A three-dimensional model of neural activity and phenomenal-behavioral patterns.

How phenomenal experience and behavior are related to neural activity in physiology and psychopathology represents a fundamental question in neuroscience and psychiatry. The phenomenal-behavior patterns may be deconstructed into basic dimensions, i.e., psychomotricity, affectivity, and thought, which might have distinct neural correlates. This work provides a data overview on the relationship of these phenomenal-behavioral dimensions with brain activity across physiological and pathological conditions (including major depressive disorder, bipolar disorder, schizophrenia, attention-deficit/hyperactivity disorder, anxiety disorders, addictive disorders, Parkinson's disease, Tourette syndrome, Alzheimer's disease, and frontotemporal dementia). Accordingly, we propose a three-dimensional model of neural activity and phenomenal-behavioral patterns. In this model, neural activity is organized into distinct units in accordance with connectivity patterns and related input/output processing, manifesting in the different phenomenal-behavioral dimensions. (1) An external neural unit, which involves the sensorimotor circuit/brain's sensorimotor network and is connected with the external environment, processes external inputs/outputs, manifesting in the psychomotor dimension (processing of exteroception/somatomotor activity). External unit hyperactivity manifests in psychomotor excitation (hyperactivity/hyperkinesia/catatonia), while external unit hypoactivity manifests in psychomotor inhibition (retardation/hypokinesia/catatonia). (2) An internal neural unit, which involves the interoceptive-autonomic circuit/brain's salience network and is connected with the internal/body environment, processes internal inputs/outputs, manifesting in the affective dimension (processing of interoception/autonomic activity). Internal unit hyperactivity manifests in affective excitation (anxiety/dysphoria-euphoria/panic), while internal unit hypoactivity manifests in affective inhibition (anhedonia/apathy/depersonalization). (3) An associative neural unit, which involves the brain's associative areas/default-mode network and is connected with the external/internal units (but not with the environment), processes associative inputs/outputs, manifesting in the thought dimension (processing of ideas). Associative unit hyperactivity manifests in thought excitation (mind-wandering/repetitive thinking/psychosis), while associative unit hypoactivity manifests in thought inhibition (inattention/cognitive deficit/consciousness loss). Finally, these neural units interplay and dynamically combine into various neural states, resulting in the complex phenomenal experience and behavior across physiology and neuropsychiatric disorders.

Systematic total arch replacement with thoraflex hybrid graft in acute type A aortic dissection: A single centre experience.

Introduction: In the last two decades, a more aggressive approach has been encouraged to treat patients with acute type A aortic dissection (ATAAD), extending the repair to the aortic arch and proximal descending thoracic aorta with the frozen elephant trunk (FET) implantation. Here, we report our single-centre experience with the FET technique for the systematic treatment of emergency type A aortic dissection. Materials and methods: Between December 2017 and January 2022, 69 consecutive patients were admitted with ATAAD; of those, 66 patients (62.9 ± 10.2 years of age, 81.8% men) underwent emergency hybrid aortic arch and FET repair with the multibranched Thoraflex hybrid graft and were enrolled in the study. Primary endpoints were 30 days- and in-hospital mortality. Secondary endpoints were postoperative morbidity and follow-up survival. To better clarify the impact of age on surgical outcomes, we have divided the study population into two groups: group A for patients <70 years of age (47 patients), and group B for patients ≥70 years (19 patients). Time-to-event analysis has been conducted using the Log-rank test and is displayed with Kaplan-Meier curves. A multiple Cox proportional Hazard model was developed to identify predictors of long-term survival with a stepwise backward/forward selection process. Results: 30-days- and in-hospital mortality were 10.6 and 13.6%, respectively. Stroke occurred in three (4.5%) patients. Two (3.0%) patients experienced spinal cord ischemia. We did not find any statistically significant difference between the two groups in terms of main post-operative outcomes. The multivariable Cox proportional hazard model showed left ventricular ejection fraction (HR: 0.83, 95% CI: 0.79-0.92, p < 0.01), peripheral vascular disease (HR: 15.8, 95% CI: 3.9-62.9, p < 0.01), coronary malperfusion (HR: 0.10, 95% CI: 0.01-0.77, p =0.03), lower limbs malperfusion (HR: 5.1, 95% CI: 1.10-23.4, p = 0.04), and cardiopulmonary bypass time (HR: 1.02, 95% CI: 1-1.04, p = 0.01) as independent predictors of long term mortality. Conclusions: Frozen elephant trunk repair to treat emergency type A aortic dissection appears to be associated with good early and mid-term clinical outcomes even in the elderly.

Evidence of alterations of Beta-endorphin levels and Mu-opioid receptor gene expression in bipolar disorder.

Despite the well-recognized effects of endogenous opioids on mood and behavior, research on its role in bipolar disorder (BD) is still limited to small or anecdotal reports. Considering that Beta-endorphins (ß-END) and Mu-opioid receptors (MOR), in particular, have a crucial activity in affective modulation, we hypothesized their alteration in BD. A cross-sectional study was conducted. We compared: (1) BD type I (BD-I) patients (n = 50) vs healthy controls (n = 27), (2) two BD-I subject subgroups: manic (MAN; n = 25) vs depressed (DEP; n = 25) subjects. Plasma levels of ß-END and MOR gene expression in peripheral blood mononuclear cells were analyzed using ELISA Immunoassay qRT-PCR. We found that subjects with BD exhibited a significant upregulation of MOR gene expression and a decrease of ß-END (p<0.0001 for both). MAN display higher MOR levels than DEP (p<0.001) and HC (p<0.0001). Plasma levels of ß-END were lower in DEP compared to MAN (p<0.05) and HC (p<0.0001). The main limitations are the cross-sectional design and the lack of a group of euthymic subjects. Although preliminary, our results suggest a dysregulation of the endogenous opioid systems in BD. In particular, both MAN and DEP showed a reduction of ß-END levels, whereas MAN was associated with MOR gene overexpression.

A unified model of the pathophysiology of bipolar disorder.

This work provides an overview of the most consistent alterations in bipolar disorder (BD), attempting to unify them in an internally coherent working model of the pathophysiology of BD. Data on immune-inflammatory changes, structural brain abnormalities (in gray and white matter), and functional brain alterations (from neurotransmitter signaling to intrinsic brain activity) in BD were reviewed. Based on the reported data, (1) we hypothesized that the core pathological alteration in BD is a damage of the limbic network that results in alterations of neurotransmitter signaling. Although heterogeneous conditions can lead to such damage, we supposed that the main pathophysiological mechanism is traceable to an immune/inflammatory-mediated alteration of white matter involving the limbic network connections, which destabilizes the neurotransmitter signaling, such as dopamine and serotonin signaling. Then, (2) we suggested that changes in such neurotransmitter signaling (potentially triggered by heterogeneous stressors onto a structurally-damaged limbic network) lead to phasic (and often recurrent) reconfigurations of intrinsic brain activity, from abnormal subcortical-cortical coupling to changes in network activity. We suggested that the resulting dysbalance between networks, such as sensorimotor networks, salience network, and default-mode network, clinically manifest in combined alterations of psychomotricity, affectivity, and thought during the manic and depressive phases of BD. Finally, (3) we supposed that an additional contribution of gray matter alterations and related cognitive deterioration characterize a clinical-biological subgroup of BD. This model may provide a general framework for integrating the current data on BD and suggests novel specific hypotheses, prompting for a better understanding of the pathophysiology of BD.

Tracing the psychopathology of bipolar disorder to the functional architecture of intrinsic brain activity and its neurotransmitter modulation: a three-dimensional model.

Bipolar disorder (BD) shows complex alterations in psychomotor, affective, and thought dimensions, as described by Kraepelin in his fundamental model of manic-depressive illness. In turn, the expression of behavioral/phenomenological dimensions is traceable to intrinsic brain activity. We reported a data overview on intrinsic brain functioning and its changes in BD. Accordingly, we proposed a three-dimensional model of the relationship between brain functioning and behavioral/phenomenological patterns, along with its application to BD. In this model, intrinsic brain activity is organized in distinct units in accordance to connectivity patterns and related setting of input/output processing, underlying the different behavioral/phenomenological dimensions. An external unit (mainly involving the sensorimotor network) is connected with the external environment and sets the exteroceptive input/somatomotor output processing, underlying the psychomotor dimension. An internal unit (mainly involving the salience network) is connected to the internal/body environment and sets the interoceptive input/visceromotor output processing, underlying the affective dimension. Finally, an associative unit (mainly involving the default-mode network) is not connected with the environment and sets the processing of associative inputs/outputs, underlying the thought dimension. In each unit, neurotransmitter signaling couples the subcortical-cortical loop, which modulates the network activity levels, in turn setting input/output processing and related expression levels of the behavioral/phenomenological dimension. Different combinations in neurotransmitter signaling favor network balancing into distinct functional brain states, which manifest in different combinations of excitation or inhibition in psychomotricity, affectivity, and thought, resulting in the manic, depressive, and mixed states of BD. Our working model might provide a coherent framework for tracing the complex BD psychopathology to core functional brain alterations.

Depression is associated with disconnection of neurotransmitter-related nuclei in multiple sclerosis.

BACKGROUND: Depression is frequently associated with multiple sclerosis (MS). However, the biological background underlying such association is poorly understood. OBJECTIVE: Investigating the functional connections of neurotransmitter-related brainstem nuclei, along with their relationship with white matter (WM) microstructure, in MS patients with depressive symptomatology (MS-D) and without depressive symptomatology (MS-nD). METHODS: Combined resting-state functional magnetic resonance imaging (fMRI) and diffusion-weighted MRI (dMRI) study on 50 MS patients, including 19 MS-D and 31 MS-nD patients, along with 37 healthy controls (HC). Main analyses performed are (1) comparison between groups of raphe nuclei (RN)-related functional connectivity (FC); (2) correlation between RN-related FC and whole brain dMRI-derived fractional anisotropy (FA) map; and (3) comparison between groups of FA in the RN-related WM area. RESULTS: (1) RN-related FC was reduced in MS-D when compared to MS-nD and HC; (2) RN-related FC positively correlated with FA in a WM cluster mainly encompassing thalamic/basal ganglia regions, including the fornix; and (3) FA in such WM area was reduced in MS-D. CONCLUSION: Depressive symptomatology in MS is specifically associated to a functional disconnection of neurotransmitter-related nuclei, which in turn may be traced to a distinct spatial pattern of WM alterations mainly involving the limbic network.

All roads lead to the motor cortex: psychomotor mechanisms and their biochemical modulation in psychiatric disorders.

Psychomotor abnormalities have been abundantly observed in psychiatric disorders like major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCH). Although early psychopathological descriptions highlighted the truly psychomotor nature of these abnormalities, more recent investigations conceive them rather in purely motor terms. This has led to an emphasis of dopamine-based abnormalities in subcortical-cortical circuits including substantia nigra, basal ganglia, thalamus, and motor cortex. Following recent findings in MDD, BD, and SCH, we suggest a concept of psychomotor symptoms in the literal sense of the term by highlighting three specifically psychomotor (rather than motor) mechanisms including their biochemical modulation. These include: (i) modulation of dopamine- and substantia nigra-based subcortical-cortical motor circuit by primarily non-motor subcortical raphe nucleus and serotonin via basal ganglia and thalamus (as well as by other neurotransmitters like glutamate and GABA); (ii) modulation of motor cortex and motor network by non-motor cortical networks like default-mode network and sensory networks; (iii) global activity in cortex may also shape regional distribution of neural activity in motor cortex. We demonstrate that these three psychomotor mechanisms and their underlying biochemical modulation are operative in both healthy subjects as well as in MDD, BD, and SCH subjects; the only difference consists in the fact that these mechanisms are abnormally balanced and thus manifest in extreme values in psychiatric disorders. We conclude that psychomotor mechanisms operate in a dimensional and cross-nosological way as their degrees of expression are related to levels of psychomotor activity (across different disorders) rather than to the diagnostic categories themselves. Psychomotor mechanisms and their biochemical modulation can be considered paradigmatic examples of a dimensional approach as suggested in RDoC and the recently introduced spatiotemporal psychopathology.

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.

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

OBJECTIVE: 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. METHODS: Using resting-state functional magnetic resonance imaging (fMRI), voxel-wise ReHo and DC were calculated-in the standard frequency band (SFB: 0.01-0.10 Hz), as well as in Slow5 (0.01-0.027 Hz) and Slow4 (0.027-0.073 Hz)-and compared between manic (n = 36), depressed (n = 43), euthymic (n = 29) patients, and healthy controls (n = 112). Finally, clinical correlations were investigated. RESULTS: Mania was mainly characterized by decreased ReHo and DC in Slow4 in the medial prefrontal cortex (as part of the default-mode network [DMN]), which in turn correlated with manic symptomatology. Conversely, depression was mainly characterized by decreased ReHo in SFB in the primary sensory-motor cortex (as part of the sensorimotor network [SMN]), which in turn correlated with depressive symptomatology. CONCLUSIONS: Our data show a functional reconfiguration of the spatiotemporal structure of intrinsic brain activity to occur in BD. Mania might be characterized by a predominance of sensorimotor over associative networks, possibly driven by a deficit of the DMN (reflecting in internal thought deficit). Conversely, depression might be characterized by a predominance of associative over sensorimotor networks, possibly driven by a deficit of the SMN (reflecting in psychomotor inhibition).

Intrinsic brain activity of subcortical-cortical sensorimotor system and psychomotor alterations in schizophrenia and bipolar disorder: A preliminary study.

OBJECTIVE: Alterations in psychomotor dimension cut across different psychiatric disorders, such as schizophrenia (SCZ) and bipolar disorder (BD). This preliminary study aimed to investigate the organization of intrinsic brain activity in the subcortical-cortical sensorimotor system in SCZ (and BD) as characterized according to psychomotor dimension. METHOD: In this resting-state functional magnetic resonance imaging (fMRI) study, functional connectivity (FC) between thalamus and sensorimotor network (SMN), along with FC from substantia nigra (SN) and raphe nuclei (RN) to basal ganglia (BG) and thalamic regions, were investigated by using an a-priori-driven and dimensional approach. This was done in two datasets: SCZ patients showing inhibited psychomotricity (n = 18) vs. controls (n = 19); SCZ patients showing excited psychomotricity (n = 20) vs. controls (n = 108). Data from a third dataset of BD in inhibited depressive or manic phases (reflecting inhibited or excited psychomotricity) were used as control. RESULTS: SCZ patients suffering from psychomotor inhibition showed decreased thalamus-SMN FC toward around-zero values paralleled by a concomitant reduction of SN-BG/thalamus FC and RN-BG/thalamus FC (as BD patients in inhibited depression). By contrast, SCZ patients suffering from psychomotor excitation exhibited increased thalamus-SMN FC toward positive values paralleled by a concomitant reduction of RN-BG/thalamus FC (as BD patients in mania). CONCLUSIONS: These findings suggest that patients exhibiting low or high levels of psychomotor activity show distinct patterns of thalamus-SMN coupling, which could be traced to specific deficit in SN- or RN-related connectivity. Notably, this was independent from the diagnosis of SCZ or BD, supporting an RDoC-like dimensional approach to psychomotricity.

Opposite effects of dopamine and serotonin on resting-state networks: review and implications for psychiatric disorders.

Alterations in brain intrinsic activity-as organized in resting-state networks (RSNs) such as sensorimotor network (SMN), salience network (SN), and default-mode network (DMN)-and in neurotransmitters signaling-such as dopamine (DA) and serotonin (5-HT)-have been independently detected in psychiatric disorders like bipolar disorder and schizophrenia. Thus, the aim of this work was to investigate the relationship between such neurotransmitters and RSNs in healthy, by reviewing the relevant work on this topic and performing complementary analyses, in order to better understand their physiological link, as well as their alterations in psychiatric disorders. According to the reviewed data, neurotransmitters nuclei diffusively project to subcortical and cortical regions of RSNs. In particular, the dopaminergic substantia nigra (SNc)-related nigrostriatal pathway is structurally and functionally connected with core regions of the SMN, whereas the ventral tegmental area (VTA)-related mesocorticolimbic pathway with core regions of the SN. The serotonergic raphe nuclei (RNi) connections involve regions of the SMN and DMN. Coherently, changes in neurotransmitters activity impact the functional configuration and level of activity of RSNs, as measured by functional connectivity (FC) and amplitude of low-frequency fluctuations/temporal variability of BOLD signal. Specifically, DA signaling is associated with increase in FC and activity in the SMN (hypothetically via the SNc-related nigrostriatal pathway) and SN (hypothetically via the VTA-related mesocorticolimbic pathway), as well as concurrent decrease in FC and activity in the DMN. By contrast, 5-HT signaling (via the RNi-related pathways) is associated with decrease in SMN activity along with increase in DMN activity. Complementally, our empirical data showed a positive correlation between SNc-related FC and SMN activity, whereas a negative correlation between RNi-related FC and SMN activity (along with tilting of networks balance toward the DMN). According to these data, we hypothesize that the activity of neurotransmitter-related neurons synchronize the low-frequency oscillations within different RSNs regions, thus affecting the baseline level of RSNs activity and their balancing. In our model, DA signaling favors the predominance of SMN-SN activity, whereas 5-HT signaling favors the predominance of DMN activity, manifesting in distinct behavioral patterns. In turn, alterations in neurotransmitters signaling (or its disconnection) may favor a correspondent functional reorganization of RSNs, manifesting in distinct psychopathological states. The here suggested model carries important implications for psychiatric disorders, providing novel and well testable hypotheses especially on bipolar disorder and schizophrenia.

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

OBJECTIVE: 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. METHOD: In this resting-state functional magnetic resonance imaging (fMRI) study on healthy (n = 67) and BD patients (n = 100), (1) functional connectivity (FC) between thalamus and SMN was calculated and correlated with FC from SN or RN to basal ganglia (BG)/thalamus in healthy; (2) using an a-priori-driven approach, thalamus-SMN FC, SN-BG/thalamus FC, and RN-BG/thalamus FC were compared between healthy and BD, focusing on manic (n = 34) and inhibited depressed (n = 21) patients. RESULTS: (1) In healthy, the thalamus-SMN FC showed a quadratic correlation with SN-BG/thalamus FC and a linear negative correlation with RN-BG/thalamus FC. Accordingly, the SN-related FC appears to enable the thalamus-SMN coupling, while the RN-related FC affects it favoring anti-correlation. (2) In BD, mania showed an increase in thalamus-SMN FC toward positive values (ie, thalamus-SMN abnormal coupling) paralleled by reduction of RN-BG/thalamus FC. By contrast, inhibited depression showed a decrease in thalamus-SMN FC toward around-zero values (ie, thalamus-SMN disconnection) paralleled by reduction of SN-BG/thalamus FC (and RN-BG/thalamus FC). The results were replicated in independent HC and BD datasets. CONCLUSIONS: These findings suggest an abnormal relationship of SMN with neurotransmitters-related areas via subcortical-cortical loops in mania and inhibited depression, finally resulting in psychomotor alterations.

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 = 109), 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.

Exploring mania-associated white matter injury by comparison with multiple sclerosis: a diffusion tensor imaging study.

Bipolar disorder (BD), especially in its active phases, has shown some neuroimaging and immunological similarities with multiple sclerosis (MS). The objective of this study was to compare white matter (WM) alterations in BD patients in manic phase (M-BD) and MS patients at early stage of disease and with low lesion burden. We compared diffusion tensor imaging (DTI)-derived fractional anisotropy (FA), mean diffusivity (MD) and radial diffusivity (RD) in a priori selected WM regions (i.e., corpus callosum and cingulum) betwixt 23 M-BD, 23 MS patients and 46 healthy controls. Both M-BD and MS showed WM changes in the corpus callosum, which, however, showed a greater impairment in MS patients. However, considering the different sub-regions of corpus callosum separately (i.e., genu, body, splenium), M-BD and MS presented an opposite pattern in spatial distribution of WM microstructure alterations, with a greater impairment in the anterior region in M-BD and in the posterior region in MS. Common features as well as divergent patterns in DTI changes are detected in M-BD and early MS, prompting a deeper investigation of analogies and differences in WM and immunological alterations of these disorders.

White matter microstructure alterations correlate with terminally differentiated CD8+ effector T cell depletion in the peripheral blood in mania: Combined DTI and immunological investigation in the different phases of bipolar disorder.

BACKGROUND: White matter (WM) microstructural abnormalities and, independently, signs of immunological activation were consistently demonstrated in bipolar disorder (BD). However, the relationship between WM and immunological alterations as well as their occurrence in the various phases of BD remain unclear. METHOD: In 60 type I BD patients - 20 in manic, 20 in depressive, 20 in euthymic phases - and 20 controls we investigated: (i) diffusion tensor imaging (DTI)-derived fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (AD) using a tract-based spatial statistics (TBSS) approach; (ii) circulating T cell subpopulations frequencies, as well as plasma levels of different cytokines; (iii) potential relationships between WM and immunological data. RESULTS: We found: (i) a significant widespread combined FA-RD alteration mainly in mania, with involvement of the body of corpus callosum (BCC) and superior corona radiata (SCR); (ii) significant increase in CD4+ T cells as well as significant decrease in CD8+ T cells and their subpopulations effector memory (CD8+ CD28-CD45RA-), terminal effector memory (CD8+ CD28-CD45RA+) and CD8+ IFNγ+ in mania; (iii) a significant relationship between WM and immunological alterations in the whole cohort, and a significant correlation of FA-RD abnormalities in the BCC and SCR with reduced frequencies of CD8+ terminal effector memory and CD8+ IFNγ+ T cells in mania only. CONCLUSIONS: Our data show a combined occurrence of WM and immunological alterations in mania. WM abnormalities highly correlated with reduction in circulating CD8+ T cell subpopulations that are terminally differentiated effector cells prone to tissue migration, suggesting that these T cells could play a role in WM alteration in BD.

Too Fast or Too Slow? Time and Neuronal Variability in Bipolar Disorder-A Combined Theoretical and Empirical Investigation.

Time is an essential feature in bipolar disorder (BP). Manic and depressed BP patients perceive the speed of time as either too fast or too slow. The present article combines theoretical and empirical approaches to integrate phenomenological, psychological, and neuroscientific accounts of abnormal time perception in BP. Phenomenology distinguishes between perception of inner time, ie, self-time, and outer time, ie, world-time, that desynchronize or dissociate from each other in BP: inner time speed is abnormally slow (as in depression) or fast (as in mania) and, by taking on the role as default-mode function, impacts and modulates the perception of outer time speed in an opposite way, ie, as too fast in depression and too slow in mania. Complementing, psychological investigation show opposite results in time perception, ie, time estimation and reproduction, in manic and depressed BP. Neuronally, time speed can be indexed by neuronal variability, ie, SD. Our own empirical data show opposite changes in manic and depressed BP (and major depressive disorder [MDD]) with abnormal SD balance, ie, SD ratio, between somatomotor and sensory networks that can be associated with inner and outer time. Taken together, our combined theoretical-empirical approach demonstrates that desynchronization or dissociation between inner and outer time in BP can be traced to opposite neuronal variability patterns in somatomotor and sensory networks. This opens the door for individualized therapeutic "normalization" of neuronal variability pattern in somatomotor and sensory networks by stimulation with TMS and/or tDCS.

Abnormal Resting-State Connectivity in a Substantia Nigra-Related Striato-Thalamo-Cortical Network in a Large Sample of First-Episode Drug-Naïve Patients With Schizophrenia.

Objective: The dopamine hypothesis is one of the most influential theories of the neurobiological background of schizophrenia (SCZ). However, direct evidence for abnormal dopamine-related subcortical-cortical circuitry disconnectivity is still lacking. The aim of this study was therefore to test dopamine-related substantia nigra (SN)-based striato-thalamo-cortical resting-state functional connectivity (FC) in SCZ. Method: Based on our a priori hypothesis, we analyzed a large sample resting-state functional magnetic resonance imaging (fMRI) dataset from first-episode drug-naïve SCZ patients (n = 112) and healthy controls (n = 82) using the SN as the seed region for an investigation of striato-thalamo-cortical FC. This was done in the standard band of slow frequency oscillations and then in its subfrequency bands (Slow4 and Slow5). Results: The analysis showed in SCZ: (1) reciprocal functional hypo-connectivity between SN and striatum, with differential patterns for Slow5 and Slow4; (2) functional hypo-connectivity between striatum and thalamus, as well as functional hyper-connectivity between thalamus and sensorimotor cortical areas, specifically in Slow4; (3) correlation of thalamo-sensorimotor functional hyper-connectivity with psychopathological symptoms. Conclusions: We demonstrate abnormal dopamine-related SN-based striato-thalamo-cortical FC in slow frequency oscillations in first-episode drug-naive SCZ. This suggests that altered dopaminergic function in the SN leads to abnormal neuronal synchronization (as indexed by FC) within subcortical-cortical circuitry, complementing the dopamine hypothesis in SCZ on the regional level of resting-state activity.