Faculty Bibliography
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144
Combining brain perturbation and neuroimaging in non-human primates
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.
PMCID:11178240
PMID: 33794355
ISSN: 1095-9572
CID: 5835852
Infrared neural stimulation with 7T fMRI: A rapid in vivo method for mapping cortical connections of primate amygdala
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.
PMCID:9947864
PMID: 33548458
ISSN: 1095-9572
CID: 5835832
A 16-Channel Dense Array for In Vivo Animal Cortical MRI/fMRI on 7T Human Scanners
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: 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.
PMID: 32991277
ISSN: 1558-2531
CID: 5835802
An Open Resource for Non-human Primate Optogenetics
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.
PMCID:7962465
PMID: 33080229
ISSN: 1097-4199
CID: 5835812
Mapping mesoscale cortical connectivity in monkey sensorimotor cortex with optical imaging and microstimulation
To map in vivo cortical circuitry at the mesoscale, we applied a novel approach to map interareal 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 interareal 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 interareal and intra-areal connections in vivo. Comparisons with feedforward and feedback anatomical connectivity are discussed.
PMCID:7541397
PMID: 32255200
ISSN: 1096-9861
CID: 5835752
Curvature domains in V4 of macaque monkey
An important aspect of visual object recognition is the ability to perceive object shape. Two basic components of complex shapes are straight and curved contours. A large body of evidence suggests a modular hierarchy for shape representation progressing from simple and complex orientation in early areas V1 and V2, to increasingly complex stages of curvature representation in V4, TEO, and TE. Here, we reinforce and extend the concept of modular representation. Using intrinsic signal optical imaging in Macaque area V4, we find sub-millimeter sized modules for curvature representation that are organized from low to high curvatures as well as domains with complex curvature preference. We propose a possible 'curvature hypercolumn' within V4. In combination with previous studies, we suggest that the key emergent functions at each stage of cortical processing are represented in systematic, modular maps.
PMCID:7707819
PMID: 33211004
ISSN: 2050-084x
CID: 5835822
Optical imaging reveals functional domains in primate sensorimotor cortex
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.
PMCID:7841645
PMID: 32711067
ISSN: 1095-9572
CID: 5835792
Synaptic organization of cortico-cortical communication in primates
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.
PMCID:7874932
PMID: 32654301
ISSN: 1460-9568
CID: 5835782
Focal Electrical Stimulation of Cortical Functional Networks
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.
PMID: 32483588
ISSN: 1460-2199
CID: 5835772
Precise Targeting of Single Microelectrodes to Orientation Pinwheel Centers
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.
PMCID:7842334
PMID: 33659313
ISSN: 2331-8325
CID: 5835842
