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Aberrant Neurofunctional Responses during Emotional and Attentional Processing Differentiate ADHD Youth with and without a Family History of Bipolar I Disorder

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Title: Aberrant Neurofunctional Responses during Emotional and Attentional Processing Differentiate ADHD Youth with and without a Family History of Bipolar I Disorder
Language: English
Authors: L. Rodrigo Patino, Allison S. Wilson, Maxwell J. Tallman, Thomas J. Blom, Melissa P. DelBello, Robert K. McNamara (ORCID 0000-0002-9703-8114)
Source: Journal of Attention Disorders. 2024 28(5):820-833.
Availability: SAGE Publications. 2455 Teller Road, Thousand Oaks, CA 91320. Tel: 800-818-7243; Tel: 805-499-9774; Fax: 800-583-2665; e-mail: journals@sagepub.com; Web site: https://sagepub.com
Peer Reviewed: Y
Page Count: 14
Publication Date: 2024
Sponsoring Agency: National Institute of Mental Health (NIMH) (DHHS/NIH)
Contract Number: R01097818
Document Type: Journal Articles
Reports - Research
Descriptors: Attention Deficit Hyperactivity Disorder, Emotional Response, Attention, Cognitive Processes, Mental Disorders, Brain Hemisphere Functions, Responses, Neurological Organization, Heredity, Children, Adolescents
Assessment and Survey Identifiers: Child Behavior Checklist
DOI: 10.1177/10870547231215292
ISSN: 1087-0547
1557-1246
Abstract: Objective: To compare neurofunctional responses in emotional and attentional networks of psychostimulant-free ADHD youth with and without familial risk for bipolar I disorder (BD). Methods: ADHD youth with (high-risk, HR, n = 48) and without (low-risk, LR, n = 50) a first-degree relative with BD and healthy controls (n = 46) underwent functional magnetic resonance imaging while performing a continuous performance task with emotional distracters. Region-of-interest analyses were performed for bilateral amygdala (AMY), ventrolateral (VLPFC) and dorsolateral (DLPFC) prefrontal cortex, and anterior (ACC) and posterior cingulate cortex (PCC). Results: Compared with HC, HR, but not LR, exhibited predominantly left-lateralized AMY, VLPFC, DLPFC, PCC, and rostral ACC hyperactivation to emotional distractors, whereas LR exhibited right VLPFC and bilateral dorsal ACC hypoactivation to attentional targets. Regional responses correlated with emotional and attention symptoms. Conclusion: Aberrant neurofunctional responses during emotional and attentional processing differentiate ADHD youth with and without a family history of BD and correlate with relevant symptoms ratings.
Abstractor: As Provided
Entry Date: 2024
Accession Number: EJ1440637
Database: ERIC
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  Value: <anid>AN0175968764;gs001mar.24;2024Mar14.04:50;v2.2.500</anid> <title id="AN0175968764-1">Aberrant Neurofunctional Responses During Emotional and Attentional Processing Differentiate ADHD Youth With and Without a Family History of Bipolar I Disorder </title> <p>Objective: To compare neurofunctional responses in emotional and attentional networks of psychostimulant-free ADHD youth with and without familial risk for bipolar I disorder (BD). Methods: ADHD youth with (high-risk, HR, n = 48) and without (low-risk, LR, n = 50) a first-degree relative with BD and healthy controls (n = 46) underwent functional magnetic resonance imaging while performing a continuous performance task with emotional distracters. Region-of-interest analyses were performed for bilateral amygdala (AMY), ventrolateral (VLPFC) and dorsolateral (DLPFC) prefrontal cortex, and anterior (ACC) and posterior cingulate cortex (PCC). Results: Compared with HC, HR, but not LR, exhibited predominantly left-lateralized AMY, VLPFC, DLPFC, PCC, and rostral ACC hyperactivation to emotional distractors, whereas LR exhibited right VLPFC and bilateral dorsal ACC hypoactivation to attentional targets. Regional responses correlated with emotional and attention symptoms. Conclusion: Aberrant neurofunctional responses during emotional and attentional processing differentiate ADHD youth with and without a family history of BD and correlate with relevant symptoms ratings.</p> <p>Keywords: bipolar I disorder; familiar risk; high-risk; adolescent; emotional processing</p> <p>This paper is dedicated to Dr. Joe Biederman. From the first time that I met him, at an NIH conference more than 20 years ago, he taught me to embrace the challenge of studying the complex relationship between ADHD and bipolar disorder. His pioneering studies that describe the unique phenotype and significant morbidity associated with comorbid ADHD and bipolar disorder helped shape the design of our study. We believe that Dr. Biederman would not be surprised by our findings, as based upon his work, he clearly understood that youth with ADHD and a family history of bipolar disorder are a distinct group compared with those without a family history of mood disorders. Additionally, Dr. Biederman's appreciation for the unique treatment needs of depressive symptoms and ADHD in youth with bipolar disorder has significantly improved the treatment of youth with bipolar disorder worldwide and has influenced the design of many subsequent treatment studies of youth with and at familial risk for bipolar disorder.</p> <hd id="AN0175968764-2">Introduction</hd> <p>Prevalence rates of attention-deficit/hyperactivity disorder (ADHD) in youth with bipolar I disorder (BD) are substantially higher than the general population ([<reflink idref="bib18" id="ref1">18</reflink>]), and ADHD commonly precedes the initial onset of BD ([<reflink idref="bib3" id="ref2">3</reflink>]; [<reflink idref="bib35" id="ref3">35</reflink>]; [<reflink idref="bib50" id="ref4">50</reflink>]). Having a first-degree relative with BD is a robust risk factor for both BD ([<reflink idref="bib37" id="ref5">37</reflink>]; [<reflink idref="bib8" id="ref6">8</reflink>]) and ADHD ([<reflink idref="bib31" id="ref7">31</reflink>]; [<reflink idref="bib46" id="ref8">46</reflink>]), and youth with ADHD and a first-degree relative with BD present with more severe mood and externalizing symptoms compared to youth with ADHD and no familiy history of BD ([<reflink idref="bib14" id="ref9">14</reflink>]; [<reflink idref="bib29" id="ref10">29</reflink>]). A meta-analysis of prospective studies found that antecedent ADHD significantly increased the risk for developing BD relative to healthy youth without ADHD, and that BD offspring with ADHD exhibit higher conversion rates compared with ADHD youth without a BD family history ([<reflink idref="bib10" id="ref11">10</reflink>]). These findings suggest that antecedent ADHD, particularly when in conjunction with BD familial risk, represents a robust risk for developing BD. However, associated central risk biomarkers present prior to the onset of BD have not been systematically characterized.</p> <p>The initial onset of BD most frequently occurs during late childhood and adolescence ([<reflink idref="bib41" id="ref12">41</reflink>]), a developmental period associated with progressive structural and functional changes in frontolimbic circuitry in typically developing youth ([<reflink idref="bib22" id="ref13">22</reflink>]; [<reflink idref="bib23" id="ref14">23</reflink>]; [<reflink idref="bib51" id="ref15">51</reflink>]). Specifically, the transition from childhood to adulthood is associated with progressive increases in ventral prefrontal cortex (PFC) top-down regulation of amygdala (AMY) reactivity to emotional stimuli ([<reflink idref="bib21" id="ref16">21</reflink>]; [<reflink idref="bib55" id="ref17">55</reflink>]; [<reflink idref="bib25" id="ref18">25</reflink>]). Compared with typically developing youth, youth who developed BD ([<reflink idref="bib11" id="ref19">11</reflink>]; [<reflink idref="bib40" id="ref20">40</reflink>]; [<reflink idref="bib47" id="ref21">47</reflink>]), as well as youth with familial risk for developing BD ([<reflink idref="bib13" id="ref22">13</reflink>]; [<reflink idref="bib30" id="ref23">30</reflink>]; [<reflink idref="bib33" id="ref24">33</reflink>]; [<reflink idref="bib39" id="ref25">39</reflink>]; [<reflink idref="bib48" id="ref26">48</reflink>]), exhibit AMY hyperactivation and abnormalities in ventrolateral PFC (VLPFC) activation when processing emotional stimuli. Our group previously reported that VLPFC hyperactivation in response to emotional stimuli at baseline predicted the development of a first mood episode in BD offspring ([<reflink idref="bib38" id="ref27">38</reflink>]). Relative to healthy youth, psychostimulant-withdrawn ADHD youth have been found to exhibit both reduced ([<reflink idref="bib52" id="ref28">52</reflink>]) and elevated ([<reflink idref="bib12" id="ref29">12</reflink>]; [<reflink idref="bib43" id="ref30">43</reflink>]) AMY responses to emotional stimuli, and stimulant-naïve ADHD youth exhibit lower right AMY responses ([<reflink idref="bib9" id="ref31">9</reflink>]). However, the latter studies did not control for BD familial risk in ADHD youth, and psychostimulant medications have been shown to impact AMY responses ([<reflink idref="bib9" id="ref32">9</reflink>]; [<reflink idref="bib26" id="ref33">26</reflink>]; [<reflink idref="bib43" id="ref34">43</reflink>]).</p> <p>In the present cross-sectional study, we used fMRI to investigate neurofunctional responses in emotional and attentional networks of ADHD youth with ("high-risk," HR) and without ("low-risk," LR) a first-degree relative with BD, and healthy comparison youth (HC). ADHD youth were either psychostimulant-naïve or had no exposure to psychostimulants for at least 3 months prior to scanning. To investigate neurofunctional responses during both emotional and attentional processing, participants performed the continuous performance task with emotional and neutral distractors (CPT-END) ([<reflink idref="bib56" id="ref35">56</reflink>]). In healthy young adults performing this task, VLPFC and AMY preferentially respond to unpleasant emotional distractors, dorsolateral prefrontal cortex (DLPFC) and posterior cingulate cortex (PCC) preferentially respond to attentional targets, and the anterior cingulate cortex (ACC) responds similarly to both emotional distractors and attentional targets ([<reflink idref="bib56" id="ref36">56</reflink>]). In view of evidence for separable roles of dorsal (dACC) and rostral (rACC) ACC subdivisions in attentional and emotional processing, respectively ([<reflink idref="bib36" id="ref37">36</reflink>]), we investigated these ACC subregions separately. Our a priori hypothesis was that ADHD youth with a BD family history would exhibit greater VLPFC and AMY activation in response to emotional distractors compared with ADHD youth without a BD family history and healthy youth. Secondary exploratory analyses examined DLPFC, PCC, and d/rACC responses, and correlations among regional neural responses, CPT-END task performance metrics, and relevant clinical symptom ratings were also investigated.</p> <hd id="AN0175968764-3">Method</hd> <p></p> <hd id="AN0175968764-4">Participants</hd> <p>Three groups of youth (10–18 years of age) were recruited: 1) youth with ADHD and at least one biological parent or sibling with BD ("high-risk," HR), 2) youth with ADHD and no first- or second-degree relative with a DSM-5 Axis I mood or psychotic disorder ("low-risk," LR), and 3) healthy controls (HC) with no personal or family history of a DSM-5 Axis I psychiatric disorder. The Structured Clinical Interview for DSM-5 (SCID-5-CV) confirmed a parental diagnosis of BD ([<reflink idref="bib20" id="ref38">20</reflink>]), and the Family Interview for Genetics Studies (FIGS) ([<reflink idref="bib34" id="ref39">34</reflink>]) was used to confirm DSM-5 BD diagnoses in first- or second-degree relatives. The Crovitz Handedness Questionnaire was used to determine hand dominance ([<reflink idref="bib15" id="ref40">15</reflink>]).</p> <p>All subjects had no contraindication to an MRI scan (e.g., braces or claustrophobia), an IQ ≥ 80 as determined by the Wechsler Abbreviated Scale of Intelligence (WASI) (Wechsler & [<reflink idref="bib53" id="ref41">53</reflink>]), no major medical or neurological illness that could influence MR results or any significant episode (>10 minutes) of loss of consciousness, and no lifetime DSM-5 substance use disorder. All ADHD youth met DSM-5 criteria for ADHD (all types) using the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime version (KSADS-PL) ([<reflink idref="bib28" id="ref42">28</reflink>]), had no current DSM-5 mood, conduct, eating or psychotic disorders, Tourette's disorder, chronic tic disorder, or autism spectrum disorder, had no exposure to psychostimulants (prescription or recreational) or other medications used for the treatment of ADHD (e.g. atomoxetine) for at least 3 months prior to screening, had no lifetime exposure to mood stabilizers or antipsychotic medications, and had no clinically significant ECG or blood pressure abnormalities. After study procedures were explained, participants and their legal guardians provided written informed assent and consent, respectively. This study was approved by the Institutional Review Board of the University of Cincinnati and was registered at clinicaltrials.gov with the identifier NCT02478788.</p> <hd id="AN0175968764-5">Symptom Rating Scales</hd> <p>ADHD symptom ratings were obtained using the clinician-administered Attention-Deficit Hyperactivity Disorder Rating Scale (ADHD-RS) ([<reflink idref="bib19" id="ref43">19</reflink>]), and inattention and hyperactivity/impulsivity subscale scores were analyzed separately. Depression symptom severity was determined using the Children's Depression Rating Scale-Revised (CDRS-R) ([<reflink idref="bib44" id="ref44">44</reflink>], [<reflink idref="bib45" id="ref45">45</reflink>]), and manic symptom severity with the Young Mania Rating Scale (YMRS) ([<reflink idref="bib57" id="ref46">57</reflink>]). Global functioning was assessed using the Children's Global Assessment Scale (CGAS) ([<reflink idref="bib49" id="ref47">49</reflink>]). ADHD youth were also rated using the Clinical Global Impression-Severity Scale (CGI-S) to assess overall illness severity ([<reflink idref="bib24" id="ref48">24</reflink>]). All clinician ratings were administered by a child and adolescent psychiatrist with established inter-rater reliabilities (kappa > 0.9). Parents completed the Child Behavior Checklist (CBCL ages 6–18, 2001) ([<reflink idref="bib1" id="ref49">1</reflink>]), and CBCL total score, internalization, externalization, and Dysregulation Profile (CBCL-DP; [<reflink idref="bib7" id="ref50">7</reflink>]) subscale scores were analyzed.</p> <hd id="AN0175968764-6">CPT-END Task</hd> <p>During the fMRI scan, subjects performed the Continuous Performance Task with Emotional and Neutral Distracters (CPT-END) ([<reflink idref="bib56" id="ref51">56</reflink>]). During the task, subjects were required to detect infrequent target stimuli (circles of varying sizes and colors) presented in the context of frequent standards (squares of various sizes and color) and infrequent distracters (images of either neutral or negative emotional valence) (see Supplemental Figure S1). The emotional and neutral pictures were taken from the International Affective Picture System (IAPS, University of Florida). Subjects were asked to press button #2 when a target was presented and to press button #1 for all other stimuli. Prior to imaging sessions, subjects were given a training session during which they were required to demonstrate an understanding of the CPT-END task. Subjects performed two separate CPT-END runs, each run comprised of 158 cues which consisted of a pseudorandomized sequence of 70% squares, 10% targets, 10% emotional distracters, and 10% neutral distracters. Stimuli were presented at 3-second intervals, in which images were presented for 2,750 milliseconds, followed by a fixation cross for 250 milliseconds. Performance metrics included total and false hit rates, reaction time (milliseconds) during correct and incorrect responses, and discriminability (0.5 + ((hit rate – false alarm rate)(1 + hit rate – false alarm rate))/(4 × hit rate (1 – false alarm rate)).</p> <hd id="AN0175968764-7">MRI Data Acquisition</hd> <p>MRI data were collected using a Philips Ingenia 3.0 Tesla MR scanner with a 32-channel phased-array head coil. Participants were fitted with earplugs and headphones and instructed to keep their heads still. High-resolution three-dimensional T1-weighted structural images were obtained using a spoiled gradient recall sequence with the following parameters: repetition time/echo time (TR/TE) = 8.05/3.68 milliseconds, flip angle = 8°, field of view (FOV) = 256 × 256 mm<sups>2</sups>, acquisition matrix = 256 × 256, and slice thickness = 1.0 mm. Participants completed an fMRI session while performing the CPT-END using a single shot, fast Fourier echo, echo planar sequence (TR/TE = 2000/30 milliseconds, FOV = 256 × 256 mm<sups>2</sups>, matrix size = 80 × 80, flip angle = 75, in plane resolution = 2.8 × 2.8 mm, slice thickness = 3 mm with no gap, each functional run contained 255 volumes, and each brain volume comprised 38 slices).</p> <hd id="AN0175968764-8">MRI Preprocessing and Analyses</hd> <p>Image preprocessing was performed using SPM-12 (Wellcome Department of Imaging Neuroscience, University College London, UK) in MATLAB R2022a (Mathworks Inc., Natick, MA). Preprocessing of the fMRI scans was performed for each run separately and involved realignment and unwarping to suppress movement artifacts and field inhomogeneities. Movement outliers were detected by Artifact Detection Tools (ART), and participants with mean motion >0.5 mm or movement outliers >50% (128 volumes) were excluded. There were no group differences in head motion (<emph>p</emph> =.22). Functional images were slice-timing corrected, and structural images were segmented and functional images co-registered to them. Spatial normalization procedure then resampled images into Montreal Neurological Institute stereotactic space removing individual morphological differences and enabling comparison of activation maps between subjects. Normalized functional images were spatially smoothed with a Gaussian kernel of FWHM = 6 mm. A high bandpass pass filter of 0.008 Hz was applied to remove slow signal drifts. At the first level analysis, the hemodynamic response of each event was modeled with a canonical hemodynamic response function. The design matrix for the first level GLM included three independent events (targets, emotional distractors, and negative distractors), relative to an implicit baseline comprising the standards (squares). There were nine regressors per run per subject: three for the different trial types and six nuisance regressors representing motion. Primary analysis was based on anatomical regions of interest extracted from the Julich-Brain atlas ([<reflink idref="bib2" id="ref52">2</reflink>]). Percent signal change from baseline (i.e. squares) for targets and emotional distracters were extracted from the bilateral DLPFC, VLPFC, AMY, dACC, rACC, and PCC using MarsBaR version 0.45. The unpleasant emotional distractors and circle blood oxygen level-dependent signal was calculated with respect to the steady-state square activation pattern. Percentage of signal change was the variable of interest entered into ROI statistical models. ROI activation values from the two separate CPT-END runs were averaged for subsequent statistical analyses.</p> <hd id="AN0175968764-9">Data Analysis</hd> <p>Group differences in demographic and clinical variables were evaluated using one-way ANOVAs for continuous variables and Chi-Square tests for categorical variables. Prior to statistical analyses, ROI values within each group were screened for significant outliers using Grubb's test (<emph>p</emph> <.05), and only a single outlier was removed if detected. There were no significant group differences in the number outliers detected/removed (HC: <emph>n</emph> = 10/1,104, LR: <emph>n</emph> = 15/1,200, HR: <emph>n</emph> = 13/1,152, <emph>p</emph> =.73). In view of evidence for the left-lateralization of emotional processing ([<reflink idref="bib4" id="ref53">4</reflink>]; [<reflink idref="bib6" id="ref54">6</reflink>]), each hemisphere was analyzed separately. Group differences in ROI activation values for each cue (emotional distractors and attentional targets) within each hemisphere were evaluated by ANOVA. Since the three groups did not differ significantly in relevant demographic variables (i.e., age, sex, hand dominance, BMI), we did not adjust for these variables. Pending a significant main effect of group (<emph>p</emph> <.05), pairwise group comparisons were performed using Tukey's (HSD) post hoc tests (two-tailed, α =.05). For the primary measures of interest for which we had a priori hypotheses regarding directionality (i.e., AMY and VLPFC responses to emotional distractors: HR > LR, HR > HC), pairwise group comparisons were assessed using one-tailed Tukey's post hoc tests. Exploratory (uncorrected) linear Pearson correlation analyses examined relationships among ROI values, CPT-END performance metrics, and symptom ratings.</p> <hd id="AN0175968764-10">Results</hd> <p></p> <hd id="AN0175968764-11">Subject Characteristics</hd> <p>A total of 144 youth (mean age 14.3 ± 2.5 years, 62.5% male; high-risk, <emph>n</emph> = 46; low-risk, <emph>n</emph> = 50; HC, <emph>n</emph> = 48) were included in the analysis. Demographic and diagnostic characteristics are presented in Table 1. There were no significant group differences in age, sex, race, hand dominance, and body mass index. A total of 18 LR ADHD patients and 21 HR ADHD patients had prior psychostimulant exposure (<emph>p</emph> =.43), and the HR group had a higher rate of combined type ADHD compared with the LR group (<emph>p</emph> =.005). As determined using the KSADS-PL, a greater number of HR subjects (<emph>n</emph> = 8/48, 16.6%) had a history of a threshold mood disorder compared with LR (<emph>n</emph> = 1/50, 2%, <emph>p</emph> =.011), and there we no subjects in either group with a history of a subthreshold mood disorder. Past mood disorders were predominantly a major depressive episode (LR <emph>n</emph> = 1; HR <emph>n</emph> = 6 and <emph>n</emph> = 1 mood dysregulation, <emph>n</emph> = 1 unspecified depressive disorder). Excluding the LR (<emph>n</emph> = 1) and HR (<emph>n</emph> = 8) subjects with a history of a mood disorder did not change the primary results. For CPT-END performance metrics, there were no significant group differences in mean reaction time during correct (<emph>p</emph> =.38) and incorrect (<emph>p</emph> =.67) responses, or total correct (<emph>p</emph> =.11) and false (<emph>p</emph> =.11) hit rates, whereas discriminability differed between groups (<emph>p</emph> <.001) (Table 1). Post-hoc tests found that HC exhibited greater discriminability compared with both LR (<emph>p</emph> =.003) and HR (<emph>p</emph> <.001) ADHD groups, and LR and HR groups did not differ (<emph>p</emph> =.29).</p> <p>Graph</p> <p>Table 1. Demographic and Clinical Characteristics.</p> <p> <ephtml> <table><colgroup><col align="left" /><col align="char" char="." /><col align="char" char="." /><col align="char" char="." /><col align="char" char="." /></colgroup><thead><tr><th align="left">Variable<xref ref-type="table-fn" rid="tfn2">a</xref></th><th align="center">HC (<italic>n</italic> = 46)</th><th align="center">LR (<italic>n</italic> = 50)</th><th align="center">HR (<italic>n</italic> = 48)</th><th align="center"><italic>p</italic>-Value<xref ref-type="table-fn" rid="tfn3">b</xref></th></tr></thead><tbody><tr><td>Age, years</td><td>14.8 ± 2.3</td><td>14.1 ± 2.5</td><td>14.0 ± 2.5</td><td>0.24</td></tr><tr><td>Sex, <italic>n</italic> (%) male</td><td>28 (61)</td><td>33 (66)</td><td>29 (60)</td><td>0.82</td></tr><tr><td>Race, <italic>n</italic> (%) Caucasian</td><td>29 (63)</td><td>33 (66)</td><td>28 (58)</td><td>0.73</td></tr><tr><td>Right-handed, <italic>n</italic> (%)</td><td>44 (96)</td><td>41 (82)</td><td>43 (90)</td><td>0.10</td></tr><tr><td>BMI, kg/m2</td><td>22.9 ± 4.5</td><td>23.9 ± 6.7</td><td>24.9 ± 7.6</td><td>0.33</td></tr><tr><td> BMI <italic>z</italic> score</td><td>0.6 ± 1.0</td><td>0.8 ± 1.2</td><td>0.9 ± 1.3</td><td>0.58</td></tr><tr><td> BMI percentile</td><td>67.6 ± 28</td><td>69.2 ± 28</td><td>72.1 ± 32</td><td>0.75</td></tr><tr><td>Prior threshold mood episode, <italic>n</italic> (%)</td><td align="center">—</td><td>1 (2)</td><td>8 (16.6)</td><td>0.01</td></tr><tr><td>ADHD combined type, <italic>n</italic> (%)</td><td align="center">—</td><td>21 (42)</td><td>33 (69)</td><td>0.005</td></tr><tr><td>Prior psychostimulant exposure, <italic>n</italic> (%)</td><td align="center">—</td><td>18 (36)</td><td>21 (44)</td><td>0.43</td></tr><tr><td colspan="5">CPT-END performance metrics</td></tr><tr><td> Mean RT correct</td><td>769.9 ± 155.0</td><td>791.6 ± 157.4</td><td>814.8 ± 154.3</td><td>0.38</td></tr><tr><td> Mean RT error</td><td>750.4 ± 154.4</td><td>762.8 ± 153.8</td><td>778.2 ± 142.8</td><td>0.67</td></tr><tr><td> Total %correct</td><td>0.97 ± 0.07</td><td>0.94 ± 0.09</td><td>0.94 ± 0.08</td><td>0.11</td></tr><tr><td> %false HIT</td><td>0.03 ± 0.07</td><td>0.06 ± 0.09</td><td>0.06 ± 0.08</td><td>0.11</td></tr><tr><td> Discriminability</td><td>0.92 ± 0.09</td><td>0.86 ± 0.11</td><td>0.84 ± 0.11</td><td><0.001</td></tr></tbody></table> </ephtml> </p> <p>1 <emph>Note</emph>. RT = reaction time.</p> <ulist> <item>2 Values are group mean ± <emph>SD</emph> or number of subjects (<emph>n</emph>) and percent (%).</item> <item>3 One-way ANOVA or χ<sups>2</sups>.</item> </ulist> <hd id="AN0175968764-12">Symptom ratings</hd> <p>Significant main effects of group were observed for ADHD-RS total score (<emph>p</emph> <.0001), both inattentive (<emph>p</emph> <.0001) and hyperactivity/impulsivity (<emph>p</emph> <.0001) subscale scores, YMRS total score (<emph>p</emph> <.0001), CDRS-R total score (<emph>p</emph> <.0001), and CGAS total score (<emph>p</emph> <.0001) (Table 2). Both LR and HR groups differed significantly from HC on all ratings (all <emph>p</emph> ≤.0001). HR ADHD youth had significantly higher hyperactivity/impulsivity subscale scores (<emph>p</emph> =.007), CDRS-R total scores (<emph>p</emph> =.019), and YMRS total scores (<emph>p</emph> <.001) compared with LR ADHD youth. For CBCL scores, significant group effects were observed for CBCL total score (<emph>p</emph> <.0001), and internalization (<emph>p</emph> <.0001), externalization (<emph>p</emph> <.0001), and CBCL-DP subscale scores (<emph>p</emph> <.0001). Both HR and LR groups differed significantly from HC on all CBCL ratings (all <emph>p</emph> <.0001). HR ADHD youth had significantly higher CBCL total scores (<emph>p</emph> <.001), as well as internalization (<emph>p</emph> =.003), externalization (<emph>p</emph> <.001), and CBCL-DP (<emph>p</emph> =.012) subscale scores compared with LR ADHD youth.</p> <p>Graph</p> <p>Table 2. Clinician and Parental Symptom Ratings.</p> <p> <ephtml> <table><colgroup><col align="left" /><col align="char" char="." /><col align="char" char="." /><col align="char" char="." /><col align="char" char="." /><col align="char" char="." /></colgroup><thead><tr><th align="left">Variable<xref ref-type="table-fn" rid="tfn4">a</xref></th><th align="center">HC (<italic>n</italic> = 46)</th><th align="center">LR (<italic>n</italic> = 50)</th><th align="center">HR (<italic>n</italic> = 48)</th><th align="center"><italic>p</italic>-Value<xref ref-type="table-fn" rid="tfn5">b</xref></th><th align="center">LR vs. HR <italic>p</italic>-value<xref ref-type="table-fn" rid="tfn6">c</xref></th></tr></thead><tbody><tr><td>ADHD-R total score</td><td>3.2 ± 3.9</td><td>33.1 ± 10.3</td><td>35.8 ± 10.3</td><td><.001</td><td>.13</td></tr><tr><td> Inattention subscore</td><td>1.9 ± 2.3</td><td>21.0 ± 4.8</td><td>20.2 ± 5.5</td><td><.001</td><td>.35</td></tr><tr><td> Hyperactive/impulsive subscore</td><td>1.3 ± 2.1</td><td>12.1 ± 8.1</td><td>15.7 ± 7.1</td><td><.001</td><td>.007</td></tr><tr><td>CDRS-R total score</td><td>18.0 ± 2.4</td><td>24.1 ± 5.9</td><td>27.0 ± 8.3</td><td><.001</td><td>.02</td></tr><tr><td>YMRS total score</td><td>0.8 ± 2.0</td><td>3.1 ± 3.3</td><td>5.5 ± 4.3</td><td><.001</td><td><.001</td></tr><tr><td>CGAS total score</td><td>88.5 ± 5.8</td><td>50.5 ± 7.3</td><td>50.5 ± 7.3</td><td><.001</td><td>.13</td></tr><tr><td>CGI-S</td><td>−</td><td>4.0 ± 0.6</td><td>4.3 ± 0.6</td><td>−</td><td>.09</td></tr><tr><td>CBCL total score<xref ref-type="table-fn" rid="tfn7">d</xref></td><td>6.8 ± 6.7</td><td>37.0 ± 18.4</td><td>53.3 ± 28.3</td><td><.001</td><td><.001</td></tr><tr><td> Exernalizing subscore</td><td>1.5 ± 1.8</td><td>8.0 ± 6.9</td><td>15.1 ± 13.0</td><td><.001</td><td><.001</td></tr><tr><td> Internalizing subscore</td><td>2.4 ± 2.5</td><td>8.2 ± 6.4</td><td>12.3 ± 8.9</td><td><.001</td><td>.003</td></tr><tr><td> Dysregulation profile</td><td>2.8 ± 2.9</td><td>20.8 ± 9.8</td><td>25.9 ± 13.2</td><td><.001</td><td>.01</td></tr></tbody></table> </ephtml> </p> <ulist> <item>4 Values are group mean ± <emph>SD</emph>.</item> <item>5 One-way ANOVA.</item> <item>6 <emph>t</emph>-Test (two-tail).</item> <item>7 Data was available in 137 of 144 participants (44 HC, 48 LR ADHD, and 45 HR ADHD).</item> </ulist> <hd id="AN0175968764-13">FMRI</hd> <p></p> <hd id="AN0175968764-14">VLPFC and AMY</hd> <p>In response to emotional distractors, significant group differences were observed for left (<emph>p</emph> =.005), but not right (<emph>p</emph> =.14), VLPFC (Figure 1a). HR exhibited greater left VLPFC activation compared to HC (+45%, <emph>p</emph> =.0017) and LR (+30%, <emph>p</emph> =.035), and LR did not differ from HC (<emph>p</emph> =.52). Significant group differences were observed for left AMY (<emph>p</emph> =.033), but not right (<emph>p</emph> =.13), AMY (Figure 1b). HR exhibited greater left AMY activation compared to HC (+27%, <emph>p</emph> =.031) and LR (+27%, <emph>p</emph> =.029), and LR did not differ from HC (<emph>p</emph> =.99). In response to attentional targets, significant group differences were observed for right VLPFC (<emph>p</emph> =.043), but not left (<emph>p</emph> =.49), VLPFC (Figure 1a). LR exhibited lower right VLPFC activation compared to HC (−19%, <emph>p</emph> =.044) but not to HR (−8%, <emph>p</emph> =.17), and HR did not differ from HC (<emph>p</emph> =.81). For attentional targets, there were no group differences for left (<emph>p</emph> =.61) and right (<emph>p</emph> =.55) AMY (Figure 1b).</p> <p>Graph: Figure 1. Neurofunctional responses to emotional distractors (Emotion) and attentional targets (Attention) (% BOLD change relative to squares) in bilateral ventrolateral prefrontal cortex (VLPFC) (a) and amygdala (AMY) (b) of healthy controls (HC, n = 46), ADHD youth without a BD family history (low-risk, LR, n = 50), and ADHD youth with a first-degree relative with BD (high-risk, HR, n = 48). Values are group mean ± S.E.M. Tukey's (HSD) post hoc tests.* p ≤.05. ** p ≤.01 versus HC. # p ≤.05 versus LR.</p> <hd id="AN0175968764-15">DLPFC and PCC</hd> <p>For emotional distractors, significant group differences were observed for left (<emph>p</emph> <.001) and right (<emph>p</emph> =.017) DLPFC activation (Figure 2a). HR exhibited greater left DLPFC activation compared to HC (+57%, <emph>p</emph> =.0002) and LR (+57%, <emph>p</emph> =.0003), and LR did not differ from HC (<emph>p</emph> =.99). For right DLPFC, HR exhibited greater activation compared to HC (+45%, <emph>p</emph> =.013) but not LR (<emph>p</emph> =.13), and LR did not differ from HC (<emph>p</emph> =.62). Significant group differences were also observed for left (<emph>p</emph> =.03) and right (<emph>p</emph> =.02) PCC (Figure 2b). HR exhibited greater left PCC activation compared to HC (+42%, <emph>p</emph> =.019) but not LR (<emph>p</emph> =.26), and LR did not differ from HC (<emph>p</emph> =.49). Similarly, HR exhibited greater right PCC activation compared to HC (+41%, <emph>p</emph> =.015) but not LR (<emph>p</emph> =.26), and LR did not differ from HC (<emph>p</emph> =.43). For attentional targets, there were no group differences for left DLPFC (<emph>p</emph> =.20) and right DLPFC (<emph>p</emph> =.19)(Figure 2a), nor for left PCC (<emph>p</emph> =.12) and right PCC (<emph>p</emph> =.07) (Figure 2b).</p> <p>Graph: Figure 2. Neurofunctional responses to emotional distractors (Emotion) and attentional targets (Attention) (% BOLD change relative to squares) in the bilateral dorsolateral prefrontal cortex (DLPFC) (a) and posterior cingulate cortex (PCC) (b) of healthy controls (HC, n = 46), ADHD youth without a BD family history (low-risk, LR, n = 50), and ADHD youth with a first-degree relative with BD (high-risk, HR, n = 48). Values are group mean ± S.E.M. Tukey's (HSD) post hoc tests.* p ≤.05. *** p ≤.001 versus HC. ### p ≤.001 versus LR.</p> <hd id="AN0175968764-16">Dorsal and rostral ACC</hd> <p>For emotional distractors, no significant group differences were observed for left dACC (<emph>p</emph> =.10) or right dACC (<emph>p</emph> =.07) (Figure 3a), and significant group differences were observed for left (<emph>p</emph> =.0004) and right (<emph>p</emph> =.03) rACC (Figure 3b). HR exhibited greater left rACC activation compared to HC (<emph>p</emph> =.001) and LR (<emph>p</emph> =.003), and LR did not differ from HC (<emph>p</emph> =.94). For the right rACC, HR exhibited greater activation compared to LR (<emph>p</emph> =.04) but not HC (<emph>p</emph> =.08), and LR did not differ from HC (<emph>p</emph> =.96).</p> <p>Graph: Figure 3. Neurofunctional responses to emotional distractors (Emotion) and attentional targets (Attention) (% BOLD change relative to squares) in the bilateral dorsal anterior cingulate cortex (dACC) (a) and rostral anterior cingulate cortex (rACC) (b) of healthy controls (HC, n = 46), ADHD youth without a BD family history (low-risk, LR, n = 50), and ADHD youth with a first-degree relative with BD (high-risk, HR, n = 48). Values are group mean ± S.E.M. Tukey's (HSD) post hoc tests.* p ≤.05. ** p ≤.01 versus HC. # p ≤.05. ## p ≤.01 versus LR.</p> <p>For attentional targets, significant group differences were observed for left (<emph>p</emph> =.012) and right (<emph>p</emph> =.023) dACC (Figure 3a). For left dACC, both HR (<emph>p</emph> =.044) and LR (<emph>p</emph> =.016) exhibited lower responses compared to HC, and for right dACC LR (<emph>p</emph> =.02) but not HR (<emph>p</emph> =.14) exhibited lower responses compared to HC. LR and HR responses were not different for either left dACC (<emph>p</emph> =.92) or right dACC (<emph>p</emph> =.69). For attentional targets there were no group differences for left rACC (<emph>p</emph> =.48) nor right rACC (<emph>p</emph> =.59) (Figure 3b).</p> <hd id="AN0175968764-17">Associations With Age</hd> <p>Among all subjects (<emph>n</emph> = 144), left AMY (<emph>r</emph> = −0.20, <emph>p</emph> =.014) and right AMY (<emph>r</emph> = −0.19, <emph>p</emph> =.021) responses to emotional distractors, but not attentional targets, were inversely correlated with increasing age. Left AMY responses were inversely correlated with age within HC (<emph>r</emph> = −0.40, <emph>p</emph> =.006) but not LR (<emph>r</emph> = −0.11, <emph>p</emph> =.46) or HR (<emph>r</emph> = −0.09, <emph>p</emph> =.49), and right AMY responses were inversely correlated with age within HC (<emph>r</emph> = −0.31, <emph>p</emph> =.039) and LR (<emph>r</emph> = −0.36, <emph>p</emph> =.01) but not HR (<emph>r</emph> = 0.09, <emph>p</emph> =.53). There were no other significant correlations between age and ROI responses to emotional distractors or attentional targets.</p> <hd id="AN0175968764-18">Associations With CPT-END Performance</hd> <p>Among all subjects (<emph>n</emph> = 144), left AMY responses to emotional distractors were positively correlated with total correct hit rate (<emph>r</emph> = 0.26, <emph>p</emph> =.0019) and discriminability (<emph>r</emph> = 0.20, <emph>p</emph> =.016), and inversely correlated with false hit rate (<emph>r</emph> = −0.26, <emph>p</emph> =.0019). Within the HR group, but not within either LR or HC groups, left AMY responses to emotional distractors were significantly correlated with total correct hit rates (<emph>r</emph> = 0.41, <emph>p</emph> =.004), discriminability (<emph>r</emph> = 0.49, <emph>p</emph> =.0003), and inversely correlated with false hit rates (<emph>r</emph> = −0.41, <emph>p</emph> =.0019). Left VLPFC responses to emotional distractors were also positively correlated with discriminability among all subjects (<emph>r</emph> = 0.17, <emph>p</emph> =.049) and within the HR group (<emph>r</emph> = 0.37, <emph>p</emph> =.009) but not LR or HC groups. Bilateral dACC responses to emotional distractors were positively correlated with discriminability among all subjects (Left: <emph>r</emph> = 0.16, <emph>p</emph> =.048; Right: <emph>r</emph> = 0.21, <emph>p</emph> =.009), and within the HR group only (Left: <emph>r</emph> = 0.41, <emph>p</emph> =.003; Right: <emph>r</emph> = 0.44, <emph>p</emph> =.002). No other significant correlations between any performance metrics and ROI responses to attentional targets were observed.</p> <hd id="AN0175968764-19">Associations With Symptom Ratings</hd> <p>Among all subjects (<emph>n</emph> = 144), left AMY responses to emotional distractors correlated with YMRS total scores (<emph>r</emph> = 0.18, <emph>p</emph> =.035), CBCL total scores (<emph>r</emph> = 0.21, <emph>p</emph> =.015), and CBCL externalization (<emph>r</emph> = 0.22, <emph>p</emph> =.011) and dysregulation (<emph>r</emph> = 0.18, <emph>p</emph> =.04) subscale scores. Similarly, right AMY responses to emotional distractors correlated with YMRS total scores (<emph>r</emph> = 0.22, <emph>p</emph> =.009), CBCL total scores (<emph>r</emph> = 0.24, <emph>p</emph> =.005), and externalization (<emph>r</emph> = 0.21, <emph>p</emph> =.013) and dysregulation (<emph>r</emph> = 0.23, <emph>p</emph> =.008) subscale scores. Left VLPFC, but not right VLPFC, responses to emotional distractors correlated with externalization (<emph>r</emph> = 0.19, <emph>p</emph> =.027) and dysregulation (<emph>r</emph> = 0.19, <emph>p</emph> =.026) subscale scores. Left DLPFC, but not right DLPFC, responses to emotional distractors correlated with CBCL total scores (<emph>r</emph> = 0.23, <emph>p</emph> =.007), externalization (<emph>r</emph> = 0.23, <emph>p</emph> =.007), and dysregulation (<emph>r</emph> = 0.24, <emph>p</emph> =.005) subscale scores.</p> <p>Among all subjects (<emph>n</emph> = 144), bilateral dACC responses to attentional targets were inversely correlated with ADHD-RS total scores (Left: <emph>r</emph> = −0.21, <emph>p</emph> =.011; Right: <emph>r</emph> = −0.21, <emph>p</emph> =.012), ADHD inattention subscale scores (Left: <emph>r</emph> = −0.22, <emph>p</emph> =.0009; Right: <emph>r</emph> = −0.22, <emph>p</emph> =.007), and CBCL internalization subscale scores (Left: <emph>r</emph> = −0.28, <emph>p</emph> =.008; Right: <emph>r</emph> = -0.26, <emph>p</emph> =.002). Left DLPFC responses to attentional targets were also inversely correlated with ADHD-RS total scores (<emph>r</emph> = −0.17, <emph>p</emph> =.04), ADHD inattention subscale scores (<emph>r</emph> = −0.20, <emph>p</emph> =.017), and CBCL internalization subscale scores (<emph>r</emph> = −0.22, <emph>p</emph> =.009). Bilateral VLPFC responses were inversely correlated with ADHD inattention subscale scores (Left: <emph>r</emph> = −0.19, <emph>p</emph> =.02; Right: <emph>r</emph> = −0.18, <emph>p</emph> =.03).</p> <hd id="AN0175968764-20">Discussion and Conclusions</hd> <p>This cross-sectional study provides evidence that psychostimulant-free ADHD youth with a family history of BD exhibit greater activation in predominantly left-lateralized VLPFC, AMY, DLPFC, and rostral ACC regions in response to emotional distractors compared with healthy youth. In contrast, ADHD youth without a BD family history did not exhibit any regional response differences to emotional distractors compared with healthy youth, but exhibit lower right VLPFC and bilateral dACC activation in response to attentional targets, and trends for blunted bilateral DLPFC and PCC responses were observed. ADHD youth with a family history of BD also exhibited greater ADHD hyperactive/impulsive subscale scores, manic and depressive symptom severity, as well as higher parent-reported ratings of externalizing, internalizing and dysregulation symptoms, compared with ADHD youth without a BD family history. Exploratory correlation analyses revealed that left and right AMY responses to emotional distractors were positively correlated with YMRS total scores, CBCL total scores and CBCL externalization and dysregulation subscale scores, whereas left VLPFC and DLPFC responses to emotional distractors were positively correlated CBCL externalization and dysregulation subscale scores. Together, these findings demonstrate that aberrant neurofunctional responses during emotional and attentional processing differentiate ADHD youth with and without a family history of BD and correlate with relevant symptoms ratings.</p> <p>In agreement with prior fMRI evidence obtained in healthy young adults (20–22 years) ([<reflink idref="bib56" id="ref55">56</reflink>]), healthy youth exhibited greater bilateral AMY activation in response to emotional distractors than attentional targets, and greater bilateral DLPFC activation in response to attentional targets than emotional distractors, during performance of the CPT-END task. Within healthy youth, increasing age was associated with a significant decline in bilateral AMY responses to emotional distractors which is consistent with prior evidence ([<reflink idref="bib21" id="ref56">21</reflink>]; [<reflink idref="bib55" id="ref57">55</reflink>]). Unlike healthy adults ([<reflink idref="bib56" id="ref58">56</reflink>]), however, healthy youth did not exhibit preferential VLPFC activation in response to emotional distractors or preferential PCC activation in response to attentional targets. Consistent with a preferential role of the dACC in attentional processing ([<reflink idref="bib36" id="ref59">36</reflink>]), healthy youth exhibited greater bilateral dACC activation in response to attentional targets compared with emotional distractors. However, they did not exhibit greater rACC activation in response to emotional distractors, which is not consistent with previous evidence for a preferential role of the rACC in emotional processing. While the reason for these discrepancies is unclear and may relate to age differences between participants, other cue-selective regional activation patterns exhibited by healthy youth provides additional support for their preferential roles in either attentional or emotional processing.</p> <p>A primary finding of the present study is that HR ADHD youth, but not LR ADHD youth, exhibited left VLPFC and AMY hyperactivation in response to emotional distractors compared with healthy youth. These findings suggest that HR ADHD youth, but not LR ADHD youth, resemble youth with BD who also exhibit AMY hyperactivation, as well as abnormalities in VLPFC activation, in response to emotional stimuli across different tasks. ([<reflink idref="bib11" id="ref60">11</reflink>]; [<reflink idref="bib40" id="ref61">40</reflink>]; [<reflink idref="bib47" id="ref62">47</reflink>]). Moreover, our findings support prior evidence that youth with familial risk for developing BD and varying clinical features (i.e., current mood disorder and/or ADHD) also exhibit AMY hyperactivation and abnormalities in VLPFC activation ([<reflink idref="bib13" id="ref63">13</reflink>]; [<reflink idref="bib30" id="ref64">30</reflink>]; [<reflink idref="bib33" id="ref65">33</reflink>]; [<reflink idref="bib39" id="ref66">39</reflink>]; [<reflink idref="bib48" id="ref67">48</reflink>]). It is notable, however, that prior studies found that aberrant AMY and/or VLPFC activation to emotional stimuli were predominantly right-lateralized whereas we observed left-lateralized hyperactivation. Our findings are however consistent with meta-analytic evidence implicating left-lateralized VLPFC-AMY circuit involvement in emotional processing ([<reflink idref="bib4" id="ref68">4</reflink>]; [<reflink idref="bib6" id="ref69">6</reflink>]), and we did find that right AMY and VLPFC activation in HR ADHD youth was numerically greater than healthy youth. Lastly, the observation that bilateral AMY responses to emotional distractors declined with age in healthy youth but not in HR ADHD youth is consistent with a delay in healthy frontolimbic maturational trajectories ([<reflink idref="bib21" id="ref70">21</reflink>]; [<reflink idref="bib55" id="ref71">55</reflink>]). Taken collectively, the present and previous results suggest that aberrant AMY and VLPFC hyperactivation in response to emotional stimuli represents a robust central risk biomarker in youth with familial risk for BD, and further indicates that AMY and VLPFC hyperactivation cannot be wholly attributed to symptoms of inattention or hyperactivity.</p> <p>HR ADHD youth, but not LR ADHD youth, also exhibited bilateral DLPFC hyperactivation in response to emotional distractors. This result is consistent with [<reflink idref="bib13" id="ref72">13</reflink>] who found that youth with a BD parent and a current mood disorder and/or ADHD exhibited left DLPFC hyperactivation in response to fearful faces compared with healthy controls. Moreover, [<reflink idref="bib54" id="ref73">54</reflink>] observed left DLPFC hyperactivation in responses to emotional faces in youth with familial risk for BD as well as youth who developed BD. In addition to its well-establish role in working memory and attention ([<reflink idref="bib16" id="ref74">16</reflink>]; [<reflink idref="bib27" id="ref75">27</reflink>]), the DLPFC has also been implicated in effortful down-regulation of negative emotions (reappraisal) which is associated with decreased AMY activation ([<reflink idref="bib42" id="ref76">42</reflink>]). DLPFC hyperactivation in response to emotional distractors observed in HR ADHD youth is therefore consistent with the adoption of a different, more effortful, processing strategy during an otherwise passive emotional task. However, HR ADHD youth also exhibited AMY hyperactivation suggesting a deficit in DLPFC-mediated AMY inhibition. Interestingly, adults with BD were found to exhibit blunted inhibitory DLPFC-AMY functional connectivity during reappraisal of negative emotional pictures compared with healthy controls ([<reflink idref="bib58" id="ref77">58</reflink>]). Additional research investigating DLPFC-AMY functional connectivity during emotional processing in HR ADHD youth is therefore warranted.</p> <p>The LR ADHD youth did not exhibit any aberrant regional responses to emotional distractors compared with healthy youth including the AMY. This finding contrasts with prior evidence for altered AMY responses to emotional stimuli in ADHD youth acutely (48 h) withdrawn from psychostimulants ([<reflink idref="bib12" id="ref78">12</reflink>]; [<reflink idref="bib43" id="ref79">43</reflink>]; [<reflink idref="bib52" id="ref80">52</reflink>]). The latter discrepancy may be attributable to differences in psychostimulant exposure proximity, and prior studies did not control for BD familial risk in ADHD youth. However, LR ADHD youth exhibited lower right VLPFC and bilateral dACC responses to attentional targets and blunted bilateral DLPFC and PCC responses to attentional targets. These regional response deficits to attentional targets are consistent with meta-analytic fMRI evidence implicating hypofunction in these regions in ADHD youth during attention tasks ([<reflink idref="bib27" id="ref81">27</reflink>]). In contrast, the HR ADHD group, which exhibited greater ADHD hyperactivity/impulsivity subscores than LR, did not exhibit this regional pattern of blunted responses to attentional targets, with the exception of reduced left dACC activation. The latter response deficit may therefore also contribute to attentional deficits observed in youth with a family history of BD. Indeed, among all subjects bilateral dACC responses to attentional targets were inversely correlated with ADHD-RS total scores and ADHD inattention subscale scores. A meta-analysis of event-related fMRI studies found that BD youth, but not HR youth, exhibited decreased right dACC activation compared with healthy youth ([<reflink idref="bib32" id="ref82">32</reflink>]), though ADHD comorbidity was not accounted for in this analysis. Together, these provide additional neurofunctional evidence for a distinction between ADHD in youth with and without a family history of BD.</p> <p>The clinical relevance of these findings is supported by the observation that regional responses to emotional distractors and attentional targets correlated with relevant symptom ratings. Specifically, among all subjects both right and left AMY responses to emotional distractors correlated positively with YMRS total scores, CBCL total scores, and CBCL externalization and dysregulation subscale scores. Moreover, left VLPFC and DLPFC responses to emotional distractors correlated with CBCL externalization and dysregulation subscale scores. It is relevant therefore that a longitudinal prospective study found that higher CBCL dysregulation subscale scores predicted the subsequent diagnosis of BD in youth with ADHD ([<reflink idref="bib7" id="ref83">7</reflink>]), and attenuated manic symptoms commonly precede, and are predictive of, the initial onset of BD ([<reflink idref="bib3" id="ref84">3</reflink>]; [<reflink idref="bib5" id="ref85">5</reflink>]; [<reflink idref="bib17" id="ref86">17</reflink>]). Regarding ADHD symptoms, bilateral dACC and left DLPFC responses to attentional targets were inversely correlated with ADHD-RS total scores and ADHD inattention subscale scores. Additionally, bilateral VLPFC responses to attentional targets were inversely correlated with ADHD inattention subscale scores. Together, these findings support relationships among aberrant regional activation patterns and clinical symptom measures to attention deficits and emotional dysregulation which have been implicated in BD risk progression.</p> <p>Taken collectively, these cross-sectional findings demonstrate that psychostimulant-free ADHD youth with and without a BD family history exhibit different aberrant responses during emotional and attentional processing compared with healthy youth. ADHD youth with a family history of BD also exhibited a more severe symptom profile, including greater manic symptom severity and parent-reported ratings of externalizing and dysregulation, compared with ADHD youth without a BD family history, and these symptoms correlated with aberrant regional responses during emotional processing. The observed differences in regional responses to emotional distractors and attentional targets provide novel evidence for a neurofunctional distinction between the pathophysiology of inattention and hyperactivity in youth with and without a BD family history, and prospective longitudinal studies are warranted to evaluate their contribution to BD risk progression.</p> <hd id="AN0175968764-21">Limitations</hd> <p>This study has notable limitations. First, the cross-sectional design prevents attributing causal relationships, and it is not known whether subjects in the different groups will develop BD in the future. Therefore, prospective longitudinal studies to evaluate the predicative validity of the primary findings are warranted. Second, this study investigated only neurofunctional responses in a priori regions of interest, and other analyses, including voxelwise and functional connectivity, are therefore needed to extend these findings. Third, while group comparisons within ROIs were corrected for multiple comparisons, no corrections were made for each individual bilateral ROI ANOVA comparisons. We felt this approach balanced the risk for Type I errors but was not overly conservative in the context of assessing multiple a priori selected ROIs. However, the present results are highly consistent with previous fMRI evidence in HR youth suggesting they are reliable. Fourth, correlational analyses were not corrected for multiple comparisons and should therefore be viewed as exploratory and hypothesis-generating. Study strengths include a well-characterized cohort of psychostimulant-free youth with ADHD and BD family history, similar group demographics, both clinician and parent-reported symptom ratings, and event-related fMRI regional neurofunctional assessments during both emotional and attentional processing.</p> <hd id="AN0175968764-22">Supplemental Material</hd> <p>Graph: Supplemental material, sj-docx-1-jad-10.1177_10870547231215292 for Aberrant Neurofunctional Responses During Emotional and Attentional Processing Differentiate ADHD Youth With and Without a Family History of Bipolar I Disorder by L. Rodrigo Patino, Allison S. Wilson, Maxwell J. Tallman, Thomas J. Blom, Melissa P. DelBello and Robert K. McNamara in Journal of Attention Disorders</p> <ref id="AN0175968764-23"> <title> References </title> <blist> <bibl id="bib1" idref="ref49" type="bt">1</bibl> <bibtext> Achenbach T. M., Rescorla L. A. (2001). Manual for the ASEBA school-age forms & profiles. 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Bipolar Disorders, 20, 349–358. https://doi.org/10.1111/bdi.12611</bibtext> </blist> </ref> <ref id="AN0175968764-24"> <title> Footnotes </title> <blist> <bibtext> The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: L.R.P receives research funding from NIH, PCORI, Abbvie, Allergan, Janssen, Johnson and Johnson, Lundbeck, Lilly, Otsuka, Pfizer, and Sunovion. M.P.D. receives research support from NIH, PCORI, Acadia, Alkermes, Janssen, Johnson and Johnson, Lundbeck, Otsuka, Pfizer, Sage, Sunovion, and Vanda. She is also a consultant or on the advisory board for Alkermes, Allergan, Janssen, Johnson and Johnson, Lundbeck, Merck, Myriad, and Sage, R.K.M. has received research support from Martek Biosciences Inc, Royal DSM Nutritional Products, LLC, Inflammation Research Foundation, Ortho-McNeil Janssen, AstraZeneca, Eli Lilly, NARSAD, and NIH, and previously served on the scientific advisory board of the Inflammation Research Foundation. The remaining authors do not have disclosures.</bibtext> </blist> <blist> <bibtext> The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported in part by R01 NIMH grant 097818 to R.K.M and M.P.D (Co-PIs); NIH had no further role in study design, in the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication.</bibtext> </blist> <blist> <bibtext> Robert K. McNamara</bibtext> </blist> <blist> <bibtext>Graph https://orcid.org/0000-0002-9703-8114</bibtext> </blist> <blist> <bibtext> Supplemental material for this article is available online.</bibtext> </blist> </ref> <aug> <p>By L. Rodrigo Patino; Allison S. Wilson; Maxwell J. Tallman; Thomas J. Blom; Melissa P. DelBello and Robert K. McNamara</p> <p>Reported by Author; Author; Author; Author; Author; Author</p> <p></p> <p>L. Rodrigo Patino is Assistant Professor of Clinical Medicine in the Department of Psychiatry and Behavioral Neuroscience at the University of Cincinnati College of Medicine. Dr. Patino is a child and adolescent psychiatrist and his primary research interests include deciphering neurodevelopmental factors and risk biomarkers associated with the development of mood disorders in youth.</p> <p>Allison S. Wilson is a medical student at the University of Cincinnati College of Medicine and is a participant in Medical Student Scholars Program in the Department of Psychiatry and Behavioral Neuroscience. Her research interests include risk factors and biomarkers for psychiatric disorders and understanding the role of neurodevelopmental factors in the progression of mood dysregulation.</p> <p>Maxwell J. Tallman is a Senior Research Associate in the Department of Psychiatry and Behavioral Neuroscience at the University of Cincinnati College of Medicine. His research interests include using multimodal neuroimaging techniques to evaluate neuropathological biomarkers in youth with or at high risk for psychiatric disorders.</p> <p>Thomas J. Blom is a Senior Research Associate in the Department of Psychiatry and Behavioral Neuroscience at the University of Cincinnati College of Medicine. His expertise includes the management of large-scale databases and biostatistics in the context of psychiatry research.</p> <p>Melissa P. DelBello is Professor of Psychiatry and Pediatrics, and Dr. Stanley and Mickey Kaplan Chair of the Department of Psychiatry and Behavioral Neuroscience at the University of Cincinnati College of Medicine. She is a child and adolescent psychiatrist with a research focus on the neurodevelopment and treatment of children and adolescents with or at risk for mood disorders.</p> <p>Robert K. McNamara is Professor of Psychiatry and Behavioral Neuroscience at the University of Cincinnati College of Medicine. His research is focused on identifying neurodevelopmental risk factors for psychiatric disorders and using multimodal neuroimaging to determine associated neurobiological mechanisms.</p> </aug> <nolink nlid="nl1" bibid="bib18" firstref="ref1"></nolink> <nolink nlid="nl2" bibid="bib35" firstref="ref3"></nolink> <nolink nlid="nl3" bibid="bib50" firstref="ref4"></nolink> <nolink nlid="nl4" bibid="bib37" firstref="ref5"></nolink> <nolink nlid="nl5" bibid="bib31" firstref="ref7"></nolink> <nolink nlid="nl6" bibid="bib46" firstref="ref8"></nolink> <nolink nlid="nl7" bibid="bib14" firstref="ref9"></nolink> <nolink nlid="nl8" bibid="bib29" firstref="ref10"></nolink> <nolink nlid="nl9" bibid="bib10" firstref="ref11"></nolink> <nolink nlid="nl10" bibid="bib41" firstref="ref12"></nolink> <nolink nlid="nl11" bibid="bib22" firstref="ref13"></nolink> <nolink nlid="nl12" bibid="bib23" firstref="ref14"></nolink> <nolink nlid="nl13" bibid="bib51" firstref="ref15"></nolink> <nolink nlid="nl14" bibid="bib21" firstref="ref16"></nolink> <nolink nlid="nl15" bibid="bib55" firstref="ref17"></nolink> <nolink nlid="nl16" bibid="bib25" firstref="ref18"></nolink> <nolink nlid="nl17" bibid="bib11" firstref="ref19"></nolink> <nolink nlid="nl18" bibid="bib40" firstref="ref20"></nolink> <nolink nlid="nl19" bibid="bib47" firstref="ref21"></nolink> <nolink nlid="nl20" bibid="bib13" firstref="ref22"></nolink> <nolink nlid="nl21" bibid="bib30" firstref="ref23"></nolink> <nolink nlid="nl22" bibid="bib33" firstref="ref24"></nolink> <nolink nlid="nl23" bibid="bib39" firstref="ref25"></nolink> <nolink nlid="nl24" bibid="bib48" firstref="ref26"></nolink> <nolink nlid="nl25" bibid="bib38" firstref="ref27"></nolink> <nolink nlid="nl26" bibid="bib52" firstref="ref28"></nolink> <nolink nlid="nl27" bibid="bib12" firstref="ref29"></nolink> <nolink nlid="nl28" bibid="bib43" firstref="ref30"></nolink> <nolink nlid="nl29" bibid="bib26" firstref="ref33"></nolink> <nolink nlid="nl30" bibid="bib56" firstref="ref35"></nolink> <nolink nlid="nl31" bibid="bib36" firstref="ref37"></nolink> <nolink nlid="nl32" bibid="bib20" firstref="ref38"></nolink> <nolink nlid="nl33" bibid="bib34" firstref="ref39"></nolink> <nolink nlid="nl34" bibid="bib15" firstref="ref40"></nolink> <nolink nlid="nl35" bibid="bib53" firstref="ref41"></nolink> <nolink nlid="nl36" bibid="bib28" firstref="ref42"></nolink> <nolink nlid="nl37" bibid="bib19" firstref="ref43"></nolink> <nolink nlid="nl38" bibid="bib44" firstref="ref44"></nolink> <nolink nlid="nl39" bibid="bib45" firstref="ref45"></nolink> <nolink nlid="nl40" bibid="bib57" firstref="ref46"></nolink> <nolink nlid="nl41" bibid="bib49" firstref="ref47"></nolink> <nolink nlid="nl42" bibid="bib24" firstref="ref48"></nolink> <nolink nlid="nl43" bibid="bib54" firstref="ref73"></nolink> <nolink nlid="nl44" bibid="bib16" firstref="ref74"></nolink> <nolink nlid="nl45" bibid="bib27" firstref="ref75"></nolink> <nolink nlid="nl46" bibid="bib42" firstref="ref76"></nolink> <nolink nlid="nl47" bibid="bib58" firstref="ref77"></nolink> <nolink nlid="nl48" bibid="bib32" firstref="ref82"></nolink> <nolink nlid="nl49" bibid="bib17" firstref="ref86"></nolink>
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Items – Name: Title
  Label: Title
  Group: Ti
  Data: Aberrant Neurofunctional Responses during Emotional and Attentional Processing Differentiate ADHD Youth with and without a Family History of Bipolar I Disorder
– Name: Language
  Label: Language
  Group: Lang
  Data: English
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AR" term="%22L%2E+Rodrigo+Patino%22">L. Rodrigo Patino</searchLink><br /><searchLink fieldCode="AR" term="%22Allison+S%2E+Wilson%22">Allison S. Wilson</searchLink><br /><searchLink fieldCode="AR" term="%22Maxwell+J%2E+Tallman%22">Maxwell J. Tallman</searchLink><br /><searchLink fieldCode="AR" term="%22Thomas+J%2E+Blom%22">Thomas J. Blom</searchLink><br /><searchLink fieldCode="AR" term="%22Melissa+P%2E+DelBello%22">Melissa P. DelBello</searchLink><br /><searchLink fieldCode="AR" term="%22Robert+K%2E+McNamara%22">Robert K. McNamara</searchLink> (ORCID <externalLink term="https://orcid.org/0000-0002-9703-8114">0000-0002-9703-8114</externalLink>)
– Name: TitleSource
  Label: Source
  Group: Src
  Data: <searchLink fieldCode="SO" term="%22Journal+of+Attention+Disorders%22"><i>Journal of Attention Disorders</i></searchLink>. 2024 28(5):820-833.
– Name: Avail
  Label: Availability
  Group: Avail
  Data: SAGE Publications. 2455 Teller Road, Thousand Oaks, CA 91320. Tel: 800-818-7243; Tel: 805-499-9774; Fax: 800-583-2665; e-mail: journals@sagepub.com; Web site: https://sagepub.com
– Name: PeerReviewed
  Label: Peer Reviewed
  Group: SrcInfo
  Data: Y
– Name: Pages
  Label: Page Count
  Group: Src
  Data: 14
– Name: DatePubCY
  Label: Publication Date
  Group: Date
  Data: 2024
– Name: SourceSuprt
  Label: Sponsoring Agency
  Group: SrcSuprt
  Data: National Institute of Mental Health (NIMH) (DHHS/NIH)
– Name: NumberContract
  Label: Contract Number
  Group: NumCntrct
  Data: R01097818
– Name: TypeDocument
  Label: Document Type
  Group: TypDoc
  Data: Journal Articles<br />Reports - Research
– Name: Subject
  Label: Descriptors
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Attention+Deficit+Hyperactivity+Disorder%22">Attention Deficit Hyperactivity Disorder</searchLink><br /><searchLink fieldCode="DE" term="%22Emotional+Response%22">Emotional Response</searchLink><br /><searchLink fieldCode="DE" term="%22Attention%22">Attention</searchLink><br /><searchLink fieldCode="DE" term="%22Cognitive+Processes%22">Cognitive Processes</searchLink><br /><searchLink fieldCode="DE" term="%22Mental+Disorders%22">Mental Disorders</searchLink><br /><searchLink fieldCode="DE" term="%22Brain+Hemisphere+Functions%22">Brain Hemisphere Functions</searchLink><br /><searchLink fieldCode="DE" term="%22Responses%22">Responses</searchLink><br /><searchLink fieldCode="DE" term="%22Neurological+Organization%22">Neurological Organization</searchLink><br /><searchLink fieldCode="DE" term="%22Heredity%22">Heredity</searchLink><br /><searchLink fieldCode="DE" term="%22Children%22">Children</searchLink><br /><searchLink fieldCode="DE" term="%22Adolescents%22">Adolescents</searchLink>
– Name: SubjectThesaurus
  Label: Assessment and Survey Identifiers
  Group: Su
  Data: <searchLink fieldCode="SU" term="%22Child+Behavior+Checklist%22">Child Behavior Checklist</searchLink>
– Name: DOI
  Label: DOI
  Group: ID
  Data: 10.1177/10870547231215292
– Name: ISSN
  Label: ISSN
  Group: ISSN
  Data: 1087-0547<br />1557-1246
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Objective: To compare neurofunctional responses in emotional and attentional networks of psychostimulant-free ADHD youth with and without familial risk for bipolar I disorder (BD). Methods: ADHD youth with (high-risk, HR, n = 48) and without (low-risk, LR, n = 50) a first-degree relative with BD and healthy controls (n = 46) underwent functional magnetic resonance imaging while performing a continuous performance task with emotional distracters. Region-of-interest analyses were performed for bilateral amygdala (AMY), ventrolateral (VLPFC) and dorsolateral (DLPFC) prefrontal cortex, and anterior (ACC) and posterior cingulate cortex (PCC). Results: Compared with HC, HR, but not LR, exhibited predominantly left-lateralized AMY, VLPFC, DLPFC, PCC, and rostral ACC hyperactivation to emotional distractors, whereas LR exhibited right VLPFC and bilateral dorsal ACC hypoactivation to attentional targets. Regional responses correlated with emotional and attention symptoms. Conclusion: Aberrant neurofunctional responses during emotional and attentional processing differentiate ADHD youth with and without a family history of BD and correlate with relevant symptoms ratings.
– Name: AbstractInfo
  Label: Abstractor
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  Data: As Provided
– Name: DateEntry
  Label: Entry Date
  Group: Date
  Data: 2024
– Name: AN
  Label: Accession Number
  Group: ID
  Data: EJ1440637
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=eric&AN=EJ1440637
RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1177/10870547231215292
    Languages:
      – Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 14
        StartPage: 820
    Subjects:
      – SubjectFull: Attention Deficit Hyperactivity Disorder
        Type: general
      – SubjectFull: Emotional Response
        Type: general
      – SubjectFull: Attention
        Type: general
      – SubjectFull: Cognitive Processes
        Type: general
      – SubjectFull: Mental Disorders
        Type: general
      – SubjectFull: Brain Hemisphere Functions
        Type: general
      – SubjectFull: Responses
        Type: general
      – SubjectFull: Neurological Organization
        Type: general
      – SubjectFull: Heredity
        Type: general
      – SubjectFull: Children
        Type: general
      – SubjectFull: Adolescents
        Type: general
      – SubjectFull: Child Behavior Checklist
        Type: general
    Titles:
      – TitleFull: Aberrant Neurofunctional Responses during Emotional and Attentional Processing Differentiate ADHD Youth with and without a Family History of Bipolar I Disorder
        Type: main
  BibRelationships:
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      – PersonEntity:
          Name:
            NameFull: L. Rodrigo Patino
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            NameFull: Allison S. Wilson
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            NameFull: Maxwell J. Tallman
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            NameFull: Thomas J. Blom
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            NameFull: Melissa P. DelBello
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            NameFull: Robert K. McNamara
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          Dates:
            – D: 01
              M: 03
              Type: published
              Y: 2024
          Identifiers:
            – Type: issn-print
              Value: 1087-0547
            – Type: issn-electronic
              Value: 1557-1246
          Numbering:
            – Type: volume
              Value: 28
            – Type: issue
              Value: 5
          Titles:
            – TitleFull: Journal of Attention Disorders
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