Different patterns of white matter and immunological alterations in the various phases of bipolar disorder

Bipolar disorder (BD) is a prevalent recurrent and chronic mental disease, clinically characterized by the occurrence of active phases of illness, mania and depression, alternated to asymptomatic periods of euthymia. Considering the complex clinical presentation of BD, our work aimed to investigate the neurobiological underpinning of the various phases of BD separately in order to detect their specific abnormalities, thus helping clarifying the pathophysiology of this disorder. Firstly, we investigated potential abnormalities of brain white matter (WM) in BD by using the diffusion tensor imaging (DTI) technique. By using a tract-based spatial statistics (TBSS) voxel-wise approach, we found a widespread alteration in WM microstructure (as evidenced by a decrease in fractional anisotropy (FA) and increase in mean diffusivity (MD) and radial diffusivity (RD) parameters) in BD, showing distinct patterns of changes in the different phases of illness. In particular, such WM abnormalities were larger in the active phases of illness (i.e., depression and mania) with respect to euthymia. Then, by using a probabilistic tractography, we coherently detected a reduction in the structural connectivity of the cingulum in mania. Secondly, we explored potential factors associated with the observed pattern of WM alterations of BD, by conducting a combined immunological-DTI study on an independent BD sample. By using a TBSS approach, we found a widespread combined FA-RD alteration mainly in the manic phase, with relatively specific involvement of the body of corpus callosum (BCC) and superior corona radiata (SCR). Then, by using flow cytometry, we detected peripheral immunological alterations in the manic phase, mainly characterized by an increase in CD4+ T cells as well as a decrease in total CD8+ T cells and their subpopulations effector memory (CD8+CD28-CD45RA-), terminal effector memory (CD8+CD28-CD45RA+) and CD8+IFN\u3b3+. Finally, an association between WM and immunological alterations was found in the whole cohort, and a correlation of FA-RD alterations in the BCC and SCR with reduced CD8+ terminal effector memory and CD8+IFN\u3b3+ T cells was detected in mania. Finally, we conducted a longitudinal study, collecting both DTI and bio-humoral follow-up data of our sample and investigating WM and immunological alterations in BD patients across their different phases of illness. The results preliminarily confirmed our previous findings in a longitudinal perspective, by showing increased FA/decreased RD in midline structures complemented by an increase in the circulating activated CD8+ T cell subsets, in BD patients passing from active phases to euthymia. Collectively, these findings suggest a new pathophysiological model of mania. Accordingly, an acute immune response may occur in mania, sustained by early generated CD4+ T cell compartment (likely with T helper function), leading to activation of CD8+ effector T cell subpopulations that leave the circulation to migrate into the brain, where exert their cytotoxic action, finally leading to WM damage. Our model thus supports a relationship between BD and immune-inflammatory neurological diseases such as multiple sclerosis. Moreover, our results suggest a prominent role of mania in BD and, interestingly, seem to be in accordance with the \u201cprimacy of mania\u201d hypothesis, where mania is described as the fire of BD and seen as the core of the pathophysiology of the illness. Finally, our data suggest a potential role for immunotherapy as an important future aid in the treatment of BD

Microstructural white-matter abnormalities and their relationship with cognitive dysfunction in obsessive-compulsive disorder

open5Background: In recent years, diffusion tensor imaging (DTI) studies have detected subtle microstructural abnormalities of white matter (WM) in obsessive-compulsive disorder (OCD). However, findings have been inconsistent, and it is unclear whether WM abnormalities are related to cognitive processes. The aim of this study was to explore the relationship of WM alterations with cognitive variables in OCD in order to investigate the structural correlates of behaviorally relevant features of the disorder. Methods: We compared DTI-derived fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) measures between OCD patients (n = 16) and healthy controls (n = 18) using a whole-brain tract-based spatial statistics (TBSS) approach. We also explored the correlations of WM alterations with clinical and cognitive variables. Results: Patients with OCD demonstrated increases in MD in the bilateral posterior corona radiata; left anterior corona radiata; bilateral superior longitudinal fasciculus; genu, body, and splenium of the corpus callosum; and left posterior limb of the internal capsule. An increase in RD values was also found in some of the same tracts (right posterior corona radiata, right superior longitudinal fasciculus, left anterior corona radiata, and corpus callosum). Furthermore, increased MD value in the internal capsule was correlated with the percentage of errors made during a target detection task, which was greater in the OCD group overall. Conclusions: These findings indicate that OCD patients show greater diffusivity in several white-matter regions. The correlation between cognitive performance and diffusivity in the internal capsule suggests that microstructural WM alternations may have functional consequences for the disorder.openMagioncalda, P; Martino, M; Ely, B.A.; Inglese, M; Stern, E. R.Magioncalda, P; Martino, M; Ely, B. A.; Inglese, M; Stern, E. R

Opposing Changes in the Functional Architecture of Large-Scale Networks in Bipolar Mania and Depression

Manic and depressive phases of bipolar disorder (BD) show opposite symptoms in psychomotor, thought, and affective dimensions. Neuronally, these may depend on distinct patterns of alterations in the functional architecture of brain intrinsic activity. Therefore, the study aimed to characterize the spatial and temporal changes of resting-state activity in mania and depression, by investigating the regional homogeneity (ReHo) and degree of centrality (DC), in different frequency bands

Opioidergic System and Functional Architecture of Intrinsic Brain Activity: Implications for Psychiatric Disorders

The opioidergic system and intrinsic brain activity, as organized in large-scale networks such as the salience network (SN), sensorimotor network (SMN), and default-mode network (DMN), play core roles in healthy behavior and psychiatric disorders. This work aimed to investigate how opioidergic signaling affects intrinsic brain activity in healthy individuals by reviewing relevant neuroanatomical, molecular, functional, and pharmacological magnetic resonance imaging studies in order to clarify their physiological links and changes in psychiatric disorders. The SN shows dense opioidergic innervations of subcortical structures and high expression levels of opioid receptors in subcortical-cortical areas, with enhanced or reduced activity with low or very high doses of opioids, respectively. The SMN shows high levels of opioid receptors in subcortical areas and functional disconnection caused by opioids. The DMN shows low levels of opioid receptors in cortical areas and inhibited or enhanced activity with low or high doses of opioids, respectively. Finally, we proposed a working model. Opioidergic signaling enhances SN and suppresses SMN (and DMN) activity, resulting in affective excitation with psychomotor inhibition; stronger increases in opioidergic signaling attenuate the SN and SMN while disinhibiting the DMN, dissociating affective and psychomotor functions from the internal states; the opposite occurs with a deficit of opioidergic signaling

The onset of the negative Carbon Isotope Excursion on dispersed organic matter as criterion for the Paleocene-Eocene boundary: uses, biases and limits

International audienceThe primary criterion ratified by the International Subcommission on Paleogene Stratigraphy (ISPS) to define the Paleocene-Eocene (P/E) boundary, and the beginning of the Paleocene-Eocene Thermal Maximum (PETM), is the onset of a prominent negative Carbon Isotope Excursion (CIE; Aubry et al., 2007), located in the lower to middle part of Chron C24r, in calcareous nannofossil Zone NP9 and at the base of planktonic foraminiferal Zone E1 of Berggren & Pearson, 2005 (see also Wade et al., 2011), also termed Zone P5 in Aubry et al. (2007). Based on cyclostratigraphy, the CIE is estimated to have spanned 150 ± 20 kyr and would reflect a major perturbation of the global carbon cycle. Organic matter (OM) may be judged as a (very) reliable material for isotopic chemostratigraphy, in both marine and terrestrial settings. Here we show several examples of successions (Belgium, Egypt, France, Spain, Tunisia, USA-Wyoming) where: 1. isotopic analyses on OM are necessary to define the P/E boundary (lack of carbonates and/or diagenetic alteration of the isotopic signal on carbonates, including calcitic shells, bulk rocks and pedogenic nodules), 2. organics are probably not the best material to precise the P/E boundary, 3. geological processes, such as hiatuses, and potential reworking of OM in channels and turbidites, may perturb the reliability of the carbon isotope results (on both organics and carbonates). Aubry, M.P. et al., 2007. Episodes, 30, 271-286. Berggren, W. A., and Pearson, P. M., 2005, J. of Foraminiferal Research, 35/4, 279-298. Wade, B.S. et al. 2011, Earth Science Reviews 104, 111-142

Altered Global Signal Topography and Its Different Regional Localization in Motor Cortex and Hippocampus in Mania and Depression

Bipolar disorder (BD) is a complex psychiatric disorder characterized by dominant symptom swings across different phases (manic, depressive, and euthymic). Different symptoms in BD such as abnormal episodic memory recall and psychomotor activity have been related to alterations in different regions, ie, hippocampus and motor cortex. How the abnormal regional distribution of neuronal activity relates to specific symptoms remains unclear, however. One possible neuronal mechanism of the relationship is the alteration of the global distribution of neuronal activity manifested in specific local regions; this can be measured as the correlation between the global signal (GS) and local regions. To understand the GS and its relationship to psychopathological symptoms, we here investigated the alteration of both GS variance and its regional topography in healthy controls and 3 phases of BD. We found that the variance of GS showed no significant difference between the 4 groups. In contrast, the GS topography was significantly altered in the different phases of BD, ie, the regions showing abnormally strong topographical GS contribution changed from hippocampus (and parahippocampus/fusiform gyrus) in depression to motor cortex in mania. Importantly, topographical GS changes in these regions correlated with psychopathological measures in both depression and mania. Taken together, our findings demonstrate the central importance of GS topography for psychopathological symptoms. This sheds lights on the neuronal mechanisms of specific psychopathological symptoms in BD, and its relevance in the relationship between global and local neuronal activities for behavior in general

Opposing patterns of neuronal variability in the sensorimotor network mediate cyclothymic and depressive temperaments

Affective temperaments have been described since the early 20th century and may play a central role in psychiatric illnesses, such as bipolar disorder (BD). However, the neuronal basis of temperament is still unclear. We investigated the relationship of temperament with neuronal variability in the resting state signal-measured by fractional standard deviation (fSD) of Blood-Oxygen-Level Dependent signal-of the different large-scale networks, that is, sensorimotor network (SMN), along with default-mode, salience and central executive networks, in standard frequency band (SFB) and its sub-frequencies slow4 and slow5, in a large sample of healthy subject (HC, n\u2009=\u2009109), as well as in the various temperamental subgroups (i.e., cyclothymic, hyperthymic, depressive, and irritable). A replication study on an independent dataset of 121 HC was then performed. SMN fSD positively correlated with cyclothymic z-score and was significantly increased in the cyclothymic temperament compared to the depressive temperament subgroups, in both SFB and slow4. We replicated our findings in the independent dataset. A relationship between cyclothymic temperament and neuronal variability, an index of intrinsic neuronal activity, in the SMN was found. Cyclothymic and depressive temperaments were associated with opposite changes in the SMN variability, resembling changes previously described in manic and depressive phases of BD. These findings shed a novel light on the neural basis of affective temperament and also carry important implications for the understanding of a potential dimensional continuum between affective temperaments and BD, on both psychological and neuronal levels

The PETM record revealed by a new integrated high-resolution dinoflagellate cyst and geochemical data from the "Sparnacian" sediments in the Paris and adjacent basins

International audienceThe Paris Basin represents an historical cradle of the Paleogene stratigraphy, where the Paleocene Epoch and the "Sparnacian Stage" have been erected (Schimper, 1874; Dollfus, 1880). As highlighted by Aubry et al. (2005), whereas the chronostratigraphic connotation of the Sparnacian Stage occurred to be controversial since its definition, modern studies of the Late Paleocene - Early Eocene interval have revealed that the so-called "Sparnacian" deposits encompass a remarkable and short (~170 kyr) episode in the Cenozoic history, the Paleocene-Eocene Thermal Maximum (PETM, ~55.8-55.6 Ma). However, due to a large development of diverse and laterally variable, predominantly lagoonal and non-marine facies, the Paris Basin Upper Paleocene-Lower Eocene succession is still poorly documented and needs an updated chronostratigraphic correlation with other Paleogene records in adjacent basins and worldwide. Since almost 45 years the dinoflagellate cyst stratigraphy has significantly contributed to correlations of the Thanetian-Ypresian deposits in the Paris and adjacent basins (Châteauneuf & Gruas-Cavagnetto, 1968, 1978; Gruas-Cavagnetto, 1974; Costa and Downie, 1976). Nevertheless, data published on dinoflagellate cysts distribution in the Paleogene sediments of those basins remain too scattered (see Aubry et al., 2005) and need to be calibrated to the most recent biozonations. With the aim at reconstructing the "Sparnacian" palaeoenvironments as well as ensuring correlation with the PETM (and its Carbon Isotopic Excursion, CIE) events and related processes, new or already well known "Sparnacian" Dieppe-Hampshire and Paris Basins key localities (Cap d'Ailly and Sotteville-sur-Mer sections, Therdonne and Sinceny cores) have been investigated in details palynologically and chemostratigraphically. According to our new high-resolution data, the CIE begins within the Mortemer Fm in terrestrial or coastal environments and continues until the top of the Soissonnais Fm (Quesnel et al, this meeting). Within the CIE, δ13Corg values fluctuate between -25 and -30 ‰, while above and below they fluctuate between -22 and -26 ‰. The CIE interval contained in the lagoonal and shallow marine units reveals an extremely pronounced (compared with other PETM records worldwide) Apectodinium-acme (70-98% of dinocyst assemblage), sometimes accompanied by Pediastrum-blooms (fresh water algae). As mentioned by Gruas-Cavagnetto (1974), dinoflagellate assemblages from the Dieppe-Hampshire and Paris Basins "Sparnacian" do not contain the key species Apectodinium augustum (nominate species of the A. augustum zone corresponding the PETM-interval worldwide, Crouch et al., 2001), whereas it is present in the northern Belgian Basin Tienen Fm (De Coninck, 1975, 1999) and is coeval there with the CIE and Apectodinium-acme interval (Steurbaut et al., 2000, 2003). However, our calibration of the Apectodinium-acme to the CIE in the Dieppe-Hampshire and Paris Basins suggests its attribution to the A. augustum zone. As it was previously noted from southern England (Powell et al., 1996), the absence of species A. augustum in the Anglo-Paris Basin may be explained by its restriction to more offshore conditions. In localities studied here dinocyst assemblages dominated by Apectodinium spp. are characterized by a significant number of longer (compared to the holotype) specimens of A. parvum, which could represent an ecological onshore substitute of species A. augustum during the PETM

Abnormal Functional Relationship of Sensorimotor Network With Neurotransmitter-Related Nuclei via Subcortical-Cortical Loops in Manic and Depressive Phases of Bipolar Disorder

Manic and depressive phases of bipolar disorder (BD) show opposite psychomotor symptoms. Neuronally, these may depend on altered relationships between sensorimotor network (SMN) and subcortical structures. The study aimed to investigate the functional relationships of SMN with substantia nigra (SN) and raphe nuclei (RN) via subcortical-cortical loops, and their alteration in bipolar mania and depression, as characterized by psychomotor excitation and inhibition

New Integrated High-Resolution Dinoflagellate Cyst Stratigraphy and Litho- and Chemostratigraphy from the Paris and Dieppe–Hampshire Basins for the “Sparnacian”

The Paris Basin represents an historical cradle of Palaeogene stratigraphy, where during the nineteenth century the Palaeocene Series and the "Sparnacian Stage'' were established. As highlighted by Aubry et al. (2005), whereas the chronostratigraphic connotation of the "Sparnacian Stage'' has been controversial since its definition, modern studies of the late Palaeocene-early Eocene interval have revealed that the so-called "Sparnacian'' deposits encompass a remarkable and short (similar to 170 kyr) episode of the Cenozoic, the Palaeocene-Eocene Thermal Maximum (PETM, similar to 55.8-55.6 Ma). Dinoflagellate assemblages from the "Sparnacian'' of the Dieppe-Hampshire and Paris basins do not contain the key species Apectodinium augustum, whereas it is present in the northern Belgian Basin Tienen Formation and is coeval there with the CIE and the Apectodinium acme interval. However, our calibration of the Apectodinium acme to the CIE in the Dieppe-Hampshire and Paris basins suggests its attribution to the A. augustum zone. The absence of species A. augustum in the Anglo-Paris Basin may be explained by its restriction to more offshore conditions