Implications for Reward Processing in Differential Responses to Loss: Impacts on Attachment Hierarchy Reorganization.

When an attachment relationship is severed, so is homeostatic maintenance, leading to dysregulation of multiple physiological systems. Expanding upon Sbarra and Hazan's original model, we suggest that the degree to which an individual's physiological systems remain dysregulated depends on the state of one's attachment hierarchy-namely, whether an individual continues to seek a lost partner for support as their primary attachment figure. To recover from the loss of a romantic partner, an individual's attachment hierarchy must be reorganized. Our model proposes that an individual will go through a series of physiological changes before their attachment hierarchy is reorganized, which can either help or hinder their recovery. We consider the role of reward processing, including endogenous opioids, in this recovery process. Along the way, we identify mechanisms for continued dysregulation of biological systems among those who take longer to recover from a loss.

Anxiety-associated and separation distress-associated behaviours in Angelman syndrome.

BACKGROUND: Anxiety is considered a 'frequent' feature in the clinical criteria for Angelman syndrome; however, the nature and severity of anxiety symptoms have not been well characterised in this population. Anxiety behaviours, especially in response to separation from a preferred caregiver, have been described clinically but have not yet been explored empirically. METHOD: This study used a combination of standardised and clinician-derived survey items to assess the frequency, nature and severity of behaviours associated with anxiety and separation distress in 100 individuals with Angelman syndrome. Family (e.g. income and maternal education) and individual (e.g. age, sex, genetic subtype, sleep difficulties and aggressive behaviours) variables were also gathered to assess possible predictors of higher anxiety levels. Approximately half of the sample was seen in clinic and assessed with standardised measures of development and daily functioning, allowing for an additional exploration of the association between anxiety symptoms and extent of cognitive impairment. RESULTS: Anxiety concerns were reported in 40% of the sample, almost 70% were reported to have a preferred caregiver and over half displayed distress when separated from that caregiver. Individuals with the deletion subtype and individuals who are younger were less likely to have anxiety behaviours. Sleep difficulties and aggressive behaviour consistently significantly predicted total anxiety, the latter suggesting a need for future studies to tease apart differences between anxiety and aggression or anger in this population. CONCLUSIONS: Anxiety concerns, especially separation distress, are common in individuals with Angelman syndrome and represent an area of unmet need for this population.

Fear of dying in panic attacks predicts suicide attempt in comorbid depressive illness: prospective evidence from the National Epidemiological Survey on Alcohol and Related Conditions.

CONTEXT: As a group, comorbid anxiety disorders among depressed persons have consistently been found to increase risk of suicide attempt (SA). Growing evidence supports the link between panic attacks (PAs) and suicidality, but prospective evidence is limited and the nature of the linkage remains unclear. The positive-feedback model of suicide suggests that PAs eliciting catastrophic cognitions may drive SA. OBJECTIVE: To prospectively examine the relationship between PAs, panic symptoms and suicidality in individuals meeting DSM-IV criteria for past-year major depressive episodes in a large epidemiological study. METHODS: In data on 2,864 participants of the National Epidemiological Survey on Alcohol and Related Conditions (NESARC) wave 1 and 2 surveys with depressive disorders, the associations of PAs and panic symptoms with subsequent suicidal ideation (SI) and SAs were assessed using logistic regression. RESULTS: Past-year PAs in wave 1 significantly increased odds for subsequent SI and attempt in the 3-year follow-up interval; however, in multivariate analyses, PAs were not a significant predictor, but PAs featuring fear of dying were. Further, among subjects with PAs, fear of dying during a PA increased the odds of subsequent SA sevenfold, even after controlling for comorbid disorders, demographic factors, and other PA symptoms. CONCLUSION: PAs characterized by prominent morbid catastrophic cognitions may mediate the transition to SIs and SAs in subjects with depressive episodes. Presence of these symptoms in clinical settings may serve as a warning sign for future suicidality.

Titi monkey father-daughter bond-related behaviors explain stress response variability.

Social interactions regulate our behavior and physiology, and strong social bonds can buffer us from stress. Coppery titi monkeys (Plecturocebus cupreus) are socially monogamous South American monkeys that display strong social bonds. Infants form selective bonds with their fathers, making them ideal for studying father-daughter bonds. We established a method for quantifying variability in expression of bond-related behaviors in females (n = 12), and the present study is the second to use this method for explaining titi monkey responses to behavioral tests. We also investigated how manipulations of oxytocin (OT) and vasopressin (AVP) influenced juvenile behavior and physiology. Subjects received acute intranasal treatments of saline, low/medium/high OT, low/high AVP, or OT receptor antagonist (OTA) prior to an acute social separation. General linear mixed-effects model results revealed fathers were significant behavioral and physiological stress buffers for their daughters, as evidenced by fewer distress vocalizations (p < 0.001), less locomotion (p < 0.001), and lower plasma cortisol (p < 0.001) in a social separation paradigm. Females vocalized less if they exhibited greater expression of bond-related behaviors with their fathers as infants (p = 0.01), and this stress-buffering effect remained even when the daughter was separated from the father (p = 0.001). While treatments did not alter behaviors, OTA treatment caused the largest rise in plasma cortisol (p < 0.001), suggesting blockade of OT receptors can inhibit fathers' stress-buffering effects. Remarkably, females with greater expression of father-daughter bond-related behaviors exhibited an overall reduced physiological separation distress response (p = 0.04). Findings from the present study advance current knowledge of the neurobiological mechanisms foundational to female bonds and help inform how social disruptions may differently impact individuals based on expression of bond-related behaviors.

Effects of Chronic and Acute Intranasal Oxytocin Treatments on Temporary Social Separation in Adult Titi Monkeys (Plecturocebus cupreus).

In socially monogamous titi monkeys, involuntary separation from a pair mate can produce behavioral distress and increased cortisol production. The neuropeptide oxytocin (OXT) is thought to play an important role in the separation response of pair-bonded species. Previous studies from our lab have shown that chronic intranasal oxytocin (IN OXT) during development can have long-term effects on adult social behavior. In the current study, we examined the chronic and acute effects of IN OXT or Saline (SAL) on the subjects' response to a brief separation from their pair mates. Subjects with a history of chronic IN OXT or SAL treatment during development received a single dose of OXT or SAL as adults 30 min before being separated from their pair mate. Chronic treatment consisted of a daily dose of IN OXT (0.8 IU/kg) or SAL (control) from 12 to 18 months of age. Subjects (N = 29) were introduced to a pair mate at 30 months of age. After the pairs had cohabitated for 5 months, pairs underwent two "Brief Separation" (OXT and SAL) and two "Non-Separation" (OXT and SAL) test sessions. Vocalizations and locomotion were measured as behavioral indices of agitation or distress during the Brief Separation and Non-Separation periods (30 min each). We collected blood samples after the Brief Separation and Non-Separation periods to measure cortisol levels. Our results showed subjects treated with chronic OXT had a reduction in long call and peep vocalizations compared to subjects treated with chronic SAL. Subjects treated with chronic SAL and acute OXT produced more peeps and long calls compared to animals treated with acute SAL; however, patterns in this response depended on sex. Cortisol and locomotion were significantly higher during the Brief Separation period compared to the Non-Separation period; however, we did not find any treatment or sex effects. We conclude that chronic IN OXT given during development blunts the separation response, while acute OXT in chronic SAL subjects had sexually dimorphic effects, which could reflect increased partner seeking behaviors in males and increased anxiety in females.

Randomized, Placebo-Controlled Prospective Clinical Trial Evaluating the Efficacy of the Assisi Anti-anxiety Device (Calmer Canine) for the Treatment of Canine Separation Anxiety.

Introduction: Separation anxiety (SA) is among the most common canine behavior disorders and affects quality-of-life for dogs and their owners. Dogs with SA show signs of anxiety during absence or perceived absence of their owners. While psychoactive medications are often helpful for treating SA, dog and human factors may limit their utility. This study explored the efficacy of a pulsed electromagnetic field (PEMF) device for treatment of canine SA. Materials and Methods: In this double-blind randomized placebo-controlled study, a screening questionnaire and baseline video confirmed the diagnosis of SA. Owners treated their dog with the device twice daily for 6 weeks, completed weekly questionnaires, and noted adverse events. Videos were taken of the dog while alone at weeks 4 and 6. Behaviors were coded and categorized as negative and positive. Questionnaire and video data at weeks 4 and 6 were compared to baseline. Results: Forty client-owned dogs with moderate to severe SA completed the study. There were no differences between groups for age, weight, or sex. In owner questionnaires, no difference in behavior or overall score was found between the active and sham groups (p > 0.05). Videos of the active group compared to the sham group showed significant reduction in negative behaviors by week 6 (p = 0.036) and higher percentage of success at week 4 (Z = 2.83, p = 0.005), at week 6 (Z = 1.65, p = 0.098), and across the full study (Z = 1.99, p = 0.047). Adverse events were reported in eight dogs (6 active, 2 sham); all resolved and were unlikely to be related to treatment. Discussion: This study supports the efficacy and safety of this PEMF device for treatment of SA in dogs. Questionnaire results may not be sensitive enough to detect subtle negative behavioral states compared to video, and may not capture other owner observed behavioral changes. A caregiver placebo effect may account for some improvement seen in both groups. Video data appear better for diagnosis and monitoring dog's behavior when left alone. Future studies should assess PEMF's impact on other anxieties or combination of anxiety disorders in dogs.

Salivary Vasopressin as A Potential Non-Invasive Biomarker of Anxiety in Dogs Diagnosed with Separation-Related Problems.

Physiological biomarkers of canine anxiety have not been extensively investigated to date. To identify new biomarkers in dogs, we compared behaviorally normal dogs (Control group, N = 13) to dogs diagnosed with separation problems (Case group, N = 13) as they were introduced into a novel environment in the presence of two strangers and subjected to a short episode of separation and reunion with the owner. During the separation phase, dogs in the Case group explored significantly less than controls and were significantly more persistent in expressing passive stress-coping strategies aimed at seeking proximity to their owners. When the owners returned, dogs with separation distress spent significantly more time jumping up on the strangers than control dogs did. Salivary oxytocin and vasopressin concentrations did not differ between samples taken before and after the separation. However, vasopressin concentrations immediately after separation were significantly higher in the Case than in the Control group and remained higher, although not significantly so, 10 minutes later. These results indicated that dogs with separation distress became more anxious than typical dogs when separated from their owner in an unfamiliar environment and provided preliminary support for the use of salivary vasopressin as a possible biomarker for anxiety-related responses in dogs.

Effects of early-life FGF2 on ultrasonic vocalizations (USVs) and the mu-opioid receptor in male Sprague-Dawley rats selectively-bred for differences in their response to novelty.

In previous studies, early-life fibroblast growth factor-2 (FGF2) administration conferred resilience to developing anxiety-like behavior in vulnerable animals in adulthood. To follow up on this work, we administered FGF2 the day after birth to animals that differ in emotional behavior and further explored its long-term effects on affective behavior and circuitry. Selectively-bred "high responder" rats (bHRs) exhibit low levels of anxiety-like and depression-like behavior, whereas selectively-bred "low responders" (bLRs) display high levels of anxiety-like and depression-like behavior. We found that early-life administration of FGF2 decreased negative affect in bLRs during the early post-natal period, as indexed by 40 kHz ultrasonic vocalizations (USVs) in response to a brief maternal separation on PND11. FGF2 also increased positive affect during the juvenile period, as measured by 50 kHz USVs in response to heterospecific hand play ("tickling") after weaning. In general, we found that bHRs produced more 50 kHz USVs than bLRs. In adulthood, we measured opioid ligand and receptor expression in brain regions implicated in USV production and affect regulation by mRNA in situ hybridization. Within multiple affective brain regions, bHRs had greater expression of the mu opioid receptor than bLRs. FGF2 increased mu opioid expression in bLRs. The bLRs had more kappa and less delta receptor expression than bHRs, and FGF2 increased prodynorphin in bLRs. Our results provide support for further investigations into the role of growth factors and endogenous opioids in the treatment of disorders characterized by altered affect, such as anxiety and depression.

My Reflections on Understanding Animal Emotions for Improving the Life of Animals in Zoos.

Scientists are often reluctant to attribute emotions to nonhuman animals that are similar to human emotions. When the author published her early studies, reviewers prohibited the word fear. Fearful behavior had to be described as agitated. The core emotional systems described by Panksepp may provide a useful framework for people who work hands-on with animals. The core systems are fear, rage, panic (separation distress), seek, lust, nurture, and play. Some scientists who deny that animals have real emotions often fail to review important areas of the literature. The areas that are sometimes left out are the effects of psychiatric medications on animals and genetic influences on differences in animal behavior. In both people and animals, genetics has an influence on both fearfulness and novelty seeking. Visualizing the seven core emotional systems as separate volume controls on a music mixing board may help zoo professionals determine the motivation of both normal and abnormal behavior. It may also help them to design more effective environmental enrichments.

Sweating away depression? The impact of intensive exercise on depression.

BACKGROUND: In periods of prolonged stress and pain the body produces endorphins to help endure pain. The PANIC system is built on the same pathways as the pain system and is characterized by behaviour that looks like depression. The term 'mental pain' in the context of feelings of loss is arguably justified in light of this relationship between the physical pain and social loss systems. It is reasonable to expect that endorphin release ameliorates depression. METHODS: Moderately depressed males (n=30) were randomly assigned to one of three groups of varying exercise intensity. Each underwent a six-week exercise programme for three days per week, one hour per day. The HAM-D, MADRS, and ANPS were administered weekly and ß-endorphin levels measured. RESULTS: Moderate- and high-intensity exercise improved depression levels, while very-low intensity exercise did not have as beneficial an effect. ß-endorphin results were inconclusive. Participants showed a slight decrease in PANIC and FEAR, and increased SEEKING. LIMITATIONS: The potential insensitivity of the assays that were utilized, and the known problems with measuring ß-endorphins, may have contributed to the findings. The lack of a state measure of the basic emotion systems is problematic, as a trait measure has to be relied upon, and this likely affected the ability to accurately detect changes over time. CONCLUSIONS: The demonstrated improvements in depressive symptoms have important implications for the clinical treatment of patients despite the hypothesis that the PANIC system is involved in the genesis and maintenance of depression not having been conclusively confirmed.

The cross-mammalian neurophenomenology of primal emotional affects: From animal feelings to human therapeutics.

The neural correlates of human emotions are easy to harvest. In contrast, the neural constitution of emotional feelings in humans has resisted systematic scientific analysis. This review summarizes how preclinical affective neuroscience initiatives are making progress in decoding the neural nature of such feelings in animal brains. This has been achieved by studying the rewarding and punishing effects of deep brain stimulation (DBS) of subcortical emotional networks (labeled SEEING, RAGE, FEAR, LUST, CARE, PANIC, and PLAY systems) that evoke distinct emotion action patterns, as well as rewarding and punishing effects in animals. The implications of this knowledge for development of new psychiatric interventions, especially depression, are discussed. Three new antidepressive therapeutics arising from this work are briefly noted: 1) DBS of the medial forebrain bundle (MFB) in humans, 2) reduction of psychological pain that may arise from excessive PANIC arousal, and 3) facilitation of social joy through the study of social play in rats The overall argument is that we may more readily develop new psychiatric interventions through preclinical models if we take animal emotional feelings seriously, as opposed to just behavioral changes, as targets for development of new treatments.