Barbara Saum

Reelin, Disabled 1, and β1 integrins are required for the formation of the radial glial scaffold in the hippocampus

The extracellular matrix molecule Reelin is required for the correct positioning of neurons during the development of the forebrain. However, the mechanism of Reelin action on neuronal migration is poorly understood. Reelin is assumed to act on neurons directly, but it may also affect the differentiation of glial cells necessary for neuronal migration. Here we show that a regular glial scaffold fails to form in vivo in the dentate gyrus of mice deficient of Reelin or Disabled 1, a neuronal adaptor protein in the Reelin signaling pathway. A subset of these defects is observed in mice that lack β1-class integrins, known to bind Reelin. Moreover, recombinant Reelin induced branching of glial processes in vitro. Our data suggest that Reelin affects glial differentiation via Disabled 1 and β1-class integrin-dependent signaling pathways.

Amygdala hyperreactivity in restrictive anorexia nervosa

Functional imaging studies had often investigated heterogeneous samples of anorexia nervosa (AN) patients with varying paradigms and methodologies that had resulted in divergent results. The present study aimed to examine these issues by studying a well-defined sample of restrictive AN patients with a disorder-specific paradigm which had been used previously. Subjects showed increased blood oxygen level dependent responses of the cingulate, frontal, insular and parietal cortices. Group comparisons demonstrated increased activity of the right amygdala in the sample of restrictive AN patients. Our results are in support of other recently published functional imaging studies and point to a pivotal role of the right amygdala in AN. Signals of the midcingulum were reduced in comparison to healthy controls. The constellation of increased activity of the amygdala and decreased activity of the cingulate cortex likely represents parts of a negative feedback loop of emotional processing. Disgust ratings correlated with the amygdala signal negatively, which points to the complex role of this structure within eating disorders.

Grey matter deficit in long-term recovered anorexia nervosa patients.

OBJECTIVE Cerebral grey matter (GM) reduction has repeatedly been shown in anorexia nervosa (AN). Evidence concerning completeness of GM restitution in recovered patients is contradictory. METHODS Five long-term recovered patients with AN were compared to symptomatic subjects and healthy controls using voxel-based morphometry. Whole brain GM, white matter and cerebrospinal fluid fractions were studied. Additionally, voxels that had shown significant GM reductions in symptomatic patients were investigated. RESULTS Recovered subjects had been severely affected when symptomatic (mean body mass index: 12.1 kg/m²) and were in remission for a very long time period (>5 years). Whole brain tissue fractions did not differ from controls. Regional analysis showed persistent GM volume reduction, in particular of the precuneus. CONCLUSIONS This study further supports the assumption that GM volume restitution is incomplete in subjects, who had previously been severely affected by anorexia nervosa. The meaning of GM reduction in long-term recovered AN patients, that is, its pathophysiological relevance, however, remains unclear. Furthermore, the precise aetiology of GM reduction remains an open question.

Frontocingular Dysfunction in Bulimia Nervosa when Confronted with Disease‐specific Stimuli

OBJECTIVE Bulimia nervosa (BN) is characterized by dysregulation of impulse control, in other words, uncontrolled eating. Functional neuroimaging studies have been sparse and have used variable methodologies. METHOD Thirteen medication-free female BN patients and 13 female healthy controls were investigated by functional magnetic resonance imaging using a disease-specific food paradigm. Stimuli were rated after the scanning procedure. RESULTS Bulimia nervosa patients showed increased fear ratings and a trend for increased disgust. Magnetic resonance imaging data of 10 BN patients could be analysed. Three BN patients had to be excluded from the analysis because of minimal blood oxygen level dependent signals. Compared with healthy controls, BN patients showed less activation of the anterior cingulate cortex, which extended into the lateral prefrontal cortex. Furthermore, the right temporal pole showed decreased reactivity. DISCUSSION This study substantiates a key role of lateral prefrontal dysfunction in BN, a brain region involved in impulse control. Furthermore, the anterior cingulate cortex, which plays a key role in emotion processing, is dysfunctional. A major limitation of this study is the small sample size.

Distinct functional and structural cerebral abnormalities in eating disorders in the light of diagnostic classification systems.

prised the cingulate cortex as well as the parietal, temporal, insular, supplementary motor and subcortical (caudate nucleus) regions [7] . A photon emission computed tomography study reported almost reverse perfusion patterns of AN and BN when subjects were compared in the resting condition and after food intake [8] . Furthermore, using magnetic resonance spectroscopy of the anterior cingulate cortex, BN patients showed a positive correlation of glutamate with ‘drive for thinness’, whereas restrictive AN subjects did not [9] . With respect to ventromedial dysfunction (including the anterior cingulate cortex), it should however be kept With DSM-5 advancing there is a debate with respect to the classification of eating disorders (EDs). In principle, the categorical approach of DSM-IV will be kept, with anorexia nervosa (AN) and bulimia nervosa (BN) representing the main ED entities. However, there are also rationales to conceptualize ED as a continuum: Most ED patients – independent of diagnostic category – are characterized by an overevaluation of shape and weight, a strong dissatisfaction with their body and an engagement in some form of weight control behavior. They often switch diagnostic categories over time, and there is genetic cross-transmission. Furthermore, about half of ED cases do not fulfill all criteria of AN or BN. Here we raise the question whether the increasing number of neurobiological studies, in particular imaging data, might contribute to this debate. One of the first functional magnetic resonance imaging (fMRI) studies was suggestive of functional cerebral substrates common to various EDs, demonstrating increased reactivity of the medial prefrontal cortex [1] . Recent fMRI studies have shown different results. One study that used words concerning body image demonstrated an increased response of the right amygdala in AN, while ventromedial abnormalities characterized BN [2] . Investigations using visual body images yielded amygdalar activation in AN, but not in BN [3, 4] . Our group used a food paradigm, which demonstrated an increased response of the right amygdala and decreased signals of the midcingulate cortex in restrictive AN [5] , while BN patients had decreased frontocingular and temporal signals [6] . Contrasting these samples directly, BN was characterized by decreased frontocingular activation, as shown in figure 1 . A further recently published fMRI investigation used the active instruction to imagine eating the food shown in the images and compared AN with BN patients [7] . Again, differences in blood oxygen level-dependent signals were demonstrated, which comReceived: November 10, 2011 Accepted after revision: March 2, 2012 Published online: September 9, 2012

Neurobiologische Korrelate bei Essstörungen: eine explorative fMRT-Längsschnittstudie

Einleitung: Erkrankungen aus dem Bereich der Essstorungen betreffen 1–4% der jungen Frauen. Die Verlaufe sind haufig durch Chronizitat und soziale Beeintrachtigung gekennzeichnet. Es wird postuliert, dass Symptome wie Untergewicht und charakteristische Denkmuster, z.B. Angst vor Gewichtszunahme, bei Patienten mit Essstorungen in Zusammenhang mit Veranderungen neuronaler Netzwerke und deren Funktionsweise stehen. Bisherige Untersuchungen mittels fMRT zeigten veranderte Aktivierungsmuster im Frontalhirn (med. prafrontaler Kortex, ant. cingularer Kortex) bei Darbietung von visuellen Nahrungsreizen. Nach unserer Kenntnis findet sich bisher keine Langsschnittuntersuchung bei Essstorungen. Studien zu Angst- und Zwangsstorungen konnten neuronale Veranderungen unter Psychotherapie bzw. im Symptomverlauf zeigen. Das Ziel dieser Pilot-Studie ist es, mogliche Veranderungen der Aktivierungsmuster bei essgestorten Patientinnen nach visueller Stimulation mit Nahrungsreizen im Verlauf zu erheben. Methodik: Es wurden 7 Patientinnen mit Essstorungen und 7 gesunde Kontrollprobandinnen mittels fMRT untersucht. Die 1. Messung der Patientinnen wurde zu Beginn eines intensiven Behandlungsprozesses durchgefuhrt, die 2. Messung folgte nach 3 Monaten. Den Studienteilnehmerinnen wurden 3 Stunden nach der letzten Mahlzeit visuelle Stimuli in Form von Nahrungsmittelaufnahmen auf Tellern und Bilder von Haushaltsgegenstanden auf neutralem Untergrund im Block-Design dargeboten. Symptomveranderungen bei den Patientinnen wahrend der Behandlung wurden uber Veranderungen von Gewicht und Schlankheitsdruck (Anorexie) bzw. Anzahl der Essanfalle und die Skala ‘Bulimie’ des EDI–2 (Bulimie) erfasst. Ergebnisse: Es handelt sich um eine erste explorative Analyse der fMRT-Daten einer Verlaufsuntersuchung bei essgestorten Patientinnen. Eine Untersuchung von Kontrollprobandinnen im Verlauf ermoglicht eine Berucksichtigung von Wiederholungseffekten. Die Abschlussauswertung wird Ende Februar 2007 vorliegen. Literatur: Roffman et al., 2005 Uher et al., 2001 Uher et al., 2004