Look me in the eye: evaluating the accuracy of smartphone-based eye tracking for potential application in autism spectrum disorder research.

BACKGROUND: Avoidance to look others in the eye is a characteristic symptom of Autism Spectrum Disorders (ASD), and it has been hypothesised that quantitative monitoring of gaze patterns could be useful to objectively evaluate treatments. However, tools to measure gaze behaviour on a regular basis at a manageable cost are missing. In this paper, we investigated whether a smartphone-based tool could address this problem. Specifically, we assessed the accuracy with which the phone-based, state-of-the-art eye-tracking algorithm iTracker can distinguish between gaze towards the eyes and the mouth of a face displayed on the smartphone screen. This might allow mobile, longitudinal monitoring of gaze aversion behaviour in ASD patients in the future. RESULTS: We simulated a smartphone application in which subjects were shown an image on the screen and their gaze was analysed using iTracker. We evaluated the accuracy of our set-up across three tasks in a cohort of 17 healthy volunteers. In the first two tasks, subjects were shown different-sized images of a face and asked to alternate their gaze focus between the eyes and the mouth. In the last task, participants were asked to trace out a circle on the screen with their eyes. We confirm that iTracker can recapitulate the true gaze patterns, and capture relative position of gaze correctly, even on a different phone system to what it was trained on. Subject-specific bias can be corrected using an error model informed from the calibration data. We compare two calibration methods and observe that a linear model performs better than a previously proposed support vector regression-based method. CONCLUSIONS: Under controlled conditions it is possible to reliably distinguish between gaze towards the eyes and the mouth with a smartphone-based set-up. However, future research will be required to improve the robustness of the system to roll angle of the phone and distance between the user and the screen to allow deployment in a home setting. We conclude that a smartphone-based gaze-monitoring tool provides promising opportunities for more quantitative monitoring of ASD.

CHANGES IN REGIONAL BRAIN ACTIVATION RELATED TO DEPRESSIVE STATE: A 2-YEAR LONGITUDINAL FUNCTIONAL MRI STUDY.

BACKGROUND: Abnormal brain activations during processing of emotional facial expressions in depressed patients have been demonstrated. We investigated the natural course of brain activation in response to emotional faces in depression, indexed by functional magnetic resonance imaging (fMRI) scans preceding and following change in depressive state. We hypothesized a decrease in activation in the amygdala, anterior cingulate cortex (ACC), and insula with a decrease in depressive pathology. METHODS: A 2-year longitudinal fMRI study was conducted as part of the Netherlands Study of Depression and Anxiety. We included 32 healthy controls and 49 depressed patients. During the second scan, 27 patients were in remission (remitters), the other 22 were not (nonremitters). All participants viewed faces with emotional expressions during scanning. RESULTS: Rostral ACC activation during processing of happy faces was predictive of a decrease in depressive state (PFWE = .003). In addition, remitters showed decreased activation of the insula over time (PFWE = .016), specifically during happy faces. Nonremitters displayed increased abnormalities in emotion recognition circuitry during the second scan compared to the first. No effect of selective serotonin reuptake inhibitor use was observed. CONCLUSIONS: Our results demonstrate that rostral ACC activation may predict changes in depressive state even at 2-year outcome. The association between change in depressed state and change in insula activation provides further evidence for the role of the insula in a network maintaining emotional and motivational states.

Age- and gender-related variations of emotion recognition in pseudowords and faces.

UNLABELLED: 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.

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.

Metaphor processing is supramodal semantic processing: The role of the bilateral lateral temporal regions in multimodal communication.

This paper presents an fMRI study on healthy adult understanding of metaphors in multimodal communication. We investigated metaphors expressed either only in coverbal gestures ("monomodal metaphors") or in speech with accompanying gestures ("multimodal metaphors"). Monomodal metaphoric gestures convey metaphoric information not expressed in the accompanying speech (e.g. saying the non-metaphoric utterance, "She felt bad" while dropping down the hand with palm facing up; here, the gesture alone indicates metaphoricity), whereas coverbal gestures in multimodal metaphors indicate metaphoricity redundant to the speech (e.g. saying the metaphoric utterance, "Her spirits fell" while dropping the hand with palm facing up). In other words, in monomodal metaphors, gestures add information not spoken, whereas the gestures in multimodal metaphors can be redundant to the spoken content. Understanding and integrating the information in each modality, here spoken and visual, is important in multimodal communication, but most prior studies have only considered multimodal metaphors where the gesture is redundant to what is spoken. Our participants watched audiovisual clips of an actor speaking while gesturing. We found that abstract metaphor comprehension recruited the lateral superior/middle temporal cortices, regardless of the modality in which the conceptual metaphor is expressed. These results suggest that abstract metaphors, regardless of modality, involve resources implicated in general semantic processing and are consistent with the role of these areas in supramodal semantic processing as well as the theory of embodied cognition.

Handling or being the concept: An fMRI study on metonymy representations in coverbal gestures.

In "Two heads are better than one," "head" stands for people and focuses the message on the intelligence of people. This is an example of figurative language through metonymy, where substituting a whole entity by one of its parts focuses attention on a specific aspect of the entity. Whereas metaphors, another figurative language device, are substitutions based on similarity, metonymy involves substitutions based on associations. Both are figures of speech but are also expressed in coverbal gestures during multimodal communication. The closest neuropsychological studies of metonymy in gestures have been nonlinguistic tool-use, illustrated by the classic apraxic problem of body-part-as-object (BPO, equivalent to an internal metonymy representation of the tool) vs. pantomimed action (external metonymy representation of the absent object/tool). Combining these research domains with concepts in cognitive linguistic research on gestures, we conducted an fMRI study to investigate metonymy resolution in coverbal gestures. Given the greater difficulty in developmental and apraxia studies, perhaps explained by the more complex semantic inferencing involved for external metonymy than for internal metonymy representations, we hypothesized that external metonymy resolution requires greater processing demands and that the neural resources supporting metonymy resolution would modulate regions involved in semantic processing. We found that there are indeed greater activations for external than for internal metonymy resolution in the temporoparietal junction (TPJ). This area is posterior to the lateral temporal regions recruited by metaphor processing. Effective connectivity analysis confirmed our hypothesis that metonymy resolution modulates areas implicated in semantic processing. We interpret our results in an interdisciplinary view of what metonymy in action can reveal about abstract cognition.

Higher interference susceptibility in reaction time task is accompanied by weakened functional dissociation between salience and default mode network.

BACKGROUND: The relationship between task-positive and task-negative components of brain networks has repeatedly been shown to be characterized by dissociated fluctuations of spontaneous brain activity. We tested whether the interaction between task-positive and task-negative brain areas during resting-state predicts higher interference susceptibility, i.e. increased reaction times (RTs), during an Attention Modulation by Salience Task (AMST). METHODS: 29 males underwent 3T resting-state Magnetic Resonance Imaging scanning. Subsequently, they performed the AMST, which measures RTs to early- and late-onset auditory stimuli while perceiving high- or low-salient visual distractors. We conducted seed-based resting-state functional connectivity (rsFC) analyses using global signal correction. We assessed general responsiveness and salience related interference in the AMST and set this into context of the resting-state functional connectivity (rsFC) between a key salience network region (dACC; task-positive region) and a key default mode network region (precuneus; task-negative region). RESULTS: With increasing RTs to high- but not low-salient pictures dACC shows significantly weakened functional dissociation to a cluster in precuneus. This cluster overlaps with a cluster that correlates in its dACC rsFC with subjects' interference, as measured of high-salient RTs relative to low-salient RTs. CONCLUSION: Our findings suggest that the interaction between salience network (SN) and default mode network (DMN) at rest predicts susceptibility to distraction. Subjects, that are more susceptible to high-salient stimuli - task-irrelevant external information - showed increased dACC rsFC toward precuneus. This is consistent with prior work in individuals with impaired attentional focus. Future studies might help to conclude whether an increased rsFC between a SN region and DMN region may serve as a predictor for clinical syndromes characterized by attentional impairments, e.g. ADHD. This could lead to an alternative, objective diagnosis and treatment of such disorders by decreasing the rsFC of these regions.

Richness in Functional Connectivity Depends on the Neuronal Integrity within the Posterior Cingulate Cortex.

The brain's connectivity skeleton-a rich club of strongly interconnected members-was initially shown to exist in human structural networks, but recent evidence suggests a functional counterpart. This rich club typically includes key regions (or hubs) from multiple canonical networks, reducing the cost of inter-network communication. The posterior cingulate cortex (PCC), a hub node embedded within the default mode network, is known to facilitate communication between brain networks and is a key member of the "rich club." Here, we assessed how metabolic signatures of neuronal integrity and cortical thickness influence the global extent of a functional rich club as measured using the functional rich club coefficient (fRCC). Rich club estimation was performed on functional connectivity of resting state brain signals acquired at 3T in 48 healthy adult subjects. Magnetic resonance spectroscopy was measured in the same session using a point resolved spectroscopy sequence. We confirmed convergence of functional rich club with a previously established structural rich club. N-acetyl aspartate (NAA) in the PCC is significantly correlated with age (p = 0.001), while the rich club coefficient showed no effect of age (p = 0.106). In addition, we found a significant quadratic relationship between fRCC and NAA concentration in PCC (p = 0.009). Furthermore, cortical thinning in the PCC was correlated with a reduced rich club coefficient after accounting for age and NAA. In conclusion, we found that the fRCC is related to a marker of neuronal integrity in a key region of the cingulate cortex. Furthermore, cortical thinning in the same area was observed, suggesting that both cortical thinning and neuronal integrity in the hub regions influence functional integration of at a whole brain level.

Emotional valence and spatial congruency differentially modulate crossmodal processing: an fMRI study.

Salient exogenous stimuli modulate attentional processes and lead to attention shifts-even across modalities and at a pre-attentive level. Stimulus properties such as hemispheric laterality and emotional valence influence processing, but their specific interaction in audio-visual attention paradigms remains ambiguous. We conducted an fMRI experiment to investigate the interaction of supramodal spatial congruency, emotional salience, and stimulus presentation side on neural processes of attention modulation. Emotionally neutral auditory deviants were presented in a dichotic listening oddball design. Simultaneously, visual target stimuli (schematic faces) were presented, which displayed either a negative or a positive emotion. These targets were presented in the left or in the right visual field and were either spatially congruent (valid) or incongruent (invalid) with the concurrent deviant auditory stimuli. According to our expectation we observed that deviant stimuli serve as attention-directing cues for visual target stimuli. Region-of-interest (ROI) analyses suggested differential effects of stimulus valence and spatial presentation on the hemodynamic response in bilateral auditory cortices. These results underline the importance of valence and presentation side for attention guidance by deviant sound events and may hint at a hemispheric specialization for valence and attention processing.

On the connection between level of education and the neural circuitry of emotion perception.

Through education, a social group transmits accumulated knowledge, skills, customs, and values to its members. So far, to the best of our knowledge, the association between educational attainment and neural correlates of emotion processing has been left unexplored. In a retrospective analysis of The Netherlands Study of Depression and Anxiety (NESDA) functional magnetic resonance imaging (fMRI) study, we compared two groups of fourteen healthy volunteers with intermediate and high educational attainment, matched for age and gender. The data concerned event-related fMRI of brain activation during perception of facial emotional expressions. The region of interest (ROI) analysis showed stronger right amygdala activation to facial expressions in participants with lower relative to higher educational attainment (HE). The psychophysiological interaction analysis revealed that participants with HE exhibited stronger right amygdala-right insula connectivity during perception of emotional and neutral facial expressions. This exploratory study suggests the relevance of educational attainment on the neural mechanism of facial expressions processing.

Does valence in the visual domain influence the spatial attention after auditory deviants? Exploratory data.

The auditory mismatch responses are elicited in absence of directed attention but are thought to reflect attention modulating effects. Little is known however, if the deviants in a stream of standards are specifically directing attention across modalities and how they interact with other attention directing signals such as emotions. We applied the well-established paradigm of left- or right-lateralized deviant syllables within a dichotic listening design. In a simple target detection paradigm with lateralized visual stimuli, we hypothesized that responses to visual stimuli would be speeded after ignored auditory deviants on the same side. Moreover, stimuli with negative valence in the visual domain could be expected to reduce this effect due to attention capture for this emotion, resulting in speeded responses to visual stimuli even when attention was directed to the opposite side by the auditory deviant beforehand. Reaction times of 17 subjects confirmed the speeding of responses after deviant events. However, reduced facilitation was observed for positive targets at the left after incongruent deviants, i.e., at the right ear. In particular, significant interactions of valence and visual field and of valence and spatial congruency emerged. Pre-attentive auditory processing may modulate attention in a spatially selective way. However, negative valence processing in the right hemisphere may override this effect. Resource allocation such as spatial attention is regulated dynamically by multimodal and emotion information processing.

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.

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.

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.

Mood modulates auditory laterality of hemodynamic mismatch responses during dichotic listening.

Hemodynamic mismatch responses can be elicited by deviant stimuli in a sequence of standard stimuli even during cognitive demanding tasks. Emotional context is known to modulate lateralized processing. Right-hemispheric negative emotion processing may bias attention to the right and enhance processing of right-ear stimuli. The present study examined the influence of induced mood on lateralized pre-attentive auditory processing of dichotic stimuli using functional magnetic resonance imaging (fMRI). Faces expressing emotions (sad/happy/neutral) were presented in a blocked design while a dichotic oddball sequence with consonant-vowel (CV) syllables in an event-related design was simultaneously administered. Twenty healthy participants were instructed to feel the emotion perceived on the images and to ignore the syllables. Deviant sounds reliably activated bilateral auditory cortices and confirmed attention effects by modulation of visual activity. Sad mood induction activated visual, limbic and right prefrontal areas. A lateralization effect of emotion-attention interaction was reflected in a stronger response to right-ear deviants in the right auditory cortex during sad mood. This imbalance of resources may be a neurophysiological correlate of laterality in sad mood and depression. Conceivably, the compensatory right-hemispheric enhancement of resources elicits increased ipsilateral processing.

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.

Impaired attribution of emotion to facial expressions in anxiety and major depression.

BACKGROUND: Recognition of others' emotions is an important aspect of interpersonal communication. In major depression, a significant emotion recognition impairment has been reported. It remains unclear whether the ability to recognize emotion from facial expressions is also impaired in anxiety disorders. There is a need to review and integrate the published literature on emotional expression recognition in anxiety disorders and major depression. METHODOLOGY/PRINCIPAL FINDINGS: A detailed literature search was used to identify studies on explicit emotion recognition in patients with anxiety disorders and major depression compared to healthy participants. Eighteen studies provided sufficient information to be included. The differences on emotion recognition impairment between patients and controls (Cohen's d) with corresponding confidence intervals were computed for each study. Over all studies, adults with anxiety disorders had a significant impairment in emotion recognition (d = -0.35). In children with anxiety disorders no significant impairment of emotion recognition was found (d = -0.03). Major depression was associated with an even larger impairment in recognition of facial expressions of emotion (d = -0.58). CONCLUSIONS/SIGNIFICANCE: Results from the current analysis support the hypothesis that adults with anxiety disorders or major depression both have a deficit in recognizing facial expression of emotions, and that this deficit is more pronounced in major depression than in anxiety.

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.