Nicholas D. Walsh

Elevated left and reduced right orbitomedial prefrontal fractional anisotropy in adults with bipolar disorder revealed by tract-based spatial statistics

CONTEXT Diffusion tensor imaging (DTI) studies in adults with bipolar disorder (BD) indicate altered white matter (WM) in the orbitomedial prefrontal cortex (OMPFC), potentially underlying abnormal prefrontal corticolimbic connectivity and mood dysregulation in BD. OBJECTIVE To use tract-based spatial statistics (TBSS) to examine WM skeleton (ie, the most compact whole-brain WM) in subjects with BD vs healthy control subjects. DESIGN Cross-sectional, case-control, whole-brain DTI using TBSS. SETTING University research institute. PARTICIPANTS Fifty-six individuals, 31 having a DSM-IV diagnosis of BD type I (mean age, 35.9 years [age range, 24-52 years]) and 25 controls (mean age, 29.5 years [age range, 19-52 years]). MAIN OUTCOME MEASURES Fractional anisotropy (FA) longitudinal and radial diffusivities in subjects with BD vs controls (covarying for age) and their relationships with clinical and demographic variables. RESULTS Subjects with BD vs controls had significantly greater FA (t > 3.0, P <or= .05 corrected) in the left uncinate fasciculus (reduced radial diffusivity distally and increased longitudinal diffusivity centrally), left optic radiation (increased longitudinal diffusivity), and right anterothalamic radiation (no significant diffusivity change). Subjects with BD vs controls had significantly reduced FA (t > 3.0, P <or= .05 corrected) in the right uncinate fasciculus (greater radial diffusivity). Among subjects with BD, significant negative correlations (P < .01) were found between age and FA in bilateral uncinate fasciculi and in the right anterothalamic radiation, as well as between medication load and FA in the left optic radiation. Decreased FA (P < .01) was observed in the left optic radiation and in the right anterothalamic radiation among subjects with BD taking vs those not taking mood stabilizers, as well as in the left optic radiation among depressed vs remitted subjects with BD. Subjects having BD with vs without lifetime alcohol or other drug abuse had significantly decreased FA in the left uncinate fasciculus. CONCLUSIONS To our knowledge, this is the first study to use TBSS to examine WM in subjects with BD. Subjects with BD vs controls showed greater WM FA in the left OMPFC that diminished with age and with alcohol or other drug abuse, as well as reduced WM FA in the right OMPFC. Mood stabilizers and depressed episode reduced WM FA in left-sided sensory visual processing regions among subjects with BD. Abnormal right vs left asymmetry in FA in OMPFC WM among subjects with BD, likely reflecting increased proportions of left-sided longitudinally aligned and right-sided obliquely aligned myelinated fibers, may represent a biologic mechanism for mood dysregulation in BD.

Neural responses to sad facial expressions in major depression following cognitive behavioral therapy

BACKGROUND Affective facial processing is an important component of interpersonal relationships. The neural substrate has been examined following treatment with antidepressant medication but not with psychological therapies. The present study investigated the neural correlates of implicit processing of sad facial expressions in depression pretreatment and posttreatment with cognitive behavioral therapy (CBT). METHODS The patient group consisted of 16 medication-free subjects (mean age 40 years) with a DSM-IV diagnosis of acute unipolar major depression, and the comparison group were 16 matched healthy volunteers. Subjects participated in a prospective study with functional magnetic resonance imaging (fMRI) at weeks 0 and 16. During the fMRI scans, subjects performed an affect recognition task with facial stimuli morphed to display varying intensities of sadness. Patients received 16 sessions of CBT. Functional magnetic resonance imaging data were analyzed for the mean activation and differential response to variable intensity (load-response) of facial affect processing. RESULTS During an acute depressive episode, patients showed elevated amygdala-hippocampal activity relative to healthy individuals. Baseline dorsal anterior cingulate activity in patients showed a significant relationship with subsequent clinical response. CONCLUSIONS These data provide further support for elevated amygdala activity in depression and suggest that anterior cingulate activity may be a predictor of treatment response to both pharmacotherapy and CBT.

Functional Coupling of the Amygdala in Depressed Patients Treated with Antidepressant Medication

The amygdala plays a central role in various aspects of affect processing and mood regulation by its rich anatomical connections to other limbic and cortical regions. It is plausible that depressive disorders, and response to antidepressant drugs, may reflect changes in the physiological coupling between the amygdala and other components of affect-related large-scale brain systems. We explored this hypothesis by mapping the functional coupling of right and left amygdalae in functional magnetic resonance imaging data acquired from 19 patients with major depressive disorder and 19 healthy volunteers, each scanned twice (at baseline and 8 weeks later) during performance of an implicit facial affect processing task. Between scanning sessions, the patients received treatment with an antidepressant drug, fluoxetine 20 mg/day. We found that the amygdala was positively coupled bilaterally with medial temporal and ventral occipital regions, and negatively coupled with the anterior cingulate cortex. Antidepressant treatment was associated with significantly increased coupling between the amygdala and right frontal and cingulate cortex, striatum, and thalamus. Treatment-related increases in functional coupling to frontal and other regions were greater for the left amygdala than for the right amygdala. These results indicate that antidepressant drug effects can be measured in terms of altered coupling between components of cortico-limbic systems and that these effects were most clearly demonstrated by enhanced functional coupling of the left amygdala.

Neural basis of the emotional Stroop interference effect in major depression

BACKGROUND A mood-congruent sensitivity towards negative stimuli has been associated with development and maintenance of major depressive disorder (MDD). The emotional Stroop task assesses interference effects arising from the conflict of emotional expressions consistent with disorder-specific self-schemata and cognitive colour-naming instructions. Functional neuroimaging studies of the emotional Stroop effect advocate a critical involvement of the anterior cingulate cortex (ACC) during these processes. METHOD Subjects were 17 medication-free individuals with unipolar MDD in an acute depressive episode (mean age 39 years), and 17 age-, gender- and IQ-matched healthy volunteers. In an emotional Stroop task, sad and neutral words were presented in various colours, and subjects were required to name the colour of words whilst undergoing functional magnetic resonance imaging (fMRI). Overt verbal responses were acquired with a clustered fMRI acquisition sequence. RESULTS Individuals with depression showed greater increases in response time from neutral to sad words relative to controls. fMRI data showed a significant engagement of left rostral ACC (BA 32) and right precuneus during sad words in patients relative to controls. Additionally, rostral ACC activation was positively correlated with latencies of negative words in MDD patients. Healthy controls did not have any regions of increased activation compared to MDD patients. CONCLUSIONS These findings provide evidence for a behavioural and neural emotional Stroop effect in MDD and highlight the importance of the ACC during monitoring of conflicting cognitive processes and mood-congruent processing in depression.

A Longitudinal Functional Magnetic Resonance Imaging Study of Verbal Working Memory in Depression After Antidepressant Therapy

BACKGROUND Impairments in the neural circuitry of verbal working memory are evident in depression. Factors of task demand and depressive state might have significant effects on its functional neuroanatomy. METHODS Two groups underwent functional magnetic resonance imaging while performing a verbal working memory task of varying cognitive load (n-back). The patient group comprised 20 medication-free individuals in an acute episode of unipolar major depression and the control group comprised 20 healthy individuals. Scans were acquired at weeks 0 (baseline), 2, and 8. Patients received treatment with fluoxetine after the baseline scan. Cerebral activations were measured for mean overall activation as well as the linear and quadratic load-response activity with increasing task demand (1-, 2-, 3-back). RESULTS There were no significant differences in performance accuracy between groups. However, a main effect of group was observed in the load-response activity in frontal and posterior cortical regions within the verbal working memory network in which patients showed a greater load-response relative to control subjects. Group by time effects were revealed in the load-response activity in the caudate and thalamus. As a marker of treatment response, a lower linear load-response at baseline in the dorsal anterior cingulate, left middle frontal, and lateral temporal cortices was associated with an improved clinical outcome. CONCLUSIONS Maintenance of performance accuracy in patients was accompanied by a significant increase in the load-response activity in frontal and posterior cortical regions within the verbal working memory network. These data also provide further support for resilience of activity in the anterior cingulate as a predictor of treatment response in depression.

Brain structure abnormalities in adolescent girls with conduct disorder

Background Conduct disorder (CD) in female adolescents is associated with a range of negative outcomes, including teenage pregnancy and antisocial personality disorder. Although recent studies have documented changes in brain structure and function in male adolescents with CD, there have been no neuroimaging studies of female adolescents with CD. Our primary objective was to investigate whether female adolescents with CD show changes in grey matter volume. Our secondary aim was to assess for sex differences in the relationship between CD and brain structure. Methods Female adolescents with CD (n = 22) and healthy control participants matched in age, performance IQ and handedness (n = 20) underwent structural magnetic resonance imaging. Group comparisons of grey matter volume were performed using voxel-based morphometry. We also tested for sex differences using archive data obtained from male CD and control participants. Results Female adolescents with CD showed reduced bilateral anterior insula and right striatal grey matter volumes compared with healthy controls. Aggressive CD symptoms were negatively correlated with right dorsolateral prefrontal cortex volume, whereas callous-unemotional traits were positively correlated with bilateral orbitofrontal cortex volume. The sex differences analyses revealed a main effect of diagnosis on right amygdala volume (reflecting reduced amygdala volume in the combined CD group relative to controls) and sex-by-diagnosis interactions in bilateral anterior insula. Conclusions We observed structural abnormalities in brain regions involved in emotion processing, reward and empathy in female adolescents with CD, which broadly overlap with those reported in previous studies of CD in male adolescents.

Meta-analytic evidence for neuroimaging models of depression: State or trait?

BACKGROUND Major Depressive Disorder (MDD) is a leading cause of disease burden worldwide. With the rapid growth of neuroimaging research on relatively small samples, meta-analytic techniques are becoming increasingly important. Here, we aim to clarify the support in fMRI literature for three leading neurobiological models of MDD: limbic-cortical, cortico-striatal and the default mode network. METHODS Searches of PubMed and Web of Knowledge, and manual searches, were undertaken in early 2011. Data from 34 case-control comparisons (n=1165) and 6 treatment studies (n=105) were analysed separately with two meta-analytic methods for imaging data: Activation Likelihood Estimation and Gaussian-Process Regression. RESULTS There was broad support for limbic-cortical and cortico-striatal models in the case-control data. Evidence for the role of the default mode network was weaker. Treatment-sensitive regions were primarily in lateral frontal areas. LIMITATIONS In any meta-analysis, the increase in the statistical power of the inference comes with the risk of aggregating heterogeneous study pools. While we believe that this wide range of paradigms allows identification of key regions of dysfunction in MDD (regardless of task), we attempted to minimise such risks by employing GPR, which models such heterogeneity. CONCLUSIONS The focus of treatment effects in frontal areas indicates that dysregulation here may represent a biomarker of treatment response. Since the dysregulation in many subcortical regions in the case-control comparisons appeared insensitive to treatment, we propose that these act as trait vulnerability markers, or perhaps treatment insensitivity. Our findings allow these models of MDD to be applied to fMRI literature with some confidence.

Subregional hippocampal deformations in major depressive disorder

BACKGROUND Hippocampal atrophy is a well reported feature of major depressive disorder, although the evidence has been mixed. The present study sought to examine hippocampal volume and subregional morphology in patients with major depressive disorder, who were all medication-free and in an acute depressive episode of moderate severity. METHODS Structural magnetic resonance imaging scans were acquired in 37 patients (mean age 42 years) and 37 age, gender and IQ-matched healthy individuals. Hippocampal volume and subregional structural differences were measured by manual tracings and identification of homologous surface points to the central core of each hippocampus. RESULTS Both right (P=0.001) and left (P=0.005) hippocampal volumes were reduced in patients relative to healthy controls (n=37 patients and n=37 controls), while only the right hippocampus (P=0.016) showed a reduced volume in a subgroup of first-episode depression patients (n=13) relative to healthy controls. Shape analysis localised the subregional deformations to the subiculum and CA1 subfield extending into the CA2-3 subfields predominantly in the tail regions in the right (P=0.017) and left (P=0.011) hippocampi. LIMITATIONS As all patients were in an acute depressive episode, effects associated with depressive state cannot be distinguished from trait effects. CONCLUSIONS Subregional hippocampal deficits are present early in the course of major depression. The deformations may reflect structural correlates underlying functional memory impairments and distinguish depression from other psychiatric disorders.

Atypical neural responses during face processing in female adolescents with conduct disorder

Objective Conduct disorder (CD) in females is associated with negative adult outcomes including mental health problems and personality disorders. Although recent neuroimaging studies have reported changes in neural activity during facial emotion processing in males with CD or callous-unemotional (CU) traits, there have been no neuroimaging studies specifically assessing females with CD. We addressed this gap by investigating whether female adolescents with CD show atypical neural activation when processing emotional or neutral faces. Method We acquired functional magnetic resonance imaging (fMRI) data from 20 female adolescents with CD and 20 female control participants while they viewed angry, sad, and neutral faces. Results An omnibus group (CD, control) by facial emotion (angry, sad, neutral) analysis of variance (ANOVA) revealed main effects of facial emotion in superior temporal cortex, fusiform gyrus, ventrolateral prefrontal cortex and insula, and main effects of group in medial orbitofrontal cortex (OFC) and right anterior insula. Female participants with CD showed reduced medial OFC and increased anterior insula responses relative to healthy controls. There were no significant group × facial emotion interactions. Lifetime CD symptoms were negatively correlated with amygdala, superior temporal cortex, fusiform gyrus, and dorsolateral prefrontal cortex activity for the contrast “all-faces versus fixation.” CU traits were negatively correlated with fusiform gyrus activity for the contrast sad versus neutral faces. Conclusion Females with CD showed atypical neural activation during the processing of all facial expressions, irrespective of valence. Our results demonstrate that severity of CD symptoms and CU traits is important in explaining abnormal patterns of neural activity.

5-HTTLPR and Early Childhood Adversities Moderate Cognitive and Emotional Processing in Adolescence

Background Polymorphisms in the promoter region of the serotonin transporter gene (5-HTTLPR) and exposure to early childhood adversities (CA) are independently associated with individual differences in cognitive and emotional processing. Whether these two factors interact to influence cognitive and emotional processing is not known. Methodology and Principal Findings We used a sample of 238 adolescents from a community study characterised by the presence of the short allele of 5-HTTLPR (LL, LS, SS) and the presence or absence of exposure to CA before 6 years of age. We measured cognitive and emotional processing using a set of neuropsychological tasks selected predominantly from the CANTAB® battery. We found that adolescents homozygous for the short allele (SS) of 5-HTTLPR and exposed to CA were worse at classifying negative and neutral stimuli and made more errors in response to ambiguous negative feedback. In addition, cognitive and emotional processing deficits were associated with diagnoses of anxiety and/or depressions. Conclusion and Significance Cognitive and emotional processing deficits may act as a transdiagnostic intermediate marker for anxiety and depressive disorders in genetically susceptible individuals exposed to CA.