The aetiology of social deficits within mental health disorders:The role of the immune system and endogenous opioids

The American National Institute for Mental Health (NIMH) has put out a set of research goals that include a long-term plan to identify more reliable endogenous explanations for a wide variety of mental health disorders (Insel, 2013). In response to this, we have identified a major symptom that underlies multiple mental health disorders – social bonding dysfunction. We suggest that endogenous opioid abnormalities can lead to altered social bonding, which is a symptom of various mental health disorders, including depression, schizophrenia and ASD. This article first outlines how endogenous opioids play a role in social bonding. Then we show their association with the body’s inflammation immune function, and review recent literature linking inflammation to mental health ‘immunophenotypes’. We finish by explaining how these immunophenotypes may be caused by alterations in the endogenous opioid system. This is the first overview of the role of inflammation across multiple disorders where we provide a biochemical explanation for why immunophenotypes might exist across diagnoses. We propose a novel mechanism of how the immune system may be causing ‘sickness-type’ behaviours (fatigue, appetite change, social withdrawal and inhibited motivation) in those who have these immunophenotypes. We hope that this novel aetiology can be used as a basis for future research in mental health

Neurobiology of Physical Exercise: Perspectives on Psychophysiological Effects and Opioidergic Neurotransmission

Abstract: Regular physical exercise promotes health and prevents and treats multiple chronic diseases. Despite the well-acknowledged health benefits, many people remain physically inactive. Affective responses induced by exercise are believed to influence future exercise behaviour. Previous studies suggest that pleasurable sensations experienced in response to exercise are regulated by the endogenous opioid system. The opioid system is also involved in the reward processing, and may modulate food reward responses after exercise, possibly contributing to subsequent caloric intake and weight loss outcomes. In this thesis, affective responses to high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) were investigated over a two-week training intervention in untrained healthy subjects and subjects with type 2 diabetes or prediabetes. Positron emission tomography (PET) was used to explore endogenous opioid release after HIIT and MICT in young healthy subjects. The interaction between exercise-induced opioid activation and changes in food reward processing were assessed using functional magnetic resonance imaging (fMRI). HIIT generated a more negative overall affective experience in comparison with MICT; however, this lessened over the training period. Thus, HIIT appears as a tolerable exercise method for sedentary adults with and without diabetes. Furthermore, HIIT induced opioid release in key brain regions implicated in emotion and pain processing and the opioid release correlated with measures of negative emotionality. In contrast, MICT did not result in significant opioid release, although increased opioid activation correlated with increased euphoria after MICT as well as with increased neural responses to palatable foods. These results indicate that the intensity of the exercise regulates endogenous opioid release and concomitant changes in affect and reward processing. Taken together, these findings may have practical implications in developing more tolerable and likeable exercise programs to enhance physical activity participation in different population groups, as well as in optimising the efficient use of exercise in health care, for example in weight loss interventions and in the treatment of various affective disorders.Tiivistelmä: Säännöllinen liikunta ylläpitää terveyttä sekä ennaltaehkäisee ja hoitaa lukuisia sairauksia. Terveyshyödyistä huolimatta moni jää kuitenkin sohvaperunaksi. Liikunnan harrastaminen riippuu osin siitä, miltä liikunta tuntuu. Aikaisempien tutkimusten perusteella aivojen opioidijärjestelmän ajatellaan olevan liikunnasta saatavan mielihyvän taustalla. Opioidijärjestelmä säätelee myös ruuan ja syömisen aiheuttamaa mielihyvää, ja se voi siten muovata liikunnan aikaansaamia muutoksia ruuan palkitsevuudessa vaikuttaen näin syömiskäyttäytymiseen ja painonhallintaan. Tässä väitöskirjatyössä tutkittiin, miltä kovatehoinen intervalliharjoittelu (highintensity interval training, HIIT) ja keskitehoinen kestävyysharjoittelu (moderate- intensity continuous training) tuntuvat kahden viikon liikuntajakson aikana liikunnallisesti passiivisilla terveillä koehenkilöillä, sekä tyypin 2 diabeetikoilla ja esidiabeetikoilla. Lisäksi positroniemissiotomografia (PET) -kuvantamisella selvitettiin aivojen opioidijärjestelmän toimintaa HIIT ja MICT harjoitusten jälkeen terveillä nuorilla miehillä. Toiminnallisen magneettikuvantamisen (fMRI) avulla tutkittiin liikunnan vaikutuksia herkullisten ruokakuvien aikaansaamiin hermostollisiin vasteisiin aivoissa. Lyhytkestoinen HIIT aiheutti huomattavasti negatiivisemman tunnekokemuksen kuin pitkäkestoinen MICT, mikä kuitenkin helpottui jo kahden viikon harjoittelujakson aikana niin terveillä kuin tyypin 2 diabeetikoilla ja esidiabeetikoilla. Näin ollen rankka HIIT voi soveltua liikuntavaihtoehdoksi myös aikaisemmin liikuntaa harrastamattomille. Lisäksi havaittiin, että liikunnan intensiteetti säätelee opioidijärjestelmän toimintaa. HIIT vapautti endogeenisiä opioideja tunteiden ja kivun säätelyyn liittyvillä aivoalueilla. Opioidien vapautuminen oli yhteydessä negatiivisiin tuntemuksiin. Vastaavaa opioidien vapautumista ei havaittu MICT:n jälkeen, joskin suurempi opioidiaktivaatio oli yhteydessä lisääntyneeseen euforisuuden tuntemukseen ja suurempiin hermostollisiin vasteisiin herkullisille ruokakuville pitkäkestoisen liikunnan jälkeen. Tutkimuksista saatuja tuloksia voidaan hyödyntää kehitettäessä uudenlaisia lähestymistapoja paitsi ihmisten liikunnalliseen aktivoimiseen, myös liikunnan tehokkaampaan hyödyntämiseen painonpudotuksessa ja esimerkiksi masennuksen ja riippuvuuksien hoidossa

Social touch and human development.

Social touch is a powerful force in human development, shaping social reward, attachment, cognitive, communication, and emotional regulation from infancy and throughout life. In this review, we consider the question of how social touch is defined from both bottom-up and top-down perspectives. In the former category, there is a clear role for the C-touch (CT) system, which constitutes a unique submodality that mediates affective touch and contrasts with discriminative touch. Top-down factors such as culture, personal relationships, setting, gender, and other contextual influences are also important in defining and interpreting social touch. The critical role of social touch throughout the lifespan is considered, with special attention to infancy and young childhood, a time during which social touch and its neural, behavioral, and physiological contingencies contribute to reinforcement-based learning and impact a variety of developmental trajectories. Finally, the role of social touch in an example of disordered development -autism spectrum disorder-is reviewed

Spinal cord stimulation in chronic pain: evidence and theory for mechanisms of action.

Well-established in the field of bioelectronic medicine, Spinal Cord Stimulation (SCS) offers an implantable, non-pharmacologic treatment for patients with intractable chronic pain conditions. Chronic pain is a widely heterogenous syndrome with regard to both pathophysiology and the resultant phenotype. Despite advances in our understanding of SCS-mediated antinociception, there still exists limited evidence clarifying the pathways recruited when patterned electric pulses are applied to the epidural space. The rapid clinical implementation of novel SCS methods including burst, high frequency and dorsal root ganglion SCS has provided the clinician with multiple options to treat refractory chronic pain. While compelling evidence for safety and efficacy exists in support of these novel paradigms, our understanding of their mechanisms of action (MOA) dramatically lags behind clinical data. In this review, we reconstruct the available basic science and clinical literature that offers support for mechanisms of both paresthesia spinal cord stimulation (P-SCS) and paresthesia-free spinal cord stimulation (PF-SCS). While P-SCS has been heavily examined since its inception, PF-SCS paradigms have recently been clinically approved with the support of limited preclinical research. Thus, wide knowledge gaps exist between their clinical efficacy and MOA. To close this gap, many rich investigative avenues for both P-SCS and PF-SCS are underway, which will further open the door for paradigm optimization, adjunctive therapies and new indications for SCS. As our understanding of these mechanisms evolves, clinicians will be empowered with the possibility of improving patient care using SCS to selectively target specific pathophysiological processes in chronic pain

Breaking down the barriers: fMRI applications in pain, analgesia and analgesics

This review summarizes functional magnetic resonance imaging (fMRI) findings that have informed our current understanding of pain, analgesia and related phenomena, and discusses the potential role of fMRI in improved therapeutic approaches to pain. It is divided into 3 main sections: (1) fMRI studies of acute and chronic pain. Physiological studies of pain have found numerous regions of the brain to be involved in the interpretation of the 'pain experience'; studies in chronic pain conditions have identified a significant CNS component; and fMRI studies of surrogate models of chronic pain are also being used to further this understanding. (2) fMRI studies of endogenous pain processing including placebo, empathy, attention or cognitive modulation of pain. (3) The use of fMRI to evaluate the effects of analgesics on brain function in acute and chronic pain. fMRI has already provided novel insights into the neurobiology of pain. These insights should significantly advance therapeutic approaches to chronic pain

Music and social bonding: 'Self-other' merging and neurohormonal mechanisms

It has been suggested that a key function of music during its development and spread amongst human populations was its capacity to create and strengthen social bonds amongst interacting group members. However, the mechanisms by which this occurs have not been fully discussed. In this paper we review evidence supporting two thus far independently investigated mechanisms for this social bonding effect: self-other merging as a consequence of inter-personal synchrony, and the release of endorphins during exertive rhythmic activities including musical interaction. In general, self-other merging has been experimentally investigated using dyads, which provide limited insight into large-scale musical activities. Given that music can provide an external rhythmic framework that facilitates synchrony, explanations of social bonding during group musical activities should include reference to endorphins, which are released during synchronised exertive movements. Endorphins (and the Endogenous Opioid System (EOS) in general) are involved in social bonding across primate species, and are associated with a number of human social behaviours (e.g. laughter, synchronised sports), as well as musical activities (e.g. singing and dancing). Furthermore, passively listening to music engages the EOS, so here we suggest that both self-other merging and the EOS are important in the social bonding effects of music. In order to investigate possible interactions between these two mechanisms, future experiments should recreate ecologically valid examples of musical activities

Laughter influences social bonding but not prosocial generosity to friends and strangers

Humans deploy a number of specific behaviours for forming social bonds, one of which is laughter. However, two questions have not yet been investigated with respect to laughter: (1) Does laughter increase the sense of bonding to those with whom we laugh? and (2) Does laughter facilitate prosocial generosity? Using changes in pain threshold as a proxy for endorphin upregulation in the brain and a standard economic game (the Dictator Game) as an assay of prosociality, we show that laughter does trigger the endorphin system and, through that, seems to enhance social bonding, but it does not reliably influence donations to others. This suggests that social bonding and prosociality may operate via different mechanisms, or on different time scales, and relate to different functional objectives

Endogenous opioid system and human sociability

Social bonds have a profound impact on our everyday life. People differ in their capacity for establishing and maintain strong, intimate relationships. These differences are characterized as attachment styles. Particularly insecure attachment style may lead to developmental and psychiatric disorders, as well as to addictive behavior (Mikulincer & Shaver 2007), which cause large societal expenses due to treatment and sickness leaves. In addition to anti-nociception and reward, the endogenous opioid system has been proposed to regulate social bonding in mammals. That could explain the link between social distress and physical pain (Panksepp & Nelson 1997). However, the role of the endogenous opioid system in human social behavior remains poorly understood (Machin & Dunbar 2011). The aim of this thesis was to investigate opioidergic basis of affiliative behavior with positron-emission tomography (PET). We approached the phenomenon from two perspectives: by 1) measuring how prosocial behavior affects endogenous opioid peptide release and 2) quantifying whether regional differences in opioid receptor availability explain differences in adult attachment styles. PET was used for quantifying endorphin release after social laughter manipulation (Study I) and levels of brain μ-opioid receptor (MOR) in baseline state (Study II). In the methodological part of the thesis (Study III), PET and MRI data were combined. Voxel-based morphometry (VBM) based indices of gray matter density (GMD) were correlated with tracer binding potentials (BPND) Social laughter increased endorphin release in brain regions such as thalamus, caudate nucleus and putamen, in subcortical areas and in frontal cortices (Study I). Adult avoidant attachment style correlated negatively with brain MOR availability in thalamus, anterior, middle and posterior cingulate cortices, and medial and lateral prefrontal cortices (Study II). In study III, gray matter density (GMD and radiotracer binding (BPND) correlated positively in multiple brain areas, suggesting a link between brain’s regional macrostructure and molecular functioning. In sum, these results highlight the crucial role of endogenous opioid system in human prosocial functioning. Furthermore, they show that PET and anatomical MR provide complementary information regarding brains molecular organization, stressing the importance of fusion imaging for understanding brain basis of sociability.Ihmisen käyttäytymiselle on tyypillistä muodostaa pitkäkestoisia ja monimuotoisia kiintymyssuhteita. Erot kiintymyskäyttäytymisessä voivat olla suuria, eikä ilmiön neurobiologista taustaa vielä täysin tunneta. Kiintymyssuhdehäiriöt liittyvät usein laajempiin mielenterveyden häiriöihin sekä mm. lisääntyneeseen päihdehakuisuuteen aikuisiällä (Egle et al. 2002). Fyysisen kivun kokemuksen sekä lievittymisen tiedetään olevan vahvasti opioidi-välitteistä. Opioidijärjestelmän ajatellaan evoluution myötä kehittyneen säätelemään fyysisen kivun lisäksi myös sosiaalista kanssakäymistä nisäkkäillä (Nelson & Panksepp 1998; Higham et al. 2011). Tämä voisi selittää yhteyden psyykkisen ja somaattisen kipukokemuksen välillä myös ihmisillä (Panksepp et al. 1978). Tässä väitöskirjatyössä pyrittiin selvittämään aivojen opioidijärjestelmän merkitystä ihmisen sosiaalisen käyttäytymisen säätelijänä kahdella tavalla: 1) mittaamalla aivoissa vapautuvan endorfiinin määrää miellyttävän sosiaalisen tilanteen jälkeen sekä 2) vertailemalla aikuisen kiintymussuhdetyypin yhteyttä aivojen u-opioidireseptoritasoihin (MOR) normaalitilassa. Menetelmänä käytettiin aivojen positroniemissiotomografiaa (PET) sekä [11C]karfentaniilia, jonka tiedetään sitoutuvan spesifisti MOR:iin keskushermostossa. Kolmannessa (3), metodologisessa osatyössä vertailtiin aivojen PET-dataa magneettikuvantamisella (MRI) saatuihin aivojen harmaan ja valkean aineen tiheyskarttoihin käyttäen vokselipohjaista menetelmää (VBM; voxel-based morphometry). Tuloksena oli, että nauraminen läheisten ystävien kanssa lisäsi endorfiinien vapautumista (I) ja välttävä kiintymyssuhdetyyppi korreloi negatiivisesti vapaana olevien MOR:ien kanssa (II) sosio-emotionaalista käyttäytymistä ohjaavilla aivoalueilla. Lisäksi (III), harmaan aineen tiheys (GMD) korreloi positiivisesti merkkiaineiden sitoutumispotentiaalin (BPND) kanssa usealla aivoalueella. Tulokset I-II lisäävät tietoa opioidijärjestelmän keskeisestä roolista ihmisen sosiaalisen käyttäymisen säätelijänä. Lisäksi, osatyön III mukaan kaksi eri aivokuvantamisessa yleisesti käytettyä mittaria (BPND ja GMD) antavat toisiaan täydentävää tietoa aivojen molekyylirakenteesta, minkä vuoksi usean modaliteetin aivokuvantaminen on välttämätöntä sosiaalisen käyttäytymisen aivoperustan ymmärtämiseksi

Examining the role of endogenous opioids on attachment and sociosexuality using the framework of evolutionary life history theory

Evolutionary life history theory has been used to examine individual differences in attachment and sociosexuality within adult romantic relationships. One proposed mechanism for the variation observed within individuals is the endogenous opioid system. Through the use of testosterone, endogenous opioids may cause decreases in mating effort and increases in parental care of long-term partnered persons. Using the framework of evolutionary life history theory, this review examines current literature on opioids, attachment, sociosexuality, and testosterone, and attempts to evaluate the potential role of the endogenous opioid system as the key underlying mechanism, which uses testosterone to mediate differences in adult romantic attachment and sociosexuality

Naltrexone Blocks Endorphins Released when Dancing in Synchrony

Group synchronised dance is hypothesised to activate the Endogenous Opioid System (EOS), thereby increasing pain threshold, and encouraging social closeness. Previous studies have been limited to the use of pain threshold as a proxy indicator of EOS activation. We conducted a double-blind administration of placebo and naltrexone (an endorphin antagonist) before groups of strangers danced in synchrony and measured both pain threshold and sense of belonging to the group after dancing. A 100 mg dose of naltrexone resulted in significant hyperalgesic effects compared to the control participants, confirming that increases in pain threshold in the control group are due to activation of the EOS and release of endorphins during synchronised dancing. However, there was no significant effect of treatment on perceptions of social closeness. Social bonding during dance may plausibly be underpinned by elements of the EOS not blocked by naltrexone and/or interactions with other neurohormones and socio-cognitive mechanisms