Risperidone and Divalproex Differentially Engage the Fronto-Striato-Temporal Circuitry in Pediatric Mania: A Pharmacological Functional Magnetic Resonance Imaging Study

Pediatric Brain Research and Intervention Center, Institute for Juvenile Research, Colbeth Clinic, University of Illinois at Chicago, IL 60608, USA.
Journal of the American Academy of Child and Adolescent Psychiatry (Impact Factor: 7.26). 02/2012; 51(2):157-170.e5. DOI: 10.1016/j.jaac.2011.10.019
Source: PubMed


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;; NCT00176202.

    • "Nevertheless, to our knowledge, there are no data on the test–retest reliability of the emotional test battery. Elements of the emotional test battery, particularly the FERT or similar tasks, have been studied in longitudinal studies of medication in patient populations (Pavuluri et al., 2012; Tranter et al., 2009) though without the inclusion of control groups, thus making it impossible to know whether changes might have in fact been due to retesting. Changes in performance in tasks over time affecting their test– retest reliability might arise due to processes such as habituation to emotional stimuli and/or learning/practice effects. "
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    ABSTRACT: Little is known of the retest reliability of emotional cognitive tasks or the impact of using different tasks employing similar emotional stimuli within a battery. We investigated this in healthy subjects. We found improved overall performance in an emotional attentional blink task (EABT) with repeat testing at one hour and one week compared to baseline, but the impact of an emotional stimulus on performance was unchanged. Similarly, performance on a facial expression recognition task (FERT) was better one week after a baseline test, though the relative effect of specific emotions was unaltered. There was no effect of repeat testing on an emotional word categorising, recall and recognition task. We found no difference in performance in the FERT and EABT irrespective of task order. We concluded that it is possible to use emotional cognitive tasks in longitudinal studies and combine tasks using emotional facial stimuli in a single battery.
    No preview · Article · Jul 2015 · Cognition and Emotion
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    • "Decreased ReHo was also found in bilateral middle temporal gyrus in patients with PBD-depression. The temporal lobe is a visual and auditory-related brain region that plays a vital role in working memory processing and facial emotion processing [44,45]. Structural and functional MRI studies have accumulated the evidence that BD is associated with the alterations in temporal lobe. "
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    ABSTRACT: Background Pediatric bipolar disorder (PBD) has attracted increasing attentions due to its high prevalence and great influence on social functions of children and adolescents. However, the pathophysiology underlying PBD remains unclear. In the present study, the resting-state functional magnetic resonance imaging (fMRI) was used to detect abnormalities of baseline brain functions in depressed PBD youth.Methods Seventeen youth with PBD-depression aged 10 - 18 years old and 18 age- and sex-matched normal controls were recruited in this study. The fMRI data under resting state were obtained on a Siemens 3.0 Tesla scanner and were analyzed using the regional homogeneity (ReHo) method. Correlations between the ReHo values of each survived area and the severity of depression symptoms in patients were further analyzed.ResultsAs compared with the control group, PBD-depression patients showed decreased ReHo in the medial frontal gyrus, bilateral middle frontal gyrus and middle temporal gyrus, and the right putamen. Significant negative correlations of the mood and feelings questionnaire scores with mean ReHo values in the medial frontal gyrus and the right middle frontal gyrus in PBD-depression patients were observed.Conclusion Our results suggest that extensive regions with altered baseline brain activities are existed in PBD-depression and these brain regions mainly locate in the fronto-limbic circuit and associated striatal structures. Moreover, the present findings also add to our understanding that there could be unique neuropathophysiological mechanisms underlying PBD-depression.
    Full-text · Article · Aug 2014 · BMC Psychiatry
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    • "Third, most patients were medicated; although activation did not differ between medicated (n = 47) and unmedicated (n = 12) patients, these post-hoc analyses were underpowered and thus susceptible to Type II error. Studies indicate that neural dysfunction may normalize with treatment, suggesting that medication may be unlikely to be driving the betweengroup differences that we observed (Chang et al. 2008; Phillips et al. 2008; Passarotti et al. 2010, 2011; Hafeman et al. 2012; Pavuluri et al. 2012). Although our sample sizes compare favorably to those in the literature , future studies with even larger samples are needed to clarify the role of psychotropic medication, co-morbidity and mood state on the neural correlates of face emotion processing. "
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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.
    Full-text · Article · Aug 2013 · Psychological Medicine
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