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1.  Domain-Specific Impairment in Cognitive Control among Remitted Youth with a History of Major Depression 
Early intervention in psychiatry  2015;10.1111/eip.12253.
Impairment in neuropsychological functioning is common in major depressive disorder (MDD), but it is not clear to what degree these deficits are related to risk (e.g., trait), scar, burden, or state effects of MDD. The objective of this study was to use neuropsychological measures, with factor scores in verbal fluency, processing speed, attention, set-shifting, and cognitive control in a unique population of young, remitted, un-medicated, early course individuals with a history of MDD in hopes of identifying putative trait markers of MDD.
Youth aged 18-23 in remission from MDD (rMDD; n = 62) and healthy controls (HC; n = 43) were assessed with neuropsychological tests at two time points. These were from four domains of executive functioning, consistent with previous literature as impaired in MDD; verbal fluency and processing speed, conceptual reasoning and set-shifting, processing speed with interference resolution, and cognitive control.
rMDD youth performed comparably to healthy controls on verbal fluency and processing speed, processing speed with interference resolution, and conceptual reasoning and set-shifting, reliably over time. Individuals with rMDD demonstrated relative decrements in cognitive control at Time 1, with greater stability than HC participants.
MDD may be characterized by regulatory difficulties that do not pertain specifically to active mood state or fluctuations in symptoms. Deficient cognitive control may represent a trait vulnerability or early course scar of MDD that may prove a viable target for secondary prevention or early remediation
PMCID: PMC4844809  PMID: 26177674
2.  Affective Personality Predictors of Disrupted Reward Learning and Pursuit in Major Depressive Disorder 
Psychiatry research  2015;230(1):56-64.
Anhedonia, the diminished anticipation and pursuit of reward, is a core symptom of major depressive disorder (MDD). Trait behavioral activation (BA), as a proxy for anhedonia, and behavioral inhibition (BI) may moderate the relationship between MDD and reward-seeking. The present studies probed for reward learning deficits, potentially due to aberrant BA and/or BI, in active or remitted MDD individuals compared to healthy controls (HC). Active MDD (Study 1) and remitted MDD (Study 2) participants completed the modified monetary incentive delay task (mMIDT), a behavioral reward-seeking task whose response window parameters were individually titrated to theoretically elicit equivalent accuracy between groups. Participants completed the BI Scale and BA Reward-Responsiveness and Drive Scales. Despite individual titration, active MDD participants won significantly less money than HCs. Higher Reward-Responsiveness scores predicted more won; Drive and BI were not predictive. Remitted MDD participants’ performance did not differ from controls’, and trait BA and BI measures did not predict r-MDD performance. These results suggest that diminished reward-responsiveness may contribute to decreased motivation and reward pursuit during active MDD, but that reward learning is intact in remission. Understanding individual reward processing deficits in MDD may inform personalized intervention addressing anhedonia and motivation deficits in select MDD patients.
PMCID: PMC4601921  PMID: 26319737
Depression; Remitted MDD; Reward Processing; Behavioral Activation; Behavioral Inhibition
3.  Targeting Ruminative Thinking in Adolescents at Risk for Depressive Relapse: Rumination-Focused Cognitive Behavior Therapy in a Pilot Randomized Controlled Trial with Resting State fMRI 
PLoS ONE  2016;11(11):e0163952.
This pilot randomized control trial was designed to examine whether Rumination-Focused Cognitive Behavior Therapy (RFCBT) reduces rumination and residual depressive symptoms among adolescents with a history of Major Depressive Disorder (MDD) who are at risk for relapse. We also examined whether these changes in symptoms were associated with changes in functional connectivity of the posterior cingulate cortex (PCC), a key node in the default mode network (DMN). Thirty-three adolescents (ages 12–18) were randomized to eight weeks of RFCBT or an assessment only (AO) control. Twenty two adolescents successfully completed fMRI scans pre- and post-intervention. Adolescents were recruited from the clinic and community and met criteria for at least one previous episode of MDD and were currently in full or partial remission. An Independent Evaluator interviewed parent and child before and after the eight-week intervention. The left PCC (-5, -50, 36) seed was used to probe resting state functional connectivity of the DMN. Adolescents who received RFCBT demonstrated reduced rumination (F = -2.76, df = 112, p < .01, 95% CI [-4.72,-0.80]) and self-report depression across eight weeks (F = -2.58, df = 113, p < .01, 95% CI [-4.21, -0.94]). Youth who received RFCBT also demonstrated significant decreases in connectivity between the left PCC and the right inferior frontal gyrus (IFG) and bilateral inferior temporal gyri (ITG). Degree of change in connectivity was correlated with changes in self-report depression and rumination. These data suggest that rumination can be reduced over eight weeks and that this reduction is associated with parallel decreases in residual depressive symptoms and decreased functional connectivity of the left PCC with cognitive control nodes. These changes may enhance the ability of vulnerable youth to stay well during the transition to adulthood.
Trial Registration: NCT01905267
PMCID: PMC5120778  PMID: 27880789
4.  Differences in Real World Executive Function between Children with Pediatric Bipolar Disorder and Children with ADHD 
Recent research evidence suggests that executive function (EF) is impaired in both pediatric bipolar disorder (PBD) and attention deficit-hyperactivity disorder (ADHD), although the underlying cognitive mechanisms are still unclear. In this study we examined EF, including cognitive and emotional control, in three pediatric groups with overlapping symptoms.
Sixteen children and adolescents with PBD, 17 children and adolescents with ADHD, Type Combined, and 13 children and adolescents with PBD and comorbid ADHD (PBD+ADHD) (mean age=12.70, SD=2.21) were assessed using the Behavioral Rating Inventory of Executive Function – Parental Report (BRIEF-PR), clinical scales and neuropsychological tests of attention, working memory and executive function.
All groups showed impairment on the Trails A and B tests. However, there were no significant group differences. On the BRIEF-PR while all three groups were impaired in General Executive Functioning and Metacognition only the two PBD groups revealed more extensive EF dysfunction, in both cognitive and emotional control domains, relative to the ADHD group. Conversely, the ADHD group exhibited selective deficits in cognitive domains such as working memory, planning/organization, monitoring, and metacognition. The two PBD groups showed greater impairment than the ADHD group in the domains of Inhibition, Shifting, Monitoring and Emotional Control. Furthermore, results from regression analyses suggest cognitive predictors of EF impairment in ADHD and mood predictors for inhibition in PBD.
The current results contribute new knowledge on domain-specific similarities and differences in executive dysfunction between PBD, ADHD, and the comorbid phenotype, which may inform the diagnostic process and cognitive intervention.
PMCID: PMC5130092  PMID: 27924149
pediatric bipolar disorder; ADHD; adolescent; executive function; emotion; trouble bipolaire pédiatrique; TDAH; adolescent; fonction exécutive; émotion
5.  A New Semantic List Learning Task to Probe Functioning of the Papez Circuit 
List learning tasks are powerful clinical tools for studying memory, yet have been relatively underutilized within the functional imaging literature. This limits understanding of regions such as the Papez circuit which support memory performance in healthy, non-demented adults.
The current study characterized list learning performance in 40 adults who completed a Semantic List Learning Task (SLLT) with a Brown-Peterson manipulation during functional MRI (fMRI). Cued recall with semantic cues, and recognition memory were assessed after imaging. Internal reliability and convergent and discriminant validity were evaluated.
Subjects averaged 38% accuracy in recall (62% for recognition), with primacy but no recency effects observed. Validity and reliability were demonstrated by showing that the SLLT was correlated with the California Verbal Learning test (CVLT), but not with executive functioning tests, and high intraclass correlation coefficient across lists for recall (.91). fMRI measurements during Encoding (vs. Silent Rehearsal) revealed significant activation in bilateral hippocampus, parahippocampus, and bilateral anterior and posterior cingulate cortex. Post-hoc analyses showed increased activation in anterior and middle hippocampus, subgenual cingulate, and mammillary bodies specific to Encoding. In addition, increasing age was positively associated with increased activation in a diffuse network, particularly frontal cortex and specific Papez regions for correctly recalled words. Gender differences were specific to left inferior and superior frontal cortex.
This is a clinically relevant list learning task that can be used in studies of groups for which the Papez circuit is damaged or disrupted, in mixed or crossover studies at imaging and clinical sites.
PMCID: PMC5065919  PMID: 26313512
Papez circuit; list learning; fMRI; imaging; memory; hippocampus
6.  Gender Differences in the Associations Among Marijuana Use, Cigarette Use, and Symptoms of Depression During Adolescence and Young Adulthood 
Addictive behaviors  2015;49:33-39.
As prevalence of marijuana use increases, it is important that we better understand how factors like gender, cigarette use, and depression are related to marijuana use during adolescence and young adulthood. We examined longitudinal relationships among these variables in adolescents moving into young adulthood who were studied longitudinally for six years.
1,263 individuals were included in the study. Participants were oversampled for ever-smoking a cigarette at baseline, when they were 15-16 years old. Frequency of cigarette smoking and marijuana use, as well as depression symptoms were assessed at baseline, 6, 15-, 24-, 60- and 72- months.
Cigarette use frequency and depression symptoms were associated with frequency of marijuana use (p-values <.001), particularly in adolescence, but there were important gender differences in these relationships. Specifically, symptoms of depression were related to marijuana use frequency among males (p<.001), but not females (p=.62). In addition, frequency of marijuana use was associated with increased cigarette use frequency, especially among males who had higher symptoms of depression (p<.001). However, this effect was not seen among females. Exploratory analyses suggested relationships between frequency of use and depression are specific to marijuana, not cigarettes.
Marijuana use is strongly related to depression symptoms and cigarette use frequency in males, indicating that in males these detrimental factors converge, whereas in females they do not. Gender differences in the factors related to marijuana use may mean that there are different risks for and consequences from use and have implications for prevention and intervention efforts.
PMCID: PMC4478142  PMID: 26036667
cigarettes; depression; gender; marijuana; nicotine; sex differences
7.  Shared white matter alterations across emotional disorders: A voxel-based meta-analysis of fractional anisotropy 
NeuroImage : Clinical  2016;12:1022-1034.
White matter (WM) integrity may represent a shared biomarker for emotional disorders (ED). Aims: To identify transdiagnostic biomarkers of reduced WM by meta-analysis of findings across multiple EDs.
Web of Science was searched systematically for studies of whole brain analysis of fractional anisotropy (FA) in adults with major depressive disorder, bipolar disorder, social anxiety disorder, obsessive-compulsive disorder or posttraumatic stress disorder compared with a healthy control (HC) group. Peak MNI coordinates were extracted from 37 studies of voxel-based analysis (892 HC and 962 with ED) and meta-analyzed using seed-based d Mapping (SDM) Version 4.31. Separate meta-analyses were also conducted for each disorder.
In the transdiagnostic meta-analysis, reduced FA was identified in ED studies compared to HCs in the left inferior fronto-occipital fasciculus, forceps minor, uncinate fasciculus, anterior thalamic radiation, superior corona radiata, bilateral superior longitudinal fasciculi, and cerebellum. Disorder-specific meta-analyses revealed the OCD group had the most similarities in reduced FA to other EDs, with every cluster of reduced FA overlapping with at least one other diagnosis. The PTSD group was the most distinct, with no clusters of reduced FA overlapping with any other diagnosis. The BD group were the only disorder to show increased FA in any region, and showed a more bilateral pattern of WM changes, compared to the other groups which tended to demonstrate a left lateralized pattern of FA reductions.
Distinct diagnostic categories of ED show commonalities in WM tracts with reduced FA when compared to HC, which links brain networks involved in cognitive and affective processing. This meta-analysis facilitates an increased understanding of the biological markers that are shared by these ED.
•A meta-analysis of FA in MDD, bipolar, social anxiety disorder, OCD and PTSD•Reduced FA in left superior longitudinal and inferior fronto-occipital fasciculi•Distinct diagnostic categories show commonalities of white matter changes.•Differences among diagnostic categories also found, PTSD most distinct•White matter integrity may be a shared biomarker for emotional disorders.
PMCID: PMC5153602  PMID: 27995068
Diffusion tensor imaging; Fractional anisotropy; Major depressive disorder; Bipolar disorder; Anxiety disorders; Meta-analysis
8.  Decreased Fronto-Limbic Activation and Disrupted Semantic-Cued List Learning in Major Depressive Disorder 
Individuals with Major Depressive Disorder (MDD) demonstrate poorer learning and memory skills relative to never-depressed comparisons (NDC). Previous studies report decreased volume and disrupted function of frontal lobes and hippocampi in MDD during memory challenge. However, it has been difficult to dissociate contributions of short-term memory and executive functioning to memory difficulties from those that might be attributable to long-term memory deficits.
Adult males (MDD, n=19; NDC, n=22) and females (MDD, n=23; NDC, n=19) performed the Semantic List Learning Task (SLLT) during fMRI. The SLLT Encoding condition consists of 15 lists, each containing 14 words. After each list, a Distractor condition occurs, followed by cued Silent Rehearsal instructions. Post-scan recall and recognition were collected. Groups were compared using block (Encoding-Silent Rehearsal) and event-related (Words Recalled) models.
MDD displayed lower recall relative to NDC. NDC displayed greater activation in several temporal, frontal, and parietal regions, for both Encoding-Silent Rehearsal and the Words Recalled analyses. Groups also differed in activation patterns in regions of the Papez circuit in planned analyses. The majority of activation differences were not related to performance, presence of medications, presence of comorbid anxiety disorder, or decreased gray matter volume in MDD.
Adults with MDD exhibit memory difficulties during a task designed to reduce the contribution of individual variability from short-term memory and executive functioning processes, parallel with decreased activation in memory and executive functioning circuits. Ecologically valid long-term memory tasks are imperative for uncovering neural correlates of memory performance deficits in adults with MDD.
PMCID: PMC4856469  PMID: 26831638
memory; depression; list learning; fMRI; serial position; hippocampus
9.  Shared dimensions of performance and activation dysfunction in cognitive control in females with mood disorders 
Brain  2015;138(5):1424-1434.
Deficits in cognitive control may represent an endophenotype for mood disorders. Ryan et al. demonstrate impaired ‘Go/No Go’ task performance in women with major depressive disorder or bipolar disorder compared to controls. However, distinct disease and performance-related activation patterns are seen with functional MRI, suggesting that the impairments are not uniform.
Deficits in cognitive control may represent an endophenotype for mood disorders. Ryan et al. demonstrate impaired ‘Go/No Go’ task performance in women with major depressive disorder or bipolar disorder compared to controls. However, distinct disease and performance-related activation patterns are seen with functional MRI, suggesting that the impairments are not uniform.
Major depressive disorder and bipolar disorder share symptoms that may reflect core mood disorder features. This has led to the pursuit of intermediate phenotypes and a dimensional approach to understand neurobiological disruptions in mood disorders. Executive dysfunction, including cognitive control, may represent a promising intermediate phenotype across major depressive disorder and bipolar disorder. This study examined dimensions of cognitive control in women with major depressive disorder or bipolar disorder in comparison to healthy control subjects using two separate, consecutive experiments. For Experiment 1, participants completed a behavioural cognitive control task (healthy controls = 150, major depressive disorder = 260, bipolar disorder = 202; age range 17–84 years). A sample of those participants (healthy controls = 17, major depressive disorder = 19, and bipolar disorder = 16) completed a similar cognitive control task in an event-related design functional magnetic resonance imaging protocol for Experiment 2. Results for Experiment 1 showed greater impairments on the cognitive control task in patients with mood disorders relative to healthy controls (P < 0.001), with more of those in the mood disorder group falling into the ‘impaired’ range when using clinical cut-offs (<5th percentile). Experiment 2 revealed only a few areas of shared activation differences in mood disorder greater than healthy controls. Activation analyses using performance as a regressor, irrespective of diagnosis, revealed within and extra-network areas that were more active in poor performers. In summary, performance and activation during cognitive control tasks may represent an intermediate phenotype for mood disorders. However, cognitive control dysfunction is not uniform across women with mood disorders, and activation is linked to performance more so than disease. These findings support subtype and dimensional approaches to understanding risk and expression of mood disorders and are a promising area of inquiry, in line with the Research Domain Criteria initiative of NIMH.
PMCID: PMC4840457  PMID: 25818869
cognitive control; mood disorders; dimensional; bipolar disorder; major depression
10.  Differential Resting State Connectivity Patterns and Impaired Semantically Cued List Learning Test Performance in Early Course Remitted MDD 
There is a well-known association between memory impairment and Major Depressive Disorder (MDD). Additionally, recent studies are also showing resting-state (rs) fMRI abnormalities in active and remitted MDD. However, no studies to date have examined both resting state connectivity and memory performance in early course remitted MDD, nor the relationship between connectivity and semantically-cued episodic memory.
Resting state MRI (rsMRI) data from two 3.0 Tesla GE scanners were collected from 34 unmedicated young adults with remitted MDD (rMDD) and 23 healthy controls (HCs) between 18–23 years of age using bilateral seeds in the hippocampus. Participants also completed a semantically-cued list-learning test and their performance was correlated with hippocampal seed-based rsMRI. Regression models were also used to predict connectivity patterns from memory performance.
After correcting for sex, rMDD performed worse than HCs on the total number of words recalled and recognized. rMDD demonstrated significant in-network hypoactivation between the hippocampus and multiple fronto-temporal regions, and multiple extra-network hyperconnectivities between the hippocampus and fronto-parietal regions when compared to HCs. Memory performance negatively predicted connectivity in HCs and positively predicted connectivity in rMDD.
Even when individuals with a history of MDD are no longer displaying active depressive symptoms, they continue to demonstrate worse memory performance, disruptions in hippocampal connectivity, and a differential relationship between episodic memory and hippocampal connectivity.
PMCID: PMC4844801  PMID: 26888619
resting-state; remitted MDD; episodic memory; functional connectivity; fMRI; hippocampus
11.  Biomarkers of intergenerational risk for depression: A review of mechanisms in longitudinal high-risk (LHR) studies 
Journal of affective disorders  2015;175:494-506.
Longitudinal research is critical for understanding the biological mechanisms underlying the development of depression. Researchers recruit high-risk cohorts to understand how risk is transmitted from one generation to the next. Biological measurements have been incorporated into these longitudinal high-risk (LHR) studies in order to illuminate mechanistic pathways.
To frame our review, we first present heritability estimates along the gene-by-environment continuum as a foundation. We then offer a Biomarkers of Intergenerational Risk for Depression (BIRD) model to describe the multiple hits individuals at risk receive and to allow for greater focus on the interactive effects of markers. BIRD allows for the known multifinality of pathways towards depression and considers the context (i.e., environment) in which these mechanisms emerge. Next, we review the extant LHR cohort studies that have assessed central nervous system (electroencephalography (EEG), neuroimaging), endocrine (hypothalamic-pituitary-adrenal axis (HPA)/cortisol), autonomic (startle, heart rate), genetic, sleep, and birth characteristics.
Results to date, in conjunction with the proposed model, point towards several pathways of discovery in understanding mechanisms, providing clear direction for future research examining potential endophenotypes.
Our review is based on relatively narrow inclusion and exclusion criteria. As such, many interesting studies were excluded, but this weakness is offset by strengths such as the increased reliability of findings.
Blanket prevention programs are inefficient and plagued by low effect sizes due to low rates of actual conversion to disorder. The inclusion of biomarkers of risk may lead to enhanced program efficiency by targeting those with greatest risk.
PMCID: PMC4405143  PMID: 25687188
Longitudinal; High-risk; Depression; Development; Biology
12.  Age and gender modulate the neural circuitry supporting facial emotion processing in adults with major depressive disorder 
Emotion processing, supported by fronto-limbic circuitry known to be sensitive to the effects of aging, is a relatively understudied cognitive-emotional domain in geriatric depression. Some evidence suggests that the neurophysiological disruption observed in emotion processing among adults with major depressive disorder (MDD) may be modulated by both gender and age. Therefore, the present study investigated the effects of gender and age on the neural circuitry supporting emotion processing in MDD.
Cross-sectional comparison of fMRI signal during performance of an emotion processing task.
Outpatient university setting.
One hundred adults recruited by MDD status, gender, and age.
Participants underwent fMRI while completing the Facial Emotion Perception Test (FEPT). They viewed photographs of faces and categorized the emotion perceived. Contrast for fMRI was of face perception minus animal identification blocks.
Effects of depression were observed in precuneus and effects of age in a number of fronto-limbic regions. Three-way interactions were present between MDD status, gender, and age in regions pertinent to emotion processing, including frontal, limbic and basal ganglia. Young women with MDD and older men with MDD exhibited hyperactivation in these regions compared to their respective same-gender healthy comparison (HC) counterparts. In contrast, older women and younger men with MDD exhibited hypoactivation compared to their respective same-gender HC counterparts.
This the first study to report gender- and age-specific differences in emotion processing circuitry in MDD. Gender-differential mechanisms may underlie cognitive-emotional disruption in older adults with MDD. The present findings have implications for improved probes into the heterogeneity of the MDD syndrome.
PMCID: PMC4241383  PMID: 25085721
emotion processing; depression; fMRI; gender; age
13.  Placebo-Activated Neural Systems are Linked to Antidepressant Responses 
JAMA psychiatry  2015;72(11):1087-1094.
High placebo responses have been observed across a wide range of pathologies, severely impacting drug development.
Here we examined neurochemical mechanisms underlying the formation of placebo effects in patients with Major Depressive Disorder (MDD).
Thirty-five medication-free MDD patients.
Design and Intervention
We performed a single-blinded two-week cross-over randomized controlled trial of two identical oral placebos (described as having either “active” or “inactive” fast-acting antidepressant-like effects) followed by a 10-week open-label treatment with a selective serotonin reuptake inhibitor (SSRI) or in some cases, another agent as clinically indicated. The volunteers were studied with PET and the μ-opioid receptor (MOR)-selective radiotracer [11C]carfentanil after each 1-week “inactive” and “active” oral placebo treatment. In addition, 1 mL of isotonic saline was administered intravenously (i.v.) within sight of the volunteer during PET scanning every 4 min over 20 min only after the 1-week active placebo treatment, with instructions that the compound may be associated with the activation of brain systems involved in mood improvement. This challenge stimulus was utilized to test the individual capacity to acutely activate endogenous opioid neurotransmision under expectations of antidepressant effect.
A University Health System.
Main Outcomes and Measures
Changes in depressive symptoms in response to “active” placebo and antidepressant. Baseline and activation measures of MOR binding.
Higher baseline MOR binding in the nucleus accumbens (NAc) was associated with better response to antidepressant treatment (r=0.48; p=0.02). Reductions in depressive symptoms after 1-week of “active” placebo treatment, compared to the “inactive”, were associated with increased placebo-induced μ-opioid neurotransmission in a network of regions implicated in emotion, stress regulation, and the pathophysiology of MDD, namely the subgenual anterior cingulate cortex, NAc, midline thalamus and amygdala (NAc: r=0.6, p<0.001). Placebo-induced endogenous opioid release in these regions was associated with better antidepressant treatment response, predicting 43% of the variance in symptom improvement at the end of the antidepressant trial.
These data demonstrate that placebo-induced activation of the μ-opioid system is implicated in the formation of placebo antidepressant effects in patients with MDD and also participate in antidepressant responses, conferring illness resiliency, during open administration.
PMCID: PMC4758856  PMID: 26421634
placebo effects; Major Depression; opioids; PET
14.  Current Neural and Behavioral Dimensional Constructs across Mood Disorders 
Our understanding of the underlying neurobiology for mood disorders is still limited. We present an integrated model for conceptualizing and understanding mood disorders drawing upon a broad literature pertinent to mood disorders. The integrated model of emotion processing and regulation incorporates the linguistic constructs of the Research Domain Criteria (RDoC) initiative. In particular, we focus on the Positive Valence domain/circuit (PVC), highlighting recent reward research and the Negative Valence domain/circuit (NVC), highlighting rumination. Furthermore, we also illustrate the Cognitive Control and Problem Solving (CCaPS) circuit, which is heavily involved in emotion regulation, as well as the default mode network (DMN) and interactions between circuits. We conclude by proposing methods for addressing challenges in the developmental study of mood disorders including using high-risk design that incorporates risk for many disorders.
PMCID: PMC4136393  PMID: 25147755
depression; bipolar; RDoC
15.  It still hurts: altered opioid activity in the brain during social rejection and acceptance in major depressive disorder 
Molecular psychiatry  2015;20(2):193-200.
The μ-opioid receptor (MOR) system, well known for dampening physical pain, is also hypothesized to dampen “social pain.” We used positron emission tomography scanning with the selective MOR radioligand [11C]carfentanil to test the hypothesis that MOR system activation in response to social rejection and acceptance is altered in medication-free patients diagnosed with current major depressive disorder (MDD, n = 17) compared to healthy controls (HCs, n = 18). During rejection, MDD patients showed reduced MOR activation (e.g., reduced endogenous opioid release) in brain regions regulating stress, mood, and motivation, and slower emotional recovery compared to HCs. During acceptance, only HCs showed increased social motivation, which was positively correlated with MOR activation in the nucleus accumbens, a reward structure. Abnormal MOR function in MDD may hinder emotional recovery from negative social interactions and decrease pleasure derived from positive interactions. Both effects may reinforce depression, trigger relapse, and contribute to poor treatment outcomes.
PMCID: PMC4469367  PMID: 25600108
depression; mu; opioid; PET; social; rejection; acceptance; stress
16.  Gender differences, Clinical Correlates and Longitudinal Outcome of Bipolar Disorder with Co-morbid Migraine 
Migraine is a common co-morbidity of bipolar disorder (BD), and is more prevalent in women than men. We hypothesized co-morbid migraine would be associated with features of illness and psychosocial risk factors which would differ by gender and impact outcome.
A retrospective analysis was conducted to assess association between self-reported, physician-diagnosed migraine, clinical variables of interest and mood outcome in subjects with DSM-IV BD (N=412) and healthy controls (HC, N=157) from the Prechter Longitudinal Study of Bipolar Disorder, 2005–2010. Informed consent was obtained from all participants.
Migraine was more common in BD (31%) than HC (6%), and had elevated risk in BD women compared to men (OR 3.5, CI 2.1, 5.8). In men, migraine was associated with BPII (OR 9.9, CI 2.3, 41.9) and mixed symptoms (OR 3.5, CI 1.0, 11.9). Migraine was associated with an earlier age at onset of BD by 2 years, more severe depression (B =.13, p=.03), and more frequent depression longitudinally (B =.13, p=.03). Migraine was associated with childhood trauma (p<.02) and high neuroticism (p<.01), and protective factors included high family adaptability (p=.05) and high extraversion (p=.01).
Migraine is a common co-morbidity with BD and may impact long-term outcome of BD, particularly depression. Clinicians should be alert for migraine co-morbidity in women, and in men with BPII. Effective treatment of migraine may impact mood outcome in BD as well as headache outcome. Joint pathophysiological mechanisms between migraine and BD may be important pathways for future study of treatments for both disorders.
PMCID: PMC4211932  PMID: 24816075
17.  Shifted Inferior Frontal Laterality in Women with Major Depressive Disorder is Related to Emotion Processing Deficits 
Psychological medicine  2013;43(7):1433-1445.
Facial emotion perception (FEP) is a critical human skill for successful social interaction, and a substantial body of literature suggests that explicit FEP is disrupted in Major Depressive Disorder (MDD). Prior research suggests that weakness in FEP may be an important phenomenon underlying patterns of emotion processing challenges in MDD and the disproportionate frequency of MDD in women.
Women with (n = 24) and without (n = 22) MDD, equivalent in age and education, completed a FEP task during fMRI.
The MDD group exhibited greater extents of frontal, parietal, and subcortical activation compared to the control group during FEP. Activation in inferior frontal gyrus (IFG) appeared shifted from a left > right pattern observed in healthy women to a bilateral pattern in MDD women. The ratio of left to right suprathreshold IFG voxels in healthy controls was nearly 3:1, whereas in the MDD group, there was a greater percent of suprathreshold IFG voxels bilaterally, with no leftward bias. In MDD, relatively greater activation in right IFG compared to left IFG (ratio score) was present and predicted FEP accuracy (r = .56, p < .004), with an inverse relationship observed between FEP and subgenual cingulate activation (r = −.46, p = .02).
This study links, for the first time, disrupted IFG activation laterality and increased subgenual cingulate activation with deficient FEP in women with MDD, providing an avenue for imaging-to-assessment translational applications in MDD.
PMCID: PMC4380502  PMID: 23298715
emotion; faces; depression; neuroimaging; laterality; women; identification
18.  Reduced emotion processing efficiency in healthy males relative to females 
This study examined sex differences in categorization of facial emotions and activation of brain regions supportive of those classifications. In Experiment 1, performance on the Facial Emotion Perception Test (FEPT) was examined among 75 healthy females and 63 healthy males. Females were more accurate in the categorization of fearful expressions relative to males. In Experiment 2, 3T functional magnetic resonance imaging data were acquired for a separate sample of 21 healthy females and 17 healthy males while performing the FEPT. Activation to neutral facial expressions was subtracted from activation to sad, angry, fearful and happy facial expressions. Although females and males demonstrated activation in some overlapping regions for all emotions, many regions were exclusive to females or males. For anger, sad and happy, males displayed a larger extent of activation than did females, and greater height of activation was detected in diffuse cortical and subcortical regions. For fear, males displayed greater activation than females only in right postcentral gyri. With one exception in females, performance was not associated with activation. Results suggest that females and males process emotions using different neural pathways, and these differences cannot be explained by performance variations.
PMCID: PMC3980801  PMID: 23196633
face emotion processing; affect perception; sex differences; gender differences
19.  Differential Prefrontal and Subcortical Circuitry Engagement During Encoding of Semantically Related Words in Patients with Late Life Depression 
Verbal memory difficulties are common among individuals with late-life depression (LLD), though there is limited knowledge about disruptions to underlying cerebral circuitry. The purpose of this study is to examine aberrations to cerebral networks implicated in encoding novel verbal semantic material among older adults with LLD.
Twenty-four older adults with early-onset LLD and 23 non-depressed comparisons (NDC) participated in the study. Participants completed a word list-learning task while undergoing fMRI.
In the context of equivalent recall and recognition of words following scanning and similar hippocampal volumes, patients with LLD exhibited less activation in structures known to be relevant for new learning and memory, including hippocampus, parahippocampal gyrus, insula, and cingulate, relative to non-ill comparisons. An important region in which the LLD group displayed greater activation than the NDC group was in inferior frontal gyrus (IFG), an area involved in cognitive control and controlled semantic/phonological retrieval and analysis; this region may be critical for LLD patients to consolidate encoded words into memory.
Functional irregularities found in LLD patients may reflect different modes of processing to-be-remembered information and/or early changes predictive of incipient cognitive decline. Future studies might consider mechanisms that could contribute to these functional differences, including HPA-axis functioning and vascular integrity, and utilize longitudinal designs in order to understand whether functional changes are predictive of incipient cognitive decline.
PMCID: PMC4337801  PMID: 24948034
depression; memory; hippocampus; aging
20.  Functional genetic variants in the vesicular monoamine transporter 1 (VMAT1) modulate emotion processing 
Molecular psychiatry  2013;19(1):129-139.
Emotional behavior is in part heritable and often disrupted in psychopathology. Identification of specific genetic variants that drive this heritability may provide important new insight into molecular and neurobiological mechanisms involved in emotionality. Our results demonstrate that the presynaptic vesicular monoamine transporter 1 (VMAT1) Thr136Ile (rs1390938) polymorphism is functional in vitro, with the Ile allele leading to increased monoamine transport into presynaptic vesicles. Moreover, we show that the Thr136Ile variant predicts differential responses in emotional brain circuits consistent with its effects in vitro. Lastly, deep sequencing of bipolar disorder (BPD) patients and controls identified several rare novel VMAT1 variants. The variant Phe84Ser was only present in individuals with BPD and leads to marked increase monoamine transport in vitro. Taken together, our data show that VMAT1 polymorphisms influence monoamine signaling, the functional response of emotional brain circuits, and risk for psychopathology.
PMCID: PMC4311877  PMID: 23337945
21.  Aberrant amygdala functional connectivity at rest in pediatric anxiety disorders 
Childhood onset of anxiety disorders is associated with greater functional impairment and burden across the lifespan. Recent work suggests that generalized anxiety disorder (GAD) is characterized by dysfunctional connectivity in amygdala-based circuits at rest in adolescents, consistent with adults. However, neural mechanisms underlying a broad spectrum of often-comorbid anxiety disorders in children remains unclear and understudied. The current study examines amygdala functional connectivity at rest in children and adolescents across comorbid anxiety disorders (ADs) including youth with primary diagnoses of GAD and social phobia (SP).
Compared with healthy controls (HCs), AD youth exhibited hyperconnectivity between the right amygdala and the insula and hypoconnectivity between the left amygdala and the ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC). Within the AD group, connectivity was not correlated with anxiety severity and only the amygdala-PCC connectivity was positively correlated with age.
Our findings indicate that youth with comorbid ADs demonstrate aberrant connectivity in the anterior limbic network (ALN) as well as the PCC at rest. This extends upon previous work suggesting alterations in amygdala circuits underlying fear learning, emotion regulation, and the processing of interoceptive states. Presence of these findings within this young, comorbid sample points to underlying common mechanisms across ADs and illuminates future targets for prevention and intervention in childhood.
PMCID: PMC4272798  PMID: 25530842
Children; Adolescent; Anxiety; Amygdala; Connectivity; Resting state; fMRI
22.  Increased Coupling of Intrinsic Networks in Remitted Depressed Youth Predicts Rumination and Cognitive Control 
PLoS ONE  2014;9(8):e104366.
Functional connectivity MRI (fcMRI) studies of individuals currently diagnosed with major depressive disorder (MDD) document hyperconnectivities within the default mode network (DMN) and between the DMN and salience networks (SN) with regions of the cognitive control network (CCN). Studies of individuals in the remitted state are needed to address whether effects derive from trait, and not state or chronic burden features of MDD.
fcMRI data from two 3.0 Tesla GE scanners were collected from 30 unmedicated (47% medication naïve) youth (aged 18–23, modal depressive episodes = 1, mean age of onset = 16.2, SD = 2.6) with remitted MDD (rMDD; modal years well = 4) and compared with data from 23 healthy controls (HCs) using four bilateral seeds in the DMN and SN (posterior cingulate cortex (PCC), subgenual anterior cingulate (sgACC), and amygdala), followed by voxel-based comparisons of the whole brain.
Compared to HCs, rMDD youth exhibited hyperconnectivities from both PCC and sgACC seeds with lateral, parietal, and frontal regions of the CCN, extending to the dorsal medial wall. A factor analysis reduced extracted data and a PCC factor was inversely correlated with rumination among rMDD youth. Two factors from the sgACC hyperconnectivity clusters were related to performance in cognitive control on a Go/NoGo task, one positively and one inversely.
Findings document hyperconnectivities of the DMN and SN with the CCN (BA 8/10), which were related to rumination and sustained attention. Given these cognitive markers are known predictors of response and relapse, hyperconnectivities may increase relapse risk or represent compensatory mechanisms.
PMCID: PMC4146466  PMID: 25162661
23.  Cognitive Functioning, Retirement Status, and Age: Results from the Cognitive Changes and Retirement among Senior Surgeons Study 
Accurate assessment of cognitive functioning is an important step in understanding how to better evaluate both clinical and cognitive competence in practicing surgeons. As part of the Cognitive Changes and Retirement among Senior Surgeons study, we examined the objective cognitive functioning of senior surgeons in relation to retirement status and age.
Study Design
Computerized cognitive tasks measuring visual sustained attention, reaction time, and visual learning and memory were administered to both practicing and retired surgeons at annual meetings of the American College of Surgeons. Data from 168 senior surgeons aged 60 and older were compared with data from 126 younger surgeons aged 45 to 59, with performance below 1.5 standard deviations or more indicating a significant difference between the groups.
Sixty-one percent of practicing senior surgeons performed within the range of the younger surgeons on all cognitive tasks. Seventy-eight percent of practicing senior surgeons aged 60 to 64 performed within the range of the younger surgeons on all tasks compared with 38% of practicing senior surgeons aged 70 and older. Forty-five percent of retired senior surgeons performed within the range of the younger surgeons on all tasks. No senior surgeon performed below the younger surgeons on all 3 tasks.
The majority of practicing senior surgeons performed at or near the level of their younger peers on all cognitive tasks, as did almost half of the retired senior surgeons. This suggests that older age does not inevitably preclude cognitive proficiency. The variability in cognitive performance across age groups and retirement status suggests the need for formal measures of objective cognitive functioning to help surgeons detect changes in cognitive performance and aid in their decisions to retire.
PMCID: PMC4083243  PMID: 20800185
24.  Emotion regulation through execution, observation, and imagery of emotional movements 
Brain and cognition  2013;82(2):219-227.
According to Damasio’s somatic marker hypothesis, emotions are generated by conveying the current state of the body to the brain through interoceptive and proprioceptive afferent input. The resulting brain activation patterns represent unconscious emotions and correlate with subjective feelings. This proposition implies a corollary that the deliberate control of motor behavior could regulate feelings. We tested this possibility, hypothesizing that engaging in movements associated with a certain emotion would enhance that emotion and/or the corresponding valence. Furthermore, because motor imagery and observation are thought to activate the same mirror-neuron network engaged during motor execution, they might also activate the same emotional processing circuits, leading to similar emotional effects. Therefore, we measured the effects of motor execution, motor imagery and observation of whole-body dynamic expressions of emotions (happiness, sadness, fear) on affective state. All three tasks enhanced the corresponding affective state, indicating their potential to regulate emotions.
PMCID: PMC4067484  PMID: 23561915
Body expression of emotion; Nonverbal behavior; Emotion regulation; Embodiment; Simulation; Motor imagery
25.  Identifying a cognitive impairment subgroup in adults with mood disorders 
Journal of affective disorders  2011;132(3):360-367.
We hypothesized that only a minority of patients with mood disorders have measurable cognitive impairment, and this minority drives the small-to-medium effect sizes detected in group studies. Removal of this minority from group statistical analyses will illustrate that the majority appear to have broadly normal cognitive functioning.
Participants were adults between the ages of 20 and 54, including 659 healthy control subjects, 84 unmedicated outpatients diagnosed with depression, 59 outpatients diagnosed with depression who were on medications at the time of the evaluation, and 43 outpatients with bipolar disorder. All completed the CNS Vital Signs computerized cognitive screening battery.
The prevalence rates of low cognitive test scores were calculated for the healthy control subjects and the patients with mood disorders. Having two scores at or below the 5th percentile occurred in 31.2% of the patients and only 8.2% of the control subjects [χ2(1)=66.67, p<.0001; Odds Ratio=5.1, 95% CI=3.4–7.7]. For the control subjects, this low false positive rate for cognitive impairment was maintained across age groups, sexes, and education levels. A larger proportion of patients with bipolar disorder (41.9%) than patients with depression (27.1–28.6%) met this criterion for cognitive impairment.
This study suggests that cognitive impairment associated with mood disorders is limited to a minority of patients with the majority being broadly cognitively normal. Future research should determine if this identified subgroup has neuroanatomical, neurophysiological, or neuroendocrine abnormalities. Cognitive screening tools of this type might be useful in selecting participants for studies.
PMCID: PMC4062916  PMID: 21439647
Computerized testing; Cognitive impairment; Depression; Bipolar disorder

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