A Neurofunctional Domains Approach to Evaluate D1/D5 Dopamine Receptor Partial Agonism on Cognition and Motivation in Healthy Volunteers With Low Working Memory Capacity.

BACKGROUND: Dopamine D1 receptor signaling plays key roles in core domains of neural function, including cognition and reward processing; however, many questions remain about the functions of circuits modulated by dopamine D1 receptor, largely because clinically viable, selective agonists have yet to be tested in humans. METHODS: Using a novel, exploratory neurofunctional domains study design, we assessed the safety, tolerability, pharmacodynamics, and pharmacokinetics of PF-06412562, a selective D1/D5R partial agonist, in healthy male volunteers who met prespecified criteria for low working memory capacity. Functional magnetic resonance imaging, electrophysiologic endpoints, and behavioral paradigms were used to assess working memory, executive function, and motivation/reward processing following multiple-dose administration of PF-06412562. A total of 77 patients were assigned PF-06412562 (3 mg twice daily and 15 mg twice daily) or placebo administered for 5 to 7 days. Due to the exploratory nature of the study, it was neither powered for any specific treatment effect nor corrected for multiple comparisons. RESULTS: Nominally significant improvements from baseline in cognitive endpoints were observed in all 3 groups; however, improvements in PF-06412562-treated patients were less than in placebo-treated participants. Motivation/reward processing endpoints were variable. PF-06412562 was safe and well tolerated, with no serious adverse events, severe adverse events, or adverse events leading to dose reduction or temporary discontinuation except for 1 permanent discontinuation due to increased orthostatic heart rate. CONCLUSIONS: PF-06412562, in the dose range and patient population explored in this study, did not improve cognitive function or motivation/reward processing more than placebo over the 5- to 7-day treatment period. CLINICALTRIALS.GOV IDENTIFIER: NCT02306876.

Anxiety positive subjects show altered processing in the anterior insula during anticipation of negative stimuli.

Prior neuroimaging studies support the hypothesis that anticipation, an important component of anxiety, may be mediated by activation within the insular and medial prefrontal cortices including the anterior cingulate cortex. However, there is an insufficient understanding of how affective anticipation differs across anxiety groups in emotional brain loci and networks. We examined 14 anxiety positive (AP) and 14 anxiety normative (AN) individuals completing an affective picture anticipation task during functional magnetic resonance imaging (fMRI). Brain activation was examined across groups for cued anticipation (to aversive or pleasant stimuli). Both groups showed greater activation in the bilateral anterior insula during cued differential anticipation (i.e., aversive vs. pleasant), and activation on the right was significantly higher in AP compared to AN subjects. Functional connectivity showed that the left anterior insula was involved in a similar network during pleasant anticipation in both groups. The left anterior insula during aversive and the right anterior insula during all anticipation conditions coactivated with a cortical network consisting of frontal and parietal lobes in the AP group to a greater degree. These results are consistent with the hypothesis that anxiety is related to greater anticipatory reactivity in the brain and that there may be functional asymmetries in the brain that interact with psychiatric traits.

Escitalopram attenuates posterior cingulate activity during self-evaluation in healthy volunteers.

Medial cortex is critically involved in self-referential processing. Little is known about how selective serotonin reuptake inhibitors (SSRIs) affect medial cortical activity during self-assessment. We hypothesized that a 3-week oral course of escitalopram,10 mg/day, would alter activity related to self-referential processing in medial cortex. Fifteen healthy females performed a self-assessment task during functional magnetic resonance imaging on two occasions--once after 3 weeks of placebo and once at the end of 3 weeks of escitalopram. Task conditions involved responding "yes" or "no" to whether various positive and negative adjectives described the subject (i.e., "self" evaluation trials) or the subject's best friend (i.e., "other" evaluation trials), whereas the comparison condition involved responding whether the valence of various adjectives was positive or negative (i.e., "word" evaluation trials). Behaviorally after escitalopram, subjects less frequently endorsed that negative adjectives described themselves. Three main neuroimaging results were observed: (1) increased activation in medial prefrontal cortex and posterior cingulate related to self minus word evaluation trials, (2) increased activation in posterior cingulate related to escitalopram minus placebo for self and word evaluation trials, and (3) drug by task interactions in the insula, cerebellum and prefrontal cortex. These results show that SSRIs change medial cortical activity and may alter self-evaluation.

Subchronic SSRI administration reduces insula response during affective anticipation in healthy volunteers.

The anterior cingulate cortex (ACC) and insula are important neural substrates for the integration of cognitive, emotional, and physiological information, as well as the coordination of responses to anticipated stimuli. Increased neural activation within these structures has been observed in individuals with anxiety and depressive disorders. Selective serotonin reuptake inhibitors (SSRIs) are among the most effective and frequently prescribed anxiolytic agents, yet it is not known whether ACC or insula underlie the effects of these drugs. We examined whether subchronic administration of a SSRI to healthy volunteers attenuates activation in ACC or insula during anticipation, an important emotional process underlying anxiety. Support for this hypothesis would help to understand where and by what process SSRIs may exert beneficial effects as anxiolytics and would provide further mechanistic evidence for functional magnetic resonance imaging (fMRI) as a biomarker for the development of anxiolytics. Fifteen volunteers participated in a double-blind, placebo-controlled, randomized cross-over study. Participants completed a pleasant and aversive picture-cued anticipation task during fMRI after taking either escitalopram (10 mg) or placebo for 21 d. We found that escitalopram significantly decreased activation in bilateral posterior and middle insula during the anticipation condition irrespective of stimulus valence and in medial prefrontal and ACC during anticipation of aversive vs. pleasant images. Reduced insular and ACC activation in healthy controls during anticipation may be integral to the therapeutic efficacy of SSRIs and may provide a mechanistic approach for the use of pharmaco-fMRI in the identification of novel pharmacotherapeutic agents in patient populations.

A novel approach to evaluate the pharmacodynamics of a selective dopamine D1/D5 receptor partial agonist (PF-06412562) in patients with stable schizophrenia.

BACKGROUND: PF-06412562 is an orally bioavailable, selective dopamine D1/D5 receptor partial agonist with a non-catechol structure under evaluation for treatment of cognitive impairment in schizophrenia. AIMS: This randomized, double-blind, placebo-controlled, parallel-group, Phase 1b study examined the pharmacokinetics and pharmacodynamics of three doses of PF-06412562 (3 mg, 9 mg, and 45 mg twice daily) over 15 days in patients with schizophrenia receiving antipsychotics. METHODS: Primary endpoints included adjunctive safety/tolerability and effects on MATRICS Consensus Cognitive Battery Working Memory domain and reward processing (Monetary Incentive Delay) tasks. Exploratory endpoints included other behavioral/neurophysiological tasks, including the N-back task. RESULTS: Among 95 subjects (78% male; mean age 34.8 years), baseline characteristics were similar across groups. The MATRICS Consensus Cognitive Battery Working Memory composite change from baseline on Day 13 improved in all groups, the smallest improvement was observed in the 45 mg group and was significantly smaller than that in the placebo group (two-sided p=0.038). For the Monetary Incentive Delay task (change from baseline in blood-oxygen-level-dependent functional magnetic resonance imaging activation in anterior ventral striatum for the contrast of cue gain>cue no gain on Day 15), no PF-06412562 dose was significantly different from placebo. No doses of PF-06412562 showed a significant difference on two-back task accuracy versus placebo. CONCLUSIONS: Adjunctive treatment with PF-06412562 was safe and well tolerated in patients with schizophrenia. PF-06412562 failed to show clinical benefit relative to placebo on assessments of cognition or reward processing in symptomatically stable patients over a 15-day treatment period. Numerous limitations due to the safety study design warrant further efficacy evaluation for this drug mechanism.

Relating constructs of attention and working memory to social withdrawal in Alzheimer's disease and schizophrenia: issues regarding paradigm selection.

Central nervous system diseases are not currently diagnosed based on knowledge of biological mechanisms underlying their symptoms. Greater understanding may be offered through an agnostic approach to traditional disease categories, where learning more about shared biological mechanisms across conditions could potentially reclassify sub-groups of patients to allow realisation of more effective treatments. This review represents the output of the collaborative group "PRISM", tasked with considering assay choices for assessment of attention and working memory in a transdiagnostic cohort of Alzheimer's disease and schizophrenia patients exhibiting symptomatic spectra of social withdrawal. A multidimensional analysis of this nature has not been previously attempted. Nominated assays (continuous performance test III, attention network test, digit symbol substitution, N-back, complex span, spatial navigation in a virtual environment) reflected a necessary compromise between the need for broad assessment of the neuropsychological constructs in question with several pragmatic criteria: patient burden, compatibility with neurophysiologic measures and availability of preclinical homologues.

Social brain, social dysfunction and social withdrawal.

The human social brain is complex. Current knowledge fails to define the neurobiological processes underlying social behaviour involving the (patho-) physiological mechanisms that link system-level phenomena to the multiple hierarchies of brain function. Unfortunately, such a high complexity may also be associated with a high susceptibility to several pathogenic interventions. Consistently, social deficits sometimes represent the first signs of a number of neuropsychiatric disorders including schizophrenia (SCZ), Alzheimer's disease (AD) and major depressive disorder (MDD) which leads to a progressive social dysfunction. In the present review we summarize present knowledge linking neurobiological substrates sustaining social functioning, social dysfunction and social withdrawal in major psychiatric disorders. Interestingly, AD, SCZ, and MDD affect the social brain in similar ways. Thus, social dysfunction and its most evident clinical expression (i.e., social withdrawal) may represent an innovative transdiagnostic domain, with the potential of being an independent entity in terms of biological roots, with the perspective of targeted interventions.

Escitalopram effects on insula and amygdala BOLD activation during emotional processing.

RATIONALE: The amygdala and insular cortex are integral to the processing of emotionally salient stimuli. We have shown in healthy volunteers that an anxiolytic agent, lorazepam, dose-dependently attenuates activation of limbic structures. OBJECTIVE: The current study investigated whether administration of a selective serotonin reuptake inhibitor (SSRI), escitalopram, alters the activation of limbic structures. We hypothesized that subchronic (21 days) SSRI treatment attenuates the activation of the amygdala and insula during processing of emotional faces. MATERIALS AND METHODS: Thirteen healthy volunteers participated in a double-blind, placebo-controlled, crossover, randomized study. After 21 days of treatment with either escitalopram or placebo, participants underwent functional magnetic resonance imaging (fMRI) during which all subjects completed an emotion face assessment task, which has been shown to elicit amygdala and insula activation. RESULTS: Subjects activated the bilateral insula and amygdala after treatment with both escitalopram and placebo. In subjects who were adherent to the protocol (as evidenced by sufficiently high urine concentrations of escitalopram), a reduction in amygdala activation was seen in the escitalopram condition compared to placebo. CONCLUSION: The current investigation provides further evidence for the mechanism of action of SSRIs through the attenuation of activation in brain regions responsible for emotion processing and provides support for the use of blood oxygenation level-dependent fMRI with pharmacological probes to help identify the specific therapeutic effect of these agents in patients with anxiety and mood disorders.

Increased amygdala activation is related to heart rate during emotion processing in adolescent subjects.

Emotions have been conceptualized as representations of bodily responses to a stimulus that critically involves the autonomic nervous system (ANS). An association between amygdala activation and ANS activity has been shown in adults. However, to date, no studies have demonstrated this association in adolescents. Examining the interaction between the ANS and amygdala in healthy adolescents may provide information about age-related changes in the association between amygdala activation and ANS measures. Therefore, the aim of this study was to examine the relationship between amygdala activation and heart rate in normal adolescents. Eighteen 12- to 17-year old adolescents participated. Heart rate data was collected during functional magnetic resonance imaging while subjects performed a facial expression matching task that reliably activates the amygdala. Adolescents showed significant amygdala activation for all facial expressions relative to the shape-matching, control task. Moreover, the degree of activation in the right amygdala for Fearful faces was significantly correlated with heart rate (Spearman's rho=0.55, p=0.018, two-tailed). This study shows that amygdala activity is related to heart rate in healthy adolescents. Thus, similar to adults, adolescents show a coupling between processing emotional events and adjusting the ANS accordingly. Furthermore, this study confirms previous adolescent studies showing amygdala activation to Fearful, Angry, and Happy faces. Finally, the results of the present study lay the foundation for future research to investigate whether adolescents with mood or anxiety disorders show an altered coupling between processing emotionally salient events and ANS activity.

Lorazepam dose-dependently decreases risk-taking related activation in limbic areas.

RATIONALE: Several studies have examined the role of different neurotransmitter systems in modulating risk-taking behavior. OBJECTIVE: This investigation was aimed to determine whether the benzodiazepine lorazepam dose-dependently alters risk-taking behavior and underlying neural substrates. MATERIALS AND METHODS: Fifteen healthy, nonsmoking, individuals (six women, nine men), aged 18-39 years (mean 27.6 +/- 1.4 years) with 12-18 years of education (mean 15.6 +/- 0.3 years) underwent functional magnetic resonance imaging while performing a risk-taking decision-making task. RESULTS: Our results show that lorazepam did not affect risky behavior at 0.25 and 1 mg, but dose-dependently attenuated activation in (a) the amygdala and medial prefrontal cortex during the response selection phase, and in (b) the bilateral insular cortex and amygdala during the outcome (i.e., rewarded or punished) phase. Furthermore, a lorazepam-induced increase in insular cortex activation was associated with less risky responses. CONCLUSIONS: Taken together, our findings support the idea that GABAergic modulation in limbic and paralimbic structures is important during both the response selection and outcome phase of risk-taking decision-making.

Impulsivity: a review.

The most debated issues in the literature of impulsivity, starting with its most common definitions are reviewed. We examine the importance of serotonin and dopamine neurotransmitters and its relationship with the two widely known experimental confounds: timing and aggression. The various explanations of the causes of impulsivity, the ability to delay rewards and how the values of reinforcements fade with time are also reviewed. We follow with the role of working memory, attention and emotions, including self-control, and the concept of impulsivity as a lost chain between knowledge and action, ending with the idea that impulsive behavior is influenced by many different mechanisms. Finally, we present a brief description of some instruments used to measure impulsivity in both animal and human literature and its relationship with decision-making processes.

Dissociation of inhibition from error processing using a parametric inhibitory task during functional magnetic resonance imaging.

Inhibition, the process that overrides and reverses the execution of a thought, action, or emotion, is important in daily life. Sixteen healthy volunteers performed a parametrically modulated motor inhibition task during functional magnetic resonance imaging. Two results were observed: (1) increased error-related anterior cingulate cortex activation and, (2) increased inferior frontal gyrus and medial prefrontal cortex activation during inhibition, irrespective of errors. Thus, the parametric nature of the task elucidated a functional dissociation of brain structures involved in motor inhibition from those involved in error processing. Additionally, this task allowed the identification of unique areas of increased activation within specific subregions of the anterior cingulate cortex related to errors made during trials with a high (dorsal anterior cingulate cortex) and low (ventral anterior cingulate cortex) inhibitory load.

Hippocampal structural asymmetry in unsuccessful psychopaths.

BACKGROUND: Structural and functional hippocampal abnormalities have been previously reported in institutionalized psychopathic and aggressive populations. This study assessed whether prior findings of a right greater than left (R > L) functional asymmetry in caught violent offenders generalize to the structural domain in unsuccessful, caught psychopaths. METHODS: Left and right hippocampal volumes were assessed using structural magnetic resonance imaging (MRI) in 23 control subjects, 16 unsuccessful psychopaths, and 12 successful (uncaught) community psychopaths and transformed into standardized space. RESULTS: Unsuccessful psychopaths showed an exaggerated structural hippocampal asymmetry (R > L) relative both to successful psychopaths and control subjects (p <.007) that was localized to the anterior region. This effect could not be explained by environmental and diagnostic confounds and constitutes the first brain imaging analysis of successful and unsuccessful psychopaths. CONCLUSIONS: Atypical anterior hippocampal asymmetries in unsuccessful psychopaths may reflect an underlying neurodevelopmental abnormality that disrupts hippocampal-prefrontal circuitry, resulting in affect dysregulation, poor contextual fear conditioning, and insensitivity to cues predicting capture.

Association between individual differences in self-reported emotional resilience and the affective perception of neutral faces.

BACKGROUND: Resilience, i.e., the ability to cope with stress and adversity, relies heavily on judging adaptively complex situations. Judging facial emotions is a complex process of daily living that is important for evaluating the affective context of uncertain situations, which could be related to the individual's level of resilience. We used a novel experimental paradigm to test the hypothesis that highly resilient individuals show a judgment bias towards positive emotions. METHODS: 65 non-treatment seeking subjects completed a forced emotional choice task when presented with neutral faces and faces morphed to display a range of emotional intensities across sadness, fear, and happiness. RESULTS: Overall, neutral faces were judged more often to be sad or fearful than happy. Furthermore, high compared to low resilient individuals showed a bias towards happiness, particularly when judging neutral faces. LIMITATIONS: This is a cross-sectional study with a non-clinical sample. CONCLUSIONS: These results support the hypothesis that resilient individuals show a bias towards positive emotions when faced with uncertain emotional expressions. This capacity may contribute to their ability to better cope with certain types of difficult situations, especially those that are interpersonal in nature.

Anterior cingulate cortex and benefit of predictive cueing on response inhibition in stimulant dependent individuals.

BACKGROUND: Methamphetamine dependence (MD) is associated with impaired response inhibition and with structural abnormalities and functional hypoactivity in the anterior cingulate cortex (ACC). The need to inhibit behavior is often forewarned by cues that do not call for immediate inhibition. We sought to determine whether such cues would engage the ACC and improve inhibition in MD individuals. METHODS: We used functional MRI to measure ACC activation during performance of a go/nogo response inhibition task in which certain go stimuli (cues) were much more likely than others (noncues) to be followed by nogo trials. Nineteen MD individuals (inpatient treatment, 25-50 days abstinence) were compared with 19 age- and education-matched healthy comparison (HC) subjects. RESULTS: MD and HC groups had statistically comparable performance, but only MD participants showed an ACC response and lower false alarm rates associated with cues as compared with noncues. Cue-related ACC activity in MD subjects was positively correlated with this cue-related improvement in inhibitory performance. CONCLUSIONS: The ACC, an area associated with error detection and response conflict, may predict the degree to which advance warning may attenuate MD individuals' difficulty with response inhibition.

Young adult stimulant users' increased striatal activation during uncertainty is related to impulsivity.

BACKGROUND: Young adults who use stimulants (e.g., cocaine, amphetamines) are at particular risk of transitioning to dependence. Previously, we demonstrated increased risk-taking in young adults who had used stimulants (Leland, D.S., Paulus, M.P., 2005. Increased risk-taking decision-making but not altered response to punishment in stimulant-using young adults. Drug. Alcohol Depend. 78, 83-90). Since outcome uncertainty is a critical element of risk, we investigated whether such individuals have different neural responses to uncertainty than their stimulant-naive peers. METHOD: Eleven young adults (age 18-25) who had used stimulants were compared with 11 age- and education-matched stimulant-naive controls using functional magnetic resonance imaging and a card prediction task with relatively certain/uncertain outcome conditions. RESULTS: The caudate, an area involved in processing salient events, was among those regions more active in users than controls in response to uncertainty. Personality measures revealed that users were more impulsive than controls, and that neural response to uncertainty in a number of areas, including the thalamus/caudate, was positively correlated with impulsivity. CONCLUSIONS: These results are consistent with the idea that young adults who have used stimulants find uncertainty particularly salient, due in part to preexisting differences in impulsivity, and may be subject to more "action pressure" when making decisions under uncertainty. This neural and personality profile may constitute a marker for increased risk of stimulant use.

Individuals with schizophrenia present hypo- and hyperactivation during implicit cueing in an inhibitory task.

BACKGROUND: The primary purpose of this investigation was to assess the neural correlates of implicit cueing during an inhibitory task in schizophrenia when performance accuracy was matched with healthy comparison subjects. METHODS: We compared 17 individuals with chronic schizophrenia (SZ; medicated, 13.9 average years of illness) and 17 healthy comparison subjects (HC) matched for hit and false alarm rates, age, and education on a visual Go/Nogo task during functional magnetic resonance imaging. In this task, one of the go stimuli also served implicitly as a cue predictive of a subsequent inhibitory (Nogo) trial. CONCLUSIONS: Findings suggest that even when matched for overall performance accuracy, individuals with SZ exhibit difficulties with inhibition and cue processing that may relate to core deficits in cognitive control and stimulus processing. In particular, these findings point towards an important role of the parietal cortex for cued inhibitory processes in healthy populations.