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.

Disrupting the prefrontal cortex diminishes the human ability to build a good reputation.

Reputation formation pervades human social life. In fact, many people go to great lengths to acquire a good reputation, even though building a good reputation is costly in many cases. Little is known about the neural underpinnings of this important social mechanism, however. In the present study, we show that disruption of the right, but not the left, lateral prefrontal cortex (PFC) with low-frequency repetitive transcranial magnetic stimulation (rTMS) diminishes subjects' ability to build a favorable reputation. This effect occurs even though subjects' ability to behave altruistically in the absence of reputation incentives remains intact, and even though they are still able to recognize both the fairness standards necessary for acquiring and the future benefits of a good reputation. Thus, subjects with a disrupted right lateral PFC no longer seem to be able to resist the temptation to defect, even though they know that this has detrimental effects on their future reputation. This suggests an important dissociation between the knowledge about one's own best interests and the ability to act accordingly in social contexts. These results link findings on the neural underpinnings of self-control and temptation with the study of human social behavior, and they may help explain why reputation formation remains less prominent in most other species with less developed prefrontal cortices.

Diminishing risk-taking behavior by modulating activity in the prefrontal cortex: a direct current stimulation study.

Studies have shown increased risk taking in healthy individuals after low-frequency repetitive transcranial magnetic stimulation, known to transiently suppress cortical excitability, over the right dorsolateral prefrontal cortex (DLPFC). It appears, therefore, plausible that differential modulation of DLPFC activity, increasing the right while decreasing the left, might lead to decreased risk taking, which could hold clinical relevance as excessively risky decision making is observed in clinical populations leading to deleterious consequences. The goal of the present study was to investigate whether risk-taking behaviors could be decreased using concurrent anodal transcranial direct current stimulation (tDCS) of the right DLPFC, which allows upregulation of brain activity, with cathodal tDCS of the left DLPCF, which downregulates activity. Thirty-six healthy volunteers performed the risk task while they received either anodal over the right with cathodal over the left DLPFC, anodal over the left with cathodal over the right DLPFC, or sham stimulation. We hypothesized that right anodal/left cathodal would decrease risk-taking behavior compared with left anodal/right cathodal or sham stimulation. As predicted, during right anodal/left cathodal stimulation over the DLPFC, participants chose more often the safe prospect compared with the other groups. Moreover, these participants appeared to be insensitive to the reward associated with the prospects. These findings support the notion that the interhemispheric balance of activity across the DLPFCs is critical in decision-making behaviors. Most importantly, the observed suppression of risky behaviors suggests that populations with boundless risk-taking behaviors leading to negative real-life consequences, such as individuals with addiction, might benefit from such neuromodulation-based approaches.

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).

Diminishing reciprocal fairness by disrupting the right prefrontal cortex.

Humans restrain self-interest with moral and social values. They are the only species known to exhibit reciprocal fairness, which implies the punishment of other individuals' unfair behaviors, even if it hurts the punisher's economic self-interest. Reciprocal fairness has been demonstrated in the Ultimatum Game, where players often reject their bargaining partner's unfair offers. Despite progress in recent years, however, little is known about how the human brain limits the impact of selfish motives and implements fair behavior. Here we show that disruption of the right, but not the left, dorsolateral prefrontal cortex (DLPFC) by low-frequency repetitive transcranial magnetic stimulation substantially reduces subjects' willingness to reject their partners' intentionally unfair offers, which suggests that subjects are less able to resist the economic temptation to accept these offers. Importantly, however, subjects still judge such offers as very unfair, which indicates that the right DLPFC plays a key role in the implementation of fairness-related behaviors.

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.

Distinctive insular forms of threespine stickleback (Gasterosteus aculeatus) from western Mediterranean islands

Neutral and adaptive variation among populations within a species is a major component of biological diversity and may be pronounced among insular populations due to geographical isolation and island specific evolutionary forces at work. Detecting and preserving potential evolutionary significant units below the species rank has become a crucial task for conservation biology. Combining genetic, phenotypic and ecological data, we investigated evolutionary patterns among the enigmatic threespine stickleback populations from western Mediterranean islands, all of which are threatened by habitat deterioration and climate change. We find indications that these populations derive from different genetic lineages, being genetically highly distinct from the stickleback of mainland Europe and the northern Atlantic as well as from each other. Mediterranean island stickleback populations are also phenotypically distinct from mainland populations but interestingly stickleback from Iceland have converged on a similar phenotype. This distinctive island stickleback phenotype seems to be driven by distinct selective regimes on islands versus continents. Overall, our results reveal the status of western Mediterranean island stickleback as evolutionarily distinct units, important for conservation of biodiversity.

The changing pace of insular life: 5000 years of microevolution in the Orkney vole (Microtus arvalis orcadensis)

Island evolution may be expected to involve fast initial morphological divergence followed by stasis. We tested this model using the dental phenotype of modern and ancient common voles (Microtus arvalis), introduced onto the Orkney archipelago (Scotland) from continental Europe some 5000 years ago. First, we investigated phenotypic divergence of Orkney and continental European populations and assessed climatic influences. Second, phenotypic differentiation among Orkney populations was tested against geography, time, and neutral genetic patterns. Finally, we examined evolutionary change along a time series for the Orkney Mainland. Molar gigantism and anterior-lobe hypertrophy evolved rapidly in Orkney voles following introduction, without any transitional forms detected. Founder events and adaptation appear to explain this initial rapid evolution. Idiosyncrasy in dental features among different island populations of Orkney voles is also likely the result of local founder events following Neolithic translocation around the archipelago. However, against our initial expectations, a second marked phenotypic shift occurred between the 4th and 12th centuries AD, associated with increased pastoral farming and introduction of competitors (mice and rats) and terrestrial predators (foxes and cats). These results indicate that human agency can generate a more complex pattern of morphological evolution than might be expected in island rodents.

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.

CHOLINERGIC MODULATION OF THALAMIC INPUT INTO THE CINGULATE CORTEX

This research demonstrates cholinergic modulation of thalamic input into the limbic cortex. A projection from the mediodorsal thalamus (MD) to the anterior cingulate cortex was defined anatomically and physiologically. Injections of horse-radish peroxidase into the anterior cingulate cortex labels neurons in the lateral, parvocellular, region of MD. Electrical Stimulation of this area produces a complex field potential in the anterior cingulate cortex which was further characterized by current density analysis and single cell recordings.^ The monsynaptic component of the response was identified as a large negative field which is maximal in layer IV of the anterior cingulate cortex. This response shows remarkable tetanic potentiation of frequencies near 7 Hz. During a train of 50 or more stimuli, the response would grow quickly and remain at a fairly stable potentiated level throughout the train.^ Cholinergic modulation of this thalamic response was demonstrated by iontophoretic application of the cholinergic agonist carbachol decreased the effectiveness of the thalamic imput by rapidly attenuation the response during a train of stimuli. The effect was apparently mediated by muscarinic receptors since the effect of carbachol was blocked by atropine but not by hexamethonium.^ To determine the source of the cingulate cortex cholinergic innervation, lesions were made in the anterior and medial thalamus and in the nucleus of the diagonal band of Broca. The effects of these lesions on choline acetyltranferase activity in the cingulate cortex were determined by a micro-radio-enzymatical assay. Only the lesions of the nucleus of the diagonal band significantly decreased the choline acetyltransferase activity in the cingulate cortex regions. Therefore, the diagonal band appears to be a major source of sensory cholinergic innervation and may be involved in gating of sensory information from the thalamus into the limbic cortex. Attempts to modulate the cingulate response to MD stimulation with electrical stimulation of the diagonal band, however were not successful.^

The contributions of the amygdala, orbital frontal cortex and hippocampal formation to primate social cognition

Deficits in social cognition are prominent symptoms of many human psychiatric disorders, but the origin of such deficits remains largely unknown. To further current knowledge regarding the neural network mediating social cognition, the present research program investigated the individual contributions of two temporal lobe structures, the amygdala and hippocampal formation, and one frontal lobe region, the orbital frontal cortex (Areas 11 and 13), to primate social cognition. Based on previous research, we hypothesized that the amygdala, hippocampal formation and orbital frontal cortex contribute significantly to the formation of new social relationships, but less to the maintenance of familiar ones. ^ Thirty-six male rhesus macaques (Macaca mulatta) served as subjects, and were divided into four experimental groups: Neurotoxic amygdala lesion (A-ibo, n = 9), neurotoxic or aspiration orbital frontal cortex lesion (O, n = 9), neurotoxic hippocampal formation lesion (H-ibo, n = 9) or sham-operated control (C, n = 9). Six social groups (tetrads) were created, each containing one member from each experimental group. The effect of lesion on established social relationships was assessed during pre- and post-surgical unrestrained social interactions, whereas the effect of lesion on the formation of new relationships was assessed during an additional phase of post-surgical testing with shuffled tetrad membership. Results indicated that these three neural structures each contribute significantly to both the formation and maintenance of social relationships. Furthermore, the amygdala appears to primarily mediate normal responses to threatening social signals, whereas the orbital frontal cortex plays a more global role in social cognition by mediating responses to both threatening and affiliative social signals. By contrast, the hippocampal formation seems to contribute to social cognition indirectly by providing access to previous experience during social judgments. ^ These conclusions were further investigated with three experiments that measured behavioral and physiological (stress hormone) reactivity to threatening stimuli, and three additional experiments that measured subjects' ability to flexibly alter behavioral responses depending on the incentive value of a food reinforcer. Data from these six experiments further confirmed and strengthened the three conclusions originating from the social behavior experiments and, when combined with the current literature, helped to formulate a simple, but testable, theoretical model of primate social cognition. ^

The contributions of the hippocampal formation, perirhinal cortex and areas TH/TF to object, spatial and contextual recognition memory in primates

Adult monkeys (Macaca mulatta) with lesions of the hippocampal formation, perirhinal cortex, areas TH/TF, as well as controls were tested on tasks of object, spatial and contextual recognition memory. ^ Using a visual paired-comparison (VPC) task, all experimental groups showed a lack of object recognition relative to controls, although this impairment emerged at 10 sec with perirhinal lesions, 30 sec with areas TH/TF lesions and 60 sec with hippocampal lesions. In contrast, only perirhinal lesions impaired performance on delayed nonmatching-to-sample (DNMS), another task of object recognition memory. All groups were tested on DNMS with distraction (dDNMS) to examine whether the use of active cognitive strategies during the delay period could enable good performance on DNMS in spite of impaired recognition memory (revealed by the VPC task). Distractors affected performance of animals with perirhinal lesions at the 10-sec delay (the only delay in which their DNMS performance was above chance). They did not affect performance of animals with areas TH/TF lesions. Hippocampectomized animals were impaired at the 600-sec delay (the only delay at which prevention of active strategies would likely affect their behavior). ^ While lesions of areas TH/TF impaired spatial location memory and object-in-place memory, hippocampal lesions impaired only object-in-place memory. The pattern of results for perirhinal cortex lesions on the different task conditions indicated that this cortical area is not critical for spatial memory. ^ Finally, all three lesions impaired contextual recognition memory processes. The pattern of impairment appeared to result from the formation of only a global representation of the object and background, and suggests that all three areas are recruited for associating information across sources. ^ These results support the view that (1) the perirhinal cortex maintains storage of information about object and the context in which it is learned for a brief period of time, (2) areas TH/TF maintain information about spatial location and form associations between objects and their spatial relationship (a process that likely requires additional time) and (3) the hippocampal formation mediates associations between objects, their spatial relationship and the general context in which these associations are formed (an integrative function that requires additional time). ^

Blood-oxygen-level-dependent (BOLD) signal changes in total cortex and subcortex, pain, reward, and vigilance regions during mechanical pressure pain after morphine administration

Morphine is the most common clinical choice in the management of severe pain. Although the molecular mechanisms of morphine have already been characterized, the cerebral circuits by which it attenuates the sensation of pain have not yet been studied in humans. The objective of this two-arm (morphine versus placebo), between-subjects study was to examine whether morphine affects pain via pain-related cortical circuits, but also via reward regions that relate to the motivational state, as well as prefrontal regions that relate to vigilance as a result of morphine's sedative effects. Cortical activity was measured by the blood-oxygen-level-dependent (BOLD) signal changes using functional magnetic resonance imaging (fMRI). ^ The novelty of this study is at three levels: (i) to develop a methodology that will assess the average BOLD signal across subjects for the pain, reward, and vigilance cortical systems; (ii) to examine whether the reward and/or sedative effects of morphine are contributing factors to cortical regions associated with the motivational state and vigilance; and (iii) to propose a neuroanatomical model related to the opioid-sensitive effects of reward and sedation as a function of cortical activity related to pain in an effort to assess future analgesics. ^ Consistent with our hypotheses, our findings showed that the decrease in total pain-related volume activated between the post- and the pre-treatment morphine group was about 78%, while the post-treatment placebo group displayed only a 5% decrease when compared to pre-treatment levels of activation. The volume increase in reward regions was 451% in the post-treatment compared to the pre-treatment morphine condition. Finally, the volumetric decrease in vigilance regions was 63% in the posttreatment compared to the pre-treatment morphine condition. ^ These findings imply that changes in the blood flow of the reward and vigilance regions may be contributing factors in producing the analgesic effect under morphine administration. Future studies need to replicate this study in a higher resolution fMRI environment and to assess the proposed neuroanatomical model in patient populations. The necessity of pain research is apparent, since pain cuts across different diseases especially chronic ones, and thus, is recognized as a vital public health developing area. ^

Dynamic population coding in primary visual cortex

More than a century ago Ramon y Cajal pioneered the description of neural circuits. Currently, new techniques are being developed to streamline the characterization of entire neural circuits. Even if this 'connectome' approach is successful, it will represent only a static description of neural circuits. Thus, a fundamental question in neuroscience is to understand how information is dynamically represented by neural populations. In this thesis, I studied two main aspects of dynamical population codes. ^ First, I studied how the exposure or adaptation, for a fraction of a second to oriented gratings dynamically changes the population response of primary visual cortex neurons. The effects of adaptation to oriented gratings have been extensively explored in psychophysical and electrophysiological experiments. However, whether rapid adaptation might induce a change in the primary visual cortex's functional connectivity to dynamically impact the population coding accuracy is currently unknown. To address this issue, we performed multi-electrode recordings in primary visual cortex, where adaptation has been previously shown to induce changes in the selectivity and response amplitude of individual neurons. We found that adaptation improves the population coding accuracy. The improvement was more prominent for iso- and orthogonal orientation adaptation, consistent with previously reported psychophysical experiments. We propose that selective decorrelation is a metabolically inexpensive mechanism that the visual system employs to dynamically adapt the neural responses to the statistics of the input stimuli to improve coding efficiency. ^ Second, I investigated how ongoing activity modulates orientation coding in single neurons, neural populations and behavior. Cortical networks are never silent even in the absence of external stimulation. The ongoing activity can account for up to 80% of the metabolic energy consumed by the brain. Thus, a fundamental question is to understand the functional role of ongoing activity and its impact on neural computations. I studied how the orientation coding by individual neurons and cell populations in primary visual cortex depend on the spontaneous activity before stimulus presentation. We hypothesized that since the ongoing activity of nearby neurons is strongly correlated, it would influence the ability of the entire population of orientation-selective cells to process orientation depending on the prestimulus spontaneous state. Our findings demonstrate that ongoing activity dynamically filters incoming stimuli to shape the accuracy of orientation coding by individual neurons and cell populations and this interaction affects behavioral performance. In summary, this thesis is a contribution to the study of how dynamic internal states such as rapid adaptation and ongoing activity modulate the population code accuracy. ^