Background and Objectives: In our previous proof-ofprinciple study, transcranial photobiomodulation (tPBM) with 1,064-nm laser was reported to significantly increase concentration changes of oxygenated hemoglobin (Δ[HbO]) and oxidized-state cytochrome c oxidase (Δ[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 Δ[HbO] and Δ[oxi-CCO] between young and older adults. Study Design/Materials and Methods: We measured sham-controlled Δ[HbO] and Δ[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 tPBMinduced Δ[HbO] and Δ[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 Δ[HbO] and Δ[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 Δ[HbO] and Δ[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 Δ[HbO] and Δ[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.

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.

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Noninvasive transcranial photobiomodulation (tPBM) with a 1064-nm laser has been reported to improve human performance on cognitive tasks as well as locally upregulate cerebral oxygen metabolism and hemodynamics. However, it is unknown whether 1064-nm tPBM also modulates electrophysiology, and specifically neural oscillations, in the human brain. The hypothesis guiding our study is that applying 1064-nm tPBM of the right prefrontal cortex enhances neurophysiological rhythms at specific frequency bands in the human brain under resting conditions. To test this hypothesis, we recorded the 64-channel scalp electroencephalogram (EEG) before, during, and after the application of 11 min of 4-cm-diameter tPBM (CW 1064-nm laser with 162 mW∕cm 2 and 107 J∕cm 2) to the right forehead of human subjects (n ¼ 20) using a within-subject, sham-controlled design. Time-resolved scalp topographies of EEG power at five frequency bands were computed to examine the tPBM-induced EEG power changes across the scalp. The results show time-dependent, significant increases of EEG spectral powers at the alpha (8 to 13 Hz) and beta (13 to 30 Hz) bands at broad scalp regions, exhibiting a front-to-back pattern. The findings provide the first sham-controlled topographic mapping that tPBM increases the strength of electrophysiological oscillations (alpha and beta bands) while also shedding light on the mechanisms of tPBM in the human brain.

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.

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.

Transcranial magnetic stimulation (TMS) is a non-invasive tool to perturb brain activity. In TMS studies, the stimulation intensity (SI) is commonly normalized to the resting motor threshold (rMT) that produces muscle responses in 50% of stimulations applied to the motor cortex (M1). Since rMT is influenced by spinal excitability and coil-to-cortex distance, responses recorded from the cortex, instead of a peripheral muscle, could provide a more accurate marker for cortical excitability. Combining TMS with electroencephalography (EEG) enables the measurement of brain-wide cortical reactivity to TMS. We quantified TMS-induced changes in oscillatory power and the phase of EEG with event-related spectral perturbation (ERSP) and inter-trial coherence (ITC). We studied the SI-dependency of ERSP and ITC responses by stimulating the dominant M1 of ten healthy volunteers using single-pulse TMS with 150 pulses at 60%, 80%, 100%, and 120% of rMT. We found SI-dependent ERSP and ITC responses in M1, most notably with the wide-band (8-70 Hz) early ITC responses averaged 20-60 ms after TMS. With approximately linear SI-dependence, the early ITC response was consistent between SIs (intraclass correlation = 0.78, ). Our results reveal the potential of oscillatory EEG responses, in place of rMT, as a measure of the cortical excitability threshold in M1.

Transcranial magnetic stimulation (TMS) can be used for evaluating the function of motor pathways. According to the principles of electromagnetism and electrophysiology, TMS activates those neurons that are suitably oriented with respect to the TMS-induced electric field. We hypothesized that TMS could potentially be able to evaluate the neuronal structure, although until now, this putative application has not been exploited. We have developed a TMS-based method to evaluate the function and structure of the motor cortex concurrently in a quantitative manner. This method produced a measure, the anisotropy index (AI), which is based on the motor-evoked potentials induced at different coil orientations. The AI was demonstrated to exhibit an association with both motor cortex excitability and neuronal structure. In the present study, we evaluated the repeatability (intrasession and intersession) of AI in three consecutive measurements. In addition, we studied the repeatability of the optimal coil angle in inducing motor-evoked potentials. Two of the measurements were conducted on the same stimulation target and the third on a remapped target. The coefficient of repeatability of the AI was 0.022 for intrasession and 0.040 for intersession assessments. For the optimal stimulation angle, the coefficients of repeatability were 3.7° and 5.1°, respectively. Both the AI and the optimal stimulation angle demonstrated good repeatability (Cronbach's α>0.760). In conclusion, the results indicate that the AI can provide a reliable estimation of local functional anisotropy changes under conditions affecting the cortex, such as during stroke or focal dysplasia.