Daniel K. Freeman

Selective Activation of Neuronal Targets With Sinusoidal Electric Stimulation

Electric stimulation of the CNS is being evaluated as a treatment modality for a variety of neurological, psychiatric, and sensory disorders. Despite considerable success in some applications, existing stimulation techniques offer little control over which cell types or neuronal substructures are activated by stimulation. The ability to more precisely control neuronal activation would likely improve the clinical outcomes associated with these applications. Here, we show that specific frequencies of sinusoidal stimulation can be used to preferentially activate certain retinal cell types: photoreceptors are activated at 5 Hz, bipolar cells at 25 Hz, and ganglion cells at 100 Hz. In addition, low-frequency stimulation (≤25 Hz) did not activate passing axons but still elicited robust synaptically mediated responses in ganglion cells; therefore, elicited neural activity is confined to within a focal region around the stimulating electrode. Our results suggest that sinusoidal stimulation provides significantly improved control over elicited neural activity relative to conventional pulsatile stimulation.

Microscopic Magnetic Stimulation of Neural Tissue

Electrical stimulation is currently used to treat a wide range of cardiovascular, sensory and neurological diseases. Despite its success, there are significant limitations to its application, including incompatibility with magnetic resonance imaging, limited control of electric fields and decreased performance associated with tissue inflammation. Magnetic stimulation overcomes these limitations but existing devices (that is, transcranial magnetic stimulation) are large, reducing their translation to chronic applications. In addition, existing devices are not effective for deeper, sub-cortical targets. Here we demonstrate that sub-millimeter coils can activate neuronal tissue. Interestingly, the results of both modelling and physiological experiments suggest that different spatial orientations of the coils relative to the neuronal tissue can be used to generate specific neural responses. These results raise the possibility that micro-magnetic stimulation coils, small enough to be implanted within the brain parenchyma, may prove to be an effective alternative to existing stimulation devices.

Multiple components of ganglion cell desensitization in response to prosthetic stimulation

Retinal prostheses aim to restore functional vision to those blinded by outer retinal diseases using electric stimulation of surviving neurons. Previous work indicates that repetitive stimulation with stimuli that activate the synaptic network reduces the sensitivity of retinal neurons to further stimulation. Such desensitization may contribute to the fading of visual percepts over time reported by human subjects. Here, we show that desensitization may be more complex than previously considered. We recorded spike trains from rabbit retinal ganglion cells and found that desensitization persists in the presence of inhibitory blockers (strychnine and picrotoxin), indicating amacrine cell inhibition is not solely responsible for reducing sensitivity in response to electric stimulation. The threshold for direct activation of the ganglion cell changes little during the simultaneous desensitization of the synaptically mediated response, indicating that desensitization likely occurs upstream of the spike generator. In addition to rapid desensitization acting over hundreds of milliseconds (τ = 176.4 ± 8.8 ms), we report the presence of slow acting desensitization with a time course of seconds (τ = 14.0 ± 1.1 s). The time courses of the two components of desensitization that we found are similar to the two phases of brightness fading seen in human subjects. This suggests that the reduction in ganglion cell firing due to desensitization may be responsible for the fading of visual percepts over time in response to prosthetic stimulation.

Encoding visual information in retinal ganglion cells with prosthetic stimulation

Retinal prostheses aim to restore functional vision to those blinded by outer retinal diseases using electric stimulation of surviving retinal neurons. The ability to replicate the spatiotemporal pattern of ganglion cell spike trains present under normal viewing conditions is presumably an important factor for restoring high-quality vision. In order to replicate such activity with a retinal prosthesis, it is important to consider both how visual information is encoded in ganglion cell spike trains, and how retinal neurons respond to electric stimulation. The goal of the current review is to bring together these two concepts in order to guide the development of more effective stimulation strategies. We review the experiments to date that have studied how retinal neurons respond to electric stimulation and discuss these findings in the context of known retinal signaling strategies. The results from such in vitro studies reveal the advantages and disadvantages of activating the ganglion cell directly with the electric stimulus (direct activation) as compared to activation of neurons that are presynaptic to the ganglion cell (indirect activation). While direct activation allows high temporal but low spatial resolution, indirect activation yields improved spatial resolution but poor temporal resolution. Finally, we use knowledge gained from in vitro experiments to infer the patterns of elicited activity in ongoing human trials, providing insights into some of the factors limiting the quality of prosthetic vision.

Effects of Remote Stimulation on the Modulated Activity of Cat Retinal Ganglion Cells

The output of retinal ganglion cells depends on local and global aspects of the visual scene. The local receptive field is well studied and classically consists of a linear excitatory center and a linear antagonistic surround. The global receptive field contains pools of nonlinear subunits that are distributed widely across the retina. The subunit pools mediate in uncertain ways various nonlinear behaviors of ganglion cells, like temporal-frequency doubling, saccadic suppression, and contrast adaptation. To clarify mechanisms of subunit function, we systematically examined the effect of remote grating patterns on the spike activity of cat X- and Y-type ganglion cells in vivo. We present evidence for two distinct subunit types based on spatiotemporal relationships between response nonlinearities elicited by remote drifting and contrast-reversing gratings. One subunit type is excitatory and activated by gratings of ∼0.1 cycles per degree, while the other is inhibitory and activated by gratings of ∼1 cycle per degree. The two subunit pools contribute to a global gain control mechanism that differentially modulates ganglion cell response dynamics, particularly for ON-center cells, where excitatory and inhibitory subunit stimulation respectively makes responses to antipreferred and preferred contrast steps more transient. We show that the excitatory subunits also have a profound influence on spatial tuning, turning cells from lowpass into bandpass filters. Based on difference-of-Gaussians model fits to tuning curves, we attribute the increased bandpass selectivity to changes in center-surround strength and relative phase and not center-surround size. A conceptual model of the extraclassical receptive field that could explain many observed phenomena is discussed.

Electric Stimulation with Sinusoids and White Noise for Neural Prostheses

We are investigating the use of novel stimulus waveforms in neural prostheses to determine whether they can provide more precise control over the temporal and spatial pattern of elicited activity as compared to conventional pulsatile stimulation. To study this, we measured the response of retinal ganglion cells to both sinusoidal and white noise waveforms. The use of cell-attached and whole cell patch clamp recordings allowed the responses to be observed without significant obstruction from the stimulus artifact. Electric stimulation with sinusoids elicited robust responses. White noise analysis was used to derive the linear kernel for the ganglion cells spiking response as well as for the underlying excitatory currents. These results suggest that in response to electric stimulation, presynaptic retinal neurons exhibit bandpass filtering characteristics with a peak response that occurs 25 ms after onset. The experimental approach demonstrated here may be useful for studying the temporal response properties of other neurons in the CNS.

Calcium channel dynamics limit synaptic release in response to prosthetic stimulation with sinusoidal waveforms.

Extracellular electric stimulation with sinusoidal waveforms has been shown to allow preferential activation of individual types of retinal neurons by varying stimulus frequency. It is important to understand the mechanisms underlying this frequency dependence as a step toward improving methods of preferential activation. In order to elucidate these mechanisms, we implemented a morphologically realistic model of a retinal bipolar cell and measured the response to extracellular stimulation with sinusoidal waveforms. We compared the frequency response of a passive membrane model to the kinetics of voltage-gated calcium channels that mediate synaptic release. The passive electrical properties of the membrane exhibited lowpass filtering with a relatively high cutoff frequency (nominal value = 717 Hz). This cutoff frequency was dependent on intra-axonal resistance, with shorter and wider axons yielding higher cutoff frequencies. However, we found that the cutoff frequency of bipolar cell synaptic release was primarily limited by the relatively slow opening kinetics of L- and T-type calcium channels. The cutoff frequency of calcium currents depended nonlinearly on stimulus amplitude, but remained lower than the cutoff frequency of the passive membrane model for a large range of membrane potential fluctuations. These results suggest that while it may be possible to modulate the membrane potential of bipolar cells over a wide range of stimulus frequencies, synaptic release will only be initiated at the lower end of this range.

The maintained discharge of rat retinal ganglion cells

Action potentials were recorded from rat retinal ganglion cell fibers in the presence of a uniform field, and the maintained discharge pattern was characterized. Spike trains recorded under ketaminexylazine. The majority of cells had multimodal interval distributions, with the first peak in the range of 25.00.97). Both ON and OFF cells show serial correlations between adjacent interspike intervals, while ON cells also showed second-order correlations. Cells with multimodal interval distribution showed a strong peak at high frequencies in the power spectra in the range of 28.9-41.4 Hz. Oscillations were present under both anesthetic conditions and persisted in the dark at a slightly lower frequency, implying that the oscillations are generated independent of any light stimulus but can be modulated by light level. The oscillation frequency varied slightly between cells of the same type and in the same eye, suggesting that multiple oscillatory generating mechanisms exist within the retina. Cells with high-frequency oscillations were described well by an integrate-and-fire model with the input consisting of Gaussian noise plus a sinusoid where the phase was jittered randomly to account for the bandwidth present in the oscillations.

Retinal Ganglion Cell Adaptation to Small Luminance Fluctuations

To accommodate the wide input range over which the visual system operates within the narrow output range of spiking neurons, the retina adjusts its sensitivity to the mean light level so that retinal ganglion cells can faithfully signal contrast, or relative deviations from the mean luminance. Given the large operating range of the visual system, the majority of work on luminance adaptation has involved logarithmic changes in light level. We report that luminance gain controls are recruited for remarkably small fluctuations in luminance as well. Using spike recordings from the rat optic tract, we show that ganglion cell responses to a brief flash of light are modulated in amplitude by local background fluctuations as little as 15% contrast. The time scale of the gain control is rapid (<125 ms), at least for on cells. The retinal locus of adaptation precedes the ganglion cell spike generator because response gain changes of on cells were uncorrelated with firing rate. The mechanism seems to reside within the inner retinal network and not in the photoreceptors, because the adaptation profiles of on and off cells differed markedly. The response gain changes follow Webers law, suggesting that network mechanisms of luminance adaptation described in previous work modulates retinal ganglion cell sensitivity, not just when we move between different lighting environments, but also as our eyes scan a visual scene. Finally, we show that response amplitude is uniformly reduced for flashes on a modulated background that has spatial contrast, indicating that another gain control that integrates luminance signals nonlinearly over space operates within the receptive field center of rat ganglion cells.

Saturation of the right-leg drive amplifier in low-voltage ECG monitors.

Electrocardiogram (ECG) monitoring is a critical tool in patient care, but its utility is often balanced with frustration from clinicians who are constantly distracted by false alarms. This has motivated the need to readdress the major factors that contribute to ECG noise with the goal of reducing false alarms. In this study, we describe a previously unreported phenomenon in which ECG noise can result from an unintended interaction between two systems: 1) the dc lead-off circuitry that is used to detect whether electrodes fall off the patient; and 2) the right-leg drive (RLD) system that is responsible for reducing ac common-mode noise that couples into the body. Using a circuit model to study this interaction, we found that in the presence of a dc lead-off system, even moderate increases in the right-leg skin-electrode resistance can cause the RLD amplifier to saturate. Such saturation can produce ECG noise because the RLD amplifier will no longer be capable of attenuating ac common-mode noise on the body. RLD saturation is particularly a problem for modern ECG monitors that use low-voltage supply levels. For example, for a 12-lead ECG and a 2 V power supply, saturation will occur when the right-leg electrode resistance reaches only 2 MΩ. We discuss several design solutions that can be used in low-voltage monitors to avoid RLD saturation.