximum time of 120 seconds.

Outcome measures

Outcome measures
Measure	Subcortical Stroke PAS n=14 Participants Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving paired associative stimulation (PAS). PAS is a combination of transcranial magnetic stimulation (TMS) and electrical stimulation of the median nerve. 180 paired stimuli are delivered at 0.25 Hz for 12 minutes. Median nerve stimuli at 300% of the perceptual threshold is applied 25ms prior to transcranial magnetic stimulation delivery over the ipsilesional (stroke) or non-dominant (control) cortex.	Subcortical Stroke PAS Sham n=14 Participants Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving sham paired associative stimulation (PAS).	Subcortical Stroke CC-PAS Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving cortico-cortical paired associative stimulation (CC-PAS). CC-PAS is a combination of TMS and electrical stimulation of the median nerve. 180 paired stimuli are delivered at 0.25 Hz for 12 minutes. The interstimulus interval ranges from 5-15 ms depending on site of stimulation.	Subcortical Stroke CC-PAS Sham Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving sham cortico-cortical paired associative stimulation (CC-PAS).	Healthy Control Group Healthy participants received noninvasive targeting of cortical locations by stereotactic neuronavigation using Transcranial Magnetic Stimulation (TMS), median nerve stimulation and arm motor function assessments. A paired associative stimulation (PAS) protocol using noninvasive stimulation was also used.	Healthy Control Sham Healthy participants receiving sham paired associative stimulation (PAS).
Abbreviated Wolf Motor Function Test Time Hand to Table Baseline	1.34 seconds Standard Deviation 1.00	1.20 seconds Standard Deviation 0.94	—	—	—	—
Abbreviated Wolf Motor Function Test Time Hand to Table 10 Minutes Post-PAS	1.22 seconds Standard Deviation 1.04	0.98 seconds Standard Deviation 0.76	—	—	—	—
Abbreviated Wolf Motor Function Test Time Stack Checkers Baseline	3.72 seconds Standard Deviation 3.91	3.26 seconds Standard Deviation 2.56	—	—	—	—
Abbreviated Wolf Motor Function Test Time Stack Checkers 10 Minutes Post-PAS	3.03 seconds Standard Deviation 2.29	3.20 seconds Standard Deviation 2.26	—	—	—	—
Abbreviated Wolf Motor Function Test Time Lift Can Baseline	7.76 seconds Standard Deviation 4.60	6.17 seconds Standard Deviation 2.52	—	—	—	—
Abbreviated Wolf Motor Function Test Time Lift Can 10 Minutes Post-PAS	7.40 seconds Standard Deviation 4.47	7.19 seconds Standard Deviation 2.93	—	—	—	—

SECONDARY outcome

Timeframe: Baseline

Population: This analysis includes participants with subcortical stroke, during the active PAS and CC-PAS assessments. Errors with data acquisition occurred with three participants in the stroke PAS assessment and two participants in the stroke CC-PAS assessment. This test was not performed for three participants receiving CC-PAS due to time constraints.

The arm function in subjects in the subcortical stroke group was evaluated by the Wolf Motor Function Test (WMFT). The test consists of timed and functional tasks and has 17 items. It is composed of 3 parts: Time, functional ability and strength and includes 15 function-based tasks and 2 strength based tasks. Items 1-6 involve timed functional tasks, items 7-14 are measures of strength, and the remaining 9 items consist of analyzing movement quality when completing various tasks. The examiner will test the less affected upper extremity followed by the most affected side. Scores are based on time taken to complete each task. The median time to complete all tasks will be be used to evaluate motor function. Larger values indicate greater upper extremity motor dysfunction.

Outcome measures

Outcome measures
Measure	Subcortical Stroke PAS n=6 Participants Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving paired associative stimulation (PAS). PAS is a combination of transcranial magnetic stimulation (TMS) and electrical stimulation of the median nerve. 180 paired stimuli are delivered at 0.25 Hz for 12 minutes. Median nerve stimuli at 300% of the perceptual threshold is applied 25ms prior to transcranial magnetic stimulation delivery over the ipsilesional (stroke) or non-dominant (control) cortex.	Subcortical Stroke PAS Sham n=11 Participants Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving sham paired associative stimulation (PAS).	Subcortical Stroke CC-PAS Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving cortico-cortical paired associative stimulation (CC-PAS). CC-PAS is a combination of TMS and electrical stimulation of the median nerve. 180 paired stimuli are delivered at 0.25 Hz for 12 minutes. The interstimulus interval ranges from 5-15 ms depending on site of stimulation.	Subcortical Stroke CC-PAS Sham Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving sham cortico-cortical paired associative stimulation (CC-PAS).	Healthy Control Group Healthy participants received noninvasive targeting of cortical locations by stereotactic neuronavigation using Transcranial Magnetic Stimulation (TMS), median nerve stimulation and arm motor function assessments. A paired associative stimulation (PAS) protocol using noninvasive stimulation was also used.	Healthy Control Sham Healthy participants receiving sham paired associative stimulation (PAS).
Wolf Motor Function Test	5.79 seconds Standard Deviation 10.74	23.30 seconds Standard Deviation 47.81	—	—	—	—

SECONDARY outcome

Timeframe: 30 minutes post-Paired Associative Stimulation, 24 hours post-Paired Associative Stimulation

Population: Only participants receiving CC-PAS were studied for this outcome. Errors with data acquisition occurred with two participants.

Three items of the WMFT were used to evaluate functional motor performance. The 3 items were selected based on task difficulty ranging from easiest (hand to table) to most difficult (stack checkers) along with a task of moderate difficulty (lift can). Each task has different control demands and number of actions required to complete successfully. Task performance will be timed, with a maximum time of 120 seconds.

Outcome measures

Outcome measures
Measure	Subcortical Stroke PAS n=14 Participants Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving paired associative stimulation (PAS). PAS is a combination of transcranial magnetic stimulation (TMS) and electrical stimulation of the median nerve. 180 paired stimuli are delivered at 0.25 Hz for 12 minutes. Median nerve stimuli at 300% of the perceptual threshold is applied 25ms prior to transcranial magnetic stimulation delivery over the ipsilesional (stroke) or non-dominant (control) cortex.	Subcortical Stroke PAS Sham n=14 Participants Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving sham paired associative stimulation (PAS).	Subcortical Stroke CC-PAS Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving cortico-cortical paired associative stimulation (CC-PAS). CC-PAS is a combination of TMS and electrical stimulation of the median nerve. 180 paired stimuli are delivered at 0.25 Hz for 12 minutes. The interstimulus interval ranges from 5-15 ms depending on site of stimulation.	Subcortical Stroke CC-PAS Sham Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving sham cortico-cortical paired associative stimulation (CC-PAS).	Healthy Control Group Healthy participants received noninvasive targeting of cortical locations by stereotactic neuronavigation using Transcranial Magnetic Stimulation (TMS), median nerve stimulation and arm motor function assessments. A paired associative stimulation (PAS) protocol using noninvasive stimulation was also used.	Healthy Control Sham Healthy participants receiving sham paired associative stimulation (PAS).
Abbreviated Wolf Motor Function Test Time Hand to Table 30 minutes post-PAS	1.09 seconds Standard Deviation 0.89	1.06 seconds Standard Deviation 0.80	—	—	—	—
Abbreviated Wolf Motor Function Test Time Hand to Table 24 hours post-PAS	1.18 seconds Standard Deviation 0.79	1.20 seconds Standard Deviation 1.10	—	—	—	—
Abbreviated Wolf Motor Function Test Time Stack Checkers 30 minutes post-PAS	3.15 seconds Standard Deviation 2.49	2.84 seconds Standard Deviation 1.41	—	—	—	—
Abbreviated Wolf Motor Function Test Time Stack Checkers 24 hours post-PAS	3.45 seconds Standard Deviation 4.78	2.81 seconds Standard Deviation 2.39	—	—	—	—
Abbreviated Wolf Motor Function Test Time Lift Can 30 minutes post-PAS	7.23 seconds Standard Deviation 3.83	7.79 seconds Standard Deviation 5.33	—	—	—	—
Abbreviated Wolf Motor Function Test Time Lift Can 24 hours post-PAS	7.23 seconds Standard Deviation 3.46	6.28 seconds Standard Deviation 2.90	—	—	—	—

SECONDARY outcome

Timeframe: 30 minutes post-Paired Associative Stimulation, 24 hours post-Paired Associative Stimulation

Long-term potentiation-like plasticity was measured using paired associative stimulation (PAS). PAS consists of repeated peripheral electric stimulation paired with Transcranial Magnetic Stimulation (TMS) applied to the motor cortex at varying interstimulus intervals. Participants receive 180 paired stimuli at 0.25 Hz for 12 minutes. Impaired long-term potentiation-like plasticity points towards reduced excitatory synaptic connectivity and deficits in sensorimotor integration. Decrease or no change in the amplitudes of motor-evoked potentials (MEPs) indicates impaired long-term potentiation-like plasticity.

Outcome measures

Outcome measures
Measure	Subcortical Stroke PAS n=6 Participants Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving paired associative stimulation (PAS). PAS is a combination of transcranial magnetic stimulation (TMS) and electrical stimulation of the median nerve. 180 paired stimuli are delivered at 0.25 Hz for 12 minutes. Median nerve stimuli at 300% of the perceptual threshold is applied 25ms prior to transcranial magnetic stimulation delivery over the ipsilesional (stroke) or non-dominant (control) cortex.	Subcortical Stroke PAS Sham n=6 Participants Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving sham paired associative stimulation (PAS).	Subcortical Stroke CC-PAS n=13 Participants Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving cortico-cortical paired associative stimulation (CC-PAS). CC-PAS is a combination of TMS and electrical stimulation of the median nerve. 180 paired stimuli are delivered at 0.25 Hz for 12 minutes. The interstimulus interval ranges from 5-15 ms depending on site of stimulation.	Subcortical Stroke CC-PAS Sham n=14 Participants Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving sham cortico-cortical paired associative stimulation (CC-PAS).	Healthy Control Group n=15 Participants Healthy participants received noninvasive targeting of cortical locations by stereotactic neuronavigation using Transcranial Magnetic Stimulation (TMS), median nerve stimulation and arm motor function assessments. A paired associative stimulation (PAS) protocol using noninvasive stimulation was also used.	Healthy Control Sham n=15 Participants Healthy participants receiving sham paired associative stimulation (PAS).
Long-term Potentiation-like Plasticity 30 minutes post-PAS	1162.76 microvolts (µV) Standard Deviation 585.18	847.61 microvolts (µV) Standard Deviation 421.28	532.66 microvolts (µV) Standard Deviation 510.49	503.87 microvolts (µV) Standard Deviation 472.50	1757.44 microvolts (µV) Standard Deviation 960.64	1310.29 microvolts (µV) Standard Deviation 684.84
Long-term Potentiation-like Plasticity 24 hours post-PAS	1176.71 microvolts (µV) Standard Deviation 737.16	749.86 microvolts (µV) Standard Deviation 352.13	424.17 microvolts (µV) Standard Deviation 410.79	445.29 microvolts (µV) Standard Deviation 438.84	1542.62 microvolts (µV) Standard Deviation 1219.24	1387.98 microvolts (µV) Standard Deviation 758.53

SECONDARY outcome

Timeframe: 30 minutes post-Paired Associative Stimulation, 24 hours post-Paired Associative Stimulation

Population: Only participants receiving CC-PAS were studied for this outcome. Errors with data acquisition occurred with two participants. Data were not collected for one participant due to EEG equipment malfunction and not collected for another participant due to time constraints.

Outcome measures

Outcome measures
Measure	Subcortical Stroke PAS n=12 Participants Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving paired associative stimulation (PAS). PAS is a combination of transcranial magnetic stimulation (TMS) and electrical stimulation of the median nerve. 180 paired stimuli are delivered at 0.25 Hz for 12 minutes. Median nerve stimuli at 300% of the perceptual threshold is applied 25ms prior to transcranial magnetic stimulation delivery over the ipsilesional (stroke) or non-dominant (control) cortex.	Subcortical Stroke PAS Sham n=12 Participants Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving sham paired associative stimulation (PAS).	Subcortical Stroke CC-PAS Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving cortico-cortical paired associative stimulation (CC-PAS). CC-PAS is a combination of TMS and electrical stimulation of the median nerve. 180 paired stimuli are delivered at 0.25 Hz for 12 minutes. The interstimulus interval ranges from 5-15 ms depending on site of stimulation.	Subcortical Stroke CC-PAS Sham Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving sham cortico-cortical paired associative stimulation (CC-PAS).	Healthy Control Group Healthy participants received noninvasive targeting of cortical locations by stereotactic neuronavigation using Transcranial Magnetic Stimulation (TMS), median nerve stimulation and arm motor function assessments. A paired associative stimulation (PAS) protocol using noninvasive stimulation was also used.	Healthy Control Sham Healthy participants receiving sham paired associative stimulation (PAS).
Electroencephalography Recordings at 30 Minutes and 24 Hours Post-PAS 30 minutes post-PAS	0.18 coefficient of coherence Standard Deviation 0.13	0.18 coefficient of coherence Standard Deviation 0.07	—	—	—	—
Electroencephalography Recordings at 30 Minutes and 24 Hours Post-PAS 24 hours post-PAS	0.18 coefficient of coherence Standard Deviation 0.07	0.17 coefficient of coherence Standard Deviation 0.06	—	—	—	—

SECONDARY outcome

Timeframe: Baseline, 10 minutes post-PAS, 30 minutes post-PAS, and 24 hours post-PAS

Population: Errors with data acquisition occurred with three participants in the stroke PAS assessment, two participants in the stroke CC-PAS assessment, and three healthy controls. Two additional control participants were not included due to data quality issues. One participant with subcortical stroke receiving PAS and two receiving CC-PAS were unable to perform the task due to severe upper extremity motor impairment.

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 evaluate SRTT performance and skill is measured as the difference in response times between repeated and random sequences. Lower response times indicate better performance and a larger positive difference in response times represents greater sequence-specific skill. Negative values represent better performance on random sequences compared to repeated sequences.

Outcome measures

Outcome measures
Measure	Subcortical Stroke PAS n=5 Participants Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving paired associative stimulation (PAS). PAS is a combination of transcranial magnetic stimulation (TMS) and electrical stimulation of the median nerve. 180 paired stimuli are delivered at 0.25 Hz for 12 minutes. Median nerve stimuli at 300% of the perceptual threshold is applied 25ms prior to transcranial magnetic stimulation delivery over the ipsilesional (stroke) or non-dominant (control) cortex.	Subcortical Stroke PAS Sham n=5 Participants Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving sham paired associative stimulation (PAS).	Subcortical Stroke CC-PAS n=12 Participants Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving cortico-cortical paired associative stimulation (CC-PAS). CC-PAS is a combination of TMS and electrical stimulation of the median nerve. 180 paired stimuli are delivered at 0.25 Hz for 12 minutes. The interstimulus interval ranges from 5-15 ms depending on site of stimulation.	Subcortical Stroke CC-PAS Sham n=12 Participants Participants with subcortical stroke in the chronic phase of recovery with mild-moderate impairment of arm function receiving sham cortico-cortical paired associative stimulation (CC-PAS).	Healthy Control Group n=15 Participants Healthy participants received noninvasive targeting of cortical locations by stereotactic neuronavigation using Transcranial Magnetic Stimulation (TMS), median nerve stimulation and arm motor function assessments. A paired associative stimulation (PAS) protocol using noninvasive stimulation was also used.	Healthy Control Sham n=15 Participants Healthy participants receiving sham paired associative stimulation (PAS).
Serial Reaction Time Task (SRTT) Performance Baseline	805.00 milliseconds (ms) Standard Deviation 188.63	1030.26 milliseconds (ms) Standard Deviation 398.40	19.21 milliseconds (ms) Standard Deviation 54.01	13.02 milliseconds (ms) Standard Deviation 67.51	45.13 milliseconds (ms) Standard Deviation 43.68	52.30 milliseconds (ms) Standard Deviation 48.71
Serial Reaction Time Task (SRTT) Performance 10 minutes post-PAS	806.00 milliseconds (ms) Standard Deviation 155.60	838.12 milliseconds (ms) Standard Deviation 172.58	-1.69 milliseconds (ms) Standard Deviation 142.72	28.38 milliseconds (ms) Standard Deviation 114.26	52.73 milliseconds (ms) Standard Deviation 53.43	57.50 milliseconds (ms) Standard Deviation 59.76
Serial Reaction Time Task (SRTT) Performance 30 minutes post-PAS	812.80 milliseconds (ms) Standard Deviation 192.42	788.40 milliseconds (ms) Standard Deviation 197.86	9.35 milliseconds (ms) Standard Deviation 36.69	3.99 milliseconds (ms) Standard Deviation 70.74	66.16 milliseconds (ms) Standard Deviation 63.71	61.61 milliseconds (ms) Standard Deviation 57.97
Serial Reaction Time Task (SRTT) Performance 24 hours post-PAS	726.00 milliseconds (ms) Standard Deviation 112.81	790.25 milliseconds (ms) Standard Deviation 199.97	-14.21 milliseconds (ms) Standard Deviation 114.31	8.94 milliseconds (ms) Standard Deviation 81.99	83.41 milliseconds (ms) Standard Deviation 82.96	77.05 milliseconds (ms) Standard Deviation 51.59

Adverse Events

Participants With Subcortical Stroke

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Healthy Controls

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Dr. Michael Borich

Emory University

Phone: 404-712-0612

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place