Berkan Guleyupoglu

Classification of methods in transcranial Electrical Stimulation (tES) and evolving strategy from historical approaches to contemporary innovations

Transcranial Electrical Stimulation (tES) encompasses all methods of non-invasive current application to the brain used in research and clinical practice. We present the first comprehensive and technical review, explaining the evolution of tES in both terminology and dosage over the past 100 years of research to present day. Current transcranial Pulsed Current Stimulation (tPCS) approaches such as Cranial Electrotherapy Stimulation (CES) descended from Electrosleep (ES) through Cranial Electro-stimulation Therapy (CET), Transcerebral Electrotherapy (TCET), and NeuroElectric Therapy (NET) while others like Transcutaneous Cranial Electrical Stimulation (TCES) descended from Electroanesthesia (EA) through Limoge, and Interferential Stimulation. Prior to a contemporary resurgence in interest, variations of transcranial Direct Current Stimulation were explored intermittently, including Polarizing current, Galvanic Vestibular Stimulation (GVS), and Transcranial Micropolarization. The development of these approaches alongside Electroconvulsive Therapy (ECT) and pharmacological developments are considered. Both the roots and unique features of contemporary approaches such as transcranial Alternating Current Stimulation (tACS) and transcranial Random Noise Stimulation (tRNS) are discussed. Trends and incremental developments in electrode montage and waveform spanning decades are presented leading to the present day. Commercial devices, seminal conferences, and regulatory decisions are noted. We conclude with six rules on how increasing medical and technological sophistication may now be leveraged for broader success and adoption of tES.

Cranial electrotherapy stimulation and transcranial pulsed current stimulation: A computer based high-resolution modeling study

The field of non-invasive brain stimulation has developed significantly over the last two decades. Though two techniques of noninvasive brain stimulation--transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS)--are becoming established tools for research in neuroscience and for some clinical applications, related techniques that also show some promising clinical results have not been developed at the same pace. One of these related techniques is cranial electrotherapy stimulation (CES), a class of transcranial pulsed current stimulation (tPCS). In order to understand further the mechanisms of CES, we aimed to model CES using a magnetic resonance imaging (MRI)-derived finite element head model including cortical and also subcortical structures. Cortical electric field (current density) peak intensities and distributions were analyzed. We evaluated different electrode configurations of CES including in-ear and over-ear montages. Our results confirm that significant amounts of current pass the skull and reach cortical and subcortical structures. In addition, depending on the montage, induced currents at subcortical areas, such as midbrain, pons, thalamus and hypothalamus are of similar magnitude than that of cortical areas. Incremental variations of electrode position on the head surface also influence which cortical regions are modulated. The high-resolution modeling predictions suggest that details of electrode montage influence current flow through superficial and deep structures. Finally we present laptop based methods for tPCS dose design using dominant frequency and spherical models. These modeling predictions and tools are the first step to advance rational and optimized use of tPCS and CES.

Reduced discomfort during high-definition transcutaneous stimulation using 6% benzocaine

Background: High-Definition transcranial Direct Current Stimulation (HD-tDCS) allows for non-invasive neuromodulation using an array of compact (approximately 1 cm2 contact area) “High-Definition” (HD) electrodes, as compared to conventional tDCS (which uses two large pads that are approximately 35 cm2). In a previous transcutaneous study, we developed and validated designs for HD electrodes that reduce discomfort over >20 min session with 2 mA electrode current. Objective: The purpose of this study was to investigate the use of a chemical pretreatment with 6% benzocaine (topical numbing agent) to further reduce subjective discomfort during transcutaneous stimulation and to allow for better sham controlled studies. Methods: Pre-treatment with 6% benzocaine was compared with control (no pretreatment) for 22 min 2 mA of stimulation, with either CCNY-4 or Lectron II electroconductive gel, for both cathodal and anodal transcutaneous (forearm) stimulation (eight different combinations). Results: Results show that for all conditions and polarities tested, stimulation with HD electrodes is safe and well tolerated and that pretreatment further reduced subjective discomfort. Conclusion: Pretreatment with a mild analgesic reduces discomfort during HD-tDCS.

Transcranial Electrical Stimulation: Transcranial Direct Current Stimulation (tDCS), Transcranial Alternating Current Stimulation (tACS), Transcranial Pulsed Current Stimulation (tPCS), and Transcranial Random Noise Stimulation (tRNS)

Transcranial electrical stimulation (tES) includes a range of devices where electric current is applied to electrodes on the head to modulate brain function. Various tES devices are applied to indications spanning neurological and psychiatric disorders, neuro-rehabilitation after injury, and altering cognition in healthy adults. All tES devices share certain common features including a waveform generator (typically current controlled), disposable electrodes or electrolyte, and an adhesive or headgear to position the electrodes. tES “dose” is defined by the size and position of electrodes and the waveform (current pattern, duration, and intensity). Many subclasses of tES are named based on dose. This chapter is largely focused on low-intensity (few mA) tES. Low-intensity tES includes transcranial direct-current stimulation (tDCS), transcranial alternating-current stimulation (tACS), and transcranial pulsed-current stimulation (tPCS). Electrode design is important for reproducibility, tolerability, and influences when and what dose can be applied. Stimulation impedance measurements monitor contact quality, while current control is typically used to ensure consistent current delivery despite electrode impedance unknowns. Computational current flow models support device design and programming by informing dose selection for a given outcome. Consensus on the safety and tolerability of tES is protocol-specific, but medical-grade tES devices minimize risk.

Informing dose design by modeling transcutaneous spinal direct current stimulation

Computational modeling of neuromodulation by electrical stimulation is necessary to inform clinical trial design and to describe the underlying mechanism of action (Ahmed, 2011, 2014; Bikson and Datta, 2012; Rahman et al., 2013). These models characterize the relationship between stimulation dose (the parameters controlled by the operator; Peterchev et al., 2012) and the resulting current flow and neuromodulation in order to advise electrotherapy design (Sunderam et al., 2010; Bikson et al., 2012). In this issue of Clinical Neurophysiology, Parazzini et al. (2014) report the first model predicting current density (J) generated by transcutaneous spinal direct current stimulation (tsDCS) in humans. We review important tsDCS model features employed by Parazzini et al. and suggest others that may influence selection of dose. Incorporating additional model features may enhance precision but at the cost of technical complexity and computational resources. It is therefore useful to evaluate the utility of the model features by considering their final effect, if any, on dose design. Ongoing data from human trials (Cogiamanian et al., 2008, 2011; Kitano and Koceja, 2009; Winkler et al., 2010; Lim and Shin, 2011) can serve for model validation. Parazzini et al. adapted three realistic human models from the ‘‘Virtual Population’’ (Christ et al., 2010) that were based on high-resolution MRIs of healthy volunteers and developed with computer-aided design representation of organ surfaces. Parazzini et al. modeled three different electrode montages, each with the anode over the spinal process of the tenth thoracic vertebra. The three cathode locations were: above the right arm, over the umbilicus and over Cz. The injected current was held constant across all montages at 3 mA. Electrodes were modeled as rectangular pads of dimensions 5 7.5 cm or 5 9.5 cm within rectangular sponges of dimensions 7 8 cm or 7 10 cm, for active and reference electrodes, respectively. The models developed by Parazzini et al. highlight important features for subsequent modeling work in tsDCS. To represent the spinal anatomy, it was necessary to precisely segment the bone, soft, and nervous tissues around the spinal cord, and thus include a wide range of tissues with varevaluate the utility of the model features by considering their final ied conductivity. This detail is then multiplied by the inter-individual differences, the impact of which was considered by modeling three subjects. Models may be used to optimize dose for maximum intensity and/or preferred focality at a given target (Dmochowski et al., 2011). For tsDCS applications such as rehabilitation, these considerations may naturally focus on relative neuromodulation of spinal cord segments across the cervical, thoracic, lumbar and sacral/ coccygeal levels while taking into consideration the function of the associated downstream peripheral nerves (Ahmed, 2011, 2014; Aguilar et al., 2011). The use of percentile-based metrics, coefficient of variation and other measures of dispersion and numerical noise reduction across the different levels of the vertebral column may facilitate dose design in this regard. The intensity and focality the of current density, or more directly electric field (E-Field), provides a basic estimate of neuromodulation (Bikson et al., 2013) but as with other nervous system structures (Chan and Nicholson, 1986; Rahman et al., 2013, 2014; Salomons, 1992) the orientation of the E-field with respect to cell morphology is also critical to describe cellular polarization and the associated functional effects (Kabakov et al., 2012; Rahman et al., 2013; Ranck, 1975). In the spinal cord, the white matter afferent/efferent tracks are, to first order, orthogonal to the spinal nerves. For tsDCS, representation of E-Field magnitude in the longitudinal and transversal components (relative to the spinal cord) may provide a basic approximation of influence on these cellular targets. These may then be aggregated at the different levels of the vertebral column (e.g., Parazzini et al. used the ratio of longitudinal and transversal components as a proxy). In addition to the features of the computational model used by Parazzini et al., other features possibly affecting stimulation dose design may be considered in tsDCS modeling. Peripheral and cranial nerve stimulation may substantially influence the physiological outcome of transcranial direct current stimulation (tDCS) but require special attention because of limited MRI resolution (typically on the order of 1 mm voxel size in more recent publications). Since myelinated white matter tracks comprise the much of the spinal cord, introducing tissue anisotropy in the spinal cord model (as has already been applied in some cranial modeling; Shahid et al., 2013, 2014; Wagner et al., 2014) may substantively change tsDCS model output. Parazzini et al. claimed, based on the models adapted from the ‘‘Virtual Population’’, the longitudinal component of the J generally dominates across the spinal column, a result that may be magnified by inclusion of spinal anisotropy. Accurate description of the path of current flow is also important. The spinal cord and protruding spinal nerve fibers are surrounded by an irregular spectrum of tissue types (CSF, fat, ligament, bone, muscle, et cetera), some of which have a fiber-like

Methods and Technologies for Low-Intensity Transcranial Electrical Stimulation: Waveforms, Terminology, and Historical Notes

Transcranial electrical stimulation (tES) encompasses all methods of noninvasive current application to the brain used in research and clinical applications. We present the first comprehensive and technical review, explaining the evolution of tES in both terminology and dosage over the past 100 years of research to the present day. Current transcranial pulsed current stimulation (tPCS) approaches such as cranial electrotherapy stimulation (CES) descended from Electrosleep (ES) through cranial electrostimulation therapy (CET), transcerebral electrotherapy (TCET), and NeuroElectric Therapy (NET) while others like transcutaneous cranial electrical stimulation (TCES) descended from electroanesthesia (EA) through Limoge and interferential stimulation (IS). Prior to a contemporary resurgence in interest, forms of transcranial direct current stimulation were explored intermittently, notably as polarizing current. The development of these approaches alongside electroconvulsive therapy (ECT) and pharmacological developments is considered. Both the roots and unique features of contemporary approaches such as transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS) are discussed. Trends and incremental developments in electrode montage and waveform spanning decades are presented leading to the present day. Commercial devices, seminal conferences, and regulatory decisions are noted, though emphasis is placed on relevance and insight into current practices.

Factors Influencing Current Flow Through the Skin during Transcranial Electrical Stimulation: Role of Waveform, Tissue Properties, and Macro-Pores

comprising sweat pores, epidermis, dermis, sweat glands, subcutis, hair follicles, and blood vessels. Skin tissue conductivity based on cylinders filled with saline (0.1 0.4 %) to mimic sweat pores/ducts was carried out. Pore density was set to be 3/cm2. The diameter of the ducts ranges from 10 to 40 μm. We conducted experiments testing varieties of electrode assembly and characterized skin and gel response. Images of forearm poststimulation was taken for each subject to characterize skin response to gel and electrode assembly. Factors influencing Current flow through the Skin during Transcranial Electrical Stimulation: Role of Waveform, Tissue properties, and Macro-pores Niranjan Khadka*, Dennis Q.Truong, Vishali Patel, Ole Seibt, Albert Mokrejs, Berkan Guleyupoglu, Chris Thomas, Marom Bikson Department of Biomedical Engineering, The City College of New York, CUNY

P 34. Inter-individual variation during transcranial direct current stimulation and normalization of dose using MRI-derived computational models

Transcranial Direct Current Stimulation (tDCS) is a non-invasive, versatile, and safe neuromodulation technology under investigation for the treatment of neuropsychiatric disorders, adjunct to rehabilitation, and cognitive enhancement in healthy adults. Despite promising results, there is variability in responsiveness. One potential source of variability is the intensity of current delivered to the brain which is a function of both the operator controlled tDCS dose (electrode montage and total applied current) and subject specific anatomy. We are interested in both the scale of this variability across anatomical typical adults and methods to normalize inter-individual variation by customizing tDCS dose. Computational FEM simulations are a standard technique to predict brain current flow during tDCS and can be based on subject specific anatomical MRI. To investigate this variability, we modeled multiple tDCS and HD-tDCS montages across eight adults. The current flow profile across all subjects and montages was influenced by gross anatomy as well as details in cortical gyri/sulci. This data suggests that subject specific modeling can facilitate consistent and more efficacious tDCS.