Monkey Prefrontal Cortex Learns to Minimize Sequence Prediction Error.

In this study, we develop a novel recurrent neural network (RNN) model of pre-frontal cortex that predicts sensory inputs, actions, and outcomes at the next time step. Synaptic weights in the model are adjusted to minimize sequence prediction error, adapting a deep learning rule similar to those of large language models. The model, called Sequence Prediction Error Learning (SPEL), is a simple RNN that predicts world state at the next time step, but that differs from standard RNNs by using its own prediction errors from the previous state predictions as inputs to the hidden units of the network.

A prefrontal network model operating near steady and oscillatory states links spike desynchronization and synaptic deficits in schizophrenia.

Schizophrenia results in part from a failure of prefrontal networks but we lack full understanding of how disruptions at a synaptic level cause failures at the network level. This is a crucial gap in our understanding because it prevents us from discovering how genetic mutations and environmental risks that alter synaptic function cause prefrontal network to fail in schizophrenia. To address that question, we developed a recurrent spiking network model of prefrontal local circuits that can explain the link between NMDAR synaptic and 0-lag spike synchrony deficits we recently observed in a pharmacological monkey model of prefrontal network failure in schizophrenia.

Shared Neural Activity But Distinct Neural Dynamics for Cognitive Control in Monkey Prefrontal and Parietal Cortex.

To better understand how prefrontal networks mediate forms of cognitive control disrupted in schizophrenia, we translated a variant of the AX continuous performance task that measures specific deficits in the human disease to 2 male monkeys and recorded neurons in PFC and parietal cortex during task performance. In the task, contextual information instructed by cue stimuli determines the response required to a subsequent probe stimulus. We found parietal neurons encoding the behavioral context instructed by cues that exhibited nearly identical activity to their prefrontal counterparts (Blackman et al.

Comparing the functional neuroanatomy of proactive and reactive control between patients with schizophrenia and healthy controls.

Cognitive control deficits are associated with impaired executive functioning in schizophrenia. The Dual Mechanisms of Control framework suggests that proactive control requires sustained dorsolateral prefrontal activity, whereas reactive control marshals a larger network. However, primate studies suggest these processes are maintained by dual-encoding regions.

Psychosis spectrum illnesses as disorders of prefrontal critical period plasticity.

Emerging research on neuroplasticity processes in psychosis spectrum illnesses-from the synaptic to the macrocircuit levels-fill key gaps in our models of pathophysiology and open up important treatment considerations. In this selective narrative review, we focus on three themes, emphasizing alterations in spike-timing dependent and Hebbian plasticity that occur during adolescence, the critical period for prefrontal system development: (1) Experience-dependent dysplasticity in psychosis emerges from activity decorrelation within neuronal ensembles. (2) Plasticity processes operate bidirectionally: deleterious environmental and experiential inputs shape microcircuits.

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.

Disparate insults relevant to schizophrenia converge on impaired spike synchrony and weaker synaptic interactions in prefrontal local circuits.

Schizophrenia results from hundreds of known causes, including genetic, environmental, and developmental insults that cooperatively increase risk of developing the disease. In spite of the diversity of causal factors, schizophrenia presents with a core set of symptoms and brain abnormalities (both structural and functional) that particularly impact the prefrontal cortex. This suggests that many different causal factors leading to schizophrenia may cause prefrontal neurons and circuits to fail in fundamentally similar ways.

If I do A, B will happen: Dissecting circuits detecting causal relations between actions and outcomes in marmoset prefrontal cortex.

In this issue of Neuron, Duan et al. (2021) use pharmacological manipulation to reveal opposing influences of anterior cingulate and orbitofrontal cortex of marmosets on decisions that are based on action-outcome associations.

A View from the Top: Prefrontal Control of Object Recognition.

In this issue of Neuron, Kar and DiCarlo (2021) demonstrate that feedback from ventrolateral prefrontal cortex (VLPFC) to inferotemporal cortex (IT) is required for object recognition. They show that inactivating VLPFC selectively degrades object recognition performance and population encoding of object identity in IT.

Cognitive Control Errors in Nonhuman Primates Resembling Those in Schizophrenia Reflect Opposing Effects of NMDA Receptor Blockade on Causal Interactions Between Cells and Circuits in Prefrontal and Parietal Cortices.

Background: The causal biology underlying schizophrenia is not well understood, but it is likely to involve a malfunction in how neurons adjust synaptic connections in response to patterns of activity in networks. We examined statistical dependencies between neural signals at the cell, local circuit, and distributed network levels in prefrontal and parietal cortices of monkeys performing a variant of the AX continuous performance task paradigm. We then quantified changes in the pattern of neural interactions across levels of scale following NMDA receptor (NMDAR) blockade and related these changes to a pattern of cognitive control errors closely matching the performance of patients with schizophrenia.

Differential Roles of Mediodorsal Nucleus of the Thalamus and Prefrontal Cortex in Decision-Making and State Representation in a Cognitive Control Task Measuring Deficits in Schizophrenia.

The mediodorsal nucleus of the thalamus (MD) is reciprocally connected with the prefrontal cortex (PFC), and although the MD has been implicated in a range of PFC-dependent cognitive functions (Watanabe and Funahashi, 2012; Mitchell and Chakraborty, 2013; Parnaudeau et al., 2018), little is known about how MD neurons in the primate participate specifically in cognitive control, a capability that reflects the ability to use contextual information (such as a rule) to modify responses to environmental stimuli. To learn how the MD-PFC thalamocortical network is engaged to mediate forms of cognitive control that are selectively disrupted in schizophrenia, we trained male monkeys to perform a variant of the AX continuous performance task, which reliably measures cognitive control deficits in patients (Henderson et al.

Learning How Neurons Fail Inside of Networks: Nonhuman Primates Provide Critical Data for Psychiatry.

Advancing psychiatry requires understanding brain malfunction at a microscopic scale, where neurons and synapses operate under constraints imposed by behavior, cognition, and neural architecture. Nonhuman primates are unmatched in approximating the structural and computational environment of the human brain.

Blocking NMDAR Disrupts Spike Timing and Decouples Monkey Prefrontal Circuits: Implications for Activity-Dependent Disconnection in Schizophrenia.

We employed multi-electrode array recording to evaluate the influence of NMDA receptors (NMDAR) on spike-timing dynamics in prefrontal networks of monkeys as they performed a cognitive control task measuring specific deficits in schizophrenia. Systemic, periodic administration of an NMDAR antagonist (phencyclidine) reduced the prevalence and strength of synchronous (0-lag) spike correlation in simultaneously recorded neuron pairs. We employed transfer entropy analysis to measure effective connectivity between prefrontal neurons at lags consistent with monosynaptic interactions and found that effective connectivity was persistently reduced following exposure to the NMDAR antagonist.

Abnormal cortical neural synchrony during working memory in schizophrenia.

Objective: To better understand the origins of working memory (WM) impairment in schizophrenia we investigated cortical oscillatory activity in people with schizophrenia (PSZ) while they performed a WM task requiring encoding, maintenance, and retrieval/manipulation processes of spatial information.

Methods: We examined time-frequency synchronous energy of cortical source signals that were derived from magnetoencephalography (MEG) localized to cortical regions using WM-related hemodynamic responses and individualized structural head-models.

Results: Compared to thirteen healthy controls (HC), twelve PSZ showed performance deficits regardless of WM-load or duration.

Implicit and Explicit Learning Mechanisms Meet in Monkey Prefrontal Cortex.

In this issue, Loonis et al. (2017) provide the first description of unique synchrony patterns differentiating implicit and explicit forms of learning in monkey prefrontal networks. Their results have broad implications for how prefrontal networks integrate the two learning mechanisms to control behavior.

Using model systems to understand errant plasticity mechanisms in psychiatric disorders.

In vivo model systems are a critical tool for gaining insight into the pathology underlying psychiatric disorders. Although modern functional imaging tools allow study of brain correlates of behavior in clinical groups and genome-wide association studies are beginning to uncover the complex genetic architecture of psychiatric disorders, there is less understanding of pathology at intervening levels of organization. Several psychiatric disorders derive from pathological neural plasticity, and studying the mechanisms that underlie these processes, including reinforcement learning and spike-timing-dependent plasticity, requires the use of animals.

Monkey Prefrontal Neurons Reflect Logical Operations for Cognitive Control in a Variant of the AX Continuous Performance Task (AX-CPT).

Unlabelled: Cognitive control is the ability to modify the behavioral response to a stimulus based on internal representations of goals or rules. We sought to characterize neural mechanisms in prefrontal cortex associated with cognitive control in a context that would maximize the potential for future translational relevance to human neuropsychiatric disease. To that end, we trained monkeys to perform a dot-pattern variant of the AX continuous performance task that is used to measure cognitive control impairment in patients with schizophrenia (MacDonald, 2008;Jones et al.

Integrating Insults: Using Fault Tree Analysis to Guide Schizophrenia Research across Levels of Analysis.

The grand challenges of schizophrenia research are linking the causes of the disorder to its symptoms and finding ways to overcome those symptoms. We argue that the field will be unable to address these challenges within psychiatry's standard neo-Kraepelinian (DSM) perspective. At the same time the current corrective, based in molecular genetics and cognitive neuroscience, is also likely to flounder due to its neglect for psychiatry's syndromal structure.

Prefrontal neurons transmit signals to parietal neurons that reflect executive control of cognition.

Prefrontal cortex influences behavior largely through its connections with other association cortices; however, the nature of the information conveyed by prefrontal output signals and what effect these signals have on computations performed by target structures is largely unknown. To address these questions, we simultaneously recorded the activity of neurons in prefrontal and posterior parietal cortices of monkeys performing a rule-based spatial categorization task. Parietal cortex receives direct prefrontal input, and parietal neurons, like their prefrontal counterparts, exhibit signals that reflect rule-based cognitive processing in this task.

Effects of ketamine on context-processing performance in monkeys: a new animal model of cognitive deficits in schizophrenia.

Cognitive deficits are at the crux of why many schizophrenia patients have poor functional outcomes. One of the cognitive symptoms experienced by schizophrenia patients is a deficit in context processing, the ability to use contextual information stored in working memory to adaptively respond to subsequent stimuli. As such, context processing can be thought of as the intersection between working memory and executive control.

Thinking in spatial terms: decoupling spatial representation from sensorimotor control in monkey posterior parietal areas 7a and LIP.

Perhaps the simplest and most complete description of the cerebral cortex is that it is a sensorimotor controller whose primary purpose is to represent stimuli and movements, and adaptively control the mapping between them. However, in order to think, the cerebral cortex has to generate patterns of neuronal activity that encode abstract, generalized information independently of ongoing sensorimotor events. A critical question confronting cognitive systems neuroscience at present therefore is how neural signals encoding abstract information emerge within the sensorimotor control networks of the brain.

A scalar neural code for categories in parietal cortex: representing cognitive variables as "more" or "less".

In this issue, Fitzgerald et al. (2013) show that LIP neurons in monkeys encode categorically distinct task conditions using a scalar code. Activity scales up or down to encode different categories, with neurons maintaining proportional levels of activity in relation to one another.

Executive control over cognition: stronger and earlier rule-based modulation of spatial category signals in prefrontal cortex relative to parietal cortex.

Human cognition is characterized by flexibility, the ability to select not only which action but which cognitive process to engage to best achieve the current behavioral objective. The ability to tailor information processing in the brain to rules, goals, or context is typically referred to as executive control, and although there is consensus that prefrontal cortex is importantly involved, at present we have an incomplete understanding of how computational flexibility is implemented at the level of prefrontal neurons and networks. To better understand the neural mechanisms of computational flexibility, we simultaneously recorded the electrical activity of groups of single neurons within prefrontal and posterior parietal cortex of monkeys performing a task that required executive control of spatial cognitive processing.

Disrupted functional connectivity for controlled visual processing as a basis for impaired spatial working memory in schizophrenia.

Although regional brain abnormalities underlying spatial working memory (SWM) deficits in schizophrenia have been identified, little is known about which brain circuits are functionally disrupted in the SWM network in schizophrenia. We investigated SWM-related interregional functional connectivity in schizophrenia using functional magnetic resonance imaging (fMRI) data collected during a memory task that required analysis of spatial information in object structure. Twelve schizophrenia patients and 11 normal control subjects participated.