Brain reactivity during aggressive response in women with premenstrual dysphoric disorder treated with a selective progesterone receptor modulator

Premenstrual dysphoric disorder (PMDD) is a psychiatric condition characterized by late luteal phase affective, cognitive, and physical impairment. The disorder causes significant suffering in about 5% of women in their reproductive age. Altered sensitivity of cognitive-affective brain circuits to progesterone and its downstream metabolite allopregnanolone is suggested to underlie PMDD symptomatology. Core mood symptoms include irritability and anger, with aggression being the behavioral outcome of these symptoms. The present study sought to investigate the neural correlates of reactive aggression during the premenstrual phase in women with PMDD, randomized to a selective progesterone receptor modulator (SPRM) or placebo. Self-reports on the Daily Record of Severity of Problems were used to assess PMDD symptoms and gonadal hormone levels were measured by liquid chromatography tandem mass spectrometry. Functional magnetic resonance imaging was performed in 30 women with PMDD, while performing the point subtraction aggression paradigm. Overall, a high SPRM treatment response rate was attained (93%), in comparison with placebo (53.3%). Women with PMDD randomized to SPRM treatment had enhanced brain reactivity in the dorsal anterior cingulate cortex and dorsomedial prefrontal cortex during the aggressive response condition. The fronto-cingulate reactivity during aggressive responses depended on treatment, with a negative relationship between brain reactivity and task-related aggressiveness found in the placebo but not the SPRM group. The findings contribute to define the role of progesterone in PMDD symptomatology, suggesting a beneficial effect of progesterone receptor antagonism, and consequent anovulation, on top-down emotion regulation, i.e., greater fronto-cingulate activity in response to provocation stimuli.publishedVersio

Dopamine Transporter and Reward Anticipation in a Dimensional Perspective : A Multimodal Brain Imaging Study

We would like to thank Christine Baron, Vincent Brulon, Stéphane LeHelleix, Stéphane Demphel, Claude Comtat, Frédéric Dollé, Philippe Gervais, and Renaud Maroy from the Service Hospitalier Frédéric Joliot for their efficient technical support and 11C radioligand preparation. They thank Marie Prat, Audrey Pepin, and Audrey Mabondo for their help in PET processing and Pr. Maria-Joao Santiago-Ribeiro and Dr Renaud de Beaurepaire for their involvement in the recruitment of participants.Peer reviewedPostprin

Multimodal Brain Imaging Study of the Dopaminergic and Reward Systems in Patients with Mental Disorders

Ce travail de thèse est consacré à l'étude en imagerie multimodale des bases neurobiologiques des pathologies psychiatriques, avec un intérêt particulier pour les voies dopaminergiques et le système de récompense. Son principal objectif est d'établir, par l’intermédiaire de la Tomographie à Emission de Positons (TEP) et l’Imagerie par Résonance Magnétique (IRM), un lien entre le système dopaminergique et le système de récompense d’un point de vue fonctionnel et structurel chez l’Homme, et en particulier chez des patients présentant des troubles psychiatriques tels que la schizophrénie, l’addiction à la cocaïne et la dépression. De nombreuses études ont démontré l’existence concomitante d’anomalies de la fonction dopaminergique et du système de récompense dans plusieurs troubles mentaux. Cependant, la connaissance des liens entre dysfonctions dopaminergiques et dysfonctions du circuit de la récompense dans les pathologies psychiatriques reste limitée. L’objectif de cette thèse est ainsi d’améliorer les connaissances sur la physiopathologie de plusieurs troubles mentaux comme la schizophrénie, l’addiction et la dépression, et de démontrer l’intérêt d’une approche dimensionnelle et de l’utilisation de l’imagerie multimodale pour l’exploration du niveau moléculaire de réseaux neuronaux fonctionnels dans la recherche en psychiatrie. En perspective, ce travail de thèse soutient l’intérêt de l’imagerie en pratique psychiatrique, car elle pourrait par la suite permettre de préciser le diagnostic, prédire les réponses aux traitements ou étudier l’évolution de la maladie au cours du temps.This work focuses on the study of the neurobiological bases of psychiatric disorders using multimodal imaging, with a particular interest in the dopaminergic pathways and the reward system. Its primary objective is to establish, through Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI), a link between the dopaminergic system and the reward system from a functional and structural point of view in humans, and especially in patients with psychiatric disorders such as schizophrenia, cocaine addiction and depression. Numerous studies have demonstrated the concomitant existence of abnormalities affecting dopaminergic function and reward system in several mental disorders. However, understanding of the linkages between dopaminergic dysfunction and dysfunction of the reward circuit in psychiatric disorders remains limited. The main aims of this thesis are to improve knowledge about the pathophysiology of several mental disorders such as schizophrenia, addiction and depression, and to demonstrate the interest of both a dimensional approach and the use of multimodal imaging in psychiatric research, to explore the molecular level of functional neural networks. In perspective, this thesis supports the interest of brain imaging in clinical practice, as it could later clarify the diagnosis, predict response to treatments or follow the course of the disease

Étude en neuro-imagerie multimodale du système dopaminergique et du système de récompense chez des patients psychiatriques

This work focuses on the study of the neurobiological bases of psychiatric disorders using multimodal imaging, with a particular interest in the dopaminergic pathways and the reward system. Its primary objective is to establish, through Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI), a link between the dopaminergic system and the reward system from a functional and structural point of view in humans, and especially in patients with psychiatric disorders such as schizophrenia, cocaine addiction and depression. Numerous studies have demonstrated the concomitant existence of abnormalities affecting dopaminergic function and reward system in several mental disorders. However, understanding of the linkages between dopaminergic dysfunction and dysfunction of the reward circuit in psychiatric disorders remains limited. The main aims of this thesis are to improve knowledge about the pathophysiology of several mental disorders such as schizophrenia, addiction and depression, and to demonstrate the interest of both a dimensional approach and the use of multimodal imaging in psychiatric research, to explore the molecular level of functional neural networks. In perspective, this thesis supports the interest of brain imaging in clinical practice, as it could later clarify the diagnosis, predict response to treatments or follow the course of the disease.Ce travail de thèse est consacré à l'étude en imagerie multimodale des bases neurobiologiques des pathologies psychiatriques, avec un intérêt particulier pour les voies dopaminergiques et le système de récompense. Son principal objectif est d'établir, par l’intermédiaire de la Tomographie à Emission de Positons (TEP) et l’Imagerie par Résonance Magnétique (IRM), un lien entre le système dopaminergique et le système de récompense d’un point de vue fonctionnel et structurel chez l’Homme, et en particulier chez des patients présentant des troubles psychiatriques tels que la schizophrénie, l’addiction à la cocaïne et la dépression. De nombreuses études ont démontré l’existence concomitante d’anomalies de la fonction dopaminergique et du système de récompense dans plusieurs troubles mentaux. Cependant, la connaissance des liens entre dysfonctions dopaminergiques et dysfonctions du circuit de la récompense dans les pathologies psychiatriques reste limitée. L’objectif de cette thèse est ainsi d’améliorer les connaissances sur la physiopathologie de plusieurs troubles mentaux comme la schizophrénie, l’addiction et la dépression, et de démontrer l’intérêt d’une approche dimensionnelle et de l’utilisation de l’imagerie multimodale pour l’exploration du niveau moléculaire de réseaux neuronaux fonctionnels dans la recherche en psychiatrie. En perspective, ce travail de thèse soutient l’intérêt de l’imagerie en pratique psychiatrique, car elle pourrait par la suite permettre de préciser le diagnostic, prédire les réponses aux traitements ou étudier l’évolution de la maladie au cours du temps

Grey matter morphology in women with premenstrual dysphoric disorder treated with a selective progesterone receptor modulator.

Premenstrual dysphoric disorder (PMDD) is characterized by severe cyclic mood symptoms emerging in the luteal phase of the menstrual cycle. The variation in progesterone levels and its metabolites during the luteal phase seems critical to the occurrence of PMDD symptoms. Notably, the efficacy of selective progesterone receptor modulator (SPRM) treatment on the mental symptoms of PMDD has been recently demonstrated. In the present study, structural magnetic resonance imaging was used to assess the effects of SPRM treatment, compared with placebo, on grey matter morphology in women with PMDD. In total, 35 women were scanned during the luteal phase, before and after three months of treatment with SPRM or placebo. Symptom severity was assessed using the Daily Record of Severity of Problems (DRSP), while gonadal hormone levels were measured by liquid chromatography-tandem mass spectrometry. Region-of-interest and whole-brain approaches were employed to perform voxel-based morphometry analyses, subcortical volumetric analyses, and surface-based morphometry analyses. No interaction or main effects of treatment and time were observed on grey matter volume and cortical surface measures (cortical thickness, gyrification index, sulcal depth, and fractal dimension). The relationship between change in brain morphology and symptom severity was also explored but no treatment-dependant grey matter structure change was related to symptom severity change. These findings suggest that SPRM treatment does not impart macrostructural changes onto grey matter structure, at least in the short term.De två sista författarna delar sistaförfattarskapet.</p

Grey matter correlates of affective and somatic symptoms of premenstrual dysphoric disorder

Ovarian hormones fluctuations across the menstrual cycle are experienced by about 58% of women in their fertile age. Maladaptive brain sensitivity to these changes likely leads to the severe psychological, cognitive, and physical symptoms repeatedly experienced by women with Premenstrual Dysphoric Disorder (PMDD) during the late luteal phase of the menstrual cycle. However, the neuroanatomical correlates of these symptoms are unknown. The relationship between grey matter structure and PMDD symptom severity was delineated using structural magnetic resonance imaging during the late luteal phase of fifty-one women diagnosed with PMDD, combined with Voxel- and Surface-Based Morphometry, as well as subcortical volumetric analyses. A negative correlation was found between depression-related symptoms and grey matter volume of the bilateral amygdala. Moreover, the severity of affective and somatic PMDD symptoms correlated with cortical thickness, gyrification, sulcal depth, and complexity metrics, particularly in the prefrontal, cingulate, and parahippocampal gyri. The present findings provide the first evidence of grey matter morphological characteristics associated with PMDD symptomatology in brain regions expressing ovarian hormone receptors and of relevance to cognitive-affective functions, thus potentially having important implications for understanding how structural brain characteristics relate to PMDD symptomatology.Shared last authorship: Inger Sundström-Poromaa and Erika Comasco.</p

Emotion-induced brain activation across the menstrual cycle in individuals with premenstrual dysphoric disorder and associations to serum levels of progesterone-derived neurosteroids

Premenstrual dysphoric disorder (PMDD) is a debilitating disorder characterized by severe mood symptoms in the luteal phase of the menstrual cycle. PMDD symptoms are hypothesized to be linked to an altered sensitivity to normal luteal phase levels of allopregnanolone (ALLO), a GABAA-modulating progesterone metabolite. Moreover, the endogenous 3β-epimer of ALLO, isoallopregnanolone (ISO), has been shown to alleviate PMDD symptoms through its selective and dose-dependent antagonism of the ALLO effect. There is preliminary evidence showing altered recruitment of brain regions during emotion processing in PMDD, but whether this is associated to serum levels of ALLO, ISO or their relative concentration is unknown. In the present study, subjects with PMDD and asymptomatic controls underwent functional magnetic resonance imaging (fMRI) in the mid-follicular and the late-luteal phase of the menstrual cycle. Brain responses to emotional stimuli were investigated and related to serum levels of ovarian steroids, the neurosteroids ALLO, ISO, and their ratio ISO/ALLO. Participants with PMDD exhibited greater activity in brain regions which are part of emotion-processing networks during the late-luteal phase of the menstrual cycle. Furthermore, activity in key regions of emotion processing networks - the parahippocampal gyrus and amygdala - was differentially associated to the ratio of ISO/ALLO levels in PMDD subjects and controls. Specifically, a positive relationship between ISO/ALLO levels and brain activity was found in PMDD subjects, while the opposite was observed in controls. In conclusion, individuals with PMDD show altered emotion-induced brain responses in the late-luteal phase of the menstrual cycle which may be related to an abnormal response to physiological levels of GABAA-active neurosteroids

Lower midbrain dopamine transporter availability in depressed patients: Report from high-resolution PET imaging

International audienceBackground: A reduced presynaptic dopamine neurotransmission has long been implicated in major depressive disorder (MDD). However, molecular imaging studies that assessed the dopamine transporter (DAT) availability have led to inconsistent results, partly due to methodological considerations, and to exclusive focus on the striatum, precluding findings in extra-striatal regions.Methods: Herein, we leveraged our database of high-resolution Positron Emission Tomography (PET) images acquired with a highly selective radiotracer, [11C]PE2I, to assess striatal and extra-striatal DAT availability in eight patients treated for depression compared to twenty-four healthy controls.Results: Statistical parametric mapping and voxel-based analyses of PET images detected a significant lower DAT availability in depressed patients within the superior part of the midbrain (right, pFWE = 0.002; left, pFWE = 0.006), a region including the ventral tegmental area and the substantia nigra from where the mesocorticolimbic and nigrostriatal dopamine pathways originate. A similar difference was found in the right dorsal putamen (pFWE = 0.012).Limitations: The statistical power was limited to detect only large effects, due to the size of the patients' sample.Conclusions: The findings support the hypothesis that a reduced presynaptic dopamine function plays a role in the pathophysiology of depression, and that extra-striatal dopamine function should be further investigated

286. Dopamine Transporter and Reward Anticipation in Psychiatric Patients: A Positron Emission Tomography and Functional Magnetic Resonance Imaging Study

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Differential grey matter structure in women with premenstrual dysphoric disorder : evidence from brain morphometry and data-driven classification

Premenstrual dysphoric disorder (PMDD) is a female-specific condition classified in the Diagnostic and Statical Manual-5th edition under depressive disorders. Alterations in grey matter volume, cortical thickness and folding metrics have been associated with a number of mood disorders, though little is known regarding brain morphological alterations in PMDD. Here, women with PMDD and healthy controls underwent magnetic resonance imaging (MRI) during the luteal phase of the menstrual cycle. Differences in grey matter structure between the groups were investigated by use of voxel- and surface-based morphometry. Machine learning and multivariate pattern analysis were performed to test whether MRI data could distinguish women with PMDD from healthy controls. Compared to controls, women with PMDD had smaller grey matter volume in ventral posterior cortices and the cerebellum (Cohen's d = 0.45-0.76). Region-of-interest analyses further indicated smaller volume in the right amygdala and putamen of women with PMDD (Cohen's d = 0.34-0.55). Likewise, thinner cortex was observed in women with PMDD compared to controls, particularly in the left hemisphere (Cohen's d = 0.20-0.74). Classification analyses showed that women with PMDD can be distinguished from controls based on grey matter morphology, with an accuracy up to 74%. In line with the hypothesis of an impaired top-down inhibitory circuit involving limbic structures in PMDD, the present findings point to PMDD-specific grey matter anatomy in regions of corticolimbic networks. Furthermore, the results include widespread cortical and cerebellar regions, suggesting the involvement of distinct networks in PMDD pathophysiology