Dorsal Anterior Cingulate Research Articles

Cortical brain volume abnormalities associated with few or multiple neuropsychiatric symptoms in Alzheimer's disease.

New research on assessing neuropsychiatric manifestations of Alzheimer´s Disease (AD) involves grouping neuropsychiatric symptoms into syndromes. Yet this approach is limited by high inter-subject variability in neuropsychiatric symptoms and a relatively low degree of concordance across studies attempting to cluster neuropsychiatric symptoms into syndromes. An alternative strategy that involves dichotomizing AD subjects into those with few versus multiple neuropsychiatric symptoms is both consonant with real-world clinical practice and can contribute to understanding neurobiological underpinnings of neuropsychiatric symptoms in AD patients. The aim of this study was to address whether the number of neuropsychiatric symptoms (i.e., presence of few [≤2] versus multiple [≥3] symptoms) in AD would be associated with degree of significant gray matter (GM) volume loss. Of particular interest was volume loss in brain regions involved in memory, emotional processing and salience brain networks, including the prefrontal, lateral temporal and parietal cortices, anterior cingulate gyrus, temporo-limbic structures and insula. We recruited 19 AD patients and 13 healthy controls, which underwent an MRI and neuropsychiatric assessment. Regional brain volumes were determined using voxel-based morphometry and other advanced imaging processing methods. Our results indicated the presence of different patterns of GM atrophy in the two AD subgroups relative to healthy controls. AD patients with multiple neuropsychiatric manifestations showed more evident GM atrophy in the left superior temporal gyrus and insula as compared with healthy controls. In contrast, AD subjects with few neuropsychiatric symptoms displayed more GM atrophy in prefrontal regions, as well as in the dorsal anterior cingulate ad post-central gyri, as compared with healthy controls. Our findings suggest that the presence of multiple neuropsychiatric symptoms is more related to the degree of atrophy in specific brain networks rather than dependent on the global severity of widespread neurodegenerative brain changes.

Decoding “us” and “them”: Neural representations of generalized group concepts.

Humans form social coalitions in every society on earth, yet we know very little about how the general concepts us and them are represented in the brain. Evolutionary psychologists have argued that the human capacity for group affiliation is a byproduct of adaptations that evolved for tracking coalitions in general. These theories suggest that humans possess a common neural code for the concepts in-group and out-group, regardless of the category by which group boundaries are instantiated. The authors used multivoxel pattern analysis to identify the neural substrates of generalized group concept representations. They trained a classifier to encode how people represented the most basic instantiation of a specific social group (i.e., arbitrary teams created in the lab with no history of interaction or associated stereotypes) and tested how well the neural data decoded membership along an objectively orthogonal, real-world category (i.e., political parties). The dorsal anterior cingulate cortex/middle cingulate cortex and anterior insula were associated with representing groups across multiple social categories. Restricting the analyses to these regions in a separate sample of participants performing an explicit categorization task, the authors replicated cross-categorization classification in anterior insula. Classification accuracy across categories was driven predominantly by the correct categorization of in-group targets, consistent with theories indicating in-group preference is more central than out-group derogation to group perception and cognition. These findings highlight the extent to which social group concepts rely on domain-general circuitry associated with encoding stimuli's functional significance. (PsycINFO Database Record

482. Reduced Medial Prefrontal Functional Connectivity with Dorsal Anterior Cingulate Predicts Rumination and Negativity Bias in Late-Life Depression

482. Reduced Medial Prefrontal Functional Connectivity with Dorsal Anterior Cingulate Predicts Rumination and Negativity Bias in Late-Life Depression

The effect of regulatory mode on procrastination: Bi-stable parahippocampus connectivity with dorsal anterior cingulate and anterior prefrontal cortex

Previous research has elucidated that procrastination can be influenced by regulatory mode orientations. However, the neural mechanism of regulatory modes affecting procrastination is not well understood. To address this question, we employed resting-state functional magnetic resonance imaging (RS-fMRI) to test the influence of two regulatory modes (assessment and locomotion) on procrastination. The behavioral results showed that procrastination was positively correlated with assessment orientation but negatively correlated with locomotion orientation. Neuroimaging results indicated that the functional connectivity between parahippocampal cortex (PHC) and dorsal anterior cingulate (dACC) was negatively correlated with assessment scores, while the functional connectivity between anterior prefrontal cortex (aPFC) and parahippocampal cortex (PHC) was negatively correlated with locomotion scores. Critically, mediation analysis showed that the different effects of two distinct regulatory modes on procrastination were mediated by PHC-dACC and aPFC-PHC functional connectivity respectively. These results suggested that people’s procrastination could be predicted by regulatory mode orientations, which is mediated by PHC connectivity with dACC and aPFC respectively. The present study extends our knowledge on procrastination and provides neural mechanism for understanding the link between regulatory mode orientations and procrastination.

Infant avoidance training alters cellular activation patterns in prefronto-limbic circuits during adult avoidance learning: I. Cellular imaging of neurons expressing the synaptic plasticity early growth response protein 1 (Egr1).

Both positive feedback learning and negative feedback learning are essential for adapting and optimizing behavioral performance. There is increasing evidence in humans and animals that the ability of negative feedback learning emerges postnatally. Our work in rats, using a two-way active avoidance task (TWA) as an experimental paradigm for negative feedback learning, revealed that medial and lateral prefrontal regions of infant rats undergo dramatic synaptic reorganization during avoidance training, resulting in improved avoidance learning in adulthood. The aim of this study was to identify changes of cellular activation patterns during the course of training and in relation to infant pretraining. We applied a quantitative cellular imaging technique using the immunocytochemical detection of the activity marker early growth response protein 1 (Egr1) as a candidate contributing to learning-induced synaptic plasticity. We found region-specific cellular activity patterns, which indicate that during the acquisition phase, Egr1 expression is specifically elevated in cellular ensembles of the orbitofrontal, dorsal anterior cingulate and hippocampal CA1 region. During memory retrieval Egr1 expression is elevated in cellular ensembles of the dentate gyrus. Moreover, we, for the first time, show here that TWA training during infancy alters adult learning- and memory-related patterns of Egr1 expression in these brain regions. It is tempting to speculate that during infant learning, specific Egr1-expressing cellular ensembles are "tagged" representing long-term memory formation, and that these cell ensembles may be reactivated during adult learning.

Strategic Motives Drive Proposers to Offer Fairly in Ultimatum Games: An fMRI Study

The hypothesis of strategic motives postulates that offering fairly in the Ultimatum Game (UG) is to avoid rejection and receive money. In this fMRI study, we used a modified UG to elucidate how proposers reached decisions of offering fairly and to what extent they considered offering selfishly with different stakes. We had proposers choose between a fair and a selfish offer with different degrees of selfishness and stake sizes. Proposers were less likely and spent more time choosing the fair offer over a slightly-selfish offer than a very selfish offer independent of stakes. Such choices evoked greater activation in the dorsal anterior cingulate cortices that typically involve in allocation of cognitive control for cost/benefit decision making. Choosing a fair offer in higher stakes evoked greater activation in the anterior cingulate gyrus (ACCg) and the areas that previously have been implicated in reward and theory of mind. Furthermore, choosing a slightly selfish offer over a fair offer evoked greater activation in the anterior cingulate sulcus, ACCg, ventral tegmental area (or substantia nigra) and anterior insular cortex signalling the higher gain and implying higher rejection risk. In conclusion, our findings favoured the hypothesis that proposers offer fairly based on the strategic motives.

Quantitative representations of an exaggerated anxiety response in the brain of female spider phobics-a parametric fMRI study.

We employed a novel parametric spider picture set in the context of a parametric fMRI anxiety provocation study, designed to tease apart brain regions involved in threat monitoring from regions representing an exaggerated anxiety response in spider phobics. For the stimulus set, we systematically manipulated perceived proximity of threat by varying a depicted spider's context, size, and posture. All stimuli were validated in a behavioral rating study (phobics n = 20; controls n = 20; all female). An independent group participated in a subsequent fMRI anxiety provocation study (phobics n = 7; controls n = 7; all female), in which we compared a whole-brain categorical to a whole-brain parametric analysis. Results demonstrated that the parametric analysis provided a richer characterization of the functional role of the involved brain networks. In three brain regions-the mid insula, the dorsal anterior cingulate, and the ventrolateral prefrontal cortex-activation was linearly modulated by perceived proximity specifically in the spider phobia group, indicating a quantitative representation of an exaggerated anxiety response. In other regions (e.g., the amygdala), activation was linearly modulated in both groups, suggesting a functional role in threat monitoring. Prefrontal regions, such as dorsolateral prefrontal cortex, were activated during anxiety provocation but did not show a stimulus-dependent linear modulation in either group. The results confirm that brain regions involved in anxiety processing hold a quantitative representation of a pathological anxiety response and more generally suggest that parametric fMRI designs may be a very powerful tool for clinical research in the future, particularly when developing novel brain-based interventions (e.g., neurofeedback training). Hum Brain Mapp 38:3025-3038, 2017. © 2017 Wiley Periodicals, Inc.

Salience network engagement with the detection of morally laden information.

Moral cognition is associated with activation of the default network, regions implicated in mentalizing about one’s own actions or the intentions of others. Yet little is known about the initial detection of moral information. We examined the neural correlates of moral processing during a narrative completion task, which included an implicit moral salience manipulation. During fMRI scanning, participants read a brief vignette and selected the most semantically congruent sentence from two options to complete the narrative. The options were immoral, moral or neutral statements. RT was fastest for the selection of neutral statements and slowest for immoral statements. Neuroimaging analyses revealed that responses involving morally laden content engaged default and executive control network brain regions including medial and rostral prefrontal cortex, and core regions of the salience network, including anterior insula and dorsal anterior cingulate. Immoral vs moral conditions additionally engaged the salience network. These results implicate the salience network in the detection of moral information, which may modulate downstream default and frontal control network interactions in the service of complex moral reasoning and decision-making processes. These findings suggest that moral cognition involves both bottom-up and top-down attentional processes, mediated by discrete large-scale brain networks and their interactions.

Potentiation of motor sub-networks for motor control but not working memory: Interaction of dACC and SMA revealed by resting-state directed functional connectivity.

The dorsal Anterior Cingulate Cortex (dACC) and the Supplementary Motor Area (SMA) are known to interact during motor coordination behavior. We previously discovered that the directional influences underlying this interaction in a visuo-motor coordination task are asymmetric, with the dACC→SMA influence being significantly greater than that in the reverse direction. To assess the specificity of this effect, here we undertook an analysis of the interaction between dACC and SMA in two distinct contexts. In addition to the motor coordination task, we also assessed these effects during a (n-back) working memory task. We applied directed functional connectivity analysis to these two task paradigms, and also to the rest condition of each paradigm, in which rest blocks were interspersed with task blocks. We report here that the previously known asymmetric interaction between dACC and SMA, with dACC→SMA dominating, was significantly larger in the motor coordination task than the memory task. Moreover the asymmetry between dACC and SMA was reversed during the rest condition of the motor coordination task, but not of the working memory task. In sum, the dACC→SMA influence was significantly greater in the motor task than the memory task condition, and the SMA→dACC influence was significantly greater in the motor rest than the memory rest condition. We interpret these results as suggesting that the potentiation of motor sub-networks during the motor rest condition supports the motor control of SMA by dACC during the active motor task condition.

Neural basis of impaired safety signaling in Obsessive Compulsive Disorder

The ability to assign safety to stimuli in the environment is integral to everyday functioning. A key brain region for this evaluation is the ventromedial prefrontal cortex (vmPFC). To investigate the importance of vmPFC safety signaling, we used neuroimaging of Pavlovian fear reversal, a paradigm that involves flexible updating when the contingencies for a threatening (CS+) and safe (CS-) stimulus reverse, in a prototypical disorder of inflexible behavior influenced by anxiety, Obsessive Compulsive Disorder (OCD). Skin conductance responses in OCD patients (n = 43) failed to differentiate during reversal compared with healthy controls (n = 35), although significant differentiation did occur during early conditioning and amygdala BOLD signaling was unaffected in these patients. Increased vmPFC activation (for CS+ > CS-) during early conditioning predicted the degree of generalization in OCD patients during reversal, whereas vmPFC safety signals were absent throughout learning in these patients. Regions of the salience network (dorsal anterior cingulate, insula, and thalamus) showed early learning task-related hyperconnectivity with the vmPFC in OCD, consistent with biased processing of the CS+. Our findings reveal an absence of vmPFC safety signaling in OCD, undermining flexible threat updating and explicit contingency knowledge. Although differential threat learning can occur to some extent in the absence of vmPFC safety signals, effective CS- signaling becomes crucial during conflicting threat and safety cues. These results promote further investigation of vmPFC safety signaling in other anxiety disorders, with potential implications for the development of exposure-based therapies, in which safety signaling is likely to play a key role.

The role of emotional inhibitory control in specific internet addiction – an fMRI study

BackgroundAddicts to specific internet applications involving communication features showed increased social anxiety, emotional competence deficits and impaired prefrontal-related inhibitory control. The dorsal Anterior Cingulate Cortex (dACC) likely plays an important role in cognitive control and negative affect (such as social exclusion, pain or anxiety). AimTo assess (social) anxiety-related inhibitory control in specific internet addiction (addicted use of games and social networks) and its relation to altered dACC activation. MethodsN=44 controls and n=51 specific internet addicts completed an anxious words-based Affective Go/No-Go task (AGN). A subsample of n=23 healthy controls and n=25 specific internet addicts underwent functional Magnetic Resonance Imaging (fMRI) while completing an Emotional Stroop Task (EST) with socially anxious, positive, negative and neutral words. Subgroups of internet gaming and social network addicts were exploratively assessed. Psychometric measures of social anxiety, emotional competence and impulsivity were additionally explored. ResultsSpecific internet addicts showed higher impulsivity, social anxiety and reduced emotional competence. Between-group differences in AGN and EST behavioral measures were not detected. No group differences were found in the dACC, but explorative analyses revealed decreased left middle and superior temporal gyrus activation during interference of socially anxious words in internet gaming and relative to social network addicts. ConclusionGiven the function of the left middle temporal gyrus in the retrieval of words or expressions during communication, our findings give a first hint that social words might be less retrievable in the semantic storage of internet gaming addicts, possibly indicating deficiencies in handling speech in social situations.

Association between neural reactivity and startle reactivity to uncertain threat in two independent samples.

Prior studies indicate that anxiety disorders are associated with heightened sensitivity to uncertain threat (U threat). Individual differences in reactivity to U threat have been measured in the laboratory with two methodologies-startle eyeblink potentiation and fMRI. While startle and fMRI are purported to relate to each other, very little research exists on whether individual differences in one measure are associated with individual differences in another and, thus, whether startle and fMRI capture shared mechanisms. Therefore, the current study was designed to investigate if and where in the brain measures of startle potentiation and fMRI BOLD signal correlate during response to U threat across two independent samples. Participants in both studies completed two threat anticipation tasks-once during collection of startle potentiation and once during fMRI. In Study 1 (n = 43), the startle and fMRI tasks both used electric shock as the threat. As an extension, in Study 2 (n = 38), the startle task used electric shock but the fMRI task used aversive images. Despite these methodological differences, greater startle potentiation to U threat was associated with greater dorsal anterior cingulate, caudate, and orbitofrontal cortex reactivity to U threat in both samples. The findings suggest that startle and fMRI measures of responding to U threat overlap, and points toward an integrated brain-behavior profile of aberrant U threat responding.

Intranasal oxytocin, but not vasopressin, augments neural responses to toddlers in human fathers

This study investigates paternal brain function with the hope of better understanding the neural basis for variation in caregiving involvement among men. The neuropeptides oxytocin (OT) and vasopressin (AVP) are implicated in paternal caregiving in humans and other species. In a double-blind, placebo-controlled, within-subject pharmaco-functional MRI experiment, we randomized 30 fathers of 1–2year old children to receive either 24IU intranasal OT before one scan and placebo before the other scan (n=15) or 20IU intranasal AVP before one scan and placebo before the other scan (n=15). Brain function was measured with fMRI as the fathers viewed pictures of their children, unknown children and unknown adults, and as they listened to unknown infant cry stimuli. Intranasal OT, but not AVP, significantly increased the BOLD fMRI response to viewing pictures of own children within the caudate nucleus, a target of midbrain dopamine projections, as well as the dorsal anterior cingulate (dACC) and visual cortex, suggesting that intranasal oxytocin augments activation in brain regions involved in reward, empathy and attention in human fathers. OT effects also varied as a function of order of administration such that when OT was given before placebo, it increased activation within several reward-related structures (substantia nigra, ventral tegmental area, putamen) more than when it was given after placebo. Neither OT nor AVP had significant main effects on the neural response to cries. Our findings suggest that the hormonal changes associated with the transition to fatherhood are likely to facilitate increased approach motivation and empathy for children, and call for future research that evaluates the potential of OT to normalize deficits in paternal motivation, as might be found among men suffering from post-partum depression.

Gray‐matter relationships to diagnostic and transdiagnostic features of drug and behavioral addictions

Alterations in neural structure have been reported in both cocaine-use disorder and gambling disorder, separately, suggesting similarities across addiction diagnoses. Individual variation in neural structure has also been associated with impulsivity, a dimensional construct implicated in addictions. This study combines categorical (diagnosis-based) and dimensional (transdiagnostic) approaches to identify neural structural alterations linked to addiction subtypes and trait impulsivity, respectively, across individuals with gambling disorder (n=35), individuals with cocaine-use disorder (n=37) and healthy comparison individuals (n=37). High-resolution T1-weighted data were analyzed using modulated voxel-based morphometry (VBM). Statistical analyses were conducted using whole-brain general-linear models, corrected for family-wise error (pFWE<.05). Categorical analyses indicated a main effect of diagnostic group on prefrontal (dorsal anterior cingulate and ventromedial prefrontal cortex) gray matter volumes (GMVs), involving decreased GMVs among cocaine-use disorder participants only. Dimensional analyses indicated a negative association between trait impulsivity and cortical (insula) and subcortical (amygdala and hippocampus) GMVs across all participants. Conjunction analysis indicated little anatomical overlap between regions identified as differentiating diagnostic groups and regions covarying with impulsivity. These data provide first evidence of neural structural differences between gambling disorder and an illicit substance-use disorder. They further indicate dissociable effects of diagnostic groupings and trait impulsivity on neural structure among individuals with behavioral and drug addictions. Study findings highlight the importance of considering both categorical and dimensional (e.g. Research Domain Criteria; RDoC) analysis approaches within the context of addictions research.

Multidimensional prediction of treatment response to antidepressants with cognitive control and functional MRI.

Predicting treatment response for major depressive disorder can provide a tremendous benefit for our overstretched health care system by reducing number of treatments and time to remission, thereby decreasing morbidity. The present study used neural and performance predictors during a cognitive control task to predict treatment response (% change in Hamilton Depression Rating Scale pre- to post-treatment). Forty-nine individuals diagnosed with major depressive disorder were enrolled with intent to treat in the open-label study; 36 completed treatment, had useable data, and were included in most data analyses. Participants included in the data analysis sample received treatment with escitalopram (n = 22) or duloxetine (n = 14) for 10 weeks. Functional MRI and performance during a Parametric Go/No-go test were used to predict per cent reduction in Hamilton Depression Rating Scale scores after treatment. Haemodynamic response function-based contrasts and task-related independent components analysis (subset of sample: n = 29) were predictors. Independent components analysis component beta weights and haemodynamic response function modelling activation during Commission errors in the rostral and dorsal anterior cingulate, mid-cingulate, dorsomedial prefrontal cortex, and lateral orbital frontal cortex predicted treatment response. In addition, more commission errors on the task predicted better treatment response. Together in a regression model, independent component analysis, haemodynamic response function-modelled, and performance measures predicted treatment response with 90% accuracy (compared to 74% accuracy with clinical features alone), with 84% accuracy in 5-fold, leave-one-out cross-validation. Convergence between performance markers and functional magnetic resonance imaging, including novel independent component analysis techniques, achieved high accuracy in prediction of treatment response for major depressive disorder. The strong link to a task paradigm provided by use of independent component analysis is a potential breakthrough that can inform ways in which prediction models can be integrated for use in clinical and experimental medicine studies.

Correlation between Traits of Emotion-Based Impulsivity and Intrinsic Default-Mode Network Activity.

Negative urgency (NU) and positive urgency (PU) are implicated in several high-risk behaviors, such as eating disorders, substance use disorders, and nonsuicidal self-injury behavior. The current study aimed to explore the possible link between trait of urgency and brain activity at rest. We assessed the amplitude of low-frequency fluctuations (ALFF) of the resting-state functional magnetic resonance imaging (fMRI) signal in 85 healthy volunteers. Trait urgency measures were related to ALFF in the lateral orbitofrontal cortex, dorsolateral prefrontal cortex, ventral and dorsal medial frontal cortex, anterior cingulate, and posterior cingulate cortex/precuneus. In addition, trait urgency measures showed significant correlations with the functional connectivity of the posterior cingulate cortex/precuneus seed with the thalamus and midbrain region. These findings suggest an association between intrinsic brain activity and impulsive behaviors in healthy humans.

Intrinsic inter-network brain dysfunction correlates with symptom dimensions in late-life depression

Prior studies have demonstrated dysfunctions within the core neurocognitive networks (the executive control [ECN], default mode [DMN] and salience [SN] networks) in late-life depression (LLD). Whether inter-network dysfunctional connectivity is present in LLD, and if such disruptions are associated with core symptom dimensions is unknown. A cross-sectional resting-state functional connectivity magnetic resonance imaging investigation was conducted of LLD (n = 39) and age- and gender-equated healthy comparison (HC) (n = 29) participants. Dual regression independent component analysis approach was used to identify components that represented the ECN, DMN and SN. The intrinsic inter-network connectivity was compared between LLD and HC participants and the relationship of inter-network connectivity abnormalities with dimensional measures was examined. Relative to HC participants, LLD subjects showed decreased inter-network connectivity between the bilateral ECN and default mode subcortical (thalamus, basal ganglia and ventral striatum) networks, and the left ECN and SN insula component; and increased inter-network connections between the left ECN and posterior DMN and salience (dorsal anterior cingulate) network components. Distinct inter-network connectivity abnormalities correlated with depression and anxiety severity, and executive dysfunction in LLD participants. LLD subjects also showed pronounced intra-network connectivity differences within the ECN, whereas fewer but significant DMN and SN disruptions were also detected. Investigating the intrinsic inter-network functional connectivity could provide a mechanistic framework to better understand the neural basis that underlies core symptom dimensions in LLD. Inter-network connectivity measures have the potential to be neuroimaging biomarkers of symptom dimensions comprising LLD, and may assist in developing symptom-specific treatment algorithms.

Neural activations are related to body-shape, anxiety, and outcomes in adolescent anorexia nervosa

Anorexia nervosa (AN) is an illness that frequently begins during adolescence and involves weight loss. Two groups of adolescent girls (AN-A, weight-recovered following AN) and (HC-A, healthy comparison) completed a functional magnetic resonance imaging task involving social evaluations, allowing comparison of neural activations during self-evaluations, friend-evaluations, and perspective-taking self-evaluations. Although the two groups were not different in their whole-brain activations, anxiety and body shape concerns were correlated with neural activity in a priori regions of interest. A cluster in medial prefrontal cortex and the dorsal anterior cingulate correlated with the body shape questionnaire; subjects with more body shape concerns used this area less during self than friend evaluations. A cluster in medial prefrontal cortex and the cingulate also correlated with anxiety such that more anxiety was associated with engagement when disagreeing rather than agreeing with social terms during self-evaluations. This data suggests that differences in the utilization of frontal brain regions during social evaluations may contribute to both anxiety and body shape concerns in adolescents with AN. Clinical follow-up was obtained, allowing exploration of whether brain function early in course of disease relates to illness trajectory. The adolescents successful in recovery used the posterior cingulate and precuneus more for friend than self evaluations than the adolescents that remained ill, suggesting that neural differences related to social evaluations may provide clinical predictive value. Utilization of both MPFC and the precuneus during social and self evaluations may be a key biological component for achieving sustained weight-recovery in adolescents with AN.

Neonatal Amygdala Functional Connectivity at Rest in Healthy and Preterm Infants and Early Internalizing Symptoms

Alterations in the normal developmental trajectory of amygdala resting state functional connectivity (rs-FC) have been associated with atypical emotional processes and psychopathology. Little is known, however, regarding amygdala rs-FC at birth or its relevance to outcomes. This study examined amygdala rs-FC in healthy, full-term (FT) infants and in very preterm (VPT) infants, and tested whether variability of neonatal amygdala rs-FC predicted internalizing symptoms at age 2years. Resting state fMRI data were obtained shortly after birth from 65 FT infants (gestational age [GA] ≥36weeks) and 57 VPT infants (GA<30 weeks) at term equivalent. Voxelwise correlation analyses were performed using individual-specific bilateral amygdala regions of interest. Total internalizing symptoms and the behavioral inhibition, depression/withdrawal, general anxiety, and separation distress subdomains were assessed in a subset (n= 44) at age 2 years using the Infant Toddler Social Emotional Assessment. In FT and VPT infants, the amygdala demonstrated positive correlations with subcortical and limbic structures and negative correlations with cortical regions, although magnitudes were decreased in VPT infants. Neonatal amygdala rs-FC predicted internalizing symptoms at age 2 years with regional specificity consistent with known pathophysiology in older populations: connectivity with the anterior insula related to depressive symptoms, with the dorsal anterior cingulate related to generalized anxiety, and with the medial prefrontal cortex related to behavioral inhibition. Amygdala rs-FC is well established in neonates. Variability in regional neonatal amygdala rs-FC predicted internalizing symptoms at 2 years, suggesting that risk for internalizing symptoms may be established in neonatal amygdala functional connectivity patterns.

Early changes in emotional processing as a marker of clinical response to SSRI treatment in depression.

Antidepressant treatment reduces behavioural and neural markers of negative emotional bias early in treatment and has been proposed as a mechanism of antidepressant drug action. Here, we provide a critical test of this hypothesis by assessing whether neural markers of early emotional processing changes predict later clinical response in depression. Thirty-five unmedicated patients with major depression took the selective serotonin re-uptake inhibitor (SSRI), escitalopram (10 mg), over 6 weeks, and were classified as responders (22 patients) versus non-responders (13 patients), based on at least a 50% reduction in symptoms by the end of treatment. The neural response to fearful and happy emotional facial expressions was assessed before and after 7 days of treatment using functional magnetic resonance imaging. Changes in the neural response to these facial cues after 7 days of escitalopram were compared in patients as a function of later clinical response. A sample of healthy controls was also assessed. At baseline, depressed patients showed greater activation to fear versus happy faces than controls in the insula and dorsal anterior cingulate. Depressed patients who went on to respond to the SSRI had a greater reduction in neural activity to fearful versus happy facial expressions after just 7 days of escitalopram across a network of regions including the anterior cingulate, insula, amygdala and thalamus. Mediation analysis confirmed that the direct effect of neural change on symptom response was not mediated by initial changes in depressive symptoms. These results support the hypothesis that early changes in emotional processing with antidepressant treatment are the basis of later clinical improvement. As such, early correction of negative bias may be a key mechanism of antidepressant drug action and a potentially useful predictor of therapeutic response.