Neuronal population dynamics during motor plan cancellation in nonhuman primates.

To understand the cortical neuronal dynamics behind movement generation and control, most studies have focused on tasks where actions were planned and then executed using different instances of visuomotor transformations. However, to fully understand the dynamics related to movement control, one must also study how movements are actively inhibited. Inhibition, indeed, represents the first level of control both when different alternatives are available and only one solution could be adopted and when it is necessary to maintain the current position. We recorded neuronal activity from a multielectrode array in the dorsal premotor cortex (PMd) of monkeys performing a countermanding reaching task that requires, in a subset of trials, them to cancel a planned movement before its onset. In the analysis of the neuronal state space of PMd, we found a subspace in which activities conveying temporal information were confined during active inhibition and position holding. Movement execution required activities to escape from this subspace toward an orthogonal subspace and, furthermore, surpass a threshold associated with the maturation of the motor plan. These results revealed further details in the neuronal dynamics underlying movement control, extending the hypothesis that neuronal computation confined in an "output-null" subspace does not produce movements.

Neuronal Modulation in the Prefrontal Cortex in a Transitive Inference Task: Evidence of Neuronal Correlates of Mental Schema Management.

When informed that A > B and B > C, humans and other animals can easily conclude that A > C. This remarkable trait of advanced animals, which allows them to manipulate knowledge flexibly to infer logical relations, has only recently garnered interest in mainstream neuroscience. How the brain controls these logical processes remains an unanswered question that has been merely superficially addressed in neuroimaging and lesion studies, which are unable to identify the underlying neuronal computations. We observed that the activation pattern of neurons in the prefrontal cortex (PFC) during pair comparisons in a highly demanding transitive inference task fully supports the behavioral performance of the two monkeys that we tested. Our results indicate that the PFC contributes to the construction and use of a mental schema to represent premises. This evidence provides a novel framework for understanding the function of various areas of brain in logic processes and impairments to them in degenerative, traumatic, and psychiatric pathologies. SIGNIFICANCE STATEMENT: In cognitive neuroscience, it is unknown how information that leads to inferential deductions are encoded and manipulated at the neuronal level. We addressed this question by recording single-unit activity from the dorsolateral prefrontal cortex of monkeys that were performing a transitive inference (TI) task. The TI required one to choose the higher ranked of two items, based on previous, indirect experience. Our results demonstrated that single-neuron activity supports the construction of an abstract, mental schema of ordered items in solving the task and that this representation is independent of the reward value that is experienced for the single items. These findings identify the neural substrates of abstract mental representations that support inferential thinking.

Dorsal Premotor Cortex Neurons Signal the Level of Choice Difficulty during Logical Decisions.

Studies on the neuronal correlates of decision making have demonstrated that the continuous flow of sensorial information is integrated by sensorimotor brain areas in order to select one among simultaneously represented targets and potential actions. In contrast, little is known about how these areas integrate memory information to lead to similar decisions. Using serial order learning, we explore how fragments of information, learned and stored independently (e.g., A > B and B > C), are linked in an abstract representation according to their reciprocal relations (such as A > B > C) and how this representation can be accessed and manipulated to make decisions. We show that manipulating information after learning occurs with increased difficulty as logical relationships get closer in the mental map and that the activity of neurons in the dorsal premotor cortex (PMd) encodes the difficulty level during target selection for motor decision making at the single-neuron and population levels.

Neural Correlations Underlying Self-Generated Decision in the Frontal Pole Cortex during a Cued Strategy Task.

We have previously shown how the Frontal Pole cortex (FPC) neurons play a unique role in both the monitoring and evaluating of self-generated decisions during feedback in a visually cued strategy task. For each trial of this task, a cue instructed one of two strategies: to either stay with the previous goal or shift to the alternative goal. Each cue was followed by a delay period, then each choice was followed by a feedback. FPC neurons show goal-selective activity exclusively during the feedback period. Here, we studied how neural correlation dynamically changes, along with a trial in FPC. We classified the cells as goal-selective and not goal-selective (NS) and analyzed the time-course of the cross-correlations in 76 pairs of neurons from each group. We compared a control epoch with the feedback epoch and we found higher correlations in the latter one between goal-selective neurons than between NS neurons, in which the correlated activity dropped during feedback. This supports the involvement of goal-selective cells in the evaluation of self-generated decisions at the feedback time. We also observed a dynamic change of the correlations in time, indicating that the connections among cell-assemblies were transient, changing between internal states at the feedback time. These results indicate that the changing of the pattern of neural correlations can underlie the flexibility of the prefrontal computations.

Both the COMT Val158Met single-nucleotide polymorphism and sex-dependent differences influence response inhibition.

Reactive and proactive controls of actions are cognitive abilities that allow one to deal with a continuously changing environment by adjusting already programmed actions. They also set forthcoming actions by evaluating the outcome of the previous ones. Earlier studies highlighted sex-related differences in the strategies and in the pattern of brain activation during cognitive tasks involving reactive and proactive control. To further identify sex-dependent characteristics in the cognitive control of actions, in this study, we have assessed whether/how differences in performance are modulated by the COMT Val158Met single-nucleotide polymorphism (SNP), a genetic factor known to influence the functionality of the dopaminergic system-in particular, at the level of the prefrontal cortex. Two groups of male and female participants were sorted according to their genotype (Val/Val, Val/Met, and Met/Met) and tested in a stop signal task, a consolidated tool for measuring executive control in experimental and clinical settings. In each group of participants, we estimated both a measure of the capacity to react to unexpected events and the ability to monitor their performance. The between-group comparison of these measures indicated a poorer ability of male individuals and Val/Val subjects in error-monitoring. These observations suggest that sex differences in inhibitory control could be influenced by the efficiency of COMT and that other sex-specific factors have to be considered. Understanding the inter-group variability of behavioral and physiological correlates of cognitive control could provide more accurate diagnostic tools for predicting the incidence and/or the development of pathologies, like ADHD, or deviant behaviors, such as drug or alcohol abuse.

The NMDAr antagonist ketamine interferes with manipulation of information for transitive inference reasoning in non-human primates.

One of the most remarkable traits of highly encephalized animals is their ability to manipulate knowledge flexibly to infer logical relationships. Operationally, the corresponding cognitive process can be defined as reasoning. One hypothesis is that this process relies on the reverberating activity of glutamate neural circuits, sustained by NMDA receptor (NMDAr) mediated synaptic transmission, in both parietal and prefrontal areas. We trained two macaque monkeys to perform a form of deductive reasoning - the transitive inference task - in which they were required to learn the relationship between six adjacent items in a single session and then deduct the relationship between nonadjacent items that had not been paired in the learning phase. When the animals had learned the sequence, we administered systemically a subanaesthetic dose of ketamine (a NMDAr antagonist) and measured their performance on learned and novel problems. We observed impairments in determining the relationship between novel pairs of items. Our results are consistent with the hypothesis that transitive inference premises are integrated during learning in a unified representation and that reducing NMDAr activity interferes with the use of this mental model, when decisions are required in comparing pairs of items that have not been learned.