Faculty Bibliography

BACKGROUND:Inflammation has been hypothesized to contribute to reward dysfunction across psychiatric conditions, but little is known about this relationship in youth. Therefore, the present study investigated the associations between general and specific markers of inflammation and neural activation during reward processing, including anticipation and attainment, in youth with diverse psychiatric symptoms. METHODS:Forty-six psychotropic medication-free youth with diverse psychiatric symptoms underwent a blood draw to measure 41 cytokines, as well as structural and functional magnetic resonance imaging. The Reward Flanker Task examined neural activation during reward anticipation and attainment. Relationships between inflammation and neural activation were assessed using data reduction techniques across the whole-brain, as well as in specific reward regions of interest (basal ganglia, anterior and mid-cingulate cortex [ACC/MCC]). RESULTS:Whole-brain principal component analyses showed that factor 3 (12 cytokines: FGF-2, Flt3-L, fractalkine, GM-CSF, IFN-α2, IFN-γ, IL-3, IL-4, IL-7, IL-17A, MDC, and VEGF) was negatively correlated with precuneus/posterior cingulate cortex activity during anticipation. Factor 2 (11 cytokines: eotaxin, IL-1α, IL-1Rα, IL-2, IL-5, IL-9, IL-12p40, IL-13, IL-15, MCP-3, and TNF-β) was negatively correlated with angular gyrus activity during attainment. ROI analyses additionally showed that multiple cytokines were related to activity in the basal ganglia (EGF, FGF-2, Flt-3L, IL-2, IL-13, IL-15, IL-1Rα, MCP-3) and ACC/MCC (Flt-3L) during attainment. C-reactive protein (CRP) was not associated with neural activation. CONCLUSIONS:Investigation of specific markers of immune function showed associations between inflammatory processes and activation of posterior default mode network, prefrontal cortex, and basal ganglia regions during multiple phases of reward processing.

INTRODUCTION/BACKGROUND:Transcranial Direct Current Stimulation (tDCS) is a non-invasive brain stimulation intervention that has been investigated for several psychiatric disorders, including Obsessive-Compulsive Disorder (OCD). As there are several candidate brain regions for targeting OCD relevant networks, clinical studies using tDCS have considerably varied in terms of the electrode montages used. Computer modeling of electric field currents induced by tDCS can help guiding the research of relevant targets for OCD. In this review, the authors used this tool to investigate targeted brain areas from previous studies of tDCS in OCD. Areas covered: A literature search for articles with the keywords "tDCS", "Transcranial Direct Current Stimulation" and "Obsessive Compulsive Disorder" was conducted to identify relevant publications. For comparing different electrode montages, electric field (EF) models were performed using high-resolution brain scan templates. Authors found 13 studies mostly showing an improvement in OCD symptoms. The electrode montages varied considerably between studies. Nonetheless, two main patterns of EFs could be identified: "focal montages", with EFs concentrated in the prefrontal cortex, and "diffuse montages", with widespread EFs over cortical areas. Expert opinion: Electric field simulation can guide future clinical trials in psychiatry, using personalized tDCS montages with distinct electrode positioning according to clusters of symptoms.

The habenula (Hb) inhibits dopaminergic reward signaling in response to negative outcomes and has been linked to numerous functional domains relevant to mental health, including reward prediction, motivation, and aversion processing. Despite its important neuroscientific and clinical implications, however, the human Hb remains poorly understood due to its small size and the associated technical hurdles to in vivo functional magnetic resonance imaging (fMRI) investigation. Using high-resolution 3T fMRI data from 68 healthy young adults acquired through the Human Connectome Project, we developed a rigorous approach for mapping the whole-brain resting-state functional connectivity of the human Hb. Our study combined an optimized strategy for defining subject-level connectivity seeds to maximize Hb BOLD sensitivity with high-quality surface-based alignment for robust functional localization and cortical sensitivity. We identified significant positive Hb connectivity with: (i) conserved brainstem targets, including the dopaminergic ventral tegmental area, serotonergic raphe nuclei, and periaqueductal gray; (ii) subcortical structures related to reward and motor function, including the nucleus accumbens, dorsal striatum, pallidum, thalamus, and cerebellum; and (iii) cortical areas associated with the Salience Network and early sensory processing, including the dorsal anterior cingulate, anterior insula, and primary visual and auditory cortices. Hb connectivity was strongly biased towards task-positive brain regions, with weak or negative connectivity observed throughout the task-negative Default Mode Network. Our study provides a detailed characterization of Hb resting-state functional connectivity in healthy young adults, demonstrating both the feasibility and clinical potential of studying the human Hb using high-resolution 3T fMRI.

Sensory phenomena (SP) are aversive or uncomfortable sensations that accompany and/or drive repetitive behaviors in obsessive-compulsive disorder (OCD). Although SP are associated with significant distress and may respond less well to standard treatments than harm-related obsessions, little is known about their underlying neurobiology. The present study used functional magnetic resonance imaging (fMRI) to measure brain functioning related to severity of SP during a "body-focused" videos task designed to elicit activation in sensorimotor brain regions. Regression analysis examined the relationship between severity of SP and activation during task using permutation analysis, cluster-level corrected for multiple comparisons (family-wise error rate p < 0.05). The distribution of SP severity was not significantly different from normal, with both high- and low-severity scores represented in the OCD sample. Severity of SP was not correlated with other clinical symptoms in OCD including general anxiety, depression, or harm avoidance. When viewing body-focused videos, patients with greater severity of SP showed increased activity in the mid-posterior insula, a relationship that remained significant when controlling for other clinical symptoms, medication status, and comorbidities. At uncorrected thresholds, SP severity was also positively related to somatosensory, mid orbitofrontal, and lateral prefrontal cortical activity. These data suggest that SP in OCD are dissociable from other symptoms in the disorder and related to hyperactivation of the insula. Future work examining neural mechanisms of SP across different disorders (tics, trichotillomania) as well as with other imaging modalities will be needed to further understand the neurobiology of these impairing symptoms.

Several psychiatric disorders involve abnormalities of interoception and associated neural circuitry centered on the insula. The development of interventions modulating interoceptive circuits could lead to novel treatment approaches for these disorders. The 5-HT3 receptor antagonist ondansetron is a good candidate for the modulation of interoceptive circuits, as 5-HT3 receptors are located abundantly on sensory pathways and ondansetron has shown some clinical utility in disorders characterized by sensory and interoceptive abnormalities. The present study tested the ability of three different doses of ondansetron to engage neural regions involved in interoception to determine the drug's utility as a therapeutic agent to target circuit abnormalities in patients. Fifty-three healthy subjects were randomized to receive a single 8-mg (n = 18), 16-mg (n = 17), or 24-mg (n = 18) dose of ondansetron and placebo before MRI scanning on separate days. Subjects performed an fMRI task previously shown to engage interoceptive circuitry in which they viewed videos depicting body movements/sensation and control videos. The results revealed a highly significant relationship between dosage and activation in bilateral insula, somatosensory and premotor regions, cingulate cortex, and temporal cortex for control but not body-focused videos. These effects were driven by a robust reduction in activation for ondansetron compared to placebo for the 24-mg group, with weaker effects for the 16-mg and 8-mg groups. In conclusion, high-dose ondansetron reduces activation of several areas important for interoception, including insula and sensorimotor cortical regions. This study reveals the potential utility of this drug in modulating hyperactivity in these regions in patients.

Introduction/UNASSIGNED:Obsessive-compulsive disorder (OCD) patients show abnormalities in decision-making and, clinically, appear to show heightened sensitivity to potential negative outcomes. Despite the importance of these cognitive processes in OCD, few studies have examined the disorder within an economic decision-making framework. Here, we investigated loss aversion, a key construct in the prospect theory that describes the tendency for individuals to be more sensitive to potential losses than gains when making decisions. Methods/UNASSIGNED: = 34) accepted or rejected a series of 50/50 gambles containing varying loss/gain values. Loss aversion was calculated as the ratio of the likelihood of rejecting a gamble with increasing potential losses to the likelihood of accepting a gamble with increasing potential gains. Decision times to accept or reject were also examined and correlated with loss aversion. Results/UNASSIGNED:analyses further indicated that unmedicated patients' increased likelihood to reject a gamble as its loss value increased could not be explained solely by greater risk aversion among patients. Unmedicated patients were also slower to accept than reject gambles, effects that were not found in the other two groups. Loss aversion was correlated with decision times in unmedicated patients but not in the other two groups. Discussion/UNASSIGNED:These data identify abnormalities of decision-making in a subgroup of OCD patients not taking psychotropic medication. The findings help elucidate the cognitive mechanisms of the disorder and suggest that future treatments could aim to target abnormalities of loss/gain processing during decision-making in this population.

Obsessive-compulsive disorder (OCD) patients show increased insula activation to disgust-inducing images compared to healthy controls (HC). We explored whether this disgust reactivity was also present in the olfactory domain by conducting the first fMRI study of olfaction in OCD. Neural activation in response to pleasant and unpleasant odors (vs. unscented air) was investigated in 15 OCD and 15 HC participants using fMRI. OCD participants (vs. HC) had increased left anterior insula activation to unpleasant odors (vs. unscented air), which positively correlated with their disgust sensitivity and ratings of the unpleasantness and intensity of those odors. OCD participants (vs. HC) showed increased activation of caudate nucleus and left anterior and posterior insula to pleasant odors (vs. unscented air), which positively correlated with their OCD symptom severity, trait anxiety, frequency of feeling disgust, and odor intensity ratings. OCD participants had increased anterior insula activation to both pleasant and unpleasant odors, which correlated with their OCD symptoms, anxiety, disgust sensitivity, and frequency of feeling disgust. OCD patients might have a negative cognitive bias and experience all stimuli, regardless of valence, as being more unpleasant than healthy people. These findings further elucidate the neural underpinnings of OCD and may contribute to more effective treatments.

BACKGROUND: There has been growing interest under the Research Domain Criteria initiative to investigate behavioral constructs and their underlying neural circuitry. Abnormalities in reward processes are salient across psychiatric conditions and may precede future psychopathology in youth. However, the neural circuitry underlying such deficits has not been well defined. Therefore, in this pilot, we studied youth with diverse psychiatric symptoms and examined the neural underpinnings of reward anticipation, attainment, and positive prediction error (PPE, unexpected reward gain). Clinically, we focused on anhedonia, known to reflect deficits in reward function. METHODS: Twenty-two psychotropic medication-free youth, 16 with psychiatric symptoms, exhibiting a full range of anhedonia, were scanned during the Reward Flanker Task. Anhedonia severity was quantified using the Snaith-Hamilton Pleasure Scale. Functional magnetic resonance imaging analyses were false discovery rate corrected for multiple comparisons. RESULTS: Anticipation activated a broad network, including the medial frontal cortex and ventral striatum, while attainment activated memory and emotion-related regions such as the hippocampus and parahippocampal gyrus, but not the ventral striatum. PPE activated a right-dominant fronto-temporo-parietal network. Anhedonia was only correlated with activation of the right angular gyrus during anticipation and the left precuneus during PPE at an uncorrected threshold. LIMITATIONS: Findings are preliminary due to the small sample size. CONCLUSIONS: This pilot characterized the neural circuitry underlying different aspects of reward processing in youth with diverse psychiatric symptoms. These results highlight the complexity of the neural circuitry underlying reward anticipation, attainment, and PPE. Furthermore, this study underscores the importance of RDoC research in youth.