Add-on pramipexole for anhedonic depression: study protocol for a randomised controlled trial and open-label follow-up in Lund, Sweden.

Introduction: Many depressed patients do not achieve remission with available treatments. Anhedonia is a common residual symptom associated with treatment resistance as well as low function and quality of life. There are currently no specific and effective treatments for anhedonia.

Preliminary Evidence of Efficacy and Target Engagement of Pramipexole in Anhedonic Depression.

Objective: To investigate feasibility and target engagement of high-dose, add-on pramipexole treatment in anhedonic depression.

Method: In this open-label pilot study, we included 12 patients with unipolar or bipolar, moderate-to-severe depression and with significant anhedonia symptoms. All patients were on a stable dose of one or a combination of antidepressants and/or mood stabilizers and received 10 weeks of adjunctive pramipexole titrated to a maximum dose of 4.

Exploring the Effects of an Acute Dose of Antipsychotic Medication on Motivation-mediated BOLD Activity Using fMRI and a Perceptual Decision-making Task.

The left inferior frontal gyrus and the bilateral ventral striatum are thought to be involved in motivation-mediated decision-making. Antipsychotics may influence this relationship, and atypical antipsychotics improve secondary negative symptoms in schizophrenia, such as loss of motivation, although the acute effects of pharmacological medication on motivation are not fully understood. In this single-blinded, randomized controlled trial, 49 healthy volunteers were randomized into three groups to receive a single dose of haloperidol, aripiprazole or placebo.

The Neural Correlates of Negative Symptoms in Schizophrenia: Examples From MRI Literature.

Negative symptoms of schizophrenia have a negative impact on psychosocial functioning and disease outcome. It is therefore important to investigate the pathophysiology underlying negative symptoms as this may aid the development of better treatment. In the current article, examples from studies investigating neural correlates of negative symptoms in schizophrenia are given.

Reduced load-dependent default mode network deactivation across executive tasks in schizophrenia spectrum disorders.

Background: Schizophrenia is associated with cognitive impairment and brain network dysconnectivity. Recent efforts have explored brain circuits underlying cognitive dysfunction in schizophrenia and documented altered activation of large-scale brain networks, including the task-positive network (TPN) and the task-negative default mode network (DMN) in response to cognitive demands. However, to what extent TPN and DMN dysfunction reflect overlapping mechanisms and are dependent on cognitive state remain to be determined.

Effects of haloperidol and aripiprazole on the human mesolimbic motivational system: A pharmacological fMRI study.

The atypical antipsychotic drug aripiprazole is a partial dopamine (DA) D2 receptor agonist, which differentiates it from most other antipsychotics. This study compares the brain activation characteristic produced by aripiprazole with that of haloperidol, a typical D2 receptor antagonist. Healthy participants received an acute oral dose of haloperidol, aripiprazole or placebo, and then performed an active aversive conditioning task with aversive and neutral events presented as sounds, while blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was carried out.

Stability of executive functions in first episode psychosis: One year follow up study.

Executive functioning is a multi-dimensional construct covering several sub-processes. The aim of this study was to determine whether executive functions, indexed by a broad range of executive measures remain stable in first episode psychosis (FEP) over time. Eighty-two patients and 107 age and gender matched healthy controls were assessed on five subdomains of executive functioning; working memory, fluency, flexibility, and inhibitory control at baseline and at 1 year follow-up.

Negative symptoms in schizophrenia are associated with aberrant striato-cortical connectivity in a rewarded perceptual decision-making task.

Background: Negative symptoms in schizophrenia have been associated with structural and functional changes in the prefrontal cortex. They often persist after treatment with antipsychotic medication which targets, in particular, the ventral striatum (VS). As schizophrenia has been suggested to arise from dysfunctional connectivity between neural networks, it is possible that residual aberrant striato-cortical connectivity in medicated patients plays a role in enduring negative symptomology.

No difference in frontal cortical activity during an executive functioning task after acute doses of aripiprazole and haloperidol.

Background: Aripiprazole is an atypical antipsychotic drug that is characterized by partial dopamine D2 receptor agonism. Its pharmacodynamic profile is proposed to be beneficial in the treatment of cognitive impairment, which is prevalent in psychotic disorders. This study compared brain activation characteristics produced by aripiprazole with that of haloperidol, a typical D2 receptor antagonist, during a task targeting executive functioning.

The human amygdala encodes value and space during decision making.

Valuable stimuli are invariably localized in space. While our knowledge regarding the neural networks supporting value assignment and comparisons is considerable, we lack a basic understanding of how the human brain integrates motivational and spatial information. The amygdala is a key structure for learning and maintaining the value of sensory stimuli and a recent non-human primate study provided initial evidence that it also acts to integrate value with spatial location, a question we address here in a human setting.

The left inferior frontal gyrus is involved in adjusting response bias during a perceptual decision-making task.

Introduction: Changing the way we make decisions from one environment to another allows us to maintain optimal decision-making. One way decision-making may change is how biased one is toward one option or another. Identifying the regions of the brain that underlie the change in bias will allow for a better understanding of flexible decision-making.

Increased amygdala and visual cortex activity and functional connectivity towards stimulus novelty is associated with state anxiety.

Novel stimuli often require a rapid reallocation of sensory processing resources to determine the significance of the event, and the appropriate behavioral response. Both the amygdala and the visual cortex are central elements of the neural circuitry responding to novelty, demonstrating increased activity to new as compared to highly familiarized stimuli. Further, these brain areas are intimately connected, and thus the amygdala may be a key region for directing sensory processing resources to novel events.

Working memory networks and activation patterns in schizophrenia and bipolar disorder: comparison with healthy controls.

Background: Schizophrenia and bipolar disorder are severe mental disorders with overlapping genetic and clinical characteristics, including cognitive impairments. An important question is whether these disorders also have overlapping neuronal deficits.

Aims: To determine whether large-scale brain networks associated with working memory, as measured with functional magnetic resonance imaging (fMRI), are the same in both schizophrenia and bipolar disorder, and how they differ from those in healthy individuals.

Further evidence for the impact of a genome-wide-supported psychosis risk variant in ZNF804A on the Theory of Mind Network.

The single-nucleotide polymorphism (SNP) rs1344706 in ZNF804A is one of the best-supported risk variants for psychosis. We hypothesized that this SNP contributes to the development of schizophrenia by affecting the ability to understand other people's mental states. This skill, commonly referred to as Theory of Mind (ToM), has consistently been found to be impaired in schizophrenia.

Aversive event anticipation affects connectivity between the ventral striatum and the orbitofrontal cortex in an fMRI avoidance task.

Ability to anticipate aversive events is important for avoiding dangerous or unpleasant situations. The motivation to avoid an event is influenced by the incentive salience of an event-predicting cue. In an avoidance fMRI task we used tone intensities to manipulate salience in order to study the involvement of the orbitofrontal cortex in processing of incentive salience.

The neural correlates of cognitive control in bipolar I disorder: an fMRI study of medial frontal cortex activation during a Go/No-go task.

In addition to dysregulation of mood, bipolar I disorder (BD I) is characterized by abnormalities in the execution of cognitive control. Hypoactivation of a specific sub-region in the cognitive control network, located in the medial frontal cortex, has been described among BD I patients. The aim of this study was to investigate whether patients with BD I showed decreased activation in this brain region as compared to healthy controls when performing a cognitive control task.

Frontotemporal hypoactivity during a reality monitoring paradigm is associated with delusions in patients with schizophrenia spectrum disorders.

Introduction: Impaired monitoring of internally generated information has been proposed to be one component in the development and maintenance of delusions. The present study investigated the neural correlates underlying the monitoring processes and whether they were associated with delusions.

Methods: Twenty healthy controls and 19 patients with schizophrenia spectrum disorders were administrated a reality monitoring paradigm during functional magnetic resonance imaging.

Incentive motivational salience and the human brain.

In this paper the concept of incentive motivational salience is briefly described, pioneering studies on the subject of the mesolimbic motivational system are reviewed, and studies we have been involved in conducting which elaborate on this subject are discussed. In particular, we aim to show that the mesolimbic motivational system is recruited as a reaction to primary and secondary reinforcers as a function of salience, that is independent of valence. Furthermore, studies showing that both psychological and pharmacological interventions can affect the function of the mesolimbic motivational system and how its' dysfunction is related to psychopathological phenomena with an emphasis on psychosis are discussed.

CACNA1C risk variant and amygdala activity in bipolar disorder, schizophrenia and healthy controls.

Objectives: Several genetic studies have implicated the CACNA1C SNP rs1006737 in bipolar disorder (BD) and schizophrenia (SZ) pathology. This polymorphism was recently found associated with increased amygdala activity in healthy controls and patients with BD. We performed a functional Magnetic Resonance Imaging (fMRI) study in a sample of BD and SZ cases and healthy controls to test for altered amygdala activity in carriers of the rs1006737 risk allele (AA/AG), and to investigate if there were differences across the diagnostic groups.

Pathway analysis of genetic markers associated with a functional MRI faces paradigm implicates polymorphisms in calcium responsive pathways.

Several lines of evidence suggest that common polygenic variation influences brain function in humans. Combining high-density genetic markers with brain imaging techniques is constricted by the practicalities of collecting sufficiently large brain imaging samples. Pathway analysis promises to leverage knowledge on function of genes to detect recurring signals of moderate effect.

Associations between variants near a monoaminergic pathways gene (PHOX2B) and amygdala reactivity: a genome-wide functional imaging study.

As the amygdala is part of the phylogenetic old brain, and its anatomical and functional properties are conserved across species, it is reasonable to assume genetic influence on its activity. A large corpus of candidate gene studies indicate that individual differences in amygdala activity may be caused by genetic variants within monoaminergic signaling pathways such as dopamine, serotonin, and norepinephrine. However, to our knowledge, the use of genome-wide data to discover genetic variants underlying individual differences in adult amygdala activity is novel.

Effect of relevance on amygdala activation and association with the ventral striatum.

While the amygdala historically has been implicated in emotional stimuli processing, recent data suggest a general role in parceling out the relevance of stimuli, regardless of their emotional properties. Using functional magnetic resonance imaging, we tested the relevance hypothesis by investigating human amygdala responses to emotionally neutral stimuli while manipulating their relevance. The task was operationalized as highly relevant if a subsequent opportunity to respond for a reward depended on response accuracy of the task, and less relevant if the reward opportunity was independent of task performance.

An association between affective lability and executive functioning in bipolar disorder.

Studies suggest altered affect regulation manifested by affective lability in manic/mixed and euthymic states in patients with bipolar disorder (BD). Altered affect regulation may arise from disturbances in interactions between the cognitive and the emotional brain networks. However, the relationship between affective lability and executive function has not previously been studied.

Arousal Modulates Activity in the Medial Temporal Lobe during a Short-Term Relational Memory Task.

This study investigated the effect of arousal on short-term relational memory and its underlying cortical network. Seventeen healthy participants performed a picture by location, short-term relational memory task using emotional pictures. Functional magnetic resonance imaging was used to measure the blood-oxygenation-level dependent signal relative to task.