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.

Irrational choices via a curvilinear representational geometry for value.

We make decisions by comparing values, but it is not yet clear how value is represented in the brain. Many models assume, if only implicitly, that the representational geometry of value is linear. However, in part due to a historical focus on noisy single neurons, rather than neuronal populations, this hypothesis has not been rigorously tested. Here, we examine the representational geometry of value in the ventromedial prefrontal cortex (vmPFC), a part of the brain linked to economic decision-making, in two male rhesus macaques. We find that values are encoded along a curved manifold in vmPFC. This curvilinear geometry predicts a specific pattern of irrational decision-making: that decision-makers will make worse choices when an irrelevant, decoy option is worse in value, compared to when it is better. We observe this type of irrational choices in behavior. Together, these results not only suggest that the representational geometry of value is nonlinear, but that this nonlinearity could impose bounds on rational decision-making.

Gaze-centered gating, reactivation, and reevaluation of economic value in orbitofrontal cortex.

During economic choice, options are often considered in alternation, until commitment. Nonetheless, neuroeconomics typically ignores the dynamic aspects of deliberation. We trained two male macaques to perform a value-based decision-making task in which two risky offers were presented in sequence at the opposite sides of the visual field, each followed by a delay epoch where offers were invisible. Surprisingly, during the two delays, subjects tend to look at empty locations where the offers had previously appeared, with longer fixations increasing the probability of choosing the associated offer. Spiking activity in orbitofrontal cortex reflects the value of the gazed offer, or of the offer associated with the gazed empty spatial location, even if it is not the most recent. This reactivation reflects a reevaluation process, as fluctuations in neural spiking correlate with upcoming choice. Our results suggest that look-at-nothing gazing triggers the reactivation of a previously seen offer for further evaluation.

Disruption of neural periodicity predicts clinical response after deep brain stimulation for obsessive-compulsive disorder.

Recent advances in surgical neuromodulation have enabled chronic and continuous intracranial monitoring during everyday life. We used this opportunity to identify neural predictors of clinical state in 12 individuals with treatment-resistant obsessive-compulsive disorder (OCD) receiving deep brain stimulation (DBS) therapy ( NCT05915741 ). We developed our neurobehavioral models based on continuous neural recordings in the region of the ventral striatum in an initial cohort of five patients and tested and validated them in a held-out cohort of seven additional patients. Before DBS activation, in the most symptomatic state, theta/alpha (9 Hz) power evidenced a prominent circadian pattern and a high degree of predictability. In patients with persistent symptoms (non-responders), predictability of the neural data remained consistently high. On the other hand, in patients who improved symptomatically (responders), predictability of the neural data was significantly diminished. This neural feature accurately classified clinical status even in patients with limited duration recordings, indicating generalizability that could facilitate therapeutic decision-making.

Insula uses overlapping codes for emotion in self and others.

In daily life, we must recognize others' emotions so we can respond appropriately. This ability may rely, at least in part, on neural responses similar to those associated with our own emotions. We hypothesized that the insula, a cortical region near the junction of the temporal, parietal, and frontal lobes, may play a key role in this process. We recorded local field potential (LFP) activity in human neurosurgical patients performing two tasks, one focused on identifying their own emotional response and one on identifying facial emotional responses in others. We found matching patterns of gamma- and high-gamma band activity for the two tasks in the insula. Three other regions (MTL, ACC, and OFC) clearly encoded both self- and other-emotions, but used orthogonal activity patterns to do so. These results support the hypothesis that the insula plays a particularly important role in mediating between experienced vs. observed emotions.

Cost-effectiveness and threshold analysis of deep brain stimulation vs. treatment-as-usual for treatment-resistant depression.

Treatment-resistant depression (TRD) affects approximately 2.8 million people in the U.S. with estimated annual healthcare costs of $43.8 billion. Deep brain stimulation (DBS) is currently an investigational intervention for TRD. We used a decision-analytic model to compare cost-effectiveness of DBS to treatment-as-usual (TAU) for TRD. Because this therapy is not FDA approved or in common use, our goal was to establish an effectiveness threshold that trials would need to demonstrate for this therapy to be cost-effective. Remission and complication rates were determined from review of relevant studies. We used published utility scores to reflect quality of life after treatment. Medicare reimbursement rates and health economics data were used to approximate costs. We performed Monte Carlo (MC) simulations and probabilistic sensitivity analyses to estimate incremental cost-effectiveness ratios (ICER; USD/quality-adjusted life year [QALY]) at a 5-year time horizon. Cost-effectiveness was defined using willingness-to-pay (WTP) thresholds of $100,000/QALY and $50,000/QALY for moderate and definitive cost-effectiveness, respectively. We included 274 patients across 16 studies from 2009-2021 who underwent DBS for TRD and had ≥12 months follow-up in our model inputs. From a healthcare sector perspective, DBS using non-rechargeable devices (DBS-pc) would require 55% and 85% remission, while DBS using rechargeable devices (DBS-rc) would require 11% and 19% remission for moderate and definitive cost-effectiveness, respectively. From a societal perspective, DBS-pc would require 35% and 46% remission, while DBS-rc would require 8% and 10% remission for moderate and definitive cost-effectiveness, respectively. DBS-pc will unlikely be cost-effective at any time horizon without transformative improvements in battery longevity. If remission rates ≥8-19% are achieved, DBS-rc will likely be more cost-effective than TAU for TRD, with further increasing cost-effectiveness beyond 5 years.

Control over a mixture of policies determines change of mind topology during continuous choice.

Behavior is naturally organized into categorically distinct states with corresponding patterns of neural activity; how does the brain control those states? We propose that states are regulated by specific neural processes that implement meta-control that can blend simpler control processes. To test this hypothesis, we recorded from neurons in the dorsal anterior cingulate cortex (dACC) and dorsal premotor cortex (PMd) while macaques performed a continuous pursuit task with two moving prey that followed evasive strategies. We used a novel control theoretic approach to infer subjects' moment-to-moment latent control variables, which in turn dictated their blend of distinct identifiable control processes. We identified low-dimensional subspaces in neuronal responses that reflected the current strategy, the value of the pursued target, and the relative value of the two targets. The top two principal components of activity tracked changes of mind in abstract and change-type-specific formats, respectively. These results indicate that control of behavioral state reflects the interaction of brain processes found in dorsal prefrontal regions that implement a mixture over low-level control policies.

Foraging Under Uncertainty Follows the Marginal Value Theorem with Bayesian Updating of Environment Representations.

Foraging theory has been a remarkably successful approach to understanding the behavior of animals in many contexts. In patch-based foraging contexts, the marginal value theorem (MVT) shows that the optimal strategy is to leave a patch when the marginal rate of return declines to the average for the environment. However, the MVT is only valid in deterministic environments whose statistics are known to the forager; naturalistic environments seldom meet these strict requirements. As a result, the strategies used by foragers in naturalistic environments must be empirically investigated. We developed a novel behavioral task and a corresponding computational framework for studying patch-leaving decisions in head-fixed and freely moving mice. We varied between-patch travel time, as well as within-patch reward depletion rate, both deterministically and stochastically. We found that mice adopt patch residence times in a manner consistent with the MVT and not explainable by simple ethologically motivated heuristic strategies. Critically, behavior was best accounted for by a modified form of the MVT wherein environment representations were updated based on local variations in reward timing, captured by a Bayesian estimator and dynamic prior. Thus, we show that mice can strategically attend to, learn from, and exploit task structure on multiple timescales simultaneously, thereby efficiently foraging in volatile environments. The results provide a foundation for applying the systems neuroscience toolkit in freely moving and head-fixed mice to understand the neural basis of foraging under uncertainty.

Pretrial predictors of conflict response efficacy in the human prefrontal cortex.

The ability to perform motor actions depends, in part, on the brain's initial state. We hypothesized that initial state dependence is a more general principle and applies to cognitive control. To test this idea, we examined human single units recorded from the dorsolateral prefrontal (dlPFC) cortex and dorsal anterior cingulate cortex (dACC) during a task that interleaves motor and perceptual conflict trials, the multisource interference task (MSIT). In both brain regions, variability in pre-trial firing rates predicted subsequent reaction time (RT) on conflict trials. In dlPFC, ensemble firing rate patterns suggested the existence of domain-specific initial states, while in dACC, firing patterns were more consistent with a domain-general initial state. The deployment of shared and independent factors that we observe for conflict resolution may allow for flexible and fast responses mediated by cognitive initial states. These results also support hypotheses that place dACC hierarchically earlier than dlPFC in proactive control.

Semi-orthogonal subspaces for value mediate a tradeoff between binding and generalization.

When choosing between options, we must associate their values with the action needed to select them. We hypothesize that the brain solves this binding problem through neural population subspaces. To test this hypothesis, we examined neuronal responses in five reward-sensitive regions in macaques performing a risky choice task with sequential offers. Surprisingly, in all areas, the neural population encoded the values of offers presented on the left and right in distinct subspaces. We show that the encoding we observe is sufficient to bind the values of the offers to their respective positions in space while preserving abstract value information, which may be important for rapid learning and generalization to novel contexts. Moreover, after both offers have been presented, all areas encode the value of the first and second offers in orthogonal subspaces. In this case as well, the orthogonalization provides binding. Our binding-by-subspace hypothesis makes two novel predictions borne out by the data. First, behavioral errors should correlate with putative spatial (but not temporal) misbinding in the neural representation. Second, the specific representational geometry that we observe across animals also indicates that behavioral errors should increase when offers have low or high values, compared to when they have medium values, even when controlling for value difference. Together, these results support the idea that the brain makes use of semi-orthogonal subspaces to bind features together.

OpenMonkeyChallenge: Dataset and Benchmark Challenges for Pose Estimation of Non-human Primates.

The ability to automatically estimate the pose of non-human primates as they move through the world is important for several subfields in biology and biomedicine. Inspired by the recent success of computer vision models enabled by benchmark challenges (e.g., object detection), we propose a new benchmark challenge called OpenMonkeyChallenge that facilitates collective community efforts through an annual competition to build generalizable non-human primate pose estimation models. To host the benchmark challenge, we provide a new public dataset consisting of 111,529 annotated (17 body landmarks) photographs of non-human primates in naturalistic contexts obtained from various sources including the Internet, three National Primate Research Centers, and the Minnesota Zoo. Such annotated datasets will be used for the training and testing datasets to develop generalizable models with standardized evaluation metrics. We demonstrate the effectiveness of our dataset quantitatively by comparing it with existing datasets based on seven state-of-the-art pose estimation models.

Hierarchical organization of rhesus macaque behavior.

Primatologists, psychologists and neuroscientists have long hypothesized that primate behavior is highly structured. However, delineating that structure has been impossible due to the difficulties of precision behavioral tracking. Here we analyzed a dataset consisting of continuous measures of the 3D position of two male rhesus macaques (Macaca mulatta) performing three different tasks in a large unrestrained environment over several hours. Using an unsupervised embedding approach on the tracked joints, we identified commonly repeated pose patterns, which we call postures. We found that macaques' behavior is characterized by 49 distinct postures, lasting an average of 0.6 seconds. We found evidence that behavior is hierarchically organized, in that transitions between poses tend to occur within larger modules, which correspond to identifiable actions; these actions are further organized hierarchically. Our behavioral decomposition allows us to identify universal (cross-individual and cross-task) and unique (specific to each individual and task) principles of behavior. These results demonstrate the hierarchical nature of primate behavior, provide a method for the automated ethogramming of primate behavior, and provide important constraints on neural models of pose generation.

Widespread coding of navigational variables in prefrontal cortex.

To navigate effectively, we must represent information about our location in the environment. Traditional research highlights the role of the hippocampal complex in this process. Spurred by recent research highlighting the widespread cortical encoding of cognitive and motor variables previously thought to have localized function, we hypothesized that navigational variables would be likewise encoded widely, especially in the prefrontal cortex, which is associated with volitional behavior. We recorded neural activity from six prefrontal regions while macaques performed a foraging task in an open enclosure. In all regions, we found strong encoding of allocentric position, allocentric head direction, boundary distance, and linear and angular velocity. These encodings were not accounted for by distance, time to reward, or motor factors. The strength of coding of all variables increased along a ventral-to-dorsal gradient. Together, these results argue that encoding of navigational variables is not localized to the hippocampus and support the hypothesis that navigation is continuous with other forms of flexible cognition in the service of action.

Abstract Value Encoding in Neural Populations But Not Single Neurons.

An important open question in neuroeconomics is how the brain represents the value of offers in a way that is both abstract (allowing for comparison) and concrete (preserving the details of the factors that influence value). Here, we examine neuronal responses to risky and safe options in five brain regions that putatively encode value in male macaques. Surprisingly, we find no detectable overlap in the neural codes used for risky and safe options, even when the options have identical subjective values (as revealed by preference) in any of the regions. Indeed, responses are weakly correlated and occupy distinct (semi-orthogonal) encoding subspaces. Notably, however, these subspaces are linked through a linear transform of their constituent encodings, a property that allows for comparison of dissimilar option types. This encoding scheme allows these regions to multiplex decision related processes: they can encode the detailed factors that influence offer value (here, risky and safety) but also directly compare dissimilar offer types. Together these results suggest a neuronal basis for the qualitatively different psychological properties of risky and safe options and highlight the power of population geometry to resolve outstanding problems in neural coding.SIGNIFICANCE STATEMENT To make economic choices, we must have some mechanism for comparing dissimilar offers. We propose that the brain uses distinct neural codes for risky and safe offers, but that these codes are linearly transformable. This encoding scheme has the dual advantage of allowing for comparison across offer types while preserving information about offer type, which in turn allows for flexibility in changing circumstances. We show that responses to risky and safe offers exhibit these predicted properties in five different reward-sensitive regions. Together, these results highlight the power of population coding principles for solving representation problems in economic choice.

Subspace orthogonalization as a mechanism for binding values to space.

When choosing between options, we must solve an important binding problem. The values of the options must be associated with information about the action needed to select them. We hypothesize that the brain solves this binding problem through use of distinct population subspaces. To test this hypothesis, we examined the responses of single neurons in five reward-sensitive regions in rhesus macaques performing a risky choice task. In all areas, neurons encoded the value of the offers presented on both the left and the right side of the display in semi-orthogonal subspaces, which served to bind the values of the two offers to their positions in space. Supporting the idea that this orthogonalization is functionally meaningful, we observed a session-to-session covariation between choice behavior and the orthogonalization of the two value subspaces: trials with less orthogonalized subspaces were associated with greater likelihood of choosing the less valued option. Further inspection revealed that these semi-orthogonal subspaces arose from a combination of linear and nonlinear mixed selectivity in the neural population. We show this combination of selectivity balances reliable binding with an ability to generalize value across different spatial locations. These results support the hypothesis that semi-orthogonal subspaces support reliable binding, which is essential to flexible behavior in the face of multiple options.

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.

Distinct population and single-neuron selectivity for executive and episodic processing in human dorsal posterior cingulate.

Posterior cingulate cortex (PCC) is an enigmatic region implicated in psychiatric and neurological disease, yet its role in cognition remains unclear. Human studies link PCC to episodic memory and default mode network (DMN), while findings from the non-human primate emphasize executive processes more associated with the cognitive control network (CCN) in humans. We hypothesized this difference reflects an important functional division between dorsal (executive) and ventral (episodic) PCC. To test this, we utilized human intracranial recordings of population and single unit activity targeting dorsal PCC during an alternated executive/episodic processing task. Dorsal PCC population responses were significantly enhanced for executive, compared to episodic, task conditions, consistent with the CCN. Single unit recordings, however, revealed four distinct functional types with unique executive (CCN) or episodic (DMN) response profiles. Our findings provide critical electrophysiological data from human PCC, bridging incongruent views within and across species, furthering our understanding of PCC function.

Macaques preferentially attend to intermediately surprising information.

Normative learning theories dictate that we should preferentially attend to informative sources, but only up to the point that our limited learning systems can process their content. Humans, including infants, show this predicted strategic deployment of attention. Here, we demonstrate that rhesus monkeys, much like humans, attend to events of moderate surprisingness over both more and less surprising events. They do this in the absence of any specific goal or contingent reward, indicating that the behavioural pattern is spontaneous. We suggest this U-shaped attentional preference represents an evolutionarily preserved strategy for guiding intelligent organisms toward material that is maximally useful for learning.

The Promise of Behavioral Tracking Systems for Advancing Primate Animal Welfare.

Recent years have witnessed major advances in the ability of computerized systems to track the positions of animals as they move through large and unconstrained environments. These systems have so far been a great boon in the fields of primatology, psychology, neuroscience, and biomedicine. Here, we discuss the promise of these technologies for animal welfare. Their potential benefits include identifying and reducing pain, suffering, and distress in captive populations, improving laboratory animal welfare within the context of the three Rs of animal research (reduction, refinement, and replacement), and applying our understanding of animal behavior to increase the "natural" behaviors in captive and wild populations facing human impact challenges. We note that these benefits are often incidental to the designed purpose of these tracking systems, a reflection of the fact that animal welfare is not inimical to research progress, but instead, that the aligned interests between basic research and welfare hold great promise for improvements to animal well-being.

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.