EEG marker of inhibitory brain activity correlates with resting-state cerebral blood flow in the reward system in major depression

Frontal alpha band asymmetry (FAA) is a marker of altered reward processing in major depressive disorder (MDD), associated with reduced approach behavior and withdrawal. However, its association with brain metabolism remains unclear. The aim of this study is to investigate FAA and its correlation with resting – state cerebral blood flow (rCBF). We hypothesized an association of FAA with regional rCBF in brain regions relevant for reward processing and motivated behavior, such as the striatum. We enrolled 20 patients and 19 healthy subjects. FAA scores and rCBF were quantified with the use of EEG and arterial spin labeling. Correlations of the two were evaluated, as well as the association with FAA and psychometric assessments of motivated behavior and anhedonia. Patients showed a left – lateralized pattern of frontal alpha activity and a correlation of FAA lateralization with subscores of Hamilton Depression Rating Scale linked to motivated behavior. An association of rCBF and FAA scores was found in clusters in the dorsolateral prefrontal cortex bilaterally (patients) and in the left medial frontal gyrus, in the right caudate head and in the right inferior parietal lobule (whole group). No correlations were found in healthy controls. Higher inhibitory right – lateralized alpha power was associated with lower rCBF values in prefrontal and striatal regions, predominantly in the right hemisphere, which are involved in the processing of motivated behavior and reward. Inhibitory brain activity in the reward system may contribute to some of the motivational problems observed in MDD.

Olfactory bulb volume predicts therapeutic outcome in major depression disorder

The volume of the olfactory bulb (OB) is strongly reduced in patients with major depressive disorder (MDD) and this group exhibits markedly decreased olfactory function. It has been suggested that olfactory input is important for maintaining balance in limbic neurocircuits. The aim of our study was to investigate whether reduced OB volume is associated with response to therapy in MDD. Twenty-four inpatients (all women, age 21-49 years, mean 38 ± 10 years SD) with MDD and 36 healthy controls (all women, age 20-52 years, mean 36 ± 10 years SD) underwent structural MRI. OB volume was compared between responders (N = 13) and non-responders (N = 11) to psychotherapy. Retest of OB volume was performed about 6 months after the end of therapy in nine of the patients. Therapy responders exhibited no significant difference in OB volume compared to healthy controls. However, average OB volume of non-responders was 23 % smaller compared to responders (p = .0011). Furthermore, OB volume was correlated with the change of depression severity (r = .46, p = .024). Volume of the OB did not change in the course of therapy. OB volume may be a biological vulnerability factor for the occurrence and/or maintenance of depression, at least in women.

Structural brain correlates of defective gesture performance in schizophrenia

INTRODUCTION The neural correlates of impaired performance of gestures are currently unclear. Lesion studies showed variable involvement of the ventro-dorsal stream particularly left inferior frontal gyrus (IFG) in gesture performance on command. However, findings cannot be easily generalized as lesions may be biased by the architecture of vascular supply and involve brain areas beyond the critical region. The neuropsychiatric syndrome of schizophrenia shares apraxic-like errors and altered brain structure without macroanatomic lesions. Schizophrenia may therefore qualify as a model disorder to test neural correlates of gesture impairments. METHODS We included 45 schizophrenia patients and 44 healthy controls in the study to investigate the structural brain correlates of defective gesturing in schizophrenia using voxel based morphometry. Gestures were tested in two domains: meaningful gestures (transitive and intransitive) on verbal command and imitation of meaningless gestures. Cut-off scores were used to separate patients with deficits, patients without deficits and controls. Group differences in gray matter (GM) volume were explored in an ANCOVA. RESULTS Patients performed poorer than controls in each gesture category (p < .001). Patients with deficits in producing meaningful gestures on command had reduced GM predominantly in left IFG, with additional involvement of right insula and anterior cingulate cortex. Patients with deficits differed from patients without deficits in right insula, inferior parietal lobe (IPL) and superior temporal gyrus. CONCLUSIONS Impaired performance of meaningful gestures on command was linked to volume loss predominantly in the praxis network in schizophrenia. Thus, the behavioral similarities between apraxia and schizophrenia are paralleled by structural alterations. However, few associations between behavioral impairment and structural brain alterations appear specific to schizophrenia.

An integrated molecular biology and computational approach to CYP1A1 expression in human brain

The cytochromes P450 comprise a superfamily of heme-containing mono-oxygenases. These enzymes metabolize numerous xenobiotics, but also play a role in metabolism of endogenous compounds. The P450 1A1 enzyme generally metabolizes polycyclic aromatic hydrocarbons, and its expression can be induced by aryl hydrocarbon receptor (AhR) activation. CYP1A1 is an exception to the generality that the majority of CYPs demonstrate highest expression in liver; CYP1Al is present in numerous extrahepatic tissues, including brain. This P450 has been observed in two forms, wildtype (WT) and brain variant (BV), arising from alternatively spliced mRNA transcripts. The CYP1A1 BV mRNA presented an exon deletion and was detected in human brain but not liver tissue of the same individuals. ^ Quantitative PCR analyses were performed to determine CYP1A1 WT and BV transcript expression levels in normal, bipolar disorder or schizophrenic groups. In our samples, we show that CYP1A1 BV mRNA, when present, is found alongside the full-length form. Furthermore, we demonstrate a significant decrease in expression of CYP1A1 in patients with bipolar disorder or schizophrenia. The expression level was not influenced by post-mortem interval, tissue pH, age, tobacco use, or lifetime antipsychotic medication load. ^ There is no indication of increased brain CYP1A1 expression in normal smokers versus non-smokers in these samples. We observed slightly increased CYP1A1 expression only in bipolar and schizophrenic smokers versus non-smokers. This may be indicative of complex interactions between neuronal chemical environments and AhR-mediated CYP1A1 induction in brain. ^ Structural homology modeling demonstrated that P450 1A1 BV has several alterations to positions/orientations of substrate recognition site residues compared to the WT isoform. Automated substrate docking was employed to investigate the potential binding of neurological signaling molecules and neurotropic drugs, as well as to differentiate specificities of the two P450 1A1 isoforms. We consistently observed that the BV isoform produced energetically favorable substrate dockings in orientations not observed for the same substrate in the WT isoform. These results demonstrated that structural differences, namely an expanded substrate access channel and active site, confer greater capacity for unique compound docking positions suggesting a metabolic profile distinct from the wildtype form for these test compounds. ^

Attention-Deficit/Hyperactivity Disorder and antidepressants and prescription medications: A pilot study

Background. Attention Deficit-Hyperactivity Disorder (AD/HD) diagnosis in children and adolescents has been on the rise over the last couple of decades and a multitude of studies have been conducted in an aim to better understand the disease. Literature has explored the role of several factors suspected of contributing to development of the disease, including: prenatal smoking exposures, environmental exposures, and low-birth weight. However, there is very limited reporting of fetal/infant exposure to antidepressants and prescription medications and the long-term behavioral outcomes, namely development of AD/HD. The purpose of this study was to evaluate the relationship between mother's exposure to prescription medications and/or antidepressants around the time of conception, during pregnancy, or while breastfeeding and the development of Attention-Deficit/Hyperactivity Disorder in offspring. Methods. Secondary analysis of data from a case-control study was performed. Exposure histories were collected for the mother and offspring. Data were collected using a secure, confidential, self-report, online survey to evaluate the relationship between antidepressant and/or prescription medication exposure and the development of AD/HD. The period of exposure to these drugs was defined as: around the time of conception, during pregnancy, or while breastfeeding. Cases were defined as a child who had been diagnosed with AD/HD. Controls were defined as a child who had not been diagnosed with AD/HD. Results. Prescription medication and antidepressant medication exposures around the time of conception, during pregnancy, or while breastfeeding were not associated with development of AD/HD. However, traumatic brain injury (OR=2.77 (1.61–4.77)) and preterm birth (OR=1.48 (1.04–2.12)) were identified as potential risk factors. These results support existing literature on AD/HD, but future work must be undertaken to better evaluate fetal/infant medication exposures and long-term behavioral outcomes.^

Attention-deficit hyperactivity disorder symptoms and lead exposure in children: A systematic review of literature

Blood lead levels > 10 µg/dL are known to affect various areas of the brain that influence behavior and cause many other health problems in children. As a result, the Centers for Disease Control and Prevention (CDC) set the blood lead action level at 10 µg/dL. However, recent research provides evidence that blood lead levels <10 µg/dL also may lead to behavioral problems in children. With the recent increase in diagnosis of Attention-Deficit Hyperactivity Disorder (ADHD) in children in the U.S. it is important to determine possible environmental toxins such as lead that may play a role in causing ADHD symptoms. The aim of this systematic review of the literature was to identify recent published studies that examine an association between blood lead levels < 10 µg/dL and ADHD symptoms in children in order to summarize their findings and describe major gaps in the literature. Although available research is limited, the articles reviewed indicate that blood lead at levels much below the CDC action level of 10 µg/dL may affect a child's level of attention, hyperactivity, impulsivity and ADHD diagnosis. Additional prospective research is warranted in order to inform the revision of current blood lead action levels as well as better elucidate the relationship between lead and ADHD diagnoses.^

Complexity analysis of spontaneous brain activity: effects of depression and antidepressant treatment

Magnetoencephalography (MEG) allows the real-time recording of neural activity and oscillatory activity in distributed neural networks. We applied a non-linear complexity analysis to resting-state neural activity as measured using whole-head MEG. Recordings were obtained from 20 unmedicated patients with major depressive disorder and 19 matched healthy controls. Subsequently, after 6 months of pharmacological treatment with the antidepressant mirtazapine 30 mg/day, patients received a second MEG scan. A measure of the complexity of neural signals, the Lempel–Ziv Complexity (LZC), was derived from the MEG time series. We found that depressed patients showed higher pre-treatment complexity values compared with controls, and that complexity values decreased after 6 months of effective pharmacological treatment, although this effect was statistically significant only in younger patients. The main treatment effect was to recover the tendency observed in controls of a positive correlation between age and complexity values. Importantly, the reduction of complexity with treatment correlated with the degree of clinical symptom remission. We suggest that LZC, a formal measure of neural activity complexity, is sensitive to the dynamic physiological changes observed in depression and may potentially offer an objective marker of depression and its remission after treatment.

Neuroanatomic-based detection algorithm for automatic labeling of brain structures in brain injury

The number and grade of injured neuroanatomic structures and the type of injury determine the degree of impairment after a brain injury event and the recovery options of the patient. However, the body of knowledge and clinical intervention guides are basically focused on functional disorder and they still do not take into account the location of injuries. The prognostic value of location information is not known in detail either. This paper proposes a feature-based detection algorithm, named Neuroanatomic-Based Detection Algorithm (NBDA), based on SURF (Speeded Up Robust Feature) to label anatomical brain structures on cortical and sub-cortical areas. Themain goal is to register injured neuroanatomic structures to generate a database containing patient?s structural impairment profile. This kind of information permits to establish a relation with functional disorders and the prognostic evolution during neurorehabilitation procedures.

Automated detection and classification of brain injury lesions on structural magnetic resonance imaging

El daño cerebral adquirido (DCA) es un problema social y sanitario grave, de magnitud creciente y de una gran complejidad diagnóstica y terapéutica. Su elevada incidencia, junto con el aumento de la supervivencia de los pacientes, una vez superada la fase aguda, lo convierten también en un problema de alta prevalencia. En concreto, según la Organización Mundial de la Salud (OMS) el DCA estará entre las 10 causas más comunes de discapacidad en el año 2020. La neurorrehabilitación permite mejorar el déficit tanto cognitivo como funcional y aumentar la autonomía de las personas con DCA. Con la incorporación de nuevas soluciones tecnológicas al proceso de neurorrehabilitación se pretende alcanzar un nuevo paradigma donde se puedan diseñar tratamientos que sean intensivos, personalizados, monitorizados y basados en la evidencia. Ya que son estas cuatro características las que aseguran que los tratamientos son eficaces. A diferencia de la mayor parte de las disciplinas médicas, no existen asociaciones de síntomas y signos de la alteración cognitiva que faciliten la orientación terapéutica. Actualmente, los tratamientos de neurorrehabilitación se diseñan en base a los resultados obtenidos en una batería de evaluación neuropsicológica que evalúa el nivel de afectación de cada una de las funciones cognitivas (memoria, atención, funciones ejecutivas, etc.). La línea de investigación en la que se enmarca este trabajo de investigación pretende diseñar y desarrollar un perfil cognitivo basado no sólo en el resultado obtenido en esa batería de test, sino también en información teórica que engloba tanto estructuras anatómicas como relaciones funcionales e información anatómica obtenida de los estudios de imagen. De esta forma, el perfil cognitivo utilizado para diseñar los tratamientos integra información personalizada y basada en la evidencia. Las técnicas de neuroimagen representan una herramienta fundamental en la identificación de lesiones para la generación de estos perfiles cognitivos. La aproximación clásica utilizada en la identificación de lesiones consiste en delinear manualmente regiones anatómicas cerebrales. Esta aproximación presenta diversos problemas relacionados con inconsistencias de criterio entre distintos clínicos, reproducibilidad y tiempo. Por tanto, la automatización de este procedimiento es fundamental para asegurar una extracción objetiva de información. La delineación automática de regiones anatómicas se realiza mediante el registro tanto contra atlas como contra otros estudios de imagen de distintos sujetos. Sin embargo, los cambios patológicos asociados al DCA están siempre asociados a anormalidades de intensidad y/o cambios en la localización de las estructuras. Este hecho provoca que los algoritmos de registro tradicionales basados en intensidad no funcionen correctamente y requieran la intervención del clínico para seleccionar ciertos puntos (que en esta tesis hemos denominado puntos singulares). Además estos algoritmos tampoco permiten que se produzcan deformaciones grandes deslocalizadas. Hecho que también puede ocurrir ante la presencia de lesiones provocadas por un accidente cerebrovascular (ACV) o un traumatismo craneoencefálico (TCE). Esta tesis se centra en el diseño, desarrollo e implementación de una metodología para la detección automática de estructuras lesionadas que integra algoritmos cuyo objetivo principal es generar resultados que puedan ser reproducibles y objetivos. Esta metodología se divide en cuatro etapas: pre-procesado, identificación de puntos singulares, registro y detección de lesiones. Los trabajos y resultados alcanzados en esta tesis son los siguientes: Pre-procesado. En esta primera etapa el objetivo es homogeneizar todos los datos de entrada con el objetivo de poder extraer conclusiones válidas de los resultados obtenidos. Esta etapa, por tanto, tiene un gran impacto en los resultados finales. Se compone de tres operaciones: eliminación del cráneo, normalización en intensidad y normalización espacial. Identificación de puntos singulares. El objetivo de esta etapa es automatizar la identificación de puntos anatómicos (puntos singulares). Esta etapa equivale a la identificación manual de puntos anatómicos por parte del clínico, permitiendo: identificar un mayor número de puntos lo que se traduce en mayor información; eliminar el factor asociado a la variabilidad inter-sujeto, por tanto, los resultados son reproducibles y objetivos; y elimina el tiempo invertido en el marcado manual de puntos. Este trabajo de investigación propone un algoritmo de identificación de puntos singulares (descriptor) basado en una solución multi-detector y que contiene información multi-paramétrica: espacial y asociada a la intensidad. Este algoritmo ha sido contrastado con otros algoritmos similares encontrados en el estado del arte. Registro. En esta etapa se pretenden poner en concordancia espacial dos estudios de imagen de sujetos/pacientes distintos. El algoritmo propuesto en este trabajo de investigación está basado en descriptores y su principal objetivo es el cálculo de un campo vectorial que permita introducir deformaciones deslocalizadas en la imagen (en distintas regiones de la imagen) y tan grandes como indique el vector de deformación asociado. El algoritmo propuesto ha sido comparado con otros algoritmos de registro utilizados en aplicaciones de neuroimagen que se utilizan con estudios de sujetos control. Los resultados obtenidos son prometedores y representan un nuevo contexto para la identificación automática de estructuras. Identificación de lesiones. En esta última etapa se identifican aquellas estructuras cuyas características asociadas a la localización espacial y al área o volumen han sido modificadas con respecto a una situación de normalidad. Para ello se realiza un estudio estadístico del atlas que se vaya a utilizar y se establecen los parámetros estadísticos de normalidad asociados a la localización y al área. En función de las estructuras delineadas en el atlas, se podrán identificar más o menos estructuras anatómicas, siendo nuestra metodología independiente del atlas seleccionado. En general, esta tesis doctoral corrobora las hipótesis de investigación postuladas relativas a la identificación automática de lesiones utilizando estudios de imagen médica estructural, concretamente estudios de resonancia magnética. Basándose en estos cimientos, se han abrir nuevos campos de investigación que contribuyan a la mejora en la detección de lesiones. ABSTRACT Brain injury constitutes a serious social and health problem of increasing magnitude and of great diagnostic and therapeutic complexity. Its high incidence and survival rate, after the initial critical phases, makes it a prevalent problem that needs to be addressed. In particular, according to the World Health Organization (WHO), brain injury will be among the 10 most common causes of disability by 2020. Neurorehabilitation improves both cognitive and functional deficits and increases the autonomy of brain injury patients. The incorporation of new technologies to the neurorehabilitation tries to reach a new paradigm focused on designing intensive, personalized, monitored and evidence-based treatments. Since these four characteristics ensure the effectivity of treatments. Contrary to most medical disciplines, it is not possible to link symptoms and cognitive disorder syndromes, to assist the therapist. Currently, neurorehabilitation treatments are planned considering the results obtained from a neuropsychological assessment battery, which evaluates the functional impairment of each cognitive function (memory, attention, executive functions, etc.). The research line, on which this PhD falls under, aims to design and develop a cognitive profile based not only on the results obtained in the assessment battery, but also on theoretical information that includes both anatomical structures and functional relationships and anatomical information obtained from medical imaging studies, such as magnetic resonance. Therefore, the cognitive profile used to design these treatments integrates information personalized and evidence-based. Neuroimaging techniques represent an essential tool to identify lesions and generate this type of cognitive dysfunctional profiles. Manual delineation of brain anatomical regions is the classical approach to identify brain anatomical regions. Manual approaches present several problems related to inconsistencies across different clinicians, time and repeatability. Automated delineation is done by registering brains to one another or to a template. However, when imaging studies contain lesions, there are several intensity abnormalities and location alterations that reduce the performance of most of the registration algorithms based on intensity parameters. Thus, specialists may have to manually interact with imaging studies to select landmarks (called singular points in this PhD) or identify regions of interest. These two solutions have the same inconvenient than manual approaches, mentioned before. Moreover, these registration algorithms do not allow large and distributed deformations. This type of deformations may also appear when a stroke or a traumatic brain injury (TBI) occur. This PhD is focused on the design, development and implementation of a new methodology to automatically identify lesions in anatomical structures. This methodology integrates algorithms whose main objective is to generate objective and reproducible results. It is divided into four stages: pre-processing, singular points identification, registration and lesion detection. Pre-processing stage. In this first stage, the aim is to standardize all input data in order to be able to draw valid conclusions from the results. Therefore, this stage has a direct impact on the final results. It consists of three steps: skull-stripping, spatial and intensity normalization. Singular points identification. This stage aims to automatize the identification of anatomical points (singular points). It involves the manual identification of anatomical points by the clinician. This automatic identification allows to identify a greater number of points which results in more information; to remove the factor associated to inter-subject variability and thus, the results are reproducible and objective; and to eliminate the time spent on manual marking. This PhD proposed an algorithm to automatically identify singular points (descriptor) based on a multi-detector approach. This algorithm contains multi-parametric (spatial and intensity) information. This algorithm has been compared with other similar algorithms found on the state of the art. Registration. The goal of this stage is to put in spatial correspondence two imaging studies of different subjects/patients. The algorithm proposed in this PhD is based on descriptors. Its main objective is to compute a vector field to introduce distributed deformations (changes in different imaging regions), as large as the deformation vector indicates. The proposed algorithm has been compared with other registration algorithms used on different neuroimaging applications which are used with control subjects. The obtained results are promising and they represent a new context for the automatic identification of anatomical structures. Lesion identification. This final stage aims to identify those anatomical structures whose characteristics associated to spatial location and area or volume has been modified with respect to a normal state. A statistical study of the atlas to be used is performed to establish which are the statistical parameters associated to the normal state. The anatomical structures that may be identified depend on the selected anatomical structures identified on the atlas. The proposed methodology is independent from the selected atlas. Overall, this PhD corroborates the investigated research hypotheses regarding the automatic identification of lesions based on structural medical imaging studies (resonance magnetic studies). Based on these foundations, new research fields to improve the automatic identification of lesions in brain injury can be proposed.

Neural basis of an inherited speech and language disorder

Investigation of the three-generation KE family, half of whose members are affected by a pronounced verbal dyspraxia, has led to identification of their core deficit as one involving sequential articulation and orofacial praxis. A positron emission tomography activation study revealed functional abnormalities in both cortical and subcortical motor-related areas of the frontal lobe, while quantitative analyses of magnetic resonance imaging scans revealed structural abnormalities in several of these same areas, particularly the caudate nucleus, which was found to be abnormally small bilaterally. A recent linkage study [Fisher, S., Vargha-Khadem, F., Watkins, K. E., Monaco, A. P. & Pembry, M. E. (1998) Nat. Genet. 18, 168–170] localized the abnormal gene (SPCH1) to a 5.6-centiMorgan interval in the chromosomal band 7q31. The genetic mutation or deletion in this region has resulted in the abnormal development of several brain areas that appear to be critical for both orofacial movements and sequential articulation, leading to marked disruption of speech and expressive language.

Selective effects of methylphenidate in attention deficit hyperactivity disorder: A functional magnetic resonance study

Functional MRI revealed differences between children with Attention Deficit Hyperactivity Disorder (ADHD) and healthy controls in their frontal–striatal function and its modulation by methylphenidate during response inhibition. Children performed two go/no-go tasks with and without drug. ADHD children had impaired inhibitory control on both tasks. Off-drug frontal–striatal activation during response inhibition differed between ADHD and healthy children: ADHD children had greater frontal activation on one task and reduced striatal activation on the other task. Drug effects differed between ADHD and healthy children: The drug improved response inhibition in both groups on one task and only in ADHD children on the other task. The drug modulated brain activation during response inhibition on only one task: It increased frontal activation to an equal extent in both groups. In contrast, it increased striatal activation in ADHD children but reduced it in healthy children. These results suggest that ADHD is characterized by atypical frontal–striatal function and that methylphenidate affects striatal activation differently in ADHD than in healthy children.

Declining brain activity in cognitively normal apolipoprotein E ɛ4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease

Cross-sectional positron emission tomography (PET) studies find that cognitively normal carriers of the apolipoprotein E (APOE) ɛ4 allele, a common Alzheimer's susceptibility gene, have abnormally low measurements of the cerebral metabolic rate for glucose (CMRgl) in the same regions as patients with Alzheimer's dementia. In this article, we characterize longitudinal CMRgl declines in cognitively normal ɛ4 heterozygotes, estimate the power of PET to test the efficacy of treatments to attenuate these declines in 2 years, and consider how this paradigm could be used to efficiently test the potential of candidate therapies for the prevention of Alzheimer's disease. We studied 10 cognitively normal ɛ4 heterozygotes and 15 ɛ4 noncarriers 50–63 years of age with a reported family history of Alzheimer's dementia before and after an interval of approximately 2 years. The ɛ4 heterozygotes had significant CMRgl declines in the vicinity of temporal, posterior cingulate, and prefrontal cortex, basal forebrain, parahippocampal gyrus, and thalamus, and these declines were significantly greater than those in the ɛ4 noncarriers. In testing candidate primary prevention therapies, we estimate that between 50 and 115 cognitively normal ɛ4 heterozygotes are needed per active and placebo treatment group to detect a 25% attenuation in these CMRgl declines with 80% power and P = 0.005 in 2 years. Assuming these CMRgl declines are related to the predisposition to Alzheimer's dementia, this study provides a paradigm for testing the potential of treatments to prevent the disorder without having to study thousands of research subjects or wait many years to determine whether or when treated individuals develop symptoms.

Aceruloplasminemia: molecular characterization of this disorder of iron metabolism.

Ceruloplasmin is an abundant alpha 2-serum glycoprotein that contains 95% of the copper found in the plasma of vertebrate species. We report here on the identification of a genetic defect in the ceruloplasmin gene in a patient previously noted to have a total absence of circulating serum ceruloplasmin in association with late-onset retinal and basal ganglia degeneration. In this patient T2 (transverse relaxation time)-weighted magnetic resonance imaging of the brain revealed basal ganglia densities consistent with iron deposition, and liver biopsy confirmed the presence of excess iron. Although Southern blot analysis of the patient's DNA was normal, PCR amplification of 18 of the 19 exons composing the human ceruloplasmin gene revealed a distinct size difference in exon 7. DNA sequence analysis of this exon revealed a 5-bp insertion at amino acid 410, resulting in a frame-shift mutation and a truncated open reading frame. The validity of this mutation was confirmed by analysis of DNA from the patient's daughter, which revealed heterozygosity for this same 5-bp insertion. The presence of this mutation in conjunction with the clinical and pathologic findings demonstrates an essential role for ceruloplasmin in human biology and identifies aceruloplasminemia as an autosomal recessive disorder of iron metabolism. These findings support previous studies that identified ceruloplasmin as a ferroxidase and are remarkably consistent with recent studies on the essential role of a homologous copper oxidase in iron metabolism in yeast. The clinical and laboratory findings suggest that additional patients with movement disorders and nonclassical Wilson disease should be examined for ceruloplasmin gene mutations.

Relationship Maintenance in Couples with a Partner Who Has Attention Deficit Hyperactivity Disorder

The body of research on the relationship functioning of adults with attention deficit hyperactivity disorder (ADHD) is relatively small; the aim of the present study is to advance our understanding of this topic. It has been estimated that three to ten percent of children and one to five percent of adults have impairing symptoms of ADHD, which is a total of 4 million children and 4-5 million adults in the U.S. (Wender, 2000). A recent prevalence study found that approximately 4.4% of adults in the U.S. meet the criteria for a diagnosis of ADHD (Kessler et al., 2006). Children with ADHD show innate temperamental characteristics, usually inattentiveness, distractibility, impulsivity, restlessness, demandingness, hyperreactivity, low tolerance for frustration, temperoutbursts, bossiness and stubbornness, and mood lability, along with an innate proclivity for academic underachievement. It has been estimated that one- to two-thirds of children with ADHD have symptoms that continue into adulthood, and for 40-50% of these adults, these symptoms are serious enough to cause impairment in functioning (Everett & Everett, 1999; Wender, 2000). Research suggests that the majority of cases are transmitted genetically, but some may be due to exposure to environmental toxins such as lead. Consumption of excess sugar or allergies to food may exacerbate or mimic ADHD symptoms in some children, but they are not a cause of ADHD (Wender, 2000). One hypothesized cause of the symptoms associated with ADHD is a deficit in the brain's executive functioning (Barkley & Gordon, 2002). Executive functioning can be conceptualized as the ability to inhibit, organize, and plan behaviors. Barkley and Gordon (2002) define it as the abilityto self-direct and regulate behaviors toward future goals, including social behaviors and goals. Other research suggests that executive functioning consists of inhibition, control of interference, verbal and nonverbal working memory, emotional regulation, attention, verbal fluency, visual scanning, and processing speed. Studies have shown impairments in these areas among adults with ADHD (Barkley & Gordon, 2002; Barkley, Murphy & Kwasnik, 1996; Goldstein, 2002).

Control of neuronal signalling pathways by CYP46A1, an enzime involved in brain cholesterol homeostasis

Tese de doutoramento, Farmácia (Biologia Celular e Molecular), Universidade de Lisboa, Faculdade de Farmácia, 2016