A tripartite view of the posterior cingulate cortex.

The posterior cingulate cortex (PCC) is one of the least understood regions of the cerebral cortex. By contrast, the anterior cingulate cortex has been the subject of intensive investigation in humans and model animal systems, leading to detailed behavioural and computational theoretical accounts of its function. The time is right for similar progress to be made in the PCC given its unique anatomical and physiological properties and demonstrably important contributions to higher cognitive functions and brain diseases. Here, we describe recent progress in understanding the PCC, with a focus on convergent findings across species and techniques that lay a foundation for establishing a formal theoretical account of its functions. Based on this converging evidence, we propose that the broader PCC region contains three major subregions - the dorsal PCC, ventral PCC and retrosplenial cortex - that respectively support the integration of executive, mnemonic and spatial processing systems. This tripartite subregional view reconciles inconsistencies in prior unitary theories of PCC function and offers promising new avenues for progress.

Dorsal Anterior Cingulate Cortex: A Bottom-Up View.

The dorsal anterior cingulate cortex (dACC) has attracted great interest from neuroscientists because it is associated with so many important cognitive functions. Despite, or perhaps because of, its rich functional repertoire, we lack a single comprehensive view of its function. Most research has approached this puzzle from the top down, using aggregate measures such as neuroimaging. We provide a view from the bottom up, with a focus on single-unit responses and anatomy. We summarize the strengths and weaknesses of the three major approaches to characterizing the dACC: as a monitor, as a controller, and as an economic structure. We argue that neurons in the dACC are specialized for representing contexts, or task-state variables relevant for behavior, and strategies, or aspects of future plans. We propose that dACC neurons link contexts with strategies by integrating diverse task-relevant information to create a rich representation of task space and exert high-level and abstract control over decision and action.

Anatomical details affect electric field predictions for non-invasive brain stimulation in non-human primates.

Non-human primates (NHPs) have become key for translational research in noninvasive brain stimulation (NIBS). However, in order to create comparable stimulation conditions for humans it is vital to study the accuracy of current modeling practices across species. Numerical models to simulate electric fields are an important tool for experimental planning in NHPs and translation to human studies. It is thus essential whether and to what extent the anatomical details of NHP models agree with current modeling practices when calculating NIBS electric fields. Here, we create highly accurate head models of two non-human primates (NHP) MR data. We evaluate how muscle tissue and head field of view (depending on MRI parameters) affect simulation results in transcranial electric and magnetic stimulation (TES and TMS). Our findings indicate that the inclusion of anisotropic muscle can affect TES electric field strength up to 22% while TMS is largely unaffected. Additionally, comparing a full head model to a cropped head model illustrates the impact of head field of view on electric fields for both TES and TMS. We find opposing effects between TES and TMS with an increase up to 24.8% for TES and a decrease up to 24.6% for TMS for the cropped head model compared to the full head model. Our results provide important insights into the level of anatomical detail needed for NHP head models and can inform future translational efforts for NIBS studies.

A taxonomy of the brain's white matter: twenty-one major tracts for the 21st century.

The functional and computational properties of brain areas are determined, in large part, by their connectivity profiles. Advances in neuroimaging and network neuroscience allow us to characterize the human brain noninvasively, but a comprehensive understanding of the human brain demands an account of the anatomy of brain connections. Long-range anatomical connections are instantiated by white matter, which itself is organized into tracts. These tracts are often disrupted by central nervous system disorders, and they can be targeted by neuromodulatory interventions, such as deep brain stimulation. Here, we characterized the connections, morphology, traversal, and functions of the major white matter tracts in the brain. There are major discrepancies across different accounts of white matter tract anatomy, hindering our attempts to accurately map the connectivity of the human brain. However, we are often able to clarify the source(s) of these discrepancies through careful consideration of both histological tract-tracing and diffusion-weighted tractography studies. In combination, the advantages and disadvantages of each method permit novel insights into brain connectivity. Ultimately, our synthesis provides an essential reference for neuroscientists and clinicians interested in brain connectivity and anatomy, allowing for the study of the association of white matter's properties with behavior, development, and disorders.

Connecting Circuits with Networks in Addiction Neuroscience: A Salience Network Perspective.

Human neuroimaging has demonstrated the existence of large-scale functional networks in the cerebral cortex consisting of topographically distant brain regions with functionally correlated activity. The salience network (SN), which is involved in detecting salient stimuli and mediating inter-network communication, is a crucial functional network that is disrupted in addiction. Individuals with addiction display dysfunctional structural and functional connectivity of the SN. Furthermore, while there is a growing body of evidence regarding the SN, addiction, and the relationship between the two, there are still many unknowns, and there are fundamental limitations to human neuroimaging studies. At the same time, advances in molecular and systems neuroscience techniques allow researchers to manipulate neural circuits in nonhuman animals with increasing precision. Here, we describe attempts to translate human functional networks to nonhuman animals to uncover circuit-level mechanisms. To do this, we review the structural and functional connections of the salience network and its homology across species. We then describe the existing literature in which circuit-specific perturbation of the SN sheds light on how functional cortical networks operate, both within and outside the context of addiction. Finally, we highlight key outstanding opportunities for mechanistic studies of the SN.

Ultra-high field (10.5T) diffusion-weighted MRI of the macaque brain.

Diffu0sion-weighted magnetic resonance imaging (dMRI) is a non-invasive imaging technique that provides information about the barriers to the diffusion of water molecules in tissue. In the brain, this information can be used in several important ways, including to examine tissue abnormalities associated with brain disorders and to infer anatomical connectivity and the organization of white matter bundles through the use of tractography algorithms. However, dMRI also presents certain challenges. For example, historically, the biological validation of tractography models has shown only moderate correlations with anatomical connectivity as determined through invasive tract-tracing studies. Some of the factors contributing to such issues are low spatial resolution, low signal-to-noise ratios, and long scan times required for high-quality data, along with modeling challenges like complex fiber crossing patterns. Leveraging the capabilities provided by an ultra-high field scanner combined with denoising, we have acquired whole-brain, 0.58 mm isotropic resolution dMRI with a 2D-single shot echo planar imaging sequence on a 10.5 Tesla scanner in anesthetized macaques. These data produced high-quality tractograms and maps of scalar diffusion metrics in white matter. This work demonstrates the feasibility and motivation for in-vivo dMRI studies seeking to benefit from ultra-high fields.

Retrosplenial Cortical Connectivity with Frontal Basal Ganglia Networks.

Previous studies of the retrosplenial cortex (RSC) have focused on its role in navigation and memory, consistent with its well-established medial temporal connections, but recent evidence also suggests a role for this region in reward and decision making. Because function is determined largely by anatomical connections, and to better understand the anatomy of RSC, we used tract-tracing methods to examine the anatomical connectivity between the rat RSC and frontostriatal networks (canonical reward and decision-making circuits). We find that, among frontal cortical regions, RSC bidirectionally connects most strongly with the anterior cingulate cortex, but also with an area of the central-medial orbito-frontal cortex. RSC projects to the dorsomedial striatum, and its terminal fields are virtually encompassed by the frontal-striatal projection zone, suggestive of functional convergence through the basal ganglia. This overlap is driven by anterior cingulate cortex, prelimbic cortex, and orbito-frontal cortex, all of which contribute to goal-directed decision making, suggesting that the RSC is involved in similar processes.

Ultra-high field (10.5 T) resting state fMRI in the macaque.

Resting state functional connectivity refers to the temporal correlations between spontaneous hemodynamic signals obtained using functional magnetic resonance imaging. This technique has demonstrated that the structure and dynamics of identifiable networks are altered in psychiatric and neurological disease states. Thus, resting state network organizations can be used as a diagnostic, or prognostic recovery indicator. However, much about the physiological basis of this technique is unknown. Thus, providing a translational bridge to an optimal animal model, the macaque, in which invasive circuit manipulations are possible, is of utmost importance. Current approaches to resting state measurements in macaques face unique challenges associated with signal-to-noise, the need for contrast agents limiting translatability, and within-subject designs. These limitations can, in principle, be overcome through ultra-high magnetic fields. However, imaging at magnetic fields above 7T has yet to be adapted for fMRI in macaques. Here, we demonstrate that the combination of high channel count transmitter and receiver arrays, optimized pulse sequences, and careful anesthesia regimens, allows for detailed single-subject resting state analysis at high resolutions using a 10.5 Tesla scanner. In this study, we uncover thirty spatially detailed resting state components that are highly robust across individual macaques and closely resemble the quality and findings of connectomes from large human datasets. This detailed map of the rsfMRI 'macaque connectome' will be the basis for future neurobiological circuit manipulation work, providing valuable biological insights into human connectomics.

Functional Segmentation of the Anterior Limb of the Internal Capsule: Linking White Matter Abnormalities to Specific Connections.

The anterior limb of the internal capsule (ALIC) carries thalamic and brainstem fibers from prefrontal cortical regions that are associated with different aspects of emotion, motivation, cognition processing, and decision-making. This large fiber bundle is abnormal in several psychiatric illnesses and a major target for deep brain stimulation. Yet, we have very little information about where specific prefrontal fibers travel within the bundle. Using a combination of tracing studies and diffusion MRI in male nonhuman primates, as well as diffusion MRI in male and female human subjects, we segmented the human ALIC into five regions based on the positions of axons from different cortical regions within the capsule. Fractional anisotropy (FA) abnormalities in patients with bipolar disorder were detected when FA was averaged in the ALIC segment that carries ventrolateral prefrontal cortical connections. Together, the results set the stage for linking abnormalities within the ALIC to specific connections and demonstrate the utility of applying connectivity profiles of large white matter bundles based on animal anatomic studies to human connections and associating disease abnormalities in those pathways with specific connections. The ability to functionally segment large white matter bundles into their components begins a new era of refining how we think about white matter organization and use that information in understanding abnormalities.SIGNIFICANCE STATEMENT The anterior limb of the internal capsule (ALIC) connects prefrontal cortex with the thalamus and brainstem and is abnormal in psychiatric illnesses. However, we know little about the location of specific prefrontal fibers within the bundle. Using a combination of animal tracing studies and diffusion MRI in animals and human subjects, we segmented the human ALIC into five regions based on the positions of axons from different cortical regions. We then demonstrated that differences in FA values between bipolar disorder patients and healthy control subjects were specific to a given segment. Together, the results set the stage for linking abnormalities within the ALIC to specific connections and for refining how we think about white matter organization in general.

Organization of the Anterior Limb of the Internal Capsule in the Rat.

Dysfunction of the orbitofrontal (OFC) and anterior cingulate (ACC) cortices has been linked with several psychiatric disorders, including obsessive-compulsive disorder, major depressive disorder, posttraumatic stress disorder, and addiction. These conditions are also associated with abnormalities in the anterior limb of the internal capsule, the white matter (WM) bundle carrying ascending and descending fibers from the OFC and ACC. Furthermore, deep-brain stimulation (DBS) for psychiatric disorders targets these fibers. Experiments in rats provide essential information on the mechanisms of normal and abnormal brain anatomy, including WM composition and perturbations. However, whereas descending prefrontal cortex (PFC) fibers in primates form a well defined and topographic anterior limb of the internal capsule, the specific locations and organization of these fibers in rats is unknown. We address this gap by analyzing descending fibers from injections of an anterograde tracer in the rat ACC and OFC. Our results show that the descending PFC fibers in the rat form WM fascicles embedded within the striatum. These bundles are arranged topographically and contain projections, not only to the striatum, but also to the thalamus and brainstem. They can therefore be viewed as the rat homolog of the primate anterior limb of the internal capsule. Furthermore, mapping these projections allows us to identify the fibers likely to be affected by experimental manipulations of the striatum and the anterior limb of the internal capsule. These results are therefore essential for translating abnormalities of human WM and effects of DBS to rodent models.SIGNIFICANCE STATEMENT Psychiatric diseases are linked to abnormalities in specific white matter (WM) pathways, and the efficacy of deep-brain stimulation relies upon activation of WM. Experiments in rodents are necessary for studying the mechanisms of brain function. However, the translation of results between primates and rodents is hindered by the fact that the organization of descending WM in rodents is poorly understood. This is especially relevant for the prefrontal cortex, abnormal connectivity of which is central to psychiatric disorders. We address this gap by studying the organization of descending rodent prefrontal pathways. These fibers course through a subcortical structure, the striatum, and share important organization principles with primate WM. These results allow us to model primate WM effectively in the rodent.

Frontal cortical and subcortical projections provide a basis for segmenting the cingulum bundle: implications for neuroimaging and psychiatric disorders.

The cingulum bundle (CB) is one of the brain's major white matter pathways, linking regions associated with executive function, decision-making, and emotion. Neuroimaging has revealed that abnormalities in particular locations within the CB are associated with specific psychiatric disorders, including depression and bipolar disorder. However, the fibers using each portion of the CB remain unknown. In this study, we used anatomical tract-tracing in nonhuman primates (Macaca nemestrina, Macaca fascicularis, Macaca mulatta) to examine the organization of specific cingulate, noncingulate frontal, and subcortical pathways through the CB. The goals were as follows: (1) to determine connections that use the CB, (2) to establish through which parts of the CB these fibers travel, and (3) to relate the CB fiber pathways to the portions of the CB identified in humans as neurosurgical targets for amelioration of psychiatric disorders. Results indicate that cingulate, noncingulate frontal, and subcortical fibers all travel through the CB to reach both cingulate and noncingulate targets. However, many brain regions send projections through only part, not all, of the CB. For example, amygdala fibers are not present in the caudal portion of the dorsal CB. These results allow segmentation of the CB into four unique zones. We identify the specific connections that are abnormal in psychiatric disorders and affected by neurosurgical interventions, such as deep brain stimulation and cingulotomy.

A biophysically constrained brain connectivity model based on stimulation-evoked potentials.

BACKGROUND: Single-pulse electrical stimulation (SPES) is an established technique used to map functional effective connectivity networks in treatment-refractory epilepsy patients undergoing intracranial-electroencephalography monitoring. While the connectivity path between stimulation and recording sites has been explored through the integration of structural connectivity, there are substantial gaps, such that new modeling approaches may advance our understanding of connectivity derived from SPES studies. NEW METHOD: Using intracranial electrophysiology data recorded from a single patient undergoing stereo-electroencephalography (sEEG) evaluation, we employ an automated detection method to identify early response components, C1, from pulse-evoked potentials (PEPs) induced by SPES. C1 components were utilized for a novel topology optimization method, modeling 3D electrical conductivity to infer neural pathways from stimulation sites. Additionally, PEP features were compared with tractography metrics, and model results were analyzed with respect to anatomical features. RESULTS: The proposed optimization model resolved conductivity paths with low error. Specific electrode contacts displaying high error correlated with anatomical complexities. The C1 component strongly correlated with additional PEP features and displayed stable, weak correlations with tractography measures. COMPARISON WITH EXISTING METHOD: Existing methods for estimating neural signal pathways are imaging-based and thus rely on anatomical inferences. CONCLUSIONS: These results demonstrate that informing topology optimization methods with human intracranial SPES data is a feasible method for generating 3D conductivity maps linking electrical pathways with functional neural ensembles. PEP-estimated effective connectivity is correlated with but distinguished from structural connectivity. Modeled conductivity resolves connectivity pathways in the absence of anatomical priors.

The use of chemogenetic actuator ligands in nonhuman primate DREADDs-fMRI.

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are engineered receptors that allow for genetically targeted, reversible manipulation of cellular activity via systemic drug administration. DREADD induced manipulations are initiated via the binding of an actuator ligand. Therefore, the use of DREADDs is contingent on the availability of actuator ligands. Actuator ligands low-dose clozapine (CLZ) and deschloroclozapine (DCZ) are highly selective for DREADDs, and, upon binding, induce physiological and behavioral changes in rodents and nonhuman primates (NHPs). Despite this reported specificity, both CLZ and DCZ have partial affinity for a variety of endogenous receptors and can induce dose-specific changes even in naïve animals. As such, this study aimed to examine the effects of CLZ and DCZ on resting-state functional connectivity (rs-FC) and intrinsic neural timescales (INTs) in naïve NHPs. In doing so, we evaluated whether CLZ and DCZ - in the absence of DREADDs - are inert by examining these ligands' effects on the intrinsic functional properties of the brain. Low-dose DCZ did not induce consistent changes in rs-FC or INTs prior to the expression of DREADDs; however, a high dose resulted in subject-specific changes in rs-FC and INTs. In contrast, CLZ administration induced consistent changes in rs-FC and INTs prior to DREADD expression in our subjects. Our results caution against the use of CLZ by explicitly demonstrating the impact of off-target effects that can confound experimental results. Altogether, these data endorse the use of low dose DCZ for future DREADD-based experiments.

A biophysically constrained brain connectivity model based on stimulation-evoked potentials.

Background: Single-pulse electrical stimulation (SPES) is an established technique used to map functional effective connectivity networks in treatment-refractory epilepsy patients undergoing intracranial-electroencephalography monitoring. While the connectivity path between stimulation and recording sites has been explored through the integration of structural connectivity, there are substantial gaps, such that new modeling approaches may advance our understanding of connectivity derived from SPES studies. New Method: Using intracranial electrophysiology data recorded from a single patient undergoing sEEG evaluation, we employ an automated detection method to identify early response components, C1, from pulse-evoked potentials (PEPs) induced by SPES. C1 components were utilized for a novel topology optimization method, modeling 3D conductivity propagation from stimulation sites. Additionally, PEP features were compared with tractography metrics, and model results were analyzed with respect to anatomical features. Results: The proposed optimization model resolved conductivity paths with low error. Specific electrode contacts displaying high error correlated with anatomical complexities. The C1 component strongly correlates with additional PEP features and displayed stable, weak correlations with tractography measures. Comparison with existing methods: Existing methods for estimating conductivity propagation are imaging-based and thus rely on anatomical inferences. Conclusions: These results demonstrate that informing topology optimization methods with human intracranial SPES data is a feasible method for generating 3D conductivity maps linking electrical pathways with functional neural ensembles. PEP-estimated effective connectivity is correlated with but distinguished from structural connectivity. Modeled conductivity resolves connectivity pathways in the absence of anatomical priors.

Surprise signals in anterior cingulate cortex: neuronal encoding of unsigned reward prediction errors driving adjustment in behavior.

In attentional models of learning, associations between actions and subsequent rewards are stronger when outcomes are surprising, regardless of their valence. Despite the behavioral evidence that surprising outcomes drive learning, neural correlates of unsigned reward prediction errors remain elusive. Here we show that in a probabilistic choice task, trial-to-trial variations in preference track outcome surprisingness. Concordant with this behavioral pattern, responses of neurons in macaque (Macaca mulatta) dorsal anterior cingulate cortex (dACC) to both large and small rewards were enhanced when the outcome was surprising. Moreover, when, on some trials, probabilities were hidden, neuronal responses to rewards were reduced, consistent with the idea that the absence of clear expectations diminishes surprise. These patterns are inconsistent with the idea that dACC neurons track signed errors in reward prediction, as dopamine neurons do. Our results also indicate that dACC neurons do not signal conflict. In the context of other studies of dACC function, these results suggest a link between reward-related modulations in dACC activity and attention and motor control processes involved in behavioral adjustment. More speculatively, these data point to a harmonious integration between reward and learning accounts of ACC function on one hand, and attention and cognitive control accounts on the other.

Prefrontal cortex.

The prefrontal cortex is a well-studied but, in terms of understanding what it is for, deeply divisive part of the brain located at the front of the head. Perhaps the least controversial feature of the prefrontal cortex is its complexity. The prefrontal cortex is anatomically, functionally, and computationally complex. It is anatomically complex, containing a number of subregions each sending and receiving projections to a unique set of other cortical and subcortical areas. This interconnectivity presents a serious challenge to efforts to localize function to prefrontal cortex, because it can seem as though information flows everywhere all at once in prefrontal networks. Perhaps as a result, prefrontal cortex is also computationally complex: working memory, abstraction, sensory attention, value-based decision making, planning, and motor control are all functions that have been attributed to the prefrontal cortex. This diversity of functions is likely to reflect the diversity of brain regions that prefrontal cortex communicates with while carrying out the computations it performs to influence behavior.

A structural and functional subdivision in central orbitofrontal cortex.

Economic choice requires many cognitive subprocesses, including stimulus detection, valuation, motor output, and outcome monitoring; many of these subprocesses are associated with the central orbitofrontal cortex (cOFC). Prior work has largely assumed that the cOFC is a single region with a single function. Here, we challenge that unified view with convergent anatomical and physiological results from rhesus macaques. Anatomically, we show that the cOFC can be subdivided according to its much stronger (medial) or weaker (lateral) bidirectional anatomical connectivity with the posterior cingulate cortex (PCC). We call these subregions cOFCm and cOFCl, respectively. These two subregions have notable functional differences. Specifically, cOFCm shows enhanced functional connectivity with PCC, as indicated by both spike-field coherence and mutual information. The cOFCm-PCC circuit, but not the cOFCl-PCC circuit, shows signatures of relaying choice signals from a non-spatial comparison framework to a spatially framed organization and shows a putative bidirectional mutually excitatory pattern.

A population-normalized tractographic fiber atlas of the anterior limb of the internal capsule: relevance to surgical neuromodulation.

OBJECTIVE: The anterior limb of the internal capsule (ALIC) is a white matter highway that connects several subcortical structures to the prefrontal cortex. Although surgical interventions in the ALIC have been used to treat a number of psychiatric illnesses, there is significant debate regarding what fibers are targeted for intervention. This debate is partially due to an incomplete understanding of connectivity in the region. METHODS: To better understand this complex structure, the authors employed a novel tractography-based approach to examine how fibers from the thalamus and subthalamic nucleus (STN) traverse the ALIC. Furthermore, the authors analyzed connections from the medial dorsal nucleus, anterior nucleus, and ventral anterior nucleus of the thalamus. RESULTS: The results showed that there is an organizational gradient of thalamic fibers medially and STN fibers laterally in the ALIC that fades more anteriorly. These findings, in combination with the known corticotopic organization described by previous studies, allow for a more thorough understanding of the organization of the white matter fibers in the ALIC. CONCLUSIONS: These results are important for understanding and targeting of neuromodulatory therapies in the ALIC and may help explain why differences in therapeutic effect are observed for different areas of the ALIC.

Oxytocin promotes social proximity and decreases vigilance in groups of African lions.

Oxytocin modulates mammalian social behavior; however, behavioral responses to intranasal oxytocin can vary across species and contexts. The complexity of social interactions increases with group dynamics, and the impacts of oxytocin on both within- and between-group contexts are unknown. We tested the effects of intranasal administration of oxytocin on social and non-social behaviors within in-group and out-group contexts in African lions. We hypothesized that, post intranasal oxytocin administration, lions would be in closer proximity with fellow group members, whereas out-group stimuli could either produce a heightened vigilance response or an attenuated one. Compared to control trials, post oxytocin administration, lions increased their time spent in close proximity (reducing their distance to the nearest neighbor) and decreased vigilance toward out-group intruders (reducing their vocalizations following a roar-playback). These results not only have important implications for understanding the evolution of social circuitry but may also have practical applications for conservation efforts.

Intrinsic timescales as an organizational principle of neural processing across the whole rhesus macaque brain.

Hierarchical temporal dynamics are a fundamental computational property of the brain; however, there are no whole brain, noninvasive investigations into timescales of neural processing in animal models. To that end, we used the spatial resolution and sensitivity of ultrahigh field functional magnetic resonance imaging (fMRI) performed at 10.5 T to probe timescales across the whole macaque brain. We uncovered within-species consistency between timescales estimated from fMRI and electrophysiology. Crucially, we extended existing electrophysiological hierarchies to whole-brain topographies. Our results validate the complementary use of hemodynamic and electrophysiological intrinsic timescales, establishing a basis for future translational work. Further, with these results in hand, we were able to show that one facet of the high-dimensional functional connectivity (FC) topography of any region in the brain is closely related to hierarchical temporal dynamics. We demonstrated that intrinsic timescales are organized along spatial gradients that closely match FC gradient topographies across the whole brain. We conclude that intrinsic timescales are a unifying organizational principle of neural processing across the whole brain.