Chang KD, Wagner C, Garrett A, Howe M, Reiss A. A preliminary functional magnetic resonance imaging study of prefrontal-amygdalar activation changes in adolescents with bipolar depression treated with lamotrigine. Bipolar Disorder 10: 426-431

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305-5540, USA.
Bipolar Disorders (Impact Factor: 4.97). 06/2008; 10(3):426-31. DOI: 10.1111/j.1399-5618.2007.00576.x
Source: PubMed


Hypotheses regarding mood dysregulation in bipolar disorder (BD) have centered on limbic overactivity with relative prefrontal underactivity during mood episodes. Therefore, we hypothesized that adolescents with bipolar depression successfully treated with lamotrigine would show decreases in amygdalar activation, and increases in prefrontal activation.
Eight adolescents with BD underwent functional magnetic resonance imaging (fMRI) at baseline and after eight weeks of lamotrigine treatment. Blocks of negatively and neutrally valenced emotional pictures were presented during scanning, and subjects were asked to rate how each picture made them feel. Activation in bilateral amygdalae and dorsolateral prefrontal cortices (DLPFC) for negative minus neutral pictures was correlated with Children's Depression Rating Scale (CDRS) scores.
Mean (SD) CDRS scores decreased significantly, from 53.0 (10.6) at baseline to 26.3 (5.3) at Week 8. This clinical improvement was correlated with decreased right amygdalar activation (r = 0.91, p = 0.002). At Week 8, but not baseline, CDRS score was positively correlated with bilateral amygdalar activation (r = 0.85, p = 0.007). DLPFC activation was not correlated with change in CDRS score.
These preliminary results indicate that adolescents with BD treated with lamotrigine demonstrated less amygdalar activation when viewing negative stimuli as depressive symptoms improved. Larger controlled studies are needed to confirm these findings.

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Available from: Amy S Garrett, Jul 16, 2014
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    • "For youth with a diagnosis of BD, lamotrigine treatment is associated with increased activation in the VLPFC and reduced activation in the amygdala, both of which were correlated with improvement in YMRS scores (Passarotti et al., 2011). Similarly, our lab reported decreased amygdala activation in youth with BD who were treated with lamotrigine, although activation was correlated with decreased severity of depression rather than mania symptoms (Chang et al., 2008). In another report, amygdala activation did not change following treatment with risperidone or divalproex, but higher amygdala activation at pre-treatment predicted less improvement in symptoms of mania (Pavuluri et al., 2011). "
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    ABSTRACT: Background: Psychotherapy for youth with mood dysregulation can help stabilize mood and improve functioning, but the neural mechanisms of this improvement are not known. In this study we investigated the changes in brain activation underlying improvement in mood symptoms. Methods: Twenty-four subjects (ages 13-17) participated: 12 patients with clinically significant symptoms of depression and/or mania, and 12 healthy comparison subjects (HC) matched for age and sex. All subjects completed functional magnetic resonance imaging while viewing facial expressions. The patients then received up to 4 months of psychotherapy and were rescanned at end of treatment. Whole brain differences between patient and control groups were assessed with a voxel-wise analysis. Changes in activation from pre- to post-treatment within the patient group were tested for correlation with changes in mood symptoms. Results: At baseline the patient group had hypoactivation in the dorsolateral prefrontal cortex (DLPFC) and hyperactivation in the posterior cingulate cortex compared to the HC group. Between pre- and post-treatment activation increased in the DLPFC and decreased in the amygdala. Increases in DLPFC activation were significantly correlated with improvement in mania symptoms. Discussion: Enhancement of frontal executive control brain regions may underlie improvement in mood dysregulation in pediatric patients at familial risk for bipolar disorder.
    Full-text · Article · Oct 2014 · Progress in Neuro-Psychopharmacology and Biological 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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    • "In this study, we identified increased VLPFC and temporal cortical activity in BDd relative to HC during response inhibition, but did not find depression-or treatment-related activity changes. Similar to our findings, the only published fMRI study in BDd adolescents used an emotion processing task, and did not include HC, but reported no change in prefrontal activity after treatment (Chang et al. 2008) suggesting that prefrontal abnormality in BD adolescents identified during depression may persist after the treatment (Singh et al. 2010). Our findings of similar behavioral response (e.g., accuracy and reaction time) between BDd adolescents and HC might be the result of more extensive recruitment of VLPFC in BDd adolescents to compensate for prefrontal dysfunction. "
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    ABSTRACT: Objective: Abnormal prefrontal and subcortical activity during cognitive control tasks is identified in non-depressed adolescents with bipolar disorder (BD); however, little is known about the neural correlates of bipolar adolescents in a depressed state (BDd). We aimed to investigate baseline versus after-treatment patterns of neural activity underlying motor response and response inhibition in adolescents with BDd. Methods: In this functional magnetic resonance imaging (fMRI) study, 10 adolescents with BDd relative to 10 age- and sex-matched healthy controls (HC) completed a well-validated go/no go block-design cognitive control task at baseline and after 6 weeks of naturalistic treatment. We used whole-brain analysis and controlled our results for multiple comparisons. Results: There was significant improvement in depression scores (mean change: 57%±28). There was no behavioral difference in BDd baseline versus HC and after treatment. BDd adolescents relative to HC had higher baseline cortical, but not subcortical, neural activity (e.g., bilateral ventrolateral prefrontal during both the go [motor control] and the no go [response inhibition] conditions, and left superior temporal during the no go condition). However, after-treatment activity relative to baseline neural activity during response inhibition was significantly increased in subcortical (e.g., right hippocampus and left thalamus), but not cortical, regions. In addition, at baseline, lower left thalamus activity was correlated with higher depression scores. Conclusions: Adolescents with BDd had baseline prefrontal and temporal hyperactivity underlying motor control and response inhibition that did not change after treatment in contrast to relatively decreased baseline subcortical activity underlying response inhibition associated with the depressive state that was increased after the treatment.
    Full-text · Article · Apr 2013 · Journal of child and adolescent psychopharmacology
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