Evidence for a Window of Enhanced Plasticity in the Human Motor Cortex Following Ischemic Stroke

Abstract

Background: In preclinical models, behavioral training early after stroke produces larger gains compared with delayed training. The effects are thought to be mediated by increased and widespread reorganization of synaptic connections in the brain. It is viewed as a period of spontaneous biological recovery during which synaptic plasticity is increased.

Objective: To look for evidence of a similar change in synaptic plasticity in the human brain in the weeks and months after ischemic stroke.

Methods: We used continuous theta burst stimulation (cTBS) to activate synapses repeatedly in the motor cortex. This initiates early stages of synaptic plasticity that temporarily reduces cortical excitability and motor-evoked potential amplitude. Thus, the greater the effect of cTBS on the motor-evoked potential, the greater the inferred level of synaptic plasticity. Data were collected from separate cohorts (Australia and UK). In each cohort, serial measurements were made in the weeks to months following stroke. Data were obtained for the ipsilesional motor cortex in 31 stroke survivors (Australia, 66.6 ± 17.8 years) over 12 months and the contralesional motor cortex in 29 stroke survivors (UK, 68.2 ± 9.8 years) over 6 months.

Results: Depression of cortical excitability by cTBS was most prominent shortly after stroke in the contralesional hemisphere and diminished over subsequent sessions (P = .030). cTBS response did not differ across the 12-month follow-up period in the ipsilesional hemisphere (P = .903).

Conclusions: Our results provide the first neurophysiological evidence consistent with a period of enhanced synaptic plasticity in the human brain after stroke. Behavioral training given during this period may be especially effective in supporting poststroke recovery.

Keywords: motor cortex; noninvasive brain stimulation; plasticity; recovery; stroke; transcranial magnetic stimulation.

Figure 1. Experimental paradigm.

A) Continuous theta burst stimulation (cTBS) response of the ipsilesional motor cortex was assessed in 31 people with stroke over 8 experimental sessions. For the contralesional motor cortex, cTBS response was assessed in 29 people with stroke over 4 experimental sessions. B) Response to cTBS was quantified as a change in MEP amplitude from baseline (left) to post stimulation (right). Pharmacological studies indicate cTBS produces a long-term depression-like response, therefore leading to a decrease in MEP amplitude . The decrease of MEP amplitude was used as a measure of plasticity. C) MEPs were recorded using surface EMG from the first dorsal interosseous muscle of the paretic hand (ipsilesional data) or non-paretic hand (contralesional data). D) Experimental paradigm at each session for the ipsilesional data (top) and contralesional data (bottom). B1 and B2 refer to blocks of baseline MEPs. P1, P2, P3 and P4 refer to blocks of MEPs recorded after continuous theta burst stimulation. Note that the differences in post cTBS timepoints for MEP collection reflects standard practice for neurophysiological experiments at each data collection site. This does not influence the analysis of cTBS responses as the modelling accounts for all time points in each participant

Figure 2. Flow of participants through experimental procedures.

The mean ± SD time post-stroke for each session is reported. MEP, motor evoked potential; PPM, permanent pacemaker

Figure 3. Continuous theta burst stimulation response for the ipsilesional hemisphere (left) and contralesional hemisphere (right).

Amplitudes of motor evoked potentials have been normalized to baseline. Error bars are standard deviation. Note, continuous theta burst stimulation is thought to induce a suppression of cortical excitability. Therefore, a larger decrease in motor evoked potential amplitude provides indication of greater plasticity. Data points below the dashed black line indicate motor evoked potential suppression. cTBS, continuous theta burst stimulation; MEP, motor evoked potential.