A paleo-neurologic investigation of the social brain hypothesis in frontotemporal dementia.

The social brain hypothesis posits that a disproportionate encephalization in primates enabled to adapt behavior to a social context. Also, it has been proposed that phylogenetically recent brain areas are disproportionally affected by neurodegeneration. Using structural and functional magnetic resonance imaging, the present study investigates brain-behavior associations and neural integrity of hyperspecialized and domain-general cortical social brain areas in behavioral variant frontotemporal dementia (bvFTD). The results revealed that both structure and function of hyperspecialized social areas in the middle portion of the superior temporal sulcus (STS) are compromised in bvFTD, while no deterioration was observed in domain general social areas in the posterior STS. While the structural findings adhered to an anterior-posterior gradient, the functional group differences only occurred in the hyperspecialized locations. Activity in specialized regions was associated with structural integrity of the amygdala and with social deficits in bvFTD. In conclusion, the results are in line with the paleo-neurology hypothesis positing that neurodegeneration primarily hits cortical areas showing increased specialization, but also with the compatible alternative explanation that anterior STS regions degenerate earlier, based on stronger connections to and trans-neuronal spreading from regions affected early in bvFTD.

Single-Unit Recordings Reveal the Selectivity of a Human Face Area.

The exquisite capacity of primates to detect and recognize faces is crucial for social interactions. Although disentangling the neural basis of human face recognition remains a key goal in neuroscience, direct evidence at the single-neuron level is limited. We recorded from face-selective neurons in human visual cortex in a region characterized by functional magnetic resonance imaging (fMRI) activations for faces compared with objects. The majority of visually responsive neurons in this fMRI activation showed strong selectivity at short latencies for faces compared with objects. Feature-scrambled faces and face-like objects could also drive these neurons, suggesting that this region is not tightly tuned to the visual attributes that typically define whole human faces. These single-cell recordings within the human face processing system provide vital experimental evidence linking previous imaging studies in humans and invasive studies in animal models.SIGNIFICANCE STATEMENT We present the first recordings of face-selective neurons in or near an fMRI-defined patch in human visual cortex. Our unbiased multielectrode array recordings (i.e., no selection of neurons based on a search strategy) confirmed the validity of the BOLD contrast (faces-objects) in humans, a finding with implications for all human imaging studies. By presenting faces, feature-scrambled faces, and face-pareidolia (perceiving faces in inanimate objects) stimuli, we demonstrate that neurons at this level of the visual hierarchy are broadly tuned to the features of a face, independent of spatial configuration and low-level visual attributes.

Limited Pairings of Electrical Micro-stimulation of the Ventral Tegmental Area and a Visual Stimulus Enhance Visual Cortical Responses.

Previous studies demonstrated that pairing a visual stimulus and electrical micro-stimulation of the ventral tegmental area (VTA-EM) for multiple days is sufficient to induce visual cortical plasticity and changes perception. However, a brief epoch of VTA-EM-stimulus pairing within a single day has been shown to result in a behavioral preference for the paired stimulus. Here, we investigated whether a brief single-day session of VTA-EM-stimulus pairings is sufficient to induce changes in visual cortical responses. We examined macaque posterior inferior temporal (PIT) cortex because previous studies demonstrated response changes after VTA-EM stimulus pairing in that area. Multi-unit recordings in PIT were interleaved with VTA-EM-stimulus pairing epochs. During the short VTA-EM-stimulus pairing epochs (60 pairings), one image (fractal) was paired with VTA-EM (STIM) whereas another, unpaired fractal was presented as control. Two other fractals (dummies) were presented only during the recordings. The difference in response between the STIM and control fractals already increased after the first VTA-EM-stimulus pairing epoch, reflecting a relative increase of the response to the STIM fractal. However, the response to the STIM fractal did not increase further with more VTA-EM-stimulus pairing epochs. The relative increase in firing rate for the paired fractal was present early in the response, in line with a local/ bottom-up origin. These effects were absent when comparing the responses to the dummies pre- and post-VTA-EM. This study shows that pairing a visual image and VTA-EM in a brief single-day session is sufficient to increase the response for the paired image in macaque PIT.

Areal differences in depth cue integration between monkey and human.

Electrophysiological evidence suggested primarily the involvement of the middle temporal (MT) area in depth cue integration in macaques, as opposed to human imaging data pinpointing area V3B/kinetic occipital area (V3B/KO). To clarify this conundrum, we decoded monkey functional MRI (fMRI) responses evoked by stimuli signaling near or far depths defined by binocular disparity, relative motion, and their combination, and we compared results with those from an identical experiment previously performed in humans. Responses in macaque area MT are more discriminable when two cues concurrently signal depth, and information provided by one cue is diagnostic of depth indicated by the other. This suggests that monkey area MT computes fusion of disparity and motion depth signals, exactly as shown for human area V3B/KO. Hence, these data reconcile previously reported discrepancies between depth processing in human and monkey by showing the involvement of the dorsal stream in depth cue integration using the same technique, despite the engagement of different regions.

Divergent Whole Brain Projections from the Ventral Midbrain in Macaques.

To understand the connectome of the axonal arborizations of dopaminergic midbrain neurons, we investigated the anterograde spread of highly sensitive viral tracers injected into the ventral tegmental area (VTA) and adjacent areas in 3 macaques. In 2 monkeys, injections were centered on the lateral VTA with some spread into the substantia nigra, while in one animal the injection targeted the medial VTA with partial spread into the ventro-medial thalamus. Double-labeling with antibodies against transduced fluorescent proteins (FPs) and tyrosine hydroxylase indicated that substantial portions of transduced midbrain neurons were dopaminergic. Interestingly, cortical terminals were found either homogeneously in molecular layer I, or more heterogeneously, sometimes forming patches, in the deeper laminae II-VI. In the animals with injections in lateral VTA, terminals were most dense in somatomotor cortex and the striatum. In contrast, when the medial VTA was transduced, dense terminals were found in dorsal prefrontal and temporal cortices, while projections to striatum were sparse. In all monkeys, orbitofrontal and occipito-parietal cortex received strong and weak innervation, respectively. Thus, the dopaminergic ventral midbrain sends heterogeneous projections throughout the brain. Furthermore, our results suggest the existence of subgroups in meso-dopaminergic neurons depending on their location in the primate ventral midbrain.

Submillimeter fMRI reveals a layout of dorsal visual cortex in macaques, remarkably similar to New World monkeys.

The macaque dorsal occipital cortex is generally thought to contain an elongated third visual area, V3d, extending along most of the rostral border of area V2. In contrast, our submillimeter retinotopic fMRI maps (0.6-mm isotropic voxels, achieved by implanted phased-array receive coils) consistently show three sectors anterior to V2d. The dorsal (mirror image) sector complies with the traditional V3d definition, and the middle (nonmirror image) sector with V3A. The ventral (mirror image) sector bends away from V2d, as does the ventrolateral posterior area (VLP) in marmosets and the dorsolateral posterior area (DLP) in owl monkeys, and represents the entire contralateral hemifield as V3A does. Its population-receptive field size, however, suggests that this ventral sector is another area at the same hierarchical level as V4d. Hence, contrary to prevailing views, the retinotopic organization of cortex rostral to V2d differs substantially from widely accepted models. Instead, it is evolutionarily largely conserved in Old and New World monkeys given its surprisingly similar overall visuotopic organization.

Common functional localizers to enhance NHP & cross-species neuroscience imaging research.

Functional localizers are invaluable as they can help define regions of interest, provide cross-study comparisons, and most importantly, allow for the aggregation and meta-analyses of data across studies and laboratories. To achieve these goals within the non-human primate (NHP) imaging community, there is a pressing need for the use of standardized and validated localizers that can be readily implemented across different groups. The goal of this paper is to provide an overview of the value of localizer protocols to imaging research and we describe a number of commonly used or novel localizers within NHPs, and keys to implement them across studies. As has been shown with the aggregation of resting-state imaging data in the original PRIME-DE submissions, we believe that the field is ready to apply the same initiative for task-based functional localizers in NHP imaging. By coming together to collect large datasets across research group, implementing the same functional localizers, and sharing the localizers and data via PRIME-DE, it is now possible to fully test their robustness, selectivity and specificity. To do this, we reviewed a number of common localizers and we created a repository of well-established localizer that are easily accessible and implemented through the PRIME-RE platform.

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.

Combining brain perturbation and neuroimaging in non-human primates.

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

Frequency- and State-Dependent Network Effects of Electrical Stimulation Targeting the Ventral Tegmental Area in Macaques.

The ventral tegmental area (VTA) is a midbrain structure at the heart of the dopaminergic system underlying adaptive behavior. Endogenous firing rates of dopamine cells in the VTA vary from fast phasic bursts to slow tonic activity. Artificial perturbations of the VTA, through electrical or optogenetic stimulation methods, generate different and sometimes even contrasting behavioral outcomes depending on stimulation parameters such as frequency, amplitude, and pulse width. Here, we investigate the global functional effects of electrical stimulation frequency (10, 20, 50, and 100 Hz) of the VTA in rhesus monkeys. We stimulated 2 animals with chronic electrodes, either awake or anesthetized, while concurrently acquiring whole-brain functional magnetic resonance imaging (fMRI) signals. In the awake state, activity as a function of stimulation frequency followed an inverted U-shape in many cortical and subcortical structures, with highest activity observed at 20 and 50 Hz and lower activity at 10 and 100 Hz. Under anesthesia, the hemodynamic responses in connected brain areas were slightly positive at 10 Hz stimulation, but decreased linearly as a function of higher stimulation frequencies. A speculative explanation for the remarkable frequency dependence of stimulation-induced fMRI activity is that the VTA makes use of different frequency channels to communicate with different postsynaptic sites.

In Vivo Identification of Thick, Thin, and Pale Stripes of Macaque Area V2 Using Submillimeter Resolution (f)MRI at 3 T.

Primate area V2 contains a repetitive pattern of thick, thin and pale cytochrome oxidase stripes that are characterized by largely discrete in- and output channels, as well as differences in function, and myelo- and cytoarchitecture. Stripes have been identified mainly using microscope-based imaging of tiny portions of superficially located V2, or by postmortem methods, hence, the quest for (quasi) noninvasive tools to study these mesoscale functional units. Only recently, stripe-like V2 patterns have been demonstrated in humans with high-field (functional) magnetic resonance imaging (f)MRI, but in both such studies only 2 stripe compartments could be identified. Although interstripe distances in monkeys are ~half of those in humans, we show that all 3 V2 stripe classes can be reliably separated using submillimeter (f)MRI (0.6 mm isotropic voxels) on regular 3 T scanners by combining contrast agents and implanted phased-array coils. Specifically, we show highly reproducible fMRI patterns, both within and across subjects, of color-selective thin and disparity-selective thick stripes. Furthermore, reliable MRI-based higher myelin-density was observed in pale stripes. Hence, this is the first study showing segregation of columns using (f)MRI-based methods in macaque cortex, which opens the possibility of studying these elementary building blocks of the visual system noninvasively on a large scale.

Fast Compensatory Functional Network Changes Caused by Reversible Inactivation of Monkey Parietal Cortex.

The brain has a remarkable capacity to recover after lesions. However, little is known about compensatory neural adaptations at the systems level. We addressed this question by investigating behavioral and (correlated) functional changes throughout the cortex that are induced by focal, reversible inactivations. Specifically, monkeys performed a demanding covert spatial attention task while the lateral intraparietal area (LIP) was inactivated with muscimol and whole-brain fMRI activity was recorded. The inactivation caused LIP-specific decreases in task-related fMRI activity. In addition, these local effects triggered large-scale network changes. Unlike most studies in which animals were mainly passive relative to the stimuli, we observed heterogeneous effects with more profound muscimol-induced increases of task-related fMRI activity in areas connected to LIP, especially FEF. Furthermore, in areas such as FEF and V4, muscimol-induced changes in fMRI activity correlated with changes in behavioral performance. Notably, the activity changes in remote areas did not correlate with the decreased activity at the site of the inactivation, suggesting that such changes arise via neuronal mechanisms lying in the intact portion of the functional task network, with FEF a likely key player. The excitation-inhibition dynamics unmasking existing excitatory connections across the functional network might initiate these rapid adaptive changes.

Homology and Specificity of Natural Sound-Encoding in Human and Monkey Auditory Cortex.

Understanding homologies and differences in auditory cortical processing in human and nonhuman primates is an essential step in elucidating the neurobiology of speech and language. Using fMRI responses to natural sounds, we investigated the representation of multiple acoustic features in auditory cortex of awake macaques and humans. Comparative analyses revealed homologous large-scale topographies not only for frequency but also for temporal and spectral modulations. In both species, posterior regions preferably encoded relatively fast temporal and coarse spectral information, whereas anterior regions encoded slow temporal and fine spectral modulations. Conversely, we observed a striking interspecies difference in cortical sensitivity to temporal modulations: While decoding from macaque auditory cortex was most accurate at fast rates (> 30 Hz), humans had highest sensitivity to ~3 Hz, a relevant rate for speech analysis. These findings suggest that characteristic tuning of human auditory cortex to slow temporal modulations is unique and may have emerged as a critical step in the evolution of speech and language.

Biological Characteristics of Connection-Wise Resting-State Functional Connectivity Strength.

Functional connectivity is defined as the statistical dependency of neurophysiological activity between 2 separate brain areas. To investigate the biological characteristics of resting-state functional connectivity (rsFC)-and in particular the significance of connection-wise variation in time-series correlations-rsFC was compared with strychnine-based connectivity measured in the macaque. Strychnine neuronography is a historical technique that induces activity in cortical areas through means of local administration of the substance strychnine. Strychnine causes local disinhibition through GABA suppression and leads to subsequent activation of functional pathways. Multiple resting-state fMRI recordings were acquired in 4 macaques (examining in total 299 imaging runs) from which a group-averaged rsFC matrix was constructed. rsFC was observed to be higher (P < 0.0001) between region-pairs with a strychnine-based connection as compared with region-pairs with no strychnine-based connection present. In particular, higher resting-state connectivity was observed in connections that were relatively stronger (weak < moderate < strong; P < 0.01) and in connections that were bidirectional (P < 0.0001) instead of unidirectional in strychnine-based connectivity. Our results imply that the level of correlation between brain areas as extracted from resting-state fMRI relates to the strength of underlying interregional functional pathways.

Functional MRI in Macaque Monkeys during Task Switching.

Nonhuman primates have proven to be a valuable animal model for exploring neuronal mechanisms of cognitive control. One important aspect of executive control is the ability to switch from one task to another, and task-switching paradigms have often been used in human volunteers to uncover the underlying neuronal processes. To date, however, no study has investigated task-switching paradigms in nonhuman primates during functional magnetic resonance imaging (fMRI). We trained two rhesus macaques to switch between arm movement, eye movement, and passive fixation tasks during fMRI. Similar to results obtained in human volunteers, task switching elicits increased fMRI activations in prefrontal cortex, anterior cingulate cortex, orbitofrontal cortex, and caudate nucleus. Our results indicate that the macaque monkey is a reliable model with which to investigate higher-order cognitive functioning such as task switching. As such, these results can pave the way for a detailed investigation of the neural basis of complex human behavior.SIGNIFICANCE STATEMENT Task switching is an important aspect of cognitive control, and task-switching paradigms have often been used to investigate higher-order executive functioning in human volunteers. We used a task-switching paradigm in the nonhuman primate during fMRI and found increased activation mainly in prefrontal areas (46, 45, frontal eye field, and anterior cingulate), in orbitofrontal area 12, and in the caudate nucleus. These data fit surprisingly well with previous human imaging data, proving that the monkey is an excellent model to study task switching with high spatiotemporal resolution tools that are currently not applicable in humans. As such, our results pave the way for a detailed interrogation of regions performing similar executive functions in humans and monkeys.

Attention Shifts Recruit the Monkey Default Mode Network.

A unifying function associated with the default mode network (DMN), which is more active during rest than under active task conditions, has been difficult to define. The DMN is activated during monitoring the external world for unexpected events, as a sentinel, and when humans are engaged in high-level internally focused tasks. The existence of DMN correlates in other species, such as mice, challenge the idea that internally focused, high-level cognitive operations, such as introspection, autobiographical memory retrieval, planning the future, and predicting someone else's thoughts, are evolutionarily preserved defining properties of the DMN. A recent human study demonstrated that demanding cognitive shifts could recruit the DMN, yet it is unknown whether this holds for nonhuman species. Therefore, we tested whether large changes in cognitive context would recruit DMN regions in female and male nonhuman primates. Such changes were measured as displacements of spatial attentional weights based on internal rules of relevance (spatial shifts) compared with maintaining attentional weights at the same location (stay events). Using fMRI in macaques, we detected that a cortical network, activated during shifts, largely overlapped with the DMN. Moreover, fMRI time courses sampled from independently defined DMN foci showed significant shift selectivity during the demanding attention task. Finally, functional clustering based on independent resting state data revealed that DMN and shift regions clustered conjointly, whereas regions activated during the stay events clustered apart. We therefore propose that cognitive shifting in primates generally recruits DMN regions. This might explain a breakdown of the DMN in many neurological diseases characterized by declined cognitive flexibility.SIGNIFICANCE STATEMENT Activation of the human default mode network (DMN) can be measured with fMRI when subjects shift thoughts between high-level internally directed cognitive states, when thinking about the self, the perspective of others, when imagining future and past events, and during mind wandering. Furthermore, the DMN is activated as a sentinel, monitoring the environment for unexpected events. Arguably, these cognitive processes have in common fast and substantial changes in cognitive context. As DMN activity has also been reported in nonhuman species, we tested whether shifts in spatial attention activated the monkey DMN. Core monkey DMN and shift-selective regions shared several functional properties, indicating that cognitive shifting, in general, might constitute one of the evolutionarily preserved functions of the DMN.

Posterior Parietal Cortex Drives Inferotemporal Activations During Three-Dimensional Object Vision.

The primate visual system consists of a ventral stream, specialized for object recognition, and a dorsal visual stream, which is crucial for spatial vision and actions. However, little is known about the interactions and information flow between these two streams. We investigated these interactions within the network processing three-dimensional (3D) object information, comprising both the dorsal and ventral stream. Reversible inactivation of the macaque caudal intraparietal area (CIP) during functional magnetic resonance imaging (fMRI) reduced fMRI activations in posterior parietal cortex in the dorsal stream and, surprisingly, also in the inferotemporal cortex (ITC) in the ventral visual stream. Moreover, CIP inactivation caused a perceptual deficit in a depth-structure categorization task. CIP-microstimulation during fMRI further suggests that CIP projects via posterior parietal areas to the ITC in the ventral stream. To our knowledge, these results provide the first causal evidence for the flow of visual 3D information from the dorsal stream to the ventral stream, and identify CIP as a key area for depth-structure processing. Thus, combining reversible inactivation and electrical microstimulation during fMRI provides a detailed view of the functional interactions between the two visual processing streams.

Decoding Grasping Movements from the Parieto-Frontal Reaching Circuit in the Nonhuman Primate.

Prehension movements typically include a reaching phase, guiding the hand toward the object, and a grip phase, shaping the hand around it. The dominant view posits that these components rely upon largely independent parieto-frontal circuits: a dorso-medial circuit involved in reaching and a dorso-lateral circuit involved in grasping. However, mounting evidence suggests a more complex arrangement, with dorso-medial areas contributing to both reaching and grasping. To investigate the role of the dorso-medial reaching circuit in grasping, we trained monkeys to reach-and-grasp different objects in the dark and determined if hand configurations could be decoded from functional magnetic resonance imaging (MRI) responses obtained from the reaching and grasping circuits. Indicative of their established role in grasping, object-specific grasp decoding was found in anterior intraparietal (AIP) area, inferior parietal lobule area PFG and ventral premotor region F5 of the lateral grasping circuit, and primary motor cortex. Importantly, the medial reaching circuit also conveyed robust grasp-specific information, as evidenced by significant decoding in parietal reach regions (particular V6A) and dorsal premotor region F2. These data support the proposed role of dorso-medial "reach" regions in controlling aspects of grasping and demonstrate the value of complementing univariate with more sensitive multivariate analyses of functional MRI (fMRI) data in uncovering information coding in the brain.

Functional Similarity of Medial Superior Parietal Areas for Shift-Selective Attention Signals in Humans and Monkeys.

We continually shift our attention between items in the visual environment. These attention shifts are usually based on task relevance (top-down) or the saliency of a sudden, unexpected stimulus (bottom-up), and are typically followed by goal-directed actions. It could be argued that any species that can covertly shift its focus of attention will rely on similar, evolutionarily conserved neural substrates for processing such shift-signals. To address this possibility, we performed comparative fMRI experiments in humans and monkeys, combining traditional, and novel, data-driven analytical approaches. Specifically, we examined correspondences between monkey and human brain areas activated during covert attention shifts. When "shift" events were compared with "stay" events, the medial (superior) parietal lobe (mSPL) and inferior parietal lobes showed similar shift sensitivities across species, whereas frontal activations were stronger in monkeys. To identify, in a data-driven manner, monkey regions that corresponded with human shift-selective SPL, we used a novel interspecies beta-correlation strategy whereby task-related beta-values were correlated across voxels or regions-of-interest in the 2 species. Monkey medial parietal areas V6/V6A most consistently correlated with shift-selective human mSPL. Our results indicate that both species recruit corresponding, evolutionarily conserved regions within the medial superior parietal lobe for shifting spatial attention.

Effective connectivity of depth-structure-selective patches in the lateral bank of the macaque intraparietal sulcus.

Extrastriate cortical areas are frequently composed of subpopulations of neurons encoding specific features or stimuli, such as color, disparity, or faces, and patches of neurons encoding similar stimulus properties are typically embedded in interconnected networks, such as the attention or face-processing network. The goal of the current study was to examine the effective connectivity of subsectors of neurons in the same cortical area with highly similar neuronal response properties. We first recorded single- and multi-unit activity to identify two neuronal patches in the anterior part of the macaque intraparietal sulcus (IPS) showing the same depth structure selectivity and then employed electrical microstimulation during functional magnetic resonance imaging in these patches to determine the effective connectivity of these patches. The two IPS subsectors we identified-with the same neuronal response properties and in some cases separated by only 3 mm-were effectively connected to remarkably distinct cortical networks in both dorsal and ventral stream in three macaques. Conversely, the differences in effective connectivity could account for the known visual-to-motor gradient within the anterior IPS. These results clarify the role of the anterior IPS as a pivotal brain region where dorsal and ventral visual stream interact during object analysis. Thus, in addition to the anatomical connectivity of cortical areas and the properties of individual neurons in these areas, the effective connectivity provides novel key insights into the widespread functional networks that support behavior.