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 I-wave 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.

Cortical Plasticity and Interneuron Recruitment in Adolescents Born to Women with Gestational Diabetes Mellitus.

Exposure to gestational diabetes mellitus (GDM) in utero is associated with a range of adverse cognitive and neurological outcomes. Previously, we reported altered neuroplastic responses to continuous theta burst stimulation (cTBS) in GDM-exposed adolescents. Recent research suggests that the relative excitability of complex oligosynaptic circuits (late I-wave circuits) can predict these responses. We aimed to determine if altered I-wave recruitment was associated with neuroplastic responses in adolescents born to women with GDM. A total of 20 GDM-exposed adolescents and 10 controls (aged 13.1 ± 1.0 years) participated. cTBS was used to induce neuroplasticity. I-wave recruitment was assessed by comparing motor-evoked potential latencies using different TMS coil directions. Recruitment of late I-waves was associated with stronger LTD-like neuroplastic responses to cTBS (p = < 0.001, R2 = 0.36). There were no differences between groups in mean neuroplasticity (p = 0.37), I-wave recruitment (p = 0.87), or the association between these variables (p = 0.41). The relationship between I-wave recruitment and the response to cTBS previously observed in adults is also present in adolescents and does not appear to be altered significantly by in utero GDM exposure. Exposure to GDM does not appear to significantly impair LTD-like synaptic plasticity or interneuron recruitment.

Age-related decline of neuroplasticity to intermittent theta burst stimulation of the lateral prefrontal cortex and its relationship with late-life memory performance.

OBJECTIVE: Advanced age is accompanied by a deterioration in memory performance that can profoundly influence activities of daily living. However, the neural processes responsible for age-related memory decline are not fully understood. Here, we used transcranial magnetic stimulation (TMS) in combination with electroencephalography (EEG) to assess age-related changes in neuroplasticity in the human prefrontal cortex. METHODS: TMS-evoked cortical potentials (TEPs) were recorded before and following the neuroplasticity-inducing intermittent theta burst stimulation (iTBS), applied to the left lateral prefrontal cortex in healthy young (n = 33, mean age 22 ± 3 years) and older adults (n = 33, mean age 68 ± 7 years). RESULTS: iTBS increased the amplitude of the positive TEP component at 60 ms after the TMS pulse (P60) in young, but not older adults. This age-related decline in P60 plasticity response was associated with poorer visuospatial associative (but not working) memory performance in older adults. CONCLUSIONS: These findings suggest that neuroplasticity in the human lateral prefrontal cortex is reduced in older relative to young adults, and this may be an important factor in age-related memory decline. SIGNIFICANCE: This may have important implications for the early detection of cognitive decline and dementia.

Variability of the cortisol awakening response and morning salivary oxytocin in late adolescence.

Exogenously administered oxytocin interacts with the hypothalamic-pituitary-adrenal (HPA) axis to modulate endogenous cortisol levels, suggesting a synergistic role for these two hormones in the response to stress, cognitive performance and the development of psycho-behavioural disorders. The cortisol awakening response (CAR) is considered a reliable measure of HPA axis function in humans. However, the CAR appears to vary considerably from day to day and may be strongly influenced by the anticipated demands of the day ahead. The level of variation intrinsic to the CAR is unclear because few studies have examined the CAR in the absence of daily environmental variation. It is not known whether oxytocin has a similar or complementary awakening response. Therefore, over three consecutive days, we examined 12 adolescents (aged 15-17 years) in a highly-controlled sleep laboratory. Saliva was collected on days 4-6 of a 9-day laboratory visit. Cortisol and oxytocin levels were determined by an enzyme-linked immunosorbent assay from saliva sampled at 0, 15, 30 and 45 minutes, and 8 and 12 hours post-awakening. CAR magnitude varied between days and was associated with sleep duration and pre-awakening sleep stage. Conversely, oxytocin levels dropped dramatically in the first 15 minutes post-awakening and were highly consistent across participants and days. Older participants had higher awakening oxytocin concentrations. Although cortisol increases and oxytocin rapidly declines upon awakening, their diurnal variation does not appear to be related at basal, peripheral levels, consistent with a previous finding that exogenously administered oxytocin only modulates cortisol under conditions of stress.

Reduced Cortical Excitability, Neuroplasticity, and Salivary Cortisol in 11-13-Year-Old Children Born to Women with Gestational Diabetes Mellitus.

BACKGROUND: Children exposed to gestational diabetes mellitus (GDM) in utero are at increased risk of neurodevelopmental difficulties, including autism and impaired motor control. However, the underlying neurophysiology is unknown. METHODS: Using transcranial magnetic stimulation, we assessed cortical excitability, long-term depression (LTD)-like neuroplasticity in 45 GDM-exposed and 12 control children aged 11-13 years. Data were analysed against salivary cortisol and maternal diabetes severity and treatment (insulin [N = 22] or metformin [N = 23]) during pregnancy. FINDINGS: GDM-exposed children had reduced cortical excitability (p = .003), LTD-like neuroplasticity (p = .005), and salivary cortisol (p < .001) when compared with control children. Higher maternal insulin resistance (IR) before and during GDM treatment was associated with a blunted neuroplastic response in children (p = .014) and this was not accounted for by maternal BMI. Additional maternal and neonatal measures, including fasting plasma glucose and inflammatory markers, predicted neurophysiological outcomes. The metformin and insulin treatment groups had similar outcomes. INTERPRETATION: These results suggest that GDM can contribute to subtle differences in child neurophysiology, and possibly cortisol secretion, persisting into early adolescence. Importantly, these effects appear to occur during second trimester, before pharmacologic treatment typically commences, and can be predicted by maternal insulin resistance. Therefore, earlier detection and treatment of GDM may be warranted. Metformin appears to be safe for these aspects of neurodevelopment.

Polymorphisms that affect GABA neurotransmission predict processing of aversive prediction errors in humans.

Learning is one of our most adaptive abilities, allowing us to adjust our expectations about future events. Aberrant learning processes may underlie disorders such as anxiety, motivating the search for the neural mechanisms that underpin learning. Animal studies have shown that the neurotransmitter GABA is required for the computation of prediction errors, the mismatches between anticipated and experienced outcomes, which drive new learning. Given that evidence from human studies is lacking, we sought to determine whether these findings extend to humans. Here, in two samples of Caucasian individuals, we investigated whether genetically determined individual differences in GABA neurotransmission predict the P3 event-related potential, an EEG component known to reflect prediction error processing. Consistent with the results of animal studies, we show that a weighted genetic risk score computed from the number of GABRB2 rs1816072 A alleles (associated with increased expression of the GABAA receptor ß2 subunit gene) and the number of ErbB4 rs7598440 T alleles (associated with increased GABA concentration) predicts optimal prediction error processing during aversive classical conditioning with both visual (Experiment 1, N = 90; p = .010) and auditory (Experiment 2; N = 92; p = .031) unconditioned stimuli. Our finding that optimal processing of aversive prediction errors is reduced in individuals genetically predisposed towards decreased GABA neurotransmission suggests a potential mechanism linking GABA and anxiety. Specifically, reduced GABA signalling via GABAA receptors could result in aberrant learning from aversive experiences and vulnerability to anxiety disorders.

Effects of induced placental and fetal growth restriction, size at birth and early neonatal growth on behavioural and brain structural lateralization in sheep.

Poor perinatal growth in humans results in asymmetrical grey matter loss in fetuses and infants and increased functional and behavioural asymmetry, but specific contributions of pre- and postnatal growth are unclear. We therefore compared strength and direction of lateralization in obstacle avoidance and maze exit preference tasks in offspring of placentally restricted (PR: 10M, 13F) and control (CON: 23M, 17F) sheep pregnancies at 18 and 40 weeks of age, and examined gross brain structure of the prefrontal cortex at 52 weeks of age (PR: 14M, 18F; CON: 23M, 25F). PR did not affect lateralization direction, but 40-week-old PR females had greater lateralization strength than CON (P = .021). Behavioural lateralization measures were not correlated with perinatal growth. PR did not alter brain morphology. In males, cross-sectional areas of the prefrontal cortex and left hemisphere correlated positively with skull width at birth, and white matter area correlated positively with neonatal growth rate of the skull (all P < .05). These studies reinforce the need to include progeny of both sexes in future studies of neurodevelopmental programming, and suggest that restricting in utero growth has relatively mild effects on gross brain structural or behavioural lateralization in sheep.

Antenatal steroid exposure in the late preterm period is associated with reduced cord blood neurotrophin-3.

BACKGROUND: Neurotrophins are proteins critically involved in neural growth, survival and differentiation, and therefore important for fetal brain development. Reduced cord blood neurotrophins have been observed in very preterm infants (<32weeks gestation) who subsequently develop brain injury. Antenatal steroid exposure can alter neurotrophin concentrations, yet studies to date have not examined whether this occurs in the late preterm infant (33-36weeks gestation), despite increasing recognition of subtle neurodevelopmental deficits in this population. AIM: To assess the impact of antenatal steroids on cord blood neurotrophins in late preterm infants following antenatal steroid exposure. STUDY DESIGN: Retrospective analysis. SUBJECTS: Late preterm infants (33-36weeks; n=119) and term infants (37-41weeks; n=129) born at the Women's and Children's Hospital, Adelaide. OUTCOME MEASURES: Cord blood neurotrophin-3 (NT-3), NT-4, nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) concentrations measured by ELISA. RESULTS: Cord blood NT-4 and NGF were increased at term compared to the late preterm period (p<0.001), while BDNF and NT-3 were not different. In the late preterm period, cord blood NT-3 was reduced when antenatal steroids were administered >24h prior to delivery (p<0.01). CONCLUSION: This study identified an association between reduced cord blood NT-3 and antenatal steroid exposure in the late preterm period. The reduced NT-3 may be a consequence of steroids inducing neuronal apoptosis, thereby reducing endogenous neuronal NT3 production, or be an action of steroids on other maternal or fetal NT-3 producing cells, which may then affect neuronal growth, differentiation and survival. Regardless of the specific mechanism, a reduction in NT-3 may have long term implications for child neurodevelopment, and emphasizes the ongoing vulnerability of the fetal brain across the full preterm period.

Programming the brain: Common outcomes and gaps in knowledge from animal studies of IUGR.

IUGR in humans is associated with impaired pre- and postnatal neurodevelopment, and subsequent postnatal cognition, resulting in lower IQ, poorer memory, visuomotor and executive function skills, as well as behavioural and attentional problems. Experimental models of IUGR are needed to allow direct testing of causality and interventions, and have benefits in reducing both confounding by comorbidities such as prematurity, and variation due to environment and genetics. This review describes and discusses experimental models of IUGR in which neurodevelopmental and cognitive outcomes of IUGR have been reported. We consider the timing of neurodevelopment relative to birth and to the period of restriction, as well as the effects of each experimental perturbation on the fetal environment and development, before discussing neurodevelopmental and cognitive outcomes for progeny as fetuses, neonates and into adolescent and adult life. Experimental IUGR induces broadly similar outcomes to human IUGR, with altered brain morphology, in particular grey matter loss and discordant trajectory of white matter development, and poorer cognition and memory reported in various studies. Nevertheless, there remain gaps in knowledge of neurodevelopment in experimental models. We end the review with recommendations for the design of future studies to further investigate the mechanisms underlying adverse neurodevelopmental consequences of IUGR, and to evaluate interventions that may subsequently improve outcomes of IUGR in humans.

The cortisol awakening response is associated with performance of a serial sequence reaction time task.

There is emerging evidence of a relationship between the cortisol awakening response (CAR) and the neural mechanisms underlying learning and memory. The aim of this study was to determine whether the CAR is associated with acquisition, retention and overnight consolidation or improvement of a serial sequence reaction time task. Salivary samples were collected at 0, 15, 30 and 45 min after awakening in 39 healthy adults on 2 consecutive days. The serial sequence reaction time task was repeated each afternoon. Participants completed the perceived stress scale and provided salivary samples prior to testing for cortisol assessment. While the magnitude of the CAR (Z score) was not associated with either baseline performance or the timed improvement during task acquisition of the serial sequence task, a positive correlation was observed with reaction times during the stable performance phase on day 1 (r=0.373, p=0.019). Residuals derived from the relationship between baseline and stable phase reaction times on day 1 were used as a surrogate for the degree of learning: these residuals were also correlated with the CAR mean increase on day 1 (r=0.357, p=0.048). Task performance on day 2 was not associated with the CAR obtained on this same day. No association was observed between the perceived stress score, cortisol at testing or task performance. These data indicate that a smaller CAR in healthy adults is associated with a greater degree of learning and faster performance of a serial sequence reaction time task. These results support recognition of the CAR as an important factor contributing to cognitive performance throughout the day.

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.

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.

Commonly-occurring polymorphisms in the COMT, DRD1 and DRD2 genes influence different aspects of motor sequence learning in humans.

Performing sequences of movements is a ubiquitous skill that involves dopamine transmission. However, it is unclear which components of the dopamine system contribute to which aspects of motor sequence learning. Here we used a genetic approach to investigate the relationship between different components of the dopamine system and specific aspects of sequence learning in humans. In particular, we investigated variations in genes that code for the catechol-O-methyltransferase (COMT) enzyme, the dopamine transporter (DAT) and dopamine D1 and D2 receptors (DRD1 and DRD2). COMT and the DAT regulate dopamine availability in the prefrontal cortex and the striatum, respectively, two key regions recruited during learning, whereas dopamine D1 and D2 receptors are thought to be involved in long-term potentiation and depression, respectively. We show that polymorphisms in the COMT, DRD1 and DRD2 genes differentially affect behavioral performance on a sequence learning task in 161 Caucasian participants. The DRD1 polymorphism predicted the ability to learn new sequences, the DRD2 polymorphism predicted the ability to perform a previously learnt sequence after performing interfering random movements, whereas the COMT polymorphism predicted the ability to switch flexibly between two sequences. We used computer simulations to explore potential mechanisms underlying these effects, which revealed that the DRD1 and DRD2 effects are possibly related to neuroplasticity. Our prediction-error algorithm estimated faster rates of connection strengthening in genotype groups with presumably higher D1 receptor densities, and faster rates of connection weakening in genotype groups with presumably higher D2 receptor densities. Consistent with current dopamine theories, these simulations suggest that D1-mediated neuroplasticity contributes to learning to select appropriate actions, whereas D2-mediated neuroplasticity is involved in learning to inhibit incorrect action plans. However, the learning algorithm did not account for the COMT effect, suggesting that prefrontal dopamine availability might affect sequence switching via other, non-learning, mechanisms. These findings provide insight into the function of the dopamine system, which is relevant to the development of treatments for disorders such as Parkinson's disease. Our results suggest that treatments targeting dopamine D1 receptors may improve learning of novel sequences, whereas those targeting dopamine D2 receptors may improve the ability to initiate previously learned sequences of movements.

Placental and fetal growth restriction, size at birth and neonatal growth alter cognitive function and behaviour in sheep in an age- and sex-specific manner.

Intrauterine growth restriction and slow neonatal growth in humans are each associated with poorer learning, memory and cognitive flexibility in childhood and adulthood. The relative contributions of pre- and post-natal growth to cognitive outcomes are unclear, however. We therefore compared performance in learning, memory and reversal tasks using a modified Y-maze at 18 and 40 weeks of age in offspring of placentally-restricted (PR: 10 M, 13 F) and control (23 M, 17 F) ovine pregnancies. We also investigated relationships between size at birth, neonatal growth rates and cognitive outcomes. PR had limited effects on cognitive outcomes, with PR males requiring more trials to solve the initial learning task than controls (P=0.037) but faster completion of reversal tasks in both sexes at 18 weeks of age. In males, neonatal growth rate correlated inversely with numbers of trials and total time required to solve memory tasks at 40 weeks of age. In females, bleat frequency in the first reversal task at 18 weeks of age correlated positively with birth weight (r=0.734, P<0.05) and neonatal growth rate (r=0.563, P<0.05). We conclude that PR induces limited effects on cognitive outcomes in sheep, with some evidence of impaired learning in males, but little effect on memory or cognitive flexibility in either sex. Rapid neonatal growth predicted improved memory task performance in males, suggesting that strategies to optimize neonatal growth may have long-term cognitive benefits but that these may be sex-specific.

A comparison of two methods for estimating 50% of the maximal motor evoked potential.

OBJECTIVES: Two commonly-used methods for setting stimulus intensities in transcranial magnetic brain stimulation studies were compared to determine which best approximated a motor evoked potential (MEP) of 50% of the maximal MEP amplitude (SI50); a suprathreshold intensity relative to resting motor threshold (rMT) or adjusting the intensity to evoke an MEP amplitude of 1mV. METHODS: Corticomotor stimulus-response curves and rMT for the right first dorsal interosseous (FDI) muscle of 176 subjects (aged 10-74 years) were retrospectively analysed. RESULTS: Regardless of subject age or sex, SI50 occurred at 127.5 ± 11.3% rMT. Except in young children, MEPs of 1 mV were significantly smaller than those evoked at SI50. CONCLUSIONS: In the inactive FDI muscle, a stimulus intensity of 127-128% rMT consistently gives the best approximation of SI50 in most subjects, except perhaps young children. SIGNIFICANCE: Setting TMS stimulus intensities relative to rMT provides a less variable inter-subject comparator, with respect to individual differences in corticomotor input-output characteristics, than adjusting the stimulator output to give an absolute MEP magnitude.

Do I turn left or right? Effects of sex, age, experience and exit route on maze test performance in sheep.

Brain development and function are susceptible to perturbation by environmental factors. Sheep are increasingly being used as a neurodevelopmental model due to timing similarities with humans, but effects of age, experience and sex on cognition are not well characterised in this species. We therefore studied memory and reversal learning in sheep using a modified Y-maze at two ages: naive 18 weeks old (18N: 23 male, 17 female), experienced 40 week old sheep that had previously been tested at 18 weeks (40E: 22 male, 17 female), and naive 40 weeks old (40N: 4 male, 10 female). Younger naive animals (18N) required more trials and time to solve the first reversal task (task R1) than 40E (P=0.007 and P<0.001 respectively). Experience also improved outcomes, with 40N sheep requiring more time to solve tasks L (P=0.034) and R1 (P=0.002) than 40E. Increasing age (40N cf. 18N) decreased bleat frequency in tasks R1, M2 and R2 (each P<0.05). In 40N females, outcomes also differed by exit method in task R1, with those that exited via an indirect route taking less time to pass tasks R1 (P=0.009) and R2 (P=0.015) than those that used a direct route. Age plus experience improved learning outcomes, demonstrating knowledge retention for 22 weeks in this species, whilst age alone affected mostly behavioral responses. These results provide comparison data, and can be utilised to improve experimental design, for studies of neurodevelopment in the sheep.

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.

Cognitive abilities in preterm and term-born adolescents.

OBJECTIVE: To investigate the influence of a range of prenatal and postnatal factors on cognitive development in preterm and term-born adolescents. STUDY DESIGN: Woodcock-Johnson III Tests of Cognitive Abilities were used to assess general intellectual ability and 6 broad cognitive abilities in 145 young adolescents aged approximately 12.5 years and born 25-41 weeks gestational age (GA). To study potential links between neurophysiologic and cognitive outcomes, corticomotor excitability was measured using transcranial magnetic stimulation and surface electromyography. The influence of various prenatal and postnatal factors on cognitive development was investigated using relative importance regression modeling. RESULTS: Adolescents with greater GA tended to have better cognitive abilities (particularly general intellectual ability, working memory, and cognitive efficiency) and higher corticomotor excitability. Corticomotor excitability explained a higher proportion of the variance in cognitive outcome than GA. But the strongest predictors of cognitive outcome were combinations of prenatal and postnatal factors, particularly degree of social disadvantage at the time of birth, birthweight percentile, and height at assessment. CONCLUSIONS: In otherwise neurologically healthy adolescents, GA accounts for little interindividual variability in cognitive abilities. The association between corticomotor excitability and cognitive performance suggests that reduced connectivity, potentially associated with brain microstructural abnormalities, may contribute to cognitive deficits in preterm children. It remains to be determined if the effects of low GA on cognitive outcomes attenuate over childhood in favor of a concomitant increase in the relative importance of heritability, or alternatively, if cognitive development is more heavily influenced by the quality of the postnatal environment.

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.

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.