Transcranial Electric Stimulation Entrains Cortical Neuronal Populations in Rats

Low intensity electric fields have been suggested to affect the ongoing neuronal activity in vitro and in human studies. However, the physiological mechanism of how weak electrical fields affect and interact with intact brain activity is not well understood. We performed in vivo extracellular and intracellular recordings from the neocortex and hippocampus of anesthetized rats and extracellular recordings in behaving rats. Electric fields were generated by sinusoid patterns at slow frequency (0.8, 1.25 or 1.7 Hz) via electrodes placed on the surface of the skull or the dura. Transcranial electric stimulation (TES) reliably entrained neurons in widespread cortical areas, including the hippocampus. The percentage of TES phase-locked neurons increased with stimulus intensity and depended on the behavioral state of the animal. TES-induced voltage gradient, as low as 1 mV/mm at the recording sites, was sufficient to phase-bias neuronal spiking. Intracellular recordings showed that both spiking and subthreshold activity were under the combined influence of TES forced fields and network activity. We suggest that TES in chronic preparations may be used for experimental and therapeutic control of brain activity.

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title: Theoretical reconstruction of field potentials and dendrodendritic synaptic interactions in olfactory bulb.
abstract: THE ORIGINAL OBJECTIVE of this research was to apply a mathematical theory of generalized dendritic neurons (36-39) to the interpretation and reconstruction of field potentials observed in the olfactory bulb of rabbit (32, 33). In the course of pursuing this objective, we were led to postulate dendrodendritic synaptic interactions which probably play an important role in sensory discrimination and adaptation in the olfactory system (40). More specifically, our initial aim was to develop a computational model, based on the known anatomical organization of the olfactory bulb and on generally accepted properties of nerve membrane, that could reconstruct the distribution of electric potential as a function of two variables, time and depth in the bulbar layers, following a synchronous antidromic volley in the lateral olfactory tract. The experimental studies of Phillips, Powell, and Shepherd (32, 33) had previously established that the recorded potentials at successive bulbar depths are highly reproducible and correlated with the histological layers of the bulb. These authors recognized the importance of this finding in relation to the symmetry and synchrony of activity in the mitral cell population; they deferred the interpretation of these potentials, in terms of specific neuronal activity, with a view to the present theoretical study.

title: Influence of electric fields on the excitability of granule cells in guinea‐pig hippocampal slices.
abstract: 1. Monosynaptic evoked potentials were recorded from the granule cell layer of slices of guinea‐pig hippocampus maintained in vitro. Current pulses of 25‐250 msec duration were passed across the slices, between gross electrodes in the bathing liquid. 2. Polarizing current modified the excitability of the granule cells as judged by changes in their population discharge during postsynaptic responses. All durations of polarization had at least qualitatively similar effects. Conventional current from dendrites to cell bodies increased excitability (and vice versa). This is consistent with altered membrane potential of a spike trigger zone, at or close to the granule cell bodies, imposed by the fraction of polarizing current which flows intracellularly. 3. In some experiments polarization also affected the presynaptic volley and (hence?) the synaptic potential. When this occurred it was in the wrong sense to explain the concomitant changes in population spike. 4. Focal polarization, where currents were applied across the cell body layer between a small electrode on the mid or outer dendritic regions and a remote gross electrode, altered granule cell excitability in the same direction as in (2). Thus conventional current injected at the dendritic electrode increased excitability. 5. The smallest effect polarizing currents caused extracellular voltage gradients of 5‐10 mV/mm, which is less than occurs in this tissue during synchronous activation of the neurons or during seizure activity. Therefore such field potentials could increased the synchrony of discharge of the granule cells.

title: Nonsynaptic modulation of neuronal activity in the brain: electric currents and extracellular ions.
abstract: Nonsynaptic interactions between neurons have been eclipsed by our increasingly detailed understanding of chemical synapses, but they do play significant roles in the nervous system. This review considers four classes of nonsynaptic interaction, mainly in mammalian brain. 1) Electrotonic (and chemical) coupling through gap junctions has effects during development and under some, often pathological, conditions in the mature brain. 2) Ephaptic transmission is mediated by electrical coupling between specific neuronal elements in the absence of specialized contacts, notably in the cerebellum, and in axon tracts affected by demyelination. 3) Field effect interactions are mediated by large extracellular currents and potential fields generated by the hippocampus and other cortical structures. Both endogenous and applied electric fields alter neuronal excitability at field strengths over a few millivolts per millimeter. Weaker fields have more subtle effects, for instance, on axonal growth during development and repair and, more controversially, in behavioral responses to environmental fields. 4) There are fluctuations in extracellular ions such as K+, which are released during neuronal activity and which alter neuronal excitability. Field effects and ion fluctuations probably have modest effects during physiological activity but have a significant impact on epileptic seizures, and can sustain them in the absence of synaptic transmission.

title: Synchronous neural afterdischarges in rat hippocampal slices without active chemical synapses.
abstract: Extracellular field potential and intracellular recordings from neurons in rat hippocampus show that, even with synaptic transmission blocked, antidromic electrical stimuli can trigger afterdischarges of up to 9 seconds duration; during these discharges action potentials of a single neuron were synchronized with extracellularly recorded population spikes. Apparently mechanisms other than recurrent chemical synapses can synchronize and recruit epileptiform events. Measurements of transmembrane potential indicate that transient extracellular electrical fields (ephaptic interactions) contribute to the observed synchrony; electrotonic coupling and changes in the concentration of extracellular ions may also contribute.

title: Simulation of hippocampal afterdischarges synchronized by electrical interactions
abstract: Recent experiments have shown that hippocampal pyramidal cells can generate synchronized action potentials even when chemical synapses are blocked. The computer simulations reported here showed that communication between cells by extracellular currents could cause this synchrony, provided that (1) individual neurons were sufficiently excitable and that (2) the resistivity of the extracellular medium was sufficiently high. Synchronization was enhanced if electronic junctions were also present.

title: Modulation by applied electric fields of Purkinje and stellate cell activity in the isolated turtle cerebellum.
abstract: Quasi steady‐state electric fields were applied across the isolated turtle cerebellum to study the relationship between applied field, neuronal morphology and the modulation of the neuronal spike firing pattern. Spiking elements were identified electrophysiologically using extracellular recording methods and by subsequent horseradish peroxidase injection, which revealed their dendritic morphology and orientation. The electric field was precisely defined by measuring the voltage gradients induced in the cerebellum by 40 s constant‐current pulses. The field was constant in the vertical (dorso‐ventral) axis and zero in the horizontal plane, in agreement with theory. Neurones were modulated by applying a sinusoidal field at frequencies between 0.05 and 1.0 Hz. Modulated cells exhibited an increase in firing frequency and fell into one of four classes, depending on the direction of the field that produced the modulation. Thus neurones were excited by: ventricle‐directed fields (V modulation), pia‐directed fields (P modulation), both of the above (V/P modulation) or showed no consistent modulation (non‐modulation). Most Purkinje somata and primary dendrites (nineteen out of twenty‐eight) and most Purkinje dendrites (eighteen out of thirty), were V modulated with maximum rate proportional to the peak field intensity. The dendrites of these cells were consistently oriented toward the pia. Among the stellate cells, the lower molecular layer stellates, with dendrites extending predominantly towards the pia, were mostly (nineteen out of thirty‐two) V modulated. The mid‐molecular layer stellates, which showed much variability in dendritic orientation, were distributed among all four of the modulation classes. The upper molecular layer stellates, with a mostly horizontal dendritic alignment, were mainly (nine out of sixteen) non‐modulated. All groups of spiking elements showed a correlation between patterns of modulation by applied fields and dendritic orientation, which suggests the degree of differential polarization of the extended cable elements of the neurone by the applied field as the basic mechanism for field‐induced excitation or inhibition. The threshold for modulation among all neurones was 15‐20 mV/mm, which is similar to the fields that modulate other nervous tissues. This suggests that many neurones can be modulated by fields of the order of 10‐20 mV/mm.

title: A model for the polarization of neurons by extrinsically applied electric fields.
abstract: A model is presented for the subthreshold polarization of a neuron by an applied electric field. It gives insight into how morphological features of a neuron affect its polarizability. The neuronal model consists of one or more extensively branched dendritic trees, a lumped somatic impedance, and a myelinated axon with nodes of Ranvier. The dendritic trees branch according to the 3/2-power rule of Rall, so that each tree has an equivalent cylinder representation. Equations for the membrane potential at the soma and at the nodes of Ranvier, given an arbitrary specified external potential, are derived. The solutions determine the contributions made by the dendritic tree and the axon to the net polarization at the soma. In the case of a spatially constant electric field, both the magnitude and sign of the polarization depend on simple combinations of parameters describing the neuron. One important combination is given by the ratio of internal resistances for longitudinal current spread along the dendritic tree trunk and along the axon. A second is given by the ratio between the DC space constant for the dendritic tree trunk and the distance between nodes of Ranvier in the axon. A third is given by the product of the electric field and the space constant for the trunk of the dendritic tree. When a neuron with a straight axon is subjected to a constant field, the membrane potential decays exponentially with distance from the soma. Thus, the soma seems to be a likely site for action potential initiation when the field is strong enough to elicit suprathreshold polarization. In a simple example, the way in which orientation of the various parts of the neuron affects its polarization is examined. When an axon with a bend is subjected to a spatially constant field, polarization is focused at the bend, and this is another likely site for action potential initiation.

title: Electrical Interactions via the Extracellular Potential Near Cell Bodies
abstract: Ephaptic interactions between a neuron and axons or dendrites passing by its cell body can be, in principle, more significant than ephaptic interactions among axons in a fiber tract. Extracellular action potentials outside axons are small in amplitude and spatially spread out, while they are larger in amplitude and much more spatially confined near cell bodies. We estimated the extracellular potentials associated with an action potential in a cortical pyramidal cell using standard one-dimensional cable theory and volume conductor theory. Their spatial and temporal pattern reveal much about the location and timing of currents in the cell, especially in combination with a known morphology, and simple experiments could resolve questions about spike initiation. From the extracellular potential we compute the ephaptically induced polarization in a nearby passive cable. The magnitude of this induced voltage can be several mV, does not spread electrotonically, and depends only weakly on the passive properties of the cable. We discuss their possible functional relevance.

title: Excitation of central nervous system neurons by nonuniform electric fields.
abstract: The goal of this study was to determine which neural elements are excited by microstimulation of the central nervous system. A cable model of a neuron including an axon, initial segment, axon hillock, soma, and simplified dendritic tree was used to study excitation with an extracellular point source electrode. The model reproduced a wide range of experimentally documented extracellular excitation patterns. The site of action potential initiation (API) was a function of the electrode position, stimulus duration, and stimulus polarity. The axon or initial segment was always the site of API at threshold. When the electrode was positioned near the cell body, the site of excitation was dependent on the stimulus amplitude. With the electrode in close proximity to the neuron, short-duration cathodic pulses produced lower thresholds with the electrode positioned over the axon than over the cell body, and long-duration stimuli produced opposite relative thresholds. This result was robust to alterations in either the maximum conductances or the intracellular resistivities of the model. The site of maximum depolarization was not always an accurate predictor of the site of API, and the temporal evolution of the changes in membrane potential played a strong role in determining the site of excitation.

title: Sensitivity of Neurons to Weak Electric Fields
abstract: Weak electric fields modulate neuronal activity, and knowledge of the interaction threshold is important in the understanding of neuronal synchronization, in neural prosthetic design, and in the public health assessment of environmental extremely low frequency fields. Previous experimental measurements have placed the threshold between 1 and 5 mV/mm, although theory predicts that elongated neurons should have submillivolt per millimeter sensitivity near 100 μV/mm. We here provide the first experimental confirmation that neuronal networks are detectably sensitive to submillivolt per millimeter electrical fields [Gaussian pulses 26 msec full width at half-maximal, 140 μV/mm root mean square (rms), 295 μV/mm peak amplitude], an order of magnitude below previous findings, and further demonstrate that these networks are more sensitive than the average single neuron threshold (185 μV/mm rms, 394 μV/mm peak amplitude) to field modulation.

title: Modeling extracellular field potentials and the frequency-filtering properties of extracellular space.
abstract: Extracellular local field potentials are usually modeled as arising from a set of current sources embedded in a homogeneous extracellular medium. Although this formalism can successfully model several properties of extracellular local field potentials, it does not account for their frequency-dependent attenuation with distance, a property essential to correctly model extracellular spikes. Here we derive expressions for the extracellular potential that include this frequency-dependent attenuation. We first show that, if the extracellular conductivity is nonhomogeneous, there is induction of nonhomogeneous charge densities that may result in a low-pass filter. We next derive a simplified model consisting of a punctual (or spherical) current source with spherically symmetric conductivity/permittivity gradients around the source. We analyze the effect of different radial profiles of conductivity and permittivity on the frequency-filtering behavior of this model. We show that this simple model generally displays low-pass filtering behavior, in which fast electrical events (such as Na(+)-mediated action potentials) attenuate very steeply with distance, whereas slower (K(+)-mediated) events propagate over larger distances in extracellular space, in qualitative agreement with experimental observations. This simple model can be used to obtain frequency-dependent extracellular field potentials without taking into account explicitly the complex folding of extracellular space.

title: In Vivo Measurement of Cortical Impedance Spectrum in Monkeys: Implications for Signal Propagation
abstract: To combine insights obtained from electric field potentials (LFPs) and neuronal spiking activity (MUA) we need a better understanding of the relative spatial summation of these indices of neuronal activity. Compared to MUA, the LFP has greater spatial coherence, resulting in lower spatial specificity and lower stimulus selectivity. A differential propagation of low- and high-frequency electric signals supposedly underlies this phenomenon, which could result from cortical tissue specifically attenuating higher frequencies, i.e., from a frequency-dependent impedance spectrum. Here we directly measure the cortical impedance spectrum in vivo in monkey primary visual cortex. Our results show that impedance is independent of frequency, is homogeneous and tangentially isotropic within gray matter, and can be theoretically predicted assuming a pure-resistive conductor. We propose that the spatial summation of LFP and MUA is determined by the size of these signals' generators and the nature of neural events underlying them, rather than by biophysical properties of gray matter.

title: Influences of sinusoidal electric fields on excitability in the rat hippocampal slice
abstract: The influence of extracellular sinusoidal electric fields on the amplitude of population spikes evoked by single test pulses in excitatory pathways to CA1 pyramidal neurons was studied in rat hippocampal slices. The fields in the tissue were of the order of EEG gradients. Stimulation at 5 Hz, a frequency representative of hippocampal theta activity, was compared with 60 Hz, which is often used in kindling procedures. Brief stimulation (5-30 s) with both 5 and 60 Hz fields (20-70 mV/cmp-p in the perfusing solution) often produced a long-term increase (longer than 10 min) of the population spike. Fields at 60 Hz, but not at 5 Hz, also induced short-term depression (1-6 min) or transient post-field excitation (15-30 s). Prolonged stimulation (3 min) emphasized this frequency dependent response: fields at 5 Hz induced long-lasting potentiation while fields at 60 Hz always resulted in progressive depression persisting for a few minutes after the end of stimulation. These effects appeared as a global response of CA1 neurons. Antidromic responses studied during blockade of synaptic transmission (0.2 mM Ca2+, 4 mM Mg2+) were depressed during and following 3 min field stimulation at either frequency, which could reflect failing calcium mechanisms in the tissue. The field influence on the potential evoked by synaptic or antidromic stimulation was independent of the phase of the sine wave at which the test pulse was delivered, arguing against a direct polarization of the cell membrane by the fields. The experimental evidence suggests a functional role for EEG-like fields in hippocampal excitability.

title: Effects of weak electric fields on the activity of neurons and neuronal networks.
abstract: Electric fields applied to brain tissue will affect cellular properties. They will hyperpolarise the ends of cells closest to the positive part of the field, and depolarise ends closest to the negative. In the case of neurons this affects excitability. How these changes in transmembrane potential are distributed depends on the length constant of the neuron, and on its geometry; if the neuron is electrically compact, the change in transmembrane potential becomes an almost linear function of distance in the direction of the field. Neurons from the mammalian hippocampus, maintained in tissue slices in vitro, are significantly affected by fields of around 1-5 V m(-1).

title: Improvement of depression following transcranial magnetic stimulation
abstract: Psychiatry as a field was transformed by the discovery and introduction of electroconvulsive therapy (ECT) as a treatment in the early part of this century. ECT demonstrated that depression was a disease of the brain and that it could be treated with a direct brain intervention. Psychiatry’s evolution continued in 1958 with the discovery of the antidepressant activity of the monoamine oxidase inhibitors. Interestingly, although the area of neuropsychopharmacology has continued to advance, the realm of physical somatic interventions in psychiatry has lagged behind. With perhaps the exception of light therapy, there were no advances in somatic interventions in psychiatry. However, in 1985, Barker et al. 1 developed a brief high intensity electromagnet capable of depolarizing cortical neurons, called transcranial magnetic stimulation (TMS). There has been much interest in the past 10 years in whether TMS might have antidepressant actions, similar to ECT but without causing a seizure and with no apparent cognitive side effects. This review examines the basic principles underlying TMS, and describes how TMS differs from electrical stimulation and the other uses of magnets.

title: Transcranial magnetic stimulation and cognitive neuroscience
abstract: Transcranial magnetic stimulation has been used to investigate almost all areas of cognitive neuroscience. This article discusses the most important (and least understood) considerations regarding the use of transcranial magnetic stimulation for cognitive neuroscience and outlines advances in the use of this technique for the replication and extension of findings from neuropsychology. We also take a more speculative look forward to the emerging development of strategies for combining transcranial magnetic stimulation with other brain imaging technologies and methods in the cognitive neurosciences.

title: Adaptive Electric Field Control of Epileptic Seizures
abstract: We describe a novel method of adaptively controlling epileptic seizure-like events in hippocampal brain slices using electric fields. Extracellular neuronal activity is continuously recorded during field application through differential extracellular recording techniques, and the applied electric field strength is continuously updated using a computer-controlled proportional feedback algorithm. This approach appears capable of sustained amelioration of seizure events in this preparation when used with negative feedback. Seizures can be induced or enhanced by using fields of opposite polarity through positive feedback. In negative feedback mode, such findings may offer a novel technology for seizure control. In positive feedback mode, adaptively applied electric fields may offer a more physiological means of neural modulation for prosthetic purposes than previously possible.

title: Transcranial Magnetic Stimulation: A Neurochronometrics of Mind
abstract: The mainstays of brain imaging techniques have been positron emission tomography (PET), functional magnetic resonance imaging (fMRI), magnetoencephalography (MEG), and event-related potentials (ERPs). These methods all record direct or indirect measures of brain activity and correlate the activity patterns with behavior. But to go beyond the correlations established by these techniques and prove the necessity of an area for a given function, cognitive neuroscientists need to be able to reverse engineer the brain -- i.e., to selectively remove components from information processing and assess their impact on the output. This book is about transcranial magnetic stimulation (TMS), a technique that emerged during the same period as neuroimaging and has made it possible to reverse engineer the human brain's role in behavioral and cognitive functions. The subject areas that can be studied using TMS run the gamut of cognitive psychology -- attention, perception, awareness, eye movements, action selection, memory, plasticity, language, numeracy, and priming. The book presents an overview of historical attempts at magnetic brain stimulation, ethical considerations of the technique's use, basic technical and practical information, the results of numerous TMS studies, and a discussion of the future of TMS in the armamentarium of cognitive neuropsychology.

title: Noninvasive brain stimulation in stroke rehabilitation
abstract: SummaryStroke is a common disorder that produces a major burden to society, largely through long-lasting motor disability in survivors. Recent studies have broadened our understanding of the processes underlying recovery of motor function after stroke. Bilateral motor regions of the brain experience substantial reorganization after stroke, including changes in the strength of interhemispheric inhibitory interactions. Our understanding of the extent to which different forms of reorganization contribute to behavioral gains in the rehabilitative process, although still limited, has led to the formulation of novel interventional strategies to regain motor function. Transcranial magnetic (TMS) and DC (tDCS) electrical stimulation are noninvasive brain stimulation techniques that modulate cortical excitability in both healthy individuals and stroke patients. These techniques can enhance the effect of training on performance of various motor tasks, including those that mimic activities of daily living. This review looks at the effects of TMS and tDCS on motor cortical function and motor performance in healthy volunteers and in patients with stroke. Both techniques can either enhance or suppress cortical excitability, and may move to the clinical arena as strategies to enhance the beneficial effects of customarily used neurorehabilitative treatments after stroke.

title: A comprehensive review of the effects of rTMS on motor cortical excitability and inhibition
abstract: Repetitive transcranial magnetic stimulation (rTMS) procedures are being widely applied in therapeutic and investigative studies. Numerous studies have investigated the effects of rTMS on cortical excitability and inhibition, yielding somewhat contradictory results. The purpose of this study was to comprehensively review this literature to guide the selection of methodology in therapeutic studies. We conducted a comprehensive review of all identified studies that investigated effects of low and/or high frequency rTMS on motor cortical excitability or inhibition. Low frequency rTMS appears to produce a transient reduction in cortical excitability as assessed by motor evoked potential (MEP) size and produces no substantial effect on cortical inhibition. High frequency rTMS appears to produce a persistent increase in MEP size and a reduction in cortical inhibition measured with paired pulse methods although few studies have investigated frequencies greater than 5Hz. A number of novel stimulation paradigms have significant potential for altering cortical excitability but require further investigation. Although commonly applied forms of rTMS have effects on cortical excitability, more substantial effects may be obtained through the use of novel stimulation paradigms or innovative approaches to the stimulation of areas connected to a potential target site. Further research is required, however, before these paradigms can be more widely adopted.

title: A Sham-Controlled Trial of a 5-Day Course of Repetitive Transcranial Magnetic Stimulation of the Unaffected Hemisphere in Stroke Patients
abstract: It has been recently shown that a single session of repetitive transcranial magnetic stimulation (rTMS) of the unaffected hemisphere can improve motor function in stroke patients; however, this improvement is short-lasting. We therefore conducted a randomized, sham-controlled, phase II trial to evaluate whether five sessions of low-frequency rTMS can increase the magnitude and duration of these effects and whether this approach is safe.  Fifteen patients with chronic stroke were randomized to receive active or sham rTMS of the unaffected hemisphere. A blinded rater assessed motor function and corticospinal excitability at baseline, during and after 2 weeks of treatment. Safety was assessed using a neuropsychologic battery and electroencephalogram.  Active rTMS resulted in a significant improvement of the motor function performance in the affected hand that lasted for 2 weeks. These effects were not observed in the sham rTMS group (affected and unaffected hand) and in the unaffected hand in the active rTMS group. Corticospinal excitability decreased in the stimulated, unaffected hemisphere and increased in the affected hemisphere. There was a significant correlation between motor function improvement and corticospinal excitability change in the affected hemisphere. Cognitive performance and electroencephalogram were not changed significantly throughout the trial in both groups of treatment.  These results support and extend the findings of previous studies on rTMS in stroke patients because five consecutive sessions of rTMS increased the magnitude and duration of the motor effects. Furthermore, this increased dose of rTMS is not associated with cognitive adverse effects and/or epileptogenic activity.

title: In vitro modulation of endogenous rhythms by AC electric fields: Syncing with clinical brain stimulation
abstract: Humans are exposed to an increasing prevalence of weak and strong AC electric fields, as part of daily life in the modern world. Further, electric fields are being deployed to modulate brain function for research and clinical applications. A single electric field pulse, applied via transcranial electrical or magnetic stimulation, can transiently excite or disrupt activity in neural circuits. In contrast, extended exposure to steady electric fields or pulse trains can result in long-term effects on neural activity including potentiation or depression. In addition, it has been demonstrated that brain stimulation with electric fields can improve cognitive performance in normal subjects (Marshall et al. 2006). The impact of electric fields on brain function has motivated the development of therapies to treat a wide range of psychiatric and neurological diseases using transcranial electrical or magnetic stimulation (Wassermann & Lisanby, 2001), as well as deep brain stimulation with implanted electrodes. 
 
The mechanisms by which electric fields affect brain function have not been fully elaborated. A recent report in The Journal of Physiology by Deans et al. (2007) presents new data on the interaction of AC electric fields down to a cellular level as well as with neuronal population dynamics. The report reveals a frequency-specific ability of AC electric fields to rhythmically polarize pyramidal neurons of the CA3 region of the hippocampus and demonstrates the ability of AC fields to alter pharmacologically induced endogenous oscillations in the hippocampus. These data have important implications for understanding the effect of environmental AC fields and therapeutic stimulation on the activity of neuronal ensembles. A central finding of this study is that an AC electric field, applied in vitro to a brain slice set to oscillate in the gamma frequency range through bath application of kainate, shifts the ongoing oscillation to centre on the applied field frequency or a subharmonic of that frequency. This review of Deans et al. (2007) is intended to elucidate the connection between their work and other recent in vitro findings concerning electric fields in the brain with some recent clinical findings pertaining to cognitive function and electric fields.

title: Treatment of depression with transcranial direct current stimulation (tDCS): A Review
abstract: Major Depression Disorder (MDD) is usually accompanied by alterations of cortical activity and excitability, especially in prefrontal areas. These are reflections of a dysfunction in a distributed cortico-subcortical, bihemispheric network. Therefore it is reasonable to hypothesize that altering this pathological state with techniques of brain stimulation may offer a therapeutic target. Besides repetitive transcranial magnetic stimulation, tonic stimulation with weak direct currents (tDCS) modulates cortical excitability for hours after the end of stimulation, thus, it is a promising non-invasive therapeutic option. Early studies from the 1960s suggested some efficacy of DC stimulation to reduce symptoms in depression, but mixed results and development of psychotropic drugs resulted in an early abandonment of this technique. In the last years tDCS protocols have been optimized. Application of the newly developed stimulation protocols in patients with major depression has shown promise in few pilot studies. Further studies are needed to identify the optimal parameters of stimulation and the clinical and patient characteristics that may condition response to tDCS.

title: Increasing Human Brain Excitability by Transcranial High-Frequency Random Noise Stimulation
abstract: For >20 years, noninvasive transcranial stimulation techniques like repetitive transcranial magnetic stimulation (rTMS) and direct current stimulation (tDCS) have been used to induce neuroplastic-like effects in the human cortex, leading to the activity-dependent modification of synaptic transmission. Here, we introduce a novel method of electrical stimulation: transcranial random noise stimulation (tRNS), whereby a random electrical oscillation spectrum is applied over the motor cortex. tRNS induces consistent excitability increases lasting 60 min after stimulation. These effects have been observed in 80 subjects through both physiological measures and behavioral tasks. Higher frequencies (100–640 Hz) appear to be responsible for generating this excitability increase, an effect that may be attributed to the repeated opening of Na+ channels. In terms of efficacy tRNS appears to possess at least the same therapeutic potential as rTMS/tDCS in diseases such as depression, while furthermore avoiding the constraint of current flow direction sensitivity characteristic of tDCS.

title: Intracellular features predicted by extracellular recordings in the hippocampus in vivo.
abstract: Multichannel tetrode array recording in awake behaving animals provides a powerful method to record the activity of large numbers of neurons. The power of this method could be extended if further information concerning the intracellular state of the neurons could be extracted from the extracellularly recorded signals. Toward this end, we have simultaneously recorded intracellular and extracellular signals from hippocampal CA1 pyramidal cells and interneurons in the anesthetized rat. We found that several intracellular parameters can be deduced from extracellular spike waveforms. The width of the intracellular action potential is defined precisely by distinct points on the extracellular spike. Amplitude changes of the intracellular action potential are reflected by changes in the amplitude of the initial negative phase of the extracellular spike, and these amplitude changes are dependent on the state of the network. In addition, intracellular recordings from dendrites with simultaneous extracellular recordings from the soma indicate that, on average, action potentials are initiated in the perisomatic region and propagate to the dendrites at 1.68 m/s. Finally we determined that a tetrode in hippocampal area CA1 theoretically should be able to record electrical signals from approximately 1, 000 neurons. Of these, 60-100 neurons should generate spikes of sufficient amplitude to be detectable from the noise and to allow for their separation using current spatial clustering methods. This theoretical maximum is in contrast to the approximately six units that are usually detected per tetrode. From this, we conclude that a large percentage of hippocampal CA1 pyramidal cells are silent in any given behavioral condition.

title: Characterization of neocortical principal cells and interneurons by network interactions and extracellular features.
abstract: Most neuronal interactions in the cortex occur within local circuits. Because principal cells and GABAergic interneurons contribute differently to cortical operations, their experimental identification and separation is of utmost important. We used 64-site two-dimensional silicon probes for high-density recording of local neurons in layer 5 of the somatosensory and prefrontal cortices of the rat. Multiple-site monitoring of units allowed for the determination of their two-dimensional spatial position in the brain. Of the approximately 60,000 cell pairs recorded, 0.2% showed robust short-term interactions. Units with significant, short-latency (<3 ms) peaks following their action potentials in their cross-correlograms were characterized as putative excitatory (pyramidal) cells. Units with significant suppression of spiking of their partners were regarded as putative GABAergic interneurons. A portion of the putative interneurons was reciprocally connected with pyramidal cells. Neurons physiologically identified as inhibitory and excitatory cells were used as templates for classification of all recorded neurons. Of the several parameters tested, the duration of the unfiltered (1 Hz to 5 kHz) spike provided the most reliable clustering of the population. High-density parallel recordings of neuronal activity, determination of their physical location and their classification into pyramidal and interneuron classes provide the necessary tools for local circuit analysis.

title: Integration and Segregation of Activity in Entorhinal-Hippocampal Subregions by Neocortical Slow Oscillations
abstract: Brain systems communicate by means of neuronal oscillations at multiple temporal and spatial scales. In anesthetized rats, we find that neocortical "slow" oscillation engages neurons in prefrontal, somatosensory, entorhinal, and subicular cortices into synchronous transitions between UP and DOWN states, with a corresponding bimodal distribution of their membrane potential. The membrane potential of hippocampal granule cells and CA3 and CA1 pyramidal cells lacked bimodality, yet it was influenced by the slow oscillation in a region-specific manner. Furthermore, in both anesthetized and naturally sleeping rats, the cortical UP states resulted in increased activity of dentate and most CA1 neurons, as well as the highest probability of ripple events. Yet, the CA3-CA1 network could self-organize into gamma bursts and occasional ripples during the DOWN state. Thus, neo/paleocortical and hippocampal networks periodically reset, self-organize, and temporally coordinate their cell assemblies via the slow oscillation.

title: Behavior-dependent short-term assembly dynamics in the medial prefrontal cortex
abstract: Although short-term plasticity is believed to play a fundamental role in cortical computation, empirical evidence bearing on its role during behavior is scarce. Here we looked for the signature of short-term plasticity in the fine-timescale spiking relationships of a simultaneously recorded population of physiologically identified pyramidal cells and interneurons, in the medial prefrontal cortex of the rat, in a working memory task. On broader timescales, sequentially organized and transiently active neurons reliably differentiated between different trajectories of the rat in the maze. On finer timescales, putative monosynaptic interactions reflected short-term plasticity in their dynamic and predictable modulation across various aspects of the task, beyond a statistical accounting for the effect of the neurons' co-varying firing rates. Seeking potential mechanisms for such effects, we found evidence for both firing pattern–dependent facilitation and depression, as well as for a supralinear effect of presynaptic coincidence on the firing of postsynaptic targets.

title: Entrainment of Neocortical Neurons and Gamma Oscillations by the Hippocampal Theta Rhythm
abstract: Although it has been tacitly assumed that the hippocampus exerts an influence on neocortical networks, the mechanisms of this process are not well understood. We examined whether and how hippocampal theta oscillations affect neocortical assembly patterns by recording populations of single cells and transient gamma oscillations in multiple cortical regions, including the somatosensory area and prefrontal cortex in behaving rats and mice. Laminar analysis of neocortical gamma bursts revealed multiple gamma oscillators of varying frequency and location, which were spatially confined and synchronized local groups of neurons. A significant fraction of putative pyramidal cells and interneurons as well as localized gamma oscillations in all recorded neocortical areas were phase biased by the hippocampal theta rhythm. We hypothesize that temporal coordination of neocortical gamma oscillators by hippocampal theta is a mechanism by which information contained in spatially widespread neocortical assemblies can be synchronously transferred to the associative networks of the hippocampus.

title: Communication between neocortex and hippocampus during sleep in rodents
abstract: Both neocortical and hippocampal networks organize the firing patterns of their neurons by prominent oscillations during sleep, but the functional role of these rhythms is not well understood. Here, we show a robust correlation of neuronal discharges between the somatosensory cortex and hippocampus on both slow and fine time scales in the mouse and rat. Neuronal bursts in deep cortical layers, associated with sleep spindles and delta waves/slow rhythm, effectively triggered hippocampal discharges related to fast (ripple) oscillations. We hypothesize that oscillation-mediated temporal links coordinate specific information transfer between neocortical and hippocampal cell assemblies. Such a neocortical–hippocampal interplay may be important for memory consolidation.

title: Boosting slow oscillations during sleep potentiates memory
abstract: There is compelling evidence that sleep contributes to the long-term consolidation of new memories. This function of sleep has been linked to slow (<1 Hz) potential oscillations, which predominantly arise from the prefrontal neocortex and characterize slow wave sleep. However, oscillations in brain potentials are commonly considered to be mere epiphenomena that reflect synchronized activity arising from neuronal networks, which links the membrane and synaptic processes of these neurons in time. Whether brain potentials and their extracellular equivalent have any physiological meaning per se is unclear, but can easily be investigated by inducing the extracellular oscillating potential fields of interest. Here we show that inducing slow oscillation-like potential fields by transcranial application of oscillating potentials (0.75 Hz) during early nocturnal non-rapid-eye-movement sleep, that is, a period of emerging slow wave sleep, enhances the retention of hippocampus-dependent declarative memories in healthy humans. The slowly oscillating potential stimulation induced an immediate increase in slow wave sleep, endogenous cortical slow oscillations and slow spindle activity in the frontal cortex. Brain stimulation with oscillations at 5 Hz—another frequency band that normally predominates during rapid-eye-movement sleep—decreased slow oscillations and left declarative memory unchanged. Our findings indicate that endogenous slow potential oscillations have a causal role in the sleep-associated consolidation of memory, and that this role is enhanced by field effects in cortical extracellular space.

title: A novel slow (< 1 Hz) oscillation of neocortical neurons in vivo: depolarizing and hyperpolarizing components
abstract: We describe a novel slow oscillation in intracellular recordings from cortical association areas 5 and 7, motor areas 4 and 6, and visual areas 17 and 18 of cats under various anesthetics. The recorded neurons (n = 254) were antidromically and orthodromically identified as corticothalamic or callosal elements receiving projections from appropriate thalamic nuclei as well as from homotopic foci in the contralateral cortex. Two major types of cells were recorded: regular- spiking (mainly slow-adapting, but also fast-adapting) neurons and intrinsically bursting cells. A group of slowly oscillating neurons (n = 21) were intracellularly stained and found to be pyramidal-shaped cells in layers III-VI, with luxuriant basal dendritic arbors. The slow rhythm appeared in 88% of recorded neurons. It consisted of slow depolarizing envelopes (lasting for 0.8–1.5 sec) with superimposed full action potentials or presumed dendritic spikes, followed by long- lasting hyperpolarizations. Such sequences recurred rhythmically at less than 1 Hz, with a prevailing oscillation between 0.3 and 0.4 Hz in 67% of urethane-anesthetized animals. While in most neurons (approximately 70%) the repetitive spikes superimposed on the slow depolarization were completely blocked by slight DC hyperpolarization, 30% of cells were found to display relatively small (3–12 mV), rapid, all-or-none potentials after obliteration of full action potentials. These fast spikes were suppressed in an all-or-none fashion at Vm more negative than -90 mV. The depolarizing envelope of the slow rhythm was reduced or suppressed at a Vm of -90 to -100 mV and its duration was greatly reduced by administration of the NMDA blocker ketamine. In keeping with this action, most (56%) neurons recorded in animals under ketamine and nitrous oxide or ketamine and xylazine anesthesia displayed the slow oscillation at higher frequencies (0.6–1 Hz) than under urethane anesthesia (0.3–0.4 Hz). In 18% of the oscillating cells, the slow rhythm mainly consisted of repetitive (15–30 Hz), relatively short-lasting (15–25 msec) IPSPs that could be revealed by bringing the Vm at more positive values than -70 mV. The long-lasting (approximately 1 sec) hyperpolarizing phase of the slow oscillation was best observed at the resting Vm and was reduced at about -100 mV. Simultaneous recording of another cell across the membrane demonstrated synchronous inhibitory periods in both neurons. Intracellular diffusion of Cl- or Cs+ reduced the amplitude and/or duration of cyclic long- lasting hyperpolaryzations.(ABSTRACT TRUNCATED AT 400

title: Cellular and network mechanisms of rhythmic recurrent activity in neocortex
abstract: The neocortex generates periods of recurrent activity, such as the slow (0.1–0.5 Hz) oscillation during slow-wave sleep. Here we demonstrate that slices of ferret neocortex maintained in vitro generate this slow (< 1 Hz) rhythm when placed in a bathing medium that mimics the extracellular ionic composition in situ. This slow oscillation seems to be initiated in layer 5 as an excitatory interaction between pyramidal neurons and propagates through the neocortex. Our results demonstrate that the cerebral cortex generates an ‘up’ or depolarized state through recurrent excitation that is regulated by inhibitory networks, thereby allowing local cortical circuits to enter into temporarily activated and self-maintained excitatory states. The spontaneous generation and failure of this self-excited state may account for the generation of a subset of cortical rhythms during sleep.

title: Sensitivity of coherent oscillations in rat hippocampus to AC electric fields
abstract: The sensitivity of brain tissue to weak extracellular electric fields is important in assessing potential public health risks of extremely low frequency (ELF) fields, and potential roles of endogenous fields in brain function. Here we determine the effect of applied electric fields on membrane potentials and coherent network oscillations. Applied DC electric fields change transmembrane potentials in CA3 pyramidal cell somata by 0.18 mV per V m−1 applied. AC sinusoidal electric fields have smaller effects on transmembrane potentials: sensitivity drops as an exponential decay function of frequency. At 50 and 60 Hz it is ∼0.4 that for DC fields. Effects of fields of ≤ 16 V m−1 peak‐to‐peak (p‐p) did not outlast application. Kainic acid (100 nm) induced coherent network oscillations in the beta and gamma bands (15–100 Hz). Applied fields of ≥ 6 V m−1 p‐p (2.1 V m−1 r.m.s.) shifted the gamma peak in the power spectrum to centre on the applied field frequency or a subharmonic. Statistically significant effects on the timing of pyramidal cell firing within the oscillation appeared at distinct thresholds: at 50 Hz, 1 V m−1 p‐p (354 mV m−1 r.m.s.) had statistically significant effects in 71% of slices, and 0.5 V m−1 p‐p (177 mV m−1 r.m.s.) in 20%. These threshold fields are consistent with current environmental guidelines. They correspond to changes in somatic potential of ∼70 μV, below membrane potential noise levels for neurons, demonstrating the emergent properties of neuronal networks can be more sensitive than measurable effects in single neurons.

title: Interaction between neocortical and hippocampal networks via slow oscillations.
abstract: Both the thalamocortical and limbic systems generate a variety of brain state-dependent rhythms but the relationship between the oscillatory families is not well understood. Transfer of information across structures can be controlled by the offset oscillations. We suggest that slow oscillation of the neocortex, which was discovered by Mircea Steriade, temporally coordinates the self-organized oscillations in the neocortex, entorhinal cortex, subiculum and hippocampus. Transient coupling between rhythms can guide bidirectional information transfer among these structures and might serve to consolidate memory traces.

title: Direct Activation of Sparse, Distributed Populations of Cortical Neurons by Electrical Microstimulation
abstract: For over a century, electrical microstimulation has been the most direct method for causally linking brain function with behavior. Despite this long history, it is still unclear how the activity of neural populations is affected by stimulation. For example, there is still no consensus on where activated cells lie or on the extent to which neural processes such as passing axons near the electrode are also activated. Past studies of this question have proven difficult because microstimulation interferes with electrophysiological recordings, which in any case provide only coarse information about the location of activated cells. We used two-photon calcium imaging, an optical method, to circumvent these hurdles. We found that microstimulation sparsely activates neurons around the electrode, sometimes as far as millimeters away, even at low currents. Our results indicate that the pattern of activated neurons likely arises from the direct activation of axons in a volume tens of microns in diameter.

title: In Vivo Electrophysiology of Central Nervous System Terminal Autoreceptors a
abstract: Evidence both for and against the existence of presynaptic autoreceptors and the related question of, if they exist, do they play a significant role in the “normal” or physiological functioning of synaptic transmission, has been presented throughout this volume (for a recent excellent and comprehensive review, see Reference 1). Some o f the controversy regarding the existence and functioning of autoreceptors derives from the techniques and conditions under which their existence and functioning have been measured. In this chapter we will review data derived from an electrophysiological technique for examining the neurophysiological consequences of autoreceptor stimulation and blockade at the terminals of central nervous system neurons in vivo that support the existence of such autoreceptors, and give some clues to the conditions under which they operate in situ. The data to be discussed concern changes in the electrical excitability of single central nervous system (CNS) axon terminals as a function of the local and systemic application of drugs, and the rate of impulses reaching the terminal fields. Thus far, the technique has been used to study apparent autoreceptor-mediated changes in terminal excitability in rat mesencephalic dopaminergic neurons projecting to neostriat~m,~-’ nucleus accumbens* prefrontal, cingulate, and entorhinal cortices,” in rat noradrenergic locus ceruleus neurons projecting to frontal cortex,’”’’ in rat serotonergic dorsal rapht neurons projecting to neo~t r ia tum,’~ in presumed glutamatergic rat corticostriatal n e u r ~ n s , ’ ~ and in monkey nigral dopaminergic neurons projecting to the putamen.’s In addition, this technique has been used to study the electrophysiological consequences of activation or blockade of presynaptic heteroreceptors in several different systems, e.g., opioid receptors on cortical noradrenergic terminal of locus ceruleus neurons,’‘ dopamine receptors on hippocampal and cortical axons projecting to ventral striatum,“.” and dopamine receptors on the terminals of presumed GABAergic (7-aminobutyric acid) striatonigral neurons.” Despite the fact that neurotransmitter rclease itself is not directly measured in these studies, the nature of the changes in terminal excitability and the conditions under which these changes are observed suggest rather strongly that many different classes of CNS neurons possess a t their terminal fields neurotransmitter receptors

title: Effects of electric fields on transmembrane potential and excitability of turtle cerebellar Purkinje cells in vitro.
abstract: 1. Transmembrane potential (TMP) responses of Purkinje cells (PCs) in isolated turtle cerebellum to externally applied quasi‐steady‐state electric fields aligned with the dendritic axis were continuously measured using simultaneous intracellular and extracellular recording. TMP was obtained by subtraction of extracellular voltage fields from intracellular potential recorded at the same depth in the cerebellum. 2. The applied field changed the TMP with the polarity and amplitude dependent on the location on the PC membrane. This response at a given location increased linearly with external field up to a threshold level, beyond which active responses appeared. 3. The basic effect on TMP consisted of depolarization in the half of the dendrite towards which the fields were directed, and hyperpolarization in the other half. A pooled TMP depth‐profile shows a steady increase in polarization from the middle of the molecular layer towards each end. This profile correlates with that predicted from previously proposed cable models, giving them empirical support for the first time. 4. Active responses were triggered by the field‐induced depolarization. Tetrodotoxin (TTX)‐sensitive action potentials arose with the primary depolarization in the somatic region. Notched, Ca2+‐dependent action potentials arose with primary depolarization in the distal and mid‐dendritic regions. 5. A TTX‐sensitive voltage plateau was triggered by TMP‐depolarization in the proximal region. It in turn activated Na+‐spike trains. The frequency of spiking was proportional to the external field. At around 160 spikes/s, the Na+ spikes inactivated, and the TMP level rose to a more depolarized plateau. This latter plateau was also TTX‐sensitive. 6. During depolarization of the distal dendritic region, sometimes a Ca2+‐dependent plateau was observed. It appears to be associated with a small conductance increase. 7. Field‐induced hyperpolarization suppressed local spiking and voltage plateaux, but remote Ca2+ spikes with reduced amplitude appeared in recordings from the proximal region. Similarly, in the distal region, low‐amplitude, remote Na+ spikes and a Na+ plateau were observed superimposed on the hyperpolarizing baseline. The Na+ plateau apparently did not contribute to shunting of membrane currents in the distal dendrite. 8. The phase characteristics of the action potentials correlate with the modulation pattern noted in our extracellular study (Chan & Nicholson, 1986). Thus, the extracellular units ("giant spikes") were probably Na+ spikes activated in the soma and spread distally. Occasionally Ca2+ spikes, with a higher threshold, might also be activated to give dual‐phase response.(ABSTRACT TRUNCATED AT 400

title: Multimodal characterization of population responses evoked by applied electric field in vitro: extracellular potential, magnetic evoked field, transmembrane potential, and current-source density analysis
abstract: An external electric field applied parallel to longitudinal axis of neurons selectively depolarizes either end and thereby activates voltage-sensitive conductance changes in a large population of neurons. Here, we characterized such population responses in the in vitro turtle cerebellum. The responses were recorded and analyzed using a multimodal approach: the magnetic evoked field was measured using a Superconducting Quantum Interference Device (SQUID) magnetometer, and concurrently the electric field potentials were recorded. Laminar profile and current-source density analysis were used to uncover the pattern of activation due to the applied electric field. Intracellular recording provided further information for identifying the elements producing the observed responses. Finally, pharmacological manipulations confirmed the nature of the conductance changes. Our results show that it is possible to activate a defined cell population of the cerebellum by an applied field and obtain a magnetic response of the order of 0.5–2 pT. A field applied from the dorsal to the ventral side of cerebellum produced tetrodotoxin-sensitive population spikes. This component was followed by a kynurenic acid (KYNA)-sensitive postsynaptic response, most likely comprised of Ca(2+)-mediated action potentials occurring at the proximal pole of the Purkinje cell dendrites and evoked by climbing fiber inputs. The applied electric field directed from the ventral to the dorsal side of cerebellum gave rise to a complex of responses that was made up of a KYNA-sensitive component (presumably synaptically activated) and an Mn(2+)-sensitive but KYNA-insensitive component (probably due to a directly activated calcium conductance change). This study provides insights into the effects of electric and magnetic fields applied to the nervous tissue of experimental animal and human studies.

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

title: Role of cortical cell type and morphology in subthreshold and suprathreshold uniform electric field stimulation in vitro

abstract: 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.



We determined whether neuronal morphology or cell type predicted responses to subthreshold and suprathreshold uniform electric fields.



We characterized the effects of subthreshold and suprathreshold 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 a whole-cell patch clamp. Neuron morphology was reconstructed after intracellular dialysis of biocytin. Based solely on volume-weighted morphology, we developed a parsimonious model of neuronal soma polarization by subthreshold electric fields.



We found that neuronal morphology correlated with somatic subthreshold polarization. Based on neuronal morphology, we predict layer V pyramidal neuronal soma to be individually the most sensitive to polarization by optimally oriented subthreshold fields. Suprathreshold electric field action potential threshold was shown to reflect both direct cell polarization and synaptic (network) activation. Layer V/VI neuron absolute electric field action potential thresholds were lower than layer II/III pyramidal neurons and interneurons. Compared with somatic current injection, electric fields promoted burst firing and modulated action potential firing times.



We present experimental data indicating that cortical neuron morphology relative to electric fields and cortical cell type are factors in determining sensitivity to sub- and supra-threshold brain stimulation.

title: A NEUROBIOLOGICAL BASIS FOR ELF GUIDELINES
abstract: It is well understood that electric currents applied directly to the body can stimulate peripheral nerve and muscle tissue; such effects can be fatal if breathing is inhibited or ventricular fibrillation is induced. Exposure to extremely low frequency electric and magnetic fields will also induce electric fields and currents within the body, but these are almost always much lower than those that can stimulate peripheral nerve tissue. Guidance on exposure to such fields is based on the avoidance of acute effects in the central nervous system. This paper reviews the physiological processes involved in nerve cell excitability in the peripheral and central nervous system, and the experimental evidence for physiologically weak electric field effects. It is concluded that the integrative properties of the synapses and neural networks of the central nervous system render cognitive function sensitive to the effects of physiologically weak electric fields, below the threshold for peripheral nerve stimulation. However, the only direct evidence of these weak field interactions within the central nervous system is the induction of phosphenes in humans—the perception of faint flickering light in the periphery of the visual field, by magnetic field exposure. Other tissues are potentially sensitive to induced electric fields through effects on voltage-gated ion channels, but the sensitivity of these ion channels is likely to be lower than those of nerve and muscle cells specialized for rapid electrical signaling. In addition, such tissues lack the integrative properties of synapses and neuronal networks that render the central nervous system potentially more vulnerable.

title: Chronometric readout from a memory trace: gamma‐frequency field stimulation recruits timed recurrent activity in the rat CA3 network
abstract: Synchronous population activity is prevalent in neurones of the central nervous system and experimentally captured as oscillatory electric fields, the frequency of which can represent the state of the neural circuit, e.g. theta (∼5 Hz) and gamma (∼40 Hz). Such field oscillations, however, are not merely a result of coherent neuronal activity. They may also play active roles in information processing in the brain. In this study, we observed that, in cultured hippocampal slices, CA3 pyramidal cells responded to single‐pulse stimuli with monosynaptic and polysynaptic potentials and firing spikes which occurred after variable latencies. The variability of the spike latencies was greatly reduced in the presence of weak electric field oscillations, especially the oscillation in the gamma‐band frequency range, that per se induced only small fluctuations in the subthreshold membrane potential, and this effect was inhibited by blockade of NMDA receptor activity. Furthermore, the latency of the firing spikes changed if the stimulus was applied at a different phase of the imposed gamma oscillations. These results may suggest that the background field oscillations serve as an extracellular time reference and assure accurate and stable decoding of a memory trace present in cortical feedback networks.

title: Slow oscillation electrical brain stimulation during waking promotes EEG theta activity and memory encoding
abstract: The application of transcranial slow oscillation stimulation (tSOS; 0.75 Hz) was previously shown to enhance widespread endogenous EEG slow oscillatory activity when applied during a sleep period characterized by emerging endogenous slow oscillatory activity. Processes of memory consolidation typically occurring during this state of sleep were also enhanced. Here, we show that the same tSOS applied in the waking brain also induced an increase in endogenous EEG slow oscillations (0.4–1.2 Hz), although in a topographically restricted fashion. Applied during wakefulness tSOS, additionally, resulted in a marked and widespread increase in EEG theta (4–8 Hz) activity. During wake, tSOS did not enhance consolidation of memories when applied after learning, but improved encoding of hippocampus-dependent memories when applied during learning. We conclude that the EEG frequency and related memory processes induced by tSOS critically depend on brain state. In response to tSOS during wakefulness the brain transposes stimulation by responding preferentially with theta oscillations and facilitated encoding.

title: Stochastic resonance and the benefits of noise: from ice ages to crayfish and SQUIDs
abstract: Noise in dynamical systems is usually considered a nuisance. But in certain nonlinear systems, including electronic circuits and biological sensory apparatus, the presence of noise can in fact enhance the detection of weak signals. This phenomenon, called stochastic resonance, may find useful application in physical, technological and biomedical contexts.

title: Stochastic Resonance in a Neuronal Network from Mammalian Brain.
abstract: Stochastic resonance, a nonlinear phenomenon in which random noise optimizes a system’s response to a signal, has been postulated to provide a role for noise in information processing in the brain. In these experiments, a time varying electric field was used to deliver both signal and noise directly to a network of neurons from mammalian brain. As the magnitude of the stochastic component of the field was increased, resonance was observed in the response of the neuronal network to a weak periodic signal. This is the first demonstration of stochastic resonance in neuronal networks from the brain.

title: Neuronal Oscillations in Cortical Networks
abstract: Clocks tick, bridges and skyscrapers vibrate, neuronal networks oscillate. Are neuronal oscillations an inevitable by-product, similar to bridge vibrations, or an essential part of the brain's design? Mammalian cortical neurons form behavior-dependent oscillating networks of various sizes, which span five orders of magnitude in frequency. These oscillations are phylogenetically preserved, suggesting that they are functionally relevant. Recent findings indicate that network oscillations bias input selection, temporally link neurons into assemblies, and facilitate synaptic plasticity, mechanisms that cooperatively support temporal representation and long-term consolidation of information.

title: Temporal contiguity requirements for long-term associative potentiation/depression in the hippocampus
abstract: A previous study utilizing the powerful ipsilateral and weak crossed projection from the entorhinal cortex to the dentate gyrus in the rat revealed that long-term potentiation is an associative process in these systems. If the weak crossed projection alone receives potentiating stimulation consisting of 8 high-frequency trains 17.5 ms in duration, it does not exhibit long-term potentiation. However, long-term potentiation can be induced in the crossed projection if it is activated concurrently with the converging ipsilateral system. The present study is designed to determine the degree of synchrony required for the associative interactions by varying the timing and order of the potentiating trains delivered to the two converging systems. The associative induction of long-term potentiation does not require perfectly synchronous activation of the converging systems. The order of the trains is crucial, however. Long-term potentiation of the crossed projection can be induced if activity in the ipsilateral system is concurrent with or follows activity in the crossed projection. Indeed, there can be as much as 20ms between the 17.5ms trains in the two systems, and long-term potentiation of the crossed projection is still induced. Activation of the ipsilateral system that precedes activation of the crossed system depresses the responses evoked by the crossed system. If potentiating stimulation of the ipsilateral system follows activation of the crossed projection by too long an interval (200 ms, for example), then the crossed projection is depressed rather than potentiated. These results are discussed with regard to the nature of the associative process permissive for the induction of long-term potentiation and lead us to the conclusion that perfect temporal contiguity is not a requirement of this prototypical elemental memory unit.

title: A Synaptically Controlled, Associative Signal for Hebbian Plasticity in Hippocampal Neurons
abstract: The role of back-propagating dendritic action potentials in the induction of long-term potentiation (LTP) was investigated in CA1 neurons by means of dendritic patch recordings and simultaneous calcium imaging. Pairing of subthreshold excitatory postsynaptic potentials (EPSPs) with back-propagating action potentials resulted in an amplification of dendritic action potentials and evoked calcium influx near the site of synaptic input. This pairing also induced a robust LTP, which was reduced when EPSPs were paired with non-back-propagating action potentials or when stimuli were unpaired. Action potentials thus provide a synaptically controlled, associative signal to the dendrites for Hebbian modifications of synaptic strength.

title: Regulation of Synaptic Efficacy by Coincidence of Postsynaptic APs and EPSPs
abstract: Activity-driven modifications in synaptic connections between neurons in the neocortex may occur during development and learning. In dual whole-cell voltage recordings from pyramidal neurons, the coincidence of postsynaptic action potentials (APs) and unitary excitatory postsynaptic potentials (EPSPs) was found to induce changes in EPSPs. Their average amplitudes were differentially up- or down-regulated, depending on the precise timing of postsynaptic APs relative to EPSPs. These observations suggest that APs propagating back into dendrites serve to modify single active synaptic connections, depending on the pattern of electrical activity in the pre- and postsynaptic neurons.

title: Hebbian modification of a hippocampal population pattern in the rat
abstract: 1 The study of the physiological role of long‐term potentiation (LTP) is often hampered by the challenge of finding a physiological event that can be used to assess synaptic strength. We explored the possibility of utilising a naturally occurring event, the hippocampal sharp wave (SPW), for the assessment of synaptic strength and the induction of LTP in vivo. 2 We used two methods in which hippocampal cells were either recorded intracellularly or extracellularly in vivo. In both cases, a linear association between the magnitude of the SPW and cellular responsiveness was observed. 3 LTP was induced by depolarising cells during SPWs by either direct intracellular current injection or extracellular microstimulation adjacent to the cell body. Both of these approaches led to an increase in the slope of the linear association between SPWs and cellular responsiveness. 4 This change was achieved without a rise in overall cell excitability, implying that the synapses providing input to CA1 cells during sharp waves had undergone potentiation. 5 Our findings show that the Hebbian pairing of cellular activation with spontaneous, naturally occurring synaptic events is capable of inducing LTP.

title: Electric field suppression of epileptiform activity in hippocampal slices.
abstract: 1. The effects of relatively small external DC electric fields on synchronous activity in CA1 and CA3 from transverse and longitudinal type hippocampal slices were studied. 2. To record neuronal activity during significant field changes, differential DC amplification was employed with a reference electrode aligned along an isopotential with the recording electrode. 3. Suppression of epileptiform activity was observed in 31 of 33 slices independent of region studied and type of slice but was highly dependent on field orientation with respect to the apical dendritic-somatic axis. 4. Modulation of neuronal activity in these experiments was readily observed at field strengths < or = 5-10 mV/mm. Suppression was seen with the field oriented (positive to negative potential) from the soma to the apical dentrites. 5. In vivo application of these results may be feasible.

title: Effects of applied electric fields on low-calcium epileptiform activity in the CA1 region of rat hippocampal slices.
abstract: It is well established that exogenous electric fields can suppress activity obtained in different models of epileptiform discharge such as penicillin and high potassium. In the low-calcium model of epilepsy, spontaneous epileptiform bursting is generated in the absence of synaptic transmission. It has been suggested that ephaptic interactions play a critical role in neuronal synchronization and burst propagation in this nonsynaptic model. We, therefore, tested the hypothesis that low-calcium bursting induced in the CA1 region of transverse and longitudinal hippocampal slices should be highly sensitive to exogenous electric fields. Uniform, low amplitude DC electric fields were applied during spontaneous low-calcium epileptiform activity. Modulation and full suppression of epileptiform activity was observed at field strengths between 1 and 5 mV/mm, a value significantly lower than in other in vitro models of epilepsy. We further investigated the hypothesis that the efficacy of electrical fields was related to changes in the extracellular space. Our results suggest that the osmolality of the perfusate can modulate the efficacy of electric fields. It was also observed that the ability of a field to suppress or modulate low-calcium activity was highly dependent on its orientation, polarity, as well as magnitude. Finally, it was observed that the extracellular potassium "waves" that normally accompany individual epileptiform events was abolished when the individual events were suppressed. These results suggest that DC fields modulate and suppress low-calcium activity by directly polarizing CA1 pyramidal cells.

title: Frequency-Dependent Electrical Stimulation of the Visual Cortex
abstract: Noninvasive cortical stimulation techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), have proved to be powerful tools for establishing causal relationships between brain regions and their functions. In the present study, we demonstrate that a new technique called transcranial alternating current stimulation (tACS) can interact with ongoing rhythmic activities in the visual cortex in a frequency-specific fashion and induce visual experiences (phosphenes). We delivered an oscillatory current over the occipital cortex with tACS. In order to observe interactions with ongoing cortical rhythms, we compared the effects of delivering tACS under conditions of light ("Light" condition) or darkness ("Dark" condition). Stimulation over the occipital cortex induced perception of continuously flickering light most effectively when the beta frequency range was applied in an illuminated room, whereas the most effective stimulation frequency shifted to the alpha frequency range during testing in darkness. Stimulation with theta or gamma frequencies did not produce any visual phenomena. The shift of the effective stimulation frequency indicates that the frequency dependency is caused by interactions with ongoing oscillatory activity in the stimulated cortex. Our results suggest that tACS can be used as a noninvasive tool for establishing a causal link between rhythmic cortical activities and their functions.

title: Response of brain tissue to chronically implanted neural electrodes
abstract: Chronically implanted recording electrode arrays linked to prosthetics have the potential to make positive impacts on patients suffering from full or partial paralysis. Such arrays are implanted into the patient's cortical tissue and record extracellular potentials from nearby neurons, allowing the information encoded by the neuronal discharges to control external devices. While such systems perform well during acute recordings, they often fail to function reliably in clinically relevant chronic settings. Available evidence suggests that a major failure mode of electrode arrays is the brain tissue reaction against these implants, making the biocompatibility of implanted electrodes a primary concern in device design. This review presents the biological components and time course of the acute and chronic tissue reaction in brain tissue, analyses the brain tissue response of current electrode systems, and comments on the various material science and bioactive strategies undertaken by electrode designers to enhance electrode performance.

title: Histological Alterations Induced by Electrode Implantation and Electrical Stimulation in the Human Brain: A Review
abstract: Electrical brain stimulation is used as a treatment for patients with intractable chronic pain and movement disorders. However, the implantation of electrodes and electrical stimulation may induce histological changes around the electrode tip. We aimed to review the histological changes in humans that were electrically stimulated in the brain.

title: Transcranial magnetic and electrical stimulation compared: Does TES activate intracortical neuronal circuits?
abstract: To determine whether, and under which conditions, transcranial electrical stimulation (TES) and transcranial magnetic stimulation (TMS) can activate similar neuronal structures of the human motor cortex, as indicated by electromyographic recordings.



Focal TMS was performed on three subjects inducing a postero-anterior directed current (p-a), TES with postero-anteriorly (p-a) and latero-medially (l-m) oriented electrodes. We analyzed the onset latencies and amplitudes (single-pulse) and intracortical inhibition and excitation (paired-pulse).



TMS p-a and TES p-a produced muscle responses with the same onset latency, while TES l-m led to 1.4-1.9 ms shorter latencies. Paired-pulse TMS p-a and TES p-a induced inhibition at short inter-stimulus intervals (ISI) (maximum: 2-3 ms) and facilitation at longer ISIs (maximum: 10 ms). No inhibition but a strong facilitation was obtained from paired-pulse TES l-m (ISIs 1-5 ms).



Our findings support the hypothesis, that current direction is the most relevant factor in determining the mode of activation for both TMS and TES: TMS p-a and TES p-a are likely to activate the corticospinal neurons indirectly. In contrast, TES l-m may preferentially activate the corticospinal fibres directly, distant of the neuronal body.



TES is a suitable tool to induce intracortical inhibition and excitation.