Negative hemodynamic response without neuronal inhibition investigated by combining optical imaging and electrophysiological recording.

Understanding the mechanisms underlying negative hemodynamic responses is critical for the interpretation of functional brain imaging signals. Negative imaging signals have been found in the visual, somatosensory and motor cortices in functional magnetic resonance imaging (fMRI) and intrinsic signal optical imaging (ISOI) studies. However, the origin of negative imaging signals is still controversial. The present study investigated the visual cortical responses to peripheral grating stimuli using multi-wavelength ISOI and electrophysiological recording. We found an increased cerebral blood volume (CBV) in the stimulus-induced regions and a decreased CBV in the adjacent regions in the visual cortex. Nevertheless, there was no significant change in blood oxygenation in the negative CBV regions. Furthermore, by combining the planar and laminar electrophysiological recordings, we did not observe significantly decreased neuronal activity in the negative CBV regions. Our results suggest that the negative hemodynamic response does not necessarily originate in decreased neuronal activity. Therefore, caution should be taken when interpreting a negative hemodynamic response as neuronal inhibition.

Electrically Evoked Responses in the Rabbit Cortex Induced by Current Steering With Penetrating Optic Nerve Electrodes.

Purpose: Current steering is a neural stimulation strategy that uses simultaneous stimulation of adjacent electrodes to produce additional intermediate stimulation sites and thus improves spatial resolution. We investigated the feasibility of current steering using electrophysiological and computational methods after implanting paired penetrating electrodes into the rabbit's optic nerve (ON). Methods: Penetrating electrodes at different interelectrode distances were implanted into the ON and electrically evoked cortical potentials (EEPs) in V1 recorded with a 6 × 8 array. The current thresholds, EEP amplitudes, and spatial distributions were analyzed during current steering. Computational simulation studies were performed based on finite element models to calculate the area and spatial distribution of recruited ON fibers using a current steering stimulation strategy. Results: Threshold reduction and EEP amplitude enhancement were found with simultaneous stimulation of closely spaced electrode pairs. Spatially shifted cortical responses were achieved using current steering, whereas the amplitudes and spatial spreads of the responses were similar to that elicited by a single electrode. Computational simulations suggested that the centroid of the ON recruitment area could be modulated by current steering while the total recruitment area did not show any appreciable variability at a fixed current intensity. Conclusions: Current steering is a useful strategy to enhance the spatial resolution of an ON prosthesis without increasing the number of physical electrodes. This study provides useful information for optimizing the design of stimulation strategies with a penetrating ON prosthesis.

Inverted optical intrinsic response accompanied by decreased cerebral blood flow are related to both neuronal inhibition and excitation.

Negative hemodynamic response has been widely reported in blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging studies, however its origin is still controversial. Optical intrinsic signal (OIS) imaging can be used to study brain activity by simultaneously recording hemodynamic signals at different wavelengths with high spatial resolution. In this study, we found transcorneal electrical stimulation (TcES) could elicit both positive OIS response (POR) and negative OIS response (NOR) in cats' visual cortex. We then investigated the property of this negative response to TcES and its relationship with cerebral blood flow (CBF) and neuronal activity. Results from laser speckle contrast imaging showed decreased CBF in the NOR region while increased CBF in the POR region. Both planar and laminar electrophysiological recordings in the middle (500-700 µm) cortical layers demonstrated that decreased and increased neuronal activities were coexisted in the NOR region. Furthermore, decreased neuronal activity was also detected in the deep cortical layers in the NOR region. This work provides evidence that the negative OIS together with the decreased CBF should be explained by mechanisms of both neuronal inhibition and excitation within middle cortical layers. Our results would be important for interpreting neurophysiological mechanisms underlying the negative BOLD signals.

Properties of electrically evoked potentials activated by optic nerve stimulation with penetrating electrodes of different modes in rabbits.

PURPOSE: To investigate the effect of different stimulation modes on cortical electrically evoked potentials (EEPs) by intraorbital optic nerve (ON) stimulation with penetrating electrodes. METHODS: A stimulating electrode array with three electrodes arranged linearly was inserted into the ON along its axis. EEPs were recorded using a 4 × 4 silver-ball electrode array in response to monopolar and bipolar stimulation mode, respectively. RESULTS: The simultaneous monopolar stimulation mode had a lower threshold than the individual monopolar stimulation mode, but elicited smaller cortical response when a fixed charge was injected. The threshold of the bipolar stimulation mode was comparable to that of individual monopolar stimulation mode. The response to the smaller spacing (150 µm) bipolar stimulation mode was similar in amplitude to that of the individual monopolar stimulation mode, but spread wider. The larger spacing (500 µm) bipolar stimulation mode elicited stronger and wider response than the individual monopolar stimulation mode. For the individual monopolar stimulation mode, stimulation with different electrodes can be differentiated even when the spacing of the two electrodes was 150 µm. CONCLUSIONS: For ON stimulation with penetrating electrodes, the monopolar stimulation mode could induce more localized cortical responses than the bipolar stimulation mode with comparable threshold and had a high stimulation selectivity. These findings may provide valuable information for the design of stimulation strategy of the penetrative ON visual prosthesis.

Spatial characteristics of evoked potentials elicited by a MEMS microelectrode array for suprachoroidal-transretinal stimulation in a rabbit.

BACKGROUND: Suprachoroidal-transretinal stimulation (STS) can potentially restore vision. This study investigated the spatial characteristics of cortical electrical evoked potentials (EEPs) elicited by STS. METHODS: A 4 × 4 thin-film platinum microelectrode stimulating array (200 µm electrode diameter and 400 µm center-to-center distance) was fabricated by a micro-electro-mechanical systems (MEMS) techniques and implanted into the suprachoroidal space of albino rabbits. RESULTS: The current threshold to elicit reliable EEPs by a single electrode was 41.6 ± 12.6 µA, corresponding to a 66.2 ± 20.1 µC · cm(-2) charge density per phase, which was lower than the reported safety limits. Spatially differentiated cortical responses could be evoked by STS through different rows or columns of electrical stimulation; furthermore, shifts in the location of the maximum cortical activities were consistent with cortical visuotopic maps; increasing the number of simultaneously stimulating electrodes increased the response amplitudes of EEPs and expanded the spatial spread as well. In addition, long-term implantation and electrical stimulation of the MEMS electrode array in suprachoroidal space are necessary to evaluate systematically the safety and biocompatibility of this approach. CONCLUSIONS: This study indicates that the STS approach by a MEMS-based platinum electrode array is a feasible alternative for visual restoration, and relatively high spatial discrimination may be achieved.

Optical imaging of visual cortical responses evoked by transcorneal electrical stimulation with different parameters.

PURPOSE: The use of phosphenes evoked by transcorneal electrical stimulation (TcES) has been proposed as a means of residual visual function evaluation and candidate selection before implantation of retinal prostheses. Compared to the subjective measures, measurement of neuronal activity in visual cortex can objectively and quantitatively explore their response properties to electrical stimulation. The purpose of this study was to investigate systematically the properties of cortical responses evoked by TcES. METHODS: The visual cortical responses were recorded using a multiwavelength optical imaging of intrinsic signals (OIS) combining with electrophysiological recording by a multichannel electrode array. The effects of different parameters of TcES on cortical responses, including the changes of hemoglobin oxygenation and cerebral blood volume, were examined. RESULTS: We found consistent OIS activation regions in visual cortex after TcES, which also showed strong evoked field potentials according to electrophysiological results. The OIS response regions were located mainly in cortical areas representing peripheral visual field. The extent of activation areas and strength of intrinsic signals were increased with higher current intensities and longer pulse widths, and the largest responses were acquired in the frequency range 10 to 20 Hz. CONCLUSIONS: Use of TcES through the ERG-jet corneal electrode may preferentially activate peripheral retina. Revealing the hemodynamic changes in visual cortex occurred after electrical stimulation can contribute to comprehension of neurophysiological underpinnings underlying prosthetic vision. This study provided an objective foundation for optimizing parameters of TcES and would bring considerable benefits in the application of TcES for assessment and screening in patients.

Using independent component analysis to remove artifacts in visual cortex responses elicited by electrical stimulation of the optic nerve.

In visual prosthesis research, electrically evoked potentials (EEPs) can be elicited by one or more biphasic current pulses delivered to the optic nerve (ON) through penetrating electrodes. Multi-channel EEPs recorded from the visual cortex usually contain large stimulus artifacts caused by instantaneous electrotonic current spread through the brain tissue. These stimulus artifacts contaminate the EEP waveform and often make subsequent analysis of the underlying neural responses difficult. This is particularly serious when investigating EEPs in response to electrical stimulation with long duration and multi-pulses. We applied independent component analysis (ICA) to remove these electrical stimulation-induced artifacts during the development of a visual prosthesis. Multi-channel signals were recorded from visual cortices of five rabbits in response to ON electrical stimulation with various stimulus parameters. ON action potentials were then blocked by lidocaine in order to acquire cortical potentials only including stimulus artifacts. Correlation analysis of reconstructed artifacts by ICA and artifacts recorded after blocking the ON indicates successful removal of artifacts from electrical stimulation by the ICA method. This technique has potential applications in studies designed to optimize the electrical stimulation parameters used by visual prostheses.

Spatiotemporal properties of multipeaked electrically evoked potentials elicited by penetrative optic nerve stimulation in rabbits.

PURPOSE: To investigate the spatiotemporal properties of the cortical responses elicited by intraorbital optic nerve (ON) stimulation with penetrating electrodes as means of designing optimal stimulation strategies for an ON visual prosthesis. METHODS: The ON of rabbits was exposed by orbital surgery for electrical stimulation. Craniotomy was performed to expose the visual cortex contralateral to the operated eye. Electrically evoked potentials (EEPs) were recorded by an electrode array positioned on the visual cortex. RESULTS: There were primarily four components (N1, P1, P2, P3) in EEPs with implicit times of 8.0 ± 0.6, 11.3 ± 1.3, 20.5 ± 1.4, and 26.9 ± 1.5 ms, respectively, when the ON was stimulated by penetrating electrodes. The thresholds to elicit these components were different, and the higher thresholds were seen with slower cortical components. The corresponding thresholds were 13.8 ± 3.1 µA for N1, 21.8 ± 4.7 µA for P1, 36.4 ± 11.4 µA for P2, and 68.4 ± 17.2 µA for P3. The time courses of the EEP components were also distinct. The locations of EEPs with the maximum P1 amplitude showed a spatial correspondence to the ON stimulation sites. Different profiles of cortical responses could be discriminated when the ON stimulation sites were separated by 150 µm. CONCLUSIONS: Multiple components with different properties were elicited in EEPs when the ON was stimulated by penetrating electrodes. Retinotopic and localized stimulation could be achieved with this stimulating approach.

Intraorbital optic nerve stimulation with penetrating electrodes: in vivo electrophysiology study in rabbits.

PURPOSE: To investigate the response properties of the electrically evoked potentials (EEPs) elicited by intraorbital optic nerve stimulation with penetrating electrodes using different stimulus parameters. METHODS: Visually evoked potentials (VEPs) were recorded as a control and for comparative purposes. Teflon-coated tungsten wire electrodes (100 microm core-diameter, 300 microm exposed tip) were inserted intraorbitally into the optic nerve. A charge-balanced biphasic current was delivered to the optic nerve via inserted wire electrodes in 26 anaesthetized rabbits. EEPs were recorded by epidural electrodes placed over the visual cortex. The charge density threshold for eliciting EEPs was determined. Stimulus pulse amplitude, duration, frequency and waveform were varied to study their effects on EEPs. After the experiments, the stimulated optic nerves were examined histologically for examination of implantation position of the stimulating electrode into the optic nerve tissue. RESULTS: EEPs were successfully elicited by intraorbital optic nerve stimulation with penetrating electrodes. The measured amplitude of the first large positive peak (P1) was smaller and the latency of P1 was shorter compared with VEPs. The measured charge density threshold to elicit EEPs was 21.36 +/- 5.64 microC/cm(2). The amplitude of P1 increased and the latency of P1 decreased with increasing pulse amplitude of fixed duration stimuli. The amplitude of P1 increased with increasing pulse duration of fixed amplitude stimuli. For fixed charge stimuli, the amplitude of P1 decreased and the latency of P1 increased as the pulse duration increased. As frequency of stimuli varied from 1 to 10 Hz, the amplitude of P1 decreased monotonically. Among the different charge-balanced biphasic pulse stimulating waveforms, the symmetrical cathode-first biphasic pulse elicited the largest amplitude of P1. CONCLUSIONS: Our study demonstrates that intraorbital optic nerve stimulation with different stimulus parameters by penetrating electrodes can evoke cortical responses with different properties. The short-duration symmetrical cathode-first biphasic pulses of current with low frequencies are more efficacious in eliciting electrophysiological responses in the visual cortex than other stimulating waveforms.