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.

Long-interval intracortical inhibition is asymmetric in young but not older adults.

Aging is typically accompanied by a decline in manual dexterity and handedness; the dominant hand executes tasks of manual dexterity more quickly and accurately than the nondominant hand in younger adults, but this advantage typically declines with age. Age-related changes in intracortical inhibitory processes might play a role in the age-related decline in manual dexterity. Long-interval intracortical inhibition (LICI) is asymmetric in young adults, with more sensitive and more powerful LICI circuits in the dominant hemisphere than in the nondominant hemisphere. Here we investigated whether the hemispheric asymmetry in LICI in younger adults persists in healthy older adults. Paired-pulse transcranial magnetic stimulation was used to measure LICI in the dominant and nondominant hemispheres of younger and older adults; LICI stimulus-response curves were obtained by varying conditioning stimulus intensity at two different interstimulus intervals [100 ms (LICI100) and 150 ms]. We have replicated the finding that LICI100 circuits are more sensitive and more powerful in the dominant than the nondominant hemisphere of young adults and extend this finding to show that the hemispheric asymmetry in LICI100 is lost with age. In the context of behavioral observations showing that dominant hand movements in younger adults are more fluent than nondominant hand movements in younger adults and dominant hand movements in older adults, we speculate a role of LICI100 in the age-related decline in manual dexterity.NEW & NOTEWORTHY In younger adults, more sensitive and more powerful long-interval intracortical inhibitory circuits are evident in the hemisphere controlling the more dexterous hand; this is not the case in older adults, for whom long-interval intracortical inhibitory circuits are symmetric and more variable than in younger adults. We speculate that the highly sensitive and powerful long-interval intracortical inhibition circuits in the dominant hemisphere play a role in manual dexterity.

Inter- and intra-subject variability of motor cortex plasticity following continuous theta-burst stimulation.

BACKGROUND: The potential of non-invasive brain stimulation (NIBS) for studying, and inducing, functionally relevant neuroplasticity is dependent on protocols that can induce lasting, robust and reliable effects. A current limiting factor is the large inter- and intra-subject variability in NIBS-induced neuroplastic responses. There has been some study of inter-subject response variability and factors that contribute to it; however, intra-subject response variability has, so far, received little investigation. OBJECTIVES: By testing participants on multiple occasions we aimed to (1) compare inter- and intra-subject variability of neuroplastic responses induced by continuous theta-burst stimulation (cTBS); (2) determine whether the transcranial magnetic stimulation (TMS) intensity used to measure cTBS-induced neuroplastic responses contributes to response variability; (3) determine whether assessment of factors known to influence response variability can be used to explain some of the variability in cTBS-induced neuroplastic responses across experimental sessions. METHODS: In three separate experimental sessions, motor-evoked potential (MEP) input-output (IO) curves were obtained before and after cTBS, and questionnaire-based assessments of physical activity and perceived stress were obtained. RESULTS: cTBS-induced MEP suppression was greatest at the upper end of the IO curve (150-180% resting motor threshold; RMT) and most consistent across subjects and across experimental sessions when assessed with a TMS intensity of 150% RMT. The magnitude of cTBS-induced MEP suppression evoked at 150% RMT correlated with self-reported perceived stress, but not with self-reported physical activity. CONCLUSIONS: The most reliable TMS intensity to probe cTBS-induced long-term depression (LTD)-like neuroplastic responses is 150% RMT. This is unlikely to simply be a ceiling effect and, we suggest, may be due to changes in the descending volley evoked at higher stimulus intensities. The perceived stress scale appears to be sufficiently sensitive to measure the influence of subject stress on LTD-like neuroplastic responses.