RESUMEN
An estimated 30 % of Major Depressive Disorder (MDD) patients exhibit resistance to conventional antidepressant treatments. Identifying reliable biomarkers of treatment-resistant depression (TRD) represents a major goal of precision psychiatry, which is hampered by the clinical and biological heterogeneity. To uncover biologically-driven subtypes of MDD, we applied an unsupervised data-driven framework to stratify 102 MDD patients on their neuroimaging signature, including extracted measures of cortical thickness, grey matter volumes, and white matter fractional anisotropy. Our novel analytical pipeline integrated different machine learning algorithms to harmonize data, perform data dimensionality reduction, and provide a stability-based relative clustering validation. The obtained clusters were characterized for immune-inflammatory peripheral biomarkers, TRD, history of childhood trauma and depressive symptoms. Our results indicated two different clusters of patients, differentiable with 67 % of accuracy: one cluster (n = 59) was associated with a higher proportion of TRD, and higher scores of energy-related depressive symptoms, history of childhood abuse and emotional neglect; this cluster showed a widespread reduction in cortical thickness (d = 0.43-1.80) and volumes (d = 0.45-1.05), along with fractional anisotropy in the fronto-occipital fasciculus, stria terminalis, and corpus callosum (d = 0.46-0.52); the second cluster (n = 43) was associated with cognitive and affective depressive symptoms, thicker cortices and wider volumes. Multivariate analyses revealed distinct brain-inflammation relationships between the two clusters, with increase in pro-inflammatory markers being associated with decreased cortical thickness and volumes. Our stratification of MDD patients based on structural neuroimaging identified clinically-relevant subgroups of MDD with specific symptomatic and immune-inflammatory profiles, which can contribute to the development of tailored personalized interventions for MDD.
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Biomarcadores , Trastorno Depresivo Mayor , Trastorno Depresivo Resistente al Tratamiento , Humanos , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/inmunología , Femenino , Masculino , Adulto , Trastorno Depresivo Resistente al Tratamiento/diagnóstico por imagen , Persona de Mediana Edad , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Imagen por Resonancia Magnética/métodos , Neuroimagen/métodos , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Aprendizaje Automático , Experiencias Adversas de la Infancia , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patologíaRESUMEN
Major depressive disorder (MDD) and bipolar disorder (BD) are highly disabling illnesses defined by different psychopathological, neuroimaging, and cognitive profiles. In the last decades, immune dysregulation has received increasing attention as a central factor in the pathophysiology of these disorders. Several aspects of immune dysregulations have been investigated, including, low-grade inflammation cytokines, chemokines, cell populations, gene expression, and markers of both peripheral and central immune activation. Understanding the distinct immune profiles characterizing the two disorders is indeed of crucial importance for differential diagnosis and the implementation of personalized treatment strategies. In this paper, we reviewed the current literature on the dysregulation of the immune response system focusing our attention on studies using inflammatory markers to discriminate between MDD and BD. High heterogeneity characterized the available literature, reflecting the heterogeneity of the disorders. Common alterations in the immune response system include high pro-inflammatory cytokines such as IL-6 and TNF-α. On the contrary, a greater involvement of chemokines and markers associated with innate immunity has been reported in BD together with dynamic changes in T cells with differentiation defects during childhood which normalize in adulthood, whereas classic mediators of immune responses such as IL-4 and IL-10 are present in MDD together with signs of immune-senescence.
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Trastorno Bipolar , Trastorno Depresivo Mayor , Humanos , Trastorno Bipolar/inmunología , Trastorno Depresivo Mayor/inmunología , Citocinas/inmunología , Mediadores de Inflamación/metabolismo , Biomarcadores , Inflamación/inmunología , Interleucina-6/inmunologíaRESUMEN
Immune-inflammatory mechanisms are promising targets for antidepressant pharmacology. Immune cell abnormalities have been reported in mood disorders showing a partial T cell defect. Following this line of reasoning we defined an antidepressant potentiation treatment with add-on low-dose interleukin 2 (IL-2). IL-2 is a T-cell growth factor which has proven anti-inflammatory efficacy in autoimmune conditions, increasing thymic production of naïve CD4 + T cells, and possibly correcting the partial T cell defect observed in mood disorders. We performed a single-center, randomised, double-blind, placebo-controlled phase II trial evaluating the safety, clinical efficacy and biological responses of low-dose IL-2 in depressed patients with major depressive (MDD) or bipolar disorder (BD). 36 consecutively recruited inpatients at the Mood Disorder Unit were randomised in a 2:1 ratio to receive either aldesleukin (12 MDD and 12 BD) or placebo (6 MDD and 6 BD). Active treatment significantly potentiated antidepressant response to ongoing SSRI/SNRI treatment in both diagnostic groups, and expanded the population of T regulatory, T helper 2, and percentage of Naive CD4+/CD8 + immune cells. Changes in cell frequences were rapidly induced in the first five days of treatment, and predicted the later improvement of depression severity. No serious adverse effect was observed. This is the first randomised control trial (RCT) evidence supporting the hypothesis that treatment to strengthen the T cell system could be a successful way to correct the immuno-inflammatory abnormalities associated with mood disorders, and potentiate antidepressant response.
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Trastorno Bipolar , Humanos , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/diagnóstico , Interleucina-2 , Antidepresivos/uso terapéutico , Biomarcadores , Resultado del TratamientoRESUMEN
Patients with schizophrenia (SZ) show impairments in both affective and cognitive dimensions of theory of mind (ToM). SZ are also particularly vulnerable to detrimental effect of adverse childhood experiences (ACE), influencing the overall course of the disorder and fostering poor social functioning. ACE associate with long-lasting detrimental effects on brain structure, function, and connectivity in regions involved in ToM. Here, we investigated whether ToM networks are differentially affected by ACEs in healthy controls (HC) and SZ, and if these effects can predict the disorder clinical outcome. 26 HC and 33 SZ performed a ToM task during an fMRI session. Whole-brain functional response and connectivity (FC) were extracted, investigating the interaction between ACEs and diagnosis. FC values significantly affected by ACEs were entered in a cross-validated LASSO regression predicting Positive and Negative Syndrome Scale (PANSS), Interpersonal Reactivity Index (IRI), and task performance. ACEs and diagnosis showed a widespread interaction at both affective and cognitive tasks, including connectivity between vmPFC, ACC, precentral and postcentral gyri, insula, PCC, precuneus, parahippocampal gyrus, temporal pole, thalamus, and cerebellum, and functional response in the ACC, thalamus, parahippocampal gyrus and putamen. FC predicted the PANSS score, the fantasy dimension of IRI, and the AToM response latency. Our results highlight the crucial role of early stress in differentially shaping ToM related brain networks in HC and SZ. These effects can also partially explain the clinical and behavioral outcomes of the disorder, extending our knowledge of the effects of ACEs.
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Experiencias Adversas de la Infancia , Esquizofrenia , Teoría de la Mente , Humanos , Esquizofrenia/diagnóstico por imagen , Teoría de la Mente/fisiología , Mapeo Encefálico , Encéfalo/diagnóstico por imagen , Imagen por Resonancia MagnéticaRESUMEN
Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitations with the largest multi-site sample size to date (N = 5365) to provide a generalizable ML classification benchmark of major depressive disorder (MDD) using shallow linear and non-linear models. Leveraging brain measures from standardized ENIGMA analysis pipelines in FreeSurfer, we were able to classify MDD versus healthy controls (HC) with a balanced accuracy of around 62%. But after harmonizing the data, e.g., using ComBat, the balanced accuracy dropped to approximately 52%. Accuracy results close to random chance levels were also observed in stratified groups according to age of onset, antidepressant use, number of episodes and sex. Future studies incorporating higher dimensional brain imaging/phenotype features, and/or using more advanced machine and deep learning methods may yield more encouraging prospects.
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Trastorno Depresivo Mayor , Humanos , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/psicología , Benchmarking , Encéfalo/diagnóstico por imagen , Neuroimagen/métodos , Aprendizaje Automático , Imagen por Resonancia Magnética/métodosRESUMEN
Depressed patients exhibit altered levels of immune-inflammatory markers both in the peripheral blood and in the cerebrospinal fluid (CSF) and inflammatory processes have been widely implicated in the pathophysiology of mood disorders. The Choroid Plexus (ChP), located at the base of each of the four brain ventricles, regulates the exchange of substances between the blood and CSF and several evidence supported a key role for ChP as a neuro-immunological interface between the brain and circulating immune cells. Given the role of ChP as a regulatory gate between periphery, CSF spaces and the brain, we compared ChP volumes in patients with bipolar disorder (BP) or major depressive disorder (MDD) and healthy controls, exploring their association with history of illness and levels of circulating cytokines. Plasma levels of inflammatory markers and MRI scans were acquired for 73 MDD, 79 BD and 72 age- and sex-matched healthy controls (HC). Patients with either BD or MDD had higher ChP volumes than HC. With increasing age, the bilateral ChP volume was larger in patients, an effect driven by the duration of illness; while only minor effects were observed in HC. Right ChP volumes were proportional to higher levels of circulating cytokines in the clinical groups, including IFN-γ, IL-13 and IL-17. Specific effects in the two diagnostic groups were observed when considering the left ChP, with positive association with IL-1ra, IL-13, IL-17, and CCL3 in BD, and negative associations with IL-2, IL-4, IL-1ra, and IFN-γ in MDD. These results suggest that ChP could represent a reliable and easy-to-assess biomarker to evaluate the brain effects of inflammatory status in mood disorders, contributing to personalized diagnosis and tailored treatment strategies.
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Trastorno Depresivo Mayor , Trastornos del Humor , Humanos , Citocinas/metabolismo , Proteína Antagonista del Receptor de Interleucina 1 , Interleucina-17 , Interleucina-13 , Plexo Coroideo/metabolismo , BiomarcadoresRESUMEN
Patients with bipolar disorder (BD) show higher immuno-inflammatory setpoints, with in vivo alterations in white matter (WM) microstructure and post-mortem infiltration of T cells in the brain. Cytotoxic CD8+ T cells can enter and damage the brain in inflammatory disorders, but little is known in BD. Our study aimed to investigate the relationship between cytotoxic T cells and WM alterations in BD. In a sample of 83 inpatients with BD in an active phase of illness (68 depressive, 15 manic), we performed flow cytometry immunophenotyping to investigate frequencies, activation status, and expression of cytotoxic markers in CD8+ and tested for their association with diffusion tensor imaging (DTI) measures of WM microstructure. Frequencies of naïve and activated CD8+ cell populations expressing Perforin, or both Perforin and Granzyme, negatively associated with WM microstructure. CD8+ Naïve cells negative for Granzyme and Perforin positively associates with indexes of WM integrity, while the frequency of CD8+ memory cells negatively associates with index of WM microstructure, irrespective of toxins expression. The resulting associations involve measures representative of orientational coherence and myelination of the fibers (FA and RD), suggesting disrupted oligodendrocyte-mediated myelination. These findings seems to support the hypothesis that immunosenescence (less naïve, more memory T cells) can detrimentally influence WM microstructure in BD and that peripheral CD8+ T cells may participate in inducing an immune-related WM damage in BD mediated by killer proteins.
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Trastorno Bipolar , Sustancia Blanca , Humanos , Sustancia Blanca/fisiología , Imagen de Difusión Tensora/métodos , Linfocitos T CD8-positivos , Granzimas , Perforina , AnisotropíaRESUMEN
Despite the increasing availability of antidepressant drugs, a high rate of patients with major depression (MDD) does not respond to pharmacological treatments. Brain-derived neurotrophic factor (BDNF)-tyrosine receptor kinase B (TrkB) signaling is thought to influence antidepressant efficacy and hippocampal volumes, robust predictors of treatment resistance. We therefore hypothesized the possible role of BDNF and neurotrophic receptor tyrosine kinase 2 (NTRK2)-related polymorphisms in affecting both hippocampal volumes and treatment resistance in MDD. A total of 121 MDD inpatients underwent 3T structural MRI scanning and blood sampling to obtain genotype information. General linear models and binary logistic regressions were employed to test the effect of genetic variations related to BDNF and NTRK2 on bilateral hippocampal volumes and treatment resistance, respectively. Finally, the possible mediating role of hippocampal volumes on the relationship between genetic markers and treatment response was investigated. A significant association between one NTRK2 polymorphism with hippocampal volumes and antidepressant response was found, with significant indirect effects. Our results highlight a possible mechanistic explanation of antidepressant action, possibly contributing to the understanding of MDD pathophysiology.
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Trastorno Depresivo Mayor , Humanos , Antidepresivos/uso terapéutico , Antidepresivos/farmacología , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/genética , Hipocampo/diagnóstico por imagen , Hipocampo/metabolismo , Polimorfismo Genético , Receptor trkB/genéticaRESUMEN
Circadian rhythm disruption is a core symptom of bipolar disorder (BD), also reflected in altered patterns of melatonin release. Reductions of grey matter (GM) volumes are well documented in BD. We hypothesized that levels and timing of melatonin secretion in bipolar depression could be associated with depressive psychopathology and brain GM integrity. The onset of melatonin secretion under dim light conditions (DLMO) and the amount of time between DLMO and midsleep (i.e. phase angle difference; PAD) were used as circadian rhythm markers. To study the time course of melatonin secretion, an exponential curve fitting the melatonin values was calculated, and the slope coefficients (SLP) were obtained for each participant. Significant differences were found between HC and BD in PAD measures and melatonin profiles. Correlations between PAD and depressive psychopathology were identified. Melatonin secretion patterns were found to be associated with GM volumes in the Striatum and Supramarginal Gyrus in BD. Our findings emphasized the role of melatonin secretion role as a biological marker of circadian synchronization in bipolar depression and provided a novel insight for a link between melatonin release and brain structure.
Asunto(s)
Trastorno Bipolar , Melatonina , Humanos , Ritmo Circadiano , Encéfalo , Cognición , SueñoRESUMEN
BACKGROUND: For many patients with major depressive disorder (MDD) adequate treatment remains elusive. Neuroimaging techniques received attention for their potential use in guiding and predicting response, but were rarely investigated in real-world psychiatric settings. AIMS: To identify structural and functional Magnetic Resonance Imaging (MRI) biomarkers associated with antidepressant response in a real-world clinical sample. METHODS: We studied 100 MDD inpatients admitted to our psychiatric ward, treated with various antidepressants upon clinical need. Hamilton Depression Rating Scale percentage decrease from admission to discharge was used as a measure of response. All patients underwent 3.0 T MRI scanning. Grey matter (GM) volumes were investigated both in a voxel-based morphometry (VBM), and in a regions of interest (ROI) analysis. In a subsample of patients, functional resting-state connectivity patterns were also explored. RESULTS: In the VBM analysis, worse response was associated to lower GM volumes in two clusters, encompassing the left hippocampus and parahippocampal gyrus, and the right superior and middle temporal gyrus. Investigating ROIs, lower bilateral hippocampi and amygdalae volumes predicted worse treatment outcomes. Functional connectivity in the right temporal and parahippocampal gyrus was also associated to response. CONCLUSION: Our results expand existing literature on the relationship between the structure and function of several brain regions and treatment response in MDD. While we are still far from routine use of MRI biomarkers in clinical practice, we confirm a possible role of these techniques in guiding treatment choices and predicting their efficacy.
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Trastorno Depresivo Mayor , Humanos , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/tratamiento farmacológico , Depresión , Encéfalo , Antidepresivos/uso terapéutico , Neuroimagen , Hipocampo/patología , Imagen por Resonancia Magnética/métodos , BiomarcadoresRESUMEN
Several factors may affect response to treatment in Major Depressive Disorder (MDD) including immune/inflammatory alterations and regional brain volumes, particularly in hippocampal regions which have shown to be influenced by inflammatory status. Neutrophil-to-lymphocyte ratio (NLR) is an inflammatory marker found to be elevated in depressed women in large population studies. Here we investigate the effect of NLR on treatment response in MDD patients, and the role of sex and hippocampal volume on influencing this relationship. A sample of 124 MDD depressed inpatients (F = 80) underwent MRI acquisition, admission NLR was calculated by dividing absolute neutrophil by absolute lymphocyte counts and depression severity was assessed at admission and discharge via the Hamilton Depression Rating Scale (HDRS). As a measure of treatment response, delta HDRS was calculated. We found a significant moderation effect of sex on the relationship between NLR and Delta HDRS: a negative relation was found in females and a positive one in males. NLR was found to negatively affect hippocampal volumes in females. Both left and right hippocampal volume positively associated with Delta HDRS. Finally, left hippocampal volume mediated the effect of NLR on Delta HDRS in females. Sex moderated the relation between inflammation and treatment response in line with previous reports linking inflammation to hampered antidepressant effect in females. Further, this effect is partially mediated by hippocampal volume, suggesting that antidepressant response may be hampered by the detrimental effect of inflammation on the brain.
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Trastorno Depresivo Mayor , Masculino , Humanos , Femenino , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/tratamiento farmacológico , Neutrófilos , Hipocampo/diagnóstico por imagen , Antidepresivos/uso terapéutico , Antidepresivos/farmacología , Linfocitos , Inflamación/tratamiento farmacológicoRESUMEN
COVID-19 survivors struggle with intense depressive and post-traumatic symptoms in sub-acute stages. Survivor guilt may affect post-acute psychopathology. Herein, we aim to unveil the potential affective mechanism underpinning post-COVID psychiatric implications by focusing on the association of survivor guilt with psychopathology and maladaptive attributional style. At one month after discharge, we evaluated symptoms of depression on The Zung Severity Rating Scale (ZSDS), post-traumatic distress on Impact of Event Scale-Revised (IES-R), and sleep disturbances on the Women's Health Initiative Insomnia Rating Scale (WHIIRS) in 195 COVID-19 survivors. Interpersonal Guilt Rating Scale (IGRS-15) rated survivor guilt. A discrepancy score between the burden of depression and post-traumatic distress symptoms was computed individually. Dysfunctional depressive attributions were assessed through the Cognition Questionnaire (CQ). Survivor guilt significantly predicts all evaluated psychopathological dimensions. Moreover, higher rates of survivor guilt were associated with an overlap between post-traumatic and depressive symptomatology, thus suggesting that survivor guilt equally sustains both psychiatric manifestations. Finally, survivor guilt fully mediated the relationship between dysfunctional depressive attributions and the discrepancy index. Our results confirm survivor guilt as a clinically relevant form of suffering related to psychopathological dimensions of post COVID-19 infection, gaining the status of a specific phenomenon and a promising treatment target.
RESUMEN
Suicide attempts in Bipolar Disorder are characterized by high levels of lethality and impulsivity. Reduced rates of amygdala and cortico-limbic habituation can identify a fMRI phenotype of suicidality in the disorder related to internal over-arousing states. Hence, we investigated if reduced amygdala and whole-brain habituation may differentiate bipolar suicide attempters (SA, n = 17) from non-suicide attempters (nSA, n = 57), and healthy controls (HC, n = 32). Habituation was assessed during a fMRI task including facial expressions of anger and fear and a control condition. Associations with suicidality and current depressive symptomatology were assessed, including machine learning procedure to estimate the potentiality of habituation as biomarker for suicidality. SA showed lower habituation compared to HC and nSA in several cortico-limbic areas, including amygdalae, cingulate and parietal cortex, insula, hippocampus, para-hippocampus, cerebellar vermis, thalamus, and striatum, while nSA displayed intermediate rates between SA and HC. Lower habituation rates in the amygdalae were also associated with higher depressive and suicidal current symptomatology. Machine learning on whole-brain and amygdala habituation differentiated SA vs. nSA with 94% and 69% of accuracy, respectively. Reduced habituation in cortico-limbic system can identify a candidate biomarker for attempting suicide, helping in detecting at-risk bipolar patients, and in developing new therapeutic interventions.
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Trastorno Bipolar , Humanos , Trastorno Bipolar/diagnóstico por imagen , Habituación Psicofisiológica , Encéfalo , Intento de Suicidio , Ideación SuicidaRESUMEN
Major depressive disorder (MDD) is a multifactorial, serious and heterogeneous mental disorder that can lead to chronic recurrent symptoms, treatment resistance and suicidal behavior. MDD often involves immune dysregulation with high peripheral levels of inflammatory cytokines that might have an influence on the clinical course and treatment response. Moreover, patients with MDD show brain volume changes as well as white matter (WM) alterations that are already existing in the early stage of illness. Mounting evidence suggests that both neuroimaging markers, such as WM integrity and blood markers, such as inflammatory cytokines might serve as predictors of treatment response in MDD. However, the relationship between peripheral inflammation, WM structure and antidepressant response is not yet clearly understood. The aim of the present review is to elucidate the association between inflammation and WM integrity and its impact on the pathophysiology and progression of MDD as well as the role of possible novel biomarkers of treatment response to improve MDD prevention and treatment strategies.
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Trastorno Depresivo Mayor , Sustancia Blanca , Humanos , Citocinas , Antidepresivos , InflamaciónRESUMEN
Cognitive impairment represents a leading residual symptom of COVID-19 infection, which lasts for months after the virus clearance. Up-to-date scientific reports documented a wide spectrum of brain changes in COVID-19 survivors following the illness's resolution, mainly related to neurological and neuropsychiatric consequences. Preliminary insights suggest abnormal brain metabolism, microstructure, and functionality as neural under-layer of post-acute cognitive dysfunction. While previous works focused on brain correlates of impaired cognition as objectively assessed, herein we investigated long-term neural correlates of subjective cognitive decline in a sample of 58 COVID-19 survivors with a multimodal imaging approach. Diffusion Tensor Imaging (DTI) analyses revealed widespread white matter disruption in the sub-group of cognitive complainers compared to the non-complainer one, as indexed by increased axial, radial, and mean diffusivity in several commissural, projection and associative fibres. Likewise, the Multivoxel Pattern Connectivity analysis (MVPA) revealed highly discriminant patterns of functional connectivity in resting-state among the two groups in the right frontal pole and in the middle temporal gyrus, suggestive of inefficient dynamic modulation of frontal brain activity and possible metacognitive dysfunction at rest. Beyond COVID-19 actual pathophysiological brain processes, our findings point toward brain connectome disruption conceivably translating into clinical post-COVID cognitive symptomatology. Our results could pave the way for a potential brain signature of cognitive complaints experienced by COVID-19 survivors, possibly leading to identify early therapeutic targets and thus mitigating its detrimental long-term impact on quality of life in the post-COVID-19 stages.
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COVID-19 , Disfunción Cognitiva , Humanos , Imagen de Difusión Tensora/métodos , Calidad de Vida , COVID-19/complicaciones , Encéfalo/fisiología , Imagen por Resonancia Magnética/métodos , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/etiología , Disfunción Cognitiva/patología , Cognición , SobrevivientesRESUMEN
Cognitive impairments figure prominently in COVID-19 survivors. Cognitive remediation therapy (CRT) improves functional outcomes reducing long-term cognitive deficits in several neurological and psychiatric conditions. Our case-control study investigates the efficacy of a CRT programme administered to COVID-19 survivors in the post-acute phase of the illness. Seventy-three COVID-19 survivors presenting cognitive impairments at one-month follow-up were enrolled. Among them, 15 patients were treated with a two-month CRT programme, and 30 non-treated patients were matched conditional to their baseline cognitive functioning. Cognitive functions were assessed before and after treatment. Depression and quality of life were also evaluated. Mixed model ANOVA revealed a significant effect over time of the CRT programme on global cognitive functioning (F = 4.56, p = 0.039), while no significant effect was observed in the untreated group. We observed a significant effect of the improvement in verbal fluency (χ2 = 7.20, p = 0.007) and executive functions (χ2 = 13.63, p < 0.001) on quality of life. A positive significant correlation was found between depressive symptomatology and verbal fluency (r = -0.35), working memory (r = -0.44), psychomotor coordination (r = -0.42), and executive functions (r = -0.33). Our results could pave the way to a plausible innovative treatment targeting cognitive impairments and ameliorating the quality of life of COVID-19 survivors.
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COVID-19 , Disfunción Cognitiva , Remediación Cognitiva , Humanos , Calidad de Vida , Estudios de Casos y Controles , Cognición , SobrevivientesRESUMEN
BACKGROUND: Bipolar disorder (BD) is linked to several structural and functional brain alterations. In addition, BD patients have a three-fold increased risk of developing insulin resistance, which is associated with neural changes and poorer BD outcomes. Therefore, we investigated the effects of insulin and two derived measures (insulin resistance and sensitivity) on white matter (WM) microstructure, resting-state (rs) functional connectivity (FC), and fractional amplitude of low-frequency fluctuation (fALFF). METHODS: BD patients (n = 92) underwent DTI acquisition, and a subsample (n = 22) underwent rs-fMRI. Blood samples were collected to determine insulin and glucose levels. The Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) were computed. DTI data were analyzed via tract-based spatial statistics and threshold-free cluster enhancement. From rs-fMRI data, both ROI-to-ROI FC matrices and fALFF maps were extracted. RESULTS: Insulin showed a widespread negative association with fractional anisotropy (FA) and a positive effect on radial diffusivity (RD) and mean diffusivity (MD). HOMA-IR exerted a significant effect on RD in the right superior longitudinal fasciculus, whereas QUICKI was positively associated with FA and negatively with RD and MD in the left superior longitudinal fasciculus, left anterior corona radiata, and forceps minor. fALFF was negatively modulated by insulin and HOMA-IR and positively associated with QUICKI in the precuneus. No significant results were found in the ROI-to-ROI analysis. CONCLUSION: Our findings suggest that WM microstructure and functional alterations might underlie the effect of IR on BD pathophysiology, even if the causal mechanisms need to be further investigated.
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Trastorno Bipolar , Resistencia a la Insulina , Insulinas , Sustancia Blanca , Humanos , Imagen de Difusión Tensora/métodos , Encéfalo , AnisotropíaRESUMEN
High levels of peripheral IL-6, a pro-inflammatory cytokine, have been indicated as a key element of the bipolar disorder (BD), allowing to differentiate BD from major depression with high accuracy and to early detect poor responders to antidepressant treatments. IL-6 may contribute to BD pathophysiology through its effects on the neurobiological underpinnings of the disorder, such as grey matter (GM) volumes and resting state functional connectivity (rs-FC) abnormalities. In this study, we primary investigate the relationship between the peripheral plasmatic level of IL-6 and GM volumes, obtained with Voxel-Based Morphometry, in 84 BD inpatients. As secondary aims, we explored if IL-6 levels may be related to self-reported psychopathological dimensions of depression (i.e. symptoms severity and cognitive biases) and seed based rs-FC of brain regions structurally associated with the cytokine. Results showed that higher level of peripheral IL-6 was associated to lower GM volumes in supragenual anterior cingulate cortex, and reduced rs-FC between this area and medial orbito-frontal cortex in BD. Furthermore, in depressed patients IL-6 positively correlated to cognitive biases typically associated to depressive episodes, such as the perceived uncontrollability of negative events, or their generalization across future and situations. Our data provide additional evidence of detrimental effect of systemic inflammation on brain structure in BD and confirm the crucial role of anterior cingulate cortex as neural underpinning of the disorder. However, future studies are needed to replicate our findings in larger samples.
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Bipolar disorder (BD) and major depressive disorder (MDD) are severe psychiatric illnesses that share among their environmental risk factors the exposure to adverse childhood experiences (ACE). Exposure to ACE has been associated with long-term changes in brain structure and the immune response. In the lasts decades, brain abnormalities including alterations of white matter (WM) microstructure and higher levels of peripheral immune/inflammatory markers have been reported in BD and MDD and an association between inflammation and WM microstructure has been shown. However, differences in these measures have been reported by comparing the two diagnostic groups. The aim of the present study was to investigate the interplay between ACE, inflammation, and WM in BD and MDD. We hypothesize that inflammation will mediate the association between ACE and WM and that this will be different in the two groups. A sample of 200 patients (100 BD, 100 MDD) underwent 3T MRI scan and ACE assessment through Childhood Trauma Questionnaire. A subgroup of 130 patients (75 MDD and 55 BD) underwent blood sampling for the assessment of immune/inflammatory markers. We observed that ACE associated with higher peripheral levels of IL-2, IL-17, bFGF, IFN-γ, TNF-α, CCL3, CCL4, CCL5, and PDGF-BB only in the BD group. Further, higher levels of CCL3 and IL-2 associated with lower FA in BD. ACE were found to differently affect WM microstructure in the two diagnostic groups and to be negatively associated with FA and AD in BD patients. Mediation analyses showed a significant indirect effect of ACE on WM microstructure mediated by IL-2. Our findings suggest that inflammation may mediate the detrimental effect of early experiences on brain structure and different mechanisms underlying brain alterations in BD and MDD.