Associations of physical fitness with cortical inhibition and excitation in adolescents and young adults.

Objective: We investigated the longitudinal associations of cumulative motor fitness, muscular strength, and cardiorespiratory fitness (CRF) from childhood to adolescence with cortical excitability and inhibition in adolescence. The other objective was to determine cross-sectional associations of motor fitness and muscular strength with brain function in adolescence. Methods: In 45 healthy adolescents (25 girls and 20 boys) aged 16-19 years, we assessed cortical excitability and inhibition by navigated transcranial magnetic stimulation (nTMS), and motor fitness by 50-m shuttle run test and Box and block test, and muscular strength by standing long jump test. These measures of physical fitness and CRF by maximal exercise were assessed also at the ages 7-9, 9-11, and 15-17 years. Cumulative measures of physical measures were computed by summing up sample-specific z-scores at ages 7-9, 9-11, and 15-17 years. Results: Higher cumulative motor fitness performance from childhood to adolescence was associated with lower right hemisphere resting motor threshold (rMT), lower silent period threshold (SPt), and lower motor evoked potential (MEP) amplitude in boys. Better childhood-to-adolescence cumulative CRF was also associated with longer silent period (SP) duration in boys and higher MEP amplitude in girls. Cross-sectionally in adolescence, better motor fitness and better muscular strength were associated with lower left and right rMT among boys and better motor fitness was associated with higher MEP amplitude and better muscular strength with lower SPt among girls. Conclusion: Physical fitness from childhood to adolescence modifies cortical excitability and inhibition in adolescence. Motor fitness and muscular strength were associated with motor cortical excitability and inhibition. The associations were selective for specific TMS indices and findings were sex-dependent.

Association between arterial health and cognition in adolescents: The PANIC study.

We investigated the associations of the measures of arterial health with cognition in adolescents and whether physical activity (PA) or sedentary time (ST) confounds these associations. One hundred sixteen adolescents (71 boys) aged 15.9 ± 0.4 participated in the study. PA and ST were assessed using a combined accelerometer/heart rate monitor. Overall cognition was computed from the results of psychomotor function, attention, working memory, and paired-associate learning tests. Pulse wave velocity was measured by impedance cardiography, carotid intima-media thickness, and carotid artery distensibility by carotid ultrasonography. Systolic and diastolic blood pressure (SBP and DBP) were measured using an aneroid sphygmomanometer. SBP was inversely associated with overall cognition (standardized regression coefficient [ß] = -0.216, 95% confidence interval (CI) -0.406 to -0.027, p = 0.025). Pulse wave velocity (ß = -0.199, 95% CI -0.382 to -0.017, p = 0.033) was inversely associated with working memory task accuracy. SBP was directly associated with reaction time in the attention (ß = 0.256, 95% CI 0.069 to 0.443, p = 0.008) and errors in the paired-associate learning tasks (ß = 0.308, 95% CI 0.126 to 0.489, p = 0.001). Blood pressure was inversely associated with overall cognition. PA or ST did not confound the associations. Results suggest that preventing high blood pressure is important for promoting cognition in adolescents.

Navigated and individual α-peak-frequency-guided transcranial magnetic stimulation in male patients with treatment-refractory schizophrenia.

BACKGROUND: Previous electroencephalography (EEG) studies have indicated altered brain oscillatory α-band activity in schizophrenia, and treatment with repetitive transcranial magnetic stimulation (rTMS) using individualized α-frequency has shown therapeutic effects. Magnetic resonance imaging-based neuronavigation methods allow stimulation of a specific cortical region and improve targeting of rTMS; therefore, we sought to study the efficacy of navigated, individual α-peak-frequency-guided rTMS (αTMS) on treatment-refractory schizophrenia. METHODS: We recruited medication-refractory male patients with schizophrenia or schizoaffective disorder in this doubleblind, sham-controlled study. We randomized patients to a 3-week course of either active αTMS or sham stimulation applied to the left dorsolateral prefrontal cortex (DLPFC). We assessed participants with the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression Scale (CGI) at baseline and after treatment. We conducted a follow-up assessment with the PANSS 3 months after intervention. RESULTS: We included 44 patients. After treatment, we observed a significantly higher PANSS total score (p = 0.029), PANSS general psychopathology score (p = 0.027) and PANSS 5-factor model cognitive-disorganized factor score (p = 0.011) in the αTMS group than the sham group. In addition, the CGI-Improvement score was significantly higher among those who received αTMS compared with sham stimulation (p = 0.048). LIMITATIONS: The limited number of study participants included only male patients. Depression was not formally evaluated. CONCLUSION: Navigated αTMS to the left DLPFC reduced total, general psychopathological, and cognitive-disorganized symptoms of schizophrenia. These results provide evidence for the therapeutic efficacy of individual α-peak-frequency-guided rTMS in treatment-refractory schizophrenia. CLINICAL TRIAL REGISTRATION: NCT01941251; ClinicalTrials.gov.

Associations between physical fitness and cerebellar gray matter volume in adolescents.

Despite the importance of the developing cerebellum on cognition, the associations between physical fitness and cerebellar volume in adolescents remain unclear. We explored the associations of physical fitness with gray matter (GM) volume of VI, VIIb and Crus I & II, which are cerebellar lobules related to cognition, in 40 (22 females; 17.9 ± 0.8 year-old) adolescents, and whether the associations were sex-specific. Peak oxygen uptake (V̇O2peak ) and power were assessed by maximal ramp test on a cycle ergometer, muscular strength with standing long jump (SLJ), speed-agility with the shuttle-run test (SRT), coordination with the Box and Block Test (BBT) and neuromuscular performance index (NPI) as the sum of SLJ, BBT and SRT z-scores. Body composition was measured using a dual-energy X-ray absorptiometry. Cerebellar volumes were assessed by magnetic resonance imaging. V̇O2peak relative to lean mass was inversely associated with the GM volume of the cerebellum (standardized regression coefficient (ß) = -0.038, 95% confidence interval (CI) -0.075 to 0.001, p = 0.044). Cumulative NPI was positively associated with the GM volume of Crus I (ß = 0.362, 95% CI 0.045 to 0.679, p = 0.027). In females, better performance in SRT was associated with a larger GM volume of Crus I (ß = -0.373, 95% CI -0.760 to -0.028, p = 0.036). In males, cumulative NPI was inversely associated with the GM volume of Crus II (ß = -0.793, 95% CI -1.579 to -0.008 p = 0.048). Other associations were nonsignificant. In conclusion, cardiorespiratory fitness, neuromuscular performance and speed-agility were associated with cerebellar GM volume, and the strength and direction of associations were sex-specific.

Cortical thickness is inversely associated with transcranial magnetic stimulation-evoked N45 potential among young adults whose heavy drinking began in adolescence.

BACKGROUND: Adolescence is a particularly vulnerable stage of development in terms of the deleterious effects of alcohol. Both lower gray matter (GM) volume and greater GABAergic activity have been associated with chronic alcohol consumption during adolescence. However, the association between these measures has not been investigated. METHODS: In this exploratory study, we compared 26 young adults with a 10year history of heavy alcohol consumption with 21 controls who used little or no alcohol. Simultaneous transcranial magnetic stimulation and electroencephalography were used to assess transcranial magnetic stimulation-evoked N45 potentials, reflecting a balance between GABAergic inhibition and N-methyl-D-aspartate (NMDA) receptor-mediated glutaminergic excitation in the brain. GM thickness was measured from magnetic resonance images and GM and N45 potentials were then correlated. RESULTS: Cortical thickness was significantly lower in several brain regions in the heavy-drinking group than the light-drinking group. The N45 amplitude was significantly larger frontally in the heavy-drinking group. Among heavy drinkers, there were several statistically significant correlations between thinner GM and larger frontal N45 amplitudes that were not detectable in the light-drinking group. The strongest correlations were detected in the frontal and parietal lobes, especially in the left superior frontal gyrus and the left supramarginal gyrus, and in both hemispheres in the superior parietal lobes. CONCLUSIONS: These findings show that a thinner cortex and greater inhibitory neurotransmission are correlated in certain brain regions among young, long-term heavy alcohol users. Studies are needed to explore the possible causal mechanisms underlying these effects.

Developmental models of motor-evoked potential features by transcranial magnetic stimulation across age groups from childhood to adulthood.

To derive the maturation of neurophysiological processes from childhood to adulthood reflected by the change of motor-evoked potential (MEP) features. 38 participants were recruited from four groups (age mean in years [SD in months], number (males)): children (7.3 [4.2], 7(4)), preadolescents (10.3 [6.9], 10(5)), adolescents (15.3 [9.8], 11(5)), and adults (26.9 [46.2], 10(5)). The navigated transcranial magnetic stimulation was performed on both hemispheres at seven stimulation intensity (SI) levels from sub- to supra-threshold and targeted to the representative cortical area of abductor pollicis brevis muscle. MEPs were measured from three hand- and two forearm-muscles. The input-output (I/O) curves of MEP features across age groups were constructed using linear mixed-effect models. Age and SI significantly affected MEP features, whereas the stimulated side had a minor impact. MEP size and duration increased from childhood to adulthood. MEP onset- and peak-latency dropped in adolescence, particularly in hand muscles. Children had the smallest MEPs with the highest polyphasia, whereas I/O curves were similar among preadolescents, adolescents, and adults. This study illustrates some of the changing patterns of MEP features across the ages, suggesting developing patterns of neurophysiological processes activated by TMS, and to motivate studies with larger sample size.

Combining Transcranial Magnetic Stimulation and Deep Brain Stimulation: Current Knowledge, Relevance and Future Perspectives.

Deep brain stimulation (DBS) has emerged as an invasive neuromodulation technique for the treatment of several neurological disorders, but the mechanisms underlying its effects remain partially elusive. In this context, the application of Transcranial Magnetic Stimulation (TMS) in patients treated with DBS represents an intriguing approach to investigate the neurophysiology of cortico-basal networks. Experimental studies combining TMS and DBS that have been performed so far have mainly aimed to evaluate the effects of DBS on the cerebral cortex and thus to provide insights into DBS's mechanisms of action. The modulation of cortical excitability and plasticity by DBS is emerging as a potential contributor to its therapeutic effects. Moreover, pairing DBS and TMS stimuli could represent a method to induce cortical synaptic plasticity, the therapeutic potential of which is still unexplored. Furthermore, the advent of new DBS technologies and novel treatment targets will present new research opportunities and prospects to investigate brain networks. However, the application of the combined TMS-DBS approach is currently limited by safety concerns. In this review, we sought to present an overview of studies performed by combining TMS and DBS in neurological disorders, as well as available evidence and recommendations on the safety of their combination. Additionally, we outline perspectives for future research by highlighting knowledge gaps and possible novel applications of this approach.

Near-threshold recruitment characteristics of motor evoked potentials in transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) can induce motor evoked potentials (MEPs). In TMS applications, near-threshold stimulation intensities (SIs) are often used for characterizing corticospinal excitability using MEPs. We aimed to characterize the individual near-threshold recruitment of MEPs and to test the assumptions related to selection of the suprathreshold SI. We utilized MEP data from a right-hand muscle induced at variable SIs. The single-pulse TMS (spTMS) data from previous studies (27 healthy volunteers), as well as data from new measurements (10 healthy volunteers) that included also MEPs modulated by paired-pulse TMS (ppTMS), were included. The probability of MEP (pMEP) was represented with individually fitted cumulative distribution function (CDF) with two parameters: resting motor threshold (rMT) and spread relative to rMT. MEPs were recorded with 110% and 120% of rMT as well as with Mills-Nithi upper threshold (UT). The individual near-threshold characteristics varied with CDF parameters: the rMT and the relative spread (median: 0.052). The rMT was lower with ppTMS than with spTMS (p < 0.001), while the relative spread remained similar (p = 0.812). At suprathreshold SIs, the probability of MEP was similar between UT and 110% of rMT (pMEP > 0.88), and higher for 120% of rMT (pMEP > 0.98). The individual near-threshold characteristics determine how probably MEPs are produced at common suprathreshold SIs. At the population level, the used SIs UT and 110% of rMT produced MEPs at similar probability. The individual variability in the relative spread parameter was large; therefore, the method of determining the proper suprathreshold SI for TMS applications is of crucial importance.

Action Selection and Motor Decision Making: Insights from Transcranial Magnetic Stimulation.

In everyday life, goal-oriented motor behaviour relies on the estimation of the rewards/costs associated with alternative actions and on the appropriate selection of movements. Motor decision making is defined as the process by which a motor plan is chosen among a set of competing actions based on the expected value. In the present literature review we discuss evidence from transcranial magnetic stimulation (TMS) studies of motor control. We focus primarily on studies of action selection for instructed movements and motor decision making. In the first section, we delve into the usefulness of various TMS paradigms to characterise the contribution of motor areas and distributed brain networks to cued action selection. Then, we address the influence of motivational information (e.g., reward and biomechanical cost) in guiding action choices based on TMS findings. Finally, we conclude that TMS represents a powerful tool for elucidating the neurophysiological mechanisms underlying action choices in humans.

TMS-EEG responses across the lifespan: Measurement, methods for characterisation and identified responses.

The combination of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) allows probing of the neurophysiology of any neocortical brain area in vivo with millisecond accuracy. TMS-EEG is particularly unique compared with other available neurophysiological methods, as it can measure the state and dynamics of excitatory and inhibitory systems separately. Because of these capabilities, TMS-EEG responses are sensitive to the brain state, and the responses are influenced by brain maturation and ageing, making TMS-EEG a suitable method to study age-specific pathophysiology. In this review, we outline the TMS-EEG measurement procedure, the existing methods used for characterising TMS-EEG responses and the challenges associated with identifying the responses. We also summarise the findings thus far on how TMS-EEG responses change across the lifespan and the TMS-EEG features that separate typical and atypical brain maturation and ageing. Finally, we give an overview of the gaps in current knowledge to provide directions for future studies.

TMS-EEG Biomarkers of Amnestic Mild Cognitive Impairment Due to Alzheimer's Disease: A Proof-of-Concept Six Years Prospective Study.

Background: Early and affordable identification of subjects with amnestic mild cognitive impairment (aMCI) who will convert to Alzheimer's disease (AD) is a major scientific challenge. Objective: To investigate the neurophysiological hallmarks of sensorimotor cortex function in aMCI under the hypothesis that some may represent the plastic rearrangements induced by neurodegeneration, hence predictors of future conversion to AD. We sought to determine (1) whether the sensorimotor network shows peculiar alterations in patients with aMCI and (2) if sensorimotor network alterations predict long-term disease progression at the individual level. Methods: We studied several transcranial magnetic stimulation (TMS)-electroencephalogram (EEG) parameters of the sensorimotor cortex in a group of patients with aMCI and followed them for 6 years. We then identified aMCI who clinically converted to AD [prodromal to AD-MCI (pAD-MCI)] and those who remained cognitively stable [non-prodromal to AD-MCI (npAD-MCI)]. Results: Patients with aMCI showed reduced motor cortex (M1) excitability and disrupted EEG synchronization [decreased intertrial coherence (ITC)] in alpha, beta and gamma frequency bands compared to the control subjects. The degree of alteration in M1 excitability and alpha ITC was comparable between pAD-MCI and npAD-MCI. Importantly, beta and gamma ITC impairment in the stimulated M1 was greater in pAD-MCI than npAD-MCI. Furthermore, an additional parameter related to the waveform shape of scalp signals, reflecting time-specific alterations in global TMS-induced activity [stability of the dipolar activity (sDA)], discriminated npAD-MCI from MCI who will convert to AD. Discussion: The above mentioned specific cortical changes, reflecting deficit of synchronization within the cortico-basal ganglia-thalamo-cortical loop in aMCI, may reflect the pathological processes underlying AD. These changes could be tested in larger cohorts as neurophysiological biomarkers of AD.

Atlas-informed computational processing pipeline for individual targeting of brain areas for therapeutic navigated transcranial magnetic stimulation.

OBJECTIVE: Navigated transcranial magnetic stimulation (nTMS) is targeted at different cortical sites for diagnostic, therapeutic, and neuroscientific purposes. Correct identification of the cortical target areas is important for achieving desired effects, but it is challenging when no direct responses arise upon target area stimulation. We aimed at utilizing atlas-based marking of cortical areas for nTMS targeting to present a convenient, rater-independent method for overlaying the individual target sites with brain anatomy. METHODS: We developed a pipeline, which fits a brain atlas to the individual brain and enables visualization of the target areas during the nTMS session. We applied the pipeline to our previous nTMS data, focusing on depression and schizophrenia patients. Furthermore, we included examples of Tourette syndrome and tinnitus therapies, as well as neurosurgical and motor mappings. RESULTS: In depression and schizophrenia patients, the visually selected dorsolateral prefrontal cortex (DLPFC) targets were close to the border between atlas areas A9/46 and A8. In the other areas, the atlas-based areas were in agreement with the treatment targets. CONCLUSIONS: The atlas-based target areas agreed well with the cortical targets selected by experts during the treatments. SIGNIFICANCE: Overlaying atlas information over the navigation view is a convenient and useful add-on for improving nTMS targeting.

Primary hand motor representation areas in healthy children, preadolescents, adolescents, and adults.

The development of the organization of the motor representation areas in children and adolescents is not well-known. This cross-sectional study aimed to provide an understanding for the development of the functional motor areas of the upper extremity muscles by studying healthy right-handed children (6-9 years, n = 10), preadolescents (10-12 years, n = 13), adolescents (15-17 years, n = 12), and adults (22-34 years, n = 12). The optimal representation site and resting motor threshold (rMT) for the abductor pollicis brevis (APB) were assessed in both hemispheres using navigated transcranial magnetic stimulation (nTMS). Motor mapping was performed at 110% of the rMT while recording the EMG of six upper limb muscles in the hand and forearm. The association between the motor map and manual dexterity (box and block test, BBT) was examined. The mapping was well-tolerated and feasible in all but the youngest participant whose rMT exceeded the maximum stimulator output. The centers-of-gravity (CoG) for individual muscles were scattered to the greatest extent in the group of preadolescents and centered and became more focused with age. In preadolescents, the CoGs in the left hemisphere were located more laterally, and they shifted medially with age. The proportion of hand compared to arm representation increased with age (p = 0.001); in the right hemisphere, this was associated with greater fine motor ability. Similarly, there was less overlap between hand and forearm muscles representations in children compared to adults (p<0.001). There was a posterior-anterior shift in the APB hotspot coordinate with age, and the APB coordinate in the left hemisphere exhibited a lateral to medial shift with age from adolescence to adulthood (p = 0.006). Our results contribute to the elucidation of the developmental course in the organization of the motor cortex and its associations with fine motor skills. It was shown that nTMS motor mapping in relaxed muscles is feasible in developmental studies in children older than seven years of age.

Functional and structural asymmetry in primary motor cortex in Asperger syndrome: a navigated TMS and imaging study.

Motor functions are frequently impaired in Asperger syndrome (AS). In this study, we examined the motor cortex structure and function using navigated transcranial magnetic stimulation (nTMS) and voxel-based morphometry (VBM) and correlated the results with the box and block test (BBT) of manual dexterity and physical activity in eight boys with AS, aged 8-11 years, and their matched controls. With nTMS, we found less focused cortical representation areas of distinct hand muscles in AS. There was hemispheric asymmetry in the motor maps, silent period duration and active MEP latency in the AS group, but not in controls. Exploratory VBM analysis revealed less gray matter in the left postcentral gyrus, especially in the face area, and less white matter in the precentral area in AS as compared to controls. On the contrary, in the right leg area, subjects with AS displayed an increased density of gray matter. The structural findings of the left hemisphere correlated negatively with BBT score in controls, whereas the structure of the right hemisphere in the AS group correlated positively with motor function as assessed by BBT. These preliminary functional (neurophysiological and behavioral) findings are indicative of asymmetry, and co-existing structural alterations may reflect the motor impairments causing the deteriorations in manual dexterity and other motor functions commonly encountered in children with AS.

Repeated Transcranial Magnetic Stimulation-Induced Motor Evoked Potentials Correlate With the Subject-Specific Serum Metabolic Profile of Creatine.

PURPOSE: Transcranial magnetic stimulation-induced motor responses have been considered to mainly reflect the electrophysiological characteristics of the central motor system. However, certain motor phenomena, such as the magnitude of repetition suppression measured with motor evoked potentials (MEPs), could also in part be influenced by metabolic processes in the peripheral muscles and in both the peripheral and central nervous system. Repetition suppression is an inhibitory phenomenon in which the amplitude of MEP decreases in comparison to that of the first MEP in a train of transcranial magnetic stimulation pulses. This study aimed to identify possible metabolic processes influencing repetition suppression. METHODS: The metabolic profiles from serum samples and repetition suppression from the right abductor pollicis brevis muscle were measured in 73 subjects (37 female subjects). Repetition suppression was measured using trains of transcranial magnetic stimulation stimuli consisting of 4 identical single pulses at 1-second intervals. The trains were repeated every 20 seconds, and 30 trains were given with a stimulation intensity of 120% of the resting motor threshold of the abductor pollicis brevis. Thus, a total of 120 stimuli were administered. RESULTS: The main finding was a significant negative relationship between serum creatine levels and the magnitude of repetition suppression (standardized ß coefficient (ß) = -0.43; P < 0.001). In other words, higher creatine levels corresponded to a smaller decrement in the MEP amplitude in response to repetition. When MEPs were not repeated, no relationship was observed (ß = 0.09; P = 0.454). Creatine is used to form phosphocreatine, which in turn is needed to resynthesize adenosine triphosphate from adenosine diphosphate in situations requiring high amounts of energy in muscles and neural cells. CONCLUSIONS: For the first time, this study demonstrated a connection between repeated MEPs and peripheral serum metabolites linked to muscle function. These findings could explain some of the intersubject variability commonly observed in MEPs when the pulses are repeated.

Maturation changes the excitability and effective connectivity of the frontal lobe: A developmental TMS-EEG study.

The combination of transcranial magnetic stimulation with simultaneous electroencephalography (TMS-EEG) offers direct neurophysiological insight into excitability and connectivity within neural circuits. However, there have been few developmental TMS-EEG studies to date, and they all have focused on primary motor cortex stimulation. In the present study, we used navigated high-density TMS-EEG to investigate the maturation of the superior frontal cortex (dorsal premotor cortex [PMd]), which is involved in a broad range of motor and cognitive functions known to develop with age. We demonstrated that reactivity to frontal cortex TMS decreases with development. We also showed that although frontal cortex TMS elicits an equally complex TEP waveform in all age groups, the statistically significant between-group differences in the topography of the TMS-evoked peaks and differences in current density maps suggest changes in effective connectivity of the right PMd with maturation. More generally, our results indicate that direct study of the brain's excitability and effective connectivity via TMS-EEG co-registration can also be applied to pediatric populations outside the primary motor cortex, and may provide useful information for developmental studies and studies on developmental neuropsychiatric disorders.

Association of the N100 TMS-evoked potential with attentional processes: A motor cortex TMS-EEG study.

The most thoroughly studied transcranial magnetic stimulation (TMS)-evoked electroencephalogram (EEG) potential (TEP), N100, is often defined as a measure of cortical inhibition. We explored the association of the N100 amplitude with attention in 51 young healthy adults. Navigated TMS with simultaneous EEG registering was applied over the left primary motor cortex at the intensity of 110% of the resting motor threshold. Attention was assessed with the Paced Auditory Serial Addition Test (PASAT). We found a negative Pearson correlation (p = .023, r = -0.317) between the left centroparietal N100 amplitude and the PASAT score. Of the participants, the 17 with the highest PASAT scores and 17 with the lowes scores were selected for further analysis, in which a significant between-group difference in the left centroparietal N100 was found (p = .017). The topographic specificity of this finding was further confirmed with linear mixed model (LMM) analysis, in which significant differences were detected in the N100 amplitude; most prominently in the left centroparietal region (p = .001). A smaller N100 amplitude was associated with better performance in the attention task. Our findings suggest that the GABA-B-ergic TEP N100 is associated with attentional processes and thus represents cortical inhibition beyond motor inhibition.

Development of corticospinal motor excitability and cortical silent period from mid-childhood to adulthood - a navigated TMS study.

OBJECTIVES: We characterized the maturation of the excitability of the motor cortex and corticospinal tract from childhood to adulthood using electric field (EF) navigated TMS and correlated the results with manual dexterity. METHODS: Both hemispheres of healthy right-handed children (6-9 years, n=10), preadolescents (10-12 years, n=13), adolescents (14-17 years, n=12) and young adults (22-34 years, n=12) of both genders were examined. The optimal cortical representation site and resting motor threshold (rMT) were determined for the abductor pollicis brevis muscle. Motor-evoked potential (MEP) latencies and amplitudes in relaxed and active states, input-output curves and silent period (SP) durations were determined. Manual dexterity was assessed with the Box and Block Test. RESULTS: rMT (in terms of maximal stimulator output or EF strength) decreased with age (P<0.001) and stabilized when reaching adolescence. The MEP amplitude (P=0.037) and latency increased (P<0.001) with age. Input-output curves showed age-dependent changes in several parameters. SP duration decreased with age (P<0.001), and demonstrated hemispheric asymmetry in the children (P=0.030). Manual dexterity correlated negatively with rMT (P<0.001). DISCUSSION: The excitation/inhibition balance develops with age and correlates with manual dexterity. Strong corticospinal inhibition was observed in the children and this was found to decrease with age. Interhemispheric asymmetry was only observed for SP duration in the children. Knowledge of normal development is crucial for the understanding of developmental disabilities and using estimates of effective EF may be advantageous in future pediatric studies.