Faculty Bibliography

The neural mechanisms through which a Pavlovian conditioned stimulus (CS) elicits innate defense responses are well understood. But a Pavlovian CS can also invigorate ongoing instrumental responding, as shown by studies of aversive Pavlovian-to-instrumental transfer (PIT). While the neural circuitry of appetitive PIT has been studied extensively, little is known about the brain mechanisms of aversive PIT. We recently showed the central amygdala (CeA) is essential for aversive PIT. In the current studies, using pharmacology and designer receptors in rodents, we demonstrate that noradrenergic (NE) activity negatively regulates PIT via brainstem locus coeruleus (LC) activity and LC projections to CeA. Our results provide evidence for a novel pathway through which response modulation occurs between brainstem neuromodulatory systems and CeA to invigorate adaptive behavior in the face of threat.

The calcium-binding protein calbindin-D28k is critical for hippocampal function and cognition, but its expression is markedly decreased in various neurological disorders associated with epileptiform activity and seizures. In Alzheimer's disease (AD) and epilepsy, both of which are accompanied by recurrent seizures, the severity of cognitive deficits reflects the degree of calbindin reduction in the hippocampal dentate gyrus (DG). However, despite the importance of calbindin in both neuronal physiology and pathology, the regulatory mechanisms that control its expression in the hippocampus are poorly understood. Here we report an epigenetic mechanism through which seizures chronically suppress hippocampal calbindin expression and impair cognition. We demonstrate that DeltaFosB, a highly stable transcription factor, is induced in the hippocampus in mouse models of AD and seizures, in which it binds and triggers histone deacetylation at the promoter of the calbindin gene (Calb1) and downregulates Calb1 transcription. Notably, increasing DG calbindin levels, either by direct virus-mediated expression or inhibition of DeltaFosB signaling, improves spatial memory in a mouse model of AD. Moreover, levels of DeltaFosB and calbindin expression are inversely related in the DG of individuals with temporal lobe epilepsy (TLE) or AD and correlate with performance on the Mini-Mental State Examination (MMSE). We propose that chronic suppression of calbindin by DeltaFosB is one mechanism through which intermittent seizures drive persistent cognitive deficits in conditions accompanied by recurrent seizures.

Throughout life, rats emit ultrasonic vocalizations (USV) when confronted with an aversive situation. However, the conditions classically used to elicit USV vary greatly with the animal's age (isolation from the dam in infancy, versus nociceptive stimulation in adults). The present study is the first to characterize USV responses to the same aversive event throughout development. Specifically, infant, juvenile and adult rats were presented with mild foot-shocks and their USV frequency, duration, and relationship with respiration and behavior were compared. In juvenile and adult rats, a single class of USV is observed with an age-dependent main frequency and duration (30 kHz/400 ms in juveniles, 22 kHz/900 ms in adults). In contrast, infant rat USV were split into two classes with specific relationships with respiration and behavior: 40 kHz/300 ms and 66 kHz/21 ms. Next, we questioned if these infant USV were also emitted in a more naturalistic context by exposing pups to interactions with the mother treating them roughly. This treatment enhanced 40-kHz USV while leaving 66-kHz USV unchanged suggesting that the use of USV goes far beyond a signal studied in terms of amount of emission, and can inform us about some aspects of the infant's affective state.

OBJECTIVES: To investigate whether response to lithium treatment in pediatric bipolar disorder can be predicted by changes in white matter microstructure in key cortico-limbic tracts involved in emotion regulation. METHODS: Eighteen clinically referred lithium-naive patients (mean age 15.5 years) were administered clinical rating scales and diffusion tensor imaging (DTI) examinations at baseline and following 4 weeks of lithium treatment. Clinical ratings were repeated following 8 weeks of treatment. Patients with Clinical Global Impressions (CGI) ratings of 1 ("very much improved") or 2 ("much improved") were classified as responders. Ten healthy volunteers received baseline and follow-up DTI examinations. Using the ENIGMA pipeline, we investigated the relationship between changes in fractional anisotropy (FA) in the cingulum hippocampus (CGH) and clinical response to lithium. RESULTS: Patients demonstrated significantly lower FA compared to healthy volunteers in the left and right CGH white matter at baseline. Following 4 weeks of lithium treatment, FA in the left CGH increased in patients, but no significant changes in FA were observed among the untreated healthy volunteers. Lithium responders had a significantly greater increase in FA compared to non-responders. Moreover, baseline (pre-treatment) FA in the left CGH white matter significantly predicted week 8 overall CGI severity score, with post hoc analyses indicating that these effects were evident for both severity of depression and mania. CONCLUSIONS: Our findings suggest that response to lithium treatment in pediatric bipolar disorder is associated with normalization of white matter microstructure in regions associated with emotion processing.

This paper explores challenges in the treatment of women suffering from disturbances in maternal identification. A review of the psychoanalytic and developmental literature focuses on the frequent finding of early-onset mother-daughter relational disturbance involving maternal narcissistic fragility and exaggerated dependency needs, intergenerational trauma, and related psychopathology including mutual affect dysregulation. A case example of a young woman with a severe anxiety disorder is presented and discussed to illustrate the challenges to the traditional psychoanalytic technique. This patient avoided pregnancy into her late thirties and entered analysis with feelings of inauthenticity, characterological masochism, and a " secret mission" to unmask the witch recurring in her dreams. Through an elaborate working-through of negative maternal transference, the analyst and patient saw through the birth of the patient's authentic self, a new approach to her career, her relationships with men, and her anticipation of the birth of a child by the sixth year of treatment. The author posits that psychoanalytic technique benefits from contemporary, attachment, and trauma research that supports the analyst's playing a more active role in approaching, co-regulating, tolerating, and integrating avoided affects and memory traces that are associated with early-onset relational disturbances worsened by the effects of violence, maltreatment, and loss.

Beginning with his Interpersonal World of the Infant (1985), Daniel Stern suggested that the infant is driven from birth to connect intersubjectively with his caregivers. By the final three months of the first year of life, as the infant begins to use protodeclarative pointing and jointly attends to the outer world, he also begins to jointly attend with his caregiver to their respective intrapsychic worlds, the mental states of his caregiver and himself. Clinically, analysts observe at this crucial point of development of secondary intersubjectivity mothers who, more often than not, respond only selectively and often unpredictably to their infants. In many instances, this may be motivated out of a mother's own need for regulation of emotion and arousal as we have shown in our empirical research. This article elaborates on clinical observations that, for the infant or young child to feel his traumatized mother's affective presence, he must try to enter mother's state of mind, while simultaneously, mother is seeking to self-regulate in the wake or the revival of trauma-associated memory traces, this at the expense of mutual regulation of emotion and arousal. We call this phenomenon traumatically skewed intersubjectivity. We find that children coconstruct with their traumatized mothers a new, shared traumatic experience by virtue of the toddler's efforts to share an intersubjective experience with a mother who is acting in response to posttraumatic reexperiencing. The problem is that the infant or young child has no point of reference to decipher the traumatized mother's social communication. And so, what is enacted leads to a new, shared traumatic event. Both the child's anxiety and aggression can, in this setting, easily become dysregulated, further triggering mother's anxiety and avoidance, leading thus to a vicious cycle that contributes to intergenerational transmission of trauma. Clinical examples and implications for psychoanalytically-oriented parent-infant psychotherapy will be discussed.

The aim of this study was to examine the relationship of maternal interpersonal violence-related posttraumatic stress disorder (IPV-PTSD), associated neural activity in response to mother-child relational stimuli, and child psychopathology indicators at child ages 12-42 months and one year later. The study tested the hypothesis that decreased maternal neural activity in regions that subserve emotion regulation would be associated with child symptoms associated with emotional dysregulation at both time points. Functional magnetic resonance imaging of 42 mothers with or without violence-exposure and associated IPV-PTSD were assessed. Their child's life-events and symptoms/behaviors indicative of high-risk subsequent PTSD diagnosis on a maternal-report questionnaire were measured one year later. Maternal IPV-PTSD severity was significantly associated with decreased ventromedial prefrontal cortex (vmPFC) activation in response to mother-child relational stimuli. Maternal IPV-PTSD severity and decreased vmPFC activation were then significantly associated with a child attachment disturbance at 12-42 months and symptoms/behaviors one year later, that were correlated with emotional dysregulation and risk for child PTSD. Maternal IPV-PTSD and child exposure to IPV were both predictive of child PTSD symptoms with maternal IPV-PTSD likely mediating the effects of child IPV exposure on child PTSD symptoms. These findings suggest that maternal IPV-PTSD severity and associated decreased vmPFC activity in response to mother-child relational stimuli are predictors of child psychopathology by age 12-42 months and one-year later. Significant findings in this paper may well be useful in understanding how maternal top-down cortico-limbic dysregulation promotes intergenerational transmission of IPV and related psychopathology and, thus should be targeted in treatment.

Women who have experienced interpersonal violence (IPV) are at a higher risk to develop posttraumatic stress disorder (PTSD), with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and impaired social behavior. Previously, we had reported impaired maternal sensitivity and increased difficulty in identifying emotions (i.e. alexithymia) among IPV-PTSD mothers. One of the aims of the present study was to examine maternal IPV-PTSD salivary cortisol levels diurnally and reactive to their child's distress in relation to maternal alexithymia. Given that mother-child interaction during infancy and early childhood has important long-term consequences on the stress response system, toddlers' cortisol levels were assessed during the day and in response to a laboratory stressor. Mothers collected their own and their 12-48month-old toddlers' salivary samples at home three times: 30min after waking up, between 2-3pm and at bedtime. Moreover, mother-child dyads participated in a 120-min laboratory session, consisting of 3 phases: baseline, stress situation (involving mother-child separation and exposure to novelty) and a 60-min regulation phase. Compared to non-PTSD controls, IPV-PTSD mothers - but not their toddlers, had lower morning cortisol and higher bedtime cortisol levels. As expected, IPV-PTSD mothers and their children showed blunted cortisol reactivity to the laboratory stressor. Maternal cortisol levels were negatively correlated to difficulty in identifying emotions. Our data highlights PTSD-IPV-related alterations in the HPA system and its relevance to maternal behavior. Toddlers of IPV-PTSD mothers also showed an altered pattern of cortisol reactivity to stress that potentially may predispose them to later psychological disorders.

BACKGROUND: Methylation of the serotonin 3A receptor gene (HTR3A) has been linked to child maltreatment and adult psychopathology. The present study examined whether HTR3A methylation might be associated with mothers' lifetime exposure to interpersonal violence (IPV), IPV-related psychopathology, child disturbance of attachment, and maternal neural activity. METHODS: Number of maternal lifetime IPV exposures and measures of maternal psychopathology including posttraumatic stress disorder (PTSD), major depression and aggressive behavior (AgB), and a measure of child attachment disturbance known as "secure base distortion" (SBD) were assessed in a sample of 35 mothers and children aged 12-42 months. Brain fMRI activation was assessed in mothers using 30-s silent film excerpts depicting menacing adult male-female interactions versus prosocial and neutral interactions. Group and continuous analyses were performed to test for associations between clinical and fMRI variables with DNA methylation. RESULTS: Maternal IPV exposure-frequency was associated with maternal PTSD; and maternal IPV-PTSD was in turn associated with child SBD. Methylation status of several CpG sites in the HTR3A gene was associated with maternal IPV and IPV-PTSD severity, AgB and child SBD, in particular, self-endangering behavior. Methylation status at a specific CpG site (CpG2_III) was associated with decreased medial prefrontal cortical (mPFC) activity in response to film-stimuli of adult male-female interactions evocative of violence as compared to prosocial and neutral interactions. CONCLUSIONS: Methylation status of the HTR3A gene in mothers is linked to maternal IPV-related psychopathology, trauma-induced brain activation patterns, and child attachment disturbance in the form of SBD during a sensitive period in the development of self-regulation.

Psychiatric disorders are amongst the most prevalent and impairing conditions in childhood and adolescence. Unfortunately, it is well known that general practitioners (GPs) and other frontline health providers (i.e., child protection workers, public health nurses, and pediatricians) are not adequately trained to address these ubiquitous problems (Braddick et al. Child and Adolescent mental health in Europe: infrastructures, policy and programmes, European Communities, 2009; Levav et al. Eur Child Adolesc Psychiatry 13:395-401, 2004). Advances in technology may offer a solution to this problem with clinical decision support systems (CDSS) that are designed to help professionals make sound clinical decisions in real time. This paper offers a systematic review of currently available CDSS for child and adolescent mental health disorders prepared according to the PRISMA-Protocols (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols). Applying strict eligibility criteria, the identified studies (n = 5048) were screened. Ten studies, describing eight original clinical decision support systems for child and adolescent psychiatric disorders, fulfilled inclusion criteria. Based on this systematic review, there appears to be a need for a new, readily available CDSS for child neuropsychiatric disorder which promotes evidence-based, best practices, while enabling consideration of national variation in practices by leveraging data-reuse to generate predictions regarding treatment outcome, addressing a broader cluster of clinical disorders, and targeting frontline practice environments.