Gabriel S. Dichter

Dopamine Transmission in the Human Striatum during Monetary Reward Tasks

Previous studies have demonstrated the ability of the [11C]raclopride positron emission tomography (PET) technique to measure behaviorally induced changes in endogenous dopamine transmission in humans. However, these studies have lacked well matched sensorimotor control conditions, making it difficult to know what sensory, cognitive, or motor features contributed to changes in dopaminergic activity. Here we report on [11C]raclopride PET studies in which healthy humans performed card selection tasks for monetary rewards. During separate scans, subjects completed a variable ratio (VR) reward schedule with a 25% reward rate in which they did not know the outcome of their responses in advance, a fixed ratio (FR) 25% reward schedule in which outcomes were fully predictable, and a sensorimotor control (SC) condition involving similar sensory and motor demands but no rewards. Relative to the SC condition, the FR schedule produced only modest increases in dopamine transmission and no decreases relative to the SC condition. In contrast, the VR schedule produced significant increases in dopamine transmission in the left medial caudate nucleus while simultaneously producing significant decreases in other areas of the caudate and putamen. These data indicate: (1) the feasibility of measuring alterations in dopamine transmission even after controlling for sensorimotor features and (2) the complex and regionally specific influence of VR schedules on dopamine transmission. The implications of these results are discussed in relation to conflicting models of dopaminergic functioning arising from studies using electrophysiological and microdialysis techniques in animals.

fMRI of alterations in reward selection, anticipation, and feedback in major depressive disorder

The purpose of the present investigation was to evaluate reward processing in unipolar major depressive disorder (MDD). Specifically, we investigated whether adults with MDD demonstrated hyporesponsivity in striatal brain regions and/or hyperresponsivity in cortical brain regions involved in conflict monitoring using a Wheel of Fortune task designed to probe responses during reward selection, reward anticipation, and reward feedback. Functional magnetic resonance imaging (fMRI) data indicated that the MDD group was characterized by reduced activation of striatal reward regions during reward selection, reward anticipation, and reward feedback, supporting previous data indicating hyporesponsivity of reward systems in MDD. Support was not found for hyperresponsivity of cognitive control regions during reward selection or reward anticipation. Instead, MDD participants showed hyperresponsivity in orbitofrontal cortex, a region associated with assessment of risk and reward, during reward selection, as well as decreased activation of the middle frontal gyrus and the rostral cingulate gyrus during reward selection and anticipation. Finally, depression severity was predicted by activation in bilateral midfrontal gyrus during reward selection. Results indicate that MDD is characterized by striatal hyporesponsivity, and that future studies of MDD treatments that seek to improve responses to rewarding stimuli should assess striatal functioning.

Reward circuitry function in autism spectrum disorders

Social interaction deficits and restricted repetitive behaviors and interests that characterize autism spectrum disorders (ASDs) may both reflect aberrant functioning of brain reward circuits. However, no neuroimaging study to date has investigated the integrity of reward circuits using an incentive delay paradigm in individuals with ASDs. In the present study, we used functional magnetic resonance imaging to assess blood-oxygen level-dependent activation during reward anticipation and outcomes in 15 participants with an ASD and 16 matched control participants. Brain activation was assessed during anticipation of and in response to monetary incentives and object image incentives previously shown to be visually salient for individuals with ASDs (e.g., trains, electronics). Participants with ASDs showed decreased nucleus accumbens activation during monetary anticipation and outcomes, but not during object anticipation or outcomes. Group × reward-type-interaction tests revealed robust interaction effects in bilateral nucleus accumbens during reward anticipation and in ventromedial prefrontal cortex during reward outcomes, indicating differential responses contingent on reward type in these regions. Results suggest that ASDs are characterized by reward-circuitry hypoactivation in response to monetary incentives but not in response to autism-relevant object images. The clinical implications of the double dissociation of reward type and temporal phase in reward circuitry function in ASD are discussed.

The Effects of Psychotherapy on Neural Responses to Rewards in Major Depression

BACKGROUND Unipolar major depressive disorder (MDD) is characterized by anomalous neurobiological responses to pleasant stimuli, a pattern that may be linked to symptoms of anhedonia. However, the potential for psychotherapy to normalize neurobiological responses to pleasant stimuli has not been evaluated. METHODS Twelve adults with and 15 adults without MDD participated in two identical functional magnetic resonance imaging scans that used a Wheel of Fortune task. Between scans, MDD outpatients received Behavioral Activation Therapy for Depression, a psychotherapy modality designed to increase engagement with rewarding stimuli and reduce avoidance behaviors. RESULTS Seventy-five percent of adults with MDD were treatment responders, achieving post-treatment Hamilton Rating Scale for Depression score of six or below. Relative to changes in brain function in the matched nondepressed group, psychotherapy resulted in functional changes in structures that mediate responses to rewards, including the paracingulate gyrus during reward selection, the right caudate nucleus (i.e., the dorsal striatum), during reward anticipation, and the paracingulate and orbital frontal gyri during reward feedback. There was no effect of diagnostic status or psychotherapy on in-scanner task-related behavioral responses. CONCLUSIONS Behavioral Activation Therapy for Depression, a psychotherapy modality designed to increase engagement with rewarding stimuli and reduce avoidance behaviors, results in improved functioning of unique reward structures during different temporal phases of responses to pleasurable stimuli, including the dorsal striatum during reward anticipation.

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders), neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette’s syndrome, conduct disorder/oppositional defiant disorder), and genetic syndromes (i.e., Fragile X syndrome, Prader–Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome). We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe reward-circuitry dysfunction, with the ultimate goal of improved intervention strategies.

Reward Circuitry Function in Autism During Face Anticipation and Outcomes

The aim of this study was to investigate reward circuitry responses in autism during reward anticipation and outcomes for monetary and social rewards. During monetary anticipation, participants with autism spectrum disorders (ASDs) showed hypoactivation in right nucleus accumbens and hyperactivation in right hippocampus, whereas during monetary outcomes, participants with ASDs showed hyperactivation in left midfrontal and anterior cingulate gyrus. Groups did not differ in nucleus accumbens responses to faces. The ASD group demonstrated hyperactivation in bilateral amygdala during face anticipation that predicted social symptom severity and in bilateral insular cortex during face outcomes. These results add to the growing body of evidence that autism is characterized by altered functioning of reward circuitry. Additionally, atypical amygdala activation during the processing of social rewards may contribute to the development or expression of autistic features.

The Neural Circuitry Mediating Shifts in Behavioral Response and Cognitive Set in Autism

BACKGROUND Recent studies have suggested that the social and cognitive impairments in autism are associated with neural processing deficits in specific brain regions. However, these studies have primarily focused on neural systems responsible for face processing and social behaviors. Although repetitive, stereotyped behaviors are a hallmark of autism, little is known about the neural mechanisms underlying these behaviors in the disorder. METHODS We used functional magnetic resonance imaging (fMRI) to investigate the neural correlates of shifts in behavioral response and cognitive set in 18 individuals with high-functioning autism and 15 neurotypical control participants. Participants performed a target detection task specifically designed to distinguish shifts in response from shifts in cognitive set. RESULTS Individuals with autism showed lower accuracy on response shifting trials, independent of whether those trials also required a shift in cognitive set. Compared with control subjects, participants with autism showed reduced activation in frontal, striatal, and parietal regions during these trials. In addition, within the autism group, the severity of restricted, repetitive behaviors was negatively correlated with activation in anterior cingulate and posterior parietal regions. CONCLUSIONS These results suggest that executive deficits and, by extension, repetitive behaviors associated with autism might reflect a core dysfunction within the brains executive circuitry.

Resting frontal brain activity: linkages to maternal depression and socio-economic status among adolescents

We tested the prediction that resting frontal brain asymmetry would be a marker of vulnerability for depression among adolescents. Baseline electroencephalographic (EEG) activity was recorded from 12 to 14-year-old adolescents whose mothers had a history of depression (high risk group) and whose mothers were lifetime-free of axis I psychopathology (low risk group). High risk adolescents demonstrated the hypothesized pattern of relative left frontal hypo-activity on alpha-band measures. Such effects were specific to the mid-frontal region and generally consistent across reference montages. Socio-economic status (SES) also predicted alpha asymmetry. When the effects of SES and risk status were jointly assessed, SES contributed unique variance to the prediction of frontal brain asymmetry. The implications of the observed relations among maternal depression, SES, and frontal brain asymmetry are discussed.

Remitted major depression is characterized by reward network hyperactivation during reward anticipation and hypoactivation during reward outcomes

BACKGROUND Although functional brain imaging has established that individuals with unipolar major depressive disorder (MDD) are characterized by frontostriatal dysfunction during reward processing, no research to date has examined the chronometry of neural responses to rewards in euthymic individuals with a history of MDD. METHOD A monetary incentive delay task was used during fMRI scanning to assess neural responses in frontostriatal reward regions during reward anticipation and outcomes in 19 participants with remitted major depressive disorder (rMDD) and in 19 matched control participants. RESULTS During the anticipation phase of the task, the rMDD group was characterized by relatively greater activation in bilateral anterior cingulate gyrus, in right midfrontal gyrus, and in the right cerebellum. During the outcome phase of the task, the rMDD group was characterized by relatively decreased activation in bilateral orbital frontal cortex, right frontal pole, left insular cortex, and left thalamus. Exploratory analyses indicated that activation within a right frontal pole cluster that differentiated groups during reward anticipation predicted the number of lifetime depressive episodes within the rMDD group. LIMITATIONS Replication with larger samples is needed. CONCLUSIONS Results suggest a double dissociation between reward network reactivity and temporal phase of the reward response in rMDD, such that rMDD is generally characterized by reward network hyperactivation during reward anticipation and reward network hypoactivation during reward outcomes. More broadly, these data suggest that aberrant frontostriatal response to rewards may potentially represent a trait marker for MDD, though future research is needed to evaluate the prospective utility of this functional neural endophenotype as a marker of MDD risk.

A systematic review of relations between resting-state functional-MRI and treatment response in major depressive disorder.

BACKGROUND Resting-state functional magnetic resonance imaging (fMRI) is a promising predictor of treatment response in major depressive disorder (MDD). METHODS A search for papers published in English was conducted using PubMed with the following words: depression, treatment, resting-state, connectivity, and fMRI. Findings from 21 studies of relations between resting-state fMRI and treatment response in MDD are presented, and common findings and themes are discussed. RESULTS The use of resting-state fMRI in research on MDD treatment response has yielded a number of consistent findings that provide a basis for understanding the potential mechanisms of action of antidepressant treatment response. These included (1) associations between response to antidepressant medications and increased functional connectivity between frontal and limbic brain regions, possibly resulting in greater inhibitory control over neural circuits that process emotions; (2) connectivity of visual recognition circuits in studies that compared treatment resistant and treatment sensitive patients; (3) response to TMS was consistently predicted by subcallosal cortex connectivity; and (4) hyperconnectivity of the default mode network and hypoconnectivity of the cognitive control network differentiated treatment-resistant from treatment-sensitive MDD patients. LIMITATIONS There was also considerable variability between studies with respect to study designs and analytic strategies that made direct comparisons across all studies difficult. CONCLUSIONS Continued standardization of study designs and analytic strategies as well as aggregation of larger datasets will allow the field to better elucidate the potential mechanisms of action of treatment response in patients with MDD to ultimately generate algorithms to predict which patients will respond to which antidepressant treatments.