Neuroimaging and electroencephalographic (EEG) methods for investigating neural circuits in mental disorders

It is increasingly recognised that dysfunction in neural circuits plays a key role in the neurobiological basis of mental disorders.  The efficacy of pharmacological and behavioural treatments for mental disorders could therefore be improved by targeting dysfunctions in neurocircuits.  However, to achieve this, a better understanding of the specific alterations in neural circuits involved in different mental disorders is required.  Such understanding can be acquired by using advanced neuroscience methods to examine the pathways and function of neurocircuits in both typically developing individuals and in those with mental disorders.  This article provides an overview of currently available neuroscience methods of investigating neural circuits, including advantages and limitations of different techniques, and highlights the importance of using multi-modal imaging in future researchÉ cada vez mais reconhecido que a disfunção nos circuitos neurais desempenha um papel fundamental na base neurobiológica dos transtornos mentais. A eficácia dos tratamentos farmacológicos e comportamentais para os transtornos mentais pode, portanto, ser melhorada por direcionar as disfunções nos neurocircuitos. No entanto, para isso, é necessário um melhor entendimento das alterações específicas nos circuitos neurais envolvidos em diferentes transtornos mentais. Tal entendimento pode ser adquirido usando-se métodos avançados de neurociência para examinar as vias e a função dos neurocircuitos em indivíduos com desenvolvimento típico e naqueles com transtornos mentais. Este artigo fornece uma visão geral dos métodos da neurociência atualmente disponíveis na investigação de circuitos neurais, incluindo vantagens e limitações de diferentes técnicas, e destaca a importância do uso de imagens multimodais em pesquisas futura

Analysis of the use of photosensitization in human glioblastoma multiforme to induce cell death

Introduction: The most frequent primary tumor of the central nervous system is the malignant glioma, being the glioblastoma (GBM), grade IV astrocytoma, the most aggressive and lethal glioma. Malignant astrocytomas are responsive for therapy targeting autophagy as temozolomide, the standard adjuvant treatment which induces autophagic cell death. Autophagy is a homeostatic intracellular process that eliminate old proteins and recycle cellular components. Mitophagy is a subtype of autophagy that regulates the removal of damaged, dysfunctional or redundant mitochondria. Parallel damage against lysosomes and mitochondria membranes using photosensitized oxidations and strong redox stress leads to activation of mitophagy and malfunction of autophagy. This mechanism of photosensitization, ultimately, causes cell death. Challenging cells with a low concentration of a photosensitizer as 1,9-dimethyl methylene blue (DMMB) combined with light- irradiation of 12 joules/cm2 have induced mitochondrial damage with activation of mitophagy and concomitant lysosome damage, in skin-derived cell lines. This experimental design was applied to U87MG GBM cells to verify if tumor cell death may be obtained with combined mitochondrial and lysosomal damages to open new therapeutic strategies for GBM and to better understand the mechanisms of mitophagy.Objectives: Our primary objective is to analyze the impact of challenging GBM cells with a low concentration of 1,9-dimethyl methylene blue (DMMB) with combined light- irradiation of 12 joules/cm2.Methodology: U87MG a human GBM cell line was used. The photodamage was performed using DMMB photosensitized by a LED with maximum emission wavelength at 630 nm providing 12 J/cm2. Cell proliferation and viability assays were performed using MTT to assess whether there was proliferation inhibition and/or alteration of cell viability after photosensitization. Quantification of cells in different stages of apoptosis, and in the various phases of the cell cycle were analyzed using flow cytometry after photosensitization. Acridine orange assay was used to assess lysosome damage. RT-PCR and Western Blotting were performed to evaluate the expression levels of the main autophagy and mitophagy genes and proteins.Partial Results: Cell proliferation and viability assays demonstrated that the concentration of DMMB to cause 50% inhibition of biological activity of cells (IC50) was 10 nM after 48h. The apoptosis and cell cycle experiments were performed in this concentration. Increase in apoptosis was observed after 24hs of photosensitization. Currently, the cell cycle flow cytometry assay has been performed, followed by the quantification of lysosomes damage by Acridine Orange assay. The genes and proteins involved in the mechanisms of autophagy and mitophagy will be determined by expression analysis through RT-PCR and Western blot assays.Discussion and Conclusion: For a future perspective, if this prove of concept is achieved, i.e. death of tumor cells by the combined approach of photosensitizer with irradiation, a new therapeutic strategy of light-activated drugs may be offered to cancer patients

Non epileptogenic Rasmussen`s encephalitis: a case report

Introduction: Rasmussen's encephalitis (RE) is a very rare chronic inflammatory unilateral encephalopathy with still unknown etiology. It predominantly affects children under the age of 10, but can also affect adolescents and adults. Current evidence on possible etiologies are divided in two main theories. The first one is based on brain inflammation caused by a reaction to a foreign antigen. The second one is based on an autoimmune disease that is limited to a single hemisphere of the brain. The common presentation is intractable and frequent focal motor seizures, often associated with progressive neurological decline, and progressive unilateral focal cortical atrophy. Progression of the inflammatory process in MRI is considered a good biomarker in RE. Objectives: Report a rare case of a female infant presenting atypical manifestations of uncommon symptoms without seizures caused by Rasmussen's encephalitis. Case Report: A ten-year-old right-handed female presented to the emergency department with sudden onset of abnormal involuntary movements of the right upper and lower limbs, face paresia of the same side and loss of attention without loss of consciousness. The involuntary contractions were brief, random, irregular, and worsened with activity, along with a positive milkmaid grip sign. She also displayed reduced movement speed and hyperactive biceps, triceps, patellar and ankle jerk reflexes. Associated with the motor abnormalities, the girl presented with a recent but progressive decrease in cognitive functions, which caused a decline in school performance and impaired reasoning, and affective blunting. She had no sign of previous neuropsychomotor development abnormality. She was taken to a quaternary hospital where a MRI and a CT of the brain were performed. MRI showed atrophy of the left cerebral hemisphere, predominantly in the operculum and head of the caudate nucleus, hypersignal in the insular cortex and adjacent white matter. CT presented with hypoattenuation of the left frontal lobe and parieto-occipital white matter associated with atrophy of the head of the caudate nucleus of the same side and enlargement of the adjacent fissures and sulcus. A subsequent PET-CT showed a left cerebral hemisphere hypometabolism, predominantly in the basal ganglia, temporal, frontal and insular lobes. Functional evaluation detected diffuse unilateral disorganization of brain electric activity, but no epileptic paroxysmal discharges were found on the electroencephalogram. After hospitalization, human immunoglobulin at the dose 2g/kg/day was used for five days. The girl remained stable, with no complications. After sixteen days, she was discharged with a rehabilitation program and follow-up care

The role of diffusion tensor imaging and tractography for deep brain stimulation planning in treatment of obsessive-compulsive disorder

Introduction: Obsessive-compulsive disorder (OCD) is a common, chronic and long-lasting mental disorder. The current first-line therapy for OCD is high doses of selective serotonin reuptake inhibitor (SSRI) and cognitive-behavioral psychotherapy. For patients with refractory symptoms, studies demonstrated that they may respond well to Deep Brain Stimulation (DBS), a technique that can modulate altered neuronal activity. Some stimulation sites are currently being used as targets to DBS and showed good response, but further analyses are necessary to improve the location of the electrodes since some patients demonstrated a poor outcome. Neuroimaging that assess white matter such as diffusion tensor image and tractography can evaluate the quality of the targets and assess the tracts that are affected by the electric field of the electrodes used in the surgery. Our hypothesis is that the patient outcome depends on the trajectory of the tracts that are affected by the electric field.Objectives: Our aim is to investigate which tracts connected with the stimulation sites contribute to clinical improvement effects and weather is possible to predict the outcomes based on connectivity.Methodology: We analyzed 4 patients (2 female) with treatment-refractory obsessive-compulsive disorder undergoing deep brain stimulation targeting the anterior limb of the internal capsule/ nucleus accumbens (ALIC). We will perform tractography analysis of the fibers using the volume of active tissue (VTA) as the region of interest. We will relate the alteration in OCD symptom severity on Yale-Brown obsessive-compulsive scale (Y-BOCS) between the condition before surgery and one-year follow-up with the tracts involved with the stimulation sites using DTI data such as fractal anisotropy and mean diffusivity.Partial Results: Half of the patients did show great improvement and the other two maintained a bad outcome. We found that active stimulation of the ALIC more lateral and posterior of the nucleus was associated with a better outcome. Currently, the description of the tracts involved in patients with better outcomes is performed. The tracts involved with this result will be determined by analysis of DTI and tractography.Discussion and Conclusion: For a future perspective, the results will be important to improve the stimulation sites in DBS surgery resulting in better outcomes

Mitochondrial dysfunction mediates neuronal cell response to DMMB photodynamic therapy

Photodynamic therapy (PDT) is a process in which a photosensitizer (PS) is exposed to specific wavelengths and generates reactive oxygen species (ROS) which act within nanometers. The low invasive nature and directed cytotoxicity of this approach render it attractive to the treatment of different conditions, including the ones that affect the central nervous system (CNS). The effect of PDT on healthy neurons is one main concern over its use in the CNS, since neuronal-like cells were shown to be particularly sensitive to certain PSs. Among available PSs, 1,9-dimethyl-methylene blue (DMMB) stands out as being resistant to reduction to its inactive leuco form and by being able to produce high levels of singlet‑oxygen. In this study, we aimed to investigate DMMB photodamage mechanisms in the hippocampal cell line HT22. Our results demonstrate that DMMB-PDT decrease in cell viability was linked with an increase in cell death and overall ROS production. Besides, it resulted in a significant increase in mitochondrial ROS production and decreased mitochondria membrane potential. Furthermore, DMMB-PDT significantly increased the presence of acidic autolysosomes, which was accompanied by an increase in ATG1 and ATG8 homologue GaBarap1 expression, and decreased DRAM1 expression. Taken together our results indicated that mitochondrial and autophagic dysfunction underlie DMMB-PDT cytotoxicity in neuronal cells.</p