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In MRI studies, spatial normalization is required to infer results at the group level. In the presence of a brain lesion, such as in stroke patients, the normalization process can be affected by tissue loss, spatial deformations, signal intensity changes, and other stroke sequelae that introduce confounds into the group analysis results. Previously, most neuroimaging studies with lesioned brains have used normalization methods optimized for intact brains, raising potential concerns about the accuracy of the resulting transformations and, in turn, their reported group level results. In this study, we demonstrate the benefits of creating an intermediate, cohort‐specific template in conjunction with diffeomorphism‐based methods to normalize structural MRI images in stroke patients. We show that including this cohort‐specific template improves accuracy compared to standard methods for normalizing lesioned brains. Critically, this method reduces overall differences in normalization accuracy between stroke patients and healthy controls, and may improve the localization and connectivity of BOLD signal in functional neuroimaging data., Proper normalization is crucial for group neuroimaging studies. However, this process is often suboptimal in lesion studies. We propose that the normalizing images to a cohort‐specific template may improve normalization of lesion studies and increase the fidelity of the group level results.

PURPOSE OF REVIEW: To address variation in the severity of gambling disorder, this review evaluates the contribution of mesocorticolimbic dopamine neurons to potential behavioral endophenotypes, the influence of individual differences in the dopamine system on gambling and related behaviors, and the possible role for dopaminergic medications in the treatment of gambling disorder. RECENT FINDINGS: Newer work has suggested that dopaminergic dysfunction can lead to increased reward anticipation and a greater sensitivity to uncertainty, which in turn may drive addictive gambling behaviors. In addition, increased impulsivity, a well-recognized risk factor for gambling disorder, has been linked to dopaminergic dysfunction. More recently, emerging evidence has suggested that dopaminergic medications can influence the discounting of delayed rewards. SUMMARY: Dopaminergic drugs that increase the salience of long-term over short-term goals may ameliorate symptoms of impulsive individuals with gambling disorder. More broadly, improved understanding of intermediate behavioral and other phenotypes with a defined neurobiological substrate may allow for personalized treatment of gambling disorder and other psychiatric conditions.

Post-traumatic stress disorder (PTSD) leads to impairments in both cognitive and affective functioning. Animal work suggests that chronic stress reduces dopamine tone, and both animal and human studies argue that changes in dopamine tone influence working memory, a core executive function. These findings give rise to the hypothesis that increasing cortical dopamine tone in individuals with greater PTSD symptomatology should improve working memory performance. In this pharmacological functional magnetic resonance imaging (fMRI) study, 30 US military veterans exhibiting a range of PTSD severity completed an emotional working memory task. Each subject received both placebo and the catechol-O-methyl transferase inhibitor tolcapone, which increases cortical dopamine tone, in randomized, double-blind, counterbalanced fashion. Mnemonic discriminability (calculated with d′, an index of the detectability of working memory signals) and response bias were evaluated in the context of task-related brain activations. Subjects with more severe PTSD showed both greater tolcapone-mediated improvements in d′ and larger tolcapone-mediated reductions in liberally-biased responding for fearful stimuli. FMRI revealed that tolcapone augmented activity within bilateral frontoparietal control regions during the decision phase of the task. Specifically, tolcapone increased cortical responses to fearful relative to neutral stimuli in higher severity PTSD subjects, and reduced cortical responses to fearful stimuli for lower severity PTSD subjects. Moreover, tolcapone modulated prefrontal connectivity with areas overlapping the default mode network. These findings suggest that enhancing cortical dopamine tone may represent an approach to remediating cognitive and affective dysfunction in individuals with more severe PTSD symptoms.

The contents of working memory must be maintained in the face of distraction, but updated when appropriate. To manage these competing demands of stability and flexibility, maintained representations in working memory are complemented by distinct gating mechanisms that selectively transmit information into and out of memory stores. The operations of such dopamine-dependent gating systems in the midbrain and striatum and their complementary dopamine-dependent memory maintenance operations in the cortex may therefore be dissociable. If true, selective increases in cortical dopamine tone should preferentially enhance maintenance over gating mechanisms. To test this hypothesis, tolcapone, a catechol-O-methyltransferase inhibitor that preferentially increases cortical dopamine tone, was administered in a randomized, double-blind, placebo-controlled, within-subject fashion to 49 participants who completed a hierarchical working memory task that varied maintenance and gating demands. Tolcapone improved performance in a condition with higher maintenance requirements and reduced gating demands, reflected in a reduction in the slope of RTs across the distribution. Resting-state fMRI data demonstrated that the degree to which tolcapone improved performance in individual participants correlated with increased connectivity between a region important for stimulus response mappings (left dorsal premotor cortex) and cortical areas implicated in visual working memory, including the intraparietal sulcus and fusiform gyrus. Together, these results provide evidence that augmenting cortical dopamine tone preferentially improves working memory maintenance.

RationaleIndividuals suffering from alcohol use disorder (AUD) demonstrate difficulty with decision-making and impulsivity that may be associated with impaired frontal cortical function. Therapeutics that enhance frontal dopamine tone could decrease impulsivity and in turn reduce alcohol consumption in individuals with AUD.ObjectivesTo determine if the catechol-O-methyltransferase (COMT) inhibitor tolcapone can attenuate alcohol consumption in individuals with AUD and whether this attenuation correlates with tolcapone-induced changes in laboratory-based decision-making tasks.MethodsWe used daily self-report and a novel group laboratory bar task to assess the effects of randomized double-blind crossover administration of tolcapone (100mg TID for 5days) on alcohol consumption and laboratory tasks assessing impulsivity in 55 non-treatment-seeking subjects with AUD.ResultsTolcapone significantly reduced self-reported alcohol consumption (t (54) = 2.05, p = 0.045). The effects of tolcapone on drinking significantly correlated with changes in impulsive decision-making, such that subjects with the greatest decrease in impulsive choice on tolcapone also reported the greatest decrease in alcohol consumption (r (45) = 0.40, p = 0.0053). We did not see effects of tolcapone on laboratory bar consumption. Adverse event (AE) reporting was low, with no significant difference in frequency or severity of AEs on tolcapone versus placebo.ConclusionsThese data demonstrate that COMT inhibitors such as tolcapone may be useful therapeutics for AUD.Trial registrationClinicalTrials.gov Identifier: NCT02740582.

Rationale Impairment in time perception, a critical component of decision-making, represents a risk factor for psychiatric conditions including substance abuse. A therapeutic that ameliorates this impairment could be advantageous in the treatment of impulsivity and decision-making disorders. Objectives Here we hypothesize that the catechol-O-methyltransferase (COMT) inhibitor tolcapone, which increases dopamine tone in frontal cortex (Ceravolo et al Synapse 43:201–207, 2002), improves time perception, with predictive behavioral, genetic, and neurobiological components. Methods Subjects (n = 66) completed a duration estimation task and other behavioral testing in each of two sessions after receiving a single oral dose of tolcapone (200 mg) or placebo in randomized, double-blind, counterbalanced, crossover fashion. Resting state fMRI data were obtained in a subset of subjects (n = 40). Subjects were also genotyped for the COMT (rs4680) polymorphism. Results Time perception was significantly improved across four proximal time points ranging from 5 to 60 s (T(524) = 2.04, p = 0.042). The degree of this improvement positively correlated with subjective measures of stress, depression, and alcohol consumption and was most robust in carriers of the COMT Val158 allele. Using seed regions defined by a previous meta-analysis (Wiener et al Neuroimage 49:1728–1740, 2010), we found not only that a connection from right inferior frontal gyrus (RIFG) to right putamen decreases in strength on tolcapone versus placebo (p

Patients with Alzheimer's disease and other dementias often make poor financial decisions, but it remains unclear whether this reflects specific failures in decision-making or more general deficits in episodic and working memory. We investigated how patients with Alzheimer's disease, behavioral variant frontotemporal dementia (bvFTD), and semantic variant primary progressive aphasia (svPPA) apply information in an intertemporal choice task between smaller intermediate and larger delayed rewards, with minimal memory demands. Multilevel modeling estimated subject-level sensitivities to three attributes of choice (the relative difference in reward magnitude, delay length, and absolute reward magnitudes) as well as baseline impulsivity. While baseline impulsivity in patients with Alzheimer's disease did not differ from controls, patients with bvFTD and svPPA were more impulsive than controls overall. Patients with Alzheimer's disease or bvFTD were less sensitive than controls to all three choice attributes, whereas patients with svPPA were less sensitive than controls to two attributes. Attenuated sensitivity to information presented during the choice was associated across all subjects with dorsomedial prefrontal atrophy for all three choice attributes. Given the minimal memory demands of our task, these findings suggest specific mechanisms underlying decision-making failures beyond episodic and working memory deficits in dementia.

Failures of self-regulation in problem and pathological gambling (PPG) are thought to emerge from failures of top-down control, reflected neurophysiologically in a reduced capacity of prefrontal cortex to influence activity within subcortical structures. In patients with addictions, these impairments have been argued to alter evaluation of reward within dopaminergic neuromodulatory systems. Previously we demonstrated that augmenting dopamine tone in frontal cortex via use of tolcapone, an inhibitor of the dopamine-degrading enzyme catechol-O-methyltransferase (COMT), reduced delay discounting, a measure of impulsivity, in healthy subjects. To evaluate this potentially translational approach to augmenting prefrontal inhibitory control, here we hypothesized that increasing cortical dopamine tone would reduce delay discounting in PPG subjects in proportion to its ability to augment top-down control. To causally test this hypothesis, we administered the COMT inhibitor tolcapone in a randomized, double-blind, placebo-controlled, within-subject study of 17 PPG subjects who performed a delay discounting task while functional MRI images were obtained. In this subject population, we found that greater BOLD activity during the placebo condition within the right inferior frontal cortex (RIFC), a region thought to be important for inhibitory control, correlated with greater declines in impulsivity on tolcapone versus placebo. Intriguingly, connectivity between RIFC and the right striatum, and not the level of activity within RIFC itself, increased on tolcapone versus placebo. Together, these findings support the hypothesis that tolcapone-mediated increases in top-down control may reduce impulsivity in PPG subjects, a finding with potential translational relevance for gambling disorders, and for behavioral addictions in general., Highlights • Nonplanning impulsivity correlates with changes in delay discounting on tolcapone. • Inferior frontal cortical activity covaries with changes in discounting on tolcapone. • The strength of frontostriatal connectivity correlates with tolcapone response. • Enhancing cortical dopamine tone may be useful in treatment of addictive disorders.

RATIONALE:The prefrontal cortex (PFC) and basal ganglia (BG) have been associated with cognitive stability and cognitive flexibility, respectively. We hypothesized that increasing PFC dopamine tone by administering tolcapone (a catechol-O-methyltransferase (COMT) inhibitor) to human subjects should promote stability; conversely, increasing BG dopamine tone by administering bromocriptine (a D2 receptor agonist) should promote flexibility. OBJECTIVE:We assessed these hypotheses by administering tolcapone, bromocriptine, and a placebo to healthy subjects who performed a saccadic eye movement task requiring stability and flexibility. METHODS:We used a randomized, double-blind, within-subject design that was counterbalanced across drug administration sessions. In each session, subjects were cued to prepare for a pro-saccade (look towards a visual stimulus) or anti-saccade (look away) on every trial. On 60% of the trials, subjects were instructed to switch the response already in preparation. We hypothesized that flexibility would be required on switch trials, whereas stability would be required on non-switch trials. The primary measure of performance was efficiency (the percentage correct divided by reaction time for each trial type). RESULTS:Subjects were significantly less efficient across all trial types under tolcapone, and there were no significant effects of bromocriptine. After grouping subjects based on Val158Met COMT polymorphism, we found that Met/Met and Val/Met subjects (greater PFC dopamine) were less efficient compared to Val/Val subjects. CONCLUSIONS:Optimal behavior was based on obeying the environmental stimuli, and we found reduced efficiency with greater PFC dopamine tone. We suggest that greater PFC dopamine interfered with the ability to flexibly follow the environment.

© The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com. The onset of adolescence is associated with an increased tendency to engage in risky behaviors and a developmental shift toward peers that contributes to increased prioritization for learning about and achieving social status. There is relatively little understanding about the specific links between these adolescent-typical phenomena, particularly regarding their neural underpinnings. Based on existing models that suggest the role of puberty in promoting adolescent status-seeking and risk-taking tendencies, we investigated the relation of pubertal hormones with behavioral and neural responses to status-relevant social information in the context of risk taking. We used a probabilistic decision task in which 11- to 13-year-old girls chose to take a risk, or not, while receiving either social rank or monetary performance feedback. While feedback type did not differentially influence risk-taking behavior, whole-brain imaging results showed that activation in the anterior insula was increased for risk taking in the social rank feedback condition compared to the monetary feedback condition. This heightened activation was more pronounced in girls with higher estradiol levels. These findings suggest that brain processes involved in adolescent risky decisions may be influenced by the desire for social-status enhancement and provide preliminary evidence for the role of pubertal hormones in enhancing this adolescent-typical social sensitivity.

© 2016 The Authors Adolescence is a developmental period characterized by a greater tendency to take risks. While the adult literature has shown that sex steroids influence reward-related brain functioning and risk taking, research on the role of these hormones during puberty is limited. In this study, we examined the relation between pubertal hormones and adolescent risk taking using a probabilistic decision-making task. In this task, participants could choose on each trial to play or pass based on explicit information about the risk level and stakes involved in their decision. We administered this task to 58 11-to-13-year-old girls while functional MRI images were obtained to examine reward-related brain processes associated with their risky choices. Results showed that higher testosterone levels were associated with increased risk taking, which was mediated by increased medial orbitofrontal cortex activation. Furthermore, higher estradiol levels were associated with increased nucleus accumbens activation, which in turn related to decreased risk taking. These findings offer potential neuroendocrine mechanisms that can explain why some adolescent girls might engage in more risk taking compared to others.

Varenicline is a smoking cessation aid for which limited data exist concerning safety during human pregnancy. This multicentre prospective observational comparative cohort study was undertaken using surveillance data collected by the European Network of Teratology Information Services. The study sample consisted of 89 varenicline exposed pregnancies and two matched comparator groups; 267 non-teratogen exposed (NTE) controls and 78 exposed to nicotine replacement therapy or bupropion (NRT/B) for smoking cessation. For all exposed pregnancies, varenicline use only occurred in the first trimester, with a considerable proportion discontinuing use in the very early stages of pregnancy. The major congenital malformation rate (n = 2/89, 2.25%) was in keeping with the expected background rate (2–4%), and was not significantly increased for first trimester varenicline-exposed infants in comparison with non-exposed controls (vs. NTE: OR 2.02, 95%CI 0.166 to 17.9, vs. NRT/B: OR 0.874, 95%CI 0.0620 to 12.3). However, the small sample size produced very imprecise risk estimates.

To date it has been unclear whether perceptual decision making and rule-based categorization reflect activation of similar cognitive processes and brain regions. On one hand, both map potentially ambiguous stimuli to a smaller set of motor responses. On the other hand, decisions about perceptual salience typically concern concrete sensory representations derived from a noisy stimulus, while categorization is typically conceptualized as an abstract decision about membership in a potentially arbitrary set. Previous work has primarily examined these types of decisions in isolation. Here we independently varied salience in both the perceptual and categorical domains in a random dot-motion framework by manipulating dot-motion coherence and motion direction relative to a category boundary, respectively. Behavioral and modeling results suggest that categorical (more abstract) information, which is more relevant to subjects’ decisions, is weighted more strongly than perceptual (more concrete) information, although they also have significant interactive effects on choice. Within the brain, BOLD activity within frontal regions strongly differentiated categorical salience and weakly differentiated perceptual salience; however, the interaction between these two factors activated similar frontoparietal brain networks. Notably, explicitly evaluating feature interactions revealed a frontal-parietal dissociation: parietal activity varied strongly with both features, but frontal activity varied with the combined strength of the information that defined the motor response. Together, these data demonstrate that frontal regions are driven by decision-relevant features and argue that perceptual decisions and rule-based categorization reflect similar cognitive processes and activate similar brain networks to the extent that they define decision-relevant stimulus-response mappings. NEW & NOTEWORTHY Here we study the behavioral and neural dynamics of perceptual categorization when decision information varies in multiple domains at different levels of abstraction. Behavioral and modeling results suggest that categorical (more abstract) information is weighted more strongly than perceptual (more concrete) information but that perceptual and categorical domains interact to influence decisions. Frontoparietal brain activity during categorization flexibly represents decision-relevant features and highlights significant dissociations in frontal and parietal activity during decision making.

When we respond to a stimulus, our decisions are based not only on external stimuli but also on our ongoing performance. If the response deviates from our goals, monitoring and decision-making brain areas interact so that future behavior may change. By taking advantage of natural variation in error salience, as measured by the RT taken to correct an error (RTEC), here we argue that an evidence accumulation framework provides a potential underlying mechanism for this variable process of error identification and correction, as evidenced by covariation of frontal monitoring and parietal decision-making processes. We study two early EEG signals linked to monitoring within medial PFC—the error-related negativity (ERN) and frontocentral theta activity—and a third EEG signal, the error positivity (Pe), that is thought to share the same parietal substrates as a signal (the P3b) proposed to reflect evidence accumulation. As predicted, our data show that on slow RTEC trials, frontal monitoring resources are less strongly employed, and the latency of the Pe is longer. Critically, the speed of the RTEC also covaries with the magnitude of subsequent neural (intertrial alpha power) and behavioral (post-error slowing) adjustments following the correction. These results are synthesized to describe a timing diagram for adaptive decision-making after errors and support a potential evidence accumulation mechanism in which error signaling is followed by rapid behavioral adjustments.

© 2015 The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. Many neuropsychiatric disorders are marked by abnormal behaviour and decision-making, but prevailing diagnostic criteria for such behaviours are typically qualitative and often ambiguous. Behavioural variant frontotemporal dementia and semantic variant primary progressive aphasia (also called semantic dementia) are two clinical variants of frontotemporal dementia with overlapping but distinct anatomical substrates known to cause profound changes in decision-making. We investigated whether abnormal decision-making in these syndromes could be more precisely characterized in terms of dissociable abnormalities in patients' subjective evaluations of valence (positive versus negative outcome) and of time (present versus future outcome). We presented 28 patients with behavioural variant frontotemporal dementia, 14 patients with semantic variant primary progressive aphasia, 25 patients with Alzheimer's disease (as disease controls), and 61 healthy older control subjects with experimental tasks assaying loss aversion and delay discounting. In general linear models controlling for age, gender, education and Mini-Mental State Examination score, patients with behavioural variant frontotemporal dementia were less averse to losses than control subjects (P < 0.001), while patients with semantic variant primary progressive aphasia discounted delayed rewards more steeply than controls (P = 0.019). There was no relationship between loss aversion and delay discounting across the sample, nor in any of the subgroups. These findings suggest that abnormal behaviours in neurodegenerative disease may result from the disruption of either of two dissociable neural processes for evaluating the outcomes of action. More broadly, these findings suggest a role for computational methods to supplement traditional qualitative characterizations in the differential diagnosis of neuropsychiatric disorders.

The onset of adolescence is associated with an increase in the behavioral tendency to explore and seek novel experiences. However, this exploration has rarely been quantified, and its neural correlates during this period remain unclear. Previously, activity within specific regions of the rostrolateral PFC (rlPFC) in adults has been shown to correlate with the tendency for exploration. Here we investigate a recently developed task to assess individual differences in strategic exploration, defined as the degree to which the relative uncertainty of rewards directs responding toward less well-evaluated choices, in 62 girls aged 11–13 years from whom resting state fMRI data were obtained in a separate session. Behaviorally, this task divided our participants into groups of explorers (n = 41) and nonexplorers (n = 21). When seed ROIs within the rlPFC were used to interrogate resting state fMRI data, we identified a lateralized connection between the rlPFC and posterior putamen/insula whose strength differentiated explorers from nonexplorers. On the basis of Granger causality analyses, the preponderant direction of influence may proceed from posterior to anterior. Together, these data provide initial evidence concerning the neural basis of exploratory tendencies at the onset of adolescence.

We model the development of the functional circuit of layer 4 (the input-recipient layer) of cat primary visual cortex. The observed thalamocortical and intracortical circuitry codevelop under Hebb-like synaptic plasticity. Hebbian development yields opponent inhibition: inhibition evoked by stimuli anticorrelated with those that excite a cell. Strong opponent inhibition enables recognition of stimulus orientation in a manner invariant to stimulus contrast. These principles may apply to cortex more generally: Hebb-like plasticity can guide layer 4 of any piece of cortex to create opposition between anticorrelated stimulus pairs, and this enables recognition of specific stimulus patterns in a manner invariant to stimulus magnitude. Properties that are invariant across a cortical column are predicted to be those shared by opponent stimulus pairs; this contrasts with the common idea that a column represents cells with similar response properties.

Although we often encounter circumstances with which we have no prior experience, we rapidly learn how to behave in these novel situations. Such adaptive behavior relies on abstract behavioral rules that are generalizable, rather than concrete rules mapping specific cues to specific responses. Though the frontal cortex is known to support concrete rule learning, less well understood are the neural mechanisms supporting the acquisition of abstract rules. Here we use a novel reinforcement learning paradigm to demonstrate that more anterior regions along the rostro-caudal axis of frontal cortex support rule learning at higher levels of abstraction. Moreover, these results indicate that when humans confront new rule learning problems, this rostro-caudal division of labor supports the search for relationships between context and action at multiple levels of abstraction simultaneously.