Julia B. Pitcher

Age and sex differences in human motor cortex input–output characteristics

Stimulus‐response curves for motor evoked potentials (MEPs) induced in a hand muscle by transcranial magnetic stimulation (TMS) were constructed for 42 subjects with the aim of identifying differences related to age and sex. There was no effect of age on the resting threshold to TMS, the maximal amplitude of the MEP that could be evoked (MEPmax) or the maximal slope of the stimulus‐response curve. However, higher stimulus intensities were required to achieve both MEPmax and the maximal slope in the older subjects. The trial‐to‐trial variability of MEPs was greater in the older subjects, particularly at intensities near threshold. There was a significant interaction between age, threshold and trial‐to‐trial variability of MEP amplitude. Overall, MEP variability fell markedly as stimulus intensity increased above threshold but less rapidly in older than in younger subjects. Females tended to have larger MEP variability than males, but age and threshold were much stronger modulators than sex. These differences in input‐output characteristics are likely to be due either to a decreased number of spinal motoneurones being activated synchronously in older subjects, or to the activation of the same number of motoneurones in a less synchronous manner, leading to phase cancellation in the surface electromyogram.

The application of spaced theta burst protocols induces long-lasting neuroplastic changes in the human motor cortex.

There is some limited evidence suggesting that the spaced application of repetitive transcranial magnetic stimulation (rTMS) protocols may extend the duration of induced neuroplastic changes. However, this has yet to be demonstrated in the human primary motor cortex (M1). We evaluated whether the paired application of an inhibitory rTMS protocol [continuous theta burst stimulation (cTBS)] at 10‐min intervals prolonged the duration of induced M1 plasticity. Motor evoked potentials (MEPs) were recorded from the right first dorsal interosseous muscle before and following single and paired cTBS protocols applied with two intensities: 80% of active motor threshold (AMT80) and 70% of resting motor threshold (RMT70). Single cTBS protocols did not significantly influence MEP amplitudes. Whereas paired trains applied at AMT80 had no effect on MEP amplitudes, paired cTBS trains at RMT70 significantly reduced them. MEP amplitudes remained suppressed for at least 2 h following the second train. Control experiments suggested that the contraction used to establish active motor threshold prior to cTBS application may be responsible for blocking the effect of paired cTBS trains at AMT80. The results suggest that the spaced application of cTBS protocols may be an effective approach for establishing long‐lasting M1 neuroplasticity only in the absence of prior voluntary motor activation. These findings may have important implications for the therapeutic application of rTMS.

INFLUENCE OF MUSCLE BLOOD FLOW ON FATIGUE DURING INTERMITTENT HUMAN HAND-GRIP EXERCISE AND RECOVERY

1. The influence of muscle blood flow on fatigue and recovery was studied in the forearm muscles of eight male subjects performing a powerful isometric hand‐grip exercise. The exercise was performed with the exercising forearm normally perfused and, on a separate occasion, with its blood flow occluded with a sphygmomanometer cuff.

Reduced corticomotor excitability and motor skills development in children born preterm

•  Children born preterm commonly experience motor and cognitive difficulties, but the physiology underlying this dysfunction is unknown. •  We used transcranial magnetic stimulation techniques and age‐appropriate assessments of motor skills development to investigate neurodevelopment in 151 children born between 25 and 41 weeks of gestation. •  Reduced gestational age at birth was associated with a reduction in corticomotor excitability that persisted in late childhood, poorer development of manual dexterity skills and reduced hemispheric lateralization of hand preference. •  We suggest this reduced corticomotor excitability at least partly reflects reduced white matter integrity and functional connectivity in the brain regions subserving movement control. •  These findings show that preterm birth, which is increasingly common, impacts neuromotor development and related physiology into adolescence. Whether this altered neurophysiology and motor function persists in adulthood is unknown.

Frequency-dependent, bi-directional plasticity in motor cortex of human adults

OBJECTIVE To determine whether the plastic changes induced in human motor cortex by afferent stimulation depend on stimulus frequency. METHODS Transcranial magnetic stimulation was used to examine changes in corticospinal excitability in 20 subjects before and after combined peripheral (motor point) and central stimulation. Peripheral stimuli were given as either low frequency (3 Hz) or high frequency (30 Hz) trains. RESULTS Low frequency stimulation induced prolonged depression of corticospinal excitability, while high frequency stimulation induced prolonged facilitation. These effects persisted for approximately 40-50 min after stimulation ceased. CONCLUSIONS Corticospinal plasticity induced by dual peripheral and central stimulation is bi-directionally-modifiable in the adult human, with the direction of change being frequency-dependent. SIGNIFICANCE Therapies using peripheral stimulation to alter human motor cortex excitability could be tailored to exploit the differential effects of stimulus frequency on the direction of the excitability change.

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.

Physiological Evidence Consistent with Reduced Neuroplasticity in Human Adolescents Born Preterm

Preterm-born children commonly experience motor, cognitive, and learning difficulties that may be accompanied by altered brain microstructure, connectivity, and neurochemistry. However, the mechanisms linking the altered neurophysiology with the behavioral outcomes are unknown. Here we provide the first physiological evidence that human adolescents born preterm at or before 37 weeks of completed gestation have a significantly reduced capacity for cortical neuroplasticity, the key overall mechanism underlying learning and memory. We examined motor cortex neuroplasticity in three groups of adolescents who were born after gestations of ≤32 completed weeks (early preterm), 33–37 weeks (late preterm), and 38–41 weeks (term) using a noninvasive transcranial magnetic brain stimulation technique to induce long-term depression (LTD)-like neuroplasticity. Compared with term-born adolescents, both early and late preterm adolescents had reduced LTD-like neuroplasticity in response to brain stimulation that was also associated with low salivary cortisol levels. We also compared neuroplasticity in term-born adolescents with that in term-born young adults, finding that the motor cortex retains a relatively enhanced neuroplastic capacity in adolescence. These findings provide a possible mechanistic link between the altered brain physiology of preterm birth and the subsequent associated behavioral deficits, particularly in learning and memory. They also suggest that altered hypothalamic–pituitary–adrenal axis function due to preterm birth may be a significant modulator of this altered neuroplasticity. This latter finding may offer options in the development of possible therapeutic interventions.

Male human motor cortex stimulus-response characteristics are not altered by aging

Evidence suggests that there are aging-related changes in corticospinal stimulus-response curve characteristics in later life. However, there is also limited evidence that these changes may only be evident in postmenopausal women and not in men. This study compared corticospinal stimulus-response curves from a group of young men [19.8 ± 1.6 yr (range 17-23 yr)] and a group of old men [n = 18, aged 64.1 ± 5.0 yr (range 55-73 yr)]. Transcranial magnetic stimulation (TMS) over the contralateral motor cortex was used to evoke motor potentials at a range of stimulus intensities in the first dorsal interosseous muscle of each hand separately. There was no effect of age group or hemisphere (i.e., left vs. right motor cortex) on motor evoked potential (MEP) amplitude or any other stimulus-response characteristic. MEP variability was strongly modulated by resting motor threshold but not by age. M-wave (but not F-wave) amplitude was reduced in old men, but expressing MEP amplitude as a ratio of M-wave amplitude did not reveal any age-related differences in cortically evoked stimulus-response characteristics. We conclude that male corticospinal stimulus-response characteristics are not altered by advancing age and that previously reported age-related changes in motor cortical excitability assessed with TMS are likely due to changes inherent in the female participants only. Future studies are warranted to fully elucidate the relationship between, and functional significance of, changes in circulating neuroactive sex hormones and motor function in later life.

Variability of Human Corticospinal Excitability Tracks the State of Action Preparation

Task-evoked trial-by-trial variability is a ubiquitous property of neural responses, yet its functional role remains largely unclear. Recent work in nonhuman primates shows that the temporal structure of neural variability in several brain regions is task-related. For example, trial-by-trial variability in premotor cortex tracks motor preparation with increasingly consistent firing rates and thus a decline in variability before movement onset. However, whether noninvasive measures of the variability of population activity available from humans can similarly track the preparation of actions remains unknown. We tested this by using single-pulse transcranial magnetic stimulation (TMS) over primary motor cortex (M1) to measure corticospinal excitability (CSE) at different times during action preparation. First, we established the basic properties of intrinsic CSE variability at rest. Then, during the task, responses (left or right button presses) were either directly instructed (forced choice) or resulted from a value decision (choice). Before movement onset, we observed a temporally specific task-related decline in CSE variability contralateral to the responding hand. This decline was stronger in fast-response compared with slow-response trials, consistent with data in nonhuman primates. For the nonresponding hand, CSE variability also decreased, but only in choice trials, and earlier compared with the responding hand, possibly reflecting choice-specific suppression of unselected actions. These findings suggest that human CSE variability measured by TMS over M1 tracks the state of motor preparation, and may reflect the optimization of preparatory population activity. This provides novel avenues in humans to assess the dynamics of action preparation but also more complex processes, such as choice-to-action transformations.

Spaced noninvasive brain stimulation: prospects for inducing long-lasting human cortical plasticity

Neuroplasticity is critical for learning, memory, and recovery of lost function following neurological damage. Noninvasive brain stimulation (NIBS) techniques can induce neuroplastic changes in the human cortex that are behaviorally relevant, raising the exciting possibility that these techniques might be therapeutically beneficial for neurorehabilitation following brain injury. However, the short duration and instability of induced effects currently limits their usefulness. To date, trials investigating the therapeutic value of neuroplasticity-inducing NIBS have used either single or multiple treatment sessions, typically repeated once-daily for 1 to 2 weeks. Although multiple stimulation sessions are presumed to have cumulative effects on neuroplasticity induction, there is little direct scientific evidence to support this “once-daily” approach. In animal models, the repeated application of stimulation protocols spaced using relatively short intervals (typically of the order of minutes) induces long-lasting and stable changes in synaptic efficacy. Likewise, learning through spaced repetition facilitates the establishment of long-term memory. In both cases, the spacing interval is critical in determining the outcome. Emerging evidence in healthy human populations suggests that the within-session spacing of NIBS protocols may be an effective approach for significantly prolonging the duration of induced neuroplastic changes. Similar to findings in the animal and learning literature, the interval at which spaced NIBS is applied seems to be a critical factor influencing the neuroplastic response. In this Point of View article, we propose that to truly exploit the therapeutic opportunities provided by NIBS, future clinical trials should consider the optimal spacing interval for repeated applications.