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Visual blindness affects many millions globally and severely impacts quality of life. One approach to overcome visual blindness is the direct electrical microstimulation of brain circuits normally engaged in visual function. Attempts to do so with traditional brain-machine interfaces (BMI) in monkeys and humans have evoked percepts (phosphenes) described as crude featureless spots of light. Here, we propose to qualitatively enhance these percepts by recruiting submillimeter units of cortical representation (cortical columns) which encode rich visual features such as color, motion, shape, and faces. A three step roadmap is proposed, comprising: (1) the mapping of column-based networks (columnar connectomes), (2) connectome-guided studies of circuitry and perception, and (3) column-targeted design of optical BMIs. We predict this approach will increase the specificity and sophistication needed for realistic, vibrant visual perception.

Contains fulltext : 239574.pdf (Publisher’s version ) (Closed access) Open science initiatives are creating opportunities to increase research coordination and impact in nonhuman primate (NHP) imaging. The PRIMatE Data and Resource Exchange community recently developed a collaboration-based strategic plan to advance NHP imaging as an integrative approach for multiscale neuroscience. 5 p.

In the cerebral cortex, the vasculature plays important homeostatic functions, especially at the highly connected complex capillary networks. The association of focal capillary ischemia with the neurodegenerative disease as well as the laminar vascular dynamics have prompted studies of vascular micro-occlusion via photothrombosis. However, technical challenges of this approach remain, including increased temporal precision of occlusion, increasing the depth of vascular occlusion, understanding how such micro-occlusion impacts local blood flow, and ultimately the neuronal effects of such changes. Here, we have developed a novel approach that employs ultra-fast multiphoton light to induce focal Rose Bengal-induced photothrombosis. We demonstrated induction of highly precise and fast occlusion of microvessels at various types and depths. The change of the microvascular architecture and hemodynamics after occlusion revealed the autoregulation and significant difference between upstream vs downstream in layer 2/3. Further, we found that micro-occlusion at two different layers within the same vascular arbor results in distinct effects on the acute flow redistribution mechanism. To examine neuronal effects of such micro-occlusion, we produced infarct of capillaries surrounding a labeled target neuron and found this induces dramatic and rapid lamina-specific degeneration in neuronal dendritic architecture. In sum, our technique enhanced the precision and power of the photothrombotic study of microvascular function. The current results pointed to the importance of laminar scale regulation within the microvascular network, a finding which may be relevant for models of neurovascular disease.

The present study aimed to evaluate magnetic resonance (MR) thermometry using proton resonance frequency shift (PRFS) during laser-induced thermotherapy (LITT), and to compare the results of using different sequences at a field strength of 7-Tesla to identify the optimal for use in ablation so that the surrounding healthy tissues may be protected from damaging in real time.LITT was applied to agarose gel phantoms and ex-vivo porcine brains. We reconstructed both magnitude and phase images to perform MR thermometry based on PRFS methods. We tested four different sequences: a gradient-echo (GRE), a segmented gradient-echo echoplanar imaging (EPI-GRE), a fast-low angle shot (FLASH), and a true fast imaging with steady precession (TRUFI). Temperature was monitored and verified using a fiber-optic thermometry device.All sequences showed good linear correlations (R = 0.97-0.99) between the measured temperature and the calculated MR-thermometry measurements. The phantom/porcine brain experiments revealed the temperature precisions at 1.53/0.69 °C (GRE), 0.61/0.43 °C (EPI-GRE), 1.64/1.32 °C (FLASH), and 0.58/1.52 °C (TRUFI), respectively. Furthermore, we performed a Bland-Altman analysis and the temperature accuracies were found to be - 1.32/- 0.60 °C (GRE), 0.42/- 0.33 °C (EPI-GRE), - 1.28/- 0.98 °C (FLASH), and 0.14/0.46 °C (TRUFI) in the phantom/porcine brain experiments, respectively.Our experiments recommend that EPI-GRE sequence be the best of the all sequences for MR temperature imaging with PRFS in the LITT on 7 T magnetic resonance imaging (MRI) systems because of its relatively higher precision and accuracy.

Advances in optical technology have revolutionized studies of brain function in freely behaving mice. Here, we describe an optical imaging and stimulation device for use in primates that easily attaches to an intracranial chamber. It consists of affordable commercially available or 3D-printed components: a monochromatic camera, a small standard lens, a wireless μLED stimulator powered by an induction coil, and an LED array for illumination. We show that the intrinsic imaging performance of this device is comparable to a standard benchtop system in revealing the functional organization of the visual cortex for awake macaques in a primate chair or under anesthesia. Imaging revealed neural modulatory effects of wireless focal optogenetic stimulation aimed at identified functional domains. With a 1 to 2 cm field of view, 100× larger than previously used in primates without head restraint, our device permits widefield optical imaging and optogenetic stimulation for ethological studies in primates.

We have previously shown that INS-fMRI is a rapid method for mapping mesoscale brain networks in the macaque monkey brain. Focal stimulation of single cortical sites led to the activation of connected cortical locations, resulting in a global connectivity map. Here, we have extended this method for mapping brainwide networks following stimulation of single subcortical sites. As a testbed, we focused on the basal nucleus of the amygdala in the macaque monkey. We describe methods to target basal nucleus locations with submillimeter precision, pulse train stimulation methods, and statistical tests for assessing non-random nature of activations. Using these methods, we report that stimulation of precisely targeted loci in the basal nucleus produced sparse and specific activations in the brain. Activations were observed in the insular and sensory association cortices as well as activations in the cingulate cortex, consistent with known anatomical connections. What is new here is that the activations were focal and, in some cases, exhibited shifting topography with millimeter shifts in stimulation site. The precision of the method enables networks mapped from different nearby sites in the basal nucleus to be distinguished. While further investigation is needed to improve the sensitivity of this method, our analyses do support the reproducibility and non-random nature of some of the activations. We suggest that INS-fMRI is a promising method for mapping large-scale cortical and subcortical networks at high spatial resolution.

Significance: We present a new optical method for modulating cortical activity in multiple locations and across multiple time points with high spatial and temporal precision. Our method uses infrared light and does not require dyes or transgenic modifications. It is compatible with a number of other stimulation and recording techniques. Aim: Infrared neural stimulation (INS) has been largely confined to single point stimuli. In this study, we expand upon this approach and develop a rapidly switched fiber array capable of generation of stimulus patterns. Our prototype is capable of stimulating at nine separate locations but is easily scalable. Approach: Our device is made of commercially available components: a solid-state infrared laser, a piezoelectric fiber coupled optical switch, and 200-μm diameter optical fibers. We validate it using intrinsic optical signal imaging of INS responses in macaque and squirrel monkey sensory cortical areas. Results: We demonstrate that our switched array can consistently generate responses in primate cortex, consistent with earlier single channel INS investigations. Conclusions: Our device can successfully target the cortical surface, either at one specific region or multiple points spread out across different areas. It is compatible with a host of other imaging and stimulation modalities.

Brain perturbation studies allow detailed causal inferences of behavioral and neural processes. Because the combination of brain perturbation methods and neural measurement techniques is inherently challenging, research in humans has predominantly focused on non-invasive, indirect brain perturbations, or neurological lesion studies. Non-human primates have been indispensable as a neurobiological system that is highly similar to humans while simultaneously being more experimentally tractable, allowing visualization of the functional and structural impact of systematic brain perturbation. This review considers the state of the art in non-human primate brain perturbation with a focus on approaches that can be combined with neuroimaging. We consider both non-reversible (lesions) and reversible or temporary perturbations such as electrical, pharmacological, optical, optogenetic, chemogenetic, pathway-selective, and ultrasound based interference methods. Method-specific considerations from the research and development community are offered to facilitate research in this field and support further innovations. We conclude by identifying novel avenues for further research and innovation and by highlighting the clinical translational potential of the methods. ispartof: NEUROIMAGE vol:235 ispartof: location:United States status: published

An important aspect of visual object recognition is the ability to perceive object shape. How the brain encodes fundamental aspects of shape information remains poorly understood. Models of object shape representation describe a multi-stage process that includes encoding of contour orientation and curvature. While modules encoding contour orientation are well established (orientation domains in V1 and V2 visual cortical areas), whether there are modules for curvature is unknown. In this study, we identify a module for curvature representation in area V4 of monkey visual cortex and illustrate a systematic representation of low to high curvature and of curvature orientation, indicative of curvature hypercolumns in V4. We suggest that identifying systematic modular organizations at each stage of the visual cortical hierarchy signifies the key computations performed.SignificanceWe use intrinsic signal optical imaging in area V4 of anesthetized macaque monkey to study the functional organization of curvature representation. We find a modular basis for cue-invariant curvature representation in area V4 of monkey visual cortex and illustrate a systematic representation from low to high curvature and of curvature orientation, replete with curvature pinwheels. This is the first report of systematic functional organization for curvature representation in the visual system. The use of optical imaging has revealed at a population level spatial details of cortical responses, something which has not been evident from previous studies of single neurons. These data support a representational architecture underlying a ‘curvature hypercolumn’ in V4.

In cortical circuitry, synaptic communication across areas is based on two types of axon terminals, small and large, with modulatory and driving roles, respectively. In contrast, it is not known whether similar synaptic specializations exist for intra-areal projections. Using anterograde tracing and three-dimensional reconstruction by electron microscopy (3D-EM), we asked whether large boutons form synapses in the circuit of somatosensory cortical areas 3b and 1. In contrast to observations in macaque visual cortex, light microscopy showed both small and large boutons not only in inter-areal pathways, but also in long-distance intrinsic connections. 3D-EM showed that correlation of surface and volume provides a powerful tool for classifying cortical endings. Principal component analysis supported this observation and highlighted the significance of the size of mitochondria as a distinguishing feature of bouton type. The larger mitochondrion and higher degree of perforated postsynaptic density associated with large rather than to small boutons support the driver-like function of large boutons. In contrast to bouton size and complexity, the size of the postsynaptic density appeared invariant across the bouton types. Comparative studies in human supported that size is a major distinguishing factor of bouton type in the cerebral cortex. In conclusion, the driver-like function of the large endings could facilitate fast dissemination of tactile information within the intrinsic and inter-areal circuitry of areas 3b and 1.

Objective: The purpose of the present study was to fabricate a novel RF coil exclusively for visualizing submillimeter tissue structure and probing neuronal activity in cerebral cortex over anesthetized and awake animals on 7T human scanners. Methods: A novel RF coil design has been proposed for visualizing submillimeter tissue structure and probing neuronal activity in cerebral cortex over anesthetized and awake animals on 7T human scanners: a local transmit coil was utilized to save space for auxiliary device installation; 16 receive-only loops were densely arranged over a 5 cm-diameter circular area, with a diameter of 1.3 cm for each loop. Results: In anesthetized macaque experiments, 60 μm T2*-weighted images were successfully obtained with cortical gyri and sulci exquisitely visualized; over awake macaques, bilateral activations of visual areas including V1, V2, V4, and MST were distinctly detected at 1 mm; over the cat, robust activations were recorded in areas 17 and 18 (V1 and V2) as well as in their connected area of lateral geniculate nucleus (LGN) at 0.3 mm resolution. Conclusion: The promising brain imaging results along with flexibility in various size use of the presented design can be an effective and maneuverable solution to take one step close towards mesoscale cortical-related imaging. Significance: High-spatial-resolution brain imaging over large animals by using ultra-high-field (UHF) MRI will be helpful to understand and reveal functional brain organizations and the underlying mechanism in diseases.

Motor cortex (M1) and somatosensory cortex (S1) are central to arm and hand control. Efforts to understand encoding in M1 and S1 have focused on temporal relationships between neural activity and movement features. However, it remains unclear how the neural activity is spatially organized within M1 and S1. Optical imaging methods are well-suited for revealing the spatio-temporal organization of cortical activity, but their application is sparse in monkey sensorimotor cortex. Here, we investigate the effectiveness of intrinsic signal optical imaging (ISOI) for measuring cortical activity that supports arm and hand control in a macaque monkey. ISOI revealed spatial domains that were active in M1 and S1 in response to instructed reaching and grasping. The lateral M1 domains overlapped the hand representation and contained a population of neurons with peak firing during grasping. In contrast, the medial M1 domain overlapped the arm representation and a population of neurons with peak firing during reaching. The S1 domain overlapped the hand representations of areas 1 and 2 and a population of neurons with peak firing upon hand contact with the target. Our single unit recordings indicate that ISOI domains report the locations of spatial clusters of functionally related neurons. ISOI is therefore an effective tool for surveilling the neocortex for “hot zones” of activity that supports movement. Combining the strengths of ISOI with other imaging modalities (e.g., fMRI, 2-photon) and with electrophysiological methods can open new frontiers in understanding the spatio-temporal organization of cortical signals involved in movement control.

In the mammalian visual system, early stages of visual form perception begin with orientation selective neurons in primary visual cortex (V1). In many species (including humans, monkeys, tree shrews, cats, and ferrets), these neurons are organized in pinwheel-like orientation columns. To study the functional organization within orientation pinwheels, it is important to target pinwheel subdomains precisely. We therefore developed a technique to provide a quantitative determination of the location of pinwheel centers (PCs). Previous studies relied solely on blood vessel images of the cortical surface to guide electrode penetrations to PCs in orientation maps. However, considerable spatial error remained using this method. In the present study, we improved the accuracy of targeting PCs by ensuring perpendicularity of electrodes and by utilizing the orientation tuning of local field potentials (LFP) recorded at or near the optically determined positions.

Decades of studies in non-human primates (NHPs) have been conducted in conditions of strict experimental control of perception and behavior in order to understand the functions of the brain. For instance, experiments focused on visual perception often involve head fixation, unnaturally long eye fixation periods, and attention to locations away from the center of gaze. These paradigms require long training periods (months to a year). While such studies have advanced our knowledge of brain function tremendously, a recurring question is how relevant the gathered data are to natural behavior. The availability of cutting-edge technologies and computational power can free us from the limitations of classical experimental paradigms and usher in a new generation of neuroscience questions focused on how the brain functions in real world settings. Here we demonstrate a small head-mounted multimodal device for stimulating and recording domain-based cortical activity in NHPs. This device consists of an intrinsic optical signal imaging camera and a wireless LED stimulator. To evaluate the functionality of this device, we compared its imaging performance in vivo to that of current benchtop intrinsic imaging systems and demonstrated the efficacy of wireless optogenetic stimulation while conducting awake intrinsic imaging. Our device device has been constructed from off the shelf components and offers multiareal and targeted stimulation and recording capabilities in minimally restrained subjects. It has a potential to contribute to our understanding of cortical encoding of perception and behavior and could have clinical relevance for the development of brain-machine interfaces.

Contains fulltext : 217200.pdf (Publisher’s version ) (Closed access) Nonhuman primate neuroimaging is on the cusp of a transformation, much in the same way its human counterpart was in 2010, when the Human Connectome Project was launched to accelerate progress. Inspired by an open data-sharing initiative, the global community recently met and, in this article, breaks through obstacles to define its ambitions. 4 p.

Background: Stroke is a major cause of life-long disability in adults, associated with poor quality of life. Virtual reality (VR)-based therapy systems are known to be helpful in improving motor functions following stroke, but recent clinical findings have not been included in the previous publications of meta-analysis studies.Aims: This meta-analysis was based on the available literature to evaluate the therapeutic potential of VR as compared to dose-matched conventional therapies (CT) in patients with stroke.Methods: We retrieved relevant articles in EMBASE, MEDLINE, PubMed, and Web of Science published between 2010 and February 2019. Peer-reviewed randomized controlled trials that compared VR with CT were included.Results: A total of 27 studies met the inclusion criteria. The analysis indicated that the VR group showed statistically significant improvement in the recovery of UL function (Fugl-Meyer Upper Extremity [FM-UE]: n = 20 studies, Mean Difference [MD] = 3.84, P = .01), activity (Box and Block Test [BBT]: n = 13, MD = 3.82, P = .04), and participation (Motor Activity Log [MAL]: n = 6, MD = 0.8, P = .0001) versus the control group.Conclusion: VR appears to be a promising therapeutic technology for UL motor rehabilitation in patients with stroke.

To map in vivo cortical circuitry at the mesoscale we applied a novel approach to map inter-areal functional connectivity. Electrical intracortical microstimulation (ICMS) in conjunction with optical imaging of intrinsic signals (OIS) was used map functional connections in somatosensory cortical areas in anesthetized squirrel monkeys. ICMS produced activations that were focal and that displayed responses which were stimulation intensity dependent. ICMS in supragranular layers of Brodmann areas 3b, 1, 2, 3a, and M1 evoked inter-areal activation patterns that were topographically appropriate and appeared consistent with known anatomical connectivity. Specifically, ICMS revealed area 3b connections with area 1; area 1 connections with areas 2 and 3a; area 2 connections with areas 1, 3a, and M1; area 3a connections with areas M1, 1, and 2; and M1 connections with areas 3a, 1, and 2. These somatosensory connectivity patterns were reminiscent of feedforward patterns observed anatomically, although feedback contributions are also likely present. Further consistent with anatomical connectivity, intra-areal and intra-areal patterns of activation were patchy with patch sizes of 200–300 μm. In summary, ICMS with OIS is a novel approach for mapping inter-areal and intra-areal connections in vivo. Comparisons with feedforward and feedback anatomical connectivity is discussed.

Significance Primate visual cortex is organized into columns that process different features of a visual scene, such as color, orientation preference, and ocular dominance. Until now, their small size has made it difficult to modulate them directly. Here, we report for the first time that focal targeting of light-sensitive ion channels (channelrhodopsins) in macaques using lentiviral vectors allows one to stimulate functional domains. We show that such targeted stimulation leads to selective activation of anatomically connected neighboring domains with similar function. Such a fine-scale optical stimulation approach is capable of mapping functionally specific domain-based neuronal networks. Its potential for linking such networks to optogenetic modulation of perception and behavior opens doors for developing targeted, domain-based neuroprosthetics., In primates, visual perception is mediated by brain circuits composed of submillimeter nodes linked together in specific networks that process different types of information, such as eye specificity and contour orientation. We hypothesized that optogenetic stimulation targeted to cortical nodes could selectively activate such cortical networks. We used viral transfection methods to confer light sensitivity to neurons in monkey primary visual cortex. Using intrinsic signal optical imaging and single-unit electrophysiology to assess effects of targeted optogenetic stimulation, we found that (i) optogenetic stimulation of single ocular dominance columns (eye-specific nodes) revealed preferential activation of nearby same-eye columns but not opposite-eye columns, and (ii) optogenetic stimulation of single orientation domains increased visual response of matching orientation domains and relatively suppressed nonmatching orientation selectivity. These findings demonstrate that optical stimulation of single nodes leads to modulation of functionally specific cortical networks related to underlying neural architecture.

Advances in modern medicine have benefited greatly from technological advances. In brain disease, early diagnosis and individualized treatment are partly limited by the precision of detection methods. For example, traditional magnetic resonance imaging (MRI) diagnostics are based primarily on ≥ 1-mm scale resolution, whereas basic units of brain function are at the submillimeter scale. The importance of mesoscale organization in the brain is becoming increasingly evident from research in non-human primates (NHPs) and is now impacting our understanding of brain disease. In this review, we highlight advances in clinical diagnosis using ultra-high-field (UHF) MRI, with a particular focus on contributions from NHP research. Impact on neurology, neurosurgery, and psychiatry are illustrated, including UHF MRI contributions to increased spatiotemporal resolutions, improved tissue contrast, and higher sensitivity to neurochemical signatures. We present a future where the early diagnosis and individualized treatment of human brain disease are aided by UHF MRI technology and NHP research.

Significance A long-standing problem in visual depth perception is how corresponding features between the two eyes are matched (the “binocular correspondence problem”). Here, we show, using optical imaging in monkey visual cortex, that this computation occurs in the near and far disparity domains of V2, and that functional organization in V2 might facilitate the pooling of disparity signals that can reduce false matches to solve the binocular correspondence problem., Stereoscopic vision depends on correct matching of corresponding features between the two eyes. It is unclear where the brain solves this binocular correspondence problem. Although our visual system is able to make correct global matches, there are many possible false matches between any two images. Here, we use optical imaging data of binocular disparity response in the visual cortex of awake and anesthetized monkeys to demonstrate that the second visual cortical area (V2) is the first cortical stage that correctly discards false matches and robustly encodes correct matches. Our findings indicate that a key transformation for achieving depth perception lies in early stages of extrastriate visual cortex and is achieved by population coding.

Nanoparticle-assisted near-infrared (NIR) bioimaging and two-photon fluorescence microscopy (TPFM) are two important technologies in biophotonic research. In this work, we synthesize the dye named 2-(4-bromophenyl)-3-(4-(4-(diphenylamino)styryl)phenyl)fumaronitrile (TPABDFN), which had a large two-photon absorption cross-section and bright NIR emission. The dyes were then encapsulated with poly(styrene- co -maleic anhydride) (PSMA), forming fluorescent nanoparticles. The TPABDFN-PSMA nanoparticles possessed high chemical and optical stability, good biocompatibility, as well as large two-photon absorption cross-section (5.56 × 10 5 GM). Furthermore, we combined NIR bioimaging and TPFM together, and utilized TPABDFN-PSMA nanoparticles as fluorescent contrast agents for two-photon excited NIR microscopic imaging, with a 1040 nm-femtosecond laser. In vivo angiography of mice ear and brain was performed. Due to the deep penetration capability of both 1040 nm-excitation and NIR emission light, a very large in vivo microscopic imaging depth (∼1.2 mm) was achieved. NIR emissive and biocompatible TPABDFN-PSMA nanoparticles have great potential in disease diagnosis and clinical therapies, where deep-tissue imaging is required.

Non-human primates (NHPs) are vital models for neuroscience research. These animals have been widely used in behavioral, electrophysiological, molecular, and more recently, multimodal neuroimaging and neuro-engineering studies. Several RF coil arrays have been designed for functional, high-resolution brain magnetic resonance imaging (MRI), but few have been designed to accommodate multimodal devices. In the present study, a 16-channel array coil was constructed for brain imaging of macaques at 3 Tesla (3 T). To construct this coil, a close-fitting helmet-shaped form was designed to host 16 coil loops for whole-brain coverage. This assembly is mountable onto stereotaxic head frame bars, and the coil functions while the monkey is in the sphinx position with a clear line of vision of stimuli presented from outside of the MRI system. In addition, 4 openings were allocated in the coil housing, allowing multimodal devices to directly access visual cortical regions such as V1-V4 and MT. Coil performance was evaluated in an anesthetized macaque by quantifying and comparing signal-to-noise ratios (SNRs), noise correlations, and g-factor maps to a vendor-supplied human pediatric coil frequently used for NHP MRI. The result from in vivo experiments showed that the NHP coil was well-decoupled, had higher SNRs in cortical regions, and improved data acquisition acceleration capability compared with a vendor-supplied human pediatric coil that has been frequently used in macaque MRI studies. Furthermore, whole-brain anatomic imaging, diffusion tensor imaging and functional brain imaging have also been conducted: the details of brain anatomical structure, such as cerebellum and brainstem, can be clearly visualized in T2-SPACE images; b0 SNR calculated from b0 maps was higher than the human pediatric coil in all regions of interest (ROIs); the time-course SNR (tSNR) map calculated for GRE-EPI images demonstrates that the presented coil can be used for high-resolution functional imaging at 3 T.

Vasculature architecture of the brain can provide revealing information about mental and neurological function and disease. Fluorescence imaging in the second near-infrared (NIR-II) regime with less light scattering is a more promising method for detecting cortical vessels than traditional visible and NIR-I modes. Methods: Clinically approved dye indocyanine green (ICG) was used for NIR-II fluorescence imaging. Here, for the first time, we developed two NIR-II fluorescence microscopy systems for brain vasculature imaging in macaque monkeys. The first is a wide-field microscope with high temporal resolution for measuring blood flow velocity and cardiac impulse period, while the second is a high spatial resolution confocal microscope producing three-dimensional maps of the cortical microvascular network. Both were designed with flexibility to image various cortical locations on the head. Results: Here, ICG was proved to have high brightness in NIR-II region and an 8-fold QY increase in serum than in water. We achieved cerebrovascular functional imaging of monkey with high temporal resolution (25 frames/second) with wide-field microscope. The blood flow velocity of capillaries can be precisely calculated and the cardiac impulse period can be monitored as well. In vivo structural imaging of cerebrovasculature was accomplished with both high spatial lateral resolution (~8 µm) and high signal to background ratio (SBR). Vivid 3D reconstructed NIR-II fluorescence confocal microscopic images up to depth of 470 μm were also realized. Conclusion: This work comprises an important advance towards studies of neurovascular coupling, stroke, and other diseases relevant to neurovascular health in humans.

Traditional electrical stimulation of brain tissue typically affects relatively large volumes of tissue spanning multiple millimeters. This low spatial resolution stimulation results in nonspecific functional effects. In addition, a primary shortcoming of these designs was the failure to take advantage of inherent functional organization in the cerebral cortex. Here, we describe a new method to electrically stimulate the brain which achieves selective targeting of single feature-specific domains in visual cortex. We provide evidence that this paradigm achieves mesoscale, functional network-specificity, and intensity dependence in a way that mimics visual stimulation. Application of this approach to known feature domains (such as color, orientation, motion, and depth) in visual cortex may lead to important functional improvements in the specificity and sophistication of brain stimulation methods and has implications for visual cortical prosthetic design.

s Functional magnetic resonance imaging (fMRI) in monkeys is important for bridging the gap between invasive animal brain studies and non-invasive human brain studies. To resolve the finer functional structure of the monkey brain, ultra-high-field (UHF) MR is essential, and high-performance, close-fitting RF receive coils are typically desired to fully leverage the intrinsic gains provided by UHF MRI. Moreover, static field (B0) inhomogeneity arising from the tissue susceptibility interface is more severe at UHF, presenting an obstacle to achieving high-resolution fMRI. B0 shim of the monkey head is challenging due to its smaller size and more complex sources of B0 offsets in multi-modal imaging tasks. In the present work, we have customized an array coil for lightly-anesthetized monkey fMRI in the 7T human scanner that combines RF and multi-coil (MC) B0 shim functionality (also referred to as AC/DC coils) to provide high imaging SNR and high-spatial-order, rapidly switchable B0-shim capability. Additional space was retained on the coil to render it compatible with monkey multi-modal imaging studies. Both MC global (whole-volume) and dynamic (slice-optimized) shim methods were tested and evaluated, and the benefits of MC shim for fMRI experiments was also studied. A minor reduction in RF coil performance was found after introducing additional B0 shim circuitry. However, the proposed RF coil provided higher image SNR and more uniform contrast compared to a commercially available coil for human knee imaging. Compared with static 2nd-order shim, the B0 inhomogeneity was reduced by 56.8%, and 95-percentile B0 offset was reduced to within 28.2 Hz through MC shim, versus 68.7 Hz with 2nd-order static shim. As a result, functional image quality could be improved, and brain activation can be better detected using the proposed AC/DC monkey coil.

Subdomains in orientation domains of primary visual cortex suggest the presence of a pinwheel-centered orientation hypercolumn., In the mammalian visual system, early stages of visual form processing begin with orientation-selective neurons in primary visual cortex (V1). In many species (including humans, monkeys, tree shrews, cats, and ferrets), these neurons are organized in a beautifully arrayed pinwheel-like orientation columns, which shift in orientation preference across V1. However, to date, the relationship of orientation architecture to the encoding of multiple elemental aspects of visual contours is still unknown. Here, using a novel, highly accurate method of targeting electrode position, we report for the first time the presence of three subdomains within single orientation domains. We suggest that these zones subserve computation of distinct aspects of visual contours and propose a novel tripartite pinwheel-centered view of an orientation hypercolumn.

We have developed INS-fMRI as a rapid and high-resolution method for mapping functional brain networks in vivo., We have developed a way to map brain-wide networks using focal pulsed infrared neural stimulation in ultrahigh-field magnetic resonance imaging (MRI). The patterns of connections revealed are similar to those of connections previously mapped with anatomical tract tracing methods. These include connections between cortex and subcortical locations and long-range cortico-cortical connections. Studies of local cortical connections reveal columnar-sized laminar activation, consistent with feed-forward and feedback projection signatures. This method is broadly applicable and can be applied to multiple areas of the brain in different species and across different MRI platforms. Systematic point-by-point application of this method may lead to fundamental advances in our understanding of brain connectomes.

Introduction: The close functional relationship between areas 3b and 1 of the somatosensory cortex is based on their reciprocal connections indicating that tactile sensation depends on the interaction of these two areas. Aim: The aim of the authors was to explore this neuronal circuit at the level of the distal finger pad representation. Method: The study was made by bidirectional tract tracing aided by neurophysiological mapping in squirrel monkeys (Saimiri sciureus). Results: Inter-areal connections between the two areas preferred the homologues representations. However, intra-areal connections were formed between the neighboring finger pad representations supporting the physiological observations. Interestingly, the size of the local input area of the injected cortical micro-region, which differed in the two areas, represented the same skin area. Conclusions: The authors propose that intra-areal connections are important in integrating information across fingers, while inter-areal connections are important in maintaining input localization during hand movement. Orv. Hetil., 2016, 157(33), 1320–1325.

Optogenetics has revolutionized neuroscience in small laboratory animals, but its effect on animal models more closely related to humans, such as non-human primates (NHPs), has been mixed. To make evidence-based decisions in primate optogenetics, the scientific community would benefit from a centralized database listing all attempts, successful and unsuccessful, of using optogenetics in the primate brain. We contacted members of the community to ask for their contributions to an open science initiative. As of this writing, 45 laboratories around the world contributed more than 1,000 injection experiments, including precise details regarding their methods and outcomes. Of those entries, more than half had not been published. The resource is free for everyone to consult and contribute to on the Open Science Framework website. Here we review some of the insights from this initial release of the database and discuss methodological considerations to improve the success of optogenetic experiments in NHPs. ispartof: NEURON vol:108 issue:6 ispartof: location:United States status: published

Significance: Current approaches to stimulating and recording from the brain have combined electrical or optogenetic stimulation with recording approaches, such as two-photon, electrophysiology (EP), and optical intrinsic signal imaging (OISI). However, we lack a label-free, all-optical approach with high spatial and temporal resolution. Aim: To develop a label-free, all-optical method that simultaneously manipulates and images brain function using pulsed near-infrared light (INS) and functional optical coherence tomography (fOCT), respectively. Approach: We built a coregistered INS, fOCT, and OISI system. OISI and EP recordings were employed to validate the fOCT signals. Results: The fOCT signal was reliable and regional, and the area of fOCT signal corresponded with the INS-activated region. The fOCT signal was in synchrony with the INS onset time with a delay of ∼30 ms. The magnitude of fOCT signal exhibited a linear correlation with the INS radiant exposure. The significant correlation between the fOCT signal and INS was further supported by OISI and EP recordings. Conclusions: The proposed fiber-based, all-optical INS-fOCT method allows simultaneous stimulation and mapping without the risk of interchannel cross-talk and the requirement of contrast injection and viral transfection and offers a deep penetration depth and high resolution.

We agree that elimination of false matches is a multistep process and show that V2 is an important step in the process. Below, we further show that by integrating disparity domain neuron responses (Fig. 1 A , large red circle) with similar preferred disparity but across different preferences of other visual features [including spatial scale, receptive field size, and phase disparity (Fig. 1 D ), based on previously published data (1, 2)], our model preserves responses to correct matching (Fig. 1 C , solid red line) and greatly attenuates responses to false matching (Fig. 1 C , dashed red line). We extend the energy model to a population level as suggested by Doi et al. (3) to account for our findings in V2 (4). We start with neurons similar to previously described single-neuron responses: Each neuron (Fig. 1 A , small blue circles) is responsive to both correct (defined by cRDS; Fig. 1 B , solid blue line) and to false (defined by aRDS; Fig. 1 B , dashed blue line) matches as predicted by … [↵][1]1To whom correspondence should be addressed. Email: dr_gangchen{at}zju.edu.cn. [1]: #xref-corresp-1-1

PURPOSE: In the mammalian visual system, early stages of visual form perception begin with orientation selective neurons in primary visual cortex (V1). In many species (including humans, monkeys, tree shrews, cats, and ferrets), these neurons are organized in beautifully arrayed orientation columns, which shift in orientation preference across V1 and are highlighted by orientation pinwheels. However, to date, the relationship of orientation architecture to the encoding of elemental aspects of visual contours is still unknown. METHODS: Using a novel highly accurate method of targeting electrode position, combining with optical image and single-unit recording, we report for the first time the presence of three functionally distinct zones within single orientation domains. RESULTS: We found evidence for three concentric sub-regions centered on the orientation-pinwheel. The central-most region contains neurons with small receptive fields and strong suppressive surrounds, while the outermost region contains neurons with larger receptive fields and weak suppressive surrounds. CONCLUSIONS: We suggest that these zones subseries computation of distinct aspects of visual contours (linear orientation, local curvature, and contour singularities). The orientation domain thus embodies a three stage visual contour processor in V1.

The computation of texture and shape involves integration of features of various orientations. Orientation networks within V1 tend to involve cells which share similar orientation selectivity. However, emergent properties in V2 require the integration of multiple orientations. We now show that, unlike interactions within V1, V1-V2 orientation interactions are much less synchronized and are not necessarily orientation dependent. We find V1-V2 orientation networks are of two types: a more tightly synchronized, orientation-preserving network and a less synchronized orientation-diverse network. We suggest that such diversity of V1-V2 interactions underlies the spatial and functional integration required for computation of higher order contour and shape in V2.

Functions of the cerebral cortex emerge via interactions of horizontally distributed neuronal populations within and across areas. However, the connectional underpinning of these interactions is not well understood. The present study explores the circuitry of column-size cortical domains within the hierarchically organized somatosensory cortical areas 3b and 1 using tract tracing and optical intrinsic signal imaging (OIS). The anatomical findings reveal that feedforward connections exhibit high topographic specificity, while intrinsic and feedback connections have a more widespread distribution. Both intrinsic and inter-areal connections are topographically oriented across the finger representations. Compared to area 3b, the low clustering of connections and small cortical magnification factor supports that the circuitry of area 1 scaffolds a sparse functional representation that integrates peripheral information from a large area that is fed back to area 3b. Fast information exchange between areas is ensured by thick axons forming a topographically organized, reciprocal pathway. Moreover, the highest density of projecting neurons and groups of axon arborization patches corresponds well with the size and locations of the functional population response reported by OIS. The findings establish connectional motifs at the mesoscopic level that underpin the functional organization of the cerebral cortex.

Nat. Neurosci. 19, 1123–1130 (2016); published online 26 August 2016; corrected after print 29 August 2016 In the version of this article initially published online, the first author's name appears as “Charles Jennings” without middle initial; it has been changed to “Charles G Jennings”. Another author's name appears in the author list as “Angela Roberts,” also without middle initial; it has been changed to “Angela C Roberts.

Deep-tissue imaging is of great significance to biological applications. In this paper, a deep-red emissive luminogen 2,3-bis(4'-(diphenylamino)-[1,1'-biphenyl]-4-yl) fumaronitrile (TPATCN) with aggregation-induced emission (AIE) feature is prepared. TPATCN molecules were then encapsulated within a polymeric matrix of Pluronic F-127 to form nanoparticles (NPs). TPATCN NPs exhibit bright three-photon fluorescence (3PF) in deep-red region, together with high chemical stability, good photostability, and biocompatibility. They are further utilized for in vivo 3PF imaging of the brain vasculature of mice, under the excitation of a 1550 nm femtosecond laser. A vivid 3D reconstruction of the brain vasculature is then built with a penetration depth of 875 µm, which is the largest in ever reported 3PF imaging based on AIE NPs. After that, by collecting both of the 3PF and third-harmonic generation signals, multichannel nonlinear optical imaging of the brain blood vessels is further realized. These results will be helpful to study the structures and functions of the brain in the future.

Background Infrared neural stimulation (INS) is a novel technique for modulating neural function. Its advantages over electrical stimulation include high spatial specificity, lack of electrical artifact and contact-free stimulation. INS acts via a rapid, focal increase in temperature. However, in order to become a viable experimental and therapeutic tool, the safety of INS must be demonstrated. Objective/hypothesis Our aim was to determine the upper limit for the radiant exposure of INS in the brain without causing damage, using an INS sequence previously shown to induce both behavioral and electrophysiological effects in rodents and non-human primates. Methods We stimulated the brains of anesthetized rodents and two squirrel monkeys using an infrared laser, depositing radiant energies from 0.3 to 0.9 J/cm 2 per pulse in 0.5 s-long 200 Hz trains. At the end of the experiment, the animals were euthanized, perfused and the brains processed using standard histological techniques. Results Radiant exposures greater than or equal to 0.4 J/cm 2 resulted in identifiable lesions in brain sections. The lesions had a shape of a parabola and could further be subdivided into three concentric zones based on the type of damage observed. Conclusions: The thermal damage threshold following our INS paradigm was between 0.3 and 0.4 J/cm 2 per pulse. This value is lower than the one found previously in peripheral nerve. The differences are likely due to the structure of the INS sequence itself, particularly the repetition rate. The results warrant further modeling and experimental work in order to delimit the INS parameter space that is both safe and effective.

Infrared neural stimulation (INS) is an alternative neurostimulation modality that uses pulsed infrared light to evoke spatially precise neural activity that does not require direct contact with neural tissue. With these advantages INS has the potential to increase our understanding of specific neural pathways and impact current diagnostic and therapeutic clinical applications. In order to develop this technique, we investigate the feasibility of INS (λ = 1.875 μm, fiber diameter = 100–400 μm) to activate and modulate neural activity in primary visual cortex (V1) of Macaque monkeys. Infrared neural stimulation was found to evoke localized neural responses as evidenced by both electrophysiology and intrinsic signal optical imaging (OIS). Single unit recordings acquired during INS indicated statistically significant increases in neuron firing rates that demonstrate INS evoked excitatory neural activity. Consistent with this, INS stimulation led to focal intensity-dependent reflectance changes recorded with OIS. We also asked whether INS is capable of stimulating functionally specific domains in visual cortex and of modulating visually evoked activity in visual cortex. We found that application of INS via 100 μm or 200 μm fiber optics produced enhancement of visually evoked OIS response confined to the eye column where INS was applied and relative suppression of the other eye column. Stimulating the cortex with a 400 μm fiber, exceeding the ocular dominance width, led to relative suppression, consistent with involvement of inhibitory surrounds. This study is the first to demonstrate that INS can be used to either enhance or diminish visual cortical response and that this can be done in a functional domain specific manner. INS thus holds great potential for use as a safe, non-contact, focally specific brain stimulation technology in primate brains.