Specifying the Neurobiological Basis of Human Attachment: Brain,Hormones, and Behavior in Synchronous and Intrusive Mothers

The mother–infant bond provides the foundation for the infant''s future mental health and adaptation and depends on the provision of species-typical maternal behaviors that are supported by neuroendocrine and motivation-affective neural systems. Animal research has demonstrated that natural variations in patterns of maternal care chart discrete profiles of maternal brain–behavior relationships that uniquely shape the infant''s lifetime capacities for stress regulation and social affiliation. Such patterns of maternal care are mediated by the neuropeptide Oxytocin and by stress- and reward-related neural systems. Human studies have similarly shown that maternal synchrony—the coordination of maternal behavior with infant signals—and intrusiveness—the excessive expression of maternal behavior—describe distinct and stable maternal styles that bear long-term consequences for infant well-being. To integrate brain, hormones, and behavior in the study of maternal–infant bonding, we examined the fMRI responses of synchronous vs intrusive mothers to dynamic, ecologically valid infant videos and their correlations with plasma Oxytocin. In all, 23 mothers were videotaped at home interacting with their infants and plasma OT assayed. Sessions were micro-coded for synchrony and intrusiveness. Mothers were scanned while observing several own and standard infant-related vignettes. Synchronous mothers showed greater activations in the left nucleus accumbens (NAcc) and intrusive mothers exhibited higher activations in the right amygdala. Functional connectivity analysis revealed that among synchronous mothers, left NAcc and right amygdala were functionally correlated with emotion modulation, theory-of-mind, and empathy networks. Among intrusive mothers, left NAcc and right amygdala were functionally correlated with pro-action areas. Sorting points into neighborhood (SPIN) analysis demonstrated that in the synchronous group, left NAcc and right amygdala activations showed clearer organization across time, whereas among intrusive mothers, activations of these nuclei exhibited greater cross-time disorganization. Correlations between Oxytocin with left NAcc and right amygdala activations were found only in the synchronous group. Well-adapted parenting appears to be underlay by reward-related motivational mechanisms, temporal organization, and affiliation hormones, whereas anxious parenting is likely mediated by stress-related mechanisms and greater neural disorganization. Assessing the integration of motivation and social networks into unified neural activity that reflects variations in patterns of parental care may prove useful for the study of optimal vs high-risk parenting.     

No Laughing Matter: Intranasal Oxytocin Administration Changes Functional Brain Connectivity during Exposure to Infant Laughter

Infant laughter is a rewarding experience. It activates neural reward circuits and promotes parental proximity and care, thus facilitating parent–infant attachment. The neuropeptide oxytocin might enhance the incentive salience of infant laughter by modulating neural circuits related to the perception of infant cues. In a randomized controlled trial with functional magnetic resonance imaging we investigated the influence of intranasally administered oxytocin on functional brain connectivity in response to infant laughter. Blood oxygenation level-dependent responses to infant laughter were measured in 22 nulliparous women who were administered oxytocin and 20 nulliparous women who were administered a placebo. Elevated oxytocin levels reduced activation in the amygdala during infant laughter and enhanced functional connectivity between the amygdala and the orbitofrontal cortex, the anterior cingulate, the hippocampus, the precuneus, the supramarginal gyri, and the middle temporal gyrus. Increased functional connectivity between the amygdala and regions involved in emotion regulation may reduce negative emotional arousal while enhancing the incentive salience of the infant laughter.     

DHEA Enhances Emotion Regulation Neurocircuits and Modulates Memory for Emotional Stimuli

Dehydroepiandrosterone (DHEA) is a neurosteroid with anxiolytic, antidepressant, and antiglucocorticoid properties. It is endogenously released in response to stress, and may reduce negative affect when administered exogenously. Although there have been multiple reports of DHEA''s antidepressant and anxiolytic effects, no research to date has examined the neural pathways involved. In particular, brain imaging has not been used to link neurosteroid effects to emotion neurocircuitry. To investigate the brain basis of DHEA''s impact on emotion modulation, patients were administered 400 mg of DHEA (N=14) or placebo (N=15) and underwent 3T fMRI while performing the shifted-attention emotion appraisal task (SEAT), a test of emotional processing and regulation. Compared with placebo, DHEA reduced activity in the amygdala and hippocampus, enhanced connectivity between the amygdala and hippocampus, and enhanced activity in the rACC. These activation changes were associated with reduced negative affect. DHEA reduced memory accuracy for emotional stimuli, and also reduced activity in regions associated with conjunctive memory encoding. These results demonstrate that DHEA reduces activity in regions associated with generation of negative emotion and enhances activity in regions linked to regulatory processes. Considering that activity in these regions is altered in mood and anxiety disorders, our results provide initial neuroimaging evidence that DHEA may be useful as a pharmacological intervention for these conditions and invite further investigation into the brain basis of neurosteroid emotion regulatory effects.     

Intergenerational Transmission of Stress in Humans

The hypothesis that offspring are affected by parental trauma or stress exposure, first noted anecdotally, is now supported empirically by data from Holocaust survivor offspring cohorts and other populations. These findings have been extended to less extreme forms of stress, where differential physical, behavioral, and cognitive outcomes are observed in affected offspring. Parental stress-mediated effects in offspring could be explained by genetics or social learning theory. Alternatively, biological variations stemming from stress exposure in parents could more directly have an impact on offspring, a concept we refer to here as ‘intergenerational transmission'', via changes to gametes and the gestational uterine environment. We further extend this definition to include the transmission of stress to offspring via early postnatal care, as animal studies demonstrate the importance of early maternal care of pups in affecting offsprings'' long-term behavioral changes. Here, we review clinical observations in offspring, noting that offspring of stress- or trauma-exposed parents may be at greater risk for physical, behavioral, and cognitive problems, as well as psychopathology. Furthermore, we review findings concerning offspring biological correlates of parental stress, in particular, offspring neuroendocrine, epigenetic, and neuroanatomical changes, in an attempt to determine the extent of parental stress effects. Although understanding the etiology of effects in offspring is currently impeded by methodological constraints, and limitations in our knowledge, we summarize current information and conclude by presenting hypotheses that have been prompted by recent studies in the field.     

The beneficial effect of oxytocin on avoidance-related facial emotion recognition depends on early life stress experience

Rationale

Previous studies have shown that oxytocin (OXT) enhances social cognitive processes. It has also been demonstrated that OXT does not uniformly facilitate social cognition. The effects of OXT administration strongly depend on the exposure to stressful experiences in early life. Emotional facial recognition is crucial for social cognition. However, no study has yet examined how the effects of OXT on the ability to identify emotional faces are altered by early life stress (ELS) experiences. Given the role of OXT in modulating social motivational processes, we specifically aimed to investigate its effects on the recognition of approach- and avoidance-related facial emotions.

Methods

In a double-blind, between-subjects, placebo-controlled design, 82 male participants performed an emotion recognition task with faces taken from the “Karolinska Directed Emotional Faces” set. We clustered the six basic emotions along the dimensions approach (happy, surprise, anger) and avoidance (fear, sadness, disgust). ELS was assessed with the Childhood Trauma Questionnaire (CTQ).

Results

Our results showed that OXT improved the ability to recognize avoidance-related emotional faces as compared to approach-related emotional faces. Whereas the performance for avoidance-related emotions in participants with higher ELS scores was comparable in both OXT and placebo condition, OXT enhanced emotion recognition in participants with lower ELS scores. Independent of OXT administration, we observed increased emotion recognition for avoidance-related faces in participants with high ELS scores.

Conclusions

Our findings suggest that the investigation of OXT on social recognition requires a broad approach that takes ELS experiences as well as motivational processes into account.     

Subjective and Neural Responses to Intravenous Alcohol in Young Adults with Light and Heavy Drinking Patterns

Heavy alcohol consumption during young adulthood is a risk factor for the development of serious alcohol use disorders. Research has shown that individual differences in subjective responses to alcohol may affect individuals'' vulnerability to developing alcoholism. Studies comparing the subjective and objective response to alcohol between light and heavy drinkers (HDs), however, have yielded inconsistent results, and neural responses to alcohol in these groups have not been characterized. We performed a double-blind, placebo-controlled, randomized crossover alcohol challenge study comparing functional magnetic resonance imaging and subjective response to intravenously administered 6% v/v ethanol to a target blood alcohol concentration of 0.08% or placebo between HDs and social drinkers (SDs). During the imaging, we presented emotional cues in order to measure how emotion modulated the effects of alcohol on the brain''s reward circuitry. We found that, at equivalent blood alcohol concentrations, HDs reported lower subjective alcohol effects than SDs. Alcohol significantly activated the nucleus accumbens in SDs, but not in HDs. Self-reported ratings of intoxication correlated with striatal activation, suggesting that activation may reflect subjective experience of intoxication. Fearful faces significantly activated the amygdala in the SDs only, and this activation was attenuated by alcohol. This study shows that HDs not only experience reduced subjective effects of alcohol, but also demonstrate a blunted response to alcohol in the brain''s reward system. Our findings indicate that reduced subjective and neural response to alcohol in HDs may be suggestive of either the development of tolerance to alcohol, or of pre-existing decreased sensitivity to alcohol''s effects.     

Toward Understanding How Early-Life Stress Reprograms Cognitive and Emotional Brain Networks

Vulnerability to emotional disorders including depression derives from interactions between genes and environment, especially during sensitive developmental periods. Adverse early-life experiences provoke the release and modify the expression of several stress mediators and neurotransmitters within specific brain regions. The interaction of these mediators with developing neurons and neuronal networks may lead to long-lasting structural and functional alterations associated with cognitive and emotional consequences. Although a vast body of work has linked quantitative and qualitative aspects of stress to adolescent and adult outcomes, a number of questions are unclear. What distinguishes ‘normal'' from pathologic or toxic stress? How are the effects of stress transformed into structural and functional changes in individual neurons and neuronal networks? Which ones are affected? We review these questions in the context of established and emerging studies. We introduce a novel concept regarding the origin of toxic early-life stress, stating that it may derive from specific patterns of environmental signals, especially those derived from the mother or caretaker. Fragmented and unpredictable patterns of maternal care behaviors induce a profound chronic stress. The aberrant patterns and rhythms of early-life sensory input might also directly and adversely influence the maturation of cognitive and emotional brain circuits, in analogy to visual and auditory brain systems. Thus, unpredictable, stress-provoking early-life experiences may influence adolescent cognitive and emotional outcomes by disrupting the maturation of the underlying brain networks. Comprehensive approaches and multiple levels of analysis are required to probe the protean consequences of early-life adversity on the developing brain. These involve integrated human and animal-model studies, and approaches ranging from in vivo imaging to novel neuroanatomical, molecular, epigenomic, and computational methodologies. Because early-life adversity is a powerful determinant of subsequent vulnerabilities to emotional and cognitive pathologies, understanding the underlying processes will have profound implications for the world''s current and future children.     

Early Adverse Experiences and the Developing Brain

Children exposed to various forms of adversity early in life are at increased risk for a broad range of developmental difficulties, affecting both cognitive and emotional adjustment. We review a growing body of evidence suggesting that exposure to adverse circumstances affects the developing brain in ways that increase risk for a myriad of problems. We focus on two forms of adversity, one in which children are exposed to childhood maltreatment in family environments, and another in which children are exposed to extreme psychosocial deprivation in contexts of institutional rearing. We discuss ways in which each of these experiences represent violations of species-expected caregiving conditions, thereby imposing challenges to the developing brain. We also review emerging data pointing to the effectiveness of early intervention in remediating neurodevelopmental consequences associated with maltreatment or institutional rearing. We conclude by discussing implications of this work for public health efforts and highlight important directions for the field.     

Impact of dopamine and cognitive impairment on neural reactivity to facial emotion in Parkinson's disease

Emotional and cognitive impairments in Parkinson's disease (PD) are prevalent, hamper interpersonal relations and reduce quality of life. It is however unclear to what extent these domains interplay in PD-related deficits and how they are influenced by dopaminergic availability. This study examined the effect of cognitive impairment and dopaminergic medication on neural and behavioral mechanisms of facial emotion recognition in PD patients. PD patients on and off dopaminergic medication and matched healthy controls underwent an emotional face matching task during functional MRI. In addition, a comprehensive neuropsychological evaluation of cognitive function was conducted. Increased BOLD response to emotional faces was found in the visual cortex of PD patients relative to controls irrespective of cognitive function and medication status. Administration of dopaminergic medication in PD patients resulted in restored behavioral accuracy for emotional faces relative to controls and decreased retrosplenial cortex BOLD response to emotion relative to off-medication state. Furthermore, cognitive impairment in PD patients was associated with reduced behavioral accuracy for non-emotional stimuli and predicted BOLD response to emotion in the anterior and posterior cingulate cortices, depending on medication status. Findings of aberrant visual and retrosplenial BOLD response to emotion are suggested to stem from altered attentional and/or emotion-driven modulation from subcortical and higher cortical regions. Our results indicate neural disruptions and behavioral deficits in emotion processing in PD patients that are dependent on dopaminergic availability and independent of cognitive function. Our findings highlight the importance of dopaminergic treatment not only for the motor symptoms but also the emotional disturbances in PD.     

Multiple trajectories of peer and parental influence and their association with the development of adolescent heavy drinking

This study used latent growth mixture modeling to identify discrete developmental patterns of heavy drinking, perceived parental disapproval of substance use, and association with peers who drink from early to late adolescence among a sample of 5591 youth. We also examined associations among these trajectories to determine how the development of heavy drinking relates to the development of perceived parental disapproval of substance use and association with peer drinkers, both separately and jointly. We found that youth who perceived that their parents maintained consistently strong disapproval of substance use throughout adolescence were much more likely to abstain from heavy drinking during this period than were youth who reported that their parents' disapproval for substance use either decreased or was maintained at only a moderate level. Furthermore, we found that across a variety of peer contexts—stable high association with drinking peers, stable low association, and increasing association—youth were at lowest risk for developing problematic patterns of heavy drinking when they perceived that their parents maintained strong disapproval of substance use throughout adolescence.     

Oxytocin Attenuates Neural Reactivity to Masked Threat Cues from the Eyes

The neuropeptide oxytocin has recently been shown to modulate covert attention shifts to emotional face cues and to improve discrimination of masked facial emotions. These results suggest that oxytocin modulates facial emotion processing at early perceptual stages prior to full evaluation of the emotional expression. Here, we used functional magnetic resonance imaging to examine whether oxytocin alters neural responses to backwardly masked angry and happy faces while controlling for attention to the eye vs the mouth region. Intranasal oxytocin administration reduced amygdala reactivity to masked emotions when attending to salient facial features, ie, the eyes of angry faces and the mouth of happy faces. In addition, oxytocin decreased neural responses within the fusiform gyrus and brain stem areas, as well as functional coupling between the amygdala and the fusiform gyrus specifically for threat cues from the eyes. Effects of oxytocin on brain activity were not attributable to differences in behavioral performance, as oxytocin had no impact on mere emotion detection. Our results suggest that oxytocin attenuates neural correlates of early arousal by threat signals from the eye region. As reduced threat sensitivity may increase the likelihood of engaging in social interactions, our findings may have important implications for clinical states of social anxiety.     

Effects of acute tryptophan depletion on neural processing of facial expressions of emotion in humans

Introduction

Acute tryptophan depletion (ATD) temporarily lowers brain serotonin (5-HT) synthesis, and behavioral studies have shown that this alters the processing of facial expressions of emotion.

Materials and methods

The neural basis for these alterations is not known. Therefore, we employed ATD and event-related functional magnetic resonance imaging (fMRI) to examine neural responses during incidental processing of fearful, happy, sad, and disgusted facial expressions. Fourteen healthy male controls (age, 28?±?10) were scanned under both placebo (SHAM) and depletion (ATD) conditions.

Results and discussion

We predicted that ATD would be associated with changes in neural activity within facial emotion-processing networks. We found that serotonergic modulation did not affect performance on the fMRI tasks, but was associated with widespread effects on neural response to components of face processing networks for fearful, disgusted, and happy but not sad expressions across differing intensities.

Conclusion

Hence, the 5-HT system affects brain function (in ‘limbic’ and ‘face processing’ regions) during incidental processing of emotional facial expressions; but this varies with emotion type and intensities.     

Childhood Trauma Exposure Disrupts the Automatic Regulation of Emotional Processing

Early-life trauma is one of the strongest risk factors for later emotional psychopathology. Although research in adults highlights that childhood trauma predicts deficits in emotion regulation that persist decades later, it is unknown whether neural and behavioral changes that may precipitate illness are evident during formative, developmental years. This study examined whether automatic regulation of emotional conflict is perturbed in a high-risk urban sample of trauma-exposed children and adolescents. A total of 14 trauma-exposed and 16 age-, sex-, and IQ-matched comparison youth underwent functional MRI while performing an emotional conflict task that involved categorizing facial affect while ignoring an overlying emotion word. Engagement of the conflict regulation system was evaluated at neural and behavioral levels. Results showed that trauma-exposed youth failed to dampen dorsolateral prefrontal cortex activity and engage amygdala–pregenual cingulate inhibitory circuitry during the regulation of emotional conflict, and were less able to regulate emotional conflict. In addition, trauma-exposed youth showed greater conflict-related amygdala reactivity that was associated with diminished levels of trait reward sensitivity. These data point to a trauma-related deficit in automatic regulation of emotional processing, and increase in sensitivity to emotional conflict in neural systems implicated in threat detection. Aberrant amygdala response to emotional conflict was related to diminished reward sensitivity that is emerging as a critical stress-susceptibility trait that may contribute to the emergence of mental illness during adolescence. These results suggest that deficits in conflict regulation for emotional material may underlie heightened risk for psychopathology in individuals that endure early-life trauma.     

Effects of oxycodone on brain responses to emotional images

Rationale

Evidence from animal and human studies suggests that opiate drugs decrease emotional responses to negative stimuli and increase responses to positive stimuli. Such emotional effects may motivate misuse of oxycodone (OXY), a widely abused opiate. Yet, we know little about how OXY affects neural circuits underlying emotional processing in humans.

Objective

We examined effects of OXY on brain activity during presentation of positive and negative visual emotional stimuli. We predicted that OXY would decrease amygdala activity to negative stimuli and increase ventral striatum (VS) activity to positive stimuli. Secondarily, we examined the effects of OXY on other emotional network regions on an exploratory basis.

Methods

In a three-session study, healthy adults (N?=?17) received placebo, 10 and 20 mg OXY under counterbalanced, double-blind conditions. At each session, participants completed subjective and cardiovascular measures and underwent functional MRI (fMRI) scanning while completing two emotional response tasks.

Results

Our emotional tasks reliably activated emotional network areas. OXY produced subjective effects but did not alter either behavioral responses to emotional stimuli or activity in our primary areas of interest. OXY did decrease right medial orbitofrontal cortex (MOFC) responses to happy faces.

Conclusions

Contrary to our expectations, OXY did not affect behavioral or neural responses to emotional stimuli in our primary areas of interest. Further, the effects of OXY in the MOFC would be more consistent with a decrease in value for happy faces. This may indicate that healthy adults do not receive emotional benefits from opiates, or the pharmacological actions of OXY differ from other opiates.     

The Impact of a Single Administration of Intranasal Oxytocin on the Recognition of Basic Emotions in Humans: A Meta-Analysis

Many studies have highlighted the potential of oxytocin (OT) to enhance facial affect recognition in healthy humans. However, inconsistencies have emerged with regard to the influence of OT on the recognition of specific emotional expressions (happy, angry, fear, surprise, disgust, and sadness). In this study, we conducted a meta-analysis of seven studies comprising 381 research participants (71 females) examining responses to the basic emotion types to assess whether OT enhances the recognition of emotion from human faces and whether this was influenced by the emotion expression and exposure time of the face. Results showed that intranasal OT administration enhances emotion recognition of faces overall, with a Hedges g effect size of 0.29. When analysis was restricted to facial expression types, significant effects of OT on recognition accuracy were specifically found for the recognition of happy and fear faces. We also found that effect sizes increased to moderate when exposure time of the photograph was restricted to early phase recognition (<300 ms) for happy and angry faces, or later phase recognition for fear faces (>300 ms). The results of the meta-analysis further suggest that OT has potential as a treatment to improve the recognition of emotion in faces, allowing individuals to improve their insight into the intentions, desires, and mental states of others.     

Effects of MDMA and Intranasal Oxytocin on Social and Emotional Processing

MDMA (±3,4-methylenedioxymethamphetamine, ‘ecstasy'') is used recreationally, reportedly because it increases feelings of empathy, sociability, and interpersonal closeness. One line of evidence suggests that MDMA produces these effects by releasing oxytocin, a peptide involved in social bonding. In the current study, we investigated the acute effects of MDMA and oxytocin on social and emotional processing in healthy human volunteers. MDMA users (N=65) participated in a 4-session, within-between-subjects study in which they received oral MDMA (0.75, 1.5 mg/kg), intranasal oxytocin (20 or 40 IU), or placebo under double-blind conditions. The primary outcomes included measures of emotion recognition and sociability (desire to be with others). Cardiovascular and subjective effects were also assessed. As expected, MDMA dose-dependently increased heart rate and blood pressure and feelings of euphoria (eg, ‘High'' and ‘Like Drug''). On measures of social function, MDMA impaired recognition of angry and fearful facial expressions, and the larger dose (1.5 mg/kg) increased desire to be with others, compared with placebo. Oxytocin produced small but significant increases in feelings of sociability and enhanced recognition of sad facial expressions. Additionally, responses to oxytocin were related to responses to MDMA with subjects on two subjective measures of sociability. Thus, MDMA increased euphoria and feelings of sociability, perhaps by reducing sensitivity to subtle signs of negative emotions in others. The present findings provide only limited support for the idea that oxytocin produces the prosocial effects of MDMA.     

Time-specific and cumulative effects of exposure to parental externalizing behavior on risk for young adult alcohol use disorder

BackgroundPrevious studies indicate that parental externalizing behavior (EB) is a robust risk factor for alcohol use disorder (AUD) in their children, and that this is due to both inherited genetic liability and environmental exposure. However, it remains unclear whether the effects of exposure to parental EB vary as a function of timing and/or chronicity.MethodsWe identified biological parents with an alcohol use disorder, drug abuse, or criminal behavior, during different periods of their child's upbringing, using Swedish national registries. Logistic regression was used to determine whether the effect of parental EB exposure during different developmental periods differentially impacted children's risk for young adult AUD (ages 19–24). In addition, we tested how multiply affected parents and/or sustained exposure to affected parents impacted risk.ResultsWhile parental EB increased risk for young adult AUD, timing of exposure did not differentially impact risk. Having a second affected parent increased the risk of AUD additionally, and sustained exposure to parental EB across multiple periods resulted in a higher risk of young adult AUD than exposure in only one period.ConclusionsIn this well-powered population study, there was no evidence of “sensitive periods” of exposure to national registry-ascertained parental EB with respect to impact on young adult AUD, but sustained exposure was more pathogenic than limited exposure. These findings suggest developmental timing does not meaningfully vary the impact, but rather there is a pervasive risk for development of young adult AUD for children and adolescents exposed to parental EB.     

Amygdala Reactivity to Emotional Faces in the Prediction of General and Medication-Specific Responses to Antidepressant Treatment in the Randomized iSPOT-D Trial

Although the cost of poor treatment outcomes of depression is staggering, we do not yet have clinically useful methods for selecting the most effective antidepressant for each depressed person. Emotional brain activation is altered in major depressive disorder (MDD) and implicated in treatment response. Identifying which aspects of emotional brain activation are predictive of general and specific responses to antidepressants may help clinicians and patients when making treatment decisions. We examined whether amygdala activation probed by emotion stimuli is a general or differential predictor of response to three commonly prescribed antidepressants, using functional magnetic resonance imaging (fMRI). A test–retest design was used to assess patients with MDD in an academic setting as part of the International Study to Predict Optimized Treatment in Depression. A total of 80 MDD outpatients were scanned prior to treatment and 8 weeks after randomization to the selective serotonin reuptake inhibitors escitalopram and sertraline and the serotonin–norepinephrine reuptake inhibitor, venlafaxine-extended release (XR). A total of 34 matched controls were scanned at the same timepoints. We quantified the blood oxygen level-dependent signal of the amygdala during subliminal and supraliminal viewing of facial expressions of emotion. Response to treatment was defined by ⩾50% symptom improvement on the 17-item Hamilton Depression Rating Scale. Pre-treatment amygdala hypo-reactivity to subliminal happy and threat was a general predictor of treatment response, regardless of medication type (Cohen''s d effect size 0.63 to 0.77; classification accuracy, 75%). Responders showed hypo-reactivity compared to controls at baseline, and an increase toward ‘normalization'' post-treatment. Pre-treatment amygdala reactivity to subliminal sadness was a differential moderator of non-response to venlafaxine-XR (Cohen''s d effect size 1.5; classification accuracy, 81%). Non-responders to venlafaxine-XR showed pre-treatment hyper-reactivity, which progressed to hypo-reactivity rather than normalization post-treatment, and hypo-reactivity post-treatment was abnormal compared to controls. Impaired amygdala activation has not previously been highlighted in the general vs differential prediction of antidepressant outcomes. Amygdala hypo-reactivity to emotions signaling reward and threat predicts the general capacity to respond to antidepressants. Amygdala hyper-reactivity to sad emotion is involved in a specific non-response to a serotonin–norepinephrine reuptake inhibitor. The findings suggest amygdala probes may help inform the personal selection of antidepressant treatments.     

Maternal Care Differentially Affects Neuronal Excitability and Synaptic Plasticity in the Dorsal and Ventral Hippocampus

Variations in early life maternal care modulate hippocampal development to program distinct emotional–cognitive phenotypes that persist into adulthood. Adult rat offspring that received low compared with high levels of maternal licking and grooming (low LG offspring) in early postnatal life show reduced long term potentiation (LTP) and impaired hippocampal-dependent memory, suggesting a ‘detrimental'' maternal effect on neural development. However, these studies focused uniquely on the dorsal hippocampus. Emerging evidence suggests a distinct role of the ventral hippocampus in mediating aggression, anxiety, and fear-memory formation, which are enhanced in low LG offspring. We report that variations in maternal care in the rat associate with opposing effects on hippocampal function in the dorsal and ventral hippocampus. Reduced pup licking associated with suppressed LTP formation in the dorsal hippocampus, but enhanced ventral hippocampal LTP. Ventral hippocampal neurons in low LG offspring fired action potentials at lower threshold voltages that were of larger amplitude and faster rise rate in comparison with those in high LG offspring. Furthermore, recordings of excitatory postsynaptic potential-to-spike coupling (E-S coupling) revealed an increase in excitability of ventral hippocampal CA1 neurons in low LG offspring. These effects do not associate with changes in miniature excitatory postsynaptic currents or paired-pulse facilitation, suggesting a specific effect of maternal care on intrinsic excitability. These findings suggest region-specific influences of maternal care in shaping neural development and synaptic plasticity.     

Modulation of Resting-State Amygdala-Frontal Functional Connectivity by Oxytocin in Generalized Social Anxiety Disorder

Generalized social anxiety disorder (GSAD) is characterized by aberrant patterns of amygdala-frontal connectivity to social signals of threat and at rest. The neuropeptide oxytocin (OXT) modulates anxiety, stress, and social behaviors. Recent functional neuroimaging studies suggest that these effects are mediated through OXT''s effects on amygdala reactivity and/or amygdala-frontal connectivity. The aim of the current study was to examine OXT''s effects on amygdala-frontal resting-state functional connectivity (rsFC) in GSAD patients and healthy controls (HCs). In a randomized, double-blind, cross-over design, 18 GSAD and 18 HC participants received intranasal OXT (24 IU or 40.32 μg) or placebo (PBO) before resting-state functional magnetic resonance imaging. In individuals with GSAD, OXT enhanced rsFC of the left and right amygdala with rostral anterior cingulate cortex (ACC)/medial prefrontal cortex (mPFC), and in doing so, reversed (ie, ‘normalized'') the reduced amygdala-frontal connectivity observed relative to HCs evident on PBO. Higher social anxiety severity in GSAD subjects correlated with lower amygdala-ACC/mPFC connectivity on PBO and higher social anxiety also correlated with greater enhancement in amygdala-frontal connectivity induced by OXT. These findings show that OXT modulates a neural circuit known for social threat processing and emotion regulation, suggesting a neural mechanism by which OXT may have a role in the pathophysiology and treatment of social anxiety disorder.