Behavioral and Neural Sustained Attention Deficits in Bipolar Disorder and Familial Risk of Bipolar Disorder

Abstract

Background Few neuroimaging studies compare individuals affected with bipolar disorder (BP), at high familial risk for BP, and at low risk to identify endophenotypes for BP. None have examined variability in attention, despite promising behavioral work in this area. We used functional magnetic resonance imaging (fMRI) methods uniquely powered to compare the neural correlates of attention variability in these three groups. Methods The current study examined 106 8–25-year-olds who completed an fMRI attention task: 24 with BP, 29 at-risk based on a first-degree relative with BP, and 53 healthy, low-risk individuals. Group differences in intra-subject variability in reaction time were examined and a sophisticated fMRI analytic approach was used to quantify precisely trial-wise associations between reaction time and brain activity. The latter has not been examined previously in BP or risk for BP. Results Relative to healthy individuals, those with BP or at-risk for BP exhibited increased reaction time variability (F(2,102)=4.26, p=.02, ηp2=0.08). Importantly, we identified blunted relationships between trial-wise variation in reaction time and brain activity in the inferior and middle frontal gyri, precuneus, cingulate cortex, caudate, and postcentral gyrus (all regions: p<.001, ηp2>0.06) in both at-risk and BP individuals compared to healthy, low-risk individuals. This blunting partially mediated group differences in reaction time variability (β=0.010, 95% Confidence Interval=[0.002–0.020], Sobel Z=2.08, p=.038). Conclusions Blunting in key frontal, cingulate, and striatal areas was evident in unaffected, at-risk individuals and in euthymic BP patients. Elucidating such novel neural endophenotypes can facilitate new approaches to BP prediction, diagnosis, and prevention.

Behavioral and Neural Sustained Attention Deficits in Disruptive Mood Dysregulation Disorder and Attention-Deficit/Hyperactivity Disorder

“…Participants were excluded for pervasive developmental disorders, schizophrenia, bipolar disorder, posttraumatic stress disorder, IQ lower than 70 on the Wechsler Abbreviated Scale of Intelligence, 30 substance abuse within the past 2 months, significant medical illness, head trauma, neurological disorder, contraindications to MRI, having a first-degree relative with bipolar disorder (given prior findings of altered RT-BOLD signal associations based on a familial history of bipolar disorder 25 ), or treatment with long-acting stimulants. Participants taking short-acting stimulant medications (n=9 DMDD; n=12 ADHD) withheld their stimulants for 48 hours before scanning, as stimulants have been shown to reduce reaction time variability.…”

“…22 Recently, this approach has been extended to study risk for and expressions of bipolar disorder. 25 Of note, these findings suggested that this analytic method, as compared to more traditional imaging analytic approaches, is better able to capture subtle differences in attentional functioning between related conditions. As such, this method might prove useful when comparing ADHD and DMDD.…”

“…While no prior neuroimaging literature examines attentional functioning in DMDD, based on prior work with this behavioral paradigm, we expected to find alterations in the relationship between trial-wise RT and BOLD activity in mainly fronto-parietal attention control regions. 22,25 …”

Timely Research in Bipolar Disorder and Attention-Deficit/Hyperactivity Disorder

“…Pagliaccio et al (5) provide evidence for the intriguing possibility that time, on the order of milliseconds -the ‘micro-architecture’ of time- can be used to dissect complex entities such as attention to faciliate mapping onto pathophysiologically salient neural circuits. They report that intrasubject variability in response time (ISVRT), considered a marker of momentary lapses of attention, was increased in those with BD, even when euthymic, and in unaffected youth at familial risk.…”

“…Can specific microarchitectural mechanisms of cognition, such as those elucidated by Pagliaccio et al (5), help predict the temporal macroarchitecture of BD or ADHD, for example aiding the determination of whether a child with attentional difficulities has ADHD or will develop BD? Or might this early attentional feature represent a faulty foundation from which other cognitive anomalies emerge with age, taking ever more specific, symptom-causing forms (8)?…”