Intracranial Directed Connectivity Links Subregions of the Prefrontal Cortex to Major Depression.

Understanding the neural basis of major depressive disorder (MDD) is vital to guiding neuromodulatory treatments. The available evidence supports the hypothesis that MDD is fundamentally a disease of cortical disinhibition, where breakdowns of inhibitory neural systems lead to diminished emotion regulation and intrusive ruminations. Recent research also points towards network changes in the brain, especially within the prefrontal cortex (PFC), as primary sources of MDD etiology. However, due to limitations in spatiotemporal resolution and clinical opportunities for intracranial recordings, this hypothesis has not been directly tested. We recorded intracranial EEG from the dorsolateral (dlPFC), orbitofrontal (OFC), and anterior cingulate cortices (ACC) in neurosurgical patients with MDD. We measured daily fluctuations in self-reported depression severity alongside directed connectivity between these PFC subregions. We focused primarily on delta oscillations (1-3 Hz), which have been linked to GABAergic inhibitory control and intracortical communication. Depression symptoms worsened when connectivity within the left vs. right PFC became imbalanced. In the left hemisphere, all directed connectivity towards the ACC, from the dlPFC and OFC, was positively correlated with depression severity. In the right hemisphere, directed connectivity between the OFC and dlPFC increased with depression severity as well. This is the first evidence that delta oscillations flowing between prefrontal subregions transiently increase intensity when people are experiencing more negative mood. These findings support the overarching hypothesis that MDD worsens with prefrontal disinhibition.

Neuroimaging of the effects of drug exposure or self-administration in rodents: A systematic review.

A systematic review of functional neuroimaging studies on drug (self-) administration in rodents is lacking. Here, we summarized effects of acute or chronic drug administration of various classes of drugs on brain function and determined consistency with human literature. We performed a systematic literature search and identified 125 studies on in vivo rodent resting-state functional magnetic resonance imaging (n = 84) or positron emission tomography (n = 41) spanning depressants (n = 27), opioids (n = 23), stimulants (n = 72), and cannabis (n = 3). Results primarily showed alterations in the striatum, consistent with the human literature. The anterior cingulate cortex and (nonspecific) prefrontal cortex were also frequently implicated. Upregulation was most often found after shorter administration and downregulation after long chronic administration, particularly in the striatum. Importantly, results were consistent across study design, administration models, imaging method, and animal states. Results provide evidence of altered resting-state brain function in rodents upon drug administration, implicating the brain's reward network analogous to human studies. However, alterations were more dynamic than previously known, with dynamic adaptation depending on the length of drug administration.

A reproducible pipeline for parcellation of the anterior limb of the internal capsule.

BACKGROUND: The anterior limb of the internal capsule (ALIC) is a white matter structure connecting the prefrontal cortex (PFC) to the brainstem, thalamus, and subthalamic nucleus. It is a target for deep brain stimulation (DBS) for obsessive-compulsive disorder. There is strong interest in improving DBS targeting by using diffusion tractography to reconstruct and target specific ALIC fiber pathways, but this methodology is susceptible to errors and lacks validation. To address these limitations, we developed a novel diffusion tractography pipeline that generates reliable and biologically validated ALIC white matter reconstructions. METHODS: Following algorithm development and refinement, we analyzed 43 control subjects each with 2 sets of 3T MRI data and a subset of 5 controls with 7T data from the Human Connectome Project. We generated 22 segmented ALIC fiber bundles (11 per hemisphere) based on prefrontal PFC regions of interest, and we analyzed the relationships among bundles. RESULTS: We successfully reproduced the topographies established by prior anatomical work using images acquired at both 3T and 7T. Quantitative assessment demonstrated significantly smaller intra-subject variability relative to inter-subject variability for both test and retest groups across all but one PFC region. We examined the overlap between fibers from different PFC regions and a response tract for obsessive-compulsive disorder deep brain stimulation, and we reconstructed the PFC hyperdirect pathway using a modified version of our pipeline. DISCUSSION: Our dMRI algorithm reliably generates biologically validated ALIC white matter reconstructions, allowing for more precise modelling of fibers for neuromodulation therapies.

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.

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.

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.

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.

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 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.

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.

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.

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.

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.

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.

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.

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.

Proceedings of the 10th annual deep brain stimulation think tank: Advances in cutting edge technologies, artificial intelligence, neuromodulation, neuroethics, interventional psychiatry, and women in neuromodulation.

The deep brain stimulation (DBS) Think Tank X was held on August 17-19, 2022 in Orlando FL. The session organizers and moderators were all women with the theme women in neuromodulation. Dr. Helen Mayberg from Mt. Sinai, NY was the keynote speaker. She discussed milestones and her experiences in developing depression DBS. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers and researchers (from industry and academia) can freely discuss current and emerging DBS technologies as well as the logistical and ethical issues facing the field. The consensus among the DBS Think Tank X speakers was that DBS has continued to expand in scope however several indications have reached the "trough of disillusionment." DBS for depression was considered as "re-emerging" and approaching a slope of enlightenment. DBS for depression will soon re-enter clinical trials. The group estimated that globally more than 244,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. This year's meeting was focused on advances in the following areas: neuromodulation in Europe, Asia, and Australia; cutting-edge technologies, closed loop DBS, DBS tele-health, neuroethics, lesion therapy, interventional psychiatry, and adaptive DBS.

Computational validity: using computation to translate behaviours across species.

We propose a new conceptual framework (computational validity) for translation across species and populations based on the computational similarity between the information processing underlying parallel tasks. Translating between species depends not on the superficial similarity of the tasks presented, but rather on the computational similarity of the strategies and mechanisms that underlie those behaviours. Computational validity goes beyond construct validity by directly addressing questions of information processing. Computational validity interacts with circuit validity as computation depends on circuits, but similar computations could be accomplished by different circuits. Because different individuals may use different computations to accomplish a given task, computational validity suggests that behaviour should be understood through the subject's point of view; thus, behaviour should be characterized on an individual level rather than a task level. Tasks can constrain the computational algorithms available to a subject and the observed subtleties of that behaviour can provide information about the computations used by each individual. Computational validity has especially high relevance for the study of psychiatric disorders, given the new views of psychiatry as identifying and mediating information processing dysfunctions that may show high inter-individual variability, as well as for animal models investigating aspects of human psychiatric disorders. This article is part of the theme issue 'Systems neuroscience through the lens of evolutionary theory'.

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.

Choice-relevant information transformation along a ventrodorsal axis in the medial prefrontal cortex.

Choice-relevant brain regions in prefrontal cortex may progressively transform information about options into choices. Here, we examine responses of neurons in four regions of the medial prefrontal cortex as macaques performed two-option risky choices. All four regions encode economic variables in similar proportions and show similar putative signatures of key choice-related computations. We provide evidence to support a gradient of function that proceeds from areas 14 to 25 to 32 to 24. Specifically, we show that decodability of twelve distinct task variables increases along that path, consistent with the idea that regions that are higher in the anatomical hierarchy make choice-relevant variables more separable. We also show progressively longer intrinsic timescales in the same series. Together these results highlight the importance of the medial wall in choice, endorse a specific gradient-based organization, and argue against a modular functional neuroanatomy of choice.