Joshua Bizzell

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.

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

BACKGROUNDnUnipolar 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.nnnMETHODSnTwelve 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.nnnRESULTSnSeventy-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.nnnCONCLUSIONSnBehavioral 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.

Hemodynamic correlates of stimulus repetition in the visual and auditory cortices: An fMRI study

We examined the effects of stimulus repetition upon the evoked hemodynamic response (HDR) in auditory and visual cortices measured by magnetic resonance imaging in two experiments. Experiment 1 focused on the effects of the interval duration between two identical stimuli on HDR. Pure auditory tones (1000 Hz) of 100-ms duration were presented singly or in pairs with intrapair intervals (IPIs: onset-to-onset) of 1, 4, and 6 s. In Experiment 2, using a within-subject design, we aimed to compare the HDR refractory period in both sensory cortices as well as the HDRs to auditory and visual stimuli. Identical auditory tone as described above and visual stimuli of 500-ms high-contrast checkerboard patterns were presented singly or in identical pairs with an IPI of 1 s. Images were acquired at 1.5 T using a gradient-echo echo-planar imaging sequence sensitive to blood oxygenation level-dependent (BOLD) contrast. Experiment 1 revealed that the HDR evoked by an auditory stimulus is followed by a refractory period of 4-6 s in the auditory cortex, as indicated by smaller HDR amplitudes to the second of each pair of stimuli. Furthermore, peak latency was dependent upon IPI, with longer latencies observed for shorter IPIs. Experiment 2 revealed that the HDR evoked in both sensory cortices by paired stimulus presentations is suppressed and delayed similarly by the refractory effects imposed by the preceding stimulus, suggesting similar refractory properties of the HDR at this specific IPI. We also provide evidence for additional neural resource allocation in response to repeated stimuli.

Abnormal Neural Activation to Faces in the Parents of Children with Autism

Parents of children with an autism spectrum disorder (ASD) show subtle deficits in aspects of social behavior and face processing, which resemble those seen in ASD, referred to as the Broad Autism Phenotype (BAP). While abnormal activation in ASD has been reported in several brain structures linked to social cognition, little is known regarding patterns in the BAP. We compared autism parents with control parents with no family history of ASD using 2 well-validated face-processing tasks. Results indicated increased activation in the autism parents to faces in the amygdala (AMY) and the fusiform gyrus (FG), 2 core face-processing regions. Exploratory analyses revealed hyper-activation of lateral occipital cortex (LOC) bilaterally in autism parents with aloof personality (BAP+). Findings suggest that abnormalities of the AMY and FG are related to underlying genetic liability for ASD, whereas abnormalities in the LOC and right FG are more specific to behavioral features of the BAP. Results extend our knowledge of neural circuitry underlying abnormal face processing beyond those previously reported in ASD to individuals with shared genetic liability for autism and a subset of genetically related individuals with the BAP.

Differences in subcortical structures in young adolescents at familial risk for schizophrenia: A preliminary study

Schizophrenia has been associated with reduced volumes of subcortical structures on magnetic resonance imaging (MRI), but the relation of these reductions to familial risk for the disorder is unclear. We investigated the effect of familial risk for schizophrenia on regional subcortical volumes during adolescence, a period marked by steep maturational changes in brain structure and the emergence of psychotic symptoms. A group of 26 non-help-seeking, first-degree relatives of patients with schizophrenia and 43 matched healthy comparisons, between 9 and 18 years of age, underwent MRI scanning and were rated for the presence of prodromal symptoms. Five subcortical regions-of-interest were tested for group differences and group by age interactions, as well as correlations with low-level prodromal symptoms in the familial risk group. Relative to comparisons, familial risk subjects demonstrated greater positive volume-age relationships in hippocampus, putamen, and globus pallidus. These results suggest that relatives of individuals with schizophrenia exhibit structural abnormalities in the subcortex as early as pre-adolescence, which may reflect altered neurodevelopment of these regions.

Neural Correlates of Schizophrenia Negative Symptoms: Distinct Subtypes Impact Dissociable Brain Circuits

Background: The negative symptoms of schizophrenia include deficits in emotional expression and motivation. These deficits are stable over the course of illness and respond poorly to current medications. Previous studies have focused on negative symptoms as a single category; however, individual symptoms might be related to separate neurological disturbances. We analyzed data from the Functional Biomedical Informatics Research Network dataset to explore the relationship between individual negative symptoms and functional brain activity during an auditory oddball task. Methods: Functional magnetic resonance imaging was conducted on 89 schizophrenia patients and 106 healthy controls during a two-tone auditory oddball task. Blood oxygenation level-dependent (BOLD) signal during the target tone was correlated with severity of five negative symptom domains from the Scale for the Assessment of Negative Symptoms. Results: The severity of alogia, avolition/apathy and anhedonia/asociality was negatively correlated with BOLD activity in distinct sets of brain regions associated with processing of the target tone, including basal ganglia, thalamus, insular cortex, prefrontal cortex, posterior cingulate and parietal cortex. Conclusions: Individual symptoms were related to different patterns of functional activation during the oddball task, suggesting that individual symptoms might arise from distinct neural mechanisms. This work has potential to inform interventions that target these symptom-related neural disruptions.

Neural mechanisms of negative reinforcement in children and adolescents with autism spectrum disorders

BackgroundPrevious research has found accumulating evidence for atypical reward processing in autism spectrum disorders (ASD), particularly in the context of social rewards. Yet, this line of research has focused largely on positive social reinforcement, while little is known about the processing of negative reinforcement in individuals with ASD.MethodsThe present study examined neural responses to social negative reinforcement (a face displaying negative affect) and non-social negative reinforcement (monetary loss) in children with ASD relative to typically developing children, using functional magnetic resonance imaging (fMRI).ResultsWe found that children with ASD demonstrated hypoactivation of the right caudate nucleus while anticipating non-social negative reinforcement and hypoactivation of a network of frontostriatal regions (including the nucleus accumbens, caudate nucleus, and putamen) while anticipating social negative reinforcement. In addition, activation of the right caudate nucleus during non-social negative reinforcement was associated with individual differences in social motivation.ConclusionsThese results suggest that atypical responding to negative reinforcement in children with ASD may contribute to social motivational deficits in this population.

Neural mechanisms of subclinical depressive symptoms in women: a pilot functional brain imaging study

BackgroundStudies of individuals who do not meet criteria for major depressive disorder (MDD) but with subclinical levels of depressive symptoms may aid in the identification of neurofunctional abnormalities that possibly precede and predict the development of MDD. The purpose of this study was to evaluate relations between subclinical levels of depressive symptoms and neural activation patterns during tasks previously shown to differentiate individuals with and without MDD.MethodsFunctional magnetic resonance imaging (fMRI) was used to assess neural activations during active emotion regulation, a resting state scan, and reward processing. Participants were twelve females with a range of depressive symptoms who did not meet criteria for MDD.ResultsIncreased depressive symptom severity predicted (1) decreased left midfrontal gyrus activation during reappraisal of sad stimuli; (2) increased right midfrontal gyrus activation during distraction from sad stimuli; (3) increased functional connectivity between a precuneus seed region and left orbitofrontal cortex during a resting state scan; and (4) increased paracingulate activation during non-win outcomes during a reward-processing task.ConclusionsThese pilot data shed light on relations between subclinical levels of depressive symptoms in the absence of a formal MDD diagnosis and neural activation patterns. Future studies will be needed to test the utility of these activation patterns for predicting MDD onset in at-risk samples.

Altered fronto-limbic activity in children and adolescents with familial high risk for schizophrenia

Early symptoms of schizophrenia tend to emerge during adolescence, hich is a critical period for development of executive and emotional processing. While individuals with familial high risk (FHR) for schizophrenia may show cognitive and emotional changes, the neural mechanisms underlying the development of these changes remain unclear. The goal of this study was to identify functional differences in fronto-striato-limbic regions in children with FHR. Functional magnetic resonance imaging (MRI) data were collected from 21 children with a first-degree family member with schizophrenia and 21 controls without FHR. Participants performed an emotional oddball task requiring both selective attention and suppression of task-irrelevant emotional information. During selective attention, the group with FHR showed enhanced activation in the inferior frontal gyrus and caudate, with decreases in middle frontal gyrus and insular activation. The FHR group also showed greater age-related recruitment of anterior cingulate, temporal and occipital cortical areas during selective attention. During emotional processing, the FHR group showed decreased anterior cingulate activation, with decreased age-related recruitment of inferior frontal, parietal and occipital areas. The results suggest that FHR for schizophrenia may be associated with abnormal hyperactivation and hypoactivation of the neural circuitry engaged during executive and emotional processing and with age-related changes in neural recruitment during adolescence.

The effects of intranasal oxytocin on reward circuitry responses in children with autism spectrum disorder

BackgroundIntranasal oxytocin (OT) has been shown to improve social communication functioning of individuals with autism spectrum disorder (ASD) and, thus, has received considerable interest as a potential ASD therapeutic agent. Although preclinical research indicates that OT modulates the functional output of the mesocorticolimbic dopamine system that processes rewards, no clinical brain imaging study to date has examined the effects of OT on this system using a reward processing paradigm. To address this, we used an incentive delay task to examine the effects of a single dose of intranasal OT, versus placebo (PLC), on neural responses to social and nonsocial rewards in children with ASD.MethodsIn this placebo-controlled double-blind study, 28 children and adolescents with ASD (age: Mu2009=u200913.43xa0years, SDu2009=u20092.36) completed two fMRI scans, one after intranasal OT administration and one after PLC administration. During both scanning sessions, participants completed social and nonsocial incentive delay tasks. Task-based neural activation and connectivity were examined to assess the impact of OT relative to PLC on mesocorticolimbic brain responses to social and nonsocial reward anticipation and outcomes.ResultsCentral analyses compared the OT and PLC conditions. During nonsocial reward anticipation, there was greater activation in the right nucleus accumbens (NAcc), left anterior cingulate cortex (ACC), bilateral orbital frontal cortex (OFC), left superior frontal cortex, and right frontal pole (FP) during the OT condition relative to PLC. Alternatively, during social reward anticipation and outcomes, there were no significant increases in brain activation during the OT condition relative to PLC. A Treatment Group × Reward Condition interaction revealed relatively greater activation in the right NAcc, right caudate nucleus, left ACC, and right OFC during nonsocial relative to social reward anticipation during the OT condition relative to PLC. Additionally, these analyses revealed greater activation during nonsocial reward outcomes during the OT condition relative to PLC in the right OFC and left FP. Finally, functional connectivity analyses generally revealed changes in frontostriatal connections during the OT condition relative to PLC in response to nonsocial, but not social, rewards.ConclusionsThe effects of intranasal OT administration on mesocorticolimbic brain systems that process rewards in ASD were observable primarily during the processing of nonsocial incentive salience stimuli. These findings have implications for understanding the effects of OT on neural systems that process rewards, as well as for experimental trials of novel ASD treatments developed to ameliorate social communication impairments in ASD.