Human-in-the-Loop Optimization of Transcranial Electrical Stimulation at the Point of Care: A Computational Perspective

Abstract

Individual differences in the responsiveness of the brain to transcranial electrical stimulation (tES) are increasingly demonstrated by the large variability in the effects of tES. Anatomically detailed computational brain models have been developed to address this variability; however, static brain models are not “realistic” in accounting for the dynamic state of the brain. Therefore, human-in-the-loop optimization at the point of care is proposed in this perspective article based on systems analysis of the neurovascular effects of tES. First, modal analysis was conducted using a physiologically detailed neurovascular model that found stable modes in the 0 Hz to 0.05 Hz range for the pathway for vessel response through the smooth muscle cells, measured with functional near-infrared spectroscopy (fNIRS). During tES, the transient sensations can have arousal effects on the hemodynamics, so we present a healthy case series for black-box modeling of fNIRS–pupillometry of short-duration tDCS effects. The block exogeneity test rejected the claim that tDCS is not a one-step Granger cause of the fNIRS total hemoglobin changes (HbT) and pupil dilation changes (p < 0.05). Moreover, grey-box modeling using fNIRS of the tDCS effects in chronic stroke showed the HbT response to be significantly different (paired-samples t-test, p < 0.05) between the ipsilesional and contralesional hemispheres for primary motor cortex tDCS and cerebellar tDCS, which was subserved by the smooth muscle cells. Here, our opinion is that various physiological pathways subserving the effects of tES can lead to state–trait variability, which can be challenging for clinical translation. Therefore, we conducted a case study on human-in-the-loop optimization using our reduced-dimensions model and a stochastic, derivative-free covariance matrix adaptation evolution strategy. We conclude from our computational analysis that human-in-the-loop optimization of the effects of tES at the point of care merits investigation in future studies for reducing inter-subject and intra-subject variability in neuromodulation.

Perspective: Disentangling the effects of tES on neurovascular unit

“…In our prior study (6), we found from modal analysis and a case study in a healthy human that the "optimal" oscillatory frequency was close to 1 Hz, meriting mechanistic investigation with respect to astrocytes and interstitial potassium. In this study, short-term (<150 s) acute tES can affect the vasculature (41) for immediate control of blood vessel response using model predictive control (MPC) (6). MPC uses an internal model of the interaction of cortical activity, local metabolic factors, and the vascular response to make predictions of the system behavior, considering neurovascular dynamics over a predefined prediction horizon, to optimize tES control actions.…”

“…Here, we postulate that the extracellular space, including the extracellular matrix plays a crucial role during online modulation by tES, which is relevant in the optimisation of the tES dose (6). For example, tES modulation of the permeability of the blood-brain barrier (11) can change the substance transport (12) including glucose that can modulate neuronal excitability (13) and neurovascular coupling [for a given insulin action (14,15)].…”

“…We postulated that the online tES effects on the NVU are important ( 3 ) to understand the after-effects of tES ( 4 ) that can be driven by the perturbation to the state of the neurovascular unit ( 5 ). Specifically, the immediate effects of tES are modulation of the state of the brain's extracellular space through the arousal pathway ( 6 ), which can modulate the excitation-inhibition (E–I) balance ( 7 ). The extracellular space, including the extracellular matrix ( 8 ), is crucial to maintain the E–I balance, and the synaptic after-effects of tES can be driven by the E–I homeostatic mechanisms ( 9 ) following tES perturbation.…”

“…Indeed, recent studies are increasingly showing a lack of online modulation of concurrent transcranial magnetic stimulation motor-evoked potentials (MEP) that are generated via transynaptic activation of pyramidal cells projected on spinal motoneurons ( 10 ). Here, we postulate that the extracellular space, including the extracellular matrix plays a crucial role during online modulation by tES, which is relevant in the optimisation of the tES dose ( 6 ). For example, tES modulation of the permeability of the blood–brain barrier ( 11 ) can change the substance transport ( 12 ) including glucose that can modulate neuronal excitability ( 13 ) and neurovascular coupling [for a given insulin action ( 14 , 15 )].…”

“…Then, the integration of signaling from various tES-evoked sources in the extracellular space can be driven by the E–I homeostatic mechanisms afterwards that may explain the (paradoxical) MEP facilitation during cathodal tDCS at 2.0 mA ( 16 ) as well as partially non-linear stimulation intensity-dependent effects ( 17 ) (that include neuronal calcium influx effects). Therefore, systems analysis of the online modulation of the neurovascular coupling ( 3 ), including the modal analysis (with frequency response function) of the coupling ( 6 ), can capture tES dose-response which was not feasible based solely on the MEP ( 16 ).…”