Brain circuitry of compulsivity.

Compulsivity is associated with alterations in the structure and the function of parallel and interacting brain circuits involved in emotional processing (involving both the reward and the fear circuits), cognitive control, and motor functioning. These brain circuits develop during the pre-natal period and early childhood under strong genetic and environmental influences. In this review we bring together literature on cognitive, emotional, and behavioral processes in compulsivity, based mainly on studies in patients with obsessive-compulsive disorder and addiction. Disease symptoms normally change over time. Goal-directed behaviors, in response to reward or anxiety, often become more habitual over time. During the course of compulsive disorders the mental processes and repetitive behaviors themselves contribute to the neuroplastic changes in the involved circuits, mainly in case of chronicity. On the other hand, successful treatment is able to normalize altered circuit functioning or to induce compensatory mechanisms. We conclude that insight in the neurobiological characteristics of the individual symptom profile and disease course, including the potential targets for neuroplasticity is an unmet need to advance the field.Dr. Soriano-Mas is funded by a ׳Miguel Servet׳ contract from the Carlos III Health Institute (CP10/00604). Dr. Goudriaan is supported by a VIDI Innovative Research Grant (Grant no. 91713354) funded by the Dutch Scientific Research Association (NWO-ZonMW). Dr. Alonso was funded by the Instituto de Salut Carlos III-FISPI14/00413. Dr. Nakamae received Grant support from MEXT KAKENHI (Nos. 24791223 and 26461753).This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.euroneuro.2015.12.00

Imaging Pain Relief in Osteoarthritis (IPRO): protocol of a double-blind randomised controlled mechanistic study assessing pain relief and prediction of duloxetine treatment outcome

Introduction: Osteoarthritis (OA) pain is a major cause of long-term disability and chronic pain in the adult population. One in five patients does not receive satisfactory pain relief, which reflects the complexity of chronic pain and the current lack of understanding of mechanisms of chronic pain. Recently, duloxetine has demonstrated clinically relevant pain relief, but only in half of treated patients with OA. Here the aim is to investigate the neural mechanisms of pain relief and neural signatures that may predict treatment response to duloxetine in chronic knee OA pain. Methods and analysis: This is an ongoing single-centre randomised placebo-controlled mechanistic study (2:1 [placebo] allocation), using a multi-modal neuroimaging approach, together with psychophysiological [quantitative sensory testing], genetics and questionnaire assessments. Eighty-one subjects with chronic knee OA pain are planned to power for between group comparisons (placebo, duloxetine-responder, and duloxetine-non-responder). Participants have a baseline assessment and, following six weeks of duloxetine (30mg for two weeks, then 60mg for four weeks), a follow-up evaluation. Brain imaging is performed at 3T with blood-oxygen-level dependent functional magnetic resonance imaging at rest and during pin-prick nociceptive stimulation for main outcome assessment; arterial spin labelling and structural imaging (T1- weighted) for secondary outcome assessment. Questionnaires evaluate pain, negative affect, quality of sleep and cognition. Ethics and dissemination: The study has been approved by the East Midlands – Nottingham 2 research ethics committee (18/EM/0189) and is being carried out under the principles of the Declaration of Helsinki (64th, 2013) and Good Clinical Practice standards. Results will be disseminated in peer-reviewed journals and at scientific conferences

Masennuslääkkeiden vaikutukset tunteiden käsittelyyn

Vertaisarvioitu. English summaryPeer reviewe

Masennuslääkkeiden vaikutukset tunteiden käsittelyyn

Masennukseen liittyy emotionaalisen tiedon käsittelyn vääristymiä. Masennuspotilaat esimerkiksi muistavat ja tulkitsevat ympäristön tapahtumia negatiivisesti vääristyneellä tavalla. Masennuksen eri hoitomuodot pyrkivät muovaamaan näitä vääristymiä. Myös masennuslääkkeet vaikuttavat emotionaalisen tiedon käsittelyyn jo ennen kuin masennusoireet väistyvät. Masennuslääkkeet heikentävät aivojen tunneverkoston keskeisten alueiden reaktiivisuutta negatiivisiin ärsykkeisiin ja voimistavat reaktiivisuutta positiivisiin ärsykkeisiin. Dorsolateraalisen etuaivokuoren aktiivisuus voimistuu, mikä viittaa parantuneeseen tunteiden säätelyyn. Masennuslääkkeet vaikuttavat myös laaja-alaisten aivoverkostojen toiminnallisiin yhteyksiin. Nämä varhaiset emotionaalisen prosessoinnin muutokset vaikuttavat ennustavan viikkoja myöhemmin saavutettavaa hoitovastetta. Emotionaalisen tiedonkäsittelyn muutokset saattaisivat siis toimia hoidon valintaa ohjaavina ennustetekijöinä, joita ei nykyisin ole kliinisessä käytössä. Masennuslääkkeiden vaikutusmekanismien tunteminen systeemitasolla on tärkeää myös uusien hoitomuotojen kehittämisen kannalta.</p

Early effects of antidepressants on emotional processing

Introduction: The mechanisms of action of antidepressants at the system level remain mainly unresolved. Antidepressants rapidly modulate emotional processing, enhancing processing of positive versus negative information, but this has been mostly demonstrated in healthy subjects and using fairly simple, controlled emotional stimuli such as emotional faces. Aim of the study: The aim of the studies of this thesis was to shed light on early antidepressant effects on emotional processing both in healthy subjects, avoiding the confounding effect of depressed mood, and in treatment-seeking depressed patients at an early stage of treatment, to elude the confounding effect of improved mood. The studies specifically aimed to reveal antidepressant effects on self-referential processing, a core factor in psychopathology of depression, and to investigate whether/how antidepressants modulate processing of complex, dynamic emotional stimuli resembling daily-life emotional situations. Methods: In Study 1 (experiments I and II), an open-label study of 30 healthy volunteers, half of the subjects received mirtazapine 15 mg two hours prior to functional magnetic resonance imaging (fMRI), and the other half was scanned without medication as a control group. Study 2 (experiments III and IV) was a double-blind, placebo-controlled study where 32 treatment-seeking depressed patients were randomized to receive escitalopram 10 mg or placebo for one week, after which fMRI was performed. In experiments I and III, neural responses to positive and negative self-referential adjectives as well as a neutral control task were assessed. In experiments II and IV participants listened to spoken emotional narratives and neural responses to the emotional content of the narratives were assessed. Results: Both mirtazapine in healthy subjects and escitalopram in depressed patients modulated self-referential processing. Mirtazapine attenuated responses to both positive and negative self-referential words in the anterior cortical midline structures (CMS, including the medial prefrontal cortex and the anterior cingulate), whereas escitalopram increased processing of positive relative to negative self-referential words. When comparing the placebo group and the escitalopram group from Study 2 separately with the healthy controls from Study 1, depressed patients receiving placebo had decreased responses of the anterior CMS to positive versus negative self-referential words, whereas no differences were found between the escitalopram group and healthy controls, implicating normalization of the negative bias in depressed patients receiving escitalopram. Both mirtazapine and escitalopram also modulated brain responses to spoken emotional narratives. Mirtazapine was found to modulate dynamic functional connectivity (measured with seed-based phase synchronization) of large-scale brain circuits, particularly potentiating functional connectivity of the anterior CMS and the limbic regions during positive parts of the narratives. Escitalopram increased synchronization of brain responses (measured with inter-subject correlation, ISC), specifically during positive parts of the narratives. Conclusions: A single dose of mirtazapine in healthy subjects and a one-week treatment with escitalopram in treatment-seeking depressed patients modulated neural responses to emotional information without any concurrent changes in mood. Both antidepressants modulated self-referential processing, a core psychological process in developing and maintaining depression. Escitalopram normalized the negatively biased self-referential processing of depressed patients in the anterior CMS. Both mirtazapine and escitalopram modulated brain responses to spoken emotional narratives, extending the previous findings of antidepressant effects based on simple emotional stimuli to complex, dynamic, every-day like emotional situations. Specifically, potentiated processing measured with novel methods of dynamic functional connectivity and ISC was found in the anterior CMS among other regions during positive emotional content of the narratives. These results suggest that antidepressants rapidly modulate processing of particularly positive emotional and self-referential information in the anterior CMS. This may be important for their later therapeutic effect.Johdanto: Masennuslääkkeiden vaikutusmekanismeja systeemitasolla tunnetaan yhä heikosti. Niiden tiedetään vaikuttavan nopeasti tunteiden prosessointiin voimistamalla positiivisen informaation prosessointia negatiiviseen verrattuna. Tämä vaikutus on kuitenkin osoitettu lähinnä terveillä koehenkilöillä sekä käyttäen koeasetelmissa yksinkertaisia ärsykkeitä, kuten emotionaalisia kasvokuvia. Tavoitteet: Tämän väitöskirjatyön osatutkimusten tavoitteena oli selvittää masennuslääkkeiden varhaisia vaikutuksia tunteiden prosessointiin sekä terveillä koehenkilöillä, välttäen näin masentuneen mielialan sekoittava vaikutus, että masentuneilla potilailla hoidon varhaisessa vaiheessa, välttäen näin korjaantuvan mielialan sekoittava vaikutus. Erityisesti tavoitteena oli tutkia masennuslääkkeiden vaikutusta itseen liittyvään prosessointiin, koska liiallinen keskittyminen omiin, usein negatiivisiin tunteisiin ja ajatuksiin on eräs masennuksen keskeisistä psykologisista ilmiöistä. Lisäksi haluttiin selvittää, kuinka masennuslääkkeet vaikuttavat monimutkaisten, tosielämän emotionaalisia tilanteita muistuttavien ärsykkeiden prosessointiin. Menetelmät: Osatutkimuksessa 1 (koeasetelmat I ja II) puolet 30 terveestä vapaaehtoisesta sai avoimessa tutkimusasetelmassa 15mg mirtatsapiinia kaksi tuntia ennen toiminnallista magneettikuvausta (fMRI) ja puolet kuvattiin verrokkiryhmänä ilman lääkitystä. Osatutkimuksessa 2 (koeasetelmat III ja IV) 32 hoitoon hakeutunutta masennuspotilasta satunnaistettiin kaksois-sokkoutetussa tutkimusasetelmassa saamaan 10mg essitalopraamia tai lumetta viikon verran, jonka jälkeen suoritettiin fMRI-kuvaus. Koeasetelmissa I ja III mitattiin aivovasteita positiivisille ja negatiivisille itseen liittyville adjektiiveille sekä neutraaleille kontrollisanoille. Koeasetelmissa II ja IV koehenkilöt kuuntelivat kuvauksen aikana tunteita herättäviä tarinoita ja tarinoiden tunnesisällön herättämät aivovasteet mitattiin. Tulokset: Sekä mirtatsapiini terveillä koehenkilöillä että essitalopraami masennuspotilailla muokkasi aivovasteita itseen liittyviä sanoja prosessoitaessa. Mirtatsapiini vaimensi sekä positiivisten että negatiivisten sanojen herättämiä vasteita odotetuilla alueilla aivojen keskilinjan kortikaalisten alueiden etuosissa (keskimmäinen etuotsalohko ja etummainen pihtipoimu), kun taas essitalopraami voimisti positiivisten sanojen prosessointia negatiivisiin nähden masennuspotilailla. Kun osatutkimuksen 2 masennuspotilaiden aivovasteita verrattiin lume- ja lääkeryhmässä erikseen osatutkimuksen 1 terveisiin verrokkeihin, havaittiin lumeryhmän reagoivan heikommin positiivisiin sanoihin negatiivisiin nähden, kun taas lääkeryhmän ja terveiden verrokeiden välillä ei ollut eroa. Essitalopraami siis palautti masennuspotilaiden negatiivisesti vääristyneen itseen liittyvän prosessoinnin normaalille, terveelle tasolle. Molemmat masennuslääkkeet muovasivat aivovasteita emotionaalisten tarinoiden tunnesisällölle. Mirtatsapiini vaikutti laaja-alaisesti aivoalueiden välisiin toiminnallisiin yhteyksiin, erityisesti voimistamalla niitä aivojen keskilinja-alueiden etuosassa ja limbisellä alueella tarinoiden positiivisuuden lisääntyessä. Essitalopraami voimisti koehenkilöiden välistä synkroniaa aivovasteissa, erityisesti positiivisen sisällön aikana. Johtopäätökset: Molemmat tutkitut masennuslääkkeet vaikuttivat tunteiden prosessointiin nopeasti, ilman samanaikaista muutosta mielialassa. Essitalopraami normalisoi masennuspotilaiden negatiivisesti vääristynyttä itseen kohdistuvaa prosessointia, jonka ajatellaan olevan tärkeä tekijä masennustilan kehittymisessä ja jatkumisessa. Molemmat tutkitut masennuslääkkeet myös muokkasivat emotionaalisten tarinoiden herättämiä aivovasteita. Tämä tulos on merkittävä lisä aiempiin löydöksiin, koska se osoittaa masennuslääkkeiden muuttavan myös monimutkaisten ja dynaamisten, lähempänä todellisia arkipäivän tunteita herättäviä tilanteita olevien emotionaalisten ärsykkeiden prosessointia. Todetut muutokset voivat olla merkittävässä roolissa myöhemmän kliinisen lääkevasteen kannalta

帯状疱疹後神経痛患者における右背外側前頭前野の血行動態の障害は、プラシーボ効果の障害および臨床症状に関与する

富山大学・富医薬博甲第323号・日比 大亮・2020/03/24公表論文IBRO Reports, Volume 8, June 2020, Pages 56-64, https://doi.org/10.1016/j.ibror.2020.01.003富山大

Antidepressants

Major depression is a severe and prevalent brain disorder with a high disability burden, hence the push for effective treatments. Antidepressants have been around since the 1950s, and although current medications are much more effective than early ones, there is still much room for improvement. "Real" antidepressants, defined as those that "repair" or "improve" the depression-causing mechanism in the brains of depressed patients, have yet to be identified. This book presents current research on depression and antidepressants, including use of antidepressants in alcohol use disorders and pregnancy, treatment-resistant depression, and development of potential new medications

State and trait characteristics of early course major depressive disorder

Contains fulltext : 109595.pdf (Publisher’s version ) (Open Access)Radboud Universiteit Nijmegen, 21 december 2012Promotores : Buitelaar, J.K., Fernandez, G.S.E. Co-promotor : Tendolkar, I

Glycogen Synthase Kinase-3β: An Investigation Of The Novel Serine 389 Phosphorylation Site

Stress associated psychiatric disorders such as depression, anxiety, and post-traumatic stress disorder affect a large proportion of the population. Reductions in the complexity of neuronal morphology and reduced neurogenesis are commonly observed outcomes following stress exposure in rodent models and may represent a mechanism for the reduced brain volume in stress sensitive regions such as the hippocampus observed in individuals diagnosed with stress associated disorders. Multiple lines of evidence suggest that glycogen synthase kinase (GSK)-B may play a role in the neurodegenerative phenotype observed following stress exposure. GSK3B is atypical in that it is inhibited by phosphorylation. This inhibitory phosphorylation has typically been studied by examining the phosphorylation state of the serine 9 (S9) site. Inhibition of GSK3B is implicated in synaptic stabilization, increased expression of trophic factors that support dendritic complexity and neurogenesis, reduced apoptosis, and the antidepressive effects of currently implemented therapeutics. It is surprising then that little research has examined the regulation of GSK3B by stress. A novel GSK3B phosphorylation site, serine 389 (S389), has recently been described that is regulated by p38 mitogen activated protein kinase (MAPK) and is independent of S9 phosphorylation by AKT. p38 MAPK is implicated in the behavioral effects of stress exposure making an understanding of its interaction with GSK3B S389 phosphorylation during stress a compelling research target. The current studies examine GSK3B regulation following variate stress exposure in stress reactive brain regions, describe the anatomical specificity of GSK3B S389 phosphorylation in the brain, and detail the behavioral phenotype of a novel mutant mouse that cannot inhibit GSK3B by S389 phosphorylation (GSK3B KI). Region specific changes in GSK3B phosphorylation were observed following stress exposure, as well as voluntary exercise, a behavior that confers stress resistance. Elevated GSK3B S389 phosphorylation was associated with increased levels of phosphorylated p38 MAPK. This pathway is implicated in the response to DNA damage, and, surprisingly, we observed that histone H2A-variant-X (H2A.X), a marker of DNA damage, was elevated following stress and exercise. Accumulated DNA damage is a proposed driver of neurodegeneration suggesting that the pathway activated by stress may be engaged to protect against such decline. Consistent with a role in the response to DNA damage, we observed a primarily nuclear localization of GSK3B S389 phosphorylation in the brain while S9 phosphorylation was found in nuclear and cytosolic compartments. Further, we observed neurodegeneration in hippocampal and cortical regions of GSK3B KI mice supporting the idea that the inhibition of GSK3B by S389 phosphorylation observed following stress and exercise may be protective. Though largely similar to wild type mice in behavioral tests, increased auditory fear conditioning was evident in GSK3B KI mice. Contextual and cued freezing was prolonged in GSK3B KI mice, a phenotype that is commonly observed in stress models. Together these findings suggest that GSK3B S389 phosphorylation is playing a critical role in neuronal integrity that is independent of GSK3B S9 phosphorylation, and that the subset of neurons protected by GSK3B S389 phosphorylation may play an important role in preventing a portion of the maladaptive behavioral changes observed following stress exposure