Transcranial direct current stimulation (tDCS) has been shown to evoke hemodynamics response; however, the mechanisms have not been investigated systematically using systems biology approaches. Our study presents a grey-box linear model that was developed from a physiologically detailed multi-compartmental neurovascular unit model consisting of the vascular smooth muscle, perivascular space, synaptic space, and astrocyte glial cell. Then, model linearization was performed on the physiologically detailed nonlinear model to find appropriate complexity (Akaike information criterion) to fit functional near-infrared spectroscopy (fNIRS) based measure of blood volume changes, called cerebrovascular reactivity (CVR), to high-definition (HD) tDCS. The grey-box linear model was applied on the fNIRS-based CVR during the first 150 seconds of anodal HD-tDCS in eleven healthy humans. The grey-box linear models for each of the four nested pathways starting from tDCS scalp current density that perturbed synaptic potassium released from active neurons for Pathway 1, astrocytic transmembrane current for Pathway 2, perivascular potassium concentration for Pathway 3, and voltage-gated ion channel current on the smooth muscle cell for Pathway 4 were fitted to the total hemoglobin concentration (tHb) changes from optodes in the vicinity of 4x1 HD-tDCS electrodes as well as on the contralateral sensorimotor cortex. We found that the tDCS perturbation Pathway 3 presented the least mean square error (MSE, median <2.5%) and the lowest Akaike information criterion (AIC, median -1.726) from the individual grey-box linear model fitting at the targeted-region. Then, minimal realization transfer function with reduced-order approximations of the grey-box model pathways was fitted to the ensemble average tHb time series. Again, Pathway 3 with nine poles and two zeros (all free parameters), provided the best Goodness of Fit of 0.0078 for Chi-Square difference test of nested pathways. Therefore, our study provided a systems biology approach to investigate the initial transient hemodynamic response to tDCS based on fNIRS tHb data. Future studies need to investigate the steady-state responses, including steady-state oscillations found to be driven by calcium dynamics, where transcranial alternating current stimulation may provide frequency-dependent physiological entrainment for system identification. We postulate that such a mechanistic understanding from system identification of the hemodynamics response to transcranial electrical stimulation can facilitate adequate delivery of the current density to the neurovascular tissue under simultaneous portable imaging in various cerebrovascular diseases.

Error-based learning is one of the basic skill acquisition mechanisms that can be modeled as a perception–action system and investigated based on brain–behavior analysis during skill training. Here, the error-related chain of mental processes is postulated to depend on the skill level leading to a difference in the contextual switching of the brain states on error commission. Therefore, the objective of this paper was to compare error-related brain states, measured with multi-modal portable brain imaging, between experts and novices during the Fundamentals of Laparoscopic Surgery (FLS) “suturing and intracorporeal knot-tying” task (FLS complex task)—the most difficult among the five psychomotor FLS tasks. The multi-modal portable brain imaging combined functional near-infrared spectroscopy (fNIRS) and electroencephalography (EEG) for brain–behavior analysis in thirteen right-handed novice medical students and nine expert surgeons. The brain state changes were defined by quasi-stable EEG scalp topography (called microstates) changes using 32-channel EEG data acquired at 250 Hz. Six microstate prototypes were identified from the combined EEG data from experts and novices during the FLS complex task that explained 77.14% of the global variance. Analysis of variance (ANOVA) found that the proportion of the total time spent in different microstates during the 10-s error epoch was significantly affected by the skill level (p < 0.01), the microstate type (p < 0.01), and the interaction between the skill level and the microstate type (p < 0.01). Brain activation based on the slower oxyhemoglobin (HbO) changes corresponding to the EEG band power (1–40 Hz) changes were found using the regularized temporally embedded Canonical Correlation Analysis of the simultaneously acquired fNIRS–EEG signals. The HbO signal from the overlying the left inferior frontal gyrus—opercular part, left superior frontal gyrus—medial orbital, left postcentral gyrus, left superior temporal gyrus, right superior frontal gyrus—medial orbital cortical areas showed significant (p < 0.05) difference between experts and novices in the 10-s error epoch. We conclude that the difference in the error-related chain of mental processes was the activation of cognitive top-down attention-related brain areas, including left dorsolateral prefrontal/frontal eye field and left frontopolar brain regions, along with a ‘focusing’ effect of global suppression of hemodynamic activation in the experts, while the novices had a widespread stimulus(error)-driven hemodynamic activation without the ‘focusing’ effect.

Transcranial direct current stimulation (tDCS) has been shown to evoke hemodynamics response; however, the mechanisms have not been investigated systematically using systems biology approaches. We postulate that such a mechanistic understanding of the hemodynamics response, called cerebrovascular reactivity (CVR) to tDCS, can facilitate adequate delivery of the tDCS current density to the neurovascular tissue in cerebrovascular diseases. Our study presents a systems biology approach to evaluate CVR during high-definition (HD) tDCS using a physiologically constrained grey-box linear model. Our grey-box linear model was developed for the multi-compartmental neurovascular unit consisting of the vascular smooth muscle, perivascular space, synaptic space, and astrocyte glial cell. The physiologically detailed model generated vessel oscillations in the frequency range of 0.05 – 0.2 Hz driven mainly by non-linear calcium dynamics. Then, model linearization was performed to develop a grey-box linear model for evaluating the acute effects during the first 150 seconds of anodal HD-tDCS in eleven healthy humans using functional near-infrared spectroscopy (fNIRS) based measure of blood volume. The grey-box linear model was fitted to the total hemoglobin concentration (tHb) changes with optodes in the vicinity of 4x1 HD-tDCS electrodes. We found that the grey-box model pathway from perivascular potassium to the vessel circumference (Pathway 3) presented the best fit to fNIRS tHb time series with the least mean square error (MSE, median < 2.5%). Then, minimal realization transfer function with reduced-order approximations of the grey-box model pathways was fitted to the average tHb time series. Pathway 3, with nine poles and two zeros (all free parameters), provided the best Chi-Square Goodness of Fit of 0.0078. Therefore, our study provided a sound systems biology approach to investigate the hemodynamic response to tDCS that needs further investigation in health, aging, and disease. Future studies can leverage transcranial alternating current stimulation for frequency-dependent physiological entrainment of relevant pathways, e.g., oscillations driven by nonlinear calcium dynamics, that can provide additional insights based on our grey-box modeling approach.

Fundamentals of Laparoscopic Surgery (FLS) is a prerequisite for board certification in general surgery in the USA. In FLS, the suturing task with intracorporeal knot tying is considered the most complex. Transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (PFC) has been shown to facilitate FLS surgical skill acquisition where 2mA tDCS for 15min with the anode over F3 (10/10 EEG montage) and cathode over F4 has improved performance score in an open knot-tying task. Since PFC has a functional organization related to the hierarchy of cognitive control, we performed functional near-infrared spectroscopy (fNIRS) to investigate PFC activation during the more complex FLS suturing task with intracorporeal knot tying. We performed fNIRS-based analysis using AtlasViewer software on two expert surgeons and four novice medical students. We found an average cortical activation mainly at the left medial PFC across the experts, while the average cortical activation across the novices was primarily at the left pars opercularis of the inferior frontal gyrus and ventral premotor cortex, inferior parietal lobule, and supramarginal gyrus. Here, the average cortical activation across the novices included not only the cognitive control related brain regions but also motor control complexity related brain regions. Therefore, we investigated the feasibility to stimulate motor complexity related PFC regions using ROAST software and identified a 4x1 high-definition (HD) tDCS montage.Clinical Relevance—This shows the feasibility of fNIRS-guided tES to individualize electrode montage that may facilitate FLS surgical training in our future studies.

Surgical skill acquisition may be facilitated with a safe application of transcranial direct current stimulation (tDCS). A preliminary meta-analysis of randomized control trials showed that tDCS was associated with significantly better improvement in surgical performance than the sham control; however, meta-analysis does not address the mechanistic understanding. It is known from skill learning studies that the hierarchy of cognitive control shows a rostrocaudal axis in the frontal lobe where a shift from posterior to anterior is postulated to mediate progressively abstract, higher-order control. Therefore, optimizing the transcranial electrical stimulation to target surgical task-related brain activation at different stages of motor learning may provide the causal link to the learning behavior. This comment paper presents the computational approach for neuroimaging guided tDCS based on open-source software pipelines and an open-data of functional near-infrared spectroscopy (fNIRS) for complex motor tasks. We performed an fNIRS-based cortical activation analysis using AtlasViewer software that was used as the target for tDCS of the motor complexity-related brain regions using ROAST software. For future studies on surgical skill training, it is postulated that the higher complexity laparoscopic suturing with intracorporeal knot tying task may result in more robust activation of the motor complexity-related brain areas when compared to the lower complexity laparoscopic tasks.