Dorsal hippocampus represents locations to avoid as well as locations to approach during approach-avoidance conflict.

Worrying about perceived threats is a hallmark of multiple psychological disorders including anxiety. This concern about future events is particularly important when an individual is faced with an approach-avoidance conflict. Potential goals to approach are known to be represented in the dorsal hippocampus during theta sweeps. Similarly, important non-local information is represented during hippocampal high synchrony events (HSEs), which are correlated with sharp-wave ripples (SWRs). It is likely that potential future threats may be similarly represented. We examined how threats and rewards were represented within the hippocampus during approach-avoidance conflicts in rats faced with a predator-like robot guarding a food reward. We found representations of the pseudo-predator during HSEs when hesitating in the nest, and during theta prior to retreating as the rats approached the pseudo-predator. After the first attack, we observed new place fields appearing at the location of the robot (not the location the rat was when attacked). The anxiolytic diazepam reduced anxiety-like behavior and altered hippocampal local field potentials, including reducing SWRs, suggesting that one potential mechanism of diazepam's actions may be through altered representations of imagined threat. These results suggest that hippocampal representation of potential threats could be an important mechanism that underlies worry and a potential target for anxiolytics.

Measuring excitation-inhibition balance through spectral components of local field potentials.

The balance between excitation and inhibition is critical to brain functioning, and dysregulation of this balance is a hallmark of numerous psychiatric conditions. Measuring this excitation-inhibition (E:I) balance in vivo has remained difficult, but theoretical models have proposed that characteristics of local field potentials (LFP) may provide an accurate proxy. To establish a conclusive link between LFP and E:I balance, we recorded single units and LFP from the prefrontal cortex (mPFC) of rats during decision making. Dynamic measures of synaptic coupling strength facilitated direct quantification of E:I balance and revealed a strong inverse relationship to broadband spectral power of LFP. These results provide a critical link between LFP and underlying network properties, opening the door for non-invasive recordings to measure E:I balance in clinical settings.

Clarifying Cognitive Control Deficits in Psychosis via Drift Diffusion Modeling and Attractor Dynamics.

BACKGROUND AND HYPOTHESIS: Cognitive control deficits are prominent in individuals with psychotic psychopathology. Studies providing evidence for deficits in proactive control generally examine average performance and not variation across trials for individuals-potentially obscuring detection of essential contributors to cognitive control. Here, we leverage intertrial variability through drift-diffusion models (DDMs) aiming to identify key contributors to cognitive control deficits in psychosis. STUDY DESIGN: People with psychosis (PwP; N = 122), their first-degree biological relatives (N = 78), and controls (N = 50) each completed 120 trials of the dot pattern expectancy (DPX) cognitive control task. We fit full hierarchical DDMs to response and reaction time (RT) data for individual trials and then used classification models to compare the DDM parameters with conventional measures of proactive and reactive control. STUDY RESULTS: PwP demonstrated slower drift rates on proactive control trials suggesting less efficient use of cue information. Both PwP and relatives showed protracted nondecision times to infrequent trial sequences suggesting slowed perceptual processing. Classification analyses indicated that DDM parameters differentiated between the groups better than conventional measures and identified drift rates during proactive control, nondecision time during reactive control, and cue bias as most important. DDM parameters were associated with real-world functioning and schizotypal traits. CONCLUSIONS: Modeling of trial-level data revealed that slow evidence accumulation and longer preparatory periods are the strongest contributors to cognitive control deficits in psychotic psychopathology. This pattern of atypical responding during the DPX is consistent with shallow basins in attractor dynamic models that reflect difficulties in maintaining state representations, possibly mediated by excess neural excitation or poor connectivity.

Reward prediction-errors weighted by cue salience produces addictive behaviours in simulations, with asymmetrical learning and steeper delay discounting.

Dysfunction in learning and motivational systems are thought to contribute to addictive behaviours. Previous models have suggested that dopaminergic roles in learning and motivation could produce addictive behaviours through pharmacological manipulations that provide excess dopaminergic signalling towards these learning and motivational systems. Redish (2004) suggested a role based on dopaminergic signals of value prediction error, while (Zhang et al., 2009) suggested a role based on dopaminergic signals of motivation. However, both models present significant limitations. They do not explain the reduced sensitivity to drug-related costs/negative consequences, the increased impulsivity generally found in people with a substance use disorder, craving behaviours, and non-pharmacological dependence, all of which are key hallmarks of addictive behaviours. Here, we propose a novel mathematical definition of salience, that combines aspects of dopamine's role in both learning and motivation within the reinforcement learning framework. Using a single parameter regime, we simulated addictive behaviours that the (Zhang et al., 2009; Redish, 2004) models also produce but we went further in simulating the downweighting of drug-related negative prediction-errors, steeper delay discounting of drug rewards, craving behaviours and aspects of behavioural/non-pharmacological addictions. The current salience model builds on our recently proposed conceptual theory that salience modulates internal representation updating and may contribute to addictive behaviours by producing misaligned internal representations (Kalhan et al., 2021). Critically, our current mathematical model of salience argues that the seemingly disparate learning and motivational aspects of dopaminergic functioning may interact through a salience mechanism that modulates internal representation updating.

Clarifying Cognitive Control Deficits in Psychosis via Drift Diffusion Modeling.

Cognitive control deficits are consistently identified in individuals with schizophrenia and other psychotic psychopathologies. In this analysis, we delineated proactive and reactive control deficits in psychotic psychopathology via hierarchical Drift Diffusion Modeling (hDDM). People with psychosis (PwP; N=123), their first-degree relatives (N=79), and controls (N=51) completed the Dot Pattern Expectancy task, which allows differentiation between proactive and reactive control. PwP demonstrated slower drift rates on proactive control trials suggesting less efficient use of cue information for proactive control. They also showed longer non-decision times than controls on infrequent stimuli sequences suggesting slower perceptual processing. An explainable machine learning analysis indicated that the hDDM parameters were able to differentiate between the groups better than conventional measures. Through DDM, we found that cognitive control deficits in psychosis are characterized by slower motor/perceptual time and slower evidence-integration primarily in proactive control.

Strategy dependent recruitment of distributed cortical circuits during spatial navigation.

Spatial navigation is a complex cognitive process that involves neural computations in distributed regions of the brain. Little is known about how cortical regions are coordinated when animals navigate novel spatial environments or how that coordination changes as environments become familiar. We recorded mesoscale calcium (Ca2+) dynamics across large swathes of the dorsal cortex in mice solving the Barnes maze, a 2D spatial navigation task where mice used random, serial, and spatial search strategies to navigate to the goal. Cortical dynamics exhibited patterns of repeated calcium activity with rapid and abrupt shifts between cortical activation patterns at sub-second time scales. We used a clustering algorithm to decompose the spatial patterns of cortical calcium activity in a low dimensional state space, identifying 7 states, each corresponding to a distinct spatial pattern of cortical activation, sufficient to describe the cortical dynamics across all the mice. When mice used serial or spatial search strategies to navigate to the goal, the frontal regions of the cortex were reliably activated for prolonged durations of time (> 1s) shortly after trial initiation. These frontal cortex activation events coincided with mice approaching the edge of the maze from the center and were preceded by temporal sequences of cortical activation patterns that were distinct for serial and spatial search strategies. In serial search trials, frontal cortex activation events were preceded by activation of the posterior regions of the cortex followed by lateral activation of one hemisphere. In spatial search trials, frontal cortical events were preceded by activation of posterior regions of the cortex followed by broad activation of the lateral regions of the cortex. Our results delineated cortical components that differentiate goal- and non-goal oriented spatial navigation strategies.

Distinct mesoscale cortical dynamics encode search strategies during spatial navigation.

Spatial navigation is a complex cognitive process that involves neural computations in distributed regions of the brain. Little is known about how cortical regions are coordinated when animals navigate novel spatial environments or how that coordination changes as environments become familiar. We recorded mesoscale calcium (Ca2+) dynamics across large swathes of the dorsal cortex in mice solving the Barnes maze, a 2D spatial navigation task where mice used random, serial, and spatial search strategies to navigate to the goal. Cortical dynamics exhibited patterns of repeated calcium activity with rapid and abrupt shifts between cortical activation patterns at sub-second time scales. We used a clustering algorithm to decompose the spatial patterns of cortical calcium activity in a low dimensional state space, identifying 7 states, each corresponding to a distinct spatial pattern of cortical activation, sufficient to describe the cortical dynamics across all the mice. When mice used serial or spatial search strategies to navigate to the goal, the frontal regions of the cortex were reliably activated for prolonged durations of time (> 1s) shortly after trial initiation. These frontal cortex activation events coincided with mice approaching the edge of the maze from the center and were preceded by temporal sequences of cortical activation patterns that were distinct for serial and spatial search strategies. In serial search trials, frontal cortex activation events were preceded by activation of the posterior regions of the cortex followed by lateral activation of one hemisphere. In spatial search trials, frontal cortical events were preceded by activation of posterior regions of the cortex followed by broad activation of the lateral regions of the cortex. Our results delineated cortical components that differentiate goal- and non-goal oriented spatial navigation strategies.

Human generalization of internal representations through prototype learning with goal-directed attention.

The world is overabundant with feature-rich information obscuring the latent causes of experience. How do people approximate the complexities of the external world with simplified internal representations that generalize to novel examples or situations? Theories suggest that internal representations could be determined by decision boundaries that discriminate between alternatives, or by distance measurements against prototypes and individual exemplars. Each provide advantages and drawbacks for generalization. We therefore developed theoretical models that leverage both discriminative and distance components to form internal representations via action-reward feedback. We then developed three latent-state learning tasks to test how humans use goal-oriented discrimination attention and prototypes/exemplar representations. The majority of participants attended to both goal-relevant discriminative features and the covariance of features within a prototype. A minority of participants relied only on the discriminative feature. Behaviour of all participants could be captured by parameterizing a model combining prototype representations with goal-oriented discriminative attention.

Optogenetic disruption of the prelimbic cortex alters long-term decision strategy but not valuation on a spatial delay discounting task.

Rats demonstrate a preference for smaller, immediate rewards over larger, delayed ones, a phenomenon known as delay-discounting (DD). Behavior arises from the interaction of multiple decision-making systems, and the medial prefrontal cortex (mPFC) has been identified as a central component in the mediation between these decision systems. To investigate the role of the prelimbic (PL) subregion of mPFC on decision strategy interaction, we compared two cohorts of rats (ChR2-opsin-expressing 'Active' and opsin-absent 'Control') on a spatial delay-discounting task while delivering in-vivo light stimulation into PL at the choice point of select trials. By analyzing the overall delay-adjustment along with deliberative and procedural behavioral strategy markers, our study revealed differences in the decision strategies used between the active and control animals despite both groups showing similar valuations. Control animals developed the expected shift from deliberative to procedural decision strategy on this task (indicated by reaching delay-stability, particularly during late-session laps); however, active-virus animals repeatedly over-adjusted around their preferred delay throughout the entire session, suggesting a significant deficit in procedural decision-making on this task. Active animals showed a significant decrease in proportion of vicarious trial and error events (VTE, a behavior correlated with deliberative processes) on delay adjustment laps relative to control animals. This points to a more nuanced role for VTE, not just in executing deliberation, but in shifting from deliberative to procedural processes. This opto-induced change in VTE was especially pronounced for late-session adjustment laps. We found no other session-by-session or lap-by-lap effects, leaving a particular role for PL in the long-term development of procedural strategies on this task.

On the Role of Theory and Modeling in Neuroscience.

In recent years, the field of neuroscience has gone through rapid experimental advances and a significant increase in the use of quantitative and computational methods. This growth has created a need for clearer analyses of the theory and modeling approaches used in the field. This issue is particularly complex in neuroscience because the field studies phenomena that cross a wide range of scales and often require consideration at varying degrees of abstraction, from precise biophysical interactions to the computations they implement. We argue that a pragmatic perspective of science, in which descriptive, mechanistic, and normative models and theories each play a distinct role in defining and bridging levels of abstraction, will facilitate neuroscientific practice. This analysis leads to methodological suggestions, including selecting a level of abstraction that is appropriate for a given problem, identifying transfer functions to connect models and data, and the use of models themselves as a form of experiment.

Differential processing of decision information in subregions of rodent medial prefrontal cortex.

Decision-making involves multiple cognitive processes requiring different aspects of information about the situation at hand. The rodent medial prefrontal cortex (mPFC) has been hypothesized to be central to these abilities. Functional studies have sought to link specific processes to specific anatomical subregions, but past studies of mPFC have yielded controversial results, leaving the precise nature of mPFC function unclear. To settle this debate, we recorded from the full dorso-ventral extent of mPFC in each of 8 rats, as they performed a complex economic decision task. These data revealed four distinct functional domains within mPFC that closely mirrored anatomically identified subregions, including novel evidence to divide prelimbic cortex into dorsal and ventral components. We found that dorsal aspects of mPFC (ACC, dPL) were more involved in processing information about active decisions, while ventral aspects (vPL, IL) were more engaged in motivational factors.

Sunk cost sensitivity during change-of-mind decisions is informed by both the spent and remaining costs.

Sunk cost sensitivity describes escalating decision commitment with increased spent resources. On neuroeconomic foraging tasks, mice, rats, and humans show similar escalations from sunk costs while quitting an ongoing countdown to reward. In a new analysis taken across computationally parallel foraging tasks across species and laboratories, we find that these behaviors primarily occur on choices that are economically inconsistent with the subject's other choices, and that they reflect not only the time spent, but also the time remaining, suggesting that these are change-of-mind re-evaluation processes. Using a recently proposed change-of-mind drift-diffusion model, we find that the sunk cost sensitivity in this model arises from decision-processes that directly take into account the time spent (costs sunk). Applying these new insights to experimental data, we find that sensitivity to sunk costs during re-evaluation decisions depends on the information provided to the subject about the time spent and the time remaining.

Etiopathogenic Models of Psychosis Spectrum Illnesses Must Resolve Four Key Features.

Etiopathogenic models for psychosis spectrum illnesses are converging on a number of key processes, such as the influence of specific genes on the synthesis of proteins important in synaptic functioning, alterations in how neurons respond to synaptic inputs and engage in synaptic pruning, and microcircuit dysfunction that leads to more global cortical information processing vulnerabilities. Disruptions in prefrontal operations then accumulate and propagate over time, interacting with environmental factors, developmental processes, and homeostatic mechanisms, eventually resulting in symptoms of psychosis and disability. However, there are 4 key features of psychosis spectrum illnesses that are of primary clinical relevance but have been difficult to assimilate into a single model and have thus far received little direct attention: 1) the bidirectionality of the causal influences for the emergence of psychosis, 2) the catastrophic clinical threshold seen in first episodes of psychosis and why it is irreversible in some individuals, 3) observed biotypes that are neurophysiologically distinct but clinically both convergent and divergent, and 4) a reconciliation of the role of striatal dopaminergic dysfunction with models of prefrontal cortical state instability. In this selective review, we briefly describe these 4 hallmark features and we argue that theoretically driven computational perspectives making use of both algorithmic and neurophysiologic models are needed to reduce this complexity and variability of psychosis spectrum illnesses in a principled manner.

Beyond Description and Deficits: How Computational Psychiatry Can Enhance an Understanding of Decision-Making in Anorexia Nervosa.

PURPOSE OF REVIEW: Despite decades of research, knowledge of the mechanisms maintaining anorexia nervosa (AN) remains incomplete and clearly effective treatments elusive. Novel theoretical frameworks are needed to advance mechanistic and treatment research for this disorder. Here, we argue the utility of engaging a novel lens that differs from existing perspectives in psychiatry. Specifically, we argue the necessity of expanding beyond two historically common perspectives: (1) the descriptive perspective: the tendency to define mechanisms on the basis of surface characteristics and (2) the deficit perspective: the tendency to search for mechanisms associated with under-functioning of decision-making abilities and related circuity, rather than problems of over-functioning, in psychiatric disorders. RECENT FINDINGS: Computational psychiatry can provide a novel framework for understanding AN because this approach emphasizes the role of computational misalignments (rather than absolute deficits or excesses) between decision-making strategies and environmental demands as the key factors promoting psychiatric illnesses. Informed by this approach, we argue that AN can be understood as a disorder of excess goal pursuit, maintained by over-engagement, rather than disengagement, of executive functioning strategies and circuits. Emerging evidence suggests that this same computational imbalance may constitute an under-investigated phenotype presenting transdiagnostically across psychiatric disorders. A variety of computational models can be used to further elucidate excess goal pursuit in AN. Most traditional psychiatric treatments do not target excess goal pursuit or associated neurocognitive mechanisms. Thus, targeting at the level of computational dysfunction may provide a new avenue for enhancing treatment for AN and related disorders.

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'.

Dorsolateral Striatal Task-initiation Bursts Represent Past Experiences More than Future Action Plans.

The dorsolateral striatum (DLS) is involved in learning and executing procedural actions. Cell ensembles in the DLS, but not the dorsomedial striatum (DMS), exhibit a burst of firing at the start of a well-learned action sequence ("task-bracketing"). However, it is currently unclear what information is contained in these bursts. Some theories suggest that these bursts should represent the procedural action sequence itself (that they should be about future action chains), whereas others suggest that they should contain representations of the current state of the world, taking into account primarily past information. In addition, the DLS local field potential shows transient bursts of power in the 50 Hz range (γ50) around the time a learned action sequence is initiated. However, it is currently unknown how bursts of activity in DLS cell ensembles and bursts of γ50 power in the DLS local field potential are related to each other. We found that DLS bursts at lap initiation in rats represented recently experienced reward locations more than future procedural actions, indicating that task-initiation DLS bursts contain primarily retrospective, rather than prospective, information to guide procedural actions. Furthermore, representations of past reward locations increased during periods of increased γ50 power in the DLS. There was no evidence of task-initiation bursts, increased γ50 power, or retrospective reward location information in the neighboring dorsomedial striatum. These data support a role for the DLS in model-free theories of procedural decision-making over planned action-chain theories, suggesting that procedural actions derive from representations of the current and recent past.SIGNIFICANCE STATEMENT While it is well-established that the dorsolateral striatum (DLS) plays a critical role in procedural decision-making, open questions remain about the kinds of representations contained in DLS ensemble activity that guide procedural actions. We found that DLS, but not DMS, cell ensembles contained nonlocal representations of past reward locations that appear moments before task-initiation DLS bursts. These retrospective representations were temporally linked to a rise in γ50 power that also preceded the characteristic DLS burst at task-initiation. These results support models of procedural decision-making based on associations between available actions and the current state of the world over models based on planning over action-chains.

Certainty and uncertainty of the future changes planning and sunk costs.

Many foraging experiments have found that subjects are suboptimal in foraging tasks, waiting out delays longer than they should given the reward structure of the environment. Additionally, theories of decision-making suggest that actions arise from interactions between multiple decision-making systems and that these systems should depend on the availability of information about the future. To explore suboptimal behavior on foraging tasks and how varying the amount of future information changed behavior, we ran rats on two matching neuroeconomic foraging tasks, Known Delay (KD) and Randomized Delay (RD), with the only difference between them being the certainty of the cost of future opportunities. Rats' decision-making strategies differed significantly based on the amount of future certainty. Rats on both tasks still showed suboptimality in decision-making through a sensitivity to sunk costs; however, rats on KD showed significantly less sensitivity to sunk costs than rats on RD. Additionally, on neither task did the rats account for travel and postreward lingering times as heavily as prereward foraging times providing evidence problematic for the Marginal Value Theorem model of foraging behavior. This suggests that while future certainty reduced decision-making errors, more complex decision-making processes unaffected by future certainty were involved and likely produced these decision-making errors within subjects on these foraging tasks. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Disrupting the medial prefrontal cortex with designer receptors exclusively activated by designer drug alters hippocampal sharp-wave ripples and their associated cognitive processes.

The hippocampus and medial prefrontal cortex (mPFC) interact during a myriad of cognitive processes including decision-making and long-term memory consolidation. Exactly how the mPFC and hippocampus interact during goal-directed decision-making remains to be fully elucidated. During periods of rest, bursts of high-frequency oscillations, termed sharp-wave ripple (SWR), appear in the local field potential. Impairing SWRs on the maze or during post-learning rest can interfere with memory-guided decision-making and memory consolidation. We hypothesize that the hippocampus and mPFC bidirectionally interact during SWRs to support memory consolidation and decision-making. Rats were trained on the neuroeconomic spatial decision-making task, Restaurant Row, to make serial stay-skip decisions where the amount of effort (delay to reward) varied upon entry to each restaurant. Hippocampal cells and SWRs were recorded in rats with the mPFC transduced with inhibitory DREADDs. We found that disrupting the mPFC impaired consolidating SWRs in the hippocampus. Hippocampal SWR rates depended on the internalized value of the reward (derived from individual flavor preferences), a parameter important in decision-making, and disrupting the mPFC changed this relationship. Additionally, we found a dissociation between SWRs that occurred while rats were on the maze dependent upon whether those SWRs occurred while the rat was anticipating food reward or during post-reward consumption.

Global disruption in excitation-inhibition balance can cause localized network dysfunction and Schizophrenia-like context-integration deficits.

Poor context integration, the process of incorporating both previous and current information in decision making, is a cognitive symptom of schizophrenia. The maintenance of the contextual information has been shown to be sensitive to changes in excitation-inhibition (EI) balance. Many regions of the brain are sensitive to EI imbalances, however, so it is unknown how systemic manipulations affect the specific regions that are important to context integration. We constructed a multi-structure, biophysically-realistic agent that could perform context-integration as is assessed by the dot pattern expectancy task. The agent included a perceptual network, a memory network, and a decision making system and was capable of successfully performing the dot pattern expectancy task. Systemic manipulation of the agent's EI balance produced localized dysfunction of the memory structure, which resulted in schizophrenia-like deficits at context integration. When the agent's pyramidal cells were less excitatory, the agent fixated upon the cue and initiated responding later than the default agent, which were like the deficits one would predict that individuals on the autistic spectrum would make. This modelling suggests that it may be possible to parse between different types of context integration deficits by adding distractors to context integration tasks and by closely examining a participant's reaction times.

Considerations for Pairing Cognitive Behavioral Therapies and Non-invasive Brain Stimulation: Ignore at Your Own Risk.

Multimodal approaches combining cognitive behavioral therapies (CBT) with non-invasive brain stimulation (NIBS) hold promise for improving the treatment of neuropsychiatric disorders. As this is a relatively new approach, it is a critical time to identify guiding principles and methodological considerations to enhance research rigor. In the current paper, we argue for a principled approach to CBT and NIBS pairings based on synergistic activation of neural circuits and identify key considerations about CBT that may influence pairing with NIBS. Careful consideration of brain-state interactions and CBT-related nuances will increase the potential for these combinations to be positively synergistic.