Mechanisms underlying activation of retinal bipolar cells through targeted electrical stimulation: a computational study

2021 ◽  
Author(s):  
Javad Paknahad ◽  
Pragya Kosta ◽  
Jean-Marie C. Bouteiller ◽  
Mark S. Humayun ◽  
Gianluca Lazzi
Keyword(s):  
Electrical Stimulation ◽  
Pulse Duration ◽  
Computational Study ◽  
Biological Response ◽  
Bipolar Cells ◽  
Retinal Neurons ◽  
Biphasic Pulse ◽  
Underlying Mechanisms ◽  
Visual Percept ◽  
Computational Platform

Abstract Objective. Retinal implants have been developed to electrically stimulate healthy retinal neurons in the progressively degenerated retina. Several stimulation approaches have been proposed to improve the visual percept induced in patients with retinal prostheses. We introduce a computational model capable of simulating the effects of electrical stimulation on retinal neurons. Leveraging this computational platform, we delve into the underlying mechanisms influencing the sensitivity of retinal neurons’ response to various stimulus waveforms. Approach. We implemented a model of spiking bipolar cells (BCs) in the magnocellular pathway of the primate retina, diffuse BC subtypes (DB4), and utilized our multiscale Admittance Method (AM)-NEURON computational platform to characterize the response of BCs to epiretinal electrical stimulation with monophasic, symmetric, and asymmetric biphasic pulses. Main Results. Our investigations yielded four notable results: (i) The latency of BCs increases as stimulation pulse duration lengthens; conversely, this latency decreases as the current amplitude increases. (ii) Stimulation with a long anodic-first symmetric biphasic pulse (duration > 8 ms) results in a significant decrease in spiking threshold compared to stimulation with similar cathodic-first pulses (from 98.2 µA to 57.5 µA). (iii) The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel was a prominent contributor to the reduced threshold of BCs in response to long anodic-first stimulus pulses. (iv) Finally, extending the study to asymmetric waveforms, our results predict a lower BCs threshold using asymmetric long anodic-first pulses compared to that of asymmetric short cathodic-first stimulation. Significance. This study predicts the effects of several stimulation parameters on spiking BCs response to electrical stimulation. Of importance, our findings shed light on mechanisms underlying the experimental observations from the literature, thus highlighting the capability of the methodology to predict and guide the development of electrical stimulation protocols to generate a desired biological response, thereby constituting an ideal testbed for the development of electroceutical devices.

Electrical stimulation of retinal neurons in epiretinal and subretinal configuration using a multicapacitor array

2012 ◽  
Vol 107 (10) ◽  
pp. 2742-2755 ◽  
Author(s):  
Max Eickenscheidt ◽  
Martin Jenkner ◽  
Roland Thewes ◽  
Peter Fromherz ◽  
Günther Zeck
Keyword(s):  
Electrical Stimulation ◽  
Ganglion Cells ◽  
Ex Vivo ◽  
Biophysical Model ◽  
Retinal Neurons ◽  
Direct Stimulation ◽  
Tungsten Electrode ◽  
Partial Restoration ◽  
Low Amplitude ◽  
Stimulation Of

Electrical stimulation of retinal neurons offers the possibility of partial restoration of visual function. Challenges in neuroprosthetic applications are the long-term stability of the metal-based devices and the physiological activation of retinal circuitry. In this study, we demonstrate electrical stimulation of different classes of retinal neurons with a multicapacitor array. The array—insulated by an inert oxide—allows for safe stimulation with monophasic anodal or cathodal current pulses of low amplitude. Ex vivo rabbit retinas were interfaced in either epiretinal or subretinal configuration to the multicapacitor array. The evoked activity was recorded from ganglion cells that respond to light increments by an extracellular tungsten electrode. First, a monophasic epiretinal cathodal or a subretinal anodal current pulse evokes a complex burst of action potentials in ganglion cells. The first action potential occurs within 1 ms and is attributed to direct stimulation. Within the next milliseconds additional spikes are evoked through bipolar cell or photoreceptor depolarization, as confirmed by pharmacological blockers. Second, monophasic epiretinal anodal or subretinal cathodal currents elicit spikes in ganglion cells by hyperpolarization of photoreceptor terminals. These stimuli mimic the photoreceptor response to light increments. Third, the stimulation symmetry between current polarities (anodal/cathodal) and retina-array configuration (epi/sub) is confirmed in an experiment in which stimuli presented at different positions reveal the center-surround organization of the ganglion cell. A simple biophysical model that relies on voltage changes of cell terminals in the transretinal electric field above the stimulation capacitor explains our results. This study provides a comprehensive guide for efficient stimulation of different retinal neuronal classes with low-amplitude capacitive currents.

Working Memory Training and Transcranial Direct Current Stimulation

2019 ◽  
pp. 105-130
Author(s):  
Jacky Au ◽  
Martin Buschkuehl ◽  
Susanne M. Jaeggi
Keyword(s):  
Working Memory ◽  
Electrical Stimulation ◽  
Direct Current ◽  
Transcranial Direct Current Stimulation ◽  
Working Memory Training ◽  
Memory Training ◽  
Transcranial Electrical Stimulation ◽  
Direct Current Stimulation ◽  
Underlying Mechanisms ◽  
The Brain

The aim of this chapter is to contribute to the discussion of the cognitive neuroscience of brain stimulation. In doing so, the authors emphasize work from their own laboratory that focuses both on working memory training and transcranial direct current stimulation. Transcranial direct current stimulation is one of the most commonly used and extensively researched methods of transcranial electrical stimulation. The chapter focuses on implementation of transcranial direct current stimulation to enhance and inform research on working memory training, and not on the underlying mechanisms of transcranial direct current stimulation. Thus, while respecting the intricacies and unknowns of the inner workings of electrical stimulation on the brain, the chapter relies on the premise that transcranial direct current stimulation is able to directly affect the electrophysiological profile of the brain and provides evidence that this in turn can influence behavior given the right parameters.

Quantitative characterization and spinal pathway mediating inhibition of spinal nociceptive transmission from the lateral reticular nucleus in the rat

1988 ◽  
Vol 59 (1) ◽  
pp. 226-247 ◽  
Author(s):  
A. J. Janss ◽  
G. F. Gebhart
Keyword(s):  
Electrical Stimulation ◽  
Spontaneous Activity ◽  
Pulse Duration ◽  
Neuronal Response ◽  
Response Threshold ◽  
Reticular Nucleus ◽  
Lateral Reticular Nucleus ◽  
Descending Inhibition ◽  
Nociceptive Transmission ◽  
Spinal Pathway

1. The modulation of spinal nociceptive transmission from the lateral reticular nucleus (LRN) was characterized for 47 spinal dorsal horn neurons in pentobarbital-anesthetized, paralyzed rats. All 47 units studied had receptive fields confined to the glabrous skin of the plantar surface of the ipsilateral hind foot and responded to mechanical stimulation as well as noxious heating (50 degrees C). Rostral projections contained in the ventrolateral quadrant of the cervical spinal cord were demonstrated for 15 of the 47 units by antidromic invasion. Glutamate- and stimulation-produced descending inhibition, the spinal pathway, and tonic descending inhibition from the LRN were systematically examined. 2. Inhibition of unit responses to heating of the skin by electrical stimulation in the LRN varied with the intensity, pulse duration (100 or 400 microseconds), and frequency (25–100 Hz) of stimulation. Greater inhibition was produced at lower intensities of stimulation with the 400-microseconds pulse duration and a frequency of 100 Hz. The effects of stimulation on spontaneous activity and responses to heat were compared in 16 experiments; inhibition of spontaneous activity was intensity dependent and did not differ significantly in magnitude from stimulation-produced inhibition of responses to heating of the skin. 3. Tracking experiments established that stimulation in the ipsilateral and contralateral ventrolateral medulla reliably attenuated unit responses to noxious heating of the skin and that stimulation in the LRN produced maximal inhibition at a low intensity of stimulation. Descending inhibition was quantitatively characterized from sites within (n = 32) and outside (n = 30) the LRN. Both the extrapolated mean stimulation threshold for inhibition and mean intensity inhibiting unit responses to heat to 50% of control were significantly lower for sites in the LRN. 4. The responses of seven spinal units to graded noxious heating of the skin were studied; all exhibited linear monotonic stimulus-response functions (SRFs) throughout the temperature range examined (42–50 degrees C). Electrical stimulation in the LRN significantly decreased the slope (42 +/- 4% of control) of the SRFs and increased the neuronal response threshold (2.0 +/- 0.7 degrees C). 5. S-glutamate (50 nmol, 0.5 microliter) was microinjected into stimulation sites within (n = 15) and distant from (n = 6) the LRN. Glutamate produced a transient (less than 7 min) but significant attenuation of neuronal responses to heat to 35 +/- 6% of control only when microinjected into the LRN.(ABSTRACT TRUNCATED AT 400 WORDS)

Kilohertz and Low-Frequency Electrical Stimulation With the Same Pulse Duration Have Similar Efficiency for Inducing Isometric Knee Extension Torque and Discomfort

2017 ◽  
Vol 96 (6) ◽  
pp. 388-394 ◽  
Author(s):  
Flávia Vanessa Medeiros ◽  
Martim Bottaro ◽  
Amilton Vieira ◽  
Tiago Pires Lucas ◽  
Karenina Arrais Modesto ◽  
...  
Keyword(s):  
Electrical Stimulation ◽  
Pulse Duration ◽  
Low Frequency ◽  
Knee Extension ◽  
Isometric Knee Extension

scholarly journals Differential localization of protein kinase C isozymes in retinal neurons.

1991 ◽  
Vol 112 (6) ◽  
pp. 1241-1247 ◽  
Author(s):  
N Usuda ◽  
Y Kong ◽  
M Hagiwara ◽  
C Uchida ◽  
M Terasawa ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Bipolar Cells ◽  
Type I ◽  
Rabbit Retina ◽  
Type Ii ◽  
Retinal Neurons ◽  
Type Iii ◽  
Kinase C ◽  
Rod Bipolar Cells

We report the immunohistochemical localization of protein kinase C isozymes (types I, II, and III) in the rabbit retina using the monospecific monoclonal antibodies MC-1a, MC-2a, and MC-3a. Using immunoblot analysis of partially purified protein kinase C preparations of rabbit retina, types II and III isozymes alone were detected. The activity of type III was the stronger. By light microscopic immunohistochemical analysis, retinal neurons were negative for type I and positive for type II and type III isozymes. Type II was more diffusely distributed through the retinal layers, but was distinctive in ganglion cells, bipolar cells, and outer segments. The immunoreactivity was stronger for type III isozyme, and it was observed in mop (rod) bipolar cells and amacrine cells. By using immunoelectron microscopy, the cytoplasm of the cell body, the axon, and dendrites of the mop bipolar cells were strongly immunoreactive for type III. The so-called rod bipolar cells were for the first time seen to form synapses with rod photoreceptor cells. These differential localizations of respective isozymes in retinal neurons suggest that each isozyme has a different site of function in each neuron.

The pulse duration of electrical stimulation influences H-reflexes but not corticospinal excitability for tibialis anterior

2014 ◽  
Vol 92 (10) ◽  
pp. 821-825
Author(s):  
Alyssa R. Hindle ◽  
Jenny W.H. Lou ◽  
David F. Collins
Keyword(s):  
Electrical Stimulation ◽  
Pulse Duration ◽  
Peroneal Nerve ◽  
Motor Evoked Potentials ◽  
Common Peroneal Nerve ◽  
H Reflex ◽  
M Wave ◽  
Recruitment Curve ◽  
Afferent Volley ◽  
The Common

The afferent volley generated by neuromuscular electrical stimulation (NMES) influences corticospinal (CS) excitability and frequent NMES sessions can strengthen CS pathways, resulting in long-term improvements in function. This afferent volley can be altered by manipulating NMES parameters. Presently, we manipulated one such parameter, pulse duration, during NMES over the common peroneal nerve and assessed the influence on H-reflexes and CS excitability. We hypothesized that compared with shorter pulse durations, longer pulses would (i) shift the H-reflex recruitment curve to the left, relative to the M-wave curve; and (ii) increase CS excitability more. Using 3 pulse durations (50, 200, 1000 μs), M-wave and H-reflex recruitment curves were collected and, in separate experiments, CS excitability was assessed by comparing motor evoked potentials elicited before and after 30 min of NMES. Despite finding a leftward shift in the H-reflex recruitment curve when using the 1000 μs pulse duration, consistent with a larger afferent volley for a given efferent volley, the increases in CS excitability were not influenced by pulse duration. Hence, although manipulating pulse duration can alter the relative recruitment of afferents and efferents in the common peroneal nerve, under the present experimental conditions it is ineffective for maximizing CS excitability for rehabilitation.

scholarly journals Starvation to Glucose Reprograms Development of Neurovascular Unit in Embryonic Retinal Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Türküler Özgümüs ◽  
Oksana Sulaieva ◽  
Ruchi Jain ◽  
Isabella Artner ◽  
Valeriya Lyssenko
Keyword(s):  
Regulatory Networks ◽  
Neurovascular Unit ◽  
Glucose Deprivation ◽  
Fetal Life ◽  
Retinal Neurons ◽  
Retinal Cells ◽  
Vascular Elements ◽  
Patients With Diabetes ◽  
Underlying Mechanisms ◽  
Energy Deprivation

Perinatal exposure to starvation is a risk factor for development of severe retinopathy in adult patients with diabetes. However, the underlying mechanisms are not completely understood. In the present study, we shed light on molecular consequences of exposure to short-time glucose starvation on the transcriptome profile of mouse embryonic retinal cells. We found a profound downregulation of genes regulating development of retinal neurons, which was accompanied by reduced expression of genes encoding for glycolytic enzymes and glutamatergic signaling. At the same time, glial and vascular markers were upregulated, mimicking the diabetes-associated increase of angiogenesis—a hallmark of pathogenic features in diabetic retinopathy. Energy deprivation as a consequence of starvation to glucose seems to be compensated by upregulation of genes involved in fatty acid elongation. Results from the present study demonstrate that short-term glucose deprivation during early fetal life differentially alters expression of metabolism- and function-related genes and could have detrimental and lasting effects on gene expression in the retinal neurons, glial cells, and vascular elements and thus potentially disrupting gene regulatory networks essential for the formation of the retinal neurovascular unit. Abnormal developmental programming during retinogenesis may serve as a trigger of reactive gliosis, accelerated neurodegeneration, and increased vascularization, which may promote development of severe retinopathy in patients with diabetes later in life.

scholarly journals Rs1h−/y exon 3-del rat model of X-linked retinoschisis with early onset and rapid phenotype is rescued by RS1 supplementation

Gene Therapy ◽  
2021 ◽  
Author(s):  
Yong Zeng ◽  
Haohua Qian ◽  
Maria Mercedes Campos ◽  
Yichao Li ◽  
Camasamudram Vijayasarathy ◽  
...  
Keyword(s):  
Rat Model ◽  
Early Onset ◽  
Photoreceptor Cell ◽  
Bipolar Cells ◽  
Subretinal Space ◽  
Severe Phenotype ◽  
Juvenile Retinoschisis ◽  
Normal Human ◽  
Retinal Structure ◽  
Underlying Mechanisms

AbstractAnimal models of X-linked juvenile retinoschisis (XLRS) are valuable tools for understanding basic biochemical function of retinoschisin (RS1) protein and to investigate outcomes of preclinical efficacy and toxicity studies. In order to work with an eye larger than mouse, we generated and characterized an Rs1h−/y knockout rat model created by removing exon 3. This rat model expresses no normal RS1 protein. The model shares features of an early onset and more severe phenotype of human XLRS. The morphologic pathology includes schisis cavities at postnatal day 15 (p15), photoreceptors that are misplaced into the subretinal space and OPL, and a reduction of photoreceptor cell numbers by p21. By 6 mo age only 1–3 rows of photoreceptors nuclei remain, and the inner/outer segment layers and the OPL shows major changes. Electroretinogram recordings show functional loss with considerable reduction of both the a-wave and b-wave by p28, indicating early age loss and dysfunction of photoreceptors. The ratio of b-/a-wave amplitudes indicates impaired synaptic transmission to bipolar cells in addition. Supplementing the Rs1h−/y exon3-del retina with normal human RS1 protein using AAV8-RS1 delivery improved the retinal structure. This Rs1h−/y rat model provides a further tool to explore underlying mechanisms of XLRS pathology and to evaluate therapeutic intervention for the XLRS condition.

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