80 research outputs found
The neurobiological basis of cognitive side effects of electroconvulsive therapy : a systematic review
Altres ajuts: M.C. is founded by the Sara Borrell postdoctoral contract [CD20/00189].Decades of research have consistently demonstrated the efficacy of electroconvulsive therapy (ECT) for the treatment of major depressive disorder (MDD), but its clinical use remains somewhat restricted because of its cognitive side effects. The aim of this systematic review is to comprehensively summarize current evidence assessing potential biomarkers of ECT-related cognitive side effects. Based on our systematic search of human studies indexed in PubMed, Scopus, and Web of Knowledge, a total of 29 studies evaluating patients with MDD undergoing ECT were reviewed. Molecular biomarkers studies did not consistently identify concentration changes in plasma S-100 protein, neuron-specific enolase (NSE), or Aβ peptides significantly associated with cognitive performance after ECT. Importantly, these findings suggest that ECT-related cognitive side effects cannot be explained by mechanisms of neural cell damage. Notwithstanding, S-100b protein and Aβ40 peptide concentrations, as well as brain-derived neurotrophic factor (BDNF) polymorphisms, have been suggested as potential predictive biomarkers of cognitive dysfunction after ECT. In addition, recent advances in brain imaging have allowed us to identify ECT-induced volumetric and functional changes in several brain structures closely related to memory performance such as the hippocampus. We provide a preliminary framework to further evaluate neurobiological cognitive vulnerability profiles of patients with MDD treated with ECT
The Global ECT-MRI Research Collaboration (GEMRIC): Establishing a multi-site investigation of the neural mechanisms underlying response to electroconvulsive therapy.
Major depression, currently the world's primary cause of disability, leads to profound personal suffering and increased risk of suicide. Unfortunately, the success of antidepressant treatment varies amongst individuals and can take weeks to months in those who respond. Electroconvulsive therapy (ECT), generally prescribed for the most severely depressed and when standard treatments fail, produces a more rapid response and remains the most effective intervention for severe depression. Exploring the neurobiological effects of ECT is thus an ideal approach to better understand the mechanisms of successful therapeutic response. Though several recent neuroimaging studies show structural and functional changes associated with ECT, not all brain changes associate with clinical outcome. Larger studies that can address individual differences in clinical and treatment parameters may better target biological factors relating to or predictive of ECT-related therapeutic response. We have thus formed the Global ECT-MRI Research Collaboration (GEMRIC) that aims to combine longitudinal neuroimaging as well as clinical, behavioral and other physiological data across multiple independent sites. Here, we summarize the ECT sample characteristics from currently participating sites, and the common data-repository and standardized image analysis pipeline developed for this initiative. This includes data harmonization across sites and MRI platforms, and a method for obtaining unbiased estimates of structural change based on longitudinal measurements with serial MRI scans. The optimized analysis pipeline, together with the large and heterogeneous combined GEMRIC dataset, will provide new opportunities to elucidate the mechanisms of ECT response and the factors mediating and predictive of clinical outcomes, which may ultimately lead to more effective personalized treatment approaches
Altered EEG Oscillatory Brain Networks During Music-Listening in Major Depression
To examine the electrophysiological underpinnings of the functional networks involved in music listening, previous approaches based on spatial independent component analysis (ICA) have recently been used to ongoing electroencephalography (EEG) and magnetoencephalography (MEG). However, those studies focused on healthy subjects, and failed to examine the group-level comparisons during music listening. Here, we combined group-level spatial Fourier ICA with acoustic feature extraction, to enable group comparisons in frequency-specific brain networks of musical feature processing. It was then applied to healthy subjects and subjects with major depressive disorder (MDD). The music-induced oscillatory brain patterns were determined by permutation correlation analysis between individual time courses of Fourier-ICA components and musical features. We found that (1) three components, including a beta sensorimotor network, a beta auditory network and an alpha medial visual network, were involved in music processing among most healthy subjects; and that (2) one alpha lateral component located in the left angular gyrus was engaged in music perception in most individuals with MDD. The proposed method allowed the statistical group comparison, and we found that: (1) the alpha lateral component was activated more strongly in healthy subjects than in the MDD individuals, and that (2) the derived frequency-dependent networks of musical feature processing seemed to be altered in MDD participants compared to healthy subjects. The proposed pipeline appears to be valuable for studying disrupted brain oscillations in psychiatric disorders during naturalistic paradigms.Peer reviewe
Metalloproteinase-9 and depression: a study in an animal model and human postmortem brain, and its role in the mechanism of action of fast-acting antidepressant drugs
RESUMEN: El trastorno depresivo mayor es una enfermedad mental común, especialmente en mujeres. El cannabidiol, el mayor componente no psicomimético del Cannabis sativa, presenta un potencial efecto antidepresivo. Por otro lado, se han observado elevados niveles de la metaloproteinasa 9 (MMP-9) en modelos de estrés crónico y en pacientes deprimidos. En esta Tesis Doctoral, profundizamos en la implicación de la MMP-9 en la depresión. Observamos un efecto antidepresivo del tratamiento subcrónico con cannabidiol y la reversión del incremento en la actividad de la MMP-9 en un modelo de depresión inducido por la administración de corticosterona. La caracterización de ratones transgénicos MMP-9 mostraron que las alteraciones en MMP-9 tienen un impacto sexo-dependiente a nivel conductual, molecular y neuroquímico. Finalmente, detectamos una elevada actividad de MMP-9 en muestras cerebrales post-mortem de mujeres deprimidas que cometieron suicidio, pero no en hombres. Estos hallazgos refuerzan la implicación sexo-dependiente de MMP-9 en la etiopatología de la depresión.ABSTRACT: Major depression is a common mental illness, especially in women. Cannabidiol, the main non-psychomimetic component of Cannabis sativa, presents a potential antidepressant effect. On the other hand, high levels of metalloproteinase 9 (MMP-9) have been observed in models of chronic stress and depressed patients. In this Doctoral Thesis, we delve into the involvement of MMP-9 in depression. We observed an antidepressant-like effect of subchronic cannabidiol administration and the normalization of elevated MMP-9 activity in the corticosterone-induced model of depression. The characterisation of MMP-9 transgenic mice showed that alterations in MMP-9 have a sex-dependent impact at the behavioural, molecular, and neurochemical levels. Finally, we detected elevated MMP-9 activity in post-mortem brain samples from depressed women who committed suicide, but not in men. These findings reinforce the sex-dependent implication of MMP-9 in the etiopathology of depression.Para la realización de este trabajo, la doctoranda ha disfrutado de un contrato predoctoral de la “Convocatorias 2018 Proyectos de I+D de GENERACIÓN DE CONOCIMIENTO y Proyectos de I+D+i RETOS INVESTIGACIÓN”, del Centro de
Investigación Biomédica en Red (CIBER).
Este trabajo ha sido financiado por:
- Ministerio de Ciencia, Innovación y Universidades (RTI2018-097534-B-I00).
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM),
Instituto de Salud Carlos III (CIBERSAM CB/07/09/0029 y CB/07/09/0008)
Neurobiological aspects of depression- Antidepressant effects on glia-neuron interaction
Major depressive disorder (MDD) is a globally spread and complex neuropsychiatric disorder. The neurobiological underpinnings of MDD are a current matter of study. The strong heterogeneity of its clinical manifestations and the lack of response in some patients make the identification of new targets and the generation of novel treatments an important issue for the treatment of MDD. Therefore, the aim of this thesis was to contribute to the discovery of new targets for antidepressants (ADs) to improve MDD treatment. Recently, it was shown in post-morten tissue of MDD patients that the number of glial cells is reduced, accompanied by atrophy of neuronal cells and decreased volume of the prefrontal cortex (PFC). Neuropsychiatric disorders also display disrupted synaptic communication and neuronal connectivity, which are reversed by ADs. Following the hypothesis that a dysregulation in the communication between glial cells and neurons is one of the key factors underlying the development of MDD, I aimed to see the effects of astrocytes on synapse homeostasis upon the effect of ADs.
I focused my study on the PFC and hippocampal areas, hence these areas are known to be highly involved in mood disorders. For examining cell-type specificity, I performed both in vitro and ex vivo experiments from naïve animals in order to not interfere with other physiological changes produced by the disease itself. In the present study, I could observe a reduction in excitatory synaptic densities in vitro, after 48h continuous AD treatment, when neurons were growing in the presence of cortical astrocytes but not when hippocampal astrocytes were present. In the absence of astrocytes or in the presence Astrocyte-Neuron Conditioned Media such effects were not seen, suggesting that a membrane-bound protein might have mediated those effects. Ex vivo experiments also revealed a reduction of synaptic markers in the adult rat PFC after short-term treatment with ADs, but not in other areas such as CA1 and CA3 of the hippocampus. Astrocytes could mediate this fast AD action as there are closely associated to synapses. For these reasons, MEGF10 receptor was studied. This molecule is a transmembrane receptor that participates in synapse elimination mostly during development. Indeed, treatment with ADs for 48 hours (h) triggered an increase in MEGF10 expression in the adult rat PFC and in primary cultured astrocytes. Therefore, the reduction in the number of synaptic densities I observed could be explained by an astrocyte-dependent
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remodelling of synapses following acute AD treatment. In support of this hypothesis, the downregulation of MEGF10 was sufficient to block ADs effects, thus no reduction in synaptic densities was observed. Taken together, these data suggest that MEGF10 could be a potential novel candidate to develop alternative treatment options for diseases characterized by synaptic aberrancies, such as MDD.
Moreover, it is important to understand which major changes are produced in disease conditions. Therefore, part of this thesis aimed to demonstrate the neurobiological basis of the heterogeneity found in depression, using two different animal models with a depressive-like phenotype (HAB, High Anxiety like Behaviour rat and WK, Wistar Kyoto rat). Differences in the number of synaptic densities and in the morphology of neurons have been found in HAB and WK compared to control animals. Finally, further studies should reveal the contribution of MEGF10 to such changes and how a pharmacological treatment may help to re-establish some of those changes
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Noninvasive Neuromodulation: Modeling and Analysis of Transcranial Brain Stimulation with Applications to Electric and Magnetic Seizure Therapy
Bridging the fields of engineering and psychiatry, this dissertation proposes a novel framework for the rational dosing of electric and magnetic seizure therapy, including electroconvulsive therapy (ECT) and magnetic seizure therapy (MST), for the treatment of psychiatric disorders such as medication resistant major depression and schizophrenia. The objective of this dissertation is to develop computational modeling tools that allow ECT and MST stimulation paradigms to be biophysically optimized ex vivo, prior to testing safety and efficacy in preclinical and clinical trials. Despite therapeutic advances, treatment resistant depression (TRD) remains a largely unmet clinical need. ECT is highly effective for TRD, but its side effects limit its real-world clinical utility. Modifications of treatment technique (e.g., electrode placement, stimulus parameters, novel paradigms such as MST) significantly improve the tolerability of convulsive therapy. However, we know relatively little about the distribution of the electric field (E-field) induced in the brain to inform spatial targeting of ECT and MST. Lacking an understanding of biophysical and physiological mechanisms, refinements in ECT/MST technique rely exclusively on time-consuming and costly clinical trials. Consequently, key questions remain unanswered about how to position the ECT electrodes or MST coil for targeted brain stimulation. Addressing this knowledge gap, this dissertation proposes a new platform that will inform an improved spatial targeting of ECT and MST through state-of-the-art computer simulations of the E-field distribution in human and nonhuman primate (NHP) brain.
Part I of this dissertation aims to develop anatomically realistic finite element models of transcranial electric and magnetic stimulation in human and NHPs incorporating tissue heterogeneity and anisotropy derived from structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) data. The NHP models of ECT and MST are created alongside the human model since NHPs are used in preclinical studies on the mechanisms of seizure therapy.
Part II of this dissertation aims to apply the model developed in Part I to electric and magnetic seizure therapy. We compute the strength and spatial distributions of the E-field induced in the brain by various ECT and MST paradigms. The relative E-field strength among various regions of interest (ROIs) is examined to select electrode/coil configurations that produce most focal stimulation of target ROIs that are considered to mediate the therapeutic action of ECT and MST. Since E-field alone is insufficient to account for individual differences in neurophysiological response, we calibrate the E-field maps relative to the neural activation threshold via in vivo measurements of the corticospinal tract response to single pulses (motor threshold, MT). We derive an empirical estimate of the neural activation threshold by coupling simulated E-field strength with individually measured MT. The E-field strength relative to an empirical neural activation threshold and corresponding volume of suprathreshold stimulation (focality) is examined to inform the selection of ECT and MST stimulus pulse amplitude that will result in focal ROI stimulation. We contrast the ECT/MST stimulation strength and focality with conventional fixed and individually titrated pulse amplitude necessary to induce a seizure (seizure threshold, ST) to study pulse amplitude adjustment as a novel means of controlling stimulation strength and focality. This work provides a basis for rational dosing of seizure therapies that could help improve their risk/benefit ratio and guide the development of safer alternatives for patients with severe psychiatric disorders
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