Norepinephrine drives persistent activity in prefrontal cortex via synergistic α1 and α2 adrenoceptors

Optimal norepinephrine levels in the prefrontal cortex (PFC) increase delay-related firing and enhance working memory, whereas stress-related or pathologically high levels of norepinephrine are believed to inhibit working memory via α1 adrenoceptors. However, it has been shown that activation of Gq-coupled and phospholipase C-linked receptors can induce persistent firing, a cellular correlate of working memory, in cortical pyramidal neurons. Therefore, despite its importance in stress and cognition, the exact role of norepinephrine in modulating PFC activity remains elusive. Using electrophysiology and optogenetics, we report here that norepinephrine induces persistent firing in pyramidal neurons of the PFC independent of recurrent fast synaptic excitation. This persistent excitatory effect involves presynaptic α1 adrenoceptors facilitating glutamate release and subsequent activation of postsynaptic mGluR5 receptors, and is enhanced by postsynaptic α2 adrenoceptors inhibiting HCN channel activity. Activation of α2 adrenoceptors or inhibition of HCN channels also enhances cholinergic persistent responses in pyramidal neurons, providing a mechanism of crosstalk between noradrenergic and cholinergic inputs. The present study describes a novel cellular basis for the noradrenergic control of cortical information processing and supports a synergistic combination of intrinsic and network mechanisms for the expression of mnemonic properties in pyramidal neurons.

Dorsolateral and ventromedial prefrontal cortex orchestrate normative choice.

Humans are noted for their capacity to over-ride self-interest in favor of normatively valued goals. We examined the neural circuitry that is causally involved in normative, fairness-related decisions by generating a temporarily diminished capacity for costly normative behavior, a 'deviant' case, through non-invasive brain stimulation (repetitive transcranial magnetic stimulation) and compared normal subjects' functional magnetic resonance imaging signals with those of the deviant subjects. When fairness and economic self-interest were in conflict, normal subjects (who make costly normative decisions at a much higher frequency) displayed significantly higher activity in, and connectivity between, the right dorsolateral prefrontal cortex (DLPFC) and the posterior ventromedial prefrontal cortex (pVMPFC). In contrast, when there was no conflict between fairness and economic self-interest, both types of subjects displayed identical neural patterns and behaved identically. These findings suggest that a parsimonious prefrontal network, the activation of right DLPFC and pVMPFC, and the connectivity between them, facilitates subjects' willingness to incur the cost of normative decisions.

Virtual reality and the role of the prefrontal cortex in adults and children

In this review, the neural underpinnings of the experience of presence are outlined. Firstly, it is shown that presence is associated with activation of a distributed network, which includes the dorsal and ventral visual stream, the parietal cortex, the premotor cortex, mesial temporal areas, the brainstem and the thalamus. Secondly, the dorsolateral prefrontal cortex (DLPFC) is identified as a key node of the network as it modulates the activity of the network and the associated experience of presence. Thirdly, children lack the strong modulatory influence of the DLPFC on the network due to their unmatured frontal cortex. Fourthly, it is shown that presence-related measures are influenced by manipulating the activation in the DLPFC using transcranial direct current stimulation (tDCS) while participants are exposed to the virtual roller coaster ride. Finally, the findings are discussed in the context of current models explaining the experience of presence, the rubber hand illusion, and out-of-body experiences.

Lateral prefrontal cortex and self-control in intertemporal choice.

Disruption of function of left, but not right, lateral prefrontal cortex (LPFC) with low-frequency repetitive transcranial magnetic stimulation (rTMS) increased choices of immediate rewards over larger delayed rewards. rTMS did not change choices involving only delayed rewards or valuation judgments of immediate and delayed rewards, providing causal evidence for a neural lateral-prefrontal cortex-based self-control mechanism in intertemporal choice.

Resisting the power of temptations: the right prefrontal cortex and self-control.

Imagine you are overweight and you spot your favorite pastry in the storefront of a bakery. How do you manage to resist this temptation? Or to give other examples, how do you manage to restrain yourself from overspending or succumbing to sexual temptations? The present article summarizes two recent studies stressing the fundamental importance of inhibition in the process of decision making. Based on the results of these studies, we dare to claim that the capacity to resist temptation depends on the activity level of the right prefrontal cortex (PFC).

The association between implicit alcohol attitudes and drinking behavior is moderated by baseline activation in the lateral prefrontal cortex

OBJECTIVE Intense alcohol consumption is a risk factor for a number of health problems. Dual-process models assume that self-regulatory behavior such as drinking alcohol is guided by both reflective and impulsive processes. Evidence suggests that (a) impulsive processes such as implicit attitudes are more strongly associated with behavior when executive functioning abilities are low, and (b) higher neural baseline activation in the lateral prefrontal cortex (PFC) is associated with better inhibitory control. The present study integrates these 2 strands of research to investigate how individual differences in neural baseline activation in the lateral PFC moderate the association between implicit alcohol attitudes and drinking behavior. METHOD Baseline cortical activation was measured with resting electroencephalography (EEG) in 89 moderate drinkers. In a subsequent behavioral testing session they completed measures of implicit alcohol attitudes and self-reported drinking behavior. RESULTS Implicit alcohol attitudes were related to self-reported alcohol consumption. Most centrally, implicit alcohol attitudes were more strongly associated with drinking behavior in individuals with low as compared with high baseline activation in the right lateral PFC. CONCLUSIONS These findings are in line with predictions made on the basis of dual-process models. They provide further evidence that individual differences in neural baseline activation in the right lateral PFC may contribute to executive functioning abilities such as inhibitory control. Moreover, individuals with strongly positive implicit alcohol attitudes coupled with a low baseline activation in the right lateral PFC may be at greater risk of developing unhealthy drinking patterns than others.

Interactions between dorsolateral and ventromedial prefrontal cortex underlie context-dependent stimulus valuation in goal-directed choice.

External circumstances and internal bodily states often change and require organisms to flexibly adapt valuation processes to select the optimal action in a given context. Here, we investigate the neurobiology of context-dependent valuation in 22 human subjects using functional magnetic resonance imaging. Subjects made binary choices between visual stimuli with three attributes (shape, color, and pattern) that were associated with monetary values. Context changes required subjects to deviate from the default shape valuation and to integrate a second attribute in order to comply with the goal to maximize rewards. Critically, this binary choice task did not involve any conflict between opposing monetary, temporal, or social preferences. We tested the hypothesis that interactions between regions of dorsolateral and ventromedial prefrontal cortex (dlPFC; vmPFC) implicated in self-control choices would also underlie the more general function of context-dependent valuation. Consistent with this idea, we found that the degree to which stimulus attributes were reflected in vmPFC activity varied as a function of context. In addition, activity in dlPFC increased when context changes required a reweighting of stimulus attribute values. Moreover, the strength of the functional connectivity between dlPFC and vmPFC was associated with the degree of context-specific attribute valuation in vmPFC at the time of choice. Our findings suggest that functional interactions between dlPFC and vmPFC are a key aspect of context-dependent valuation and that the role of this network during choices that require self-control to adjudicate between competing outcome preferences is a specific application of this more general neural mechanism.

Prefrontal Thinning Affects Functional Connectivity and Regional Homogeneity of the Anterior Cingulate Cortex in Depression

Major depressive disorder (MDD) is associated with structural and functional alterations in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC). Enhanced ACC activity at rest (measured using various imaging methodologies) is found in treatment-responsive patients and is hypothesized to bolster treatment response by fostering adaptive rumination. However, whether structural changes influence functional coupling between fronto-cingulate regions and ACC regional homogeneity (ReHo) and whether these functional changes are related to levels of adaptive rumination and treatment response is still unclear. Cortical thickness and ReHo maps were calculated in 21 unmedicated depressed patients and 35 healthy controls. Regions with reduced cortical thickness defined the seeds for the subsequent functional connectivity (FC) analyses. Patients completed the Response Style Questionnaire, which provided a measure of adaptive rumination associated with better response to psychotherapy. Compared with controls, depressed patients showed thinning of the right anterior PFC, increased prefrontal connectivity with the supragenual ACC (suACC), and higher ReHo in the suACC. The suACC clusters of increased ReHo and FC spatially overlapped. In depressed patients, suACC ReHo scores positively correlated with PFC thickness and with FC strength. Moreover, stronger fronto-cingulate connectivity was related to higher levels of adaptive rumination. Greater suACC ReHo and connectivity with the right anterior PFC seem to foster adaptive forms of self-referential processing associated with better response to psychotherapy, whereas prefrontal thinning impairs the ability of depressed patients to engage the suACC during a major depressive episode. Bolstering the function of the suACC may represent a potential target for treatment.