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. Some trials have shown that dopamine agonist pramipexole is efficacious for treating depression, but more data is needed before it could become ready for clinical prime time. Given its mechanism of action, pramipexole might be a useful treatment for a depression subtype characterised by significant anhedonia and lack of motivation-symptoms associated with dopaminergic hypofunction. We recently showed, in an open-label pilot study, that add-on pramipexole is a feasible treatment for depression with significant anhedonia, and that pramipexole increases reward-related activity in the ventral striatum. We will now confirm or refute these preliminary results in a randomised controlled trial (RCT) and an open-label follow-up study. METHODS AND ANALYSIS: Eighty patients with major depression (bipolar or unipolar) or dysthymia and significant anhedonia according to the Snaith Hamilton Pleasure Scale (SHAPS) are randomised to either add-on pramipexole or placebo for 9 weeks. Change in anhedonia symptoms per the SHAPS is the primary outcome, and secondary outcomes include change in core depressive symptoms, apathy, sleep problems, life quality, anxiety and side effects. Accelerometers are used to assess treatment-associated changes in physical activity and sleep patterns. Blood and brain biomarkers are investigated as treatment predictors and to establish target engagement. After the RCT phase, patients continue with open-label treatment in a 6-month follow-up study aiming to assess long-term efficacy and tolerability of pramipexole. ETHICS AND DISSEMINATION: The study has been approved by the Swedish Ethical Review Authority and the Swedish Medical Products Agency. The study is externally monitored according to Good Clinical Practice guidelines. Results will be disseminated via conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05355337 and NCT05825235.

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 4.5 mg salt/day. All patients were rated with the Dimensional Anhedonia Rating Scale (DARS), the Montgomery Åsberg Depression Rating (MADRS) and the Snaith Hamilton Pleasure Scale (SHAPS). Serum high-sensitivity C-reactive protein (hs-CRP) was analyzed pre- and post-treatment. Eight patients underwent fMRI pre- and post-treatment and a simplified version of the monetary incentive delay task was used to investigate the effect of treatment on striatal activity during reward anticipation. Results: DARS, MADRS and SHAPS scores all improved significantly over 10 weeks of pramipexole treatment (p<0.01). Mean levels of hs-CRP decreased significantly over the course of treatment from mean 3.8 mg/L at baseline to 2.6 mg/L at endpoint (p<0.01). There were significant treatment-associated increases in reward related activity in several brain areas including the right lateral putamen, anterior left caudate, left posterior putamen, right dorsal caudate, left anterior putamen, and the right nucleus accumbens. Conclusions: This is the first study to suggest efficacy and target engagement of pramipexole in anhedonic depression. Larger randomized controlled trials are needed to confirm or refute these preliminary findings.

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. Between 4.0 and 5.6 h later, participant's brain blood-oxygen-level dependent (BOLD) activity was recorded using functional magnetic resonance imaging (fMRI) while completing a perceptual decision-making fMRI task consisting of one neutral and one motivated condition. Response bias, reflecting the participant's willingness to say that the target stimulus is present, was calculated using signal detection theory. Concurrent with widespread changes in BOLD signal in the motivated vs. neutral condition, a less conservative, mathematically optimal response bias was observed in the motivated condition across the whole sample. Within-group differences in BOLD signal in the left inferior frontal gyrus and bilateral ventral striatum were observed between conditions in the aripiprazole and haloperidol groups, but not in the placebo group. No robust between-group differences in brain activity in the left inferior frontal gyrus or the bilateral ventral striatum were found. Overall, we found no robust evidence for an effect of either aripiprazole or haloperidol on motivationally mediated behavior. An interesting pattern of correlations possibly related to pharmacologically induced alterations in the dopamine system was observed, although findings remain inconclusive and must be replicated in larger samples.

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. Investigations using both structural and functional magnetic resonance imaging are presented at different levels of symptomatology descriptions, from the more heterogenous construct of negative symptoms to more single discrete symptoms. Some methods to improve imaging studies of negative symptoms in schizophrenia are also suggested.

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. METHODS: In the current study, we investigated the recruitment of TPN and DMN using independent component analysis in patients with schizophrenia spectrum disorders (n = 29) and healthy controls (n = 21) during two different executive tasks probing planning/problem-solving and spatial working memory. RESULTS: We found reduced load-dependent DMN deactivation across tasks in patients compared to controls. Furthermore, we observed only moderate associations between the TPN and DMN activation across groups, implying that the two networks reflect partly independent mechanisms. Additionally, whereas TPN activation was associated with task performance in both tasks, no such associations were found for DMN. CONCLUSION: These results support a general load-dependent DMN dysfunction in schizophrenia spectrum disorder across two demanding executive tasks that is not merely an epiphenomenon of cognitive dysfunction.

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. The fMRI task, targeting the mesolimbic motivational system that is thought to be disturbed in psychosis, was based on the conditioned avoidance response (CAR) animal model - a widely used test of therapeutic potential of antipsychotic drugs. In line with the CAR animal model, the present results show that subjects given haloperidol were not able to avoid more aversive than neutral task trials, even though the response times were shorter during aversive events. In the aripiprazole and placebo groups more aversive than neutral events were avoided. Accordingly, the task-related BOLD-fMRI response in the mesolimbic motivational system was diminished in the haloperidol group compared to the placebo group, particularly in the ventral striatum, whereas the aripiprazole group showed task-related activations intermediate of the placebo and haloperidol groups. The current results show differential effects on brain function by aripiprazole and haloperidol, probably related to altered DA transmission. This supports the use of pharmacological fMRI to study antipsychotic properties in humans.

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. Results showed that patients performed significantly poorer than controls on all executive measures at both assessment points. In general executive functions remained stable from baseline to follow-up, although both groups improved on measures of inhibitory control and flexibility. In phonemic fluency, controls showed a slight improvement while patients showed a slight decline. Investigation of individual trajectories revealed some fluctuations in both groups over time, but mainly supports the group level findings. The implications of these results are discussed.

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. METHODS: Healthy participants received an acute oral dose of haloperidol, aripiprazole or placebo before performing an executive functioning task while blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was carried out. RESULTS: There was a tendency towards reduced performance in the aripiprazole group compared to the two other groups. The image analysis yielded a strong task-related BOLD-fMRI response within each group. An uncorrected between-group analysis showed that aripiprazole challenge resulted in stronger activation in the frontal and temporal gyri and the putamen compared with haloperidol challenge, but after correcting for multiple testing there was no significant group difference. CONCLUSION: No significant group differences between aripiprazole and haloperidol in frontal cortical activation were obtained when corrected for multiple comparisons. This study is registered in ClinicalTrials.gov (identifier: 2009-016222-14).

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. The present study examined the relationship between striato-cortical connectivity and negative symptoms in medicated schizophrenia patients. METHODS: We manipulated motivation in a perceptual decision-making task during functional magnetic resonance imaging. Comparing healthy controls (n = 21) and medicated patients with schizophrenia (n = 18) we investigated how motivation-mediated changes in VS activation affected functional connectivity with the frontal cortex, and how changes in connectivity strength from the neutral to motivated condition related to negative symptom severity. RESULTS: A pattern of aberrant striato-cortical connectivity was observed in the presence of intact VS, but altered left inferior frontal gyrus (IFG) motivation-mediated activation in patients. The more severe the patient's negative symptoms, the less the connectivity strength between the right VS and left IFG changed from the neutral to the motivated condition. Despite aberrant striato-cortical connectivity and altered recruitment of the left IFG among patients, both patients and healthy controls adopted a more liberal response strategy in the motivated compared to the neutral condition. CONCLUSIONS: The present findings suggest that there is a link between dysfunctional striato-cortical connectivity and negative symptom severity, and offer a possible explanation as to why negative symptoms persist after treatment with antipsychotics.

Cognitive Effort and Schizophrenia Modulate Large-Scale Functional Brain Connectivity.

Schizophrenia (SZ) is characterized by cognitive dysfunction and disorganized thought, in addition to hallucinations and delusions, and is regarded a disorder of brain connectivity. Recent efforts have been made to characterize the underlying brain network organization and interactions. However, to which degree connectivity alterations in SZ vary across different levels of cognitive effort is unknown. Utilizing independent component analysis (ICA) and methods for delineating functional connectivity measures from functional magnetic resonance imaging (fMRI) data, we investigated the effects of cognitive effort, SZ and their interactions on between-network functional connectivity during 2 levels of cognitive load in a large and well-characterized sample of SZ patients (n = 99) and healthy individuals (n = 143). Cognitive load influenced a majority of the functional connections, including but not limited to fronto-parietal and default-mode networks, reflecting both decreases and increases in between-network synchronization. Reduced connectivity in SZ was identified in 2 large-scale functional connections across load conditions, with a particular involvement of an insular network. The results document an important role of interactions between insular, default-mode, and visual networks in SZ pathophysiology. The interplay between brain networks was robustly modulated by cognitive effort, but the reduced functional connectivity in SZ, primarily related to an insular network, was independent of cognitive load, indicating a relatively general brain network-level dysfunction.

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. We measured haemodynamic responses (fMRI) in amygdala while manipulating the value and spatial configuration of stimuli in a simple stimulus-reward task. Subjects responded significantly faster and showed greater amygdala activation when a reward was dependent on a spatial specific response, compared to when a reward required less spatial specificity. Supplemental analysis supported this spatial specificity by demonstrating that the pattern of amygdala activity varied based on whether subjects responded to a motivational target presented in the ipsilateral or contralateral visual space. Our data show that the human amygdala integrates information about space and value, an integration of likely importance for assigning cognitive resources towards highly valuable stimuli in our environment.

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. METHODS: An event-related, perceptual decision-making task where participants had to detect a picture of an animal amongst distractors was used during functional magnetic resonance imaging. Positive and negative financial motivation were used to affect a change in response bias, and changes in decision-making behavior were quantified using signal detection theory. RESULTS: Response bias became relatively more liberal during both positive and negative motivated trials compared to neutral trials. For both motivational conditions, the larger the liberal shift in bias, the greater the left inferior frontal gyrus (IFG) activity. There was no relationship between individuals' belief that they used a different strategy and their actual change in response bias. CONCLUSIONS: The present findings suggest that the left IFG plays a role in adjusting response bias across different decision environments. This suggests a potential role for the left IFG in 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. Although knowledge regarding the neurocircuit of novelty detection is gradually increasing, we still lack a basic understanding of the conditions that are necessary and sufficient for novelty-specific responses in human amygdala and the visual cortices, and if these brain areas interact during detection of novelty. In the present study, we investigated the response of amygdala and the visual cortex to novelty, by comparing functional MRI activity between 1st and 2nd time presentation of a series of emotional faces in an event-related task. We observed a significant decrease in amygdala and visual cortex activity already after a single stimulus exposure. Interestingly, this decrease in responsiveness was less for subjects with a high score on state anxiety. Further, novel faces stimuli were associated with a relative increase in the functional coupling between the amygdala and the inferior occipital gyrus (BA 18). Thus, we suggest that amygdala is involved in fast sensory boosting that may be important for attention reallocation to novel events, and that the strength of this response depends on individual state anxiety.

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. METHOD: Patients with schizophrenia (n = 100) and bipolar disorder (n = 100) and a healthy control group (n = 100) performed a 2-back working memory task while fMRI data were acquired. The imaging data were analysed using independent component analysis to extract large-scale networks of task-related activations. RESULTS: Similar working memory networks were activated in all groups. However, in three out of nine networks related to the experimental task there was a graded response difference in fMRI signal amplitudes, where patients with schizophrenia showed greater activation than those with bipolar disorder, who in turn showed more activation than healthy controls. Secondary analysis of the patient groups showed that these activation patterns were associated with history of psychosis and current elevated mood in bipolar disorder. CONCLUSIONS: The same brain networks were related to working memory in schizophrenia, bipolar disorder and controls. However, some key networks showed a graded hyperactivation in the two patient groups, in line with a continuum of neuronal abnormalities across psychotic disorders.

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.

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. Using functional magnetic resonance imaging, we previously showed that in healthy individuals rs1344706 impacted on activity and connectivity of key areas of the ToM network, including the dorsomedial prefrontal cortex, temporo-parietal junction, and the posterior cingulate cortex, which show aberrant activity in schizophrenia patients, too. We aimed to replicate these results in an independent sample of 188 healthy German volunteers. In order to assess the reliability of brain activity elicited by the ToM task, 25 participants performed the task twice with an interval of 14 days showing excellent accordance in recruitment of key ToM areas. Confirming our previous results, we observed decreasing activity of the left temporo-parietal junction, dorsomedial prefrontal cortex, and the posterior cingulate cortex with increasing number of risk alleles during ToM. Complementing our replication sample with the discovery sample, analyzed in a previous report (total N=297), further revealed negative genotype effects in the left dorsomedial prefrontal cortex as well as in the temporal and parietal regions. In addition, as shown previously, rs1344706 risk allele dose positively predicted increased frontal-temporo-parietal connectivity. These findings confirm the effects of the psychosis risk variant in ZNF804A on the dysfunction of the ToM network.

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. During encoding participants were instructed to associate a statement with either a presented (viewed condition) or an imagined picture (imagined condition). During the monitoring session in the scanner, participants were presented with old and new statements and their task was to identify whether a given statement was associated with the viewed condition, imagined condition, or if it was new. RESULTS: Patients showed significantly reduced accuracy in the imagined condition with performance negatively associated with degree of delusions. This was accompanied with reduced activity in the left dorsolateral prefrontal cortex and left hippocampus in the patient group. The severity of delusions was negatively correlated with the blood-oxygenation-level dependent response in the left hippocampus. CONCLUSIONS: The results suggest that weakened monitoring is associated with delusions in patients with schizophrenia spectrum disorder, and that this may be mediated by a frontotemporal dysfunction.

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. In the task, cues predicting either aversive or neutral avoidable tones were presented. Ventral striatum, amygdala and anterior insula activations were significantly stronger during presentation of cues for aversive than neutral tones. A psychophysiological interaction analysis showed stronger connectivity between the ventral striatum and the orbitofrontal cortex during aversive than neutral conditions. The present study shows an interaction between the ventral striatum, a structure previously linked to negative incentive salience, and the orbitofrontal cortex supporting a role for this region in processing salience. In addition, this study replicates previous findings suggesting that the task is robust.

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. Twenty-four BD I patients and 24 healthy controls performed a Go/No-go task during a functional magnetic resonance imaging (fMRI) session. Performance and response times were recorded. The BD I subjects had significantly slower response times and more patients made errors of omission compared to the healthy controls during the task. Both BD I subjects and healthy controls demonstrated activations in the brain region of interest during the task, but analyses revealed no statistically significant differences between groups. Although the patients display some deviances in behavioural measures, this study reveals no significant differences between BD I subjects and healthy controls in recruitment of the medial frontal cortex during a Go/No-go task.

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. METHODS: Rs1006737 was genotyped in 250 individuals (N = 66 BD, 61 SZ and 123 healthy controls), all of Northern European origin, who underwent an fMRI negative faces matching task. Statistical tests were performed with a model correcting for sex, age, diagnostic category and medication status in the total sample, and then in each diagnostic group. RESULTS: In the total sample, carriers of the risk allele had increased activation in the left amygdala. Group-wise analyses showed that this effect was significant in the BD group, but not in the other diagnostic groups. However, there was no significant interaction effect for the risk allele between BD and the other groups. CONCLUSIONS: These results indicate that CACNA1C SNP rs1006737 affects amygdala activity during emotional processing across all diagnostic groups. The current findings add to the growing body of knowledge of the pleiotropic effect of this polymorphism, and further support that ion channel dysregulation is involved in the underlying mechanisms of BD and SZ.