Volition and conflict in human medial frontal cortex

Controversy surrounds the role of human medial frontal cortex in controlling actions. Although damage to this area leads to severe difficulties in spontaneously initiating actions, the precise mechanisms underlying such "volitional" deficits remain to be established. Previous studies have implicated the medial frontal cortex in conflict monitoring and the control of voluntary action, suggesting that these key processes are functionally related or share neural substrates. Here, we combine a novel behavioral paradigm with functional imaging of the oculomotor system to reveal, for the first time, a functional subdivision of the pre-supplementary motor area (pre-SMA) into anatomically distinct areas that respond exclusively to either volition or conflict. We also demonstrate that activity in the supplementary eye field (SEF) distinguishes between success and failure in changing voluntary action plans during conflict, suggesting a role for the SEF in implementing the resolution of conflicting actions. We propose a functional architecture of human medial frontal cortex that incorporates the generation of action plans and the resolution of conflict.     

Reasoning, learning, and creativity: frontal lobe function and human decision-making

The frontal lobes subserve decision-making and executive control--that is, the selection and coordination of goal-directed behaviors. Current models of frontal executive function, however, do not explain human decision-making in everyday environments featuring uncertain, changing, and especially open-ended situations. Here, we propose a computational model of human executive function that clarifies this issue. Using behavioral experiments, we show that unlike others, the proposed model predicts human decisions and their variations across individuals in naturalistic situations. The model reveals that for driving action, the human frontal function monitors up to three/four concurrent behavioral strategies and infers online their ability to predict action outcomes: whenever one appears more reliable than unreliable, this strategy is chosen to guide the selection and learning of actions that maximize rewards. Otherwise, a new behavioral strategy is tentatively formed, partly from those stored in long-term memory, then probed, and if competitive confirmed to subsequently drive action. Thus, the human executive function has a monitoring capacity limited to three or four behavioral strategies. This limitation is compensated by the binary structure of executive control that in ambiguous and unknown situations promotes the exploration and creation of new behavioral strategies. The results support a model of human frontal function that integrates reasoning, learning, and creative abilities in the service of decision-making and adaptive behavior.     

Frontal cortex and reward-guided learning and decision-making

Reward-guided decision-making and learning depends on distributed neural circuits with many components. Here we focus on recent evidence that suggests four frontal lobe regions make distinct contributions to reward-guided learning and decision-making: the lateral orbitofrontal cortex, the ventromedial prefrontal cortex and adjacent medial orbitofrontal cortex, anterior cingulate cortex, and the anterior lateral prefrontal cortex. We attempt to identify common themes in experiments with human participants and with animal models, which suggest roles that the areas play in learning about reward associations, selecting reward goals, choosing actions to obtain reward, and monitoring the potential value of switching to alternative courses of action.     

Internally generated preactivation of single neurons in human medial frontal cortex predicts volition

Understanding how self-initiated behavior is encoded by neuronal circuits in the human brain remains elusive. We recorded the activity of 1019 neurons while twelve subjects performed self-initiated finger movement. We report progressive neuronal recruitment over ～1500 ms before subjects report making the decision to move. We observed progressive increase or decrease in neuronal firing rate, particularly in the supplementary motor area (SMA), as the reported time of decision was approached. A population of 256 SMA neurons is sufficient to predict in single trials the impending decision to move with accuracy greater than 80% already 700 ms prior to subjects' awareness. Furthermore, we predict, with a precision of a few hundred ms, the actual time point of this voluntary decision to move. We implement a computational model whereby volition emerges once a change in internally generated firing rate of neuronal assemblies crosses a threshold.     

Perceptual learning and dynamic changes in primary visual cortex

Perceptual learning is the improved performance that follows practice in a perceptual task. In this issue of Neuron, Yotsumoto et al. use fMRI to show that stimuli presented at the location used in training initially evoke greater activation in primary visual cortex than stimuli presented elsewhere, but this difference disappears once learning asymptotes.     

Attracting dynamics of frontal cortex ensembles during memory-guided decision-making

A common theoretical view is that attractor-like properties of neuronal dynamics underlie cognitive processing. However, although often proposed theoretically, direct experimental support for the convergence of neural activity to stable population patterns as a signature of attracting states has been sparse so far, especially in higher cortical areas. Combining state space reconstruction theorems and statistical learning techniques, we were able to resolve details of anterior cingulate cortex (ACC) multiple single-unit activity (MSUA) ensemble dynamics during a higher cognitive task which were not accessible previously. The approach worked by constructing high-dimensional state spaces from delays of the original single-unit firing rate variables and the interactions among them, which were then statistically analyzed using kernel methods. We observed cognitive-epoch-specific neural ensemble states in ACC which were stable across many trials (in the sense of being predictive) and depended on behavioral performance. More interestingly, attracting properties of these cognitively defined ensemble states became apparent in high-dimensional expansions of the MSUA spaces due to a proper unfolding of the neural activity flow, with properties common across different animals. These results therefore suggest that ACC networks may process different subcomponents of higher cognitive tasks by transiting among different attracting states.     

Temporal evolution of a decision-making process in medial premotor cortex

The events linking sensory discrimination to motor action remain unclear. It is not known, for example, whether the motor areas of the frontal lobe receive the result of the discrimination process from other areas or whether they actively participate in it. To investigate this, we trained monkeys to discriminate between two mechanical vibrations applied sequentially to the fingertips; here subjects had to recall the first vibration, compare it to the second one, and indicate with a hand/arm movement which of the two vibrations had the higher frequency. We recorded the activity of single neurons in medial premotor cortex (MPC) and found that their responses correlate with the diverse stages of the discrimination process. Thus, activity in MPC reflects the temporal evolution of the decision-making process leading to action selection during this perceptual task.     

Perceptual learning reduces interneuronal correlations in macaque visual cortex

Responses of neurons in early visual cortex change little with training and appear insufficient to account for perceptual learning. Behavioral performance, however, relies on population activity, and the accuracy of a population code is constrained by correlated noise among neurons. We tested whether training changes interneuronal correlations in the dorsal medial superior temporal area, which is involved in multisensory heading perception. Pairs of single units were recorded simultaneously in two groups of subjects: animals trained extensively in a heading discrimination task, and "naive" animals that performed a passive fixation task. Correlated noise was significantly weaker in trained versus naive animals, which might be expected to improve coding efficiency. However, we show that the observed uniform reduction in noise correlations leads to little change in population coding efficiency when all neurons are decoded. Thus, global changes in correlated noise among sensory neurons may be insufficient to account for perceptual learning.     

The neuronal activity of the medial wall of the frontal cortex in rats at various stages of learning

Unit activity of the medial wall of the rat prefrontal cortex was studied during delayed response of spatial choice. Recording was performed in two groups of animals at different levels of learning. Several types of spatio-selective neurones were revealed. Probable relationships of unit activity changes and level of learning are discussed.     

Cognitive neuroscience: resolving conflict in and over the medial frontal cortex

The medial surface of the brain's frontal lobe has been implicated both in the voluntary initiation of action and in monitoring actions in situations where several conflicting responses are possible. Recent work casts light on how these functions are parcelled out in the medial frontal cortex.     

Meeting of minds: the medial frontal cortex and social cognition

Social interaction is a cornerstone of human life, yet the neural mechanisms underlying social cognition are poorly understood. Recently, research that integrates approaches from neuroscience and social psychology has begun to shed light on these processes, and converging evidence from neuroimaging studies suggests a unique role for the medial frontal cortex. We review the emerging literature that relates social cognition to the medial frontal cortex and, on the basis of anatomical and functional characteristics of this brain region, propose a theoretical model of medial frontal cortical function relevant to different aspects of social cognitive processing.     

Representation of others' action by neurons in monkey medial frontal cortex

Successful social interaction depends on not only the ability to identify with others but also the ability to distinguish between aspects of self and others. Although there is considerable knowledge of a shared neural substrate between self-action and others' action, it remains unknown where and how in the brain the action of others is uniquely represented. Exploring such agent-specific neural codes is important because one's action and intention can differ between individuals. Moreover, the assignment of social agency breaks down in a range of mental disorders. Here, using two monkeys monitoring each other's action for adaptive behavioral planning, we show that the medial frontal cortex (MFC) contains a group of neurons that selectively encode others' action. These neurons, observed in both dominant and submissive monkeys, were significantly more prevalent in the dorsomedial convexity region of the MFC including the pre-supplementary motor area than in the cingulate sulcus region of the MFC including the rostral cingulate motor area. Further tests revealed that the difference in neuronal activity was not due to gaze direction or muscular activity. We suggest that the MFC is involved in self-other differentiation in the domain of motor action and provides a fundamental neural signal for social learning.     

Structure learning in human sequential decision-making

Studies of sequential decision-making in humans frequently find suboptimal performance relative to an ideal actor that has perfect knowledge of the model of how rewards and events are generated in the environment. Rather than being suboptimal, we argue that the learning problem humans face is more complex, in that it also involves learning the structure of reward generation in the environment. We formulate the problem of structure learning in sequential decision tasks using Bayesian reinforcement learning, and show that learning the generative model for rewards qualitatively changes the behavior of an optimal learning agent. To test whether people exhibit structure learning, we performed experiments involving a mixture of one-armed and two-armed bandit reward models, where structure learning produces many of the qualitative behaviors deemed suboptimal in previous studies. Our results demonstrate humans can perform structure learning in a near-optimal manner.     

Human medial frontal cortex mediates unconscious inhibition of voluntary action

Within the medial frontal cortex, the supplementary eye field (SEF), supplementary motor area (SMA), and pre-SMA have been implicated in the control of voluntary action, especially during motor sequences or tasks involving rapid choices between competing response plans. However, the precise roles of these areas remain controversial. Here, we study two extremely rare patients with microlesions of the SEF and SMA to demonstrate that these areas are critically involved in unconscious and involuntary motor control. We employed masked-prime stimuli that evoked automatic inhibition in healthy people and control patients with lateral premotor or pre-SMA damage. In contrast, our SEF/SMA patients showed a complete reversal of the normal inhibitory effect--ocular or manual--corresponding to the functional subregion lesioned. These findings imply that the SEF and SMA mediate automatic effector-specific suppression of motor plans. This automatic mechanism may contribute to the participation of these areas in the voluntary control of action.     

Word retrieval learning modulates right frontal cortex in patients with left frontal damage

Previous studies have suggested that recovery or compensation of language function after a lesion in the left hemisphere may depend on mechanisms in the right hemisphere. However, a direct relationship between performance and right hemisphere activity has not been established. Here, we show that patients with left frontal lesions and partially recovered aphasia learn, at a normal rate, a novel word retrieval task that requires the damaged cortex. Verbal learning is accompanied by specific response decrements in right frontal and right occipital cortex, strongly supporting the compensatory role of the right hemisphere. Furthermore, responses in left occipital cortex are abnormal and not modulated by practice. These findings indicate that frontal cortex is a source of top-down signals during learning.     

Selective increase in the extracellular D-serine contents by D-cycloserine in the rat medial frontal cortex

A partial agonist of the N-methyl-D-aspartate (NMDA) receptor, D-cycloserine, acting at its glycine modulatory site, ameliorates the neuropsychiatric symptoms that are mimicked by NMDA antagonists and include cognitive disturbances, antipsychotic-resistant schizophrenic symptoms and cerebellar ataxia. To obtain a further insight into the mechanisms of the therapeutic efficacies of D-cycloserine, we investigated the effects of the systemic administration of D-cycloserine on the extracellular contents of an endogenous NMDA co-agonist, D-serine, in the medial frontal cortex of the rat using an in vivo dialysis technique. An acute intraperitoneal injection of D-cycloserine (50 and 100 mg/kg) caused an increase in extracellular concentrations of D-serine without significant effects on those of L-serine, glycine, L-glutamate, L-aspartate, L-glutamine, L-asparagine, L-alanine, L-threonine and taurine in the medial frontal cortex. The selective increase in the extracellular D-serine contents may, at least partially, be associated with the facilitating effects of D-cycloserine on the NMDA receptor functions in addition to its direct stimulation of the NMDA receptor glycine site.     

DNA and RNA and the cytoarchitecture of human frontal cortex

DNA and RNA were studied in the layers of human prefrontal cortex by quantitative microchemical analyses on microtome-prepared serial frozen sections. Eleven cortical specimens from six autopsy brains were assayed. The mean total number of cells per mm³ of fresh cortex was estimated from DNA values. The number in layer I (61,000) was falsely high because of the inclusion of cells from the pia mater. From a plateau of 82,000-86,000 in layers II, IIIa and IIIb, the number of cells rose to 91,000 and 113,000 in layers IIIc and IV, respectively. The mean number was slightly lower in layer V, then gradually rose through layer VI to 127,000 cells in white matter. Per unit dry weight, DNA and cells varied much less than per unit volume; values averaged 14 per cent higher in layers II and IV than in neighbouring layers and in white matter were 20 per cent lower than in layer I. Intracortical patterns of RNA and RNA/cell reflected chiefly the distribution of neuronal cell bodies. Per unit fresh volume, RNA roughly paralleled DNA in layers I-V; through layer VI and into white matter RNA declined as DNA rose, reflecting the decline in neurons and increasing predominance of glial cells of lower RNA content. Per unit dry weight, RNA rose 50 per cent from layer I to layer II; a plateau of high values extended through layers II-V, then RNA declined rapidly through layer VI to a level in white matter that was 28 per cent of the value in layer II. Mean RNA/cell in cortex was 9-8 pg, with a maximum in layer IIIb (11.4 pg); in subcortical white matter it was 5.3 pg.     

Increasing effects of S-methyl-l-cysteine on the extracellular d-serine concentrations in the rat medial frontal cortex

In an in vivo dialysis experiment, the intra-medial frontal cortex infusion of a system A and Asc-1 transporter inhibitor, S-methyl-l-cysteine, caused a concentration-dependent increase in the dialysate contents of an endogenous coagonist for the N-methyl-d-aspartate (NMDA) type glutamate receptor, d-serine, in the cortical portion. These results suggest that these neutral amino acid transporters could control the extracellular d-serine signaling in the brain and be a target for the development of a novel threapy for neuropsychiatric disorders with an NMDA receptor dysfunction.     

Alterations in time-place learning induced by lesions to the rat medial prefrontal cortex

This experiment examined the effect of medial prefrontal lesions on time-place learning in the rat. During the first phase, prior to lesioning, rats received training on an interval time-place task. Food was available on each of four levers for 3 consecutive min of a 12-min session. The levers provided food in the same sequence on all trials. Rats restricted the majority of their presses on each lever to the time in each session when it provided food and were able to anticipate when a lever was going to provide food. During the second phase some rats received lesions that were restricted to the medial prefrontal cortex. Following these very restricted lesions, rats continued pressing a lever after it stopped providing food (i.e. perseverated, as if their internal clock was running slow). The third phase involved changing the order in which the levers provided food. Lesions had no discernable effect on the rats' ability to learn the correct sequence of food availability. However, this change made the rats' timing perseveration even more noticeable. Our results suggest the medial prefrontal cortex is not necessary for acquisition of time-place sequencing information. However, lesions do appear to produce perseveration on components of the sequence.