Cortical thickness of the dorsolateral prefrontal cortex predicts strategic choices in economic games

Human prosociality has been traditionally explained in the social sciences in terms of internalized social norms. Recent neuroscientific studies extended this traditional view of human prosociality by providing evidence that prosocial choices in economic games require cognitive control of the impulsive pursuit of self-interest. However, this view is challenged by an intuitive prosociality view emphasizing the spontaneous and heuristic basis of prosocial choices in economic games. We assessed the brain structure of 411 players of an ultimatum game (UG) and a dictator game (DG) and measured the strategic reasoning ability of 386. According to the reflective norm-enforcement view of prosociality, only those capable of strategically controlling their selfish impulses give a fair share in the UG, but cognitive control capability should not affect behavior in the DG. Conversely, we support the intuitive prosociality view by showing for the first time, to our knowledge, that strategic reasoning and cortical thickness of the dorsolateral prefrontal cortex were not related to giving in the UG but were negatively related to giving in the DG. This implies that the uncontrolled choice in the DG is prosocial rather than selfish, and those who have a thicker dorsolateral prefrontal cortex and are capable of strategic reasoning (goal-directed use of the theory of mind) control this intuitive drive for prosociality as a means to maximize reward when there are no future implications of choices.Humans are a cooperative species, and the question of why humans are so cooperative has been a subject of considerable interest in social and biological sciences (1–4). The traditional answer in the social sciences highlights critical roles of social norms and cultural values internalized as personal values and social preferences (5, 6). Recent neuroscientific studies of brain structure and activity extended this traditional view of human prosociality by showing that players of economic games act prosocially when they cognitively control selfish impulses (7–13). Experimental evidence shows that prosocial choices in economic games positively relate to local gray matter volume and thickness and the activation of brain areas that control selfish impulsive drives, such as the dorsolateral prefrontal cortex (DLPFC) and temporoparietal junction (TPJ) (7–9). Furthermore, impairment of cognitive control by disruption of DLPFC function prevents rejection of unfair offers in the ultimatum game (UG), which some authors considered prosocial and fairness-seeking behavior (10–13). Recently, this reflective view of human prosociality has been challenged by an alternative view emphasizing the intuitive nature of prosocial behavior, subsumed under intuitive prosociality (14) or heuristic cooperation (15–17). Support for the intuitive and automatic nature of prosocial behavior is provided by findings that prosocial choices are promoted under time pressure (15, 16, 18), under cognitive load (19–21), or after priming by successful experiences of intuitive decision making (15, 22). Also, participants who expressed more positive emotional words and less inhibitory words during and after an economic game cooperated more (23). Additionally, increased activity in the lateral prefrontal cortex was negatively related to fairness-seeking behavior in an economic game (24). According to the heuristic prosociality model (14–17), humans are predisposed to cooperate in social exchange situations. People fail to behave in a prosocial manner in social exchanges when this predisposition is overridden by strategic reasoning to secure their self-interest. By comparing participants’ behaviors in two economic games with brain structural differences and strategic reasoning abilities, we provide evidence that strategic reasoning controls, and thus reduces rather than promotes, game players’ prosocial behavior.The contrast between two simple, two-person economic games—namely, the dictator game (DG) and the UG—is often used to support the reflective prosocial model by demonstrating how strategic reasoning affects game players’ decisions. In both games, one player freely decides how much of a fixed reward to take and how much to leave for the other player. The difference between the two games is that the other player in the UG (termed “responder”) has the option to reject the decision made by the first player (termed “proposer”), causing both to earn nothing. This option is not provided to the second player in the DG, who plays the role of a “recipient”. The recipient simply receives whatever the first player (“dictator”) gives. The level of giving by the proposer in the UG is usually higher than that by the dictator in the DG (25). This is attributed to the proposer’s strategic reasoning, which requires inference of the recipient’s internal state and prediction of the resulting response (e.g., anger on the basis of unfair giving and subsequent rejection) (8, 9, 13). Given that neuroimaging and neuroendocrinological studies showed that negative emotions are associated with rejection of unfair offers (24, 26, 27), UG proposers may anticipate negative responses to unfair offers. UG proposers anticipate norm-enforcing responses (rejection of the offer) to norm-violating behavior (taking most of the reward) and strategically adjust giving behavior to secure acceptance by the responder. Thus, those capable of using strategic reasoning are expected to make fair offers in the UG compared with those who struggle to control their selfish drive for immediate reward.In contrast, in the DG, which requires no strategic reasoning to earn as much as possible, strategic control over selfish impulses is expected not to influence the player’s choices. Spitzer et al. (9) confirmed this by showing a positive correlation between the difference in giving in the UG and the DG (i.e., a measure of strategic reasoning) and activity of the right DLPFC and the lateral orbitofrontal cortex. Given earlier findings implicating the DLPFC in cognitive control of impulsive behavior (28–33), this is taken to support the reflective model of prosociality, in which prosocial behavior requires cognitive control of the impulsive drive toward selfish behavior. Steinbeis et al. (8) provided further support via a comparison of young children’s choices in the two economic games. Children took a large share in the DG while providing fairer amounts to responders in the UG. The children’s more generous giving in the UG may be based upon strategic reasoning regarding the possible consequences of not giving enough in the UG—that is, receiving no reward due to rejection by the other child—which plays no role in the DG. Thus, the difference in giving between the UG and the DG is considered to reflect the use of strategic reasoning in the UG. The strategic choices of more giving in the UG than in the DG is related to children’s age, cortical thickness, and activity of their left DLPFC. As children age and their DLPFC develops further, they become able to control their selfish drive and adjust their behavior to the anticipated negative consequences.This interpretation of UG–DG difference in prosocial giving as a reflection of strategic reasoning (8, 9) assumes that the default choice in the DG is impulsive and selfish. Younger children and those with a thinner DLPFC are presumably less capable of strategically adjusting their decisions to deal with anticipated responses and would impulsively pursue their own benefits in both the UG and the DG. In contrast, older children and those with a thicker DLPFC are more likely to have enhanced cognitive control, which can be used to strategically adjust their choices, especially in the UG but not in the DG. Therefore, a UG–DG positive reward transfer difference is produced by strategists’ control over the selfish impulses in the UG, whereas those who fail to control such impulses in the UG claim a considerable share in both games (Fig. 1A). In contrast, the alternative, intuitive prosociality model assumes that the uncontrolled choice is prosocial in both the UG and the DG, rather than selfish. Strategists control this impulse toward prosociality in the DG where immediate pursuit of self-interest causes no strategic problem (Fig. 1B). Nonstrategists do not control this impulse and provide a fair share in both games. Thus, a difference due to strategic reasoning is predicted to exist in the DG but not in the UG. The reflective and intuitive prosociality models thus make distinct predictions regarding the relationship between DLPFC thickness and behavior in the UG and DG. The reflective model predicts a positive relationship between DLPFC thickness and giving in the UG, whereas the intuitive model predicts a negative relationship between DLPFC thickness and giving in the DG.Open in a separate windowFig. 1.Schematic representations of how strategic considerations generate the difference between strategists (ST) and nonstrategists (Non-ST) in the UG and DG. A shows the prediction that strategic considerations should improve fair behavior in the UG. B shows the prediction that strategic considerations should depress fair behavior in the DG.These two alternative accounts of differences in giving in the UG and DG (8, 9) provide a way to test the intuitive selfishness assumption against the intuitive prosociality assumption. We first successfully replicated earlier findings that strategic behavior is more pronounced among those who had a thicker DLPFC than those who had a thinner DLPFC (8) in a study of 411 adult, nonstudent participants who played both the UG and DG and from whom brain structural images were obtained. Then, we found for the first time, to our knowledge, that local gray matter thickness of the DLPFC negatively correlated with giving in the DG but was not correlated with giving in the UG (Fig. 2 C and D). We further measured the strategic reasoning of 386 of these participants using a newly developed test of strategic reasoning, measured 411 participants’ Machiavellianism (34, 35) score, and found that those exhibiting better strategic reasoning behaved more selfishly in the DG than those with poor strategic reasoning, but no relationship was found between task performance and fairness in the UG. These striking findings provide strong evidence supporting the intuitive prosociality prediction depicted in Fig. 1B but not the reflective prosociality prediction shown in Fig. 1A.Open in a separate windowFig. 2.Brain areas in the Destrieu Atlas (A), the relationship of cortical thickness of the DLPFC (middle frontal gyrus) and strategic choice (UG–DG) (B), the relationship of its right cortical thickness and giving in the UG and DG (C), and the relationship of its left cortical thickness and giving in the UG and DG (D). The horizontal axis represents the residual cortical thickness adjusted for participants’ age, sex, and ICV. The vertical axis represents the mean strategic choice of the players, giving in the UG or the DG within 0.1-mm intervals of residual cortical thickness. Each interval spans 0.1 mm on the horizontal axis segment. The size of each circle shows the number of players who fell within the interval. Error bars are SEs. n = 411. Correlations are after adjusting for age, sex, and ICV.     

Resting-state functional MRI in depression unmasks increased connectivity between networks via the dorsal nexus

To better understand intrinsic brain connections in major depression, we used a neuroimaging technique that measures resting state functional connectivity using functional MRI (fMRI). Three different brain networks—the cognitive control network, default mode network, and affective network—were investigated. Compared with controls, in depressed subjects each of these three networks had increased connectivity to the same bilateral dorsal medial prefrontal cortex region, an area that we term the dorsal nexus. The dorsal nexus demonstrated dramatically increased depression-associated fMRI connectivity with large portions of each of the three networks. The discovery that these regions are linked together through the dorsal nexus provides a potential mechanism to explain how symptoms of major depression thought to arise in distinct networks—decreased ability to focus on cognitive tasks, rumination, excessive self-focus, increased vigilance, and emotional, visceral, and autonomic dysregulation—could occur concurrently and behave synergistically. It suggests that the newly identified dorsal nexus plays a critical role in depressive symptomatology, in effect “hot wiring” networks together; it further suggests that reducing increased connectivity of the dorsal nexus presents a potential therapeutic target.     

Repeated high-frequency transcranial magnetic stimulation over the dorsolateral prefrontal cortex reduces cigarette craving and consumption

Aims   To evaluate the effect of repeated high-frequency transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC), combined with either smoking or neutral cues, on cigarette consumption, dependence and craving.
Design   Participants were divided randomly to real and sham stimulation groups. Each group was subdivided randomly into two subgroups presented with either smoking-related or neutral pictures just before the daily TMS intervention. Ten daily rTMS sessions were applied every week-day and then a maintenance phase was conducted in which rTMS sessions were less frequent.
Setting   Single-site, out-patient, randomized, double-blind, sham-controlled.
Participants   Forty-eight chronic smokers who smoked at least 20 cigarettes per day and were motivated to quit smoking. Healthy males and females were recruited from the general population using advertisements in newspapers and on internet websites.
Intervention   Ten daily rTMS sessions were administered using a standard figure-8 coil over the DLPFC. Stimulation included 20 trains/day at 100% of motor threshold. Each train consisted of 50 pulses at 10 Hz with an inter-train interval of 15 seconds.
Measurements   Cigarette consumption was evaluated objectively by measuring cotinine levels in urine samples and subjectively by participants' self-reports. Dependence and craving were evaluated by standard questionnaires.
Findings   Ten daily rTMS sessions over the DLPFC reduced cigarette consumption and nicotine dependence. Furthermore, treatment blocked the craving induced by daily presentation of smoking-related pictures. However, these effects tended to dissipate over time.
Conclusions   Multiple high-frequency rTMS of the DLPFC can attenuate nicotine craving.     

Noninvasive brain stimulation over dorsolateral prefrontal cortex for pain perception and executive function in aging

ObjectivesBased on the evidence that the dorsolateral prefrontal cortex (DLPFC) is the main region affected by the aging process, and that tDCS modulates cortical excitability, the aim of the study is to prove the feasibility of tDCS for pain perception and executive function of community-dwelling elderly individuals.MethodsWe performed a double-blind, single-arm trial, including a sham period. 5 consecutive anodal tDCS was applied over DLPFC of twenty-four elderly for 20 min during each intervention periods (in order of Sham-1 mA–2 mA). First, we classified chronic non-inflammatory pain sites into three domain (Neck and upper extremity, low back, lower extremity). Then, we used visual analogue scale, pain self-efficacy scale, Tampa scale for kinesiophobia, and Global perceived Effect scale to observe the change in pain perception, as well as Trailing Making Test and Timed Up and Go (dual) to observe the change in executive function. The changes in maximal grip strength and 12-item Short Form survey were measured secondarily.ResultsIn the results, we observed significant improvement in pain perception and quality of life, while executive function and grip strength did not change significantly.ConclusionOur findings demonstrated the feasibility of tDCS for aging-related pain perception and suggest that further randomized controlled trials with longer duration are necessary to examine the effects on executive function.     

Involvement of human left dorsolateral prefrontal cortex in perceptual decision making is independent of response modality

Perceptual decision making typically entails the processing of sensory signals, the formation of a decision, and the planning and execution of a motor response. Although recent studies in monkeys and humans have revealed possible neural mechanisms for perceptual decision making, much less is known about how the decision is subsequently transformed into a motor action and whether or not the decision is represented at an abstract level, i.e., independently of the specific motor response. To address this issue, we used functional MRI to monitor changes in brain activity while human subjects discriminated the direction of motion in random-dot visual stimuli that varied in coherence and responded with either button presses or saccadic eye movements. We hypothesized that areas representing decision variables should respond more to high- than to low-coherence stimuli independent of the motor system used to express a decision. Four areas were found that fulfilled this condition: left posterior dorsolateral prefrontal cortex (DLPFC), left posterior cingulate cortex, left inferior parietal lobule, and left fusifom/parahippocampal gyrus. We previously found that, when subjects made categorical decisions about degraded face and house stimuli, left posterior DLPFC showed a greater response to high- relative to low-coherence stimuli. Furthermore, the left posterior DLPFC appears to perform a comparison of signals from sensory processing areas during perceptual decision making. These data suggest that the involvement of left posterior DLPFC in perceptual decision making transcends both task and response specificity, thereby enabling a flexible link among sensory evidence, decision, and action.     

Thickness of ventromedial prefrontal cortex in humans is correlated with extinction memory

The ventromedial prefrontal cortex (vmPFC) has been implicated in fear extinction [Phelps, E. A., Delgado, M. R., Nearing, K. I. & Ledoux, J. E. (2004) Neuron 43, 897-905; Herry, C. & Garcia, R. (2003) Behav. Brain Res. 146, 89-96]. Here, we test the hypothesis that the cortical thickness of vmPFC regions is associated with how well healthy humans retain their extinction memory a day after having been conditioned and then extinguished. Fourteen participants underwent a 2-day fear conditioning and extinction protocol. The conditioned stimuli (CSs) were pictures of virtual lights, and the unconditioned stimulus (US) was an electric shock. On day 1, participants received 5 CS+US pairings (conditioning), followed by 10 CS trials with no US (extinction). On day 2, the CS was presented alone to test for extinction memory. Skin conductance response (SCR) was the behavioral index of conditioning and extinction. Participants underwent MRI scans to obtain structural images, from which cortical thickness was measured. We performed a vertex-based analysis across the entire cortical surface and a region-of-interest analysis of a priori hypothesized territories to measure cortical thickness and map correlations between this measure and SCR. We found significant, direct correlation between thickness of the vmPFC, specifically medial orbitofrontal cortex, and extinction retention. That is, thicker medial orbitofrontal cortex was associated with lower SCR to the conditioned stimulus during extinction recall (i.e., greater extinction memory). These results suggest that the size of the vmPFC might explain individual differences in the ability to modulate fear among humans.     

Age-dependent changes in prefrontal intrinsic connectivity

The prefrontal cortex continues to mature after puberty and into early adulthood, mirroring the time course of maturation of cognitive abilities. However, the way in which prefrontal activity changes during peri- and postpubertal cortical maturation is largely unknown. To address this question, we evaluated the developmental stage of peripubertal rhesus monkeys with a series of morphometric, hormonal, and radiographic measures, and conducted behavioral and neurophysiological tests as the monkeys performed working memory tasks. We compared firing rate and the strength of intrinsic functional connectivity between neurons in peripubertal vs. adult monkeys. Notably, analyses of spike train cross-correlations demonstrated that the average magnitude of functional connections measured between neurons was lower overall in the prefrontal cortex of peripubertal monkeys compared with adults. The difference resulted because negative functional connections (indicative of inhibitory interactions) were stronger and more prevalent in peripubertal compared with adult monkeys, whereas the positive connections showed similar distributions in the two groups. Our results identify changes in the intrinsic connectivity of prefrontal neurons, particularly that mediated by inhibition, as a possible substrate for peri- and postpubertal advances in cognitive capacity.The prefrontal cortex, the brain area associated with the highest-level cognitive operations, is known to undergo a protracted period of development (1–3). A virtually linear increase in performance with age has been observed in tasks that assess visuospatial working memory, executive control, and resistance to distraction, a process that continues well after puberty and into early adulthood (4, 5). The accrual of cognitive capacities during this period parallels structural changes of the prefrontal cortex in humans and nonhuman primates (6–10). Imaging studies in humans suggest that patterns of brain activation associated with working memory tasks undergo distinct changes between childhood and adulthood, supporting the idea of prolonged prefrontal maturation (11–14). However, how the patterns of prefrontal activation change during cortical maturation remains unclear. A possible mechanism that could account for variations in prefrontal responses—and which could have a significant functional impact (15)—is an overall change in the distribution of intrinsic functional connections, i.e., those between neurons within the prefrontal cortex. The intrinsic connectivity of a network is directly related to the correlation structure of neuronal responses, and this determines in a fundamental way the information-coding properties of the network and its ability to sustain activity on its own (16–18). In this study, we sought to determine if the strengths of functional connections inferred from multisite neurophysiological recordings differ between peripubertal and adult monkeys.     

Lateral prefrontal cortex contributes to maladaptive decisions

Humans consistently make suboptimal decisions involving random events, yet the underlying neural mechanisms remain elusive. Using functional MRI and a matching pennies game that captured subjects' increasing tendency to predict the break of a streak as it continued [i.e., the "gambler's fallacy" (GF)], we found that a strong blood oxygen level-dependent response in the left lateral prefrontal cortex (LPFC) to the current outcome preceded the use of the GF strategy 10 s later. Furthermore, anodal transcranial direct current stimulation over the left LPFC, which enhances neuronal firing rates and cerebral excitability, increased the use of the GF strategy, and made the decisions more "sticky." These results reveal a causal role of the LPFC in implementing suboptimal decision strategy guided by false world models, especially when such strategy requires great resources for cognitive control.     

Orbitofrontal cortex and dorsal striatum functional connectivity predicts incubation of opioid craving after voluntary abstinence

We recently introduced a rat model of incubation of opioid craving after voluntary abstinence induced by negative consequences of drug seeking. Here, we used resting-state functional MRI to determine whether longitudinal functional connectivity changes in orbitofrontal cortex (OFC) circuits predict incubation of opioid craving after voluntary abstinence. We trained rats to self-administer for 14 d either intravenous oxycodone or palatable food. After 3 d, we introduced an electric barrier for 12 d that caused cessation of reward self-administration. We tested the rats for oxycodone or food seeking under extinction conditions immediately after self-administration training (early abstinence) and after electric barrier exposure (late abstinence). We imaged their brains before self-administration and during early and late abstinence. We analyzed changes in OFC functional connectivity induced by reward self-administration and electric barrier–induced abstinence. Oxycodone seeking was greater during late than early abstinence (incubation of oxycodone craving). Oxycodone self-administration experience increased OFC functional connectivity with dorsal striatum and related circuits that was positively correlated with incubated oxycodone seeking. In contrast, electric barrier–induced abstinence decreased OFC functional connectivity with dorsal striatum and related circuits that was negatively correlated with incubated oxycodone seeking. Food seeking was greater during early than late abstinence (abatement of food craving). Food self-administration experience and electric barrier–induced abstinence decreased or maintained functional connectivity in these circuits that were not correlated with abated food seeking. Opposing functional connectivity changes in OFC with dorsal striatum and related circuits induced by opioid self-administration versus voluntary abstinence predicted individual differences in incubation of opioid craving.

High rates of relapse perpetuate opioid addiction and are a major obstacle in addressing the US opioid crisis (1, 2). In humans, relapse and craving are often triggered by reexposure to cues and contexts previously associated with drug use (3, 4). In rats with a history of opioid (heroin or oxycodone) self-administration, opioid seeking progressively increases or incubates during homecage forced abstinence (5, 6). However, a main limitation of most current animal models of incubation of drug craving and relapse is that prior to relapse testing, abstinence is experimenter-imposed or forced (6, 7). This contrasts with the human condition where abstinence is often self-imposed due to adverse consequences of drug seeking (8).Based on these considerations, we recently introduced a rat model of incubation of oxycodone craving after “voluntary abstinence” induced by adverse consequences of drug seeking (9). The model is based on the electric barrier conflict model (10) that was more recently adapted to study relapse to drug seeking (11). In our modified model, we induce abstinence by introducing an electric barrier near the drug-paired lever that rats must cross to gain access to oxycodone. As shock intensity increases over days, rats decrease their oxycodone intake and eventually stop self-administering oxycodone. We then assess relapse to drug seeking during early and late abstinence in the absence of oxycodone or shock. We found that oxycodone seeking in the relapse tests is greater after 15 and 30 abstinence days than after 1 d, demonstrating incubation of oxycodone craving after electric barrier–induced abstinence (9). Unexpectedly, in both sexes, the incubation effect was stronger after electric barrier–induced abstinence than after homecage forced abstinence (9).In the present study, we determined whether functional connectivity changes that develop during oxycodone self-administration and subsequent electric barrier–induced abstinence would predict individual differences in incubation of oxycodone craving. We measured functional connectivity of orbitofrontal cortex (OFC)–related circuits using resting-state functional MRI (fMRI) (12, 13), a noninvasive brain imaging technique that longitudinally measures synchronous activity between brain regions. Resting-state fMRI has been used to characterize the relationship between brain activity and behaviors in both humans (14, 15) and laboratory animals (16, 17). Our group developed a rat resting-state fMRI protocol (18) and used it to investigate neural mechanisms in rodent models of neurological and psychiatric disorders (17, 19). Here, we compared the fMRI measures of rats with a history of oxycodone self-administration to drug-naïve rats trained to self-administer palatable food pellets that we use in our studies on relapse to drug seeking after food choice-induced abstinence (20).We focused on the OFC as the seed region for assessing longitudinal functional connectivity changes because previous human imaging studies reported that craving induced by heroin cues is associated with increased OFC activity (21, 22). In rats, cue-induced reinstatement of heroin seeking after extinction (23), incubation of heroin seeking after forced abstinence (24, 25), and relapse to fentanyl seeking after food choice-induced abstinence (26) are associated with increased Fos expression and other immediate early genes in OFC. Additionally, reversible inactivation of OFC decreases incubated heroin and oxycodone seeking after forced abstinence (25, 27) and relapse to fentanyl seeking after food choice-induced abstinence (26). Finally, heroin self-administration causes long-lasting impairments of OFC-mediated decision-making processes (28).     

Fiber density between rhinal cortex and activated ventrolateral prefrontal regions predicts episodic memory performance in humans

The prefrontal cortex (PFC) is assumed to contribute to goal-directed episodic encoding by exerting cognitive control on medial temporal lobe (MTL) memory processes. However, it is thus far unclear to what extent the contribution of PFC-MTL interactions to memory manifests at a structural anatomical level. We combined functional magnetic resonance imaging and fiber tracking based on diffusion tensor imaging in 28 young, healthy adults to quantify the density of white matter tracts between PFC regions that were activated during the encoding period of a verbal free-recall task and MTL subregions. Across the cohort, the strength of fiber bundles linking activated ventrolateral PFC regions and the rhinal cortex (comprising the peri- and entorhinal cortices) of the MTL correlated positively with free-recall performance. These direct white matter connections provide a basis through which activated regions in the PFC can interact with the MTL and contribute to interindividual differences in human episodic memory.     

Sleep deprivation and the control of ventilation

Sleep deprivation is common in acutely ill patients because of their underlying disease and can be compounded by aggressive medical care. While sleep deprivation has been shown to produce a number of psychological and physiologic events, the effects on respiration have been minimally evaluated. We therefore studied resting ventilation and ventilatory responses to hypoxia and hypercapnia before and after 24 h of sleeplessness in 13 healthy men. Hypoxic ventilatory responses (HVR) were measured during progressive isocapnic hypoxia, and hypercapnic ventilatory responses (HCVR) were measured using a rebreathing technique. Measures of resting ventilation, i.e., minute ventilation, tidal volume, arterial oxygen saturation, and end-tidal gas concentrations, did not change with short-term sleep deprivation. Both HVR and HCVR, however, decreased significantly after a single night without sleep. The mean hypoxic response decreased 29% from a slope of 1.20 +/- 0.22 (SEM) to 0.85 +/- 0.15 L/min/% saturation (p less than 0.02), and the slope of the HCVR decreased 24% from 2.07 +/- 0.17 to 1.57 +/- 0.15 L/min/mmHg PCO2 (p less than 0.01). These data indicate that ventilatory chemosensitivity may be substantially attenuated by even short-term sleep deprivation. This absence of sleep could therefore contribute to hypoventilation in acutely ill patients.     

Hyperpolarization-activated graded persistent activity in the prefrontal cortex

We describe a phenomenon of hyperpolarization-activated graded persistent activity (HAGPA) in prefrontal cortex neurons. Successive hyperpolarizing pulses induced increasingly higher rates of tonic firing that remained stable for tens of seconds, allowing the neuron to retain a memory of the previous history of stimulation. This phenomenon occurred at the cellular level and in the absence of neuromodulators. Neurons with HAGPA had a sag during hyperpolarization, and blocking h-current eliminated the sag and prevented HAGPA, suggesting that the activation of this hyperpolarization-activated cationic current was necessary for the occurrence of the phenomenon. A single-neuron biophysical model including h-current modulation by intracellular calcium was able to display HAGPA. This form of neuronal memory not only allows the transformation of inhibition into an increase of firing rate, but also endows neurons with a mechanism to compute the properties of successive inputs into persistent activity, thus solving a difficult computational problem.     

Total pancreatectomy increases the metabolic response to glucagon in humans

To evaluate the impact of glucagon deficiency on the response to glucagon replacement, we infused physiological doses of glucagon (1.25 ng/kg X min) into 9 totally pancreatectomized (PX) diabetic patients (C-peptide, undetectable) 1) for 24 h during their usual diet and insulin regimen and/or 2) for 6 h in a fasted insulin-withdrawn state. During both glucagon infusions, plasma glucagon rose from 46 +/- 2 (+/- SE) pg/ml (0-10% 3500 mol wt glucagon) to 112 +/- 9 pg/ml. In the 24-h study (n = 4), glucagon significantly increased mean 24-h glucose levels (272 +/- 27 mg/dl; P less than 0.05) and glycosuria (29 +/- 5 g/day; P less than 0.01) compared to preinfusion (158 +/- 14 mg/dl and 4 +/- 4 g/day, respectively) and postinfusion (200 +/- 35 mg/dl and 3 +/- 2 g/day) control periods. Blood ketones did not change. The 24-h glucagon infusion significantly lowered the fasting levels of the glucogenic amino acids aspartate (43%; P less than 0.01), threonine (46%; P less than 0.05), serine (46%; P less than 0.02), glycine (47%; P less than 0.01), and methionine (34%; P less than 0.02). Fasting alanine levels decreased from 835 +/- 236 to 393 +/- 66 microM (P less than 0.05). The 6-h glucagon infusion caused a 101 +/- 14 mg/dl maximal plasma glucose increment in PX (n = 8) vs. 33 +/- 11 in 5 insulin-withdrawn type I diabetic patients serving as controls (P = 0.022). Furthermore, when glucagon was infused at a higher rate (3 ng/kg X min) in 12 additional type I diabetic patients, the mean maximal plasma glucose increment (54 +/- 15 mg/dl) was still less than half that in PX, despite a 3-fold higher infusion plasma glucagon level (326 +/- 37 pg/ml). The 6-h glucagon infusion caused a significant decrease in the concentrations of glucogenic amino acids in the glucagon-deficient patients, but not in the type I diabetic patients. We conclude that 1) glucagon replacement in the PX patient markedly alters blood glucose and glucogenic amino acids, but not ketone levels; and 2) the metabolic response to glucagon is considerably more pronounced in PX patients than in type I diabetic patients. These data suggest that glucagon responsiveness is enhanced in the chronic hormone-deficient state.     

Anticipation of conflict monitoring in the anterior cingulate cortex and the prefrontal cortex

The anterior cingulate cortex (ACC) has been suggested as a monitoring center that is responsible for online detection of response conflicts. In this view, the conflict signal detected by the ACC is transmitted to other brain regions, such as the dorsal part of the lateral prefrontal cortex (lPFC), to increase the level of cognitive control. In this functional MRI (fMRI) study, we examined the conflict resolution that goes beyond online detection of response conflicts. Participants learned pseudoarithmetic problem-solving tasks that involve stimulus-response mapping rules with high or low conflicts. On half of the trials, participants had a preview of the upcoming operator that allowed advance preparation for the mapping rules. The preview significantly reduced the conflict effects on latency. During the preview, both the ACC and lPFC were activated in anticipation of conflict, and this anticipatory activation was highly predictive of the subsequent latency. These results suggest that the ACC and lPFC are responsible for both anticipatory preparation and online adjustment in response to conflicts. The results also confirm the roles of the lPFC and ACC in managing conflict during problem solving and extend these roles to include responding to anticipation of conflicts that may arise between incompatible stimulus-response mappings maintained in working memory during preparation.     

Kappa opioids selectively control dopaminergic neurons projecting to the prefrontal cortex

Dopaminergic afferents arising from the ventral tegmental area (VTA) are crucial elements in the neural circuits that mediate arousal, motivation, and reinforcement. Two major targets of these afferents are the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). Whereas dopamine (DA) in the mPFC has been implicated in working memory and attentional processes, DA in the NAc is required for responding to reward predictive cues. These distinct functions suggest a role for independent firing patterns of dopaminergic neurons projecting to these brain regions. In fact, DA release in mPFC and NAc can be differentially modulated. However, to date, electrophysiological studies have largely overlooked heterogeneity among VTA neurons. Here, we provide direct evidence for differential neurotransmitter control of DA neural activity and corresponding DA release based on projection target. Kappa opioid receptor agonists inhibit VTA DA neurons that project to the mPFC but not those that project to the NAc. Moreover, DA levels in the mPFC, but not the NAc, are reduced after local infusion of kappa opioid receptor agonists into the VTA. These findings demonstrate that DA release in specific brain regions can be independently regulated by opioid targeting of a subpopulation of VTA DA neurons. Selective control of VTA DA neurons projecting to the mPFC has important implications for understanding addiction, attention disorders, and schizophrenia, all of which are associated with DA dysfunction in the mPFC.     

Rapid metabolic evolution in human prefrontal cortex

Human evolution is characterized by the rapid expansion of brain size and drastic increase in cognitive capabilities. It has long been suggested that these changes were accompanied by modifications of brain metabolism. Indeed, human-specific changes on gene expression or amino acid sequence were reported for a number of metabolic genes, but actual metabolite measurements in humans and apes have remained scarce. Here, we investigate concentrations of more than 100 metabolites in the prefrontal and cerebellar cortex in 49 humans, 11 chimpanzees, and 45 rhesus macaques of different ages using gas chromatography-mass spectrometry (GC-MS). We show that the brain metabolome undergoes substantial changes, both ontogenetically and evolutionarily: 88% of detected metabolites show significant concentration changes with age, whereas 77% of these metabolic changes differ significantly among species. Although overall metabolic divergence reflects phylogenetic relationships among species, we found a fourfold acceleration of metabolic changes in prefrontal cortex compared with cerebellum in the human lineage. These human-specific metabolic changes are paralleled by changes in expression patterns of the corresponding enzymes, and affect pathways involved in synaptic transmission, memory, and learning.     

Memory fields of neurons in the primate prefrontal cortex

Many prefrontal (PF) neurons convey information about both an object’s identity (what) and its location (where). To explore how they represent conjunctions of what and where, we explored the receptive fields of their mnemonic activity (i.e., their “memory fields”) by requiring monkeys to remember both an object and its location at many positions throughout a wide portion of central vision. Many PF neurons conveyed object information and had highly localized memory fields that emphasized the contralateral, but not necessarily foveal, visual field. These results indicate that PF neurons can simultaneously convey precise location and object information and thus may play a role in constructing a unified representation of a visual scene.