Accessibility of cortical regions to focal TES: Dependence on spatial position, safety, and practical constraints.

Transcranial electric stimulation (TES) can modulate intrinsic neural activity in the brain by injecting weak currents through electrodes attached to the scalp. TES has been widely used as a neuroscience tool to investigate how behavioural and physiological variables of brain function are modulated by electric stimulation of specific brain regions. For an unambiguous interpretation of TES experiments, it is important that the electric fields can be steered towards one or several brain regions-of-interest. However, the conductive proprieties of the human head impose inherent physical limitations on how focal the electric fields in the brain produced by multi-electrode TES can be. As a rule of thumb, it is not feasible to selectively target deep brain areas with TES, although focusing the field in some specific deeper locations might be possible due to favourable conductive properties in the surrounding tissue. In the present study, we first propose a computationally efficient method for the automatic determination of electrode placements and stimulation intensities to optimally affect a given target position. We provide a robust implementation of the optimization procedure that is able to adhere to safety constraints, while explicitly controlling both the number of active electrodes and the angular deviation of the field in the target area relative to the desired field direction. Leveraging the high computational efficiency of our method, we systematically assess the achievable focality of multi-electrode TES for all cortex positions, thereby investigating the dependence on the chosen constraints. Our results provide comprehensive insight into the limitations regarding the achievable TES dose and focality that are imposed by the biophysical constraints and the safety considerations of TES.

How to target inter-regional phase synchronization with dual-site Transcranial Alternating Current Stimulation.

Large-scale synchronization of neural oscillations is a key mechanism for functional information exchange among brain areas. Dual-site Transcranial Alternating Current Stimulation (ds-TACS) has been recently introduced as non-invasive technique to manipulate the temporal phase relationship of local oscillations in two connected cortical areas. While the frequency of ds-TACS is matched, the phase of stimulation is either identical (in-phase stimulation) or opposite (anti-phase stimulation) in the two cortical target areas. In-phase stimulation is thought to synchronize the endogenous oscillations and hereby to improve behavioral performance. Conversely, anti-phase stimulation is thought to desynchronize neural oscillations in the two areas, which is expected to decrease performance. Critically, in- and anti-phase ds-TACS should only differ with respect to temporal phase, while all other stimulation parameters such as focality and stimulation intensity should be matched to enable an unambiguous interpretation of the behavioral effects. Using electric field simulations based on a realistic head geometry, we tested how well this goal has been met in studies, which have employed ds-TACS up to now. Separating the induced electrical fields in their spatial and temporal components, we investigated how the chosen electrode montages determined the spatial field distribution and the generation of phase variations in the injected electric fields. Considering the basic physical mechanisms, we derived recommendations for an optimized stimulation montage. The latter allows for a principled design of in- and anti-phase ds-TACS conditions with matched spatial distributions of the electric field. This knowledge will help cognitive neuroscientists to design optimal ds-TACS configurations, which are suited to probe unambiguously the causal contribution of phase coupling to specific cognitive processes in the human brain.

Can Transcranial Electrical Stimulation Localize Brain Function?

Transcranial electrical stimulation (TES) uses constant (TDCS) or alternating currents (TACS) to modulate brain activity. Most TES studies apply low-intensity currents through scalp electrodes (≤2 mA) using bipolar electrode arrangements, producing weak electrical fields in the brain (<1 V/m). Low-intensity TES has been employed in humans to induce changes in task performance during or after stimulation. In analogy to focal transcranial magnetic stimulation, TES-induced behavioral effects have often been taken as evidence for a causal involvement of the brain region underlying one of the two stimulation electrodes, often referred to as the active electrode. Here, we critically review the utility of bipolar low-intensity TES to localize human brain function. We summarize physiological substrates that constitute peripheral targets for TES and may mediate subliminal or overtly perceived peripheral stimulation during TES. We argue that peripheral co-stimulation may contribute to the behavioral effects of TES and should be controlled for by "sham" TES. We discuss biophysical properties of TES, which need to be considered, if one wishes to make realistic assumptions about which brain regions were preferentially targeted by TES. Using results from electric field calculations, we evaluate the validity of different strategies that have been used for selective spatial targeting. Finally, we comment on the challenge of adjusting the dose of TES considering dose-response relationships between the weak tissue currents and the physiological effects in targeted cortical areas. These considerations call for caution when attributing behavioral effects during or after low-intensity TES studies to a specific brain region and may facilitate the selection of best practices for future TES studies.

Towards precise brain stimulation: Is electric field simulation related to neuromodulation?

BACKGROUND: Recent research on neural and behavioral consequences of transcranial direct current stimulation (tDCS) has highlighted the impact of individual factors, such as brain anatomy which determines current field distribution and may thus significantly impact stimulation effects. Computational modeling approaches may significantly advance our understanding of such factors, but the association of simulation-based tDCS-induced fields and neurophysiological outcomes has not been investigated. OBJECTIVES: To provide empirical evidence for the relationship between tDCS-induced neurophysiological outcomes and individually induced electric fields. METHODS: We applied tDCS during eyes-closed resting-state functional resonance imaging (rsfMRI) and assessed pre-post magnetic resonance spectroscopy (MRS) in 24 participants. We aimed to quantify effects of 15-min tDCS using the "classical" left SM1-right supraorbital area montage on sensorimotor network (SMN) strength and gamma-aminobutyric acid (GABA) and glutamate concentrations, implementing a cross-over counterbalanced design with three stimulation conditions. Additional structural anatomical MRI sequences and recordings of individual electrode configurations allowed individual electric field simulations based on realistic head models of all participants for both conditions. RESULTS: On a neurophysiological level, we observed the expected reduction of GABA concentrations and increase in SMN strength, both during anodal and cathodal compared to sham tDCS, replicating previous results. The magnitudes of neurophysiological modulations induced by tDCS were significantly associated with simulation-based electric field strengths within the targeted left precentral gyrus. CONCLUSION: Our findings corroborate previous reports on tDCS-induced neurophysiological modulations and further advance the understanding of underlying mechanisms by providing first empirical evidence for the association of the injected electric field and neuromodulatory effects.

Evaluation of a Modified High-Definition Electrode Montage for Transcranial Alternating Current Stimulation (tACS) of Pre-Central Areas.

OBJECTIVE: To evaluate a modified electrode montage with respect to its effect on tACS-dependent modulation of corticospinal excitability and discomfort caused by neurosensory side effects accompanying stimulation. METHODS: In a double-blind cross-over design, the classical electrode montage for primary motor cortex (M1) stimulation (two patch electrodes over M1 and contralateral supraorbital area) was compared with an M1 centre-ring montage. Corticospinal excitability was evaluated before, during, immediately after and 15 minutes after tACS (10 min., 20 Hz vs. 30 s low-frequency transcranial random noise stimulation). RESULTS: Corticospinal excitability increased significantly during and immediately after tACS with the centre-ring montage. This was not the case with the classical montage or tRNS stimulation. Level of discomfort was rated on average lower with the centre-ring montage. CONCLUSIONS: In comparison to the classic montage, the M1 centre-ring montage enables a more focal stimulation of the target area and, at the same time, significantly reduces neurosensory side effects, essential for placebo-controlled study designs.

Enhancing Predicted Efficacy of Tumor Treating Fields Therapy of Glioblastoma Using Targeted Surgical Craniectomy: A Computer Modeling Study.

OBJECTIVE: The present work proposes a new clinical approach to TTFields therapy of glioblastoma. The approach combines targeted surgical skull removal (craniectomy) with TTFields therapy to enhance the induced electrical field in the underlying tumor tissue. Using computer simulations, we explore the potential of the intervention to improve the clinical efficacy of TTFields therapy of brain cancer. METHODS: We used finite element analysis to calculate the electrical field distribution in realistic head models based on MRI data from two patients: One with left cortical/subcortical glioblastoma and one with deeply seated right thalamic anaplastic astrocytoma. Field strength was assessed in the tumor regions before and after virtual removal of bone areas of varying shape and size (10 to 100 mm) immediately above the tumor. Field strength was evaluated before and after tumor resection to assess realistic clinical scenarios. RESULTS: For the superficial tumor, removal of a standard craniotomy bone flap increased the electrical field strength by 60-70% in the tumor. The percentage of tissue in expected growth arrest or regression was increased from negligible values to 30-50%. The observed effects were highly focal and targeted at the regions of pathology underlying the craniectomy. No significant changes were observed in surrounding healthy tissues. Median field strengths in tumor tissue increased with increasing craniectomy diameter up to 50-70 mm. Multiple smaller burr holes were more efficient than single craniectomies of equivalent area. Craniectomy caused no significant field enhancement in the deeply seated tumor, but rather a focal enhancement in the brain tissue underlying the skull defect. CONCLUSIONS: Our results provide theoretical evidence that small and clinically feasible craniectomies may provide significant enhancement of TTFields intensity in cerebral hemispheric tumors without severely compromising brain protection or causing unacceptable heating in healthy tissues. A clinical trial is being planned to validate safety and efficacy.