Cortex Of Nonhuman Primates Research Articles

Convergent effects of different anesthetics on changes in phase alignment of cortical oscillations.

Many anesthetics cause loss of responsiveness despite having diverse underlying molecular and circuit actions. To explore the convergent effects of these drugs, we examined how anesthetic doses of ketamine and dexmedetomidine affected oscillations in the prefrontal cortex of nonhuman primates. Both anesthetics caused increases in phase locking in the ventrolateral and dorsolateral prefrontal cortex, within and across hemispheres. However, the nature of the phase locking varied. Activity in different subregions within a hemisphere became more anti-phase with both drugs. Local analyses within a region suggested that this finding could be explained by broad cortical distance-based effects, such as large traveling waves. By contrast, homologous areas across hemispheres became more in-phase. Our results suggest that both anesthetics induce strong patterns of cortical phase alignment that are markedly different from those in the awake state, and that these patterns may be a common feature driving loss of responsiveness from different anesthetic drugs.

Monkey lateral prefrontal cortex subregions differentiate between perceptual exposure to visual stimuli.

Each day, humans must parse visual stimuli with varying amounts of perceptual experience, ranging from incredibly familiar to entirely new. Even when choosing a novel to buy at a bookstore, one sees covers they have repeatedly experienced intermixed with recently released titles. Visual exposure to stimuli has distinct neural correlates in the lateral prefrontal cortex (LPFC) of nonhuman primates. However, it is currently unknown if this function may be localized to specific subregions within LPFC. Specifically, we aimed to determine whether the posterior fundus of area 46 (p46f), an area that responds to deviations from learned sequences, also responds to less frequently presented stimuli outside of the sequential context. We compare responses in p46f to the adjacent subregion, posterior ventral area 46 (p46v), which we propose may be more likely to show exposure-dependent responses due to its proximity to novelty responsive regions. To test whether p46f or p46v represent perceptual exposure, we performed awake functional magnetic resonance imaging (fMRI) on three male monkeys as they observed visual stimuli that varied in their number of daily presentations. Here we show that p46v, but not p46f, shows preferential activation to stimuli with low perceptual exposure, further localizing exposure-dependent effects in monkey LPFC. These results align with previous research that has found novelty responses in ventral LPFC and are consistent with the proposal that p46f performs a sequence-specific function. Further, they expand on our knowledge of the specific role of LPFC subregions and localize perceptual exposure processing within this broader brain region.

Neural Basis of Categorical Representations of Animal Body Silhouettes.

Neural activities differentiating bodies versus non-body stimuli have been identified in the occipitotemporal cortex of both humans and nonhuman primates. However, the neural mechanisms of coding the similarity of different individuals' bodies of the same species to support their categorical representations remain unclear. Using electroencephalography (EEG) and magnetoencephalography (MEG), we investigated the temporal and spatial characteristics of neural processes shared by different individual body silhouettes of the same species by quantifying the repetition suppression of neural responses to human and animal (chimpanzee, dog, and bird) body silhouettes showing different postures. Our EEG results revealed significant repetition suppression of the amplitudes of early frontal/central activity at 180-220 ms (P2) and late occipitoparietal activity at 220-320 ms (P270) in response to animal (but not human) body silhouettes of the same species. Our MEG results further localized the repetition suppression effect related to animal body silhouettes in the left supramarginal gyrus and left frontal cortex at 200-440 ms after stimulus onset. Our findings suggest two neural processes that are involved in spontaneous categorical representations of animal body silhouettes as a cognitive basis of human-animal interactions.

Behavior-related visual activations in the auditory cortex of nonhuman primates

While it is well established that sensory cortical regions traditionally thought to be unimodal can be activated by stimuli from modalities other than the dominant one, functions of such foreign-modal activations are still not clear. Here we show that visual activations in early auditory cortex can be related to whether or not the monkeys engaged in audio-visual tasks, to the time when the monkeys reacted to the visual component of such tasks, and to the correctness of the monkeys’ response to the auditory component of such tasks. These relationships between visual activations and behavior suggest that auditory cortex can be recruited for visually-guided behavior and that visual activations can prime auditory cortex such that it is prepared for processing future sounds. Our study thus provides evidence that foreign-modal activations in sensory cortex can contribute to a subject’s ability to perform tasks on stimuli from foreign and dominant modalities.

A semi-automated pipeline for finite element modeling of electric field induced in nonhuman primates by transcranial magnetic stimulation

BackgroundTranscranial magnetic stimulation (TMS) is used to treat a range of brain disorders by inducing an electric field (E-field) in the brain. However, the precise neural effects of TMS are not well understood. Nonhuman primates (NHPs) are used to model the impact of TMS on neural activity, but a systematic method of quantifying the induced E-field in the cortex of NHPs has not been developed. New methodThe pipeline uses statistical parametric mapping (SPM) to automatically segment a structural MRI image of a rhesus macaque into five tissue compartments. Manual corrections are necessary around implants. The segmented tissues are tessellated into 3D meshes used in finite element method (FEM) software to compute the TMS induced E-field in the brain. The gray matter can be further segmented into cortical laminae using a volume preserving method for defining layers. ResultsModels of three NHPs were generated with TMS coils placed over the precentral gyrus. Two coil configurations, active and sham, were simulated and compared. The results demonstrated a large difference in E-fields at the target. Additionally, the simulations were calculated using two different E-field solvers and were found to not significantly differ. Comparison with existing methodsCurrent methods segment NHP tissues manually or use automated methods for only the brain tissue. Existing methods also do not stratify the gray matter into layers. ConclusionThe pipeline calculates the induced E-field in NHP models by TMS and can be used to plan implant surgeries and determine approximate E-field values around neuron recording sites.

Propofol-mediated Unconsciousness Disrupts Progression of Sensory Signals through the Cortical Hierarchy.

A critical component of anesthesia is the loss of sensory perception. Propofol is the most widely used drug for general anesthesia, but the neural mechanisms of how and when it disrupts sensory processing are not fully understood. We analyzed local field potential and spiking recorded from Utah arrays in auditory cortex, associative cortex, and cognitive cortex of nonhuman primates before and during propofol-mediated unconsciousness. Sensory stimuli elicited robust and decodable stimulus responses and triggered periods of stimulus-related synchronization between brain areas in the local field potential of Awake animals. By contrast, propofol-mediated unconsciousness eliminated stimulus-related synchrony and drastically weakened stimulus responses and information in all brain areas except for auditory cortex, where responses and information persisted. However, we found stimuli occurring during spiking Up states triggered weaker spiking responses than in Awake animals in auditory cortex, and little or no spiking responses in higher order areas. These results suggest that propofol's effect on sensory processing is not just because of asynchronous Down states. Rather, both Down states and Up states reflect disrupted dynamics.

Corticocortical connections of the rostral forelimb area in rats: a quantitative tract-tracing study.

The rostral forelimb area (RFA) in the rat is a premotor cortical region based on its dense efferent projections to primary motor cortex. This study describes corticocortical connections of RFA and the relative strength of connections with other cortical areas. The goal was to provide a better understanding of the cortical network in which RFA participates, and thus, determine its function in sensorimotor behavior. The RFA of adult male Long-Evans rats (n= 6) was identified using intracortical microstimulation techniques and injected with the tract-tracer, biotinylated dextran amine (BDA). In post-mortem tissue, locations of BDA-labeled terminal boutons and neuronal somata were plotted and superimposed on cortical field boundaries. Quantitative estimates of terminal boutons in each region of interest were based on unbiased stereological methods. The results demonstrate that RFA has dense connections with primary motor cortex and frontal cortex medial and lateral to RFA. Moderate connections were found with insular cortex, primary somatosensory cortex (S1), the M1/S1 overlap zone, and lateral somatosensory areas. Cortical connections of RFA in rat are strikingly similar to cortical connections of the ventral premotor cortex in non-human primates, suggesting that these areas share similar functions and allow greater translation of rodent premotor cortex studies to primates.

Laminar Distribution of Cannabinoid Receptor 1 in the Prefrontal Cortex of Nonhuman Primates.

Cannabis is an annual herb of the genus Cannabis, with a history of medical use going back thousands of years. However, its abuse causes many side-effects, including confusion of consciousness, alienation, and mental disorders such as schizophrenia and depression. Research conducted on rodents suggests that there are two types of cannabinoid receptors-cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R). CB1R is found mostly in the central nervous system, particularly in the prefrontal cortex (PFC), and alterations in its expression in the PFC have been strongly linked to mental disorders. Within the layers of the PFC, Brodmann area 46 is associated with the processing of complex cognitive information. However, it remains unclear whether CB1R is expressed in the PFC 46 area of non-human primate. In this work, we applied western blotting along with immunofluorescent histochemical staining to investigate the distribution pattern of CB1R in the PFC of nonhuman primate, Our findings reveal that CB1R is highly expressed in the monkey PFC, especially in area 46. Furthermore, CB1R exhibits a layered distribution pattern within area 46 of the PFC, with the inner granular layer displaying the highest expression levels. Additionally, CB1R+PV+ cells are widely distributed in lay II-VI of area 46, with layer IV showing notable prevalence. In conclusion, CB1R is distributed in the PV interneurons in area 46 of the prefrontal cortex, particularly in layer IV, suggesting that cannabis may modulate PFC activities via regulating interneuron in the PFC. And cannabis-induced side effects may be caused by abnormal expression of CB1R.

Cortical Lewy body injections induce long-distance pathogenic alterations in the non-human primate brain

Aggregation of α-synuclein (α-syn) is the cornerstone of neurodegenerative diseases termed synucleinopathies, which include Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA). These synucleinopathies are characterized by the deposit of aggregated α-syn in intracellular inclusions observable in neurons and glial cells. In PD and DLB, these aggregates, predominantly located in neurons, are called Lewy Bodies (LBs). These LBs are one of the pathological hallmarks of PD and DLB, alongside dopaminergic neuron loss in the substantia nigra. Previous studies have demonstrated the ability of PD patient-derived LB fractions to induce nigrostriatal neurodegeneration and α-syn pathology when injected into the striatum or the enteric nervous system of non-human primates. Here, we report the pathological consequences of injecting these LB fractions into the cortex of non-human primates. To this end, we inoculated mesencephalic PD patient-derived LB fractions into the prefrontal cortex of baboon monkeys terminated one year later. Extensive analyses were performed to evaluate pathological markers known to be affected in LB pathologies. We first assessed the hypothesized presence of phosphorylated α-syn at S129 (pSyn) in the prefrontal cortices. Second, we quantified the neuronal, microglial, and astrocytic cell survival in the same cortices. Third, we characterized these cortical LB injections’ putative impact on the integrity of the nigrostriatal system. Overall, we observed pSyn accumulation around the injection site in the dorsal prefrontal cortex, in connected cortical regions, and further towards the striatum, suggesting α-syn pathological propagation. The pathology was also accompanied by neuronal loss in these prefrontal cortical regions and the caudate nucleus, without, however, loss of nigral dopamine neurons. In conclusion, this pilot study provides novel data demonstrating the toxicity of patient-derived extracts, their potential to propagate from the cortex to the striatum in non-human primates, and a possible primate model of DLB.

Laminar neural dynamics of auditory evoked responses: Computational modeling of local field potentials in auditory cortex of non-human primates

Evoked neural responses to sensory stimuli have been extensively investigated in humans and animal models both to enhance our understanding of brain function and to aid in clinical diagnosis of neurological and neuropsychiatric conditions. Recording and imaging techniques such as electroencephalography (EEG), magnetoencephalography (MEG), local field potentials (LFPs), and calcium imaging provide complementary information about different aspects of brain activity at different spatial and temporal scales. Modeling and simulations provide a way to integrate these different types of information to clarify underlying neural mechanisms.In this study, we aimed to shed light on the neural dynamics underlying auditory evoked responses by fitting a rate-based model to LFPs recorded via multi-contact electrodes which simultaneously sampled neural activity across cortical laminae. Recordings included neural population responses to best-frequency (BF) and non-BF tones at four representative sites in primary auditory cortex (A1) of awake monkeys. The model considered major neural populations of excitatory, parvalbumin-expressing (PV), and somatostatin-expressing (SOM) neurons across layers 2/3, 4, and 5/6. Unknown parameters, including the connection strength between the populations, were fitted to the data. Our results revealed similar population dynamics, fitted model parameters, predicted equivalent current dipoles (ECD), tuning curves, and lateral inhibition profiles across recording sites and animals, in spite of quite different extracellular current distributions. We found that PV firing rates were higher in BF than in non-BF responses, mainly due to different strengths of tonotopic thalamic input, whereas SOM firing rates were higher in non-BF than in BF responses due to lateral inhibition.In conclusion, we demonstrate the feasibility of the model-fitting approach in identifying the contributions of cell-type specific population activity to stimulus-evoked LFPs across cortical laminae, providing a foundation for further investigations into the dynamics of neural circuits underlying cortical sensory processing.

Detectability of optogenetic stimulation in inferior temporal cortex in non-human primates depends on the plausibility of a corresponding visual event in the external world

Detectability of optogenetic stimulation in inferior temporal cortex in non-human primates depends on the plausibility of a corresponding visual event in the external world

Alteration of functional connectivity in the cortex and major brain networks of non-human primates following focused ultrasound exposure in the dorsal striatum

BackgroundFocused ultrasound (FUS) is a non-invasive neuromodulation technology that is being investigated for potential treatment of neurological and psychiatric disorders. FUS combined with microbubbles can temporarily open the intact blood-brain barrier (BBB) of animals and humans, and facilitate drug delivery. FUS exposure, either with or without microbubbles, has been demonstrated to alter the behavior of non-human primates (NHP), and previous studies have demonstrated the transient and long-term effects of FUS neuromodulation on functional connectivity using resting state functional MRI. The behavioral effects of FUS vary depending on whether or not it is applied in conjunction with microbubbles to open the BBB, but it is unknown whether opening the BBB affects functional connectivity differently than FUS alone. ObjectiveTo compare the effects of applying FUS alone (FUS neuromodulation) and FUS with microbubbles (FUS-BBB opening) on changes of resting state functional connectivity in NHP. MethodsWe applied 2 min FUS exposure without (neuromodulation) and with microbubbles (BBB opening) in the dorsal striatum of lightly anesthetized non-human primates, and acquired resting state functional MRI 40 min respectively after FUS exposure. The functional connectivity (FC) in the cortex and major brain networks between the two approaches were measured and compared. ResultsWhen applying FUS exposure to the caudate nucleus of NHP, we found that both FUS neuromodulation can activate FC between caudate and insular cortex, while inhibiting the FC between caudate and motor cortex. FUS-BBB opening can activate FC between the caudate and medial prefrontal cortex, and within the frontotemporal network (FTN). We also found both FUS and FUS-BBB opening can significantly activate FC within the default mode network (DMN). ConclusionThe results suggest applying FUS to a deep brain structure can alter functional connectivity in the DMN and FTN, and that FUS neuromodulation and FUS-mediated BBB opening can have different effects on patterns of functional connectivity.

Cortical Layer Markers Expression and Increased Synaptic Density in Interstitial Neurons of the White Matter from Drug-Resistant Epilepsy Patients.

The interstitial neurons in the white matter of the human and non-human primate cortex share a similar developmental origin with subplate neurons and deep-layer cortical neurons. A subset of interstitial neurons expresses the molecular markers of subplate neurons, but whether interstitial neurons express cortical layer markers in the adult human brain remains unexplored. Here we report the expression of cortical layer markers in interstitial neurons in the white matter of the adult human brain, supporting the hypothesis that interstitial neurons could be derived from cortical progenitor cells. Furthermore, we found increased non-phosphorylated neurofilament protein (NPNFP) expression in interstitial neurons in the white matter of drug-resistant epilepsy patients. We also identified the expression of glutamatergic and g-aminobutyric acid (GABAergic) synaptic puncta that were distributed in the perikarya and dendrites of interstitial neurons. The density of glutamatergic and GABAergic synaptic puncta was increased in interstitial neurons in the white matter of drug-resistant epilepsy patients compared with control brain tissues with no history of epilepsy. Together, our results provide important insights of the molecular identity of interstitial neurons in the adult human white matter. Increased synaptic density of interstitial neurons could result in an imbalanced synaptic network in the white matter and participate as part of the epileptic network in drug-resistant epilepsy.

Decoding spatial locations from primate lateral prefrontal cortex neural activity during virtual navigation

Objective. Decoding the intended trajectories from brain signals using a brain-computer interface system could be used to improve the mobility of patients with disabilities. Approach. Neuronal activity associated with spatial locations was examined while macaques performed a navigation task within a virtual environment. Main results. Here, we provide proof of principle that multi-unit spiking activity recorded from the lateral prefrontal cortex (LPFC) of non-human primates can be used to predict the location of a subject in a virtual maze during a navigation task. The spatial positions within the maze that require a choice or are associated with relevant task events can be better predicted than the locations where no relevant events occur. Importantly, within a task epoch of a single trial, multiple locations along the maze can be independently identified using a support vector machine model. Significance. Considering that the LPFC of macaques and humans share similar properties, our results suggest that this area could be a valuable implant location for an intracortical brain-computer interface system used for spatial navigation in patients with disabilities.

A context-dependent switch from sensing to feeling in the primate amygdala.

The skin transmits affective signals that integrate into our social vocabulary. As the socio-affective aspects of touch are likely processed in the amygdala, we compare neural responses to social grooming and gentle airflow recorded from the amygdala and the primary somatosensory cortex of non-human primates. Neurons in the somatosensory cortex respond to both types of tactile stimuli. In the amygdala, however, neurons do not respond to individual grooming sweeps even though grooming elicits autonomic states indicative of positive affect. Instead, many show changes in baseline firing rates that persist throughout the grooming bout. Such baseline fluctuations are attributed to social context because the presence of the groomer alone can account for the observed changes in baseline activity. It appears, therefore, that during grooming, the amygdala stops responding to external inputs on a short timescale but remains responsive to social context (or the associated affective states) on longer time scales.

Altered dendritic morphology in dorsolateral prefrontal cortex of nonhuman primates prenatally exposed to maternal immune activation

Women who contract a viral or bacterial infection during pregnancy have an increased risk of giving birth to a child with a neurodevelopmental or psychiatric disorder. The effects of maternal infection are likely mediated by the maternal immune response, as preclinical animal models have confirmed that maternal immune activation (MIA) leads to long lasting changes in offspring brain and behavior development. The present study sought to determine the impact of MIA-exposure during the first or second trimester on neuronal morphology in dorsolateral prefrontal cortex (DLPFC) and hippocampus from brain tissue obtained from MIA-exposed and control male rhesus monkey (Macaca mulatta) during late adolescence. MIA-exposed offspring display increased neuronal dendritic branching in pyramidal cells in DLPFC infra- and supragranular layers relative to controls, with no significant differences observed between offspring exposed to maternal infection in the first and second trimester. In addition, the diameter of apical dendrites in DLPFC infragranular layer is significantly decreased in MIA-exposed offspring relative to controls, irrespective of trimester exposure. In contrast, alterations in hippocampal neuronal morphology of MIA-exposed offspring were not evident. These findings demonstrate that a maternal immune challenge during pregnancy has long-term consequences for primate offspring dendritic structure, selectively in a brain region vital for socioemotional and cognitive development.

Spatially resolved gene regulatory and disease-related vulnerability map of the adult Macaque cortex

Single cell approaches have increased our knowledge about the cell type composition of the non-human primate (NHP), but a detailed characterization of area-specific regulatory features remains outstanding. We generated single-cell transcriptomic and chromatin accessibility (single-cell ATAC) data of 358,237 cells from prefrontal cortex (PFC), primary motor cortex (M1) and primary visual cortex (V1) of adult female cynomolgus monkey brain, and integrated this dataset with Stereo-seq (spatial enhanced resolution omics-sequencing) of the corresponding cortical areas to assign topographic information to molecular states. We identified area-specific chromatin accessible sites and their targeted genes, including the cell type-specific transcriptional regulatory network associated with excitatory neurons heterogeneity. We reveal calcium ion transport and axon guidance genes related to specialized functions of PFC and M1, identified the similarities and differences between adult macaque and human oligodendrocyte trajectories, and mapped the genetic variants and gene perturbations of human diseases to NHP cortical cells. This resource establishes a transcriptomic and chromatin accessibility combinatory regulatory landscape at a single-cell and spatially resolved resolution in NHP cortex.

Functional interactions among neurons within single columns of macaque V1.

Recent developments in high-density neurophysiological tools now make it possible to record from hundreds of single neurons within local, highly interconnected neural networks. Among the many advantages of such recordings is that they dramatically increase the quantity of identifiable, functional interactions between neurons thereby providing an unprecedented view of local circuits. Using high-density, Neuropixels recordings from single neocortical columns of primary visual cortex in nonhuman primates, we identified 1000s of functionally interacting neuronal pairs using established crosscorrelation approaches. Our results reveal clear and systematic variations in the synchrony and strength of functional interactions within single cortical columns. Despite neurons residing within the same column, both measures of interactions depended heavily on the vertical distance separating neuronal pairs, as well as on the similarity of stimulus tuning. In addition, we leveraged the statistical power afforded by the large numbers of functionally interacting pairs to categorize interactions between neurons based on their crosscorrelation functions. These analyses identified distinct, putative classes of functional interactions within the full population. These classes of functional interactions were corroborated by their unique distributions across defined laminar compartments and were consistent with known properties of V1 cortical circuitry, such as the lead-lag relationship between simple and complex cells. Our results provide a clear proof-of-principle for the use of high-density neurophysiological recordings to assess circuit-level interactions within local neuronal networks.

Emergence of Distinct Neural Subspaces in Motor Cortical Dynamics during Volitional Adjustments of Ongoing Locomotion.

The ability to modulate ongoing walking gait with precise, voluntary adjustments is what allows animals to navigate complex terrains. However, how the nervous system generates the signals to precisely control the limbs while simultaneously maintaining locomotion is poorly understood. One potential strategy is to distribute the neural activity related to these two functions into distinct cortical activity coactivation subspaces so that both may be conducted simultaneously without disruptive interference. To investigate this hypothesis, we recorded the activity of primary motor cortex in male nonhuman primates during obstacle avoidance on a treadmill. We found that the same neural population was active during both basic unobstructed locomotion and volitional obstacle avoidance movements. We identified the neural modes spanning the subspace of the low-dimensional dynamics in primary motor cortex and found a subspace that consistently maintains the same cyclic activity throughout obstacle stepping, despite large changes in the movement itself. All of the variance corresponding to this large change in movement during the obstacle avoidance was confined to its own distinct subspace. Furthermore, neural decoders built for ongoing locomotion did not generalize to decoding obstacle avoidance during locomotion. Our findings suggest that separate underlying subspaces emerge during complex locomotion that coordinates ongoing locomotor-related neural dynamics with volitional gait adjustments. These findings may have important implications for the development of brain-machine interfaces.SIGNIFICANCE STATEMENT Locomotion and precise, goal-directed movements are two distinct movement modalities with known differing requirements of motor cortical input. Previous studies have characterized the cortical activity during obstacle avoidance while walking in rodents and felines, but, to date, no such studies have been completed in primates. Additionally, in any animal model, it is unknown how these two movements are represented in primary motor cortex (M1) low-dimensional dynamics when both activities are performed at the same time, such as during obstacle avoidance. We developed a novel obstacle avoidance paradigm in freely moving nonhuman primates and discovered that the rhythmic locomotion-related dynamics and the voluntary, gait-adjustment movement separate into distinct subspaces in M1 cortical activity. Our analysis of decoding generalization may also have important implications for the development of brain-machine interfaces.

From Circuit Principles to Human Psychiatric Disorders

Progress in mapping the human brain using diffusion tensor imaging and similar tractography approaches has raised hopes that noninvasive methods can be leveraged to understand connections in humans and their change in brain diseases. These hopes rest on the knowledge that the primate cortex is a complex communication center, whose disruption is at the core of psychiatric diseases [e.g., (1)]. We provide an overview of principles derived from the study of the systematic variation of the cortex and connections in nonhuman primates to highlight how they can be used to inform the specificity of connections with imaging of the human brain.