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.

Transcranial Photobiomodulation (tPBM) With 1,064-nm Laser to Improve Cerebral Metabolism of the Human Brain In Vivo.

BACKGROUND AND OBJECTIVES: In our previous proof-of-principle study, transcranial photobiomodulation (tPBM) with 1,064-nm laser was reported to significantly increase concentration changes of oxygenated hemoglobin (∆[HbO]) and oxidized-state cytochrome c oxidase (∆[oxi-CCO]) in the human brain. This paper further investigated (i) its validity in two different subsets of young human subjects at two study sites over a period of 3 years and (ii) age-related effects of tPBM by comparing sham-controlled increases of ∆[HbO] and ∆[oxi-CCO] between young and older adults. STUDY DESIGN/MATERIALS AND METHODS: We measured sham-controlled ∆[HbO] and ∆[oxi-CCO] using broadband near-infrared spectroscopy (bb-NIRS) in 15 young (26.7 ± 2.7 years of age) and 5 older (68.2 ± 4.8 years of age) healthy normal subjects before, during, and after right-forehead tPBM/sham stimulation with 1,064-nm laser. Student t tests were used to test statistical differences in tPBM-induced ∆[HbO] and ∆[oxi-CCO] (i) between the 15 young subjects and those of 11 reported previously and (ii) between the two age groups measured in this study. RESULTS: Statistical analysis showed that no significant difference existed in ∆[HbO] and ∆[oxi-CCO] during and post tPBM between the two subsets of young subjects at two study sites over a period of 3 years. Furthermore, the two age groups showed statistically identical net increases in sham-controlled ∆[HbO] and ∆[oxi-CCO]. CONCLUSIONS: This study provided strong evidence to validate/confirm our previous findings that tPBM with 1,064-nm laser enables to increase cerebral ∆[HbO] and ∆[oxi-CCO] in the human brain, as measured by bb-NIRS. Overall, it demonstrated the robust reproducibility of tPBM being able to improve cerebral hemodynamics and metabolism of the human brain in vivo in both young and older adults. Lasers Surg. Med. © 2020 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals, Inc.

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.

Cortical Inhibition of Face and Jaw Muscle Activity and Discomfort Induced by Repetitive and Paired-Pulse TMS During an Overt Object Naming Task.

Modulatory effects of transcranial magnetic stimulation (TMS) strongly depend on the stimulation parameters. Here, we compared the immediate, task-locked inhibitory effects on speech-related muscles and the tolerability of different TMS protocols during a language production task. Repetitive TMS (rTMS) and paired-pulse TMS (PP) were applied in 13 healthy subjects over the primary motor cortex (M1) during a finger-tapping/tongue-twisting tasks. The lowest subject-specific TMS intensity leading to movement disruptions was used for TMS over left-sided speech-related areas during picture naming. Here, time-locked PP and rTMS (10/30/50 Hz; randomized sequence) were applied. Cortical silent periods (cSPs) were analyzed from electromyography obtained from various face muscles. 30 Hz- and 50 Hz-rTMS reliably evoked tongue movement disruption (ICC = 0.65) at lower rTMS intensities compared to 10 Hz-rTMS or PP. CSPs were elicited from the left hemisphere by all TMS protocols, most reliably by PP (p < 0.001). Also, cSPs with longest durations were induced by PP. Exploratory analyses of PP suggest that the trials with strongest motor inhibitory effects (presence of cSP) were associated with more articulatory naming errors, hence hinting at the utility of TMS-elicited, facial cSP for mapping of language production areas. Higher-frequency rTMS and PP evoked stronger inhibitory effects as compared to 10 Hz-rTMS during a language task, thus enabling a probably more efficient and tolerable routine for language mapping. The spatial distribution of cranial muscle cSPs implies that TMS might affect not only M1, but also distant parts of the language network.

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.

Modulation of motor cortical excitability with auditory stimulation.

Loud sounds have been demonstrated to increase motor cortex excitability when transcranial magnetic stimulation (TMS) is synchronized with auditory evoked N100 potential measured from electroencephalography (EEG). The N100 potential is generated by an afferent response to sound onset and feature analysis, and upon novel sound it is also related to the arousal reaction. The arousal reaction is known to originate from the ascending reticular activating system of the brain stem and to modulate neuronal activity throughout the central nervous system. In this study we investigated the difference in motor evoked potentials (MEPs) when deviant and novelty stimuli were randomly interspersed in a train of standard tones. Twelve healthy subjects participated in this study. Three types of sound stimuli were used: 1) standard stimuli (800 Hz), 2) deviant stimuli (560 Hz), and 3) novelty stimuli (12 different sounds). In each stimulus sequence 600 stimuli were given. Of these, 90 were deviant stimuli randomly placed between the standard stimuli. Each of 12 novel sounds was presented once in pseudorandomized order. TMS was randomly mixed with the sound stimuli so that it was either synchronized with the individual N100 or trailed the sound onset by 200 ms. All sounds elicited an increase in motor cortex excitability. The type of sound had no significant effect. We also demonstrated that TMS timed at 200-ms intervals caused a significant increment of MEPs. This contradicted our hypothesis that MEP amplitudes to TMS synchronized with N100 would be greater than those to TMS at 200 ms after a sound and remains unexplained. NEW & NOTEWORTHY We demonstrated modulation of motor cortical excitability with parallel auditory stimulus by combining navigated transcranial magnetic stimulation (TMS) with auditory stimuli. TMS was synchronized with auditory evoked potentials considered to be generated by the unconscious attention call process in the auditory system.

Abnormal motor cortical adaptation to external stimulus in Unverricht-Lundborg disease (progressive myoclonus type 1, EPM1).

Unverricht-Lundborg disease (EPM1) is associated with progressive functional and anatomic changes in the thalamus and motor cortex. The neurophysiological mechanisms behind the impaired thalamocortical system were studied through short-term adaptation of the motor cortex to transcranial magnetic stimulation (TMS) via repetition suppression (RS) phenomenon. RS is considered to be related to neural processing of external stimuli. We hypothesized that this neural processing is progressively impaired in EPM1 from adolescence to adulthood. Eight adult patients with EPM1 (age: 40 ± 13 yr), six adolescent patients with EPM1 (age: 16 ± 1 yr), and ten adult controls (age: 35 ± 12 yr) were studied using navigated TMS and RS study protocol including trains of four repeated stimuli with intertrain interval of 20 s and interstimulus interval of 1 s. Changes in RS were investigated from adolescence to adulthood in EPM1 by comparing with adult controls. In controls, the RS was seen as 50-55% reduction in motor response amplitudes to TMS after the first stimulus. RS was mild or missing in EPM1. RS from first to second stimulus within the stimulus trains was significantly stronger in adolescent patients than in adult patients ( P = 0.046). Abnormal RS correlated with the myoclonus severity of the patients. In agreement with our hypothesis, neural processing of external stimuli is progressively impaired in EPM1 possibly due to anatomically impaired thalamocortical system or inhibitory tonus preventing sufficient adaptive reactiveness to stimuli. Our results suggest that RS abnormality might be used as a biomarker in the therapeutic trials for myoclonus. NEW & NOTEWORTHY Unverricht-Lundborg disease (EPM1) is associated with impaired thalamocortical function, which we studied in 8 adult and 6 adolescent patients and in 10 adult controls through repetition suppression (RS) of the motor cortex. We hypothesized that neural processing is progressively impaired in EPM1 from adolescence to adulthood. RS was normal in controls, whereas it was mild or missing in EPM1. Stronger RS was seen in adolescent patients than in adult patients correlating with the myoclonus severity.

Correction to: Extent and Location of the Excitatory and Inhibitory Cortical Hand Representation Maps: A Navigated Transcranial Magnetic Stimulation Study.

The original version of this article unfortunately contained an error. An error in the transformation between coordinate systems used to derive part of the results has been noticed.

Efficient Mapping of the Motor Cortex with Navigated Biphasic Paired-Pulse Transcranial Magnetic Stimulation.

Navigated transcranial magnetic stimulation (nTMS) can be applied to locate cortical muscle representations. Usually, single TMS pulses are targeted to the motor cortex with the help of neuronavigation and by measuring motor evoked potential (MEP) amplitudes from the peripheral muscles. The efficacy of single-pulse TMS to induce MEPs has been shown to increase by applying facilitatory paired-pulse TMS (ppTMS). Therefore, the aim was to study whether the facilitatory ppTMS could enable more efficient motor mapping. Biphasic single-pulse TMS and ppTMS with inter-stimulus intervals (ISIs) of 1.4 and 2.8 ms were applied to measure resting motor thresholds (rMTs) as a percentage of the maximal stimulator output and to determine the cortical representation areas of the right first dorsal interosseous muscle in healthy volunteers. The areas, shapes, hotspots, and center of gravities (CoGs) of the representations were calculated. Biphasic ppTMS with ISI of 1.4 ms resulted in lower rMTs than those obtained with the other protocols (p = 0.001). With ISI of 2.8 ms, rMT was lower than with single-pulse TMS (p = 0.032). The ppTMS mapping was thus performed with lower intensity than when using single-pulse TMS. The areas, shapes, hotspots, and CoGs of the muscle representations were in agreement. Hence, biphasic ppTMS has potential in the mapping of cortical hand representations in healthy individuals as an alternative for single-pulses, but with lower stimulation intensity by utilizing cortical facilitatory mechanism. This could improve application of nTMS in subjects with low motor tract excitability.

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.

Heavy alcohol use in adolescence is associated with altered cortical activity: a combined TMS-EEG study.

Long-term alcohol use affects cognitive and neurophysiological functioning as well as structural brain development. Combining simultaneous electroencephalogram (EEG) recording with transcranial magnetic stimulation (TMS) enables direct, in vivo exploration of cortical excitability and assessment of effective and functional connectivity. In the central nervous system, the effects of alcohol are particularly mediated by alterations in gamma-aminobutyric acid (GABA)ergic neurotransmission, and TMS-evoked potentials (TEPs) N45 and N100 in EEG are known to reflect GABAergic function. However, no previous studies have examined the effects of long-term alcohol use in adolescence on TEPs. In this study, a total of 27 young adults with heavy alcohol use in adolescence and 25 age-matched, gender-matched and education-matched controls with little or no alcohol use participated in TMS-EEG measurements. The motor cortex (M1) was stimulated with an intensity of 90 percent of the resting motor threshold of the abductor pollicis brevis muscle. No significant differences were found in the resting motor threshold, TEP latencies or neuropsychological functioning between the groups. We observed an increase in the global mean field power in the time window of 54- to 75-millisecond post-TMS, as well as significant topographical differences in the P60 and N100 in those with a history of heavy drinking. Furthermore, there was a marked increase in the GABAergic N45 amplitude in alcohol users. These findings suggest that long-term alcohol use in adolescence, even when not meeting the diagnostic criteria for a disorder, is associated with changes in connectivity and cortical excitability.

Development of cortical motor circuits between childhood and adulthood: A navigated TMS-HdEEG study.

Motor functions improve during childhood and adolescence, but little is still known about the development of cortical motor circuits during early life. To elucidate the neurophysiological hallmarks of motor cortex development, we investigated the differences in motor cortical excitability and connectivity between healthy children, adolescents, and adults by means of navigated suprathreshold motor cortex transcranial magnetic stimulation (TMS) combined with high-density electroencephalography (EEG). We demonstrated that with development, the excitability of the motor system increases, the TMS-evoked EEG waveform increases in complexity, the magnitude of induced activation decreases, and signal spreading increases. Furthermore, the phase of the oscillatory response to TMS becomes less consistent with age. These changes parallel an improvement in manual dexterity and may reflect developmental changes in functional connectivity. Hum Brain Mapp 38:2599-2615, 2017. © 2017 Wiley Periodicals, Inc.

Minimum-Norm Estimation of Motor Representations in Navigated TMS Mappings.

Navigated transcranial magnetic stimulation (nTMS) can be applied to locate and outline cortical motor representations. This may be important, e.g., when planning neurosurgery or focused nTMS therapy, or when assessing plastic changes during neurorehabilitation. Conventionally, a cortical location is considered to belong to the motor cortex if the maximum electric field (E-field) targeted there evokes a motor-evoked potential in a muscle. However, the cortex is affected by a broad E-field distribution, which tends to broaden estimates of representation areas by stimulating also the neighboring areas in addition to the maximum E-field location. Our aim was to improve the estimation of nTMS-based motor maps by taking into account the E-field distribution of the stimulation pulse. The effect of the E-field distribution was considered by calculating the minimum-norm estimate (MNE) of the motor representation area. We tested the method on simulated data and then applied it to recordings from six healthy volunteers and one stroke patient. We compared the motor representation areas obtained with the MNE method and a previously introduced interpolation method. The MNE hotspots and centers of gravity were close to those obtained with the interpolation method. The areas of the maps, however, depend on the thresholds used for outlining the areas. The MNE method may improve the definition of cortical motor areas, but its accuracy should be validated by comparing the results with maps obtained with direct cortical stimulation of the cortex where the E-field distribution can be better focused.

Alternative Stimulation Intensities for Mapping Cortical Motor Area with Navigated TMS.

Navigated transcranial magnetic stimulation (nTMS) is becoming a popular tool in pre-operative mapping of functional motor areas. The stimulation intensities used in the mapping are commonly suprathreshold intensities with respect to the patient's resting motor threshold (rMT). There is no consensus on which suprathreshold intensity should be used nor on the optimal criteria for selecting the appropriate stimulation intensity (SI). In this study, the left motor cortices of 12 right-handed volunteers (8 males, age 24-61 years) were mapped using motor evoked potentials with an SI of 110 and 120 % of rMT and with an upper threshold (UT) estimated by the Mills-Nithi algorithm. The UT was significantly lower than 120 % of rMT (p < 0.001), while no significant difference was observed between UT and 110 % of rMT (p = 0.112). The representation sizes followed a similar trend, i.e. areas computed based on UT (5.9 cm(2)) and 110 % of rMT (5.0 cm(2)) being smaller than that of 120 % of rMT (8.8 cm(2)) (p ≤ 0.001). There was no difference in representation sizes between 110 % of rMT and UT. The variance in representation size was found to be significantly lower with UT compared to 120 % of rMT (p = 0.048, uncorrected), while there was no difference between 110 % of rMT and UT or 120 % of rMT. Indications of lowest inter-individual variation in representation size were observed with UT; this is possibly due to the fact that it takes into account the individual input-output characteristics of the motor cortex. Therefore, the UT seems to be a good option for SI in motor mapping applications to outline functional motor areas with nTMS and it could potentially reduce the inter-individual variation caused by the selection of SI in motor mapping in pre-surgical applications and radiosurgery planning.

Extent and Location of the Excitatory and Inhibitory Cortical Hand Representation Maps: A Navigated Transcranial Magnetic Stimulation Study.

Voluntary muscle action and control are modulated by the primary motor cortex, which is characterized by a well-defined somatotopy. Muscle action and control depend on a sensitive balance between excitatory and inhibitory mechanisms in the cortex and in the corticospinal tract. The cortical locations evoking excitatory and inhibitory responses in brain stimulation can be mapped, for example, as a pre-surgical procedure. The purpose of this study was to find the differences between excitatory and inhibitory motor representations mapped using navigated transcranial magnetic stimulation (nTMS). The representations of small hand muscles were mapped to determine the areas and the center of gravities (CoGs) in both hemispheres of healthy right-handed volunteers. The excitatory representations were obtained via resting motor evoked potential (MEP) mapping, with and without a stimulation grid. The inhibitory representations were mapped using the grid and measuring corticospinal silent periods (SPs) during voluntary muscle contraction. The excitatory representations were larger on the dominant hemisphere compared with the non-dominant (p < 0.05). The excitatory CoGs were more medial (p < 0.001) and anterior (p < 0.001) than the inhibitory CoGs. The use of the grid did not influence the areas or the CoGs. The results support the common hypothesis that the MEP and SP representations are located at adjacent sites. Furthermore, the dominant hemisphere seems to be better organized for controlling excitatory motor functions with respect to TMS. In addition, the inhibitory representations could provide further information about motor reorganization and aid in surgery planning when the functional cortical representations are located in abnormal cortical regions.

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.

TMS combined with EEG: Recommendations and open issues for data collection and analysis.

Transcranial magnetic stimulation (TMS) evokes neuronal activity in the targeted cortex and connected brain regions. The evoked brain response can be measured with electroencephalography (EEG). TMS combined with simultaneous EEG (TMS-EEG) is widely used for studying cortical reactivity and connectivity at high spatiotemporal resolution. Methodologically, the combination of TMS with EEG is challenging, and there are many open questions in the field. Different TMS-EEG equipment and approaches for data collection and analysis are used. The lack of standardization may affect reproducibility and limit the comparability of results produced in different research laboratories. In addition, there is controversy about the extent to which auditory and somatosensory inputs contribute to transcranially evoked EEG. This review provides a guide for researchers who wish to use TMS-EEG to study the reactivity of the human cortex. A worldwide panel of experts working on TMS-EEG covered all aspects that should be considered in TMS-EEG experiments, providing methodological recommendations (when possible) for effective TMS-EEG recordings and analysis. The panel identified and discussed the challenges of the technique, particularly regarding recording procedures, artifact correction, analysis, and interpretation of the transcranial evoked potentials (TEPs). Therefore, this work offers an extensive overview of TMS-EEG methodology and thus may promote standardization of experimental and computational procedures across groups.

Identifying novel biomarkers with TMS-EEG - Methodological possibilities and challenges.

Biomarkers are essential for understanding the underlying pathologies in brain disorders and for developing effective treatments. Combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) is an emerging neurophysiological tool that can be used for biomarker development. This method can identify biomarkers associated with the function and dynamics of the inhibitory and excitatory neurotransmitter systems and effective connectivity between brain areas. In this review, we outline the current state of the TMS-EEG biomarker field by summarizing the existing protocols and the possibilities and challenges associated with this methodology.