Moderating Effects of Harm Avoidance on Resting-State Functional Connectivity of the Anterior Insula

As an index of behavioral inhibition and an individual’s propensity to avoid, rather than seek, potentially dangerous situations, harm avoidance has been linked to internalizing psychopathology. Altered connectivity within intrinsic functional neural networks has been linked to internalizing psychopathology; however, less is known about the effects of harm avoidance on functional connectivity within and between these networks. Importantly, harm avoidance may be distinguishable from trait anxiety and have clinical relevance as a risk factor for psychopathology. To this end, the current study aimed to examine associations between harm avoidance and resting state functional connectivity. A sample of undergraduate students (n=92) completed a resting state functional magnetic resonance imaging (fMRI) scan and self-report measures of harm avoidance and trait anxiety. Results indicated a main effect of harm avoidance on functional connectivity, such that higher harm avoidance was associated with decreased connectivity between the right anterior insula and clusters in the precuneus/PCC, left lateral parietal lobe, and left superior/middle frontal gyrus. Higher harm avoidance was also associated with decreased connectivity between the left anterior insula and precuneus/PCC. There were no effects of trait anxiety on functional connectivity of the anterior insula. Overall, the results indicate that individual differences in harm avoidance relate to disruptions in internetwork connectivity that may contribute to deficits in appropriately modulating attentional focus

AN INTEGRATIVE MODEL OF PERSONALITY DISORDER: PART 3: MECHANISM-BASED APPROACH TO THE PHARMACOTHERAPY OF PERSONALITY DISORDER: AN EMERGING CONCEPT

Temperament traits of Novelty Seeking, Harm Avoidance, Reward Dependence, and Persistence, are well defined in terms of their neural circuitry, neurochemical modulators, and patterns of associative learning. When heritably excessive, each of these traits may become a mechanistically fundamental biogenetic trait vulnerability for personality disorder. The other main risk factor for personality disorder is environmental, notably abuse, neglect, and psychological trauma. The emerging concept of mechanism-based pharmacotherapy aims to activate the brain’s homeostasis as the only available delivery system to re-calibrate complex neurophysiological participants in each of the temperament traits. In a positive feedback, a homeostasis-driven improvement of excessive temperament is expected to facilitate maturation of neocortical networks of cognition, most reliably in expert psychotherapy (Part I of this paper) and, ultimately, thereby improve top-down cortical control of subcortical affect reactivity. As an emerging concept informed by neuroscience and clinical research, mechanism based pharmacotherapy has the potential to be superior to traditional symptom-based treatments. Such mechanism-based approach illustrates what the pharmacological treatment of Research Domain Criteria (RDoC) might look like

Reward processing in self-harm

Self-harm is a complex yet common behaviour, which can be learned instrumentally through positive and negative reinforcement. It is thought to be processed in part via the reward system. Evidence for this comes mainly from pain research and studies combining neuroimaging with pain application in populations with self-harm. However, relatively little is understood about how reward processes may sustain self-harm. It is also equally important to understand whether biases in how rewards are processed contribute to difficulties managing self-harm, for example self-reported escalation, loss of control and relapse. To address these gaps in our understand- ing, this thesis has systematically reviewed the literature on reward mechanisms involved in self-harm, and reward processing biases that may be associated with self-harm. It has experi- mentally investigated whether processes underpinned by the reward system, such as incentive salience and approach biases, are involved in motivation for self-harm using a Dot Probe task and an Incentive Delay task. Finally, it has experimentally investigated whether biases process- ing non-salient rewards (as opposed to self-harm a potentially ‘salient’ reward) are present in young people with self-harm using an Incentive Delay task and Probabilistic Reversal Learn- ing task, with a particular focus on behavioural motivation, and reward learning as related to compulsivity. Evidence for incentive salience and approach biases towards self-harm was lim- ited in this thesis. However, other findings showed that avoidance of self-harm stimuli may be associated with ambivalence towards self-harm in young people. There was limited evidence to support the role of compulsivity in repetitive self-harm measured using a PRL task, or that individuals with self-harm exhibit differences in reward sensitivity as compared with controls. However, reward processing biases associated with comorbid depression and borderline person- ality disorder may contribute to self-harm in these individuals. Areas for future research and the implications of these results are discussed.Open Acces

Altered Brain Networks In Patients with Psychogenic Non-Epileptic Seizures (PNES) Using Ultra High Field MRI

Background: Psychogenic Non-epileptic Seizures (PNES) are attacks that appear similar to epileptic attacks. However, they lack abnormal electrical discharges in the brain and have psychological underpinnings and causes. The gold standard of diagnosis is video-EEG which is not widely accessible, creating a poor prognosis for patients. Resting state functional magnetic resonance imaging can aid in the diagnosis and treatment of PNES by helping better understand brain networks in patients with PNES. This study examines brain networks in patients with PNES with a focus on the default mode network and salience network. Methods: Twelve patients with PNES between the ages of 18-56 and twelve age- and sex- matched healthy participants between the ages of 18-59 were recruited. Participants underwent 7T resting-state fMRI scanning. Independent Components Analysis (ICA) and whole brain functional connectivity making use of region of interest analysis (ROI) was used to study the default mode network and the salience network. Results: No Significant differences in functional connectivity between regions in the default mode network (DMN) as well as the salience network (SN) were found when comparing patients with PNES to healthy control participants. Conclusions: In the current study patients with PNES do not show altered connectivity between brain regions in the default mode network as well as the salience network. Limitations and future directions of the current study will be discussed

The biological origins of rituals: An interdisciplinary perspective

Ritual behavior is ubiquitous, marking animal motor patterns, normal and psychopathological behavior in human individuals as well as every human culture. Moreover, formal features of rituals appear to be highly conserved along phylogeny and characterized by a circular and spatio-temporal structure typical of habitual behavior with internal repetition of non-functional acts and redirection of attention to the "script" of the performance. A continuity, based on highly conserved cortico-striatal loops, can be traced from animal rituals to human individual and collective rituals with psychopathological compulsions at the crossing point. The transition from "routinization" to "ritualization" may have been promoted to deal with environmental unpredictability in non-social contexts and, through motor synchronization, to enhance intra-group cohesion and communication in social contexts. Ultimately, ritual, following its biological constraints exerts a "homeostatic" function on the environment (social and non-social) under conditions of unpredictability

Obsessive-Compulsive Disorder

Although Obsessive-Compulsive Disorder (OCD) has been known since the ancient times, the exact etiology and pathogenesis of OCD unfortunately still remain unknown. In addition, the therapeutic approaches elaborated for the treatment of OCD as a whole are not perfect, and this disorder as a rule is characterized by unfavorable course and lack of full therapeutic response. In the current book some modern data on pathogenesis, phenomenology and treatment of OCD are presented. Besides, the data on co-morbidity of OCD with other neurological and psychiatric disorders are also included. This book is intended for broad circle of readers, but mostly for psychiatrists, psychologists and neurologists

Kainate receptor auxiliary subunits NETO1 and NETO2 in anxiety and fear-related behaviors

Anxiety disorders are the most prevalent mental illnesses in Europe, yet, their molecular basis is poorly understood. Unraveling the molecular mechanisms underlying the occurrence and maintenance of anxiety is crucial for effective drug development to treat anxiety disorders. In this thesis work, I focused on the NETO1 and NETO2 auxiliary proteins for kainate receptors (KARs) that tightly modulate the functional properties of the receptor. Because variants in KAR genes have been associated with psychiatric diseases in humans, and with anxiety-like behavior in mice, we hypothesized that NETO1 and NETO2 regulate anxiety through their modulation of KARs. Therefore, the aim of this thesis was to investigate the role of NETO1 and NETO2 in the regulation of anxiety and fear, and to evaluate their potential as novel treatment targets for anxiety disorders. To test our hypothesis, I first carried out a comprehensive behavioral screen of Neto1+/+, Neto1-/-, Neto2+/+ and Neto2-/- mouse anxiety-like and fear-related behaviors. We showed that neither NETO1 nor NETO2 regulated anxiety-like behavior in mice. However, Neto2-/- mice had reduced activity in novel environments without effect on locomotor activity in familiar environments, stress physiology or depression-like behaviors. In cued fear conditioning, Neto2-/- but not Neto1-/- mice had increased fear expression and delayed extinction. To establish the molecular and cellular mechanisms modulating the fear phenotype of the Neto2-/- mice, I investigated its expression pattern by in situ hybridization in the core fear network, composed of the medial prefrontal cortex, the amygdala and the hippocampus. Neto2 was widely expressed in all of these regions and in both excitatory and inhibitory neurons. Accordingly, the NETO2 protein was detectable in the same regions. We next established that in the synapses of these brain regions, the abundance of GLUK2/3 and GLUK5 KAR subunits was reduced 20–40% in the absence of NETO2. By focusing on the amygdala, the central brain region for the processing of fear-inducing stimuli and fear learning, we observed immature features of parvalbumin-expressing inhibitory neurons in Neto2-/- mice. Furthermore, we found a higher amplitude and frequency of miniature excitatory post-synaptic currents specifically in the basolateral amygdala, which is a critical brain region for fear memory consolidation. Concurrent with these results, dendritic spine density in thin dendrites was higher in Neto2-/- compared to Neto2+/+ mice. Taken together, these findings imply stronger glutamatergic synapses within the amygdala in the absence of NETO2. Finally, using the c-Fos immediate early gene as a marker for neuronal activation, we found increased activation of amygdala neurons in Neto2-/- compared to Neto2+/+ mice after fear acquisition. Higher activation of the amygdala may be related to stronger associative learning and be represented behaviorally by higher levels of fear expression during fear conditioning. To summarize, we showed that in the absence of NETO2, mice demonstrate higher conditioned fear expression and extinction delay suggestive of a higher overall conditionability, which is a symptom of posttraumatic stress disorder (PTSD). Furthermore, we established that neither Neto1 nor Neto2 is required for innate anxiety-like behaviors. We propose that the reduced KAR abundance at the synapses of Neto2-/- mice, together with the immaturity and increased excitability of the amygdala, and with the stronger activation of local circuits within the amygdala during fear acquisition underlie the higher conditionability and delayed fear extinction phenotype. Our findings suggest directions for future mechanistic studies on the role of NETO2 in fear conditionability. Taken together, this work showed for the first time that Neto2 is required for normal fear expression and conditioning, and that it modulates amygdala function during associative fear learning, findings with putative therapeutic significance for PTSD.Ahdistuneisuushäiriöt ovat yleisimpiä mielenterveyden häiriöitä, mutta niiden molekyylitason syntymekanismeista tiedetään vasta vähän. Näiden mekanismien selvittäminen on tärkeää henkilökohtaistettujen hoitomuotojen kehittämiseksi. Tässä väitöskirjatyössä tutkittiin NETO1- ja NETO2-proteiineja, jotka sitoutuvat kainaattireseptoreihin (KAR) ja säätelevät niiden toiminnallisia ominaisuuksia. Koska KAR:ien tietyt geenimuodot ovat ihmisellä yhdistetty psykiatrisiin sairauksiin ja hiirillä ahdistuneisuustyyppiseen käyttäytymiseen, hypoteesimme oli, että NETO1 ja NETO2 säätelevät ahdistuneisuutta KAR:ien välityksellä. Väitöskirjatyössä tutkimme NETO1:n ja NETO2:n roolia ahdistuneisuuden ja pelon säätelyssä, sekä mahdollisina uusina hoitokohteina ahdistuneisuushäiriöissä. Selvitimme ensin käyttäytymiskokein Neto1+/+-, Neto1-/--, Neto2+/+- sekä Neto2-/--hiirten ahdistustyyppistä- ja pelkokäyttäytymistä. Osoitimme, ettei Neto1 tai Neto2 säätele ahdistustyyppistä käyttäytymistä hiirellä. Neto2-/--hiirten aktiivisuus oli kuitenkin vähentynyt uudessa ympäristössä. Näiden hiirten aktiivisuus kotihäkissä oli normaalia, eikä niillä ollut muutoksia stressifysiologiassa tai masennustyyppisessä käyttäytymisessä. Testasimme sekä Neto1-/-- että Neto2-/--hiirten pelkoehdollistumista ehdolliseen ärsykkeeseen. Neto1-/--hiiret eivät eronneet verrokeista, mutta Neto2-/--hiirten pelkokäyttäytyminen oli voimakkaampaa ja pelkoehdollistumisen purkautuminen hitaampaa kuin verrokkihiirillä. Tutkimme seuraavaksi in situ hybridisaatiolla missä soluissa Neto2 ilmentyy aivojen pelkoverkostoon kuuluvilla aivoalueilla (mediaalinen etuotsalohko, mantelitumake ja aivoturso). Neto2 ilmentyi laajasti kaikilla näillä alueilla, sekä eksitoivissa että inhiboivissa hermosoluissa. Vastaavasti, NETO2-proteiini ilmentyi samoilla aivoalueilla. Seuraavaksi osoitimme, että NETO2:n puuttuessa näiden alueiden synapseissa GLUK2/3 ja GLUK5 KAR-alayksiköiden määrä väheni 20-40 %. Väitöskirjan toinen osatyö keskittyi tutkimaan mantelitumaketta, joka prosessoi pelkoärsykkeitä ja on tärkeä aivoalue pelko-oppimisessa. Tutkimme amygdalan parvalbumiinia ilmentävien hermosolujen ja perineuronaalisten verkostojen lukumäärää ja osoitimme, että näiden amygdalan erilaistumiseen yhdistettyjen markkereiden määrä oli muuttunut Neto2-/--hiirillä, viitaten siihen, että Neto2 säätelee amygdalan kypsymistä. Lisäksi havaitsimme, että näiden hiirten miniatyyrisilla eksitoivilla postsynaptisilla virroilla oli suurempi amplitudi sekä taajuus basolateraalisessa amygdalassa, joka säätelee pelkoon liittyvien muistijälkien konsolidaatiota. Näihin tuloksiin sopien, Neto2-/--hiirillä oli Neto2+/+-hiiriin verrattuna enemmän haarakkeita ohuissa tuojahaarakkeissa. Tuloksemme viittaavat siihen, että NETO2:n puute mantelitumakkeessa vahvistaa glutamatergisia synapseja. Käyttäen c-FOS-proteiinia hermosolujen aktiivisuuden markkerina, osoitimme, että pelkoon liittyvän muistijäljen muodostuminen liittyi voimakkaampaan mantelitumakkeen hermosolujen aktivoitumiseen Neto2-/-- kuin Neto2+/+-hiirillä. Mantelitumakkeen voimakkaampi aktivaatio voi liittyä vahvempaan assosiatiiviseen oppimiseen, ja se voi esiintyä käyttäytymistasolla voimakkaampana pelon ilmentymisenä pelkoehdollistumisen aikana. Osoitimme siis, että NETO2 tarvitaan normaaliin pelkoehdollistumiseen ja sen purkautumiseen. Molemmat ilmiöt liittyvät korkeampaan ehdollistettavuuteen, mikä on yksi traumaperäisen stressihäiriön oire. Lisäksi osoitimme, etteivät Neto1 tai Neto2 ole välttämättömiä luontaiselle ahdistustyyppiselle käyttäytymiselle. Esitämme, että Neto2-/--hiirten pelkoehdollistumisfenotyyppi johtuu sekä kainaattireseptorien alhaisemmasta määrästä pelkoa säätelevillä aivoalueilla, että erityisesti amygdalan kehityksen ja toiminnan häiriöistä. Tämä väitöskirjatutkimus osoitti ensimmäisenä, että Neto2 tarvitaan normaaliin pelkokäyttäytymiseen ja –ehdollistumiseen, ja että se säätelee mantelitumakkeen toimintaa assosiatiivisessa pelko-oppimisessa. Nämä tulokset auttavat ymmärtämään traumaperäisen stressihäiriön neurobiologisia mekanismeja ja voivat olla avuksi uusien hoitomuotojen kehittämisessä

Pavlovian-to-Instrumental Transfer across Mental Disorders: A Review

A mechanism known as Pavlovian-to-instrumental transfer (PIT) describes a phenomenon by which the values of environmental cues acquired through Pavlovian conditioning can motivate instrumental behavior. PIT may be one basic mechanism of action control that can characterize mental disorders on a dimensional level beyond current classification systems. Therefore, we review human PIT studies investigating subclinical and clinical mental syndromes. The literature prevails an inhomogeneous picture concerning PIT. While enhanced PIT effects seem to be present in non-substance-related disorders, overweight people, and most studies with AUD patients, no altered PIT effects were reported in tobacco use disorder and obesity. Regarding AUD and relapsing alcohol-dependent patients, there is mixed evidence of enhanced or no PIT effects. Additionally, there is evidence for aberrant corticostriatal activation and genetic risk, e.g., in association with high-risk alcohol consumption and relapse after alcohol detoxification. In patients with anorexia nervosa, stronger PIT effects elicited by low caloric stimuli were associated with increased disease severity. In patients with depression, enhanced aversive PIT effects and a loss of action-specificity associated with poorer treatment outcomes were reported. Schizophrenic patients showed disrupted specific but intact general PIT effects. Patients with chronic back pain showed reduced PIT effects. We provide possible reasons to understand heterogeneity in PIT effects within and across mental disorders. Further, we strengthen the importance of reliable experimental tasks and provide test-retest data of a PIT task showing moderate to good reliability. Finally, we point toward stress as a possible underlying factor that may explain stronger PIT effects in mental disorders, as there is some evidence that stress per se interacts with the impact of environmental cues on behavior by selectively increasing cue-triggered wanting. To conclude, we discuss the results of the literature review in the light of Research Domain Criteria, suggesting future studies that comprehensively assess PIT across psychopathological dimensions

Identifying emotional components of event-related potentials in the brain functioning of individuals with contamination obsessions and comparison with healthy control group

The present study aimed to examine the emotional components of event-related potentials (ERPs) in individuals with contamination OCD and compare them with a healthy control group. A convenience sample of 45 participants was included, consisting of 30 individuals diagnosed with contamination-type OCD and 15 individuals in a healthy control group. Both groups participated in an ERP study where they encountered a computer-based task presenting both contamination and neutral pictures, while their brain activity was recorded. The data were analyzed using repeated measures analysis of variance (RANOVA) with SPSS-24 and Matlab software. Findings suggest that in P3 amplitude, only individuals with OCD exhibited a larger positive amplitude (p < 0.05) in response to contaminated pictures compared to neutral pictures and in N2 amplitude, only individuals with OCD exhibited a larger negative amplitude (p < 0.05) in response to contaminated pictures compared to neutral pictures in the central vertex (Fz). These findings hold promising implications for the development of more targeted and effective treatments for contamination OCD, emphasizing the importance of emotion-oriented approaches to address the unique neural patterns observed in the frontal vertex