Azadeh Yazdan-Shahmorad

Polarity of cortical electrical stimulation differentially affects neuronal activity of deep and superficial layers of rat motor cortex.

BACKGROUND Cortical electrical stimulation (CES) techniques are practical tools in neurorehabilitation that are currently being used to test models of functional recovery after neurologic injury. However, the mechanisms by which CES has therapeutic effects, are not fully understood. OBJECTIVE In this study, we investigated the effects of CES on unit activity of different neuronal elements in layers of rat primary motor cortex after the offset of stimulation. We evaluated the effects of monopolar CES pulse polarity (anodic-first versus cathodic-first) using various stimulation frequencies and amplitudes on unit activity after stimulation. METHODS A penetrating single shank silicon microelectrode array enabled us to span the entirety of six layer motor cortex allowing simultaneous electrophysiologic recordings from different depths after monopolar CES. Neural spiking activity before the onset and after the offset of CES was modeled using point processes fit to capture neural spiking dynamics as a function of extrinsic stimuli based on generalized linear model methods. RESULTS We found that neurons in lower layers have a higher probability of being excited after anodic CES. Conversely, neurons located in upper cortical layers have a higher probability of being excited after cathodic stimulation. The opposing effects observed following anodic versus cathodic stimulation in upper and lower layers were frequency- and amplitude-dependent. CONCLUSIONS The data demonstrates that the poststimulus changes in neural activity after manipulation of CES parameters changes according to the location (depth) of the recorded units in rat primary motor cortex. The most effective pulse polarity for eliciting action potentials after stimulation in lower layers was not as effective in upper layers. Likewise, lower amplitudes and frequencies of CES were more effective than higher amplitudes and frequencies for eliciting action potentials. These results have important implications in the context of maximizing efficacy of CES for neurorehabilitation and neuroprosthetic applications.

Strategies for optical control and simultaneous electrical readout of extended cortical circuits.

BACKGROUND To dissect the intricate workings of neural circuits, it is essential to gain precise control over subsets of neurons while retaining the ability to monitor larger-scale circuit dynamics. This requires the ability to both evoke and record neural activity simultaneously with high spatial and temporal resolution. NEW METHOD In this paper we present approaches that address this need by combining micro-electrocorticography (μECoG) with optogenetics in ways that avoid photovoltaic artifacts. RESULTS We demonstrate that variations of this approach are broadly applicable across three commonly studied mammalian species - mouse, rat, and macaque monkey - and that the recorded μECoG signal shows complex spectral and spatio-temporal patterns in response to optical stimulation. COMPARISON WITH EXISTING METHODS While optogenetics provides the ability to excite or inhibit neural subpopulations in a targeted fashion, large-scale recording of resulting neural activity remains challenging. Recent advances in optical physiology, such as genetically encoded Ca(2+) indicators, are promising but currently do not allow simultaneous recordings from extended cortical areas due to limitations in optical imaging hardware. CONCLUSIONS We demonstrate techniques for the large-scale simultaneous interrogation of cortical circuits in three commonly used mammalian species.

In-vivo Evaluation of Chronically Implanted Neural Microelectrode Arrays Modified with Poly (3,4-ethylenedioxythiophene) Nanotubes

The interface between neural prostheses and neural tissue plays a significant role in the long term performance of these devices. Conducting polymers have been used to modify the electrical properties of neural microelectrodes. The objective of this study was to evaluate recording chronic neural activity of neural microelectrodes that were modified with nanofibers-templated of poly (3,4-ethylenedioxythiophene) (PEDOT) nanotubes over seven week periods using impedance spectroscopy and signal-to-noise ratio measurements. PEDOT nanotubes-coated sites were found to have lower impedance and higher signal-to-noise ratio than control site.

High gamma power in ECoG reflects cortical electrical stimulation effects on unit activity in layers V/VI

OBJECTIVE Cortical electrical stimulation (CES) has been used extensively in experimental neuroscience to modulate neuronal or behavioral activity, which has led this technique to be considered in neurorehabilitation. Because the cortex and the surrounding anatomy have irregular geometries as well as inhomogeneous and anisotropic electrical properties, the mechanism by which CES has therapeutic effects is poorly understood. Therapeutic effects of CES can be improved by optimizing the stimulation parameters based on the effects of various stimulation parameters on target brain regions. APPROACH In this study we have compared the effects of CES pulse polarity, frequency, and amplitude on unit activity recorded from rat primary motor cortex with the effects on the corresponding local field potentials (LFP), and electrocorticograms (ECoG). CES was applied at the surface of the cortex and the unit activity and LFPs were recorded using a penetrating electrode array, which was implanted below the stimulation site. ECoGs were recorded from the vicinity of the stimulation site. MAIN RESULTS Time-frequency analysis of LFPs following CES showed correlation of gamma frequencies with unit activity response in all layers. More importantly, high gamma power of ECoG signals only correlated with the unit activity in lower layers (V-VI) following CES. Time-frequency correlations, which were found between LFPs, ECoGs and unit activity, were frequency- and amplitude-dependent. SIGNIFICANCE The signature of the neural activity observed in LFP and ECoG signals provides a better understanding of the effects of stimulation on network activity, representative of large numbers of neurons responding to stimulation. These results demonstrate that the neurorehabilitation and neuroprosthetic applications of CES targeting layered cortex can be further improved by using field potential recordings as surrogates to unit activity aimed at optimizing stimulation efficacy. Likewise, the signatures of unit activity observed as changes in high gamma power in ECoGs suggest that future cortical stimulation studies could rely on less invasive feedback schemes that incorporate surface stimulation with ECoG reporting of stimulation efficacy.

Demonstration of a setup for chronic optogenetic stimulation and recording across cortical areas in non-human primates

Although several studies have shown the feasibility of using optogenetics in non-human primates (NHP), reliable largescale chronic interfaces have not yet been reported for such studies in NHP. Here we introduce a chronic setup that permits repeated, daily optogenetic stimulation and large-scale recording from the same sites in NHP cortex. The setup combines optogenetics with a transparent artificial dura (AD) and high-density micro-electrocorticography (μECoG). To obtain expression across large areas of cortex, we infused AAV5-CamKIIa-C1V1-EYFP viral vector using an infusion technique based on convection-enhanced delivery (CED) in primary somatosensory (S1) and motor (M1) cortices. By epifluorescent imaging through AD we were able to confirm high levels of expression covering about 110 mm2 of S1 and M1. We then incorporated a 192-channel μECoG array spanning 192 mm2 into the AD for simultaneous electrophysiological recording during optical stimulation. The array consists of patterned Pt-Au-Pt metal traces embedded in ~10 μm Parylene-C insulator. The parylene is sufficiently transparent to allow minimally attenuated optical access for optogenetic stimulation. The array was chronically implanted over the opsin-expressing areas in M1 and S1 for over two weeks. Optical stimulation was delivered via a fiber optic placed on the surface of the AD. With this setup, we recorded reliable evoked activity following light stimulation at several locations. Similar responses were recorded across tens of days, however a decline in the light-evoked signal amplitude was observed during this period due to the growth of dural tissue over the array. These results show the feasibility of a chronic interface for combined largescale optogenetic stimulation and cortical recordings across days.

4D wavelet noise suppression of MR diffusion tensor data

Diffusion tensor imaging (DTI) is known to be promising for providing anatomical information about white-matter fiber bundles that cannot be obtained by other non-invasive in vivo imaging methods. However, its application is limited because of its low signal-to-noise ratio and significant imaging artifacts. To improve the accuracy of tissue structural and architectural characterization with diffusion tensor imaging 4D wavelet denoising technique is used to improve the signal to noise ratio (SNR) of diffusion tensor images. To evaluate the proposed method, a high SNR data set is built by repeating and averaging the data acquisition several times and is compared to the denoised data. Our results revealed that wavelets would effectively reduce the noise in DTI data with less blurring of tissue types, especially in the white matter. It would suggest that by using the 4D wavelet noise suppression, one could decrease the acquisition time and still have an acceptable SNR.

Laminar Characterization of Spiking Activity in the Rat Motor Cortex

The neocortex is a six-layered tissue consisting of different cell types. How does unit activity in the different layers of the motor cortex relate to movement? Does implantation in a particular layer improve direction decoding ability for a neuroprosthetic device? We simultaneously recorded unit activity in different layers of the rat motor cortex using chronic multi-site silicon electrodes. We used a combination of histology and electrophysiological signatures of Local Field Potentials (LFPs) to accurately localize the electrode sites in the different layers of the cortex. We analyzed 142 units from two animals and found that 40 units (28%) in Layers II to V showed significant modulation with respect to movement. Of these units that showed significant modulation, 9/20 (45%) of units in Layers II/III encoded directional information as compared to 15/19 (79%) of the units in Layers IV/V. These preliminary results suggest that units in Layers IV/V relatively contain more directional information than other layers of the cortex.

MRSI brain tumor characterization using wavelet and wavelet packets feature spaces and artificial neural networks

Magnetic resonance spectroscopic imaging (MRSI) is a non-invasive technique for assessing biochemical fingerprint of tissue composition. The need to differentiate between normal and abnormal tissues and determine type of abnormality before biopsy or surgery motivated development and application of MRSI. There are several technical reasons that make the brain easier than other organs to be examined with MRSI. This work presents our proposed methods and results for the analysis of the brain spectra of patients with three tumor types (malignant glioma, astrocytoma, and oligodendroglioma). After extracting features from MRSI data using wavelet and wavelet packets, we use artificial neural networks to determine the abnormal spectra and the type of abnormality. We evaluated the proposed methods using clinical and simulated MRSI data and biopsy results. The MRSI analysis results were correct 97% of the time when classifying the spectra of the clinical MRSI data into normal tissue, tumor, and radiation necrosis. They were correct 72% and 83% of the time when determining tumor types using the clinical and simulated MRSI data, respectively.

Widespread optogenetic expression in macaque cortex obtained with MR-guided, convection enhanced delivery (CED) of AAV vector to the thalamus

BACKGROUND In non-human primate (NHP) optogenetics, infecting large cortical areas with viral vectors is often a difficult and time-consuming task. Previous work has shown that parenchymal delivery of adeno-associated virus (AAV) in the thalamus by convection-enhanced delivery (CED) can lead to large-scale transduction via axonal transport in distal areas including cortex. We used this approach to obtain widespread cortical expression of light-sensitive ion channels. NEW METHOD AAV vectors co-expressing channelrhodopsin-2 (ChR2) and yellow fluorescent protein (YFP) genes were infused into thalamus of three rhesus macaques under MR-guided CED. After six to twelve weeks recovery, in vivo optical stimulation and single cell recording in the cortex was carried out using an optrode in anesthetized animals. Post-mortem immunostaining against YFP was used to estimate the distribution and level of expression of ChR2 in thalamus and cortex. RESULTS Histological analysis revealed high levels of transduction in cortical layers. The patterns of expression were consistent with known thalamo-cortico-thalamic circuits. Dense expression was seen in thalamocortiocal axonal fibers in layers III, IV and VI and in pyramidal neurons in layers V and VI, presumably corticothalamic neurons. In addition we obtained reliable in vivo light-evoked responses in cortical areas with high levels of expression. COMPARISON WITH EXISTING METHODS Thalamic CED is very efficient in achieving large expressing areas in comparison to convectional techniques both in minimizing infusion time and in minimizing damage to the brain. CONCLUSION MR-guided CED infusion into thalamus provides a simplified approach to transduce large cortical areas by thalamo-cortico-thalamic projections in primate brain.

Linear Electrode Depth Estimation in Rat Motor Cortex by Laminar Analysis of Ketamine-Xylazine-Induced Oscillations

While the development of silicon-substrate microelectrode arrays has enabled chronic recording of single unit activity from multiple neurons simultaneously, accurate interpretation of the signals depend on the anatomical placement of the electrodes. Toward this end, this paper develops an in vivo method for identifying the placement of electrodes based on laminar analysis of ketamine-xylazien-induced field potential oscillations in rat motor cortex. The proposed method is based on finding the polarity reversal in laminar oscillations which is reported to appear in upper part of layer V in laminar High Voltage Spindles (HVSs) of rat cortical column. Analysis of histological images showed a 21 mum error in the estimate of the polarity reversal depth compared to the expected range (850-1050 mum). One out of the four rats did not undergo a phase reversal. Histology verified that the electrode was placed deeper than 1050 jim. We propose that this method can be used to determine an estimate of laminar electrodes implanted in rat motor cortex