Liliana Ramona Demenescu

Regional brain volume in depression and anxiety disorders

CONTEXT Major depressive disorder (MDD), panic disorder, and social anxiety disorder are among the most prevalent and frequently co-occurring psychiatric disorders in adults and may have, at least in part, a common etiology. OBJECTIVE To identify the unique and shared neuroanatomical profile of depression and anxiety, controlling for illness severity, medication use, sex, age of onset, and recurrence. DESIGN Cross-sectional study. SETTING Netherlands Study of Depression and Anxiety. PARTICIPANTS Outpatients with MDD (n = 68), comorbid MDD and anxiety (n = 88), panic disorder, and/or social anxiety disorder without comorbid MDD (n = 68) and healthy controls (n = 65). MAIN OUTCOME MEASURES Volumetric magnetic resonance imaging was conducted for voxel-based morphometry analyses. We tested voxelwise for the effects of diagnosis, age at onset, and recurrence on gray matter density. Post hoc, we studied the effects of use of medication, illness severity, and sex. RESULTS We demonstrated lower gray matter volumes of the rostral anterior cingulate gyrus extending into the dorsal anterior cingulate gyrus in MDD, comorbid MDD and anxiety, and anxiety disorders without comorbid MDD, independent of illness severity, sex, and medication use. Furthermore, we demonstrated reduced right lateral inferior frontal volumes in MDD and reduced left middle/superior temporal volume in anxiety disorders without comorbid MDD. Also, patients with onset of depression before 18 years of age showed lower volumes of the subgenual prefrontal cortex. CONCLUSIONS Our findings indicate that reduced volume of the rostral-dorsal anterior cingulate gyrus is a generic effect in depression and anxiety disorders, independent of illness severity, medication use, and sex. This generic effect supports the notion of a shared etiology and may reflect a common symptom dimension related to altered emotion processing. Specific involvement of the inferior frontal cortex in MDD and lateral temporal cortex in anxiety disorders without comorbid MDD, on the other hand, may reflect disorder-specific symptom clusters. Early onset of depression is associated with a distinct neuroanatomical profile that may represent a vulnerability marker of depressive disorder.

Neuroticism modulates amygdala-prefrontal connectivity in response to negative emotional facial expressions

Neuroticism is associated with the experience of negative affect and the development of affective disorders. While evidence exists for a modulatory role of neuroticism on task induced brain activity, it is unknown how neuroticism affects brain connectivity, especially the crucial coupling between the amygdala and the prefrontal cortex. Here we investigate this relation between functional connectivity and personality in response to negative facial expressions. Sixty healthy control participants, from the Netherlands Study on Depression and Anxiety (NESDA), were scanned during an emotional faces gender decision task. Activity and functional amygdala connectivity (psycho-physiological interaction [PPI]) related to faces of negative emotional valence (angry, fearful and sad) was compared to neutral facial expressions, while neuroticism scores were entered as a regressor. Activity for fearful compared to neutral faces in the dorsomedial prefrontal (dmPFC) cortex was positively correlated with neuroticism scores. PPI analyses revealed that right amygdala-dmPFC connectivity for angry and fearful compared to neutral faces was positively correlated with neuroticism scores. In contrast, left amygdala-anterior cingulate cortex (ACC) connectivity for angry, fearful and sad compared to neutral faces was negatively related to neuroticism levels. DmPFC activity has frequently been associated with self-referential processing in social cognitive tasks. Our results therefore suggest that high neurotic participants display stronger self-referential processing in response to negative emotional faces. Second, in line with previous reports on ACC function, the negative correlation between amygdala-ACC connectivity and neuroticism scores might indicate that those high in neuroticism display diminished control function of the ACC over the amygdala. These connectivity patterns might be associated with vulnerability to developing affective disorders such as depression and anxiety.

Enhanced amygdala reactivity to emotional faces in adults reporting childhood emotional maltreatment

In the context of chronic childhood emotional maltreatment (CEM; emotional abuse and/or neglect), adequately responding to facial expressions is an important skill. Over time, however, this adaptive response may lead to a persistent vigilance for emotional facial expressions. The amygdala and the medial prefrontal cortex (mPFC) are key regions in face processing. However, the neurobiological correlates of face processing in adults reporting CEM are yet unknown. We examined amygdala and mPFC reactivity to emotional faces (Angry, Fearful, Sad, Happy, Neutral) vs scrambled faces in healthy controls and unmedicated patients with depression and/or anxiety disorders reporting CEM before the age of 16 years (n = 60), and controls and patients who report no childhood abuse (n = 75). We found that CEM was associated with enhanced bilateral amygdala reactivity to emotional faces in general, and independent of psychiatric status. Furthermore, we found no support for differential mPFC functioning, suggesting that amygdala hyper-responsivity to emotional facial perception in adults reporting CEM may be independent from top-down influences of the mPFC. These findings may be key in understanding the increased emotional sensitivity and interpersonal difficulties, that have been reported in individuals with a history of CEM.

Resting-state functional connectivity abnormalities in limbic and salience networks in social anxiety disorder without comorbidity

The neurobiology of social anxiety disorder (SAD) is not yet fully understood. Structural and functional neuroimaging studies in SAD have identified abnormalities in various brain areas, particularly the amygdala and elements of the salience network. This study is the first to examine resting-state functional brain connectivity in a drug-naive sample of SAD patients without psychiatric comorbidity and healthy controls, using seed regions of interest in bilateral amygdala, in bilateral dorsal anterior cingulate cortex for the salience network, and in bilateral posterior cingulate cortex for the default mode network. Twelve drug-naive SAD patients and pair-wise matched healthy controls, all drawn from the Netherlands Study of Depression and Anxiety sample, underwent resting-state fMRI. Group differences were assessed with voxel-wise gray matter density as nuisance regressor. All results were cluster corrected for multiple comparisons (Z>2.3, p<.05). Relative to control subjects, drug-naive SAD patients demonstrated increased negative right amygdala connectivity with the left middle temporal gyrus, left supramarginal gyrus and left lateral occipital cortex. In the salience network patients showed increased positive bilateral dorsal anterior cingulate connectivity with the left precuneus and left lateral occipital cortex. Default mode network connectivity was not different between groups. These data demonstrate that drug-naive SAD patients without comorbidity show differences in functional connectivity of the amygdala, and of areas involved in self-awareness, some of which have not been implicated in SAD before.

Functional Magnetic Resonance Imaging Correlates of Emotional Word Encoding and Recognition in Depression and Anxiety Disorders

BACKGROUND Major depressive disorder (MDD), panic disorder, and social anxiety disorder are among the most prevalent and frequently co-occurring psychiatric disorders in adults and may be characterized by a common deficiency in processing of emotional information. METHODS We used functional magnetic resonance imaging during the performance of an emotional word encoding and recognition paradigm in patients with MDD (n = 51), comorbid MDD and anxiety (n = 59), panic disorder and/or social anxiety disorder without comorbid MDD (n = 56), and control subjects (n = 49). In addition, we studied effects of illness severity, regional brain volume, and antidepressant use. RESULTS Patients with MDD, prevalent anxiety disorders, or both showed a common hyporesponse in the right hippocampus during positive (>neutral) word encoding compared with control subjects. During negative encoding, increased insular activation was observed in both depressed groups (MDD and MDD + anxiety), whereas increased amygdala and anterior cingulate cortex activation during positive word encoding were observed as depressive state-dependent effects in MDD only. During recognition, anxiety patients showed increased inferior frontal gyrus activation. Overall, effects were unaffected by medication use and regional brain volume. CONCLUSIONS Hippocampal blunting during positive word encoding is a generic effect in depression and anxiety disorders, which may constitute a common vulnerability factor. Increased insular and amygdalar involvement during negative word encoding may underlie heightened experience of, and an inability to disengage from, negative emotions in depressive disorders. Our results emphasize a common neurobiological deficiency in both MDD and anxiety disorders, which may mark a general insensitiveness to positive information.

Aberrant limbic and salience network resting-state functional connectivity in panic disorder without comorbidity

BACKGROUND Panic disorder (PD) is a prevalent and debilitating disorder but its neurobiology is still poorly understood. We investigated resting-state functional connectivity (RSFC) in PD without comorbidity in three networks that have been linked to PD before. This could provide new insights in how functional integration of brain regions involved in fear and panic might relate to the symptomatology of PD. METHODS Eleven PD patients without comorbidity and eleven pair-wise matched healthy controls underwent resting-state fMRI. We used seed regions-of-interest in the bilateral amygdala (limbic network), the bilateral dorsal anterior cingulate cortex (dACC) (salience network), and the bilateral posterior cingulate cortex (default mode network). RSFC of these areas was assessed using seed-based correlations. All results were cluster corrected for multiple comparisons (Z>2.3, p<.05). RESULTS Abnormalities were identified in the limbic network with increased RSFC between the right amygdala and the bilateral precuneus in PD patients. In the salience network the dACC demonstrated altered connectivity with frontal, parietal and occipital areas. LIMITATIONS The small sample size and hypothesis-driven approach could restrict finding additional group differences that may exist. Other caveats are reflected in the use of medication by two participants and the acquisition of the resting-state scan at the end of a fixed imaging protocol. CONCLUSION We found altered RSFC in PD between areas involved in emotion regulation and emotional and somatosensory stimulus processing, as well as an area engaged in self-referential processing, not implicated in models for PD before. These findings extend existing functional neuroanatomical models of PD, as the altered RSFC may underlie increased sensitivity for bodily symptoms.

Amygdala activation and its functional connectivity during perception of emotional faces in social phobia and panic disorder

Social phobia (SP) and panic disorder (PD) have been associated with aberrant amygdala responses to threat-related stimuli. The aim of the present study was to examine amygdala function and its connectivity with medial prefrontal cortex (mPFC) during emotional face perception in PD and SP, and the role of illness severity. Blood oxygen level dependent responses while perceiving emotional facial expressions were compared in 14 patients with PD, 17 patients with SP, 8 patients with comorbid PD and SP, and 16 healthy controls. We found that PD, but not SP, was associated with amygdala and lingual gyrus hypoactivation during perception of angry, fearful, happy and neutral faces, compared to healthy participants. No significant effect of PD and SP diagnoses was found on amygdala-mPFC connectivity. A positive correlation of anxiety symptom severity was found on amygdala-dorsal anterior cingulate and dorsal mPFC connectivity during perception of fearful faces. Amygdala hypoactivation suggests reduced responsiveness to positive and negative emotional faces in PD. Symptom severity, but not the presence of PD and SP diagnosis per se, explains most of the abnormalities in amygdala-mPFC connectivity during perception of fearful faces.

Functional MRI correlates of visuospatial planning in out-patient depression and anxiety

van Tol MJ, van der Wee NJA, Demenescu LR, Nielen MMA, Aleman A, Renken R, van Buchem MA, Zitman FG, Veltman DJ. Functional MRI correlates of visuospatial planning in out‐patient depression and anxiety.

Altered functional connectivity density in major depressive disorder at rest

Major depressive disorder is characterized by abnormal brain connectivity at rest. Currently, most studies investigating resting-state activity rely on a priori restrictions on specific networks or seed regions, which may bias observations. We hence sought to elicit functional alterations in a hypothesis-free approach. We applied functional connectivity density (FCD) to identify abnormal connectivity for each voxel in the whole brain separately. Comparing resting-state fMRI in 21 MDD patients and 23 matched healthy controls, we identified atypical connections for regions exhibiting abnormal FCD and compared our results to those of an independent component analysis (ICA) on networks previously investigated in MDD. Patients showed reduced FCD in mid-cingulate cortex (MCC) and increased FCD in occipital cortex (OCC). These changes in global FCD were driven by abnormal local connectivity changes and reduced functional connectivity (FC) toward the left amygdala for MCC, and increased FC toward the right supplementary motor area for OCC. The altered connectivity was not reflected in ICA comparison of the salience and visual networks. Abnormal FC in MDD is present in cingulate and OCC in terms of global FCD. This converges with previous structural and metabolic findings; however, these particular changes in connectivity would not have been identified using canonical seed regions or networks. This implies the importance of FC measures in the investigation of brain pathophysiology in depression.

Age- and Gender-Related Variations of Emotion Recognition in Pseudowords and Faces

Background/Study Context: The ability to interpret emotionally salient stimuli is an important skill for successful social functioning at any age. The objective of the present study was to disentangle age and gender effects on emotion recognition ability in voices and faces. Methods: Three age groups of participants (young, age range: 18–35 years; middle-aged, age range: 36–55 years; and older, age range: 56–75 years) identified basic emotions presented in voices and faces in a forced-choice paradigm. Five emotions (angry, fearful, sad, disgusted, and happy) and a nonemotional category (neutral) were shown as encoded in color photographs of facial expressions and pseudowords spoken in affective prosody. Results: Overall, older participants had a lower accuracy rate in categorizing emotions than young and middle-aged participants. Females performed better than males in recognizing emotions from voices, and this gender difference emerged in middle-aged and older participants. The performance of emotion recognition in faces was significantly correlated with the performance in voices. Conclusion: The current study provides further evidence for a general age and gender effect on emotion recognition; the advantage of females seems to be age- and stimulus modality-dependent.