Enhanced Prefrontal Function With Pharmacotherapy on a Response Inhibition Task in Adolescent Bipolar Disorder

Abstract

Objective-The aim of the current study is to determine whether pharmacotherapy normalizes cognitive circuitry function supporting voluntary behavioral inhibition in adolescent bipolar disorder (ABD).Method-Healthy controls (HC) and unmedicated patients with ABD in manic, mixed or hypomanic episodes are matched on demographics and IQ (n=13 per group; Mean age=14.4 ±2.4 years). fMRI studies are performed at baseline and after 14 weeks, during which time patients with ABD are treated initially with second generation antipsychotics (SGAs) followed by lamotrigine monotherapy. A Response Inhibition Task is administered in which a planned motor response, already on the way' to execution, has to be voluntarily inhibited on the trials where a stop signal is presented at varying delays between the cue to respond and response initiation. There are six blocks, each with a predominant rate of "Go" or "Stop" trials and separated by a 10 sec rest/ fixation period.Results-All patients showed significant improvement in both the manic and depressive symptoms from baseline (p<.001). Behavioral data showed that accuracy improved over 14 weeks in patients and HC. Significant time by group interaction effects [F(1, 24) =5.34, p<.03] for the difference between Stop vs. Go blocks showed greater increases of activation in prefrontal (left inferior and middle frontal gyri and medial frontal gyrus bilaterally) and temporal (left superior temporal gyrus and right middle temporal gyrus) regions, and greater decreases in activation in right putamen and bilateral thalamus at follow-up in the ABD group. Increased ventrolateral prefrontal cortex function was related to clinical treatment response.Conclusions-Treatment with SGAs followed by lamotrigine monotherapy enhances prefrontal and temporal lobe activity during a Response Inhibition Task demonstrating the reversal of disorder-relevant neural circuitry dysfunction in patients with ABD. Patients are not slowed down in performance with this treatment regime. Keywordsfrontal; striatum; bipolar; child; fMRI; cognition In adolescent bipolar disorder (ABD), inattention, impulsivity and behavioral dis-inhibition are prominent and persist even after achieving mood stability. 4 The frontostriatal circuitry that supports motor response inhibition has been shown to be affected in ABD. 5 Appropriate goals of treatment, therefore, are to aim for mood stabilization, reducing motor response inhibition problems, and reversing the related frontostriatal deficits in ABD. Lamotrigine is one such medication that is used to stabilize mood in ABD 6 and adult bipolar disorder (BD) 7;8 due to its glutamatergic attenuating function that is believed to have the potential to improve cognitive function related to motor response inhibition problems. [9][10][11] There is preliminary evidence from two fMRI studies indicating that lamotrigine may enhance brain circuitry function in bipolar disorder. 6;12 In a study of patients with ABD performing an affective task requiring the rating of emotions in pictures, re...

Neural Correlates of Treatment in Adolescents with Bipolar Depression During Response Inhibition

“…Our results of no behavioral difference in depressed group relative to HC, but abnormal neural activity underlying cognitive control in cortical (lateral prefrontal for executing inhibitory control processes and temporal for attentional processing) and subcortical (hippocampus [Fusar-Poli et al 2009], an important region for emotion processing in addition to memory encoding, retention, and retrieval; and thalamus [Li et al 2008], a major relay center that sends inhibitory signals to striatum and motor cortex to stop prepotent responses) are similar to the majority of available studies in non-depressed BD adolescents (Blumberg et al 2003;Chang et al 2004;Leibenluft et al 2007;Passarotti et al 2010;Pavuluri et al 2010;Singh et al 2010). In addition, increased activity of cortical and/or subcortical regions during response inhibition (e.g., no go condition) in this study in BDd relative to HC was similar to the studies in adolescents with nondepressed BD (Blumberg et al 2003;Chang et al 2004;Singh et al 2010).…”

“…Available studies report significant neurocognitive deficits (e.g., response inhibition, attention, working memory) (Pavuluri et al 2006a,b;Joseph et al 2008) and abnormal prefrontal and subcortical activity in response to cognitive control tasks in adolescents with non-depressed BD (Blumberg et al 2003;Chang et al 2004;Leibenluft et al 2007;Passarotti et al 2010;Pavuluri et al 2010;Singh et al 2010). Findings in adults with BD suggest that the depressed state may manifest different cognitive control deficits than do euthymic and hypomanic states (Malhi et al 2007); however, no study has investigated neural correlates of cognitive control in BDd adolescents before and after treatment.…”

Psychoradiology: The Frontier of Neuroimaging in Psychiatry

“…Apart from the illness-related deficits, treatment effect also has been revealed. For example, Pavuluri et al (69) found that secondgeneration antipsychotics showed enhanced prefrontal and temporal lobe activity in patients with adolescent BD. These deficits have promise as potential biomarkers in the clinical diagnosis of and treatment planning for BD (70).…”

Neuroradiological Imaging Studies in Bipolar Disorder

“…[41] Psikiyatride Güncel Yaklaşımlar -Current Approaches in Psychiatry İleriye dönük klinik çalışmalardaki fMRG sonuçlarına göre, bazı çalışma-larda prefrontal korteks ve temporal bölgelerdeki değişiklikler lamatrojin tedavisi ile normalleşmiştir. [42][43][44] Diğer uzunlamasına çalışmalarda amigdala ve prefrontal korteksteki değişiklikler ile klinik iyileşme arasında korelasyon bulunmuştur. [45,46] Fakat bu değişiklikler üzerinde tedavinin mi genel klinik iyileşmenin mi etkisi olduğu kesin değildir.…”