Risperidone and Divalproex Differentially Engage the Fronto-Striato-Temporal Circuitry in Pediatric Mania: A Pharmacological Functional Magnetic Resonance Imaging Study
ABSTRACT The current study examined the impact of risperidone and divalproex on affective and working memory circuitry in patients with pediatric bipolar disorder (PBD).
This was a six-week, double-blind, randomized trial of risperidone plus placebo versus divalproex plus placebo for patients with mania (n = 21; 13.6 ± 2.5 years of age). Functional magnetic resonance imaging (fMRI) outcomes were measured using a block design, affective, N-back task with angry, happy, and neutral face stimuli at baseline and at 6-week follow-up. Matched healthy controls (HC; n = 15, 14.5 ± 2.8 years) were also scanned twice.
In post hoc analyses on the significant interaction in a 3×2×2 analysis of variance (ANOVA) that included patient groups and HC, the risperidone group showed greater activation after treatment in response to the angry face condition in the left subgenual anterior cingulate cortex (ACC) and striatum relative to the divalproex group. The divalproex group showed greater activation relative to the risperidone group in the left inferior frontal gyrus and right middle temporal gyrus. Over the treatment course, the risperidone group showed greater change in activation in the left ventral striatum than the divalproex group, and the divalproex group showed greater activation change in left inferior frontal gyrus and right middle temporal gyrus than the risperidone group. Furthermore, each patient group showed increased activation relative to HC in fronto-striato-temporal regions over time. The happy face condition was potentially less emotionally challenging in this study and did not elicit notable findings.
When patients performed a working memory task under emotional duress inherent in the paradigm, divalproex enhanced activation in a fronto-temporal circuit whereas risperidone increased activation in the dopamine (D₂) receptor-rich ventral striatum. Clinical trial registration information-Risperidone and Divalproex Sodium With MRI Assessment in Pediatric Bipolar; http://www.clinicaltrials.gov; NCT00176202.
Full-textDOI: · Available from: Mani N Pavuluri, Nov 03, 2014
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ABSTRACT: Research in bipolar disorder (BD) implicates fronto-limbic-striatal dysfunction during face emotion processing but it is unknown how such dysfunction varies by task demands, face emotion and patient age. Method During functional magnetic resonance imaging (fMRI), 181 participants, including 62 BD (36 children and 26 adults) and 119 healthy comparison (HC) subjects (57 children and 62 adults), engaged in constrained and unconstrained processing of emotional (angry, fearful, happy) and non-emotional (neutral) faces. During constrained processing, subjects answered questions focusing their attention on the face; this was processed either implicitly (nose width rating) or explicitly (hostility; subjective fear ratings). Unconstrained processing consisted of passive viewing. Pediatric BD rated neutral faces as more hostile than did other groups. In BD patients, family-wise error (FWE)-corrected region of interest (ROI) analyses revealed dysfunction in the amygdala, inferior frontal gyrus (IFG), anterior cingulate cortex (ACC) and putamen. Patients with BD showed amygdala hyperactivation during explicit processing (hostility ratings) of fearful faces and passive viewing of angry and neutral faces but IFG hypoactivation during implicit processing of neutral and happy faces. In the ACC and striatum, the direction of dysfunction varied by task demand: BD demonstrated hyperactivation during unconstrained processing of angry or neutral faces but hypoactivation during constrained processing (implicit or explicit) of angry, neutral or happy faces. Findings suggest amygdala hyperactivation in BD while processing negatively valenced and neutral faces, regardless of attentional condition, and BD IFG hypoactivation during implicit processing. In the cognitive control circuit involving the ACC and putamen, BD neural dysfunction was sensitive to task demands.Psychological Medicine 08/2013; DOI:10.1017/S003329171300202X · 5.43 Impact Factor
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ABSTRACT: BACKGROUND: We investigated affect recognition and the impact of emotional valence on working memory (using happy, angry, and neutral faces) in pediatric patients with bipolar disorder (BD) and healthy control (HC) subjects.Method Subjects (N=70) consisted of unmedicated patients with BD type I (BD I, n=23) and type II (BD II, n=16) and matched HC subjects (n=31). All subjects completed tasks of emotion recognition (Chicago Pediatric Emotional Acuity Task; Chicago PEAT) and working memory for happy, angry, and neutral faces (Affective N-Back Memory Task; ANMT). RESULTS: Compared to HC subjects, BD patients performed significantly more poorly when identifying the intensity of happy and angry expressions on the Chicago PEAT, and demonstrated working-memory impairments regardless of the type of facial emotional stimuli. Pediatric BD patients displayed the most impaired accuracy and reaction time performance with negative facial stimuli relative to neutral stimuli, but did not display this pattern with positive stimuli. Only BD I patients displayed working-memory deficits, while both BD I and BD II patients displayed emotion-identification impairments. Results remained significant after controlling for co-morbid ADHD and mood state. CONCLUSIONS: Both BD I and BD II youth demonstrate emotion-identification deficits. BD youth also demonstrate working-memory impairments for facial stimuli irrespective of emotional valence; however, working-memory deficits were the most pronounced with negative emotional stimuli. These deficits appear to be specific to BD I patients, and suggest therefore that a more severe form of illness is characterized by more severe social-cognitive impairment.Psychological Medicine 05/2012; 42(12):1-11. DOI:10.1017/S0033291712000797 · 5.43 Impact Factor
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ABSTRACT: A deeper understanding of how the relationships between impulsivity, reward systems and executive function deficits may be similar or different in attention-deficit/hyperactivity disorder (ADHD) and pediatric bipolar disorder (PBD) is fundamental for better defining phenotypy in these two developmental illnesses, and moving towards improved treatment and intervention. We focus our article on recent neurocognitive and neuroimaging data examining the behavioral and neural aspects of poor behavior regulation, response inhibition and reward systems in ADHD and PBD. In light of recent research evidence, we propose that the common behavioral manifestations of impulsivity in ADHD and PBD may indeed originate from different neural mechanisms mediated by altered reward systems. In order to define and differentiate these mechanisms, unlike previous approaches, our theoretical model examines the interface of the dorsal frontostriatal circuit, involved in behavior regulation, and the ventral frontostriatal circuit, which is involved in reward-related and affect processes. Preliminary evidence suggests that the neural systems involved in impulsivity, reward systems and executive function engage differently in the two illnesses. In PBD, 'emotional impulsivity' is predominantly 'bottom-up' and emotionally/motivationally driven, and stems from ventral frontostriatal circuitry dysfunction. By contrast, in ADHD 'cognitive impulsivity' is predominantly 'top-down' and more 'cognitively driven', and stems from dorsal frontostriatal dysfunction. We discuss this evidence in view of clinically relevant questions and implications for illness-based intervention. We conclude that the reward-related mechanisms underlying the interactions between executive function, behavior regulation and impulsivity in PBD and ADHD may be differentially compromised, and in accordance differently shape the clinical symptoms of impulsivity and goal-directed behavior.Expert Review of Neurotherapeutics 06/2011; 11(6):897-914. DOI:10.1586/ern.11.71 · 2.83 Impact Factor