Neuromodulation of safety and surprise in the early stages of infant development: affective homeostatic regulation in bodily and mental functions.

Developing a sense of internal safety and security depends mainly on others: numerous neuromodulators play a significant role in the homeostatic process, regulating the importance of proximity to a caregiver and experiencing feelings that enable us to regulate our interdependence with our conspecifics since birth. This array of neurofunctional structures have been called the SEPARATION DISTRESS system (now more commonly known as the PANIC/ GRIEF system). This emotional system is mainly involved in the production of depressive symptoms. The disruption of this essential emotional balance leads to the onset of feelings of panic followed by depression. We will focus on the neuropeptides that play a crucial role in social approach behavior in mammals, which enhance prosocial behavior and facilitate the consolidation of social bonds. We propose that most prosocial behaviors are regulated through the specific neuromodulators acting on salient intersubjective stimuli, reflecting an increased sense of inner confidence (safety) in social relationships. This review considers the neurofunctional link between the feelings that may ultimately be at the base of a sense of inner safety and the central neuromodulatory systems. This link may shed light on the clinical implications for the development of early mother-infant bonding and the depressive clinical consequences when this bond is disrupted, such as in post-partum depression, depressive feelings connected to, addiction, neurofunctional disorders, and psychological trauma.

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.

Tickling, a Technique for Inducing Positive Affect When Handling Rats.

Handling small animals such as rats can lead to several adverse effects. These include the fear of humans, resistance to handling, increased injury risk for both the animals and the hands of their handlers, decreased animal welfare, and less valid research data. To minimize negative effects on experimental results and human-animal relationships, research animals are often habituated to being handled. However, the methods of habituation are highly variable and often of limited effectiveness. More potently, it is possible for humans to mimic aspects of the animals' playful rough-and-tumble behavior during handling. When applied to laboratory rats in a systematic manner, this playful handling, referred to as tickling, consistently gives rise to positive behavioral responses. This article provides a detailed description of a standardized rat tickling technique. This method can contribute to future investigations into positive affective states in animals, make it easier to handle rats for common husbandry activities such as cage changing or medical/research procedures such as injection, and be implemented as a source of social enrichment. It is concluded that this method can be used to efficiently and practicably reduce rats' fearfulness of humans and improve their welfare, as well as reliably model positive affective states.

Drug-sensitive Reward in Crayfish: Exploring the Neural Basis of Addiction with Automated Learning Paradigms.

Results of recent work from our labs and those of others have broadened perspectives on addiction beyond a human-specific, cognitive phenomenon. Addictive plant alkaloids are defensive compounds which have arisen to counter herbivory. With insects the true targets of the coevolutionary arms race, humans may be little more than collateral damage when impacted by 'human' drugs of abuse. The present paper summarizes recent contributions, with a primary focus on our own research in crayfish, where we characterize the behavioral and neural consequences resulting from chronic and acute exposure to psychostimulant and addictive drugs. Substituted phenethylamines, like amphetamine and cocaine, exhibit a wide range of effects in crayfish with direct parallels to those described from mammalian preparations. Unconditioned effects include intoxication and psychostimulation, where repeated exposure is accompanied by tolerance and sensitization, respectively. Psychostimulants exhibit powerful reinforcing properties in conditioned place preference, subject to extinction and reinstatement. Crayfish readily self-administer amphetamines using instrumental learning approaches. With a nervous system modular and uniquely accessible to neural probing, crayfish offer unique opportunities for studying the basic biological mechanisms of drug effects, for exploring how the appetitive disposition is implemented, and for examining how this is related to the rewarding action of drugs of abuse.

The Affective Core of the Self: A Neuro-Archetypical Perspective on the Foundations of Human (and Animal) Subjectivity.

Psychologists usually considered the "Self" as an object of experience appearing when the individual perceives its existence within the conscious field. In accordance with such a view, the self-representing capacity of the human mind has been related to corticolimbic learning processes taking place within individual development. On the other hand, Carl Gustav Jung considered the Self as the core of our personality, in its conscious and unconscious aspects, as well as in its actual and potential forms. According to Jung, the Self originates from an inborn dynamic structure integrating the essential drives of our "brain-mind," and leading both to instinctual behavioral actions and to archetypal psychological experiences. Interestingly, recent neuroethological studies indicate that our subjective identity rests on ancient neuropsychic processes that humans share with other animals as part of their inborn constitutional repertoire. Indeed, brain activity within subcortical midline structures (SCMSs) is intrinsically related to the emergence of prototypical affective states, that not only influence our behavior in a flexible way, but alter our conscious field, giving rise to specific feelings or moods, which constitute the first form of self-orientation in the world. Moreover, such affective dynamics play a central role in the organization of individual personality and in the evolution of all other (more sophisticated) psychological functions. Therefore, on the base of the convergence between contemporary cutting-edge scientific research and some psychological intuitions of Jung, we intend here to explore the first neuroevolutional layer of human mind, that we call the affective core of the Self.

Use of tramadol in psychiatric care: A comprehensive review and report of two cases.

Tramadol is widely prescribed for treating acute and chronic forms of pain. It is a weak mu-receptor opioid agonist and also increases concentrations of serotonin and noradrenaline within the limbic system of the brain. The therapeutic range of tramadol is relatively wide. Compared with other opioid agonists, there is little risk for developing tolerance and for abuse. Recent models of depression emphasise the subjective experience of a depressive mood as being, in part, a psychologically painful state. It is well established that psychological stress due to social separation/loss, disruption or be-trayal of pre-existent significant interpersonal bonds is mediated by the activation of the mammalian PANIC (separation-distress) system. It is also known that this kind of stress can be soothed very effectively by very low doses of endogenous or exogenous opioid receptor agonists. These observations raise the question of whether tramadol can be an effective and safe treat-ment option for some forms of anxiety and depression in which elements of social loss or betrayal are in-volved. In support of this possibility, two clinical cases are presented, and ideas for development of new ap-proaches targeting the endogenous opioidergic system in clinical practice are discussed.

Primary Emotional Systems and Personality: An Evolutionary Perspective.

The present article highlights important concepts of personality including stability issues from the perspective of situational demands and stability over the life-course. Following this more introductory section, we argue why individual differences in primary emotional systems may represent the phylogenetically oldest parts of human personality. Our argumentation leads to the need to increasingly consider individual differences in the raw affects/emotions of people to understand human personality in a bottom-up fashion, which can be coordinated with top-down perspectives. In support of this idea, we also review existing evidence linking individual differences in primal emotions as assessed with the Affective Neuroscience Personality Scales and the widely accepted Big Five Model of Personality. In this context, we provide additional evidence on the link between primal emotions and personality in German and Chinese sample populations. In short, this article addresses evolutionary perspectives in the evaluation of human personality, highlighting some of the ancestral emotional urges that probably still control variations in the construction of human personality structures. Moreover, we address how individual differences in primary emotional systems can illuminate linkages to major human psychopathologies and the potential advantages and disadvantages of carrying a certain personality trait within certain cultural/environmental niches.

Reconciling cognitive and affective neuroscience perspectives on the brain basis of emotional experience.

The "affective" and "cognitive" neuroscience approaches to understanding emotion (AN and CN, respectively) represent potentially synergistic, but as yet unreconciled, theoretical perspectives, which may in part stem from the methods that these distinct perspectives routinely employ-one focusing on animal brain emotional systems (AN) and one on diverse human experimental approaches (CN). Here we present an exchange in which each approach (1) describes its own theoretical perspective, (2) offers a critique of the other perspective, and then (3) responds to each other's critique. We end with a summary of points of agreement and disagreement, and describe possible future experiments that could help resolve the remaining controversies. Future work should (i) further characterize the structure/function of subcortical circuitry with respect to its role in generating emotion, and (ii) further investigate whether sub-neocortical activations alone are sufficient (as opposed to merely necessary) for affective experiences, or whether subsequent cortical representation of an emotional response is also required.

The Psycho-Neurology of Cross-Species Affective/Social Neuroscience: Understanding Animal Affective States as a Guide to Development of Novel Psychiatric Treatments.

During the past half century of research with preclinical animal models, affective neuroscience has helped identify and illuminate the functional neuroanatomies and neurochemistries of seven primary process, i.e., genetically provided emotional systems of mammalian brains. All are subcortically localized, allowing animal models to guide the needed behavioral and neuroscientific analyses at levels of detail that cannot be achieved through human research, including modern brain imaging. They consist of the following neuronal processes: SEEKING/Enthusiasm, RAGE/Anger, FEAR/Anxiety, sexual LUST/Passion, maternal CARE/Nurturance, separation-distress PANIC/Grief and PLAY/Social Joy. Several of these systems figure heavily in social bonding. I will focus here especially on the genesis of depression. Its genesis is significantly influenced by (i) sustained overactivity of the separation-distress PANIC system reflecting severed social bonds and the excessive "psychological pain" of loneliness that can, if sustained, lead to a downward cascade known as psychological despair, and (ii) the despair phase that follows the acute PANIC response, which is characterized by abnormally low activity of the SEEKING, the so-called brain reward networks, leading to amotivational states that characterize depression. Depressive affect is promoted by such brain affective mechanisms of social attachments and social loss as well as diminished arousability of the SEEKING system, leading to chronic dysphoria. To understand why depression feels so bad, we must understand the neural mechanisms that mediate such social feelings.

Positive Emotional Learning Induces Resilience to Depression: A Role for NMDA Receptor-mediated Synaptic Plasticity.

BACKGROUND: Positive emotions have been shown to induce resilience to depression and anxiety in humans, as well as increase cognitive abilities (learning, memory and problem solving) and improve overall health. In rats, frequency modulated 50-kHz ultrasonic vocalizations (Hedonic 50-kHz USVs) reflect a positive affective state and are best elicited by rough-and-tumble play. METHODS: The effect of positive affect induced by rough-and tumble play was examined on models of depression and learning and memory. The molecular and pharmacological basis of play induced positive affect was also examined. RESULTS: Rough-and-tumble play induced Hedonic 50-kHz USVs, lead to resilience to depression and anxiety, and facilitation of learning and memory. These effects are mediated, in part, by increased NMDAR expression and activation in the medial prefrontal cortex. CONCLUSIONS: We hypothesize that positive affect induces resilience to depression by facilitating NMDAR-dependent synaptic plasticity in the medial prefrontal cortex. Targeting MPFC synaptic plasticity may lead to novel treatments for depression.

Individual differences in Affective Neuroscience Personality Scale (ANPS) primary emotional traits and depressive tendencies.

BACKGROUND: The present study investigated individual differences in the Affective Neuroscience Personality Scales (ANPS), representing measures of primary emotional systems, and depressive tendencies in two independent samples. METHODS: In order to be able to find support for a continuum model with respect to the relation of strength in the cross-species "affective neuroscience" taxonomy of primary emotional systems, we investigated ANPS measured personality traits in a psychologically mostly healthy population (n=614 participants) as well as a sample of clinically depressed people (n=55 depressed patients). RESULTS: In both normal and depressed samples robust associations appeared between higher FEAR and SADNESS scores and depressive tendencies. A similar - albeit weaker - association was observed with lower SEEKING system scores and higher depressive tendencies, an effect again seen in both samples. LIMITATIONS: The study is of cross-sectional nature and therefore only associations between primary emotional systems and depressive tendencies were evaluated. CONCLUSIONS: These results show that similar associations between ANPS monitored primary emotional systems and tendencies toward depression can be observed in both healthy and depressed participants. This lends support for a continuum of affective changes accompanying depression, potentially reflecting differences in specific brain emotional system activities in both affectively normal as well as clinically depressed individuals.

An Affective Neuroscience Framework for the Molecular Study of Internet Addiction.

Internet addiction represents an emerging global health issue. Increasing efforts have been made to characterize risk factors for the development of Internet addiction and consequences of excessive Internet use. During the last years, classic research approaches from psychology considering personality variables as vulnerability factor, especially in conjunction with neuroscience approaches such as brain imaging, have led to coherent theoretical conceptualizations of Internet addiction. Although such conceptualizations can be valuable aid, the research field is currently lacking a comprehensive framework for determining brain-based and neurochemical markers of Internet addiction. The present work aims at providing a framework on the molecular level as a basis for future research on the neural and behavioral level, in order to facilitate a comprehensive neurobiological model of Internet addiction and its clinical symptomatology. To help establish such a molecular framework for the study of Internet addiction, we investigated in N = 680 participants associations between individual differences in tendencies toward Internet addiction measured by the Generalized Problematic Internet Use Scale-2 (GPIUS-2) and individual differences in primary emotional systems as assessed by the Affective Neuroscience Personality Scales (ANPS). Regression analysis revealed that the ANPS scales FEAR and SADNESS were the ANPS scales most robustly positively linked to several (sub)scales of the GPIUS-2. Also the scales SEEKING, CARE and PLAY explain variance in some of the GPIUS-2 subscales. As such, these scales are negatively linked to the GPIUS-2 subscales. As the ANPS has been constructed on substantial available brain data including an extensive molecular body with respect to evolutionary highly conserved emotional circuitry in the ancient mammalian brain, the present study gives first ideas on putative molecular mechanisms underlying different facets of Internet addiction as derived from associations between tendencies toward Internet addiction and individual differences in primary emotional systems. For example, as SADNESS is linked to the overall GPIUS-2 score, and the neuropeptide oxytocin is known to downregulate SADNESS, it is conceivable that the neuropeptide might play a role in Internet addition on the molecular level. Our findings provide a theoretical framework potentially illuminating the molecular underpinnings of Internet addiction. Finally, we also present data on the ANPS and smartphone addiction at the end of the paper. Similar to the reported associations between the ANPS and the GPIUS-2, these correlations might provide an initial outline for a framework guiding future studies that aim to address the molecular basis of smartphone addiction.

Music chills: The eye pupil as a mirror to music's soul.

This study evaluated whether music-induced aesthetic "chill" responses, which typically correspond to peak emotional experiences, can be objectively monitored by degree of pupillary dilation. Participants listened to self-chosen songs versus control songs chosen by other participants. The experiment included an active condition where participants made key presses to indicate when experiencing chills and a passive condition (without key presses). Chills were reported more frequently for self-selected songs than control songs. Pupil diameter was concurrently measured by an eye-tracker while participants listened to each of the songs. Pupil size was larger within specific time-windows around the chill events, as monitored by key responses, than in comparison to pupil size observed during 'passive' song listening. In addition, there was a clear relationship between pupil diameter within the chills-related time-windows during both active and passive conditions, thus ruling out the possibility that chills-related pupil dilations were an artifact of making a manual response. These findings strongly suggest that music chills can be visible in the moment-to-moment changes in the size of pupillary responses and that a neuromodulatory role of the central norepinephrine system is thereby implicated in this phenomenon.

Primary emotional traits in patients with personality disorders.

There is a longstanding tradition that connects temperament pathology and personality disorders. Emotions are the major constituents of temperament. In mammals, seven primary emotions have been identified: SEEKING, FEAR, CARE, RAGE, SADNESS/PANIC, LUST and PLAY. The study aimed at exploring the relationship between primary emotions and personality disorders (PDs). Five hundred forty-six patients with different degrees and qualities of personality pathology, admitted to treatment in specialized PD services, were diagnosed according to Structured Clinical Interview for DSM-IV Axis II Personality Disorders, and their primary emotional profiles were assessed by the Affective Neuroscience Personality Scales. The Affective Neuroscience Personality Scales explained 19% of the variance in borderline and avoidant criteria. The DSM-IV PD categories displayed different patterns of association to the primary emotions, e.g. the borderline PD profile suggested low thresholds for RAGE and SADNESS, but on the positive side a propensity for SEEKING. In contrast, the dependent PD profile suggested a low threshold for SADNESS but a high threshold for RAGE and SEEKING. The results are promising for a more coherent and evolution-based overall theory of PDs, and the correlations found in this study indicate testable causal pathways to PDs. Copyright © 2016 John Wiley & Sons, Ltd.

Correction: The Role of Nature and Nurture for Individual Differences in Primary Emotional Systems: Evidence from a Twin Study.

[This corrects the article DOI: 10.1371/journal.pone.0151405.].

The Role of Nature and Nurture for Individual Differences in Primary Emotional Systems: Evidence from a Twin Study.

The present study investigated for the first time the relative importance of genetics and environment on individual differences in primary emotionality as measured with the Affective Neuroscience Personality Scales (ANPS) by means of a twin-sibling study design. In N = 795 participants (n = 303 monozygotic twins, n = 172 dizygotic twins and n = 267 non-twin full siblings), moderate to strong influences of genetics on individual differences in these emotional systems are observed. Lowest heritability estimates are presented for the SEEKING system (33%) and highest for the PLAY system (69%). Further, multivariate genetic modeling was applied to the data showing that associations among the six ANPS scales were influences by both, a genetic as well as an environmental overlap between them. In sum, the study underlines the usefulness of the ANPS for biologically oriented personality psychology research.

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.

Brain Emotion Systems, Personality, Hopelessness, Self/Other Perception, and Gambling Cognition: A Structural Equation Model.

The aim of this study was to explore the relations between gambling, brain emotion systems, personality, self/other perception, and hopelessness in an Italian community. Dimensions of gambling, positive and negative emotions, self/other perception, personality and hopelessness were assessed in a community sample of 235 adults aged 19-59 years. Two structural models were tested. We found a significant correlation between problem gambling and impulsivity, which in association with aggressivity and negative personality dimensions may help explain the psychopathology factor, i.e. a latent variable involving neurotic personality, hopelessness, high sensation seeking, low metacognitive responsiveness, and disorganized patterns of interpersonal relationships. These results contribute to develop a theoretical framework of gambling in relation with personality factors and provide a new approach for clinical intervention of problem gambling that relies on a solid multidimensional perspective.

Ultra-Low-Dose Buprenorphine as a Time-Limited Treatment for Severe Suicidal Ideation: A Randomized Controlled Trial.

OBJECTIVE: Suicidal ideation and behavior currently have no quick-acting pharmacological treatments that are suitable for independent outpatient use. Suicidality is linked to mental pain, which is modulated by the separation distress system through endogenous opioids. The authors tested the efficacy and safety of very low dosages of sublingual buprenorphine as a time-limited treatment for severe suicidal ideation. METHOD: This was a multisite randomized double-blind placebo-controlled trial of ultra-low-dose sublingual buprenorphine as an adjunctive treatment. Severely suicidal patients without substance abuse were randomly assigned to receive either buprenorphine or placebo (in a 2:1 ratio), in addition to their ongoing individual treatments. The primary outcome measure was change in suicidal ideation, as assessed by the Beck Suicide Ideation Scale at the end of each of 4 weeks of treatment. RESULTS: Patients who received ultra-low-dose buprenorphine (initial dosage, 0.1 mg once or twice daily; mean final dosage=0.44 mg/day; N=40) had a greater reduction in Beck Suicide Ideation Scale scores than patients who received placebo (N=22), both after 2 weeks (mean difference -4.3, 95% CI=-8.5, -0.2) and after 4 weeks (mean difference=-7.1, 95% CI=-12.0, -2.3). Concurrent use of antidepressants and a diagnosis of borderline personality disorder did not affect the response to buprenorphine. No withdrawal symptoms were reported after treatment discontinuation at the end of the trial. CONCLUSIONS: The time-limited, short-term use of very low dosages of sublingual buprenorphine was associated with decreased suicidal ideation in severely suicidal patients without substance abuse. Further research is needed to establish the efficacy, safety, dosing, and appropriate patient populations for this experimental treatment.

Top-down versus bottom-up perspectives on clinically significant memory reconsolidation.

Lane et al. are right: Troublesome memories can be therapeutically recontextualized. Reconsolidation of negative/traumatic memories within the context of positive/prosocial affects can facilitate diverse psychotherapies. Although neural mechanisms remain poorly understood, we discuss how nonlinear dynamics of various positive affects, heavily controlled by primal subcortical networks, may be critical for optimal benefits.