Large-scale multimodal surface neural interfaces for primates

Abstract

Deciphering the function of neural circuits can help with the understanding of brain function and treating neurological disorders. Progress toward this goal relies on the development of chronically stable neural interfaces capable of recording and modulating neural circuits with high spatial and temporal precision across large areas of the brain. Advanced innovations in designing high-density neural interfaces for small animal models have enabled breakthrough discoveries in neuroscience research. Developing similar neurotechnology for larger animal models such as nonhuman primates (NHPs) is critical to gain significant insights for translation to humans, yet still it remains elusive due to the challenges in design, fabrication, and system-level integration of such devices. This review focuses on implantable surface neural interfaces with electrical and optical functionalities with emphasis on the required technological features to realize scalable multimodal and chronically stable implants to address the unique challenges associated with nonhuman primate studies.

Keywords: Neuroscience; Optoelectronics.

Graphical abstract

Figure 1

Overview of neural interfaces with electrical and optical modalities The type of signal recorded is associated with each readout method. For interfaces with electrical modalities, the review focuses on ECoG/μ-ECoG interfaces.

Figure 2

Nonhuman primate μ-ECoG arrays: large scale, high density, high channel count systems (A) The Neural Matrix: a 1008-ch multiplexed array. Inset: Each electrode is connected to a unit cell consisting of two flexible silicon transistors. Scale bar: 100 μm. (B) Schematic representation of the electrode array placement on the cortical surface. The circle represents the full implant area; the shaded orange area denotes the region of electrode contacts. The recording area spans premotor, primary motor, and primary sensory cortices. ArcS, arcuate sulcus; CS, central sulcus; IPS, intraparietal sulcus; PMd, dorsal premotor cortex; M1, primary motor cortex; S1, primary sensory cortex. (C) The neural matrix array and its interconnect cables packaged in an artificial dura for subdural implantation. (D) Intraoperative views of 1152- (top) and 128- (bottom) channel arrays placed on the cortical surface. For both arrays, the yellow squares indicate the approximate measurement areas. (CS); central sulcus, IPS; intraparietal sulcus. (E) Somatotopic mapping of digit representation area based on high gamma activity measurements of the somatosensory evoked potentials (SEP) with the 1152-ch array (up) and 128-ch array (down). D1 (red): thumb digit, D2 (green): index digit, D3 (blue): middle digit, D4 (yellow): ring digit, D5 (magenta): little digit. (F) Configuration diagram (top) and photograph (bottom) showing the stacking strategy used to obtain the 1152-ch array by stacking nine 128-ch arrays and their recording units. Panels reproduced with permission from: (A–C, D–F²³).

Figure 3

Genetic modification of large brain areas: convection enhanced delivery (CED) of optogenetics viral vector in NHPs (A and B) Cortical injection. (A) Top, baseline coronal magnetic resonance (MR) image before the cortical injection of the viral vector. Bottom, spread of the virus co-infused with a contrast agent for the same MR coronal slice as in the top panel. (B) Left, epifluorescence image 3 months post infusion showing large areas of expression across somatosensory and motor cortices of a macaque. Right: epifluorescence image thresholded revealing an estimated surface area of expression of 130 mm². White dots indicate injection sites. (C and D) Thalamic injection. (C) Coronal sections of real-time MR images showing the distribution volume of the viral vector co-infused with a contrast agent before (top), and 75 min after (bottom) the thalamic infusion. (D) Top, surface epifluorescent image showing the expression of the virus in the cortical areas eight weeks after the thalamic infusion. Bottom, coronal tissue sections from approximately the same sites shown with dashed lines in the top panel. YFP staining shows expression patterns consistent with the epifluorescence images in top panel. Panels reproduced with permission from: (A, B, C, and D⁸¹).

Figure 4

Strategies for large-scale surface optogenetic in NHPs (A–C) Laser stimulation with simultaneous ECoG recording via an optical window and transparent arrays. (A) A silicone artificial dura (top) is placed in a titanium chronic chamber (bottom) as a replacement of the native dura to provide long-term optical access to motor and sensory cortices after infusion of an optogenetic viral vector. (B) 96-ch μ-ECoG array (left), two 96-ch arrays spanning motor and sensory cortices (middle), fiber optic delivering laser-pulsed light for combined optical stimulation and large-scale recording (right). (C) Example of μ-ECoG traces recorded during pulsed optical stimulation (blue ticks) from electrodes of the motor cortex (M1) (red) and from the somatosensory cortex (S1) (green) close to the respective stimulation sites shown in the top left inset. The pseudocolor map on the bottom left inset shows the spatial distribution of the high-gamma energy of evoked responses across the array for the M1 stimulation. (D) High-density implantable LED arrays “Opto-Array” equipped with a thermal sensor (top) and chronically implanted over a macaque’s primary visual cortex V1 (bottom). (E and F) LED stimulation with simultaneous ECoG recording with opaque arrays. (E) 64-ch μ-ECoG array (yellow) and complementary shaped 8-sites LED array (red) (top) implanted on the cortical surface of a macaque monkey (bottom). (F) Top: Schematic representation of the locations of LEDs (numbered squares), electrodes (black dots), and virus injection sites (open green circles). Bottom: example of traces recorded during photostimulation. Blue and red lines show the average waveforms of responses to LED5 in the injection area (blue square) and to LED1 in an area that was not injected (red square), respectively. Panels reproduced with permission from: (A–C, D, E, and F).

Figure 5

Combined functional and structural imaging (A) Schematic (left) and photography (right) of the imaging set-up used for structural and functional imaging: a titanium chamber and a silicone artificial dura are chronically implanted to provide imaging access to a 12-mm diameter region of premotor and motor cortex using an objective lens. (B) Widefield 1P image of microvasculature of the cortical area within the chamber. In this study, it was used to assess expression of genetically encoded calcium reporter and to establish vasculature markers for navigating to specific sites of the cortex. (C) Two-photon C$a^{2+}$ image showing single-cell resolution functional signals from motor cortex. Panels reproduced from.

Figure 6

Optogenetic stimulation with simultaneous functional imaging readout (A) Two-photon image of neurons from the visual cortex (V1) expressing a genetically encoded calcium indicator (GCaMP). The colored regions of interest (ROIs) indicate neurons that responded to both visual and optical stimuli in panel (B and C), respectively. (B) Top: a differential fluorescence image (stimulated (F) – baseline (F0)) driven by visual stimuli consisting of gratings patches (inset). Bottom, calcium signals from 10 neurons (colors from panel (A)) in response to 9 varied visual stimuli (presentation times in gray). (C) Top, widefield optogenetic stimulation evoked responses in the same neurons. Bottom, 8 sequential identical optogenetic stimulations evoked equivalent responses. Panels reproduced from.

Figure 7

Combined large-scale ECoG recording and structural imaging (A) In vivo optical coherence tomography (OCTA) images showing the microvasculature of the sensorimotor cortex of a macaque before (top) and 3 h after (bottom) inducing a focal ischemic lesion (stroke). (B) Grayscale picture of a μ-ECoG array on the sensorimotor cortex of an NHP (left). Green box indicates the region imaged on the right panel. OCTA of the cortex as imaged through the array (right). Panels reproduced with permission from (A and B³³).