Katie L. Bessette

White matter abnormalities in adolescents with major depressive disorder

The purpose of this study was to identify areas of abnormal white matter microstructure in adolescents with Major Depressive Disorder (MDD) using diffusion tensor imaging (DTI). Fractional anisotropy (FA) values representing preferential diffusivity along major tracts were examined using tract-based spatial statistics across the whole brain in adolescents ages 13–19 with MDD (n = 31) compared with demographically-matched healthy controls (n = 31). We not only examined frontal lobe tracts that have been most frequently identified as abnormal in previous DTI studies of older depressed patients, but also tested for FA group differences across the whole brain to determine if adolescent depression was related to any other regional white matter abnormality. MDD-diagnosed adolescents had significantly lower FA in many regions concentrated predominantly in the frontal lobe. There also was strong evidence for lower FA in bilateral anterior/posterior limbs of the internal capsules, as well as tracts through the midbrain, left external capsule, right thalamic radiation and left inferior longitudinal fasciculus. Consistent with previous findings in depressed young and elderly adults, the current study found evidence for abnormal microstructure in white matter connections of the frontal lobe in MDD adolescents. There also was strong evidence for FA abnormalities in corpus callosum genu, internal and external capsule tracts, thalamus and midbrain, notable for both the relative magnitude of these effects and absence from most previous white matter studies of depression. These abnormalities might represent important markers of early life-onset depression.

A preliminary study of the effects of working memory training on brain function

Working memory (WM) training improves WM ability in Attention-Deficit/Hyperactivity Disorder (ADHD), but its efficacy for non-cognitive ADHD impairments ADHD has been sharply debated. The purpose of this preliminary study was to characterize WM training-related changes in ADHD brain function and see if they were linked to clinical improvement. We examined 18 adolescents diagnosed with DSM-IV Combined-subtype ADHD before and after 25 sessions of WM training using a frequently employed approach (Cogmed™) using a nonverbal Sternberg WM fMRI task, neuropsychological tests, and participant- and parent-reports of ADHD symptom severity and associated functional impairment. Whole brain SPM8 analyses identified ADHD activation deficits compared to 18 non-ADHD control participants, then tested whether impaired ADHD frontoparietal brain activation would increase following WM training. Post hoc tests examined the relationships between neural changes and neurocognitive or clinical improvements. As predicted, WM training increased WM performance, ADHD clinical functioning, and WM-related ADHD brain activity in several frontal, parietal and temporal lobe regions. Increased left inferior frontal sulcus region activity was seen in all Encoding, Maintenance, and Retrieval Sternberg task phases. ADHD symptom severity improvements were most often positively correlated with activation gains in brain regions known to be engaged for WM-related executive processing; improvement of different symptom types had different neural correlates. The responsiveness of both amodal WM frontoparietal circuits and executive process-specific WM brain regions was altered by WM training. The latter might represent a promising, relatively unexplored treatment target for researchers seeking to optimize clinical response in ongoing ADHD WM training development efforts.

Attenuated intrinsic connectivity within cognitive control network among individuals with remitted depression: Temporal stability and association with negative cognitive styles.

Many individuals with major depressive disorder (MDD) experience cognitive dysfunction including impaired cognitive control and negative cognitive styles. Functional connectivity magnetic resonance imaging studies of individuals with current MDD have documented altered resting‐state connectivity within the default‐mode network and across networks. However, no studies to date have evaluated the extent to which impaired connectivity within the cognitive control network (CCN) may be present in remitted MDD (rMDD), nor have studies examined the temporal stability of such attenuation over time. This represents a major gap in understanding stable, trait‐like depression risk phenotypes. In this study, resting‐state functional connectivity data were collected from 52 unmedicated young adults with rMDD and 47 demographically matched healthy controls, using three bilateral seeds in the CCN (dorsolateral prefrontal cortex, inferior parietal lobule, and dorsal anterior cingulate cortex). Mean connectivity within the entire CCN was attenuated among individuals with rMDD, was stable and reliable over time, and was most pronounced with the right dorsolateral prefrontal cortex and right inferior parietal lobule, results that were corroborated by supplemental independent component analysis. Attenuated connectivity in rMDD appeared to be specific to the CCN as opposed to representing attenuated within‐network coherence in other networks (e.g., default‐mode, salience). In addition, attenuated connectivity within the CCN mediated relationships between rMDD status and cognitive risk factors for depression, including ruminative brooding, pessimistic attributional style, and negative automatic thoughts. Given that these cognitive markers are known predictors of relapse, these results suggest that attenuated connectivity within the CCN could represent a biomarker for trait phenotypes of depression risk. Hum Brain Mapp 38:2939–2954, 2017.

Disrupted engagement of networks supporting hot and cold cognition in remitted major depressive disorder

BACKGROUND Major depressive disorder (MDD) is characterized by dysfunction in cognitive and emotional systems. However, the neural network correlates of cognitive control (cold cognition) and emotion processing (hot cognition) during the remitted state of MDD (rMDD) remain unclear and not fully probed, which has important implications for identifying intermediate phenotypes of depression risk. METHODS 43 young adults with rMDD and 33 healthy controls (HCs) underwent fMRI while completing separate tasks of cold cognition (Parametric Go/No-Go test) and hot cognition (Facial Emotion Processing Test). Two 2 group (rMDD, HC) × 2 event (sad/fearful faces, correct rejections) factorial models of activation were calculated in SPM8. Functional activation was evaluated in the salience and emotional network (SEN) and the cognitive control network (CCN), including hypothesized interaction between group and task within the CCN. RESULTS Individuals with rMDD demonstrated greater spatial extent of suprathreshold activation within the SEN during sad faces relative to HCs. There were several regions within the CCN in which HCs showed greater activation than rMDD during correct rejections of lures, whereas individuals with rMDD showed greater activation than HCs during sad or fearful faces. LIMITATIONS Results were not directly compared with active MDD. CONCLUSIONS These results provide evidence of deficient CCN engagement during cognitive control in rMDD (dysfunctional cold cognition). Elevated SEN activation during sad faces could represent heightened salience of negative emotional faces in rMDD; elevated CCN activation during emotional faces in rMDD could represent compensatory regulatory control. These group differences may represent vulnerability factors, scars of prior depressive episodes, or processes maintaining wellness.

The relationship of impulsivity and cortical thickness in depressed and non-depressed adolescents

Major Depressive Disorder (MDD) is recognized to be heterogeneous in terms of brain structure abnormality findings across studies, which might reflect previously unstudied traits that confer variability to neuroimaging measurements. The purpose of this study was to examine the relationships between different types of trait impulsivity and MDD diagnosis on adolescent brain structure. We predicted that adolescents with depression who were high on trait impulsivity would have more abnormal cortical structure than depressed patients or non-MDD who were low on impulsivity. We recruited 58 subjects, including 29 adolescents (ages 12–19) with a primary DSM-IV diagnosis of MDD and a history of suicide attempt and 29 demographically-matched healthy control participants. Our GLM-based analyses sought to describe differences in the linear relationships between cortical thickness and impulsivity trait levels. As hypothesized, we found significant moderation effects in rostral middle frontal gyrus and right paracentral lobule cortical thickness for different subscales of the Barratt Impulsiveness Scale. However, although these brain-behavior relationships differed between diagnostic study groups, they were not simple additive effects as we had predicted. For the middle frontal gyrus, non-MDD participants showed a strong positive association between cortical thickness and BIS-11 Motor scores, while MDD-diagnosed participants showed a negative association. For Non-Planning Impulsiveness, paracentral lobule cortical thickness was observed with greater impulsivity in MDD, but no association was found for controls. In conclusion, the findings confirm that dimensions of impulsivity have discrete neural correlates, and show that relationships between impulsivity and brain structure are expressed differently in adolescents with MDD compared to non-MDD.

Multivariate Imaging Genetics Study of MRI Gray Matter Volume and SNPs Reveals Biological Pathways Correlated with Brain Structural Differences in Attention Deficit Hyperactivity Disorder

Background Attention deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder affecting children, adolescents, and adults. Its etiology is not well understood, but it is increasingly believed to result from diverse pathophysiologies that affect the structure and function of specific brain circuits. Although one of the best-studied neurobiological abnormalities in ADHD is reduced fronto-striatal-cerebellar gray matter (GM) volume, its specific genetic correlates are largely unknown. Methods In this study, T1-weighted MR images of brain structure were collected from 198 adolescents (63 ADHD-diagnosed). A multivariate parallel independent component analysis (Para-ICA) technique-identified imaging genetic relationships between regional GM volume and single nucleotide polymorphism data. Results Para-ICA analyses extracted 14 components from genetic data and 9 from MR data. An iterative cross-validation using randomly chosen subsamples indicated acceptable stability of these ICA solutions. A series of partial correlation analyses controlling for age, sex, and ethnicity revealed two genotype–phenotype component pairs significantly differed between ADHD and non-ADHD groups, after a Bonferroni correction for multiple comparisons. The brain phenotype component not only included structures frequently found to have abnormally low volume in previous ADHD studies but was also significantly associated with ADHD differences in symptom severity and performance on cognitive tests frequently found to be impaired in patients diagnosed with the disorder. Pathway analysis of the genotype component identified several different biological pathways linked to these structural abnormalities in ADHD. Conclusion Some of these pathways implicate well-known dopaminergic neurotransmission and neurodevelopment hypothesized to be abnormal in ADHD. Other more recently implicated pathways included glutamatergic and GABA-eric physiological systems; others might reflect sources of shared liability to disturbances commonly found in ADHD, such as sleep abnormalities.

Effect of trait anxiety on cognitive test performance in adolescents with and without attention-deficit/hyperactivity disorder.

ABSTRACT Introduction: Attention-deficit/hyperactivity disorder (ADHD) and anxiety are frequently comorbid disorders associated with different types of abnormal performance on neuropsychological tests. Although some studies have shown that comorbid anxiety alters ADHD test performance, results inconsistently show both improvements and worsening of different abilities, with failures to replicate across different anxiety disorders. Alternatively, trait anxiety may reflect a more stable influence on ADHD test performance than various diagnosable anxiety disorders. Method: To better understand the possible enhancing or deleterious effects of anxiety on ADHD cognitive impairments, this study examined the effect of individual differences in trait anxiety measured by the Multidimensional Anxiety Scale for Children (MASC) on a battery of computerized, rapid-performance tests measuring attention and impulsivity-related performance in 98 Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition (DSM–IV) Combined-Subtype ADHD adolescents and 123 healthy controls. It was hypothesized that trait anxiety would attenuate response inhibition and attention deficits in ADHD. Results: ADHD-diagnosed adolescents with higher trait anxiety performed better on indices of sustained attention, reaction time, and motor variability, and had altered overall test-performance strategy, while response inhibition was affected in both ADHD and non-ADHD. Conclusions: This study provides the first evidence that pathological levels of anxiety are not needed to see differences in ADHD neuropsychological test performance. Instead, mildly elevated trait anxiety confers a protective influence by reducing the degree of impairment seen in ADHD. These findings suggest that better performing ADHD adolescents might have optimized levels of cortical arousal, and raise new questions about how best to identify the neurobiological substrates responsible for the beneficial effects.

Cognitive control and network disruption in remitted depression: a correlate of childhood adversity

Abstract Individuals in a major depressive episode often display impairment in cognitive control, and this impairment exists outside of the acute phase of illness. Impairment in cognitive control also has been associated with exposure to childhood adversity (CA). The current study examined whether exposure to CA can explain variance in a component of cognitive control—inhibitory control—independent of diagnostic status in young adults with and without a history of depression. Healthy control individuals (n = 40) and individuals with remitted major depressive disorder (n = 53) completed a task measuring inhibitory control, reported level of CA and completed a scanning session to assess gray matter volume and resting state connectivity in regions associated with cognitive control. The results demonstrate that higher levels of CA were associated with poorer inhibitory control, reduced right middle frontal gyrus gray matter, decreased connectivity of salience and emotion networks and increased connectivity in cognitive control networks, even after controlling for diagnostic status, residual depression symptoms and current stressors. Together, the results suggest that inhibitory control impairment and intrinsic connectivity changes may be characterized as developmental sequelae of early stress exposure.

Multidimensional imaging techniques for prediction of treatment response in major depressive disorder

&NA; A large number of studies have attempted to use neuroimaging tools to aid in treatment prediction models for major depressive disorder (MDD). Most such studies have reported on only one dimension of function and prediction at a time. In this study, we used three different tasks across domains of function (emotion processing, reward anticipation, and cognitive control, plus resting state connectivity completed prior to start of medication to predict treatment response in 13–36 adults with MDD. For each experiment, adults with MDD were prescribed only label duloxetine (all experiments), whereas another subset were prescribed escitalopram. We used a KeyNet (both Task derived masks and Key intrinsic Network derived masks) approach to targeting brain systems in a specific match to tasks. The most robust predictors were (Dichter et al., 2010) positive response to anger and (Gong et al., 2011) negative response to fear within relevant anger and fear TaskNets and Salience and Emotion KeyNet (Langenecker et al., 2018) cognitive control (correct rejections) within Inhibition TaskNet (negative) and Cognitive Control KeyNet (positive). Resting state analyses were most robust for Cognitive control Network (positive) and Salience and Emotion Network (negative). Results differed by whether an ‐fwhm or ‐acf (more conservative) adjustment for multiple comparisons was used. Together, these results implicate the importance of future studies with larger sample sizes, multidimensional predictive models, and the importance of using empirically derived masks for search areas. HighlightsIncreased activation to angry faces and decreased activation during correct rejections were associated with better treatment response.Network predictors of treatment response included cognitive control network and salience and emotion network.Activation in anticipation of reward was not a good predictor of treatment response.

Cognitive control neuroimaging measures differentiate between those with and without future recurrence of depression

Background Major Depressive Disorder (MDD) is a prevalent, disruptive illness. A majority of those with MDD are at high risk for recurrence and increased risk for morbidity and mortality. This study examined whether multimodal baseline (and retest) Cognitive Control performance and neuroimaging markers (task activation and neural connectivity between key brain nodes) could differentiate between those with and without future recurrence of a major depressive (MD) episode within one year. We hypothesized that performance and neuroimaging measures of Cognitive Control would identify markers that differ between these two groups. Methods A prospective cohort study of young adults (ages 18–23) with history (h) of early-onset MDD (N = 60), now remitted, and healthy young adults (N = 49). Baseline Cognitive Control measures of performance, task fMRI and resting state connectivity (and reliability retest 4–12 weeks later) were used to compare those with future recurrence of MDD (N = 21) relative to those without future recurrence of MDD (N = 34 with resilience). The measures tested were (1) Parametric Go/No-Go (PGNG) performance, and task activation for (2) PGNG Correct Rejections, (3) PGNG Commission errors, and (4 & 5), resting state connectivity analyses of Cognitive Control Network to and from subgenual anterior cingulate. Results Relative to other groups at baseline, the group with MDD Recurrence had less bilateral middle frontal gyrus activation during commission errors. MDD Recurrence exhibited greater connectivity of right middle frontal gyrus to subgenual anterior cingulate (SGAC). SGAC connectivity was also elevated in this group to numerous regions in the Cognitive Control Network. Moderate to strong ICCs were present from test to retest, and highest for rs-fMRI markers. There were modest, significant correlations between task, connectivity and behavioral markers that distinguished between groups. Conclusion Markers of Cognitive Control function could identify those with early course MD who are at risk for depression recurrence. Those at high risk for recurrence would benefit from maintenance or preventative treatments. Future studies could test and validate these markers as potential predictors, accounting for sample selection and bias in feature detection.