Cortico-cortical connectivity is influenced by levodopa in tremor-dominant Parkinson's disease.

Resting tremor is the most common presenting motor symptom in Parkinson's disease (PD). The supplementary motor area (SMA) is a main target of the basal-ganglia-thalamo-cortical circuit and has direct, facilitatory connections with the primary motor cortex (M1), which is important for the execution of voluntary movement. Dopamine potentially modulates SMA and M1 activity, and both regions have been implicated in resting tremor. This study investigated SMA-M1 connectivity in individuals with PD ON and OFF dopamine medication, and whether SMA-M1 connectivity is implicated in resting tremor. Dual-site transcranial magnetic stimulation was used to measure SMA-M1 connectivity in PD participants ON and OFF levodopa. Resting tremor was measured using electromyography and accelerometry. Stimulating SMA inhibited M1 excitability OFF levodopa, and facilitated M1 excitability ON levodopa. ON medication, SMA-M1 facilitation was significantly associated with smaller tremor than SMA-M1 inhibition. The current findings contribute to our understanding of the neural networks involved in PD which are altered by levodopa medication and provide a neurophysiological basis for the development of interventions to treat resting tremor.

Covariation of the amplitude and latency of motor evoked potentials elicited by transcranial magnetic stimulation in a resting hand muscle.

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique used to study human neurophysiology. A single TMS pulse delivered to the primary motor cortex can elicit a motor evoked potential (MEP) in a target muscle. MEP amplitude is a measure of corticospinal excitability and MEP latency is a measure of the time taken for intracortical processing, corticofugal conduction, spinal processing, and neuromuscular transmission. Although MEP amplitude is known to vary across trials with constant stimulus intensity, little is known about MEP latency variation. To investigate MEP amplitude and latency variation at the individual level, we scored single-pulse MEP amplitude and latency in a resting hand muscle from two datasets. MEP latency varied from trial to trial in individual participants with a median range of 3.9 ms. Shorter MEP latencies were associated with larger MEP amplitudes for most individuals (median r = - 0.47), showing that latency and amplitude are jointly determined by the excitability of the corticospinal system when TMS is delivered. TMS delivered during heightened excitability could discharge a greater number of cortico-cortical and corticospinal cells, increasing the amplitude and, by recurrent activation of corticospinal cells, the number of descending indirect waves. An increase in the amplitude and number of indirect waves would progressively recruit larger spinal motor neurons with large-diameter fast-conducting fibers, which would shorten MEP onset latency and increase MEP amplitude. In addition to MEP amplitude variability, understanding MEP latency variability is important given that these parameters are used to help characterize pathophysiology of movement disorders.

Reduced Cerebellar Brain Inhibition Measured Using Dual-Site TMS in Older Than in Younger Adults.

Dual-site transcranial magnetic stimulation (TMS) can be used to measure the cerebellar inhibitory influence on the primary motor cortex, known as cerebellar brain inhibition (CBI), which is thought to be important for motor control. The aim of this study was to determine whether age-related differences in CBI (measured at rest) were associated with an age-related decline in bilateral motor control measured using the Purdue Pegboard task, the Four Square Step Test, and a 10-m walk. In addition, we examined test re-test reliability of CBI measured using dual-site TMS with a figure-of-eight coil in two sessions. There were three novel findings. First, CBI was less in older than in younger adults, which is likely underpinned by an age-related loss of Purkinje cells. Second, greater CBI was associated with faster 10-m walking performance in older adults, but slower 10-m walking performance in younger adults. Third, moderate intraclass correlation coefficients (ICCs: 0.53) were found for CBI in younger adults; poor ICCs were found for CBI (ICC: 0.40) in older adults. Together, these results have important implications for the use of dual-site TMS to increase our understanding of age- and disease-related changes in cortical motor networks, and the role of functional connectivity in motor control.

Test Re-test Reliability of Dual-site TMS Measures of SMA-M1 Connectivity Differs Across Inter-stimulus Intervals in Younger and Older Adults.

Dual-site transcranial magnetic stimulation (TMS) is a promising tool to measure supplementary motor area and primary motor cortex (SMA-M1) connectivity in younger and older adults, and could be used to understand the pathophysiology of movement disorders. However, test re-test reliability of dual-site TMS measures of SMA-M1 connectivity has not been established. We examined the reliability of SMA-M1 connectivity using dual-site TMS in two sessions in 30 younger and 30 older adults. For dual-site TMS, a conditioning pulse delivered to SMA (140% of active motor threshold) preceded a test pulse delivered to M1 (intensity that elicited MEPs of ~1 mV) by inter-stimulus intervals (ISI) of 6 ms, 7 ms, and 8 ms. Moderate intraclass correlation coefficients (ICC) were found for SMA-M1 connectivity at an ISI of 7 ms in younger (ICC: 0.69) and older adults (ICC: 0.68). Poor ICCs were found for SMA-M1 connectivity at ISIs of 6 ms and 8 ms in both age groups (ICC range: 0.01-0.40). We report evidence for stable measures of SMA-M1 connectivity at an ISI of 7 ms in both age groups. These findings are foundational for future research developing evidence-based interventions to strengthen SMA-M1 connectivity to improve bilateral motor control in older adults and populations with movement disorders.

Good test-retest reliability of a paired-pulse transcranial magnetic stimulation protocol to measure short-interval intracortical facilitation.

Transcranial magnetic stimulation (TMS) is used frequently to study human physiology, including the indirect-wave (I-wave) circuits generating short-interval intracortical facilitation (SICF). Growing evidence implicates SICF in plasticity and motor learning, suggesting that SICF is likely of functional relevance in both health and disease. To date, test-retest reliability has not been established for measures of SICF: given the clear potential of SICF to be used as a diagnostic tool, it is critical to establish the reliability of the paired-pulse TMS protocol to measure SICF. We investigated the test-retest reliability of SICF measured using paired-pulse TMS. SICF was measured in two sessions in 20 young adults using single- and paired-pulse TMS. Single-pulse TMS was set at an intensity that elicited MEPs of 1 mV (SI1mV) and paired-pulse TMS was set with the first stimulus at SI1mV, the second stimulus (S2) 90% of resting motor threshold (RMT), and a total of 20 interstimulus intervals (ISI; 1.1-4.9 ms with a 0.2 ms step). Large intraclass correlation coefficients (ICC) indicate good test-retest reliability between sessions for all SICF peaks (ICCs ranging from 0.73 to 0.79). The ISI at which SICF was maximal within individuals was consistent at all three peaks across both experimental sessions. Results showed good test-retest reliability of SICF at all three peaks when using a standard paired-pulse protocol to measure SICF. This finding suggests that paired-pulse TMS can be used to reliably probe the excitability of the interneuronal circuits that generate SICF. This provides a strong platform for future research to investigate the functional role of I-wave circuitry, including the role of I-wave circuitry in motor control decline in healthy older adults and individuals with movement disorders.

Differential plasticity of extensor and flexor motor cortex representations following visuomotor adaptation.

Representations within the primary motor cortex (M1) are capable of rapid functional changes following motor learning, known as use-dependent plasticity. GABAergic inhibition plays a role in use-dependent plasticity. Evidence suggests a different capacity for plasticity of distal and proximal upper limb muscle representations. However, it is unclear whether the motor cortical representations of forearm flexor and extensor muscles also have different capacities for plasticity. The current study used transcranial magnetic stimulation to investigate motor cortex excitability and inhibition of forearm flexor and extensor representations before and after performance of a visuomotor adaptation task that primarily targeted flexors and extensors separately. There was a decrease in extensor and flexor motor-evoked potential (MEP) amplitude after performing the extensor adaptation, but no change in flexor and extensor MEP amplitude after performing the flexor adaptation. There was also a decrease in motor cortical inhibition in the extensor following extensor adaptation, but no change in motor cortical inhibition in the flexor muscle following flexor adaptation or either of the non-prime mover muscles. Findings suggest that the forearm extensor motor cortical representation exhibits plastic change following adaptive motor learning, and broadly support the distinct neural control of forearm flexor and extensor muscles.