Intrinsic and extrinsic control impact motivation and outcome sensitivity: the role of anhedonia, stress, and anxiety.

Background: Motivated behaviors vary widely across individuals and are controlled by a range of environmental and intrinsic factors. However, due to a lack of objective measures, the role of intrinsic extrinsic control of motivation in psychiatric disorders remains poorly understood.

Methods: We developed a novel multi-factorial behavioral task that separates the distinct contributions of intrinsic extrinsic control, and determines their influence on motivation and outcome sensitivity in a range of contextual environments.

Sustained effects of repeated levodopa (L-DOPA) administration on reward circuitry, effort-based motivation, and anhedonia in depressed patients with higher inflammation.

Inflammatory biomarkers like C-reactive protein (CRP) are elevated in a subset of patients with depression and have been associated with lower functional connectivity (FC) in a ventral striatum (VS) to ventromedial prefrontal cortex (vmPFC) reward circuit and symptoms of anhedonia. Evidence linking these relationships to the effects of inflammation on dopamine is consistent with our recent findings that acute levodopa (L-DOPA) increased VS-vmPFC FC in association with deceased anhedonia in depressed patients with higher but not lower CRP (>2 versus ≤ 2 mg/L). To determine whether repeated L-DOPA administration caused sustained effects on FC and behavior in these patients, medically stable depressed outpatients with CRP > 2 mg/L and anhedonia (n = 18) received one week of three doses of L-DOPA (150-450 mg/day/week with carbidopa) or placebo in a randomized order.

Using Computational Phenotyping to Identify Divergent Strategies for Effort Allocation Across the Psychosis Spectrum.

Background And Hypothesis: Disturbances in effort-cost decision-making have been highlighted as a potential transdiagnostic process underpinning negative symptoms in individuals with schizophrenia. However, recent studies using computational phenotyping show that individuals employ a range of strategies to allocate effort, and use of different strategies is associated with unique clinical and cognitive characteristics. Building on prior work in schizophrenia, this study evaluated whether effort allocation strategies differed in individuals with distinct psychotic disorders.

A randomized proof-of-mechanism trial of TNF antagonism for motivational anhedonia and related corticostriatal circuitry in depressed patients with high inflammation.

Chronic, low-grade inflammation has been associated with motivational deficits in patients with major depression (MD). In turn, impaired motivation has been linked to poor quality of life across psychiatric disorders. We thus determined effects of the anti-inflammatory drug infliximab-a potent tumor necrosis factor (TNF) antagonist-on behavioral and neural measures of motivation in 42 medically stable, unmedicated MD patients with a C-reactive protein > 3mg/L.

Brain-based graph-theoretical predictive modeling to map the trajectory of anhedonia, impulsivity, and hypomania from the human functional connectome.

Clinical assessments often fail to discriminate between unipolar and bipolar depression and identify individuals who will develop future (hypo)manic episodes. To address this challenge, we developed a brain-based graph-theoretical predictive model (GPM) to prospectively map symptoms of anhedonia, impulsivity, and (hypo)mania. Individuals seeking treatment for mood disorders (n = 80) underwent an fMRI scan, including (i) resting-state and (ii) a reinforcement-learning (RL) task.

Brain-based graph-theoretical predictive modeling to map the trajectory of transdiagnostic symptoms of anhedonia, impulsivity, and hypomania from the human functional connectome.

Clinical assessments often fail to discriminate between unipolar and bipolar depression and identify individuals who will develop future (hypo)manic episodes. To address this challenge, we developed a brain-based graph-theoretical predictive model (GPM) to prospectively map symptoms of anhedonia, impulsivity, and (hypo)mania. Individuals seeking treatment for mood disorders (n = 80) underwent an fMRI scan, including (i) resting-state and (ii) a reinforcement-learning (RL) task.

Hormone sensitivity predicts the beneficial effects of transdermal estradiol on reward-seeking behaviors in perimenopausal women: A randomized controlled trial.

Unlabelled: Depression is highly prevalent during the menopause transition (perimenopause), and often presents with anxious and anhedonic features. This increased vulnerability for mood symptoms is likely driven in part by the dramatic hormonal changes that are characteristic of the menopause transition, as prior research has linked fluctuations in estradiol (E2) to emergence of depressed mood in at risk perimenopausal women. Transdermal estradiol (TE2) has been shown to reduce the severity of depression in clinically symptomatic women, particularly in those with recent stressful life events.

Distinct profiles of anhedonia and reward processing and their prospective associations with quality of life among individuals with mood disorders.

Leading professional health bodies have called for the wider adoption of Patient Reported Outcome Measures, such as quality of life, in research and clinical practice as a means for understanding why the global burden of depression continues to climb despite increased rates of treatment use. Here, we examined whether anhedonia-an often recalcitrant and impairing symptom of depression-along with its neural correlates, was associated with longitudinal changes in patient-reported quality of life among individuals seeking treatment for mood disorders. We recruited 112 participants, including n = 80 individuals with mood disorders (58 unipolar, 22 bipolar) and n = 32 healthy controls (63.

A mesocorticolimbic signature of pleasure in the human brain.

Pleasure is a fundamental driver of human behaviour, yet its neural basis remains largely unknown. Rodent studies highlight opioidergic neural circuits connecting the nucleus accumbens, ventral pallidum, insula and orbitofrontal cortex as critical for the initiation and regulation of pleasure, and human neuroimaging studies exhibit some translational parity. However, whether activation in these regions conveys a generalizable representation of pleasure regulated by opioidergic mechanisms remains unclear.

Effects of acute stress and depression on functional connectivity between prefrontal cortex and the amygdala.

Stress is known to be a significant risk factor for the development of Major Depressive Disorder (MDD), yet the neural mechanisms that underlie this risk are poorly understood. Prior work has heavily implicated the corticolimbic system in the pathophysiology of MDD. In particular, the prefrontal cortex (PFC) and amygdala play a central role in regulating the response to stress, with dorsal PFC and ventral PFC exhibiting reciprocal excitatory and inhibitory influences on amygdala subregions.

Functional connectivity in reward circuitry and symptoms of anhedonia as therapeutic targets in depression with high inflammation: evidence from a dopamine challenge study.

Increased inflammation in major depressive disorder (MDD) has been associated with low functional connectivity (FC) in corticostriatal reward circuits and symptoms of anhedonia, relationships which may involve the impact of inflammation on synthesis and release of dopamine. To test this hypothesis while establishing a platform to examine target engagement of potential therapies in patients with increased inflammation, medically stable unmedicated adult MDD outpatients enrolled to have a range of inflammation (as indexed by plasma C-reactive protein [CRP] levels) were studied at two visits involving acute challenge with the dopamine precursor levodopa (L-DOPA; 250 mg) and placebo (double-blind, randomized order ~1-week apart). The primary outcome of resting-state (rs)FC in a classic ventral striatum to ventromedial prefrontal cortex reward circuit was calculated using a targeted, a priori approach.

Vigor, Effort-Related Aspects of Motivation and Anhedonia.

In this chapter we provide an overview of the pharmacological and circuit mechanisms that determine the willingness to expend effort in pursuit of rewards. A particular focus will be on the role of the mesolimbic dopamine system, as well the contributing roles of limbic and cortical brains areas involved in the evaluation, selection, and invigoration of goal-directed actions. We begin with a review of preclinical studies, which have provided key insights into the brain systems that are necessary and sufficient for effort-based decision-making and have characterized novel compounds that enhance selection of high-effort activities.

Inflammation as a Pathophysiologic Pathway to Anhedonia: Mechanisms and Therapeutic Implications.

Anhedonia, characterized by a lack of motivation, interest, or ability to experience pleasure, is a prominent symptom of depression and other psychiatric disorders and has been associated with poor response to standard therapies. One pathophysiologic pathway receiving increased attention for its potential role in anhedonia is inflammation and its effects on the brain. Exogenous administration of inflammatory stimuli to humans and laboratory animals has reliably been found to affect neurotransmitters and neurocircuits involved in reward processing, including the ventral striatum and ventromedial prefrontal cortex, in association with reduced motivation.

Inflammation is associated with future depressive symptoms among older adults.

Inflammation has been reliably associated with depression. However, the directionality of this association is poorly understood, with evidence that elevated inflammation may promote and precede the development of depression, as well as arise following its expression. Using data from older adults ( ​= ​1,072, ages 60-73) who participated in the ongoing longitudinal St.

Aiding and Abetting Anhedonia: Impact of Inflammation on the Brain and Pharmacological Implications.

Exogenous administration of inflammatory stimuli to humans and laboratory animals and chronic endogenous inflammatory states lead to motivational deficits and ultimately anhedonia, a core and disabling symptom of depression present in multiple other psychiatric disorders. Inflammation impacts neurotransmitter systems and neurocircuits in subcortical brain regions including the ventral striatum, which serves as an integration point for reward processing and motivational decision-making. Many mechanisms contribute to these effects of inflammation, including decreased synthesis, release and reuptake of dopamine, increased synaptic and extrasynaptic glutamate, and activation of kynurenine pathway metabolites including quinolinic acid.

Acute drug effects differentially predict desire to take dextroamphetamine again for work and recreation.

Rationale: Misuse of dextroamphetamine occurs in work and recreational contexts. While acute drug effects broadly predict abuse liability, few studies have considered the relationship between acute effects and context.

Objectives: This study examined how individual differences in acute effects of dextroamphetamine relate to desire to take dextroamphetamine again in different contexts.

Reduced adaptation of glutamatergic stress response is associated with pessimistic expectations in depression.

Stress is a significant risk factor for the development of major depressive disorder (MDD), yet the underlying mechanisms remain unclear. Preclinically, adaptive and maladaptive stress-induced changes in glutamatergic function have been observed in the medial prefrontal cortex (mPFC). Here, we examine stress-induced changes in human mPFC glutamate using magnetic resonance spectroscopy (MRS) in two healthy control samples and a third sample of unmedicated participants with MDD who completed the Maastricht acute stress task, and one sample of healthy control participants who completed a no-stress control manipulation.

Two scene navigation systems dissociated by deliberate versus automatic processing.

Successfully navigating the world requires avoiding boundaries and obstacles in one's immediately-visible environment, as well as finding one's way to distant places in the broader environment. Recent neuroimaging studies suggest that these two navigational processes involve distinct cortical scene processing systems, with the occipital place area (OPA) supporting navigation through the local visual environment, and the retrosplenial complex (RSC) supporting navigation through the broader spatial environment. Here we hypothesized that these systems are distinguished not only by the scene information they represent (i.

Mapping Disease Course Across the Mood Disorder Spectrum Through a Research Domain Criteria Framework.

Background: The National Institute of Mental Health Research Domain Criteria (RDoC) initiative aims to establish a neurobiologically valid framework for classifying mental illness. Here, we examined whether the RDoC construct of reward learning and three aspects of its underlying neurocircuitry predicted symptom trajectories in individuals with mood pathology.

Methods: Aligning with the RDoC approach, we recruited individuals (n = 80 with mood disorders [58 unipolar and 22 bipolar] and n = 32 control subjects; 63.