Interspecies activation correlations reveal functional correspondences between marmoset and human brain areas.

The common marmoset has enormous promise as a nonhuman primate model of human brain functions. While resting-state functional MRI (fMRI) has provided evidence for a similar organization of marmoset and human cortices, the technique cannot be used to map the functional correspondences of brain regions between species. This limitation can be overcome by movie-driven fMRI (md-fMRI), which has become a popular tool for noninvasively mapping the neural patterns generated by rich and naturalistic stimulation. Here, we used md-fMRI in marmosets and humans to identify whole-brain functional correspondences between the two primate species. In particular, we describe functional correlates for the well-known human face, body, and scene patches in marmosets. We find that these networks have a similar organization in both species, suggesting a largely conserved organization of higher-order visual areas between New World marmoset monkeys and humans. However, while face patches in humans and marmosets were activated by marmoset faces, only human face patches responded to the faces of other animals. Together, the results demonstrate that higher-order visual processing might be a conserved feature between humans and New World marmoset monkeys but that small, potentially important functional differences exist.

Joint-embeddings reveal functional differences in default-mode network architecture between marmosets and humans.

The default-mode network (DMN) is a distributed functional brain system integral for social and higher-order cognition in humans with implications in a myriad of neuropsychological disorders. In this study, we compared the functional architecture of the DMN between humans and marmosets to assess their similarities and differences using joint gradients. This approach permits simultaneous large-scale mapping of functional systems across the cortex of humans and marmosets, revealing evidence of putative homologies between them. In doing so, we find that the DMN architecture of the marmoset exhibits differences along its anterolateral-posterior axis. Specifically, the anterolateral node of the DMN (dorsolateral prefrontal cortex) displayed weak connections and inconsistent connection topographies as compared to its posterior DMN-nodes (posterior cingulate and posterior parietal cortices). We also present evidence that the marmoset medial prefrontal cortex and temporal lobe areas correspond to other macroscopical distributed functional systems that are not part of the DMN. Given the importance of the marmoset as a pre-clinical primate model for higher-order cognitive functioning and the DMN's relevance to cognition, our results suggest that the marmoset may lack the capacity to integrate neural information to subserve cortical dynamics that are necessary for supporting diverse cognitive demands.

Single-shot spiral diffusion-weighted imaging at 7T using expanded encoding with compressed sensing.

PURPOSE: The expanded encoding model incorporates spatially- and time-varying field perturbations for correction during reconstruction. To date, these reconstructions have used the conjugate gradient method with early stopping used as implicit regularization. However, this approach is likely suboptimal for low-SNR cases like diffusion or high-resolution MRI. Here, we investigate the extent that ℓ 1 $$ {\ell}_1 $$ -wavelet regularization, or equivalently compressed sensing (CS), combined with expanded encoding improves trade-offs between spatial resolution, readout time and SNR for single-shot spiral DWI at 7T. The reconstructions were performed using our open-source graphics processing unit-enabled reconstruction toolbox, "MatMRI," that allows inclusion of the different components of the expanded encoding model, with or without CS. METHODS: In vivo accelerated single-shot spirals were acquired with five acceleration factors (R) (2×-6×) and three in-plane spatial resolutions (1.5, 1.3, and 1.1 mm). From the in vivo reconstructions, we estimated diffusion tensors and computed fractional anisotropy maps. Then, simulations were used to quantitatively investigate and validate the impact of CS-based regularization on image quality when compared to a known ground truth. RESULTS: In vivo reconstructions revealed improved image quality with retainment of small features when CS was used. Simulations showed that the joint use of the expanded encoding model and CS improves accuracy of image reconstructions (reduced mean-squared error) over the range of R investigated. CONCLUSION: The expanded encoding model and CS regularization are complementary tools for single-shot spiral diffusion MRI, which enables both higher spatial resolutions and higher R.

Functional Organization of Frontoparietal Cortex in the Marmoset Investigated with Awake Resting-State fMRI.

Frontoparietal networks contribute to complex cognitive functions in humans and macaques, such as working memory, attention, task-switching, response suppression, grasping, reaching, and eye movement control. However, there has been no comprehensive examination of the functional organization of frontoparietal networks using functional magnetic resonance imaging in the New World common marmoset monkey (Callithrix jacchus), which is now widely recognized as a powerful nonhuman primate experimental animal. In this study, we employed hierarchical clustering of interareal blood oxygen level-dependent signals to investigate the hypothesis that the organization of the frontoparietal cortex in the marmoset follows the organizational principles of the macaque frontoparietal system. We found that the posterior part of the lateral frontal cortex (premotor regions) was functionally connected to the anterior parietal areas, while more anterior frontal regions (frontal eye field [FEF]) were connected to more posterior parietal areas (the region around the lateral intraparietal area [LIP]). These overarching patterns of interareal organization are consistent with a recent macaque study. These findings demonstrate parallel frontoparietal processing streams in marmosets and support the functional similarities of FEF-LIP and premotor-anterior parietal pathways between marmoset and macaque.

Divergence of rodent and primate medial frontal cortex functional connectivity.

With the medial frontal cortex (MFC) centrally implicated in several major neuropsychiatric disorders, it is critical to understand the extent to which MFC organization is comparable between humans and animals commonly used in preclinical research (namely rodents and nonhuman primates). Although the cytoarchitectonic structure of the rodent MFC has mostly been conserved in humans, it is a long-standing question whether the structural analogies translate to functional analogies. Here, we probed this question using ultra high field fMRI data to compare rat, marmoset, and human MFC functional connectivity. First, we applied hierarchical clustering to intrinsically define the functional boundaries of the MFC in all three species, independent of cytoarchitectonic definitions. Then, we mapped the functional connectivity "fingerprints" of these regions with a number of different brain areas. Because rats do not share cytoarchitectonically defined regions of the lateral frontal cortex (LFC) with primates, the fingerprinting method also afforded the unique ability to compare the rat MFC and marmoset LFC, which have often been suggested to be functional analogs. The results demonstrated remarkably similar intrinsic functional organization of the MFC across the species, but clear differences between rodent and primate MFC whole-brain connectivity. Rat MFC patterns of connectivity showed greatest similarity with premotor regions in the marmoset, rather than dorsolateral prefrontal regions, which are often suggested to be functionally comparable. These results corroborate the viability of the marmoset as a preclinical model of human MFC dysfunction, and suggest divergence of functional connectivity between rats and primates in both the MFC and LFC.

An open access resource for functional brain connectivity from fully awake marmosets.

The common marmoset (Callithrix jacchus) is quickly gaining traction as a premier neuroscientific model. However, considerable progress is still needed in understanding the functional and structural organization of the marmoset brain to rival that documented in longstanding preclinical model species, like mice, rats, and Old World primates. To accelerate such progress, we present the Marmoset Functional Brain Connectivity Resource (marmosetbrainconnectome.org), currently consisting of over 70 h of resting-state fMRI (RS-fMRI) data acquired at 500 µm isotropic resolution from 31 fully awake marmosets in a common stereotactic space. Three-dimensional functional connectivity (FC) maps for every cortical and subcortical gray matter voxel are stored online. Users can instantaneously view, manipulate, and download any whole-brain functional connectivity (FC) topology (at the subject- or group-level) along with the raw datasets and preprocessing code. Importantly, researchers can use this resource to test hypotheses about FC directly - with no additional analyses required - yielding whole-brain correlations for any gray matter voxel on demand. We demonstrate the resource's utility for presurgical planning and comparison with tracer-based neuronal connectivity as proof of concept. Complementing existing structural connectivity resources for the marmoset brain, the Marmoset Functional Brain Connectivity Resource affords users the distinct advantage of exploring the connectivity of any voxel in the marmoset brain, not limited to injection sites nor constrained by regional atlases. With the entire raw database (RS-fMRI and structural images) and preprocessing code openly available for download and use, we expect this resource to be broadly valuable to test novel hypotheses about the functional organization of the marmoset brain.

Integration of an RF coil and commercial field camera for ultrahigh-field MRI.

PURPOSE: To develop an RF coil with an integrated commercial field camera for ultrahigh field (7T) neuroimaging. The RF coil would operate within a head-only gradient coil and be subject to the corresponding design constraints. The RF coil can thereafter be used for subject-specific correction of k-space trajectories-notably in gradient-sensitive sequences such as single-shot spiral imaging. METHODS: The transmit and receive performance was evaluated before and after the integration of field probes, whereas field probes were evaluated when in an optimal configuration external to the coil and after their integration. Diffusion-weighted EPI and single-shot spiral acquisitions were employed to evaluate the efficacy of correcting higher order field perturbations and the consequent effect on image quality. RESULTS: Field probes had a negligible effect on RF-coil performance, including the transmit efficiency, transmit uniformity, and mean SNR over the brain. Modest reductions in field-probe signal lifetimes were observed, caused primarily by nonidealities in the gradient and shim fields of the head-only gradient coil at the probe positions. The field-monitoring system could correct up to second-order field perturbations in single-shot spiral imaging. CONCLUSION: The integrated RF coil and field camera was capable of concurrent-field monitoring within a 7T head-only scanner and facilitated the subsequent correction of k-space trajectories during spiral imaging.

Activation of gastrointestinal ileal brake response with dietary slowly digestible carbohydrates, with no observed effect on subjective appetite, in an acute randomized, double-blind, crossover trial.

PURPOSE: To test the hypothesis that oral ingestion of slowly digestible carbohydrates (SDCs) that reach the ileum triggers the ileal brake as indicated by delayed gastric emptying, reduced glycemic response, and decreased subjective appetite. METHODS: The study was a five-arm, randomized, double-blind, crossover trial with a 1-week washout period between treatments (n = 20; 9 females, 11 males). Five treatments consisted of three SDC ingredients [raw corn starch, isomaltooligosaccharide (IMO), sucromalt], and an IMO/sucromalt combination, shown in vitro to have slow and extended digestion profiles, and a rapidly digestible carbohydrate control (maltodextrin). Carbohydrates (26 g) were incorporated into yogurt [300 g total; carbohydrate (~ 77 g), fat (~ 0.2 g), and protein (~ 9 g)] with closely matched energy content (346 kcal) and viscosity (~ 30,000 cP). Outcomes were measured in a 4 h postprandial period. RESULTS: Mean gastric half-emptying times were moderately though significantly increased for the raw corn starch and IMO treatments (P < 0.05), but they could be sub-divided into larger effect responder (n = 11) and non-responder groups (n = 9). Longer time for glycemic response to return to baseline was associated with increased gastric half-emptying time in an exploratory subset of data removing gastric half-emptying times > 3.5 h (P = 0.02). No significant differences in appetite ratings were observed. CONCLUSION: SDCs caused slower gastric emptying rate through activation of the ileal brake, as closely matched semi-solid yogurts were used and only rate of carbohydrate digestion differed. Extending glycemic response through consumption of SDCs was associated with triggering the ileal brake. TRIAL REGISTRATION: ClinicalTrials.gov NCT03630445, August 2018, retrospectively registered.

Cortico-Subcortical Functional Connectivity Profiles of Resting-State Networks in Marmosets and Humans.

Understanding the similarity of cortico-subcortical networks topologies between humans and nonhuman primate species is critical to study the origin of network alternations underlying human neurologic and neuropsychiatric diseases. The New World common marmoset (Callithrix jacchus) has become popular as a nonhuman primate model for human brain function. Most marmoset connectomic research, however, has exclusively focused on cortical areas, with connectivity to subcortical networks less extensively explored. Here, we aimed to first isolate patterns of subcortical connectivity with cortical resting-state networks in awake marmosets using resting-state fMRI, then to compare these networks with those in humans using connectivity fingerprinting. In this study, we used 5 marmosets (4 males, 1 female). While we could match several marmoset and human resting-state networks based on their functional fingerprints, we also found a few striking differences, for example, strong functional connectivity of the default mode network with the superior colliculus in marmosets that was much weaker in humans. Together, these findings demonstrate that many of the core cortico-subcortical networks in humans are also present in marmosets, but that small, potentially functionally relevant differences exist.SIGNIFICANCE STATEMENT The common marmoset is becoming increasingly popular as an additional preclinical nonhuman primate model for human brain function. Here we compared the functional organization of cortico-subcortical networks in marmosets and humans using ultra-high field fMRI. We isolated the patterns of subcortical connectivity with cortical resting-state networks (RSNs) in awake marmosets using resting-state fMRI and then compared these networks with those in humans using connectivity fingerprinting. While we could match several marmoset and human RSNs based on their functional fingerprints, we also found several striking differences. Together, these findings demonstrate that many of the core cortico-subcortical RSNs in humans are also present in marmosets, but that small, potentially functionally relevant differences exist.

Schrödinger filtering: a precise EEG despiking technique for EEG-fMRI gradient artifact.

In EEG data acquired in the presence of fMRI, gradient-related spike artifacts contaminate the signal following the common preprocessing step of average artifact subtraction. Spike artifacts compromise EEG data quality since they overlap with the EEG signal in frequency, thereby confounding frequency-based inferences on activity. As well, spike artifacts can inflate or deflate correlations among time series, thereby confounding inferences on functional connectivity. We present Schrödinger filtering, which uses the Schrödinger equation to decompose the spike-containing input. The basis functions of the decomposition are localized and pulse-shaped, and selectively capture the various input peaks, with the spike components clustered at the beginning of the spectrum. Schrödinger filtering automatically subtracts the spike components from the data. On real and simulated data, we show that Schrödinger filtering (1) simultaneously accomplishes high spike removal and high signal preservation without affecting evoked activity, and (2) reduces spurious pairwise correlations in spontaneous activity. In these regards, Schrödinger filtering was significantly better than three other despiking techniques: median filtering, amplitude thresholding, and wavelet denoising. These results encourage the use of Schrödinger filtering in future EEG-fMRI pipelines, as well as in other spike-related applications (e.g., fMRI motion artifact removal or action potential extraction).

Mesoscale hierarchical organization of primary somatosensory cortex captured by resting-state-fMRI in humans.

The primary somatosensory cortex (S1) plays a key role in the processing and integration of afferent somatosensory inputs along an anterior-to-posterior axis, contributing towards necessary human function. It is believed that anatomical connectivity can be used to probe hierarchical organization, however direct characterization of this principle in-vivo within humans remains elusive. Here, we use resting-state functional connectivity as a complement to anatomical connectivity to investigate topographical principles of human S1. We employ a novel approach to examine mesoscopic variations of functional connectivity, and demonstrate a topographic organisation spanning the region's hierarchical axis that strongly correlates with underlying microstructure while tracing along architectonic Brodmann areas. Our findings characterize anatomical hierarchy of S1 as a 'continuous spectrum' with evidence supporting a functional boundary between areas 3b and 1. The identification of this topography bridges the gap between structure and connectivity, and may be used to help further current understanding of sensorimotor deficits.

Structural alterations in cortical and thalamocortical white matter tracts after recovery from prefrontal cortex lesions in macaques.

Unilateral damage to the frontoparietal network typically impairs saccade target selection within the contralesional visual hemifield. Severity of deficits and the degree of recovery have been associated with widespread network dysfunction, yet it is not clear how these behavioural and functional brain changes relate with the underlying structural white matter tracts. Here, we investigated whether recovery after unilateral prefrontal cortex (PFC) lesions was associated with changes in white matter microstructure across large-scale frontoparietal cortical and thalamocortical networks. Diffusion-weighted imaging was acquired in four male rhesus macaques at pre-lesion, week 1, and week 8-16 post-lesion when target selection deficits largely recovered. Probabilistic tractography was used to reconstruct cortical frontoparietal fiber tracts, including the superior longitudinal fasciculus (SLF) and transcallosal fibers connecting the PFC or posterior parietal cortex (PPC), as well as thalamocortical fiber tracts connecting the PFC and PPC to thalamic nuclei. We found that the two animals with small PFC lesions showed increased fractional anisotropy in both cortical and thalamocortical fiber tracts when behaviour had recovered. However, we found that fractional anisotropy decreased in cortical frontoparietal tracts after larger PFC lesions yet increased in some thalamocortical tracts at the time of behavioural recovery. These findings indicate that behavioural recovery after small PFC lesions may be supported by both cortical and subcortical areas, whereas larger PFC lesions may have induced widespread structural damage and hindered compensatory remodeling in the cortical frontoparietal network.

Effects of phase regression on high-resolution functional MRI of the primary visual cortex.

High-resolution functional MRI studies have become a powerful tool to non-invasively probe the sub-millimeter functional organization of the human cortex. Advances in MR hardware, imaging techniques and sophisticated post-processing methods have allowed high resolution fMRI to be used in both the clinical and academic neurosciences. However, consensus within the community regarding the use of gradient echo (GE) or spin echo (SE) based acquisition remains largely divided. On one hand, GE provides a high temporal signal-to-noise ratio (tSNR) technique sensitive to both the macro- and micro-vascular signal while SE based methods are more specific to microvasculature but suffer from lower tSNR and specific absorption rate limitations, especially at high field and with short repetition times. Fortunately, the phase of the GE-EPI signal is sensitive to vessel size and this provides a potential avenue to reduce the macrovascular weighting of the signal (phase regression, Menon 2002). In order to determine the efficacy of this technique at high-resolution, phase regression was applied to GE-EPI timeseries and compared to SE-EPI to determine if GE-EPI's specificity to the microvascular compartment improved. To do this, functional data was collected from seven subjects on a neuro-optimized 7 T system at 800 µm isotropic resolution with both GE-EPI and SE-EPI while observing an 8 Hz contrast reversing checkerboard. Phase data from the GE-EPI was used to create a microvasculature-weighted time series (GE-EPI-PR). Anatomical imaging (MP2RAGE) was also collected to allow for surface segmentation so that the functional results could be projected onto a surface. A multi-echo gradient echo sequence was collected and used to identify venous vasculature. The GE-EPI-PR surface activation maps showed a high qualitative similarity with SE-EPI and also produced laminar activity profiles similar to SE-EPI. When the GE-EPI and GE-EPI-PR distributions were compared to SE-EPI it was shown that GE-EPI-PR had similar distribution characteristics to SE-EPI (p < 0.05) across the top 60% of cortex. Furthermore, it was shown that GE-EPI-PR has a higher contrast-to-noise ratio (0.5 ± 0.2, mean ± std. dev. across layers) than SE-EPI (0.27 ± 0.07) demonstrating the technique has higher sensitivity than SE-EPI. Taken together this evidence suggests phase regression is a useful method in low SNR studies such as high-resolution fMRI.

Effects of MP2RAGE B1+ sensitivity on inter-site T1 reproducibility and hippocampal morphometry at 7T.

Most neuroanatomical studies are based on T1-weighted MR images, whose intensity profiles are not solely determined by the tissue's longitudinal relaxation times (T1), but also affected by varying non-T1 contributions, hampering data reproducibility. In contrast, quantitative imaging using the MP2RAGE sequence, for example, allows direct characterization of the brain based on the tissue property of interest. Combined with 7 Tesla (7T) MRI, this offers unique opportunities to obtain robust high-resolution brain data characterized by a high reproducibility, sensitivity and specificity. However, specific MP2RAGE parameter choices - e.g., to emphasize intracortical myelin-dependent contrast variations - can substantially impact image quality and cortical analyses through remnants of B1+-related intensity variations, as illustrated in our previous work. To follow up on this: we (1) validate this protocol effect using a dataset acquired with a particularly B1+ insensitive set of MP2RAGE parameters combined with parallel transmission excitation; and (2) extend our analyses to evaluate the effects on hippocampal morphometry. The latter remained unexplored initially, but can provide important insights related to generalizability and reproducibility of neurodegenerative research using 7T MRI. We confirm that B1+ inhomogeneities have a considerably variable effect on cortical T1 estimates, as well as on hippocampal morphometry depending on the MP2RAGE setup. While T1 differed substantially across datasets initially, we show the inter-site T1 comparability improves after correcting for the spatially varying B1+ field using a separately acquired Sa2RAGE B1+ map. Finally, removal of B1+ residuals affects hippocampal volumetry and boundary definitions, particularly near structures characterized by strong intensity changes (e.g. cerebral spinal fluid). Taken together, we show that the choice of MP2RAGE parameters can impact T1 comparability across sites and present evidence that hippocampal segmentation results are modulated by B1+ inhomogeneities. This calls for careful (1) consideration of sequence parameters when setting acquisition protocols, as well as (2) acquisition of a B1+ map to correct MP2RAGE data for potential B1+ variations to allow comparison across datasets.

Minimal specifications for non-human primate MRI: Challenges in standardizing and harmonizing data collection.

Recent methodological advances in MRI have enabled substantial growth in neuroimaging studies of non-human primates (NHPs), while open data-sharing through the PRIME-DE initiative has increased the availability of NHP MRI data and the need for robust multi-subject multi-center analyses. Streamlined acquisition and analysis protocols would accelerate and improve these efforts. However, consensus on minimal standards for data acquisition protocols and analysis pipelines for NHP imaging remains to be established, particularly for multi-center studies. Here, we draw parallels between NHP and human neuroimaging and provide minimal guidelines for harmonizing and standardizing data acquisition. We advocate robust translation of widely used open-access toolkits that are well established for analyzing human data. We also encourage the use of validated, automated pre-processing tools for analyzing NHP data sets. These guidelines aim to refine methodological and analytical strategies for small and large-scale NHP neuroimaging data. This will improve reproducibility of results, and accelerate the convergence between NHP and human neuroimaging strategies which will ultimately benefit fundamental and translational brain science.

Muting, not fragmentation, of functional brain networks under general anesthesia.

Changes in resting-state functional connectivity (rs-FC) under general anesthesia have been widely studied with the goal of identifying neural signatures of consciousness. This work has commonly revealed an apparent fragmentation of whole-brain network structure during unconsciousness, which has been interpreted as reflecting a break-down in connectivity and a disruption of the brain's ability to integrate information. Here we show, by studying rs-FC under varying depths of isoflurane-induced anesthesia in nonhuman primates, that this apparent fragmentation, rather than reflecting an actual change in network structure, can be simply explained as the result of a global reduction in FC. Specifically, by comparing the actual FC data to surrogate data sets that we derived to test competing hypotheses of how FC changes as a function of dose, we found that increases in whole-brain modularity and the number of network communities - considered hallmarks of fragmentation - are artifacts of constructing FC networks by thresholding based on correlation magnitude. Taken together, our findings suggest that deepening levels of unconsciousness are instead associated with the increasingly muted expression of functional networks, an observation that constrains current interpretations as to how anesthesia-induced FC changes map onto existing neurobiological theories of consciousness.

Automatic determination of the regularization weighting for wavelet-based compressed sensing MRI reconstructions.

PURPOSE: To present a method that automatically, rapidly, and in a noniterative manner determines the regularization weighting for wavelet-based compressed sensing reconstructions. This method determines level-specific regularization weighting factors from the wavelet transform of the image obtained from zero-filling in k-space. METHODS: We compare reconstruction results obtained by our method, λauto , to the ones obtained by the L-curve, λLcurve , and the minimum NMSE, λNMSE . The comparisons are done using in vivo data; then, simulations are used to analyze the impact of undersampling and noise. We use NMSE, Pearson's correlation coefficient, high-frequency error norm, and structural similarity as reconstruction quality indices. RESULTS: Our method, λauto , provides improved reconstructed image quality to that obtained by λLcurve regardless of undersampling or SNR and comparable quality to λNMSE at high SNR. The method determines the regularization weighting prospectively with negligible computational time. CONCLUSION: Our main finding is an automatic, fast, noniterative, and robust procedure to determine the regularization weighting. The impact of this method is to enable prospective and tuning-free wavelet-based compressed sensing reconstructions.

Radiofrequency coil for routine ultra-high-field imaging with an unobstructed visual field.

Many neuroscience applications have adopted functional MRI as a tool to investigate the healthy and diseased brain during the completion of a task. While ultra-high-field MRI has allowed for improved contrast and signal-to-noise ratios during functional MRI studies, it remains a challenge to create local radiofrequency coils that can accommodate an unobstructed visual field and be suitable for routine use, while at the same time not compromise performance. Performance (both during transmission and reception) can be improved by using close-fitting coils; however, maintaining sensitivity over the whole brain often requires the introduction of coil elements proximal to the eyes, thereby partially occluding the subject's visual field. This study presents a 7 T head coil, with eight transmit dipoles and 32 receive loops, that is designed to remove visual obstructions from the subject's line of sight, allowing for an unencumbered view of visual stimuli, the reduction of anxiety induced from small enclosures, and the potential for eye-tracking measurements. The coil provides a practical solution for routine imaging, including a split design (anterior and posterior halves) that facilitates subject positioning, including those with impaired mobility, and the placement of devices required for patient comfort and motion reduction. The transmit and receive coils displayed no degradation of performance due to adaptions to the design topology (both mechanical and electrical) required to create an unobstructed visual field. All computer-aided design files, electromagnetic simulation models, transmit field maps and local specific absorption rate matrices are provided to promote reproduction.

Altered Resting-State Functional Connectivity Between Awake and Isoflurane Anesthetized Marmosets.

The common marmoset (Callithrix jacchus) is a New World primate that is becoming increasingly popular as a preclinical model. To assess functional connectivity (FC) across the marmoset brain, resting-state functional MRI (RS-fMRI) is often performed under isoflurane anesthesia to avoid the effects of motion, physiological stress, and training requirements. In marmosets, however, it remains unclear how isoflurane anesthesia affects patterns of FC. Here, we investigated the effects of isoflurane on FC when delivered with either medical air or 100% pure oxygen, two canonical methods of inhalant isoflurane anesthesia delivery. The results demonstrated that when delivered with either medical air or 100% oxygen, isoflurane globally decreased FC across resting-state networks that were identified in awake marmosets. Generally, although isoflurane globally decreased FC in resting-state networks, the spatial structure of the networks was preserved. Outside of the context of RS networks, we indexed pair-wise functional connectivity between regions across the brain and found that isoflurane substantially altered interhemispheric and thalamic FC. Taken together, these findings indicate that RS-fMRI under isoflurane anesthesia is useful to evaluate the global structure of functional networks, but may obfuscate important nodes of some network components when compared to data acquired in fully awake marmosets.

Dynamic Reconfiguration, Fragmentation, and Integration of Whole-Brain Modular Structure across Depths of Unconsciousness.

General anesthetics are routinely used to induce unconsciousness, and much is known about their effects on receptor function and single neuron activity. Much less is known about how these local effects are manifest at the whole-brain level nor how they influence network dynamics, especially past the point of induced unconsciousness. Using resting-state functional magnetic resonance imaging (fMRI) with nonhuman primates, we investigated the dose-dependent effects of anesthesia on whole-brain temporal modular structure, following loss of consciousness. We found that higher isoflurane dose was associated with an increase in both the number and isolation of whole-brain modules, as well as an increase in the uncoordinated movement of brain regions between those modules. Conversely, we found that higher dose was associated with a decrease in the cohesive movement of brain regions between modules, as well as a decrease in the proportion of modules in which brain regions participated. Moreover, higher dose was associated with a decrease in the overall integrity of networks derived from the temporal modules, with the exception of a single, sensory-motor network. Together, these findings suggest that anesthesia-induced unconsciousness results from the hierarchical fragmentation of dynamic whole-brain network structure, leading to the discoordination of temporal interactions between cortical modules.