Reproducibility of neuroplastic responses induced by continuous theta-burst stimulation

See Attache

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

Long-interval facilitation and inhibition are differentially affected by conditioning stimulus intensity over different time courses

Intracortical facilitatory and inhibitory processes in the primary motor cortex (M1) play an important role in both the preparation and execution of motor tasks. Here we aimed to (1) confirm the existence of, and further characterise, intracortical facilitation at long conditioning-test stimulus intervals at subthreshold conditioning stimulus (CS) intensities and (2) identify the threshold for long-interval intracortical inhibition (LICI) at different inter-stimulus intervals (ISIs). To examine facilitation, stimulus-response curves at ISIs of 100 and 150 ms were obtained using a range of subthreshold CS intensities. LICI stimulus-response curves were also obtained using varying CS intensities at ISIs of 100 (LICI100) and 150 ms (LICI150). Facilitation of the conditioned MEP was observed at subthreshold CS intensities at an ISI of 100 ms. LICI100 was observed at a lower CS intensity than LICI150. First, we provide evidence of a long-interval facilitation and provide some evidence consistent with a cortical origin of this facilitation. Second, the lower threshold for evoking LICI100 than LICI150 suggests an intensity-duration effect whereby a more intense CS results in longer duration LICI. Investigation of the interaction between LICI and long-interval facilitation might help to elucidate the functional importance of these processes

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

Probing changes in corticospinal excitability following theta burst stimulation of the human primary motor cortex

Objective: To determine whether the intensity of transcranial magnetic stimulation (TMS) used to probe changes in corticospinal excitability influences the measured plasticity response to theta burst stimulation (TBS) of the human primary motor cortex. Methods: Motor evoked potential (MEP) input/output (I/O) curves were recorded before and following continuous TBS (cTBS) (Experiment 1; n = 18) and intermittent TBS (iTBS) (Experiment 2; n = 18). Results: The magnitude and consistency of MEP depression induced by cTBS was greatest when probed using stimulus intensities at or above 150% of resting motor threshold (RMT). In contrast, facilitation of MEPs following iTBS was strongest and most consistent at 110% of RMT. Conclusions: The plasticity response to both cTBS and iTBS is influenced by the stimulus intensity used to probe the induced changes in corticospinal excitability. Significance: The results highlight the importance of the test stimulus intensity used to assess TBS-induced changes in corticospinal excitability when interpreting neuroplasticity data, and suggest that a number of test intensities may be required to reliably probe the plasticity response

The effects of age and biological sex on the association between I-wave recruitment and the response to cTBS: an exploratory study

The neuroplastic response to continuous theta burst stimulation (cTBS) is inherently variable. The measurement of I-wave latencies has been shown to strongly predict the magnitude and direction of the response to cTBS, whereby longer latencies are associated with stronger long-term depression-like responses. However, potential differences in this association relating to age and sex have not been explored. We performed cTBS and measured I-wave recruitment (via MEP latencies) in 66 participants (31 female) ranging in age from 11 to 78 years. The influence of age and sex on the association between I-wave recruitment and the response to cTBS was tested using linear regression models. In contrast to previous studies, there was not a significant association between Iwave latencies and cTBS response at the group level (p = 0.142, R2 = 0.033). However, there were interactions between I-waves and both age and sex when predicting cTBS response. Subgroup analysis revealed that preferential late I-wave recruitment predicted cTBS response in adolescent females, but not in adolescent or adult males or adult females. These data suggest that the generalisability of I-wave measurement in predicting the response to cTBS may be lower than initially believed. Prediction models should include age and sex, rather than I-wave latencies alone, as our findings suggest that, while each factor alone is not a strong predictor, these factors interact to influence the response to cTBS.Jago M. Van Dam, Lynton Graetz, Julia B. Pitcher, Mitchell R. Goldsworth

Reinventing fisheries management

XXVI+435hlm.;23c

P11-15 Gestation length and fetal growth have independent effects on corticospinal development in children: the PREMOCODE study

Objectives: Children born preterm (i.e. <37 weeks gestational age [GA]) often exhibit motor dysfunction at school age when compared to their term-born peers suggesting preterm birth alters normal corticospinal development. However, some preterm children are also experience fetal growth restriction in utero. Here we used transcranial magnetic stimulation to characterise the effects of GA at birth on corticospinal development in non-cerebral palsy children and differentiate its effects from those of sub-optimal fetal growth i.e. birthweight centile (BW%). Methods: 148 children (11.6±0.6 years) born at 22 41 weeks GA participated. Active (aMT), resting motor thresholds (rMT) and stimulusresponse curves were obtained for left and right motor cortex (M1) projections to a hand muscle. BW% was calculated using the GROW centile calculator. Data were analysed using repeated measures ANCOVA, correlation and regression analyses. Results: At least one MT and one stimulus-response curve was obtained from 137 and 58 children respectively. None of these had a GA<27 weeks. Shortened GA was linearly associated with increased rMT and aMT in both hemispheres, and reduced maximal evoked response amplitude (F[2,58] = 4.1, P = 0.05) and area under the left M1 curve only (F[2,58] = 5.1, P = 0.03). Low BW% was independently associated with increased rMT only in the right M1 (r = 0.31, P = 0.008, N = 78). Conclusions: Even in the mildly preterm, reduced GA and BW% are associated with delayed or abnormal corticospinal development that is still evident in late childhood. Left motor cortex (M1) excitability appears most affected by shortened GA, while low BW% preferentially reduces right M1 excitability. These data may underestimate the effect as children with the lowest cortical excitability could not be fully assessed with TMS. Delayed or abnormal corticospinal development probably contributes to non-cerebral palsy motor dysfunction in preterm children.J.B. Pitcher, R.D. Higgins, N.R. Burns, J.S. Robinson, T.J. Nettelbeck, R.R. Haslam, M.C. Riddin

Combined transcranial alternating current stimulation and continuous theta burst stimulation: a novel approach for neuroplasticity induction

Non-invasive brain stimulation can induce functionally relevant plasticity in the human cortex, making it potentially useful as a therapeutic tool. However, the induced changes are highly variable between individuals, potentially limiting research and clinical utility. One factor that might contribute to this variability is the level of cortical inhibition at the time of stimulation. The alpha rhythm (~ 8–13 Hz) recorded with electroencephalography (EEG) is thought to reflect pulsatile cortical inhibition; therefore, targeting non-invasive brain stimulation to particular phases of the alpha rhythm may provide an approach to enhance plasticity induction. Transcranial alternating current stimulation (tACS) has been shown to entrain cortical oscillations in a frequency-specific manner. We investigated whether the neuroplastic response to continuous theta burst stimulation (cTBS) was enhanced by timing bursts of stimuli to the peak or the trough of a tACS-imposed alpha rhythm. While motor evoked potentials (MEPs) were unaffected when cTBS was applied in-phase with the peak of the tACS-imposed oscillation, MEP depression was enhanced when cTBS was applied in-phase with the trough. This enhanced MEP depression was dependent on the individual peak frequency of the endogenous alpha rhythm recorded with EEG prior to stimulation, and was strongest in those participants classified as non-responders to standard cTBS. These findings suggest that tACS may be used in combination with cTBS to enhance the plasticity response. Furthermore, the peak frequency of endogenous alpha, as measured with EEG, may be used as a simple marker to pre-select those individuals likely to benefit from this approach