Cortex Of Monkeys Research Articles

Functional imaging and anatomical connections in squirrel monkeys reveal parietal-frontal circuits underlying eye movements.

The posterior parietal cortex (PPC) of squirrel monkeys contains subregions where long trains of intracortical microstimulation evoke complex, behaviorally meaningful movements. Recently, we showed that such stimulation of a part of the PPC in the caudal lateral sulcus (LS) elicits eye movements in these monkeys. Here, we studied the functional and anatomical connections of this oculomotor region we call parietal eye field (PEF) with frontal eye field (FEF) and other cortical regions in 2 squirrel monkeys. We demonstrated these connections with intrinsic optical imaging and injections of anatomical tracers. Optical imaging of frontal cortex during stimulation of the PEF evoked focal functional activation within FEF. Tracing studies confirmed the functional PEF-FEF connections. Moreover, tracer injections revealed PEF connections with other PPC regions on the dorsolateral and medial brain surface, cortex in the caudal LS, and visual and auditory cortical association areas. Subcortical projections of PEF were primarily with superior colliculus, and pontine nuclei as well as nuclei of the dorsal posterior thalamus and caudate. These findings suggest that PEF in squirrel monkey is homologous to lateral intraparietal (LIP) area of macaque, supporting the notion that these brain circuits are organized similarly to mediate ethologically relevant oculomotor behaviors.

Spared Premotor Areas Undergo Rapid Nonlinear Changes in Functional Organization Following a Focal Ischemic Infarct in Primary Motor Cortex of Squirrel Monkeys.

Recovery of motor function after stroke is accompanied by reorganization of movement representations in spared cortical motor regions. It is widely assumed that map reorganization parallels recovery, suggesting a causal relationship. We examined this assumption by measuring changes in motor representations in eight male and six female squirrel monkeys in the first few weeks after injury, a time when motor recovery is most rapid. Maps of movement representations were derived using intracortical microstimulation techniques in primary motor cortex (M1), ventral premotor cortex (PMv), and dorsal premotor cortex (PMd) in 14 adult squirrel monkeys before and after a focal infarct in the M1 distal forelimb area. Maps were derived at baseline and at either 2 (n = 7) or 3 weeks (n = 7) postinfarct. In PMv the forelimb maps remained unchanged at 2 weeks but contracted significantly (-42.4%) at 3 weeks. In PMd the forelimb maps expanded significantly (+110.6%) at 2 weeks but contracted significantly (-57.4%) at 3 weeks. Motor deficits were equivalent at both time points. These results highlight two features of plasticity after M1 lesions. First, significant contraction of distal forelimb motor maps in both PMv and PMd is evident by 3 weeks. Second, an unpredictable nonlinear pattern of reorganization occurs in the distal forelimb representation in PMd, first expanding at 2 weeks, and then contracting at 3 weeks postinjury. Together with previous results demonstrating reliable map expansions in PMv several weeks to months after M1 injury, the subacute time period may represent a critical window for the timing of therapeutic interventions.SIGNIFICANCE STATEMENT The relationship between motor recovery and motor map reorganization after cortical injury has rarely been examined in acute/subacute periods. In nonhuman primates, premotor maps were examined at 2 and 3 weeks after injury to primary motor cortex. Although maps are known to expand late after injury, the present study demonstrates early map expansion at 2 weeks (dorsal premotor cortex) followed by contraction at 3 weeks (dorsal and ventral premotor cortex). This nonlinear map reorganization during a time of gradual behavioral recovery suggests that the relationship between map plasticity and motor recovery is much more complex than previously thought. It also suggests that rehabilitative motor training may have its most potent effects during this early dynamic phase of map reorganization.

A physical neural mass model framework for the analysis of oscillatory generators from laminar electrophysiological recordings

Cortical function emerges from the interactions of multi-scale networks that may be studied at a high level using neural mass models (NMM) that represent the mean activity of large numbers of neurons. Here, we provide first a new framework called laminar NMM, or LaNMM for short, where we combine conduction physics with NMMs to simulate electrophysiological measurements. Then, we employ this framework to infer the location of oscillatory generators from laminar-resolved data collected from the prefrontal cortex in the macaque monkey. We define a minimal model capable of generating coupled slow and fast oscillations, and we optimize LaNMM-specific parameters to fit multi-contact recordings. We rank the candidate models using an optimization function that evaluates the match between the functional connectivity (FC) of the model and data, where FC is defined by the covariance between bipolar voltage measurements at different cortical depths. The family of best solutions reproduces the FC of the observed electrophysiology by selecting locations of pyramidal cells and their synapses that result in the generation of fast activity at superficial layers and slow activity across most depths, in line with recent literature proposals. In closing, we discuss how this hybrid modeling framework can be more generally used to infer cortical circuitry.

FTO-dependent m6A modification of Plpp3 in circSCMH1-regulated vascular repair and functional recovery following stroke

Vascular repair is considered a key restorative measure to improve long-term outcomes after ischemic stroke. N6-methyladenosine (m6A), the most prevalent internal modification in eukaryotic mRNAs, functionally mediates vascular repair. However, whether circular RNA SCMH1 (circSCMH1) promotes vascular repair by m6A methylation after stroke remains to be elucidated. Here, we identify the role of circSCMH1 in promoting vascular repair in peri-infarct cortex of male mice and male monkeys after photothrombotic (PT) stroke, and attenuating the ischemia-induced m6A methylation in peri-infarct cortex of male mice after PT stroke. Mechanically, circSCMH1 increased the translocation of ubiquitination-modified fat mass and obesity-associated protein (FTO) into nucleus of endothelial cells (ECs), leading to m6A demethylation of phospholipid phosphatase 3 (Plpp3) mRNA and subsequently the increase of Plpp3 expression in ECs. Our data demonstrate that circSCMH1 enhances vascular repair via FTO-regulated m6A methylation after stroke, providing insights into the mechanism of circSCMH1 in promoting stroke recovery.

Ventral premotor cortex encodes task relevant features during eye and head movements

Visual exploration of the environment is achieved through gaze shifts or coordinated movements of the eyes and the head. The kinematics and contributions of each component can be decoupled to fit the context of the required behavior, such as redirecting the visual axis without moving the head or rotating the head without changing the line of sight. A neural controller of these effectors, therefore, must show code relating to multiple muscle groups, and it must also differentiate its code based on context. In this study we tested whether the ventral premotor cortex (PMv) in monkey exhibits a population code relating to various features of eye and head movements. We constructed three different behavioral tasks or contexts, each with four variables to explore whether PMv modulates its activity in accordance with these factors. We found that task related population code in PMv differentiates between all task related features and conclude that PMv carries information about task relevant features during eye and head movements. Furthermore, this code represents both lower-level (effector and movement direction) and higher-level (context) information.

Neonatal exposures to sevoflurane in rhesus monkeys alter synaptic ultrastructure in later life.

Repeated or prolonged early life exposure to anesthesia is neurotoxic in animals and associated with neurocognitive impairment in later life in humans. We used electron microscopy with unbiased stereological sampling to assess synaptic ultrastructure in dorsolateral prefrontal cortex (dlPFC) and hippocampal CA1 of female and male rhesus monkeys, four years after three 4-h exposures to sevoflurane during the first five postnatal weeks. This allowed us to ascertain long-term consequences of anesthesia exposure without confounding effects of surgery or illness. Synapse areas were reduced in the largest synapses in CA1 and dlPFC, predominantly in perforated spinous synapses in CA1 and nonperforated spinous synapses in dlPFC. Mitochondrial morphology and localization changed subtly in both areas. Synapse areas in CA1 correlated with response to a mild social stressor. Thus, exposure to anesthesia in infancy can cause long-term ultrastructural changes in primates, which may be substrates for long-term alterations in synaptic transmission and behavioral deficits.

Neural recovery after cortical injury: Effects of MSC derived extracellular vesicles on motor circuit remodeling in rhesus monkeys.

Reorganization of motor circuits in the cortex and corticospinal tract are thought to underlie functional recovery after cortical injury, but the mechanisms of neural plasticity that could be therapeutic targets remain unclear. Recent work from our group have shown that systemic treatment with mesenchymal stem cell derived (MSCd) extracellular vesicles (EVs) administered after cortical damage to the primary motor cortex (M1) of rhesus monkeys resulted in a robust recovery of fine motor function and reduced chronic inflammation. Here, we used immunohistochemistry for cfos, an activity-dependent intermediate early gene, to label task-related neurons in the surviving primary motor and premotor cortices, and markers of axonal and synaptic plasticity in the spinal cord. Compared to vehicle, EV treatment was associated with a greater density of cfos+ pyramidal neurons in the deep layers of M1, greater density of cfos+ inhibitory interneurons in premotor areas, and lower density of synapses on MAP2+lower motor neurons in the cervical spinal cord. These data suggest that the anti-inflammatory effects of EVs may reduce injury-related upper motor neuron damage and hyperexcitability, as well as aberrant compensatory re-organization in the cervical spinal cord to improve motor function.

The Analysis of the Accuracy of Support Vector Regression Classification of a Neural Dataset Originating in the Motor Cortex of a Macaque Monkey

Neural decoding is a constantly adapting field of applied machine learning, using many different machine learning algorithms to analyze neural data. One such analysis of neural data is the interpretation and analysis of data originating the motoro cortex and the prediction of stimuli given to an organism using the motor response. In looking at a specific dataset, containing data from the motor cortex of a macaque monkey, where its neural response to directional stimuli was measured. Two different neural decoding algorithms were previously used to analyze this dataset, yet the highest accuracy they yielded was below 90%. There is a need for machine-learning based neural decoding algorithms to decode movement-relating neural data with higher accuracy. Support vector regression (SVR), a linear-regression based model of the machine learning algorithm support vector machines, was chosen for analysis. In this study, we aim to evaluate the predictive accuracy of SVR using a dataset obtained from a macaque monkey. The model predicted the directional stimuli with an accuracy of 82.47% percent.

OR04-1 The Developmental Origin and the Specification of the Adrenal Cortex in Humans and Cynomolgus Monkeys

Abstract The adrenal cortex and gonads are the two major endocrine hubs that participate in the hormonal regulation of vital aspects of mammalian homeostasis. Accordingly, their developmental aberrancies drive various congenital and adult-onset diseases. Lineage tracing studies in mice reveal that the adrenal cortex and gonads originate from a common progenitor, the adrenogonadal primordium. However, the specification pathways of the adrenal cortex and gonads and their lineage relationship remain poorly understood in humans. Here, we conduct the high resolution spatial and temporal lineage trajectory mapping of early human adrenal and gonadal lineages using single cell transcriptomics and histologic profiling on human embryos at 3-8 week post fertilization. We find that in humans, the adrenocortical lineage originates in a temporally and spatially distinct fashion from the gonadal lineage, arising earlier and more anteriorly within the coelomic epithelium. The adrenal primordium arises from adrenogenic coelomic epithelium via an epithelial-to-mesenchymal-like transition, which then progresses into the steroidogenic fetal zone via both direct and indirect routes. Notably, we find that adrenocortical and gonadal lineages exhibit distinct HOX codes, suggesting distinct anterior-posterior regionalization. Together, our assessment of the early divergence of these lineages challenges the paradigm established in rodents and present evidence that the specification programs directing the formation of adrenal glands and gonads differ between rodents and humans. The molecular details of early lineage diversification of human adrenals and gonads will serve as both a framework for understanding the molecular pathology of human disorders. Presentation: Saturday, June 11, 2022 11:30 a.m. - 11:45 a.m.

Bounded rational decision-making models suggest capacity-limited concurrent motor planning in human posterior parietal and frontal cortex.

While traditional theories of sensorimotor processing have often assumed a serial decision-making pipeline, more recent approaches have suggested that multiple actions may be planned concurrently and vie for execution. Evidence for the latter almost exclusively stems from electrophysiological studies in posterior parietal and premotor cortex of monkeys. Here we study concurrent prospective motor planning in humans by recording functional magnetic resonance imaging (fMRI) during a delayed response task engaging movement sequences towards multiple potential targets. We find that also in human posterior parietal and premotor cortex delay activity modulates both with sequence complexity and the number of potential targets. We tested the hypothesis that this modulation is best explained by concurrent prospective planning as opposed to the mere maintenance of potential targets in memory. We devise a bounded rationality model with information constraints that optimally assigns information resources for planning and memory for this task and determine predicted information profiles according to the two hypotheses. When regressing delay activity on these model predictions, we find that the concurrent prospective planning strategy provides a significantly better explanation of the fMRI-signal modulations. Moreover, we find that concurrent prospective planning is more costly and thus limited for most subjects, as expressed by the best fitting information capacities. We conclude that bounded rational decision-making models allow relating both behavior and neural representations to utilitarian task descriptions based on bounded optimal information-processing assumptions.

Retrosplenial cortex microglia and perineuronal net densities are associated with memory impairment in aged rhesus macaques.

Synapse loss and altered plasticity are significant contributors to memory loss in aged individuals. Microglia, the innate immune cells of the brain, play critical roles in maintaining synapse function, including through a recently identified role in regulating the brain extracellular matrix. This study sought to determine the relationship between age, microglia, and extracellular matrix structure densities in the macaque retrosplenial cortex. Twenty-nine macaques ranging in age from young adult to aged were behaviorally characterized on 3 distinct memory tasks. Microglia, parvalbumin (PV)-expressing interneurons and extracellular matrix structures, known as perineuronal nets (PNNs), were immuno- and histochemically labeled. Our results indicate that microglia densities increase in the retrosplenial cortex of aged monkeys, while the proportion of PV neurons surrounded by PNNs decreases. Aged monkeys with more microglia had fewer PNN-associated PV neurons and displayed slower learning and poorer performance on an object recognition task. Stepwise regression models using age and the total density of aggrecan, a chondroitin sulfate proteoglycan of PNNs, better predicted memory performance than did age alone. Together, these findings indicate that elevated microglial activity in aged brains negatively impacts cognition in part through mechanisms that alter PNN assembly in memory-associated brain regions.

Large-depth three-photon fluorescence microscopy imaging of cortical microvasculature on nonhuman primates with bright AIE probe In vivo

Multiphoton microscopy has been a powerful tool in brain research, three-photon fluorescence microscopy is increasingly becoming an emerging technique for neurological research of the cortex in depth. Nonhuman primates play important roles in the study of brain science because of their neural and vascular similarity to humans. However, there are few research results of three-photon fluorescence microscopy on the brain of nonhuman primates due to the lack of optimized imaging systems and excellent fluorescent probes. Here we introduced a bright aggregation-induced emission (AIE) probe with excellent three-photon fluorescence efficiency as well as facile synthesis process and we validated its biocompatibility in the macaque monkey. We achieved a large-depth vascular imaging of approximately 1 mm in the cerebral cortex of macaque monkey with our lab-modified three-photon fluorescence microscopy system and the AIE probe. Functional measurement of blood velocity in deep cortex capillaries was also performed. Furthermore, the comparison of cortical deep vascular structure parameters across species was presented on the monkey and mouse cortex. This work is the first in vivo three-photon fluorescence microscopic imaging research on the macaque monkey cortex reaching the imaging depth of ∼1 mm with the bright AIE probe. The results demonstrate the potential of three-photon microscopy as primate-compatible method for imaging fine vascular networks and will advance our understanding of vascular function in normal and disease in humans.

The developmental origin and the specification of the adrenal cortex in humans and cynomolgus monkeys

The developmental origin and the specification of the adrenal cortex in humans and cynomolgus monkeys

The ventral striatum contributes to the activity of the motor cortex and motor outputs in monkeys.

The ventral striatum (VSt) is thought to be involved in the vigor of motivated behavior and is suggested to be a limbic-motor interface between limbic areas involved in motivational processes and neural circuits regulating behavioral outputs. However, there is little direct evidence demonstrating the involvement of the VSt in motor control for motivated behaviors. To clarify the functional role of the VSt in motor control, we investigated the effect of reversible pharmacological inactivation of the VSt on the oscillatory activity of the sensorimotor cortices and motor outputs in two macaque monkeys. VSt inactivation reduced movement-related activities of the primary motor cortex and premotor area at 15–120 Hz and increased those at 5–7 Hz. These changes were accompanied by reduced torque outputs but had no effect on the correct performance rate. The present study provides direct evidence that the VSt regulates activities of the motor cortices and motor output.

Orbitofrontal cortex contributes to the comparison of values underlying economic choices

Economic choices between goods entail the computation and comparison of subjective values. Previous studies examined neuronal activity in the orbitofrontal cortex (OFC) of monkeys choosing between different types of juices. Three groups of neurons were identified: offer value cells encoding the value of individual offers, chosen juice cells encoding the identity of the chosen juice, and chosen value cells encoding the value of the chosen offer. The encoded variables capture both the input (offer value) and the output (chosen juice, chosen value) of the decision process, suggesting that values are compared within OFC. Recent work demonstrates that choices are causally linked to the activity of offer value cells. Conversely, the hypothesis that OFC contributes to value comparison has not been confirmed. Here we show that weak electrical stimulation of OFC specifically disrupts value comparison without altering offer values. This result implies that neuronal populations in OFC participate in value comparison.

Classification of overlapping spikes using convolutional neural networks and long short term memory

Spike sorting is one of the key techniques to understand brain activity. In this paper, we propose a novel deep learning approach based on convolutional neural networks (CNN) and long short term memory (LSTM) to implement overlapping spike sorting. The results of the simulated data demonstrated that the clustering accuracy was greater than 99.9% and 99.0% for non-overlapping spikes and overlapping spikes, respectively. Moreover, the proposed method performed better than our previous deep learning approach named “1D-CNN”. In addition, the experimental data recorded from the primary visual cortex of a macaque monkey were used to evaluate the proposed method in a practical application. It was shown that the method could successfully isolate most overlapping spikes of different neurons (ranging from two to five). In summary, the CNN + LSTM method proposed in this paper is of great advantage for overlapping spike sorting with high accuracy. It lays the foundation for application in more challenging works, such as distinguishing the simultaneous recordings of multichannel neuronal activities.

Neuronal population dynamics during motor plan cancellation in nonhuman primates

To understand the cortical neuronal dynamics behind movement generation and control, most studies have focused on tasks where actions were planned and then executed using different instances of visuomotor transformations. However, to fully understand the dynamics related to movement control, one must also study how movements are actively inhibited. Inhibition, indeed, represents the first level of control both when different alternatives are available and only one solution could be adopted and when it is necessary to maintain the current position. We recorded neuronal activity from a multielectrode array in the dorsal premotor cortex (PMd) of monkeys performing a countermanding reaching task that requires, in a subset of trials, them to cancel a planned movement before its onset. In the analysis of the neuronal state space of PMd, we found a subspace in which activities conveying temporal information were confined during active inhibition and position holding. Movement execution required activities to escape from this subspace toward an orthogonal subspace and, furthermore, surpass a threshold associated with the maturation of the motor plan. These results revealed further details in the neuronal dynamics underlying movement control, extending the hypothesis that neuronal computation confined in an "output-null" subspace does not produce movements.

Modular Organization of Signal Transmission in Primate Somatosensory Cortex.

Axonal patches are known as the major sites of synaptic connections in the cerebral cortex of higher order mammals. However, the functional role of these patches is highly debated. Patches are formed by populations of nearby neurons in a topographic manner and are recognized as the termination fields of long-distance lateral connections within and between cortical areas. In addition, axons form numerous boutons that lie outside the patches, whose function is also unknown. To better understand the functional roles of these two distinct populations of boutons, we compared individual and collective morphological features of axons within and outside the patches of intra-areal, feedforward, and feedback pathways by way of tract tracing in the somatosensory cortex of New World monkeys. We found that, with the exception of tortuosity, which is an invariant property, bouton spacing and axonal convergence properties differ significantly between axons within patch and no-patch domains. Principal component analyses corroborated the clustering of axons according to patch formation without any additional effect by the type of pathway or laminar distribution. Stepwise logistic regression identified convergence and bouton density as the best predictors of patch formation. These findings support that patches are specific sites of axonal convergence that promote the synchronous activity of neuronal populations. On the other hand, no-patch domains could form a neuroanatomical substrate to diversify the responses of cortical neurons.

Depression induced by low-frequency repetitive transcranial magnetic stimulation to ventral medial frontal cortex in monkeys

The medial frontal cortex (MFC), especially its ventral part, has long been of great interest with respect to the pathology of mood disorders. A number of human brain imaging studies have demonstrated the abnormalities of this brain region in patients with mood disorders, however, whether it is critically and causally involved in the pathogenesis of such disorders remains to be fully elucidated. In this study, we examined how the suppression of neural activity in the ventral region of the MFC (vMFC) affects the behavioral and physiological states of monkeys by using repetitive transcranial magnetic stimulation (rTMS). By using low-frequency rTMS (LF-rTMS) as an inhibitory intervention, we found that LF-rTMS targeting the vMFC temporarily induced a depression-like state in monkeys, which was characterized by a reduced movement activity level, impaired sociability, and decreased motivation level, as well as increased plasma cortisol level. On the other hand, no such significant changes in behavioral and physiological states were observed when targeting the other MFC regions, dorsal or posterior. We further found that the administration of an antidepressant agent, ketamine, ameliorated the abnormal behavioral and physiological states induced by the LF-rTMS intervention. These findings causally indicate the involvement of the vMFC in the regulation of mood and the validity of the LF-rTMS-induced dysfunction of the vMFC as a nonhuman primate model of depression.

High Resolution Ex Vivo Diffusion Tensor Distribution MRI of Neural Tissue

Neural tissue microstructure plays a key role in developmental, physiological and pathophysiological processes. In the continuing quest to characterize it at ever finer length scales, we use a novel diffusion tensor distribution (DTD) paradigm to probe microstructural features much smaller than the nominal MRI voxel size. We first assume the DTD is a normal tensor variate distribution constrained to lie on the manifold of positive definite matrices, characterized by a mean and covariance tensor. We then estimate the DTD using Monte Carlo signal inversion combined with parsimonious model selection framework that exploits a hierarchy of symmetries of mean and covariance tensors. High resolution multiple pulsed field gradient (mPFG) MRI measurements were performed on a homogeneous isotropic diffusion phantom (PDMS) for control, and excised visual cortex and spinal cord of macaque monkey to investigate the capabilities of DTD MRI in revealing neural tissue microstructural features using strong gradients not typically available in clinical MRI scanners. DTD-derived stains and glyphs, which disentangle size, shape, and orientation heterogeneities of microscopic diffusion tensors, are presented for all samples along with the distribution of the mean diffusivity (MD) within each voxel. We also present a new glyph to visualize the symmetric (kurtosis) and asymmetric parts of the fourth-order covariance tensor. An isotropic mean diffusion tensor and zero covariance tensor was found for the isotropic PDMS phantom, as expected, while the covariance tensor (both symmetric and asymmetric parts) for neural tissue was non-zero indicating that the kurtosis tensor may not be sufficient to fully describe the microstructure. Cortical layers were clearly delineated in the higher moments of the MD spectrum consistent with histology, and microscopic anisotropy was detected in both gray and white matter of neural tissue. DTD MRI captures crossing and splaying white matter fibers penetrating into the cortex, and skewed fiber diameter distributions in the white matter tracts within the cortex and spinal cord. DTD MRI was also shown to subsume diffusion tensor imaging (DTI) while providing additional microstructural information about tissue heterogeneity and microscopic anisotropy within each voxel.