Thomas Radman

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

BACKGROUND 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. OBJECTIVE We determined whether neuronal morphology or cell type predicted responses to subthreshold and suprathreshold uniform electric fields. METHODS 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. RESULTS 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. CONCLUSIONS 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.

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

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.

Testosterone Depletion in Adult Male Rats Increases Mossy Fiber Transmission, LTP, and Sprouting in Area CA3 of Hippocampus

Androgens have dramatic effects on neuronal structure and function in hippocampus. However, androgen depletion does not always lead to hippocampal impairment. To address this apparent paradox, we evaluated the hippocampus of adult male rats after gonadectomy (Gdx) or sham surgery. Surprisingly, Gdx rats showed increased synaptic transmission and long-term potentiation of the mossy fiber (MF) pathway. Gdx rats also exhibited increased excitability and MF sprouting. We then addressed the possible underlying mechanisms and found that Gdx induced a long-lasting upregulation of MF BDNF immunoreactivity. Antagonism of Trk receptors, which bind neurotrophins, such as BDNF, reversed the increase in MF transmission, excitability, and long-term potentiation in Gdx rats, but there were no effects of Trk antagonism in sham controls. To determine which androgens were responsible, the effects of testosterone metabolites DHT and 5α-androstane-3α,17β-diol were examined. Exposure of slices to 50 nm DHT decreased the effects of Gdx on MF transmission, but 50 nm 5α-androstane-3α,17β-diol had no effect. Remarkably, there was no effect of DHT in control males. The data suggest that a Trk- and androgen receptor-sensitive form of MF transmission and synaptic plasticity emerges after Gdx. We suggest that androgens may normally be important in area CA3 to prevent hyperexcitability and aberrant axon outgrowth but limit MF synaptic transmission and some forms of plasticity. The results also suggest a potential explanation for the maintenance of hippocampal-dependent cognitive function after androgen depletion: a reduction in androgens may lead to compensatory upregulation of MF transmission and plasticity.

One-dimensional representation of a neuron in a uniform electric field

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.

Effects of high-frequency stimulation on epileptiform activity in vitro : ON/OFF control paradigm

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

In vitro modulation of endogenous rhythms by AC electric fields: Syncing with clinical brain stimulation

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.

A novel framework for AC field-effects on action potential coherence and phase

Small electric fields will polarize neurons by only a small amount for this reason small electric fields have previously been suggested to have no physiologically relevant effects. We propose a mechanism whereby AC extracellular fields incrementally polarize a neurons membrane and thus modulate the coherence and phase of synaptically driven action potentials. Knowing that a membrane polarizes in proportion to field strength (DeltaV = cE), and that spike timing changes linearly with increasing steady-state field strength (Deltat prop E), we make a number of quantitative predictions on the effects of AC extracellular fields on a neurons spike timing oscillating fields will shift firing times with mean falling within or the oscillatory cycle (the rising edge). This mean firing time advances with increasing field strength and decreasing injected ramp slope, i.e. it increases with cE/Vdot. This effect is proportional to the inverse of the driving synaptic membrane potential slope Deltat=DeltaV/Vdot dot cE/Vdot. The strength of coherence as measured by Rayleigh coefficient (vector strength) also increases with cE/Vdot. The predictions were verified in rat hippocampal A pyramidal neurons.