Leslie A. Hulvershorn

A preliminary study of functional connectivity in comorbid adolescent depression

Major depressive disorder (MDD) begins frequently in adolescence and is associated with severe outcomes, but the developmental neurobiology of MDD is not well understood. Research in adults has implicated fronto-limbic neural networks in the pathophysiology of MDD, particularly in relation to the subgenual anterior cingulate cortex (ACC). Developmental changes in brain networks during adolescence highlight the need to examine MDD-related circuitry in teens separately from adults. Using resting state functional magnetic resonance imaging (fMRI), this study examined functional connectivity in adolescents with MDD (n=12) and healthy adolescents (n=14). Seed-based connectivity analysis revealed that adolescents with MDD have decreased functional connectivity in a subgenual ACC-based neural network that includes the supragenual ACC (BA 32), the right medial frontal cortex (BA 10), the left inferior (BA 47) and superior frontal cortex (BA 22), superior temporal gyrus (BA 22), and the insular cortex (BA 13). These preliminary data suggest that MDD in adolescence is associated with abnormal connectivity within neural circuits that mediate emotion processing. Future research in larger, un-medicated samples will be necessary to confirm this finding. We conclude that hypothesis-driven, seed-based analyses of resting state fMRI data hold promise for advancing our current understanding of abnormal development of neural circuitry in adolescents with MDD.

Toward Dysfunctional Connectivity: A Review of Neuroimaging Findings in Pediatric Major Depressive Disorder

Child and adolescent psychiatric neuroimaging research typically lags behind similar advances in adult disorders. While the pediatric depression imaging literature is less developed, a recent surge in interest has created the need for a synthetic review of this work. Major findings from pediatric volumetric and functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI) and resting state functional connectivity studies converge to implicate a corticolimbic network of key areas that work together to mediate the task of emotion regulation. Imaging the brain of children and adolescents with unipolar depression began with volumetric studies of isolated brain regions that served to identify key prefrontal, cingulate and limbic nodes of depression-related circuitry elucidated from more recent advances in DTI and functional connectivity imaging. Systematic review of these studies preliminarily suggests developmental differences between findings in youth and adults, including prodromal neurobiological features, along with some continuity across development.

Neural Activation During Facial Emotion Processing in Unmedicated Bipolar Depression, Euthymia, and Mania

BACKGROUND Studies incorporating direct comparisons across all phases of bipolar (BP) disorder are needed to elucidate the pathophysiology of bipolar disorder. However, functional neuroimaging studies that differentiate bipolar mood states from each other and from healthy subjects are few and have yielded inconsistent findings. METHODS One hundred five unmedicated adults were recruited: 30 with current bipolar depression (BPD), 30 with current bipolar hypomania or mania (BPM), 15 bipolar euthymic (BPE), and 30 healthy control subjects (HC). All subjects were diagnosed with DSM-IV BP (type I or II) using a structured clinical interview. Groups were age- and gender-ratio matched. In 3T functional magnetic resonance imaging experiments, subjects completed a negative facial emotion matching task. RESULTS Bipolar euthymic and BPD groups exhibited increased amygdala activation compared with HCs in response to the negative faces; however, in the BPM group, this increase was not seen. Conversely, both BPE and BPM groups had increased activation in the insula relative to HCs, but in the BPD group, this effect was not seen. All three BP groups exhibited increased activation of the putamen compared with HCs. In the cortical areas, the BPM group exhibited decreased left lateral orbitofrontal cortex activation compared with both BPEs and HCs, increased dorsal anterior cingulate cortex activation compared with the BPD group, and increased dorsolateral prefrontal cortical activation compared with all other groups. CONCLUSIONS Both state- and trait-related abnormalities in corticolimbic activation were seen in response to the negative facial emotion processing in a large sample of unmedicated adults across BP mood states.

Abnormal amygdala functional connectivity associated with emotional lability in children with attention-deficit/hyperactivity disorder

OBJECTIVE A substantial proportion of children with attention-deficit/hyperactivity disorder (ADHD) also display emotion regulation deficits manifesting as chronic irritability, severe temper outbursts, and aggression. The amygdala is implicated in emotion regulation, but its connectivity and relation to emotion regulation in ADHD has yet to be explored. The purpose of this study was to examine the relationship between intrinsic functional connectivity (iFC) of amygdala circuits and emotion regulation deficits in youth with ADHD. METHOD Bilateral amygdala iFC was examined using functional magnetic resonance imaging in 63 children with ADHD, aged 6 to 13 years. First, we examined the relationship between amygdala IFC and parent ratings of emotional lability (EL) in children with ADHD. Second, we compared amygdala iFC across subgroups of children with ADHD and high EL (n = 18), ADHD and low EL (n = 20), and typically developing children (TDC), all with low EL (n = 19). RESULTS Higher EL ratings were associated with greater positive iFC between the amygdala and rostral anterior cingulate cortex in youth with ADHD. EL scores were also negatively associated with iFC between bilateral amygdala and posterior insula/superior temporal gyrus. Patterns of amygdala-cortical iFC in ADHD participants with low EL were not different from the comparison group, and the effect sizes for these comparisons were smaller than those for the trend-level differences observed between the high-EL and TDC groups. CONCLUSIONS In children with ADHD and a range of EL, deficits in emotion regulation were associated with altered amygdala-cortical iFC. When comparing groups that differed on ADHD status but not EL, differences in amygdala iFC were small and nonsignificant, highlighting the specificity of this finding to emotional deficits, independent of other ADHD symptoms.

Emotional Response Inhibition in Bipolar Disorder: A Functional Magnetic Resonance Imaging Study of Trait- and State-Related Abnormalities

BACKGROUND Impaired response inhibition and poor impulse control are hallmarks of the manic phase of bipolar disorder but are also present during depressive and, to a lesser degree, euthymic periods. The neural mechanisms underlying these impairments are poorly understood, including how mechanisms are related to bipolar trait or state effects. METHODS One-hundred four unmedicated participants with bipolar mania (BM) (n = 30), bipolar depression (BD) (n = 30), bipolar euthymia (BE) (n = 14), and healthy control subjects (n = 30) underwent functional magnetic resonance imaging during emotional and nonemotional go/no-go tasks. The go/no-go task requires participants to press a button for go stimuli, while inhibiting the response to no-go trials. In separate blocks, participants inhibited the response to happy faces, sad faces, or letters. RESULTS The BE group had higher insula activity during happy face inhibition and greater activity in left inferior frontal gyrus during sad face inhibition, demonstrating bipolar trait effects. Relative to the BE group, BD and BM groups demonstrated lower insula activity during inhibition of happy faces, though the depressed sample had lower activity than manic patients. The BD and BM groups had a greater response to inhibiting sad faces in emotion processing and regulation regions, including putamen, insula, and lateral prefrontal cortex. The manic group also had higher activity in insula and putamen during neutral letter inhibition. CONCLUSIONS These results suggest distinct trait- and state-related neural abnormalities during response inhibition in bipolar disorder, with implications for future research and treatment.

Cortical activation deficits during facial emotion processing in youth at high risk for the development of substance use disorders

BACKGROUND Recent longitudinal studies demonstrate that addiction risk may be influenced by a cognitive, affective and behavioral phenotype that emerges during childhood. Relatively little research has focused on the affective or emotional risk components of this high-risk phenotype, including the relevant neurobiology. METHODS Non-substance abusing youth (N=19; mean age=12.2) with externalizing psychopathology and paternal history of a substance use disorder and demographically matched healthy comparisons (N=18; mean age=11.9) were tested on a facial emotion matching task during functional MRI. This task involved matching faces by emotions (angry, anxious) or matching shape orientation. RESULTS High-risk youth exhibited increased medial prefrontal, precuneus and occipital cortex activation compared to the healthy comparison group during the face matching condition, relative to the control shape condition. The occipital activation correlated positively with parent-rated emotion regulation impairments in the high-risk group. CONCLUSIONS These findings suggest a preexisting abnormality in cortical activation in response to facial emotion matching in youth at high risk for the development of problem drug or alcohol use. These cortical deficits may underlie impaired affective processing and regulation, which in turn may contribute to escalating drug use in adolescence.

Using Stimulants to Treat ADHD-Related Emotional Lability

Emotional lability, or sudden strong shifts in emotion, commonly occurs in youth with attention-deficit/hyperactivity disorder. Although these symptoms are impairing and disruptive, relatively little research has addressed their treatment, likely due to the difficulty of reliable and valid assessment. Promising signals for symptom improvement have come from recent studies using stimulants in adults, children and adolescents. Similarly, neuroimaging studies have begun to identify neurobiological mechanisms underlying stimulants’ impact on emotion regulation capacities. Here, we review these recent clinical and neuroimaging findings, as well as neurocognitive models for emotional lability in ADHD, issues of relevance to prescribers and the important role of psychiatric comorbidity with treatment choices.

Differential Resting-State Functional Connectivity of Striatal Subregions in Bipolar Depression and Hypomania.

Bipolar disorder (BP) is characterized by periods of depression (BPD) and (hypo)mania (BPM), but the underlying state-related brain circuit abnormalities are not fully understood. Striatal functional activation and connectivity abnormalities have been noted in BP, but consistent findings have not been reported. To further elucidate striatal abnormalities in different BP states, this study investigated differences in resting-state functional connectivity of six striatal subregions in BPD, BPM, and healthy control (HC) subjects. Ninety medication-free subjects (30 BPD, 30 BPM, and 30 HC), closely matched for age and gender, were scanned using 3T functional magnetic resonance imaging (fMRI) acquired at resting state. Correlations of low-frequency blood oxygen level dependent signal fluctuations for six previously described striatal subregions were used to obtain connectivity maps of each subregion. Using a factorial design, main effects for differences between groups were obtained and post hoc pairwise group comparisons performed. BPD showed increased connectivity of the dorsal caudal putamen with somatosensory areas such as the insula and temporal gyrus. BPM group showed unique increased connectivity between left dorsal caudate and midbrain regions, as well as increased connectivity between ventral striatum inferior and thalamus. In addition, both BPD and BPM exhibited widespread functional connectivity abnormalities between striatal subregions and frontal cortices, limbic regions, and midbrain structures. In summary, BPD exhibited connectivity abnormalities of associative and somatosensory subregions of the putamen, while BPM exhibited connectivity abnormalities of associative and limbic caudate. Most other striatal subregion connectivity abnormalities were common to both groups and may be trait related.

Developmental Resting State Functional Connectivity for Clinicians

Resting state functional magnetic imaging (fMRI) is a novel means to examine functional brain networks. It allows investigators to identify functional networks defined by distinct, spontaneous signal fluctuations. Resting state functional connectivity (RSFC) studies examining child and adolescent psychiatric disorders are being published with increasing frequency, despite concerns about the impact of motion on findings. Here we review important RSFC findings on typical brain development and recent publications on child and adolescent psychiatric disorders. We close with a summary of the major findings and current strengths and limitations of RSFC studies.

Confirmatory test of two factors and four subtypes of bipolar disorder based on lifetime psychiatric co-morbidity

BACKGROUND The first aim was to use confirmatory factor analysis (CFA) to test a hypothesis that two factors (internalizing and externalizing) account for lifetime co-morbid DSM-IV diagnoses among adults with bipolar I (BPI) disorder. The second aim was to use confirmatory latent class analysis (CLCA) to test the hypothesis that four clinical subtypes are detectible: pure BPI; BPI plus internalizing disorders only; BPI plus externalizing disorders only; and BPI plus internalizing and externalizing disorders. METHOD A cohort of 699 multiplex BPI families was studied, ascertained and assessed (1998-2003) by the National Institute of Mental Health Genetics Initiative Bipolar Consortium: 1156 with BPI disorder (504 adult probands; 594 first-degree relatives; and 58 more distant relatives) and 563 first-degree relatives without BPI. Best-estimate consensus DSM-IV diagnoses were based on structured interviews, family history and medical records. MPLUS software was used for CFA and CLCA. RESULTS The two-factor CFA model fit the data very well, and could not be improved by adding or removing paths. The four-class CLCA model fit better than exploratory LCA models or post-hoc-modified CLCA models. The two factors and four classes were associated with distinctive clinical course and severity variables, adjusted for proband gender. Co-morbidity, especially more than one internalizing and/or externalizing disorder, was associated with a more severe and complicated course of illness. The four classes demonstrated significant familial aggregation, adjusted for gender and age of relatives. CONCLUSIONS The BPI two-factor and four-cluster hypotheses demonstrated substantial confirmatory support. These models may be useful for subtyping BPI disorders, predicting course of illness and refining the phenotype in genetic studies.