Conditions Sufficient for Nonsynaptic Epileptogenesis in the CA1 Region of Hippocampal Slices

Journal of Neurophysiology. Jan, 2002  |  Pubmed ID: 11784730

Nonsynaptic mechanisms exert a powerful influence on seizure threshold. It is well-established that nonsynaptic epileptiform activity can be induced in hippocampal slices by reducing extracellular Ca(2+) concentration. We show here that nonsynaptic epileptiform activity can be readily induced in vitro in normal (2 mM) Ca(2+) levels. Those conditions sufficient for nonsynaptic epileptogenesis in the CA1 region were determined by pharmacologically mimicking the effects of Ca(2+) reduction in normal Ca(2+) levels. Increasing neuronal excitability, by removing extracellular Mg(2+) and increasing extracellular K(+) (6-15 mM), induced epileptiform activity that was suppressed by postsynaptic receptor antagonists [D-(-)-2-amino-5-phosphonopentanoic acid, picrotoxin, and 6,7-dinitroquinoxaline-2,3-dione] and was therefore synaptic in nature. Similarly, epileptiform activity induced when neuronal excitability was increased in the presence of K(Ca) antagonists (verruculogen, charybdotoxin, norepinephrine, tetraethylammonium salt, and Ba(2+)) was found to be synaptic in nature. Decreases in osmolarity also failed to induce nonsynaptic epileptiform activity in the CA1 region. However, increasing neuronal excitability (by removing extracellular Mg(2+) and increasing extracellular K(+)) in the presence of Cd(2+), a nonselective Ca(2+) channel antagonist, or veratridine, a persistent sodium conductance enhancer, induced spontaneous nonsynaptic epileptiform activity in vitro. Both novel models were characterized using intracellular and ion-selective electrodes. The results of this study suggest that reducing extracellular Ca(2+) facilitates bursting by increasing neuronal excitability and inhibiting Ca(2+) influx, which might, in turn, enhance a persistent sodium conductance. Furthermore, these data show that nonsynaptic mechanisms can contribute to epileptiform activity in normal Ca(2+) levels.

Local Suppression of Epileptiform Activity by Electrical Stimulation in Rat Hippocampus in Vitro

The Journal of Physiology. Mar, 2003  |  Pubmed ID: 12562909

High frequency electrical stimulation of deep brain structures (DBS) has been effective at controlling abnormal neuronal activity in Parkinson's patients and is now being applied for the treatment of pharmacologically intractable epilepsy. The mechanisms underlying the therapeutic effects of DBS are unknown. In particular, the effect of the electrical stimulation on neuronal firing remains poorly understood. Previous reports have showed that uniform electric fields with both AC (continuous sinusoidal) or DC waveforms could suppress epileptiform activity in vitro. In the present study, we tested the effects of monopolar electrode stimulation and low-duty cycle AC stimulation protocols, which more closely approximate those used clinically, on three in vitro epilepsy models. Continuous sinusoidal stimulation, 50 % duty-cycle sinusoidal stimulation, and low (1.68 %) duty-cycle pulsed stimulation (120 micros, 140 Hz) could completely suppress spontaneous low-Ca2+ epileptiform activity with average thresholds of 71.11 +/- 26.16 microA, 93.33 +/- 12.58 microA and 300 +/- 100 microA, respectively. Continuous sinusoidal stimulation could also completely suppress picrotoxin- and high-K+-induced epileptiform activity with either uniform or localized fields. The suppression generated by the monopolar electrode was localized to a region surrounding the stimulation electrode. Potassium concentration and transmembrane potential recordings showed that AC stimulation was associated with an increase in extracellular potassium concentration and neuronal depolarization block; AC stimulation efficacy was not orientation-selective. In contrast, DC stimulation blocked activity by membrane hyperpolarization and was orientation-selective, but had a lower threshold for suppression.

Ionic Mechanisms Underlying Spontaneous CA1 Neuronal Firing in Ca2+-free Solution

Biophysical Journal. Mar, 2003  |  Pubmed ID: 12609911

Hippocampal CA1 neurons exposed to zero-[Ca(2+)] solutions can generate periodic spontaneous synchronized activity in the absence of synaptic function. Experiments using hippocampal slices showed that, after exposure to zero-[Ca(2+)](0) solution, CA1 pyramidal cells depolarized 5-10 mV and started firing spontaneous action potentials. Spontaneous single neuron activity appeared in singlets or was grouped into bursts of two or three action potentials. A 16-compartment, 23-variable cable model of a CA1 pyramidal neuron was developed to study mechanisms of spontaneous neuronal bursting in a calcium-free extracellular solution. In the model, five active currents (a fast sodium current, a persistent sodium current, an A-type transient potassium current, a delayed rectifier potassium current, and a muscarinic potassium current) are included in the somatic compartment. The model simulates the spontaneous bursting behavior of neurons in calcium-free solutions. The mechanisms underlying several aspects of bursting are studied, including the generation of triplet bursts, spike duration, burst termination, after-depolarization behavior, and the prolonged inactive period between bursts. We show that the small persistent sodium current can play a key role in spontaneous CA1 activity in zero-calcium solutions. In particular, it is necessary for the generation of an after-depolarizing potential and prolongs both individual bursts and the interburst interval.

Neuronal Aggregate Formation Underlies Spatiotemporal Dynamics of Nonsynaptic Seizure Initiation

Journal of Neurophysiology. Apr, 2003  |  Pubmed ID: 12686586

High-frequency activity often precedes seizure onset. We found that electrographic seizures, induced in vitro using the low-Ca(2+) model, start with high-frequency (>150 Hz) activity that then decreases in frequency while increasing in amplitude. Multichannel and unit recordings showed that the mechanism of this transition was the progressive formation of larger neuronal aggregates. Thus the apparent high-frequency activity, at seizure onset, can reflect the simultaneous recording of several slower firing aggregates. Aggregate formation rate can be accelerated by reducing osmolarity. Because synaptic transmission is blocked when extracellular Ca(2+) is reduced, nonsynaptic mechanisms (gap junctions, field effects) must be sufficient for aggregate formation and recruitment.

Depolarization Block of Neurons During Maintenance of Electrographic Seizures

Journal of Neurophysiology. Oct, 2003  |  Pubmed ID: 12801897

Epileptic seizures are associated with neuronal hyperactivity. Here, however, we investigated whether continuous neuronal firing is necessary to maintain electrographic seizures. We studied a class of "low-Ca2+" ictal epileptiform bursts, induced in rat hippocampal slices, that are characterized by prolonged (2-15 s) interruptions in population spike generation. We found that, during these interruptions, neuronal firing was suppressed rather than desynchronized. Intracellular current injection, application of extracellular uniform electric fields, and antidromic stimulation showed that the source of action potential disruption was depolarization block. The duration of the extracellular potassium transients associated with each ictal burst was not affected by disruptions in neuronal firing. Application of phenytoin or veratridine indicated a critical role for the persistent sodium current in maintaining depolarization block. Our results show that continuous neuronal firing is not necessary for the maintenance of experimental electrographic seizures.

Effects of Uniform Extracellular DC Electric Fields on Excitability in Rat Hippocampal Slices in Vitro

The Journal of Physiology. May, 2004  |  Pubmed ID: 14978199

The effects of uniform steady state (DC) extracellular electric fields on neuronal excitability were characterized in rat hippocampal slices using field, intracellular and voltage-sensitive dye recordings. Small electric fields (1 s) changes in neuronal excitability. Electric fields perpendicular to the apical-dendritic axis did not induce somatic polarization, but did modulate orthodromic responses, indicating an effect on afferents. These results demonstrate that DC fields can modulate neuronal excitability in a time-dependent manner, with no clear threshold, as a result of interactions between neuronal compartments, the non-linear properties of the cell membrane, and effects on afferents.

Tissue Resistance Changes and the Profile of Synchronized Neuronal Activity During Ictal Events in the Low-calcium Model of Epilepsy

Journal of Neurophysiology. Jul, 2004  |  Pubmed ID: 14999050

Population spikes vary in size during prolonged epileptic ("ictal") discharges, indicating variations in neuronal synchronization. Here we investigate the role of changes in tissue electrical resistivity in this process. We used the rat hippocampal slice, low-Ca(2+) model of epilepsy and measured changes in pyramidal layer extracellular resistance during the course of electrographic seizures. During each burst, population spike frequency decreased, whereas amplitude and spatial synchronization increased; after the main discharge, there could be brief secondary discharges that, in contrast with those in the primary discharge, started with high-amplitude population spikes. Mean resistivity increased from 1,231 Omega.cm immediately before the burst to a maximum of 1,507 Omega.cm during the burst. There was no significant increase during the first 0.5-1 s of the field burst, but resistance then increased (tau approximately 5 s), reaching its peak at the end of the burst, and then decayed slowly (tau approximately 10 s). In further experiments, we modulated the efficacy of electrical field effects by changing perfusate osmolarity. Reducing osmolarity by 40-70 mOsm increased preburst resistivity by 19%; it reduced minimum population spike frequency (x0.6-0.7) and increased both maximum population spike amplitude (x1.5-2.3) and spatial synchronization (x1.4-2.5, cross-correlation over 0.5 mm) during bursts. Increasing osmolarity by 20-40 mOsm had the opposite effects. These results suggest that, during each field burst, field effects between neurons gradually become more effective as cells swell, thereby modulating burst dynamics and facilitating the rapid synchronization of secondary discharges.

Model of the Effect of Extracellular Fields on Spike Time Coherence

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2004  |  Pubmed ID: 17271327

Accurate spike timing is emerging as an important concept in the encoding of sensory stimuli. Accurately timed spiking has been recorded in-vivo in the visual and auditory cortex, many layers removed from the primary sensory neurons. This temporal accuracy may be maintained despite noisy synaptic transmission by the simultaneous firing of multiple neurons. Here we show in simulations that a coherent polarization of a population of neurons through extracellular fields can further increase the coherence of the population's firing times. We discuss the potential relevance of such a common input as an external "clock" signal in a spatio-temporal code.

Electrical Stimulation of Excitable Tissue: Design of Efficacious and Safe Protocols

Journal of Neuroscience Methods. Feb, 2005  |  Pubmed ID: 15661300

The physical basis for electrical stimulation of excitable tissue, as used by electrophysiological researchers and clinicians in functional electrical stimulation, is presented with emphasis on the fundamental mechanisms of charge injection at the electrode/tissue interface. Faradaic and non-Faradaic charge transfer mechanisms are presented and contrasted. An electrical model of the electrode/tissue interface is given. The physical basis for the origin of electrode potentials is given. Various methods of controlling charge delivery during pulsing are presented. Electrochemical reversibility is discussed. Commonly used electrode materials and stimulation protocols are reviewed in terms of stimulation efficacy and safety. Principles of stimulation of excitable tissue are reviewed with emphasis on efficacy and safety. Mechanisms of damage to tissue and the electrode are reviewed.

Bio-heat Transfer Model of Deep Brain Stimulation Induced Temperature Changes

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2006  |  Pubmed ID: 17946574

There is a growing interest in the use of chronic deep brain stimulation (DBS) for the treatment of medically refractory movement disorders and other neurological and psychiatric conditions. Fundamental questions remain about the physiologic effects and safety of DBS. Previous basic research studies have focused on the direct polarization of neuronal membranes by electrical stimulation. The goal of this paper is to provide information on the thermal effects of DBS using finite element models to investigate the magnitude and spatial distribution of DBS induced temperature changes. The parameters investigated include: stimulation waveform, lead selection, brain tissue electrical and thermal conductivity, blood perfusion, metabolic heat generation during the stimulation. Our results show that clinical deep brain stimulation protocols will increase the temperature of surrounding tissue by up to 0.8 deg C depending on stimulation/tissue parameters.

Rational Modulation of Neuronal Processing with Applied Electric Fields

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2006  |  Pubmed ID: 17946911

Traditional approaches to electrical stimulation, using trains of supra-threshold pulses to trigger action potentials, may be replaced or augmented by using 'rational' sub-threshold stimulation protocols that incorporate knowledge of single neuron geometry, inhomogeneous tissue properties, and nervous system information coding. Sub-threshold stimulation, at intensities (well) below those sufficient to trigger action potentials, may none-the-less exert a profound effect on brain function through modulation of concomitant neuronal activity. For example, small DC fields may coherently polarize a network of neurons and thus modulate the simultaneous processing of afferent synaptic input as well as resulting changes in synaptic plasticity. Through 'activity-dependent plasticity', sub-threshold fields may allow specific targeting of pathological networks and are thus particularly suitable to overcome the poor anatomical focus of noninvasive (transcranial) electrical stimulation. Additional approaches to improve targeting in transcranial stimulation using novel electrode configurations are also introduced.

Suppression of Neural Activity with High Frequency Stimulation

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2006  |  Pubmed ID: 17946913

Deep brain stimulation (DBS) has been shown to generate suppression of abnormal neural activity in patients with Parkinson's disease and epilepsy. High frequency stimulation is applied to the brain through depth electrodes in the range of 50 to 200 Hz. Yet the mechanisms underlying the suppression effect have not yet been elucidated. In order to study directly the effect of HFS in the brain, sinusoidal stimulation was applied in the in-vitro brain slice preparation. Sinusoidal stimulation was chosen in order to observe the activity during the stimulation by filtering the stimulation artifact. Sinusoidal stimulation at 50 Hz applied to the CA1 region of the hippocampus was observed to block epileptiform activity in three separate models of epilepsy induced by low-calcium, high potassium and picrotoxin (GABA A blocker). Stimulation applied to the alveus showed that activity in both the cell bodies (evoked potentials) and in the axons (compound action potentials) is suppressed. The frequency range of this effect is nearly identical to that of DBS with maximum suppression effect between 50 and 200 Hz. The effect could not be attributed to desynchronization or damage and was associated with increased extracellular potassium concentrations. These data provide new insights into the effects of HFS on neuronal elements and show that HFS can block axonal activity through non-synaptic mechanisms.

Amplification of Small Electric Fields by Neurons; Implications for Spike Timing

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2006  |  Pubmed ID: 17947123

Small (down to 1 mV/mm) electric fields will polarize neurons by only a small amount; for this reason small electric fields have previously been considered to have no physiologically relevant effects. However, here we propose a novel mechanism by which the non-linear properties of single neurons 'amplify' very small electric fields. Specifically, an amplified change in timing of action potential firing (DeltaT) is inversely proportional to the slope of depolarizing ramp stimulation and proportional to the amount of polarization (DeltaV) caused by the electric fields: DeltaT=DeltaV/(ramp slope). Thus, when responding to slow depolarizing synaptic input, small electric fields can have significant effects on spike timing. Hippocampal CA1 pyramidal neurons were depolarized with injections of depolarizing current ramps approximating synaptic input. Simultaneously, neurons were polarized by either DC holding currents or extracellular uniform DC electrical fields and the resulting changes in spike timing quantified. Consistent with our hypothesis, the polarization induced by each method was found to affect firing time linearly with the amount of polarization, scaled (amplified) with the inverse of the injected ramp slope consistent with our hypothesis.

Bio-heat Transfer Model of Deep Brain Stimulation-induced Temperature Changes

Journal of Neural Engineering. Dec, 2006  |  Pubmed ID: 17124335

There is a growing interest in the use of chronic deep brain stimulation (DBS) for the treatment of medically refractory movement disorders and other neurological and psychiatric conditions. Fundamental questions remain about the physiologic effects of DBS. Previous basic research studies have focused on the direct polarization of neuronal membranes by electrical stimulation. The goal of this paper is to provide information on the thermal effects of DBS using finite element models to investigate the magnitude and spatial distribution of DBS-induced temperature changes. The parameters investigated include stimulation waveform, lead selection, brain tissue electrical and thermal conductivities, blood perfusion, metabolic heat generation during the stimulation and lead thermal conductivity/heat dissipation through the electrode. Our results show that clinical DBS protocols will increase the temperature of surrounding tissue by up to 0.8 degrees C depending on stimulation/tissue parameters.

The Effect of Neuronal Population Size on the Development of Epileptiform Discharges in the Low Calcium Model of Epilepsy

Neuroscience Letters. Jan, 2007  |  Pubmed ID: 17097230

The CA1 region of the rat hippocampal slice generates spontaneous electrographic seizures (field bursts) when exposed to ACSF containing < or = 0.2 mM calcium. It has been proposed that, particularly during the early part of a field burst, synchronised activity in small independent aggregates of neurons results in low amplitude irregular population spikes and subsequent fusion of aggregates generates high amplitude, regular discharging spikes. In the present experiments, we have tested the hypothesis that progression from aggregate formation to aggregate fusion requires a critical mass of participating neurons. We found that isolated CA1 segments >2 mm are still able to generate high amplitude, regular discharging population spikes, but when segment length is reduced to 1-2 mm, only 29% generate spikes with these characteristics; in the remainder, the field burst shows a DC shift+/-low amplitude irregular population spikes. No field bursts were seen in segments < 0.7 mm or in 50% of those 0.7-1 mm in length (in the remaining 50%, only the DC component of the field burst was present). Exposing 1-2 mm segments to hypo-osmolar perfusate induced a return of high amplitude rhythmic discharging population spikes in the field burst. We interpret these observations by indicating that progression from aggregate formation to aggregate fusion requires a critical neuronal mass and can be enhanced by reducing osmolarity of the perfusate.

Spike Timing Amplifies the Effect of Electric Fields on Neurons: Implications for Endogenous Field Effects

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Mar, 2007  |  Pubmed ID: 17360926

Despite compelling phenomenological evidence that small electric fields (<5 mV/mm) can affect brain function, a quantitative and experimentally verified theory is currently lacking. Here we demonstrate a novel mechanism by which the nonlinear properties of single neurons "amplify" the effect of small electric fields: when concurrent to suprathreshold synaptic input, small electric fields can have significant effects on spike timing. For low-frequency fields, our theory predicts a linear dependency of spike timing changes on field strength. For high-frequency fields (relative to the synaptic input), the theory predicts coherent firing, with mean firing phase and coherence each increasing monotonically with field strength. Importantly, in both cases, the effects of fields on spike timing are amplified with decreasing synaptic input slope and increased cell susceptibility (millivolt membrane polarization per field amplitude). We confirmed these predictions experimentally using CA1 hippocampal neurons in vitro exposed to static (direct current) and oscillating (alternating current) uniform electric fields. In addition, we develop a robust method to quantify cell susceptibility using spike timing. Our results provide a precise mechanism for a functional role of endogenous field oscillations (e.g., gamma) in brain function and introduce a framework for considering the effects of environmental fields and design of low-intensity therapeutic neurostimulation technologies.

Effects of High-frequency Stimulation on Epileptiform Activity in Vitro: ON/OFF Control Paradigm

Epilepsia. Sep, 2008  |  Pubmed ID: 18397296

To determine the effects of high-frequency electrical stimulation on electrographic seizure activity during and after stimulation (ON-effect and OFF-effect).

Transcranial Current Stimulation Focality Using Disc and Ring Electrode Configurations: FEM Analysis

Journal of Neural Engineering. Jun, 2008  |  Pubmed ID: 18441418

We calculated the electric fields induced in the brain during transcranial current stimulation (TCS) using a finite-element concentric spheres human head model. A range of disc electrode configurations were simulated: (1) distant-bipolar; (2) adjacent-bipolar; (3) tripolar; and three ring designs, (4) belt, (5) concentric ring, and (6) double concentric ring. We compared the focality of each configuration targeting cortical structures oriented normal to the surface ('surface-radial' and 'cross-section radial'), cortical structures oriented along the brain surface ('surface-tangential' and 'cross-section tangential') and non-oriented cortical surface structures ('surface-magnitude' and 'cross-section magnitude'). For surface-radial fields, we further considered the 'polarity' of modulation (e.g. superficial cortical neuron soma hyper/depolarizing). The distant-bipolar configuration, which is comparable with commonly used TCS protocols, resulted in diffuse (un-focal) modulation with bi-directional radial modulation under each electrode and tangential modulation between electrodes. Increasing the proximity of the two electrodes (adjacent-bipolar electrode configuration) increased focality, at the cost of more surface current. At similar electrode distances, the tripolar-electrodes configuration produced comparable peak focality, but reduced radial bi-directionality. The concentric-ring configuration resulted in the highest spatial focality and uni-directional radial modulation, at the expense of increased total surface current. Changing ring dimensions, or use of two concentric rings, allow titration of this balance. The concentric-ring design may thus provide an optimized configuration for targeted modulation of superficial cortical neurons.

Effects of Glucose and Glutamine Concentration in the Formulation of the Artificial Cerebrospinal Fluid (ACSF)

Brain Research. Jul, 2008  |  Pubmed ID: 18533132

The composition of the ACSF is fundamental in controlling the extracellular environment of the brain slice preparation. 'Typical' formulations lack amino acids and contain a higher concentration of glucose (10 mM) than in the cerebrospinal fluid (0.47-4.4 mM). We examined the effects of different concentrations of glutamine, the most abundant amino acid in the CSF, and glucose on rat hippocampal slice physiology. Bipolar paired-pulse stimulation was applied to the Schaffer collaterals and population spikes were monitored in the CA1 pyramidal layer for approximately 1 hour. Addition of glutamine (0.5 mM) to slices superfused with 10 mM of glucose did not enhance population spike amplitude. Higher concentration of glutamine (2-5 mM) resulted in spreading-depression. Decreasing glucose concentration from 10 mM to 5 mM, in the absence of glutamine, attenuated population spikes. Decreasing glucose to 2 mM, in the absence of glutamine, suppressed evoked population spikes. Superfusing brain slices with ACSF containing 'physiological' concentrations of both glucose (2 mM) and glutamine (0.5 mM) similarly suppressed population spikes. In separate experiments, during high-K+ induced epileptiform activity, glutamine (0.5 mM) did not affect the burst duration, frequency or waveform. These results suggest that the concentration of glucose in ACSF should conservatively be 10 mM in order to maximize paired-pulse population responses while the presence of physiological concentration of glutamine (0.5 mM) has minimal effects on paired-pulse responses and high-K+ induced epileptiform activity. These results are discussed in the context of fundamental differences between in vitro brain slice superfusion and in vivo brain perfusion.

Transcranial Direct Current Stimulation for Major Depression: a General System for Quantifying Transcranial Electrotherapy Dosage

Current Treatment Options in Neurology. Sep, 2008  |  Pubmed ID: 18782510

There has been a recent resurgence of interest in therapeutic modalities using transcranial weak electrical stimulation through scalp electrodes, such as trans-cranial direct current stimulation (tDCS), as a means of experimentally modifying and studying brain function and possibly treating psychiatric conditions. A range of electrotherapy paradigms have been investigated, but no consistent method has been indicated for reporting reproducible stimulation "dosage." Anecdotal reports, case studies, and limited clinical trials with small numbers suggest that tDCS may be effective in treating some patients with depression, but methods for selecting the optimal stimulation parameters ("dosage") are not clear, and there is no conclusive indication that tDCS is an effective treatment for depression. Larger, controlled studies are necessary to determine its safety and efficacy in a clinical setting. If tDCS can be established as an effective treatment for depression, it would represent a particularly attractive electrotherapy option, as it is a relatively benign and affordable treatment modality. An accurate system for describing reproducible treatment parameters is essential so that further studies can yield evidence-based guidelines for the clinical use of transcranial current stimulation. Development of appropriate parameters requires a biophysical understanding of how electrotherapy affects brain function and should include different paradigms for different clinical applications. As with any dosage guidelines, such a system does not supersede physician judgment on safety.

Establishing Safety Limits for Transcranial Direct Current Stimulation

Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. Jun, 2009  |  Pubmed ID: 19394269

Gyri-precise Head Model of Transcranial Direct Current Stimulation: Improved Spatial Focality Using a Ring Electrode Versus Conventional Rectangular Pad

Brain Stimulation. Oct, 2009  |  Pubmed ID: 20648973

The spatial resolution of conventional transcranial direct current stimulation (tDCS) is considered to be relatively diffuse owing to skull dispersion. However, we show that electric fields may be clustered at distinct gyri/sulci sites because of details in tissue architecture/conductivity, notably cerebrospinal fluid (CSF). We calculated the cortical electric field/current density magnitude induced during tDCS using a high spatial resolution (1 mm3) magnetic resonance imaging (MRI)-derived finite element human head model; cortical gyri/sulci were resolved. The spatial focality of conventional rectangular-pad (7 x 5 cm2) and the ring (4 x 1) electrode configurations were compared. The rectangular-pad configuration resulted in diffuse (unfocal) modulation, with discrete clusters of electric field magnitude maxima. Peak-induced electric field magnitude was not observed directly underneath the pads, but at an intermediate lobe. The 4 x 1 ring resulted in enhanced spatial focality, with peak-induced electric field magnitude at the sulcus and adjacent gyri directly underneath the active electrode. Cortical structures may be focally targeted by using ring configurations. Anatomically accurate high-resolution MRI-based forward-models may guide the "rational" clinical design and optimization of tDCS.

Bio-heat Transfer Model of Transcranial DC Stimulation: Comparison of Conventional Pad Versus Ring Electrode

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2009  |  Pubmed ID: 19964238

Transcranial Direct Current Stimulation (tDCS) is a non-invasive procedure where a weak electrical current is applied across the scalp to modulate brain function. The proliferation of this therapy has been accompanied by isolated reports regarding concern about their safety namely skin irritation. The potential cause of skin irritation has sometimes been attributed to increased scalp temperature during stimulation. We have developed novel technology for tDCS that improves spatial focality at the cost of increased stimulation electrode current density; high density tDCS (HD-tDCS). The goal of this paper was to provide information on the thermal effects of tDCS using a MRI-derived finite element human head model. The tissue temperature increases of tDCS using conventional rectangular-pad (7 x 5 cm(2)) and HD-tDCS using the ring (4 x 1) electrode configurations were compared using a bio-heat model. Our results indicate that clinical tDCS do not increase tissue temperature and 4 x 1 ring configurations leads to a negligible increase in scalp temperature.

One-dimensional Representation of a Neuron in a Uniform Electric Field

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2009  |  Pubmed ID: 19964438

The neocortex is the most common target of sub-dural electrotherapy and non-invasive brain stimulation modalities including transcranial magnetic stimulation (TMS) and transcranial direct current simulation (tDCS). Specific neuronal elements targeted by cortical stimulation are considered to underlie therapeutic effects, but the exact cell-type(s) affected by these methods remains poorly understood. We determined if neuronal morphology predicted responses to subthreshold uniform electric fields. We characterized the effects of subthreshold electrical stimulation on identified cortical neurons in vitro. Uniform electric fields were applied to rat motor cortex brain slices, while recording from interneurons and pyramidal cells across cortical layers, using whole cell patch clamp. Neuron morphology was reconstructed following intracellular dialysis of biocytin. Based solely on volume-weighted morphology, we developed a simplified model of neuronal polarization by sub-threshold electric field: an electrotonically linear cylinder that further predicts polarization at distal dendritic tree terminations. We found that neuronal morphology correlated with somatic sub-threshold polarization. Layer V/VI pyramidal neuron somata (individually) and dendrites (averaging across neurons) were most sensitive to sub-threshold fields. This analysis was extended to predict a terminal polarization of a human cortical neuron as 1.44 mV during tDCS.

Gyri -precise Head Model of Transcranial DC Stimulation: Improved Spatial Focality Using a Ring Electrode Versus Conventional Rectangular Pad

Brain Stimulation. Oct, 2009  |  Pubmed ID: 20161455

The spatial resolution of conventional transcranial direct current stimulation (tDCS) is considered to be relatively diffuse owing to skull dispersion. However, here we show that electric fields may be clustered at distinct gyri/sulci sites due to details in tissue architecture/conductivity notably cerebrospinal fluid (CSF). We calculated the cortical electric field/current density magnitude induced during tDCS using a high spatial resolution (1 mm(3)) MRI-derived finite element human head model; cortical gyri/sulci were resolved. The spatial focality of conventional rectangular-pad (7 x 5 cm(2)) and the ring (4 x 1) electrode configurations were compared. The rectangular-pad configuration resulted in diffuse (un-focal) modulation, with discrete clusters of electric field magnitude maxima. Peak induced electric field magnitude was not observed directly underneath the pads, but at an intermediate lobe. The 4 x 1 ring resulted in enhanced spatial focality, with peak induced electric field magnitude at the sulcus and adjacent gyri directly underneath the active electrode. Cortical structures may be focally targeted using ring configurations. Anatomically accurate high resolution MRI-based forward-models may guide the 'rational' clinical design and optimization of tDCS.

Role of Cortical Cell Type and Morphology in Subthreshold and Suprathreshold Uniform Electric Field Stimulation in Vitro

Brain Stimulation. Oct, 2009  |  Pubmed ID: 20161507

The neocortex is the most common target of subdural electrotherapy and noninvasive brain stimulation modalities, including transcranial magnetic stimulation (TMS) and transcranial current simulation (TCS). Specific neuronal elements targeted by cortical stimulation are considered to underlie therapeutic effects, but the exact cell type(s) affected by these methods remains poorly understood.

Transcranial Direct Current Stimulation in Patients with Skull Defects and Skull Plates: High-resolution Computational FEM Study of Factors Altering Cortical Current Flow

NeuroImage. Oct, 2010  |  Pubmed ID: 20435146

Preliminary positive results of transcranial direct current stimulation (tDCS) in enhancing the effects of cognitive and motor training indicate that this technique might also be beneficial in traumatic brain injury or patients who had decompressive craniectomy for trauma and cerebrovascular disease. One perceived hurdle is the presence of skull defects or skull plates in these patients that would hypothetically alter the intensity and location of current flow through the brain. We aimed to model tDCS using a magnetic resonance imaging (MRI)-derived finite element head model with several conceptualized skull injuries. Cortical electric field (current density) peak intensities and distributions were compared with the healthy (skull intact) case. The factors of electrode position (C3-supraorbital or O1-supraorbital), electrode size skull defect size, skull defect state (acute and chronic) or skull plate (titanium and acrylic) were analyzed. If and how electric current through the brain was modulated by defects was found to depend on a specific combination of factors. For example, the condition that led to largest increase in peak cortical electric field was when one electrode was placed directly over a moderate sized skull defect. In contrast, small defects midway between electrodes did not significantly change cortical currents. As the conductivity of large skull defects/plates was increased (chronic to acute to titanium), current was shunted away from directly underlying cortex and concentrated in cortex underlying the defect perimeter. The predictions of this study are the first step to assess safety of transcranial electrical therapy in subjects with skull injuries and skull plates.

Electrodes for High-definition Transcutaneous DC Stimulation for Applications in Drug Delivery and Electrotherapy, Including TDCS

Journal of Neuroscience Methods. Jul, 2010  |  Pubmed ID: 20488204

Transcutaneous electrical stimulation is applied in a range of biomedical applications including transcranial direct current stimulation (tDCS). tDCS is a non-invasive procedure where a weak direct current (<2 mA) is applied across the scalp to modulate brain function. High-definition tDCS (HD-tDCS) is a technique used to increase the spatial focality of tDCS by passing current across the scalp using <12 mm diameter electrodes. The purpose of this study was to design and optimize "high-definition" electrode-gel parameters for electrode durability, skin safety and subjective pain. Anode and cathode electrode potential, temperature, pH and subjective sensation over time were assessed during application of 2 mA direct current, for up to 22 min on agar gel or subject forearms. A selection of five types of solid-conductors (Ag pellet, Ag/AgCl pellet, rubber pellet, Ag/AgCl ring and Ag/AgCl disc) and seven conductive gels (Signa, Spectra, Tensive, Redux, BioGel, Lectron and CCNY-4) were investigated. The Ag/AgCl ring in combination with CCNY-4 gel resulted in the most favorable outcomes. Under anode stimulations, electrode potential and temperature rises were generally observed in all electrode-gel combinations except for Ag/AgCl ring and disc electrodes. pH remained constant for all solid-conductors except for both Ag and rubber pellet electrodes with Signa and CCNY-4 gels. Sensation ratings were independent of stimulation polarity. Ag/AgCl ring electrodes were found to be the most comfortable followed by Ag, rubber and Ag/AgCl pellet electrodes across all gels.

Low-intensity Electrical Stimulation Affects Network Dynamics by Modulating Population Rate and Spike Timing

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Nov, 2010  |  Pubmed ID: 21068312

Clinical effects of transcranial electrical stimulation with weak currents are remarkable considering the low amplitude of the electric fields acting on the brain. Elucidating the processes by which small currents affect ongoing brain activity is of paramount importance for the rational design of noninvasive electrotherapeutic strategies and to determine the relevance of endogenous fields. We propose that in active neuronal networks, weak electrical fields induce small but coherent changes in the firing rate and timing of neuronal populations that can be magnified by dynamic network activity. Specifically, we show that carbachol-induced gamma oscillations (25-35 Hz) in rat hippocampal slices have an inherent rate-limiting dynamic and timing precision that govern susceptibility to low-frequency weak electric fields (<50 Hz; <10 V/m). This leads to a range of nonlinear responses, including the following: (1) asymmetric power modulation by DC fields resulting from balanced excitation and inhibition; (2) symmetric power modulation by lower frequency AC fields with a net-zero change in firing rate; and (3) half-harmonic oscillations for higher frequency AC fields resulting from increased spike timing precision. These underlying mechanisms were elucidated by slice experiments and a parsimonious computational network model of single-compartment spiking neurons responding to electric field stimulation with small incremental polarization. Intracellular recordings confirmed model predictions on neuronal timing and rate changes, as well as spike phase-entrainment resonance at 0.2 V/m. Finally, our data and mechanistic framework provide a functional role for endogenous electric fields, specifically illustrating that modulation of gamma oscillations during theta-modulated gamma activity can result from field effects alone.

Toward Rational Design of Electrical Stimulation Strategies for Epilepsy Control

Epilepsy & Behavior : E&B. Jan, 2010  |  Pubmed ID: 19926525

Electrical stimulation is emerging as a viable alternative for patients with epilepsy whose seizures are not alleviated by drugs or surgery. Its attractions are temporal and spatial specificity of action, flexibility of waveform parameters and timing, and the perception that its effects are reversible unlike resective surgery. However, despite significant advances in our understanding of mechanisms of neural electrical stimulation, clinical electrotherapy for seizures relies heavily on empirical tuning of parameters and protocols. We highlight concurrent treatment goals with potentially conflicting design constraints that must be resolved when formulating rational strategies for epilepsy electrotherapy, namely, seizure reduction versus cognitive impairment, stimulation efficacy versus tissue safety, and mechanistic insight versus clinical pragmatism. First, treatment markers, objectives, and metrics relevant to electrical stimulation for epilepsy are discussed from a clinical perspective. Then the experimental perspective is presented, with the biophysical mechanisms and modalities of open-loop electrical stimulation, and the potential benefits of closed-loop control for epilepsy.

Cutaneous Perception During TDCS: Role of Electrode Shape and Sponge Salinity

Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. Apr, 2011  |  Pubmed ID: 21075048

Transcranial DC Stimulation in Fibromyalgia: Optimized Cortical Target Supported by High-resolution Computational Models

The Journal of Pain : Official Journal of the American Pain Society. May, 2011  |  Pubmed ID: 21497140

In this study we aimed to determine current distribution and short-term analgesic effects of transcranial direct current stimulation (tDCS) in fibromyalgia using different electrode montages. For each electrode montage, clinical effects were correlated with predictions of induced cortical current flow using magnetic resonance imaging-derived finite element method head model. Thirty patients were randomized into 5 groups (Cathodal-M1 [primary motor cortex], Cathodal-SO [supra-orbital area], Anodal-M1, Anodal-SO, and Sham) to receive tDCS application (2 mA, 20 minutes) using an extracephalic montage. Pain was measured using a visual numerical scale (VNS), pressure pain threshold (PPT), and a body diagram (BD) evaluating pain area. There was significant pain reduction in cathodal-SO and anodal-SO groups indexed by VNS. For PPT there was a trend for a similar effect in anodal-SO group. Computer simulation indicated that the M1-extracephalic montage produced dominantly temporo-parietal current flow, consistent with lack of clinical effects with this montage. Conversely, the SO-extracephalic montage produced current flow across anterior prefrontal structures, thus supporting the observed analgesic effects. Our clinical and modeling findings suggest that electrode montage, considering both electrodes, is critical for the clinical effects of M1-tDCS as electric current needs to be induced in areas associated with the pain matrix. These results should be taken into consideration for the design of pain tDCS studies. PERSPECTIVE: Results in this article support that electrode montage is a critical factor to consider for the clinical application of tDCS for pain control, as there is an important correlation between the location of induced electrical current and tDCS-induced analgesic effects.

Optimized Multi-electrode Stimulation Increases Focality and Intensity at Target

Journal of Neural Engineering. Aug, 2011  |  Pubmed ID: 21659696

Transcranial direct current stimulation (tDCS) provides a non-invasive tool to elicit neuromodulation by delivering current through electrodes placed on the scalp. The present clinical paradigm uses two relatively large electrodes to inject current through the head resulting in electric fields that are broadly distributed over large regions of the brain. In this paper, we present a method that uses multiple small electrodes (i.e. 1.2 cm diameter) and systematically optimize the applied currents to achieve effective and targeted stimulation while ensuring safety of stimulation. We found a fundamental trade-off between achievable intensity (at the target) and focality, and algorithms to optimize both measures are presented. When compared with large pad-electrodes (approximated here by a set of small electrodes covering 25 cm(2)), the proposed approach achieves electric fields which exhibit simultaneously greater focality (80% improvement) and higher target intensity (98% improvement) at cortical targets using the same total current applied. These improvements illustrate the previously unrecognized and non-trivial dependence of the optimal electrode configuration on the desired electric field orientation and the maximum total current (due to safety). Similarly, by exploiting idiosyncratic details of brain anatomy, the optimization approach significantly improves upon prior un-optimized approaches using small electrodes. The analysis also reveals the optimal use of conventional bipolar montages: maximally intense tangential fields are attained with the two electrodes placed at a considerable distance from the target along the direction of the desired field; when radial fields are desired, the maximum-intensity configuration consists of an electrode placed directly over the target with a distant return electrode. To summarize, if a target location and stimulation orientation can be defined by the clinician, then the proposed technique is superior in terms of both focality and intensity as compared to previous solutions and is thus expected to translate into improved patient safety and increased clinical efficacy.

Individualized Model Predicts Brain Current Flow During Transcranial Direct-current Stimulation Treatment in Responsive Stroke Patient

Brain Stimulation. Jul, 2011  |  Pubmed ID: 21777878

Although numerous published reports have demonstrated the beneficial effects of transcranial direct-current stimulation (tDCS) on task performance, fundamental questions remain regarding the optimal electrode configuration on the scalp. Moreover, it is expected that lesioned brain tissue will influence current flow and should therefore be considered (and perhaps leveraged) in the design of individualized tDCS therapies for stroke. The current report demonstrates how different electrode configurations influence the flow of electrical current through brain tissue in a patient who responded positively to a tDCS treatment targeting aphasia. The patient, a 60-year-old man, sustained a left hemisphere ischemic stroke (lesion size = 87.42 mL) 64 months before his participation. In this study, we present results from the first high-resolution (1 mm(3)) model of tDCS in a brain with considerable stroke-related damage; the model was individualized for the patient who received anodal tDCS to his left frontal cortex with the reference cathode electrode placed on his right shoulder. We modeled the resulting brain current flow and also considered three additional reference electrode positions: right mastoid, right orbitofrontal cortex, and a "mirror" configuration with the anode over the undamaged right cortex. Our results demonstrate the profound effect of lesioned tissue on resulting current flow and the ability to modulate current pattern through the brain, including perilesional regions, through electrode montage design. The complexity of brain current flow modulation by detailed normal and pathologic anatomy suggest: (1) That computational models are critical for the rational interpretation and design of individualized tDCS stroke-therapy; and (2) These models must accurately reproduce head anatomy as shown here.

Guidelines for Precise and Accurate Computational Models of TDCS

Brain Stimulation. Jul, 2011  |  Pubmed ID: 21782547

Clinical Research with Transcranial Direct Current Stimulation (tDCS): Challenges and Future Directions

Brain Stimulation. Apr, 2011  |  Pubmed ID: 22037126

BACKGROUND: Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that delivers low-intensity, direct current to cortical areas facilitating or inhibiting spontaneous neuronal activity. In the past 10 years, tDCS physiologic mechanisms of action have been intensively investigated giving support for the investigation of its applications in clinical neuropsychiatry and rehabilitation. However, new methodologic, ethical, and regulatory issues emerge when translating the findings of preclinical and phase I studies into phase II and III clinical studies. The aim of this comprehensive review is to discuss the key challenges of this process and possible methods to address them. METHODS: We convened a workgroup of researchers in the field to review, discuss, and provide updates and key challenges of tDCS use in clinical research. MAIN FINDINGS/DISCUSSION: We reviewed several basic and clinical studies in the field and identified potential limitations, taking into account the particularities of the technique. We review and discuss the findings into four topics: (1) mechanisms of action of tDCS, parameters of use and computer-based human brain modeling investigating electric current fields and magnitude induced by tDCS; (2) methodologic aspects related to the clinical research of tDCS as divided according to study phase (ie, preclinical, phase I, phase II, and phase III studies); (3) ethical and regulatory concerns; and (4) future directions regarding novel approaches, novel devices, and future studies involving tDCS. Finally, we propose some alternative methods to facilitate clinical research on tDCS.

Real-time Intraoperative Detection of Tissue Hypoxia in Gastrointestinal Surgery by Wireless Pulse Oximetry

Surgical Endoscopy. May, 2011  |  Pubmed ID: 20972585

Dehiscence or leakage after bowel anastomoses is associated with high morbidity and mortality. Perfusion and local tissue oxygenation (StO2), independent of systemic oxygen saturation, are fundamental determinants of anastomotic viability. Because current technology is limited for monitoring local StO2 at bowel anastomoses, our goal was to construct a wireless pulse oximeter (WiPOX) to monitor real-time intraoperative tissue oxygenation, permitting identification of compromised anastomotic perfusion.

Fundamentals of Transcranial Electric and Magnetic Stimulation Dose: Definition, Selection, and Reporting Practices

Brain Stimulation. Nov, 2011  |  Pubmed ID: 22305345

BACKGROUND: The growing use of transcranial electric and magnetic (EM) brain stimulation in basic research and in clinical applications necessitates a clear understanding of what constitutes the dose of EM stimulation and how it should be reported. METHODS: This paper provides fundamental definitions and principles for reporting of dose that encompass any transcranial EM brain stimulation protocol. RESULTS: The biologic effects of EM stimulation are mediated through an electromagnetic field injected (via electric stimulation) or induced (via magnetic stimulation) in the body. Therefore, transcranial EM stimulation dose ought to be defined by all parameters of the stimulation device that affect the electromagnetic field generated in the body, including the stimulation electrode or coil configuration parameters: shape, size, position, and electrical properties, as well as the electrode or coil current (or voltage) waveform parameters: pulse shape, amplitude, width, polarity, and repetition frequency; duration of and interval between bursts or trains of pulses; total number of pulses; and interval between stimulation sessions and total number of sessions. Knowledge of the electromagnetic field generated in the body may not be sufficient but is necessary to understand the biologic effects of EM stimulation. CONCLUSIONS: We believe that reporting of EM stimulation dose should be guided by the principle of reproducibility: sufficient information about the stimulation parameters should be provided so that the dose can be replicated.

Left Lateralizing Transcranial Direct Current Stimulation Improves Reading Efficiency

Brain Stimulation. May, 2011  |  Pubmed ID: 22305346

BACKGROUND: Poor reading efficiency is the most persistent problem for adults with developmental dyslexia. Previous research has demonstrated a relationship between left posterior temporal cortex (pTC) function and reading ability, regardless of dyslexia status. OBJECTIVE/HYPOTHESIS: In this study, we tested whether enhancing left lateralization of pTC using transcranial direct current stimulation (tDCS) improves reading efficiency in adults without dyslexia. METHOD: Twenty-five right-handed adults with no history of learning disorder participated. Real and sham "Left lateralizing" tDCS were applied to the pTC in separate sessions. Standardized word and nonword reading tests were given immediately after stimulation. RESULTS: Modeling of the induced electrical field confirmed that tDCS was likely to increase left pTC excitability and reduce right pTC excitability as intended. Relative to sham, real tDCS induced improvements in word reading efficiency in below average readers. CONCLUSIONS: Enhancing left lateralization of the pTC using tDCS improves word reading efficiency in below-average readers. This demonstrates that left lateralization of the pTC plays a role in reading ability, and provides stimulation parameters that could be used for a trial of tDCS in adults with developmental dyslexia. Such short-term gains could amplify the effect of appropriate reading interventions when performed in conjunction with them.

A Pilot Study of the Tolerability and Effects of High-Definition Transcranial Direct Current Stimulation (HD-tDCS) on Pain Perception

The Journal of Pain : Official Journal of the American Pain Society. Feb, 2012  |  Pubmed ID: 22104190

Several brain stimulation technologies are beginning to evidence promise as pain treatments. However, traditional versions of 1 specific technique, transcranial direct current stimulation (tDCS), stimulate broad regions of cortex with poor spatial precision. A new tDCS design, called high definition tDCS (HD-tDCS), allows for focal delivery of the charge to discrete regions of the cortex. We sought to preliminarily test the safety and tolerability of the HD-tDCS technique as well as to evaluate whether HD-tDCS over the motor cortex would decrease pain and sensory experience. Twenty-four healthy adult volunteers underwent quantitative sensory testing before and after 20 minutes of real (n = 13) or sham (n = 11) 2 mA HD-tDCS over the motor cortex. No adverse events occurred and no side effects were reported. Real HD-tDCS was associated with significantly decreased heat and cold sensory thresholds, decreased thermal wind-up pain, and a marginal analgesic effect for cold pain thresholds. No significant effects were observed for mechanical pain thresholds or heat pain thresholds. HD-tDCS appears well tolerated, and produced changes in underlying cortex that are associated with changes in pain perception. Future studies are warranted to investigate HD-tDCS in other applications, and to examine further its potential to affect pain perception. PERSPECTIVE: This article presents preliminary tolerability and efficacy data for a new focal brain stimulation technique called high definition transcranial direct current stimulation. This technique may have applications in the management of pain.