Opposing roles for amygdala and vmPFC in the return of appetitive conditioned responses in humans

Learning accounts of addiction and obesity emphasize the persistent power of Pavlovian reward cues to trigger craving and increase relapse risk. While extinction can reduce conditioned responding, Pavlovian relapse phenomena-the return of conditioned responding following successful extinction-challenge the long-term success of extinction-based treatments. Translational laboratory models of Pavlovian relapse could therefore represent a valuable tool to investigate the mechanisms mediating relapse, although so far human research has mostly focused on return of fear phenomena. To this end we developed an appetitive conditioning paradigm with liquid food rewards in combination with a 3-day design to investigate the return of appetitive Pavlovian responses and the involved neural structures in healthy subjects. Pavlovian conditioning (day 1) was assessed in 62 participants, and a subsample (n = 33) further completed extinction (day 2) and a reinstatement test (day 3). Conditioned responding was assessed on explicit (pleasantness ratings) and implicit measures (reaction time, skin conductance, heart rate, startle response) and reinstatement effects were further evaluated using fMRI. We observed a return of conditioned responding during the reinstatement test, evident by enhanced skin conductance responses, accompanied by enhanced BOLD responses in the amygdala. On an individual level, psychophysiological reinstatement intensity was significantly anticorrelated with ventromedial prefrontal cortex (vmPFC) activation, and marginally anticorrelated with enhanced amygdala-vmPFC connectivity during late reinstatement. Our results extend evidence from return of fear phenomena to the appetitive domain, and highlight the role of the vmPFC and its functional connection with the amygdala in regulating appetitive Pavlovian relapse

Body weight changes and incidence of cachexia after stroke

Background: Body weight loss is a frequent complication after stroke, and its adverse effect on clinical outcome has been shown in several clinical trials. The purpose of this prospective longitudinal single-centre observational study was to investigate dynamical changes of body composition and body weight after ischemic stroke and an association with functional outcome. Methods: Sixty-seven consecutive patients (age 69 ± 11 years, body mass index 27.0 ± 4.1 kg/m2, 42% female patient, mean ± SD) with acute ischemic stroke with mild to moderate neurological deficit (National Institute of Health Stroke Scale median 4, ranged 0–12) were analysed in the acute phase (4 ± 2 days) and at 12 months (389 ± 26 days) follow-up. Body composition was examined by dual energy X-ray absorptiometry. Cachexia was defined according to the consensus definition by body weight loss ≥5% within 1 year and additional clinical signs. Lean tissue wasting was considered if a ratio of upper and lower limbs lean mass sum to squared height (kg/m2) was ≤5.45 kg/m2 for female patient and ≤7.25 kg/m2 for male patient. Results: According to the body weight changes after 12 months, 42 (63%) patients had weight gain or stable weight, 11 (16%) patients had moderate weight loss, and 14 (21%) patients became cachectic. A relative decline of 19% of fat tissue and 6.5% of lean tissue was observed in cachectic patients, while no changes of lean tissue were observed in non-cachectic patients after 12 months. The modified Rankin Scale was 48% higher (2.1 ± 1.6, P < 0.05), Barthel Index was 22% lower (71 ± 39, P < 0.01), and handgrip strength was 34% lower (21.9 ± 13.0, P < 0.05) in cachectic compared to non-cachectic patients after 12 months. The low physical performance if defined by Barthel Index <60 points was linked to the lean tissue wasting (OR 44.8, P < 0.01), presence of cachexia (OR 20.8, P < 0.01), and low body mass index <25 kg/m2 (OR 11.5, P < 0.05). After adjustment for cofounders, lean tissue wasting remained independently associated with the low physical performance at 12 months follow-up (OR 137.9, P < 0.05). Conclusions: In this cohort study, every fifth patient with ischemic stroke fulfilled the criteria of cachexia within 12 months after index event. The incidence of cachexia was 21%. Cachectic patients showed the lowest functional and physical capacity

Mechanisms of appetitive classical conditioning and extinction in healthy human subjects

Die appetitiven Pawlow’schen Lernmechanismen der Konditionierung, Extinktion und des Reinstatements sind von entscheidender Bedeutung für das Verständnis der Entstehung, Aufrechterhaltung, Therapie und Rückfallphänomene von Abhängigkeitserkrankungen. Bislang mangelt es an Studien, die appetitive Konditionierungs- und Extinktionsprozesse im Humanmodell untersuchen, während Reinstatement-Effekte gänzlich unerforscht sind. Dieser Mangel wird gewöhnlich auf die Schwierigkeit zurückgeführt, ein geeignetes psychophysiologisches Maß zu finden, das sensitiv konditionierte Reaktionen beim Menschen erfasst. Die vorliegende Dissertation zielte daher darauf ab, die behavioralen, physiologischen und neuronalen Korrelate appetitiver Pawlow’scher Lernprozesse in gesunden Probanden zu erkunden. Studie I untersuchte die Eignung von Eyetracking-Maßen zur Abbildung konditionierter Reaktionen in appetitiven Lernparadigmen und verglich diese mit weiteren psychophysiologischen Maßen. Zusätzlich wurde geprüft, ob sich Lernprozesse anhand des Pupillenverhaltens mit Hilfe computationaler Modellierung ableiten lassen. Konditionierte Reaktionen zeigten sich durch stärkere Pupillendilatation, längere Blickverweildauer und eine kürzere Lidschlagdauer auf den belohnungsankündigenden Stimulus. Das Pearce-Hall-Modell mit aufmerksamkeitsgewichtetem Prädiktionsfehler konnte die Pupillenreaktion am besten vorhersagen. In Studie II wurde untersucht, ob sich der appetitive Reinstatement-Effekt als Modell des Rückfallgeschehens psychophysiologisch abbilden lässt und welche neuronalen Strukturen diesem Lernprozess zugrunde liegen. Ein erfolgreiches Reinstatement konnte anhand der Hautleitfähigkeitsreaktion festgestellt werden und wurde auf neuronaler Ebene durch eine erhöhte Amygdala-Aktivierung gezeigt. Die vmPFC-Aktivität korrelierte negativ mit dem beobachteten Reinstatement-Effekt der Hautleitfähigkeit. Diese Ergebnisse belegen den Wert von Eyetracking-Maßen als robuste und sensitive Indizes appetitiver Konditionierungsprozesse und weisen der Amygdala und dem vmPFC gegenläufige Funktionen bei Pawlow’schen Rückfallprozessen zu. Damit tragen die Ergebnisse zu einem größeren Verständnis von appetitiven Lernprozessen beim Menschen bei und liefern wertvolle neue Maße und Erkenntnisse, um Abhängigkeitserkrankungen besser zu untersuchen und zu verstehen.Appetitive Pavlovian learning mechanisms like conditioning, extinction and reinstatement are of fundamental importance for the understanding of the etiology, maintenance, treatment and relapse of addiction disorders. The investigation of appetitive conditioning and extinction in humans remains sparse, while reinstatement has thus far never been successfully modeled in humans. This paucity is commonly attributed to the lack of an adequate psychophysiological measure that sensitively reflects conditioned responding. The aim of this thesis was to explore the behavioral, physiological and neural correlates of appetitive Pavlovian learning processes in healthy participants. Study I evaluated the applicability of eye-tracking measures for representing conditioned responding and compared them to further psychophysiological measures. Additionally, this study investigated whether learning mechanisms could be inferred from the pupil response using computational modeling techniques. Conditioned responding was reflected through greater pupil dilation, longer gaze duration and shorter eye blink duration on the reward-predicting stimulus. A Pearce-Hall attention-weighted model most accurately predicted the trial-by-trial pupil response. Study II examined whether appetitive reinstatement could be psychophysiologically modeled in humans and what neural structures underlie this learning process. Successful reinstatement was indicated through an enhanced skin conductance response and correlated positively with amygdala activation, while vmPFC activation correlated negatively with the reinstatement effect observed in the skin conductance response. These results emphasize the value of eye-tracking measures as robust and sensitive indices for measuring appetitive conditioning processes and assign amygdala and vmPFC opposing roles in the return of Pavlovian reinstatement processes. These results thereby contribute to our knowledge of appetitive learning mechanisms in humans and provide valuable new measures and insights for exploring and understanding addiction disorders

Heart failure and sleep‐disordered breathing : susceptibility to reduced muscle strength and preclinical congestion (SICA‐HF cohort)

Aims Increased sympathetic activation in patients with heart failure (HF) and sleep-disordered breathing (SDB) provokes cardiac decompensation and protein degradation and could lead to muscle wasting and muscle weakness. The aim of this study was to investigate the differences in body composition, muscle function, and the susceptibility of preclinical congestion among patients with HF and SDB compared with those without SDB. Methods and results We studied 111 outpatients with stable HF who were enrolled into the Studies Investigating Co-morbidities Aggravating Heart Failure. Echocardiography, short physical performance battery (SPPB), cardiopulmonary exercise testing, dual-energy X-ray absorptiometry, bioelectrical impedance analysis (BIA), tests of muscle strength, and polygraphy were performed. SDB was defined as apnoea/hypopnoea index (AHI) >5 per hour of sleep. Central sleep apnoea (CSA) and obstructive sleep apnoea (OSA) were defined as AHI >50% of central or obstructive origin, respectively. A total of 74 patients (66.7%) had any form of SDB [CSA (24 patients, 32.4%), OSA (47 patients, 63.5%)]. Patients with SDB showed increased muscle weakness (chair stand), reduced muscle strength, and lower values of SPPB score (P < 0.05). Patients with SDB did not show overt clinical signs of cardiac decompensation compared with those without SDB (P > 0.05) but had increased amounts of water (total body water, intracellular, and extracellular) measured using BIA (P < 0.05). Increased amounts of total body water were associated with the severity of SDB and inversely with muscle strength and exercise capacity measured by anaerobic threshold (P < 0.05). Altogether, 17 patients had muscle wasting. Of these, 11 (65%) patients had SDB (statistically not significant). Conclusions SDB is highly prevalent in patients with HF. Patients with SDB have lower muscle strength and tend to be more susceptible to preclinical congestion.Projekt DEAL 202