Biological markers in noninvasive brain stimulation trials in major depressive disorder: a systematic review

Objectives: The therapeutic effects of transcranial magnetic stimulation (TMS) and transcranial direct current stimulation in patients with major depression have shown promising results; however, there is a lack of mechanistic studies using biological markers (BMs) as an outcome. Therefore, our aim was to review noninvasive brain stimulation trials in depression using BMs. Methods: The following databases were used for our systematic review: MEDLINE, Web of Science, Cochrane, and SCIELO. We examined articles published before November 2012 that used TMS and transcranial direct current stimulation as an intervention for depression and had BM as an outcome measure. The search was limited to human studies written in English. Results: Of 1234 potential articles, 52 articles were included. Only studies using TMS were found. Biological markers included immune and endocrine serum markers, neuroimaging techniques, and electrophysiological outcomes. In 12 articles (21.4%), end point BM measurements were not significantly associated with clinical outcomes. All studies reached significant results in the main clinical rating scales. Biological marker outcomes were used as predictors of response, to understand mechanisms of TMS, and as a surrogate of safety. Conclusions: Functional magnetic resonance imaging, single-photon emission computed tomography, positron emission tomography, magnetic resonance spectroscopy, cortical excitability, and brain-derived neurotrophic factor consistently showed positive results. Brain-derived neurotrophic factor was the best predictor of patients’ likeliness to respond. These initial results are promising; however, all studies investigating BMs are small, used heterogeneous samples, and did not take into account confounders such as age, sex, or family history. Based on our findings, we recommend further studies to validate BMs in noninvasive brain stimulation trials in MDD.

Facilitative effects of bi-hemispheric tDCS in cognitive deficits of Parkinson Disease patients

Parkinson’s disease (PD) is a progressive neurodegenerative disorder, primarily characterized by motor symptoms such as tremor, rigidity, bradykinesia, stiffness, slowness and impaired equilibrium. Although the motor symptoms have been the focus in PD, slight cognitive deficits are commonly found in non-demented and non-depressed PD patients, even in early stages of the disease, which have been linked to the subsequent development of pathological dementia. Thus, strongly reducing the quality of life (QoL). Both levodopa therapy and deep brain stimulation (DBS) have yield controversial results concerning the cognitive symptoms amelioration in PD patients. That does not seems to be the case with transcranial direct current stimulation (tDCS), although better stimulation parameters are needed. Therefore we hypothesize that simultaneously delivering cathodal tDCS (or ctDCS), over the right prefrontal cortex delivered with anodal tDCS (or atDCS) to left prefrontal cortex could be potentially beneficial for PD patients, either by mechanisms of homeostatic plasticity and by increases in the extracellular dopamine levels over the striatum.

[Letter to the editor] Sustained effects of a neural-based intervention in a refractory case of Tourette syndrome

There are only a few treatments available for Tourette syndrome (TS). These treatments frequently do notwork in patients with moderate to severe TS [1]. Neuroimaging studies show a correlation between tics severity and increased activation over motor pathways, along with reduced activation over the control areas of the cortico-striato-thalamo-cortical circuits [2]. Moreover, the temporal pattern of tic generation suggests that cortical activation especially in the SMA precedes subcortical activation [3]. Following this assumption, here we explored the brain effects of 10-daily sessions of cathodal transcranial Direct Current Stimulation (tDCS) delivered over the pre-SMA in a patient with refractory and severe TS and also assessed whether those changes were long lasting (up to 6 months).

Dynamic piezoelectric stimulation enhances osteogenic differentiation of human adipose stem cells

This work reports on the influence of the substrate polarization of electroactive β-PVDF on human adipose stem cells (hASCs) differentiation under static and dynamic conditions. hASCs were cultured on different β-PVDF surfaces (non-poled and “poled -”) adsorbed with fibronectin and osteogenic differentiation was determined using a quantitative alkaline phosphatase assay. “Poled -” β-PVDF samples promote higher osteogenic differentiation, which is even higher under dynamic conditions. It is thus demonstrated that electroactive membranes can provide the necessary electromechanical stimuli for the differentiation of specific cells and therefore will support the design of suitable tissue engineering strategies, such as bone tissue engineering.

From the periphery to the brain: Lipocalin-2, a friend or foe?

Lipocalin-2 (LCN2) is an acute-phase protein that, by binding to iron-loaded siderophores, acts as a potent bacteriostatic agent in the iron-depletion strategy of the immune system to control pathogens. The recent identification of a mammalian siderophore also suggests a physiological role for LCN2 in iron homeostasis, specifically in iron delivery to cells via a transferrin-independent mechanism. LCN2 participates, as well, in a variety of cellular processes, including cell proliferation, cell differentiation and apoptosis, and has been mostly found up-regulated in various tissues and under inflammatory states, being its expression regulated by several inducers. In the central nervous system less is known about the processes involving LCN2, namely by which cells it is produced/secreted, and its impact on cell proliferation and death, or in neuronal plasticity and behaviour. Importantly, LCN2 recently emerged as a potential clinical biomarker in multiple sclerosis and in ageing-related cognitive decline. Still, there are conflicting views on the role of LCN2 in pathophysiological processes, with some studies pointing to its neurodeleterious effects, while others indicate neuroprotection. Herein, these various perspectives are reviewed and a comprehensive and cohesive view of the general function of LCN2, particularly in the brain, is provided.

Assessing the application of polypropylene multifilament yarns in brain phantoms

The currently available clinical imaging methods do not provide highly detailed information about location and severity of axonal injury or the expected recovery time of patients with traumatic brain injury [1]. High-Definition Fiber Tractography (HDFT) is a novel imaging modality that allows visualizing and quantifying, directly, the degree of axons damage, predicting functional deficits due to traumatic axonal injury and loss of cortical projections. This imaging modality is based on diffusion technology [2]. The inexistence of a phantom able to mimic properly the human brain hinders the possibility of testing, calibrating and validating these medical imaging techniques. Most research done in this area fails in key points, such as the size limit reproduced of the brain fibers and the quick and easy reproducibility of phantoms [3]. For that reason, it is necessary to develop similar structures matching the micron scale of axon tubes. Flexible textiles can play an important role since they allow producing controlled packing densities and crossing structures that match closely the human crossing patterns of the brain. To build a brain phantom, several parameters must be taken into account in what concerns to the materials selection, like hydrophobicity, density and fiber diameter, since these factors influence directly the values of fractional anisotropy. Fiber cross-section shape is other important parameter. Earlier studies showed that synthetic fibrous materials are a good choice for building a brain phantom [4]. The present work is integrated in a broader project that aims to develop a brain phantom made by fibrous materials to validate and calibrate HDFT. Due to the similarity between thousands of hollow multifilaments in a fibrous arrangement, like a yarn, and the axons, low twist polypropylene multifilament yarns were selected for this development. In this sense, extruded hollow filaments were analysed in scanning electron microscope to characterize their main dimensions and shape. In order to approximate the dimensional scale to human axons, five types of polypropylene yarns with different linear density (denier) were used, aiming to understand the effect of linear density on the filament inner and outer areas. Moreover, in order to achieve the required dimensions, the polypropylene filaments cross-section was diminished in a drawing stage of a filament extrusion line. Subsequently, tensile tests were performed to characterize the mechanical behaviour of hollow filaments and to evaluate the differences between stretched and non-stretched filaments. In general, an increase of the linear density causes the increase in the size of the filament cross section. With the increase of structure orientation of filaments, induced by stretching, breaking tenacity increases and elongation at break decreases. The production of hollow fibers, with the required characteristics, is one of the key steps to create a brain phantom that properly mimics the human brain that may be used for the validation and calibration of HDFT, an imaging approach that is expected to contribute significantly to the areas of brain related research.

Cognitive stimulation for portuguese older adults with cognitive impairment: a randomized controlled trial of efficacy, comparative duration, feasibility and experiential relevance

Although some studies point to cognitive stimulation as a beneficial therapy for older adults with cognitive impairments, this area of research and practice is still lacking dissemination and is underrepresented in many countries. Moreover, the comparative effects of different intervention durations remain to be established and, besides cognitive effects, pragmatic parameters, such as cost-effectiveness and experiential relevance to participants, are seldom explored. In this work, we present a randomized con- trolled wait-list trial evaluating 2 different intervention durations (standard 1⁄4 17 vs brief 1⁄4 11 sessions) of a cognitive stimulation program developed for older adults with cognitive impairments with or without dementia. 20 participants were randomly assigned to the standard duration intervention program (17 sessions, 1.5 months) or to a wait-list group. At postintervention of the standard intervention group, the wait-list group crossed over to receive the brief intervention program (11 sessions, 1 month). Changes in neuropsychological, functionality, quality of life, and caregiver outcomes were evaluated. Experience during intervention and costs and feasibility were also evaluated. The current cognitive stimulation programs (ie, standard and brief) showed high values of experiential relevance for both intervention durations. High adherence, completion rates, and reasonable costs were found for both formats. Further studies are needed to definitively establish the potential efficacy, optimal duration, cost-effectiveness, and experiential relevance for participants of cognitive intervention approaches.

Cognitive rehabilitation in a visual variant of Alzheimer's disease

Alzheimer's disease (AD) is commonly associated with marked memory deficits; however, nonamnestic variants have been consistently described as well. Posterior cortical atrophy (PCA) is a progressive degenerative condition in which posterior regions of the brain are predominantly affected, therefore resulting in a pattern of distinctive and marked visuospatial symptoms, such as apraxia, alexia, and spatial neglect. Despite the growing number of studies on cognitive and neural bases of the visual variant of AD, intervention studies remain relatively sparse. Current pharmacological treatments offer modest efficacy. Also, there is a scarcity of complementary nonpharmacological interventions with only two previous studies of PCA. Here we describe a highly educated 57-year-old patient diagnosed with a visual variant of AD who participated in a cognitive intervention program (comprising reality orientation, cognitive stimulation, and cognitive training exercises). Neuropsychological assessment was performed across moments (baseline, postintervention, follow-up) and consisted mainly of verbal and visual memory. Baseline neuropsychological assessment showed deficits in perceptive and visual-constructive abilities, learning and memory, and temporal orientation. After neuropsychological rehabilitation, we observed small improvements in the patient's cognitive functioning, namely in verbal memory, attention, and psychomotor abilities. This study shows evidence of small beneficial effects of cognitive intervention in PCA and is the first report of this approach with a highly educated patient in a moderate stage of the disease. Controlled studies are needed to assess the potential efficacy of cognition-focused approaches in these patients, and, if relevant, to grant their availability as a complementary therapy to pharmacological treatment and visual aids.

Transcranial direct current stimulation based metaplasticity protocols in working memory

It has been already shown that delivering tDCS that are spaced by an interval alters its impact on motor plasticity. These effects can be explained, based on metaplasticity in which a previous modification of activity in a neuronal network can change the effects of subsequent interventions in the same network. But to date there is limited data assessing metaplasticity effects in cognitive functioning.

Neurocognitive profile and cognitive intervention in Alzheimer's disease

Tese de Doutoramento em Psicologia (Especialidade de Psicologia Clínica)

A network approach to brain aging through multimodal neuroimaging

Tese de Doutoramento em Ciências da Saúde.

The choroid plexus is modulated by various peripheral stimuli: implications to diseases of the central nervous system

The blood brain barrier (BBB) and the blood cerebrospinal fluid barrier (BCSFB) form the barriers of the brain. These barriers are essential not only for the protection of the brain, but also in regulating the exchange of cells and molecules in and out of the brain. The choroid plexus (CP) epithelial cells and the arachnoid membrane form the BCSFB. The CP is structurally divided into two independent compartments: one formed by a unique and continuous line of epithelial cells that rest upon a basal lamina; and, a second consisting of a central core formed by connective and highly vascularized tissue populated by diverse cell types (fibroblasts, macrophages and dendritic cells). Here, we review how the CP transcriptome and secretome vary depending on the nature and duration of the stimuli to which the CP is exposed. Specifically, when the peripheral stimulation is acute the CP response is rapid, strong and transient, whereas if the stimulation is sustained in time the CP response persists but it is weaker. Furthermore, not all of the epithelium responds at the same time to peripheral stimulation, suggesting the existence of a synchrony system between individual CP epithelial cells.

The bounds of education in the human brain connectome

Inter-individual heterogeneity is evident in aging; education level is known to contribute for this heterogeneity. Using a cross-sectional study design and network inference applied to resting-state fMRI data, we show that aging was associated with decreased functional connectivity in a large cortical network. On the other hand, education level, as measured by years of formal education, produced an opposite effect on the long-term. These results demonstrate the increased brain efficiency in individuals with higher education level that may mitigate the impact of age on brain functional connectivity.

The role of IFNγ in higher brain function: in health and under chronic stress

Tese de Doutoramento em Ciências da Saúde