Exploring the neurobiology of OCD: clinical implications.

Background Attention-Deficit/Hyperactivity Disorder Combined Type (ADHD-CT) is one of the most common neurodevelopmental disorders, estimated as prevalent in 5.3% of young people worldwide. In addition to its core symptoms of inattention and hyperactivity/impulsivity, up to 50% of young people with ADHD-CT exhibit clinically significant gross and fine motor problems. Emerging research suggests that these motor problems may be associated with co-occurring Autism Spectrum Disorder (ASD) symptoms. However, little is currently known about the underlying neurobiology of these problems or their functional impact. The overarching aim of this thesis was to advance current understanding of the motor problems experienced by young people with ADHD-CT, from both a neurobehavioural perspective, using ocular motor measures, and from a clinical, functional perspective. This approach was conceptualised in the context of the International Classification of Functioning, Disability and Health (ICF, 2001) framework. Method Participants were young males aged 7 to 15 years old either diagnosed with ADHD-CT or without ADHD-CT (i.e. Typically Developing, TD). Sample sizes varied for each study (from N = 24 to N = 58) and were convenience samples. Neurobehavioural studies (1 and 2) utilised saccade adaptation and volitional saccade ocular motor paradigms. Functional studies (3 and 4) utilised the Children’s Assessment of Participation and Enjoyment (CAPE) and a customised parent questionnaire on the occurrence of accidental injuries (e.g., bruises, cuts) respectively. Motor proficiency was assessed using the Movement ABC–2 (MABC-2). Dimensional measures of ADHD-CT symptoms (Conners Rating Scale-Revised), ASD symptoms (Social Responsiveness Scale), anxiety and emotional-behavioural disturbance (Developmental Behavioural Checklist) were also quantified. The two groups were compared on outcome variables, and associations between dimensional variables were measured. Results Motor problems and neurobehavioural (ocular motor) findings: Study 1 and 2 revealed anomalous saccade adaptation in young people with ADHD-CT, and significantly larger saccade amplitudes with altered main sequence (peak velocity: amplitude) relationships for volitional saccades. These findings reflected impairments in processes that monitor the mismatch between eye and target position, and adjust saccade amplitude, velocity and duration accordingly; processes that rely on the functional integrity of the cerebellum. Motor problems and participation: Study 3 revealed young people with ADHD-CT participated in activities that were located closer to home and reported greater enjoyment of their activities compared to TD young people. The results indicated that young people with ADHD-CT who participated in more solitary and home-based activities have greater emotional-behavioural disturbance. Motor problems and accidental injuries: Study 4 revealed a significantly greater number of parent-reported accidental injuries for young people with ADHD-CT, compared with TD young people, which was correlated with increased hyperactivity/impulsivity, ASD, and anxiety symptoms, but not motor proficiency. Conclusion This thesis advances current understanding of motor problems in young people with ADHD-CT from neurobehavioural, clinical and functional perspectives. The pattern of ocular motor deficits in Studies 1 and 2 suggest that motor problems in ADHD-CT may be underpinned by disruption to cerebellar neural circuitry, potentially representing neurobiological overlap with ASD. Differences in participation context and increased accidental injuries highlight the importance of assessing these areas of function clinically, to develop appropriate interventions for young people with ADHD-CT. This may be especially pertinent for those young people with ADHD-CT who have additional ASD and emotional-behavioural symptomology.

Adolescent responses to psychological problems were examined using a five wave longitudinal design over a 12 month period. A total of 715 adolescents were followed at three monthly intervals from just prior to finishing high school through their first year out of school. Of the total sample, 53.1 percent complied with all five waves of data collection. Compliers were more likely to be girls and those with a greater interest in mental health. These Australian adolescents were shown to confide their psychological problems overwhelmingly to friends, with about 70 percent seeking help from friends at each wave. This compared with 30 percent who sought help from their family, and only 5-10 percent who turned to professional sources of help. The peer group was shown to be the primary source of emotional support. The prevalence of minor psychiatric morbidity was very high, with 20 to 30 percent of the sample suffering from psychological distress at any time. This was comparable with other studies of adolescent mental health, confirming that late adolescence and finishing school was a period of considerable distress. Symptoms of minor affective disorder were more common in girls than boys, also consistent with other findings. Although psychological symptoms were an important predictor of help­ seeking, such behavior was shown to have multiple predictors. A range of variables from the social-psychological approach to illness behavior were hypothesised to increase vulnerability to psychological problems and thereby encourage help­ seeking behavior. The major proposition of illness behavior research, that factors other than symptoms influence illness behavior, was strongly supported. Emotional vulnerability factors were shown to vary in their predictive value over the different help-seeking contexts. Help-seeking from friends, family and professionals were found to be distinct domains with different facilitators and inhibitors. Turning to friends for support was predicted by being female, perceived psychological distress, private self-consciousness and fear of the stigma attached to psychological illness. These factors both facilitated help-seeking from friends and inhibited it in those with symptoms. Seeking help from the peer group, of the help­ seeking behaviors, was most affected by vulnerability factors, but was also shown to be a result of peer group socialisation processes. Family help-seeking was the least affected by vulnerability to psychological problems. Facilitators of family help-seeking were shown to be availability of confiding relationships and being female. Only lacking a confiding relationship inhibited family help-seeking in those who were distressed. Those few adolescents who sought professional help were best predicted by psychological distress and life events. Professional help was the most disorder and problem driven type of help-seeking. So few young people sought professional help partly because their problems may not have been seen as appropriate for professional intervention. Furthering the usual predictive nature of help-seeking studies, the effectiveness of help-seeking, in terms of subsequent psychological distress, was also examined. A disturbing finding was that none of the three types of help-seeking reduced minor affective symptoms three months later. Seeking help was unrelated to mental health outcome. This was discussed as a consequence of the type of help offered in most help-seeking episodes. A focus on the self and how one feels is maladaptive for many adolescents. Self-focus reinforces and encourages an overconcern with the self, which generally results in the amplification, rather than reduction, of psychological symptoms. With so many adolescents clearly suffering from psychological distress, the needs of these young people did not appear to be being met by either their informal social support networks or professional services. The help-seeking habits of adolescents need to be considered to provide appropriate services. There was a need for peer based services where skills could be learned to reduce the emotional arousal caused by the many psychological problems of adolescence.

The term aimpulsivitya encompasses a multitude of behaviours that are poorly conceived, premature, inappropriate, and that frequently result in unwanted or deleterious outcomes. Impulsivity manifests as impatience carelessness, risk-taking, sensation-seeking and pleasure-seeking, an underestimated sense of harm, and extroversion. Impulsivity is a core symptom of a broad spectrum of psychiatric disorders. Through focusing on different aspects of impulsive behavior, it has proved possible to devise a variety of behavioral paradigms to measure impulsivity in both human and non-human subjects. These can be broadly divided into two categories: those measuring impulsive action or motoric impulsivity, and those measuring impulsive choice or impulsive decision-making. Impulsive action can be broadly defined as the inability to withhold from making a response. Within the framework of behavioral neuroscience and cognitive psychology, impulse control has been described as an active inhibitory mechanism which modulates the internally or externally driven pre-potent desire for primary reinforcers such as food, sex or other highly desirable rewards. This inhibitory control mechanism may provide the substrate by which rapid conditioned responses and reflexes are transiently suppressed, so that slower cognitive mechanisms can guide behavior. This process is referred to as response inhibition. Two of the most common tests used to study inhibitory processes are the go/no-go and stop-signal reaction time tasks. Impulsivity is also evident in the making of impulsive decisions or choices as well as in impulsive actions. Here, there is no qpre-potentq response that is primed and then forcibly inhibited, but a decision-making processes. Impulsive decision making or impulsive choice is defined as initiating actions without adequately considering other possible choices or consequences. Impulsive choice is typically measured in the delay discounting paradigm. In tis paradigm, the tendency to prefer small immediate rewards over larger, more delayed reinforcers is measured. Impulsive choice is defined by a greater tendency to value or choose smaller, more immediate reinforcers. Impulsivity is a multi-faceted behaviour. This behaviour may be studied by subdividing it into different processes neuroanatomically and neurochemically. Neuroanatomical data support the suggestion that behavioral disinhibition (impulsive action / motoric impulsivity) and delay-discounting (impulsive choice / decision making) differ in the degree to which various components of frontostriatal loops are implicated in their regulation. The dorsal prefrontal cortex does not appear to be involved in mediating impulsive choice, yet does have some role in regulating inhibitory processes. In contrast, there appears to be a pronounced role for the orbitofrontal cortex and basolateral amygdala in controlling impulsive choice. Other structures, however, such as the nucleus accumbens and subthalamic nucleus may

The Ethics of Introspection: Reducing Healthcare Costs and Inspiring Wellbeing with Ancient Philosophy

In the light of recent development of neurosciences, multiple studies aim to establish brain dysfunctions linked to psychiatric disorders. Schizophrenia is a severe long-term mental illness and recent research identified neurobiological changes with psychopathological effects. The dopamine hypothesis has been one of the most enduring theories dominating the etiopathogenesis of schizophrenia. This theory is supported by the efficacy and potency of many antipsychotic drugs acting on dopamine and on another neurotransmitter with effects on dopamine, the serotonin. The dopamine theory postulates a mesolimbic dopaminergic hyperactivity linked to positive symptoms and a prefrontal cortex dopaminergic hypoactivity causing negative and cognitive symptoms in schizophrenia. Multiple theories implicating dysfunctions of glutamate and GABA prefrontal neurons integrate the above-mentioned dopamine abnormalities. Schizophrenia is also conceptualized as a disconnection syndrome, therefore a lack of coordination between different cortical regions is argued, with emphasis on cortico-thalamic circuits. The thalamo-cortical dysconnectivity implies decreased connections between thalamus and dorsolateral prefrontal cortex. In order to control perceptive and cognitive processes, the GABA prefrontal neurons are synchronized in the γ frequency band (30-80 Hz). In schizophrenia, there is a disturbed synchronicity in γ band and an increased activity in θ band, consistent with a hyper polarization with reduced control function of the prefrontal cortex. Also, chronic stress is associated with an inappropriate immune activation. Stress may increase pro-inflammatory cytokine. The activated immune system in turn activates the enzyme indoleamine 2,3-dioxygenase (IDO) of the tryptophan/kynurenine metabolism which influences the serotonergic and glutamatergic neurotransmission. Epigenetic mechanisms may stem for the environmental contributions to schizophrenia, too. DNA methylation or histone acetylation could imply an active or inactive transcription in the case of some well-known enzymes intervening in the pathophysiology of schizophrenia like BDNF, COMT, GAD1 or RELN gene. According to the “theory of self” in schizophrenia the structures implicated in “sense of self” elaboration are ventral medial, dorsal medial prefrontal cortex, anterior and posterior cingulate cortex, superior temporal sulcus, inferior parietal cortex.

Approximately 70% of the general population experience a traumatic event during lifetime. However, only a small proportion develop Posttraumatic Stress Disorder (PTSD) (5.6%). Considerable efforts have been made to investigate individual differences as well as characteristics of the trauma itself that both may contribute to the development of PTSD. The experience of child maltreatment (CM) in contrast to the experience of a traumatic event during adulthood has repeatedly found to be correlated to significant higher rates of PTSD. On a neurocognitive level, cognitive dysfunctions together with functional and structural brain alterations seem to characterize individuals with PTSD compared to traumatized healthy subjects. Although a cumulative effect of trauma can be assumed, the role of type and timing of CM has become of particular interest when investigating neurocognitive correlates contributing to the development of PTSD. Emerging evidence points to sensitive periods and specificity of CM-subtypes to differentially impact neurocognitive correlates in individuals with and without PTSD. However, research is still at a very early stage. The development of PTSD in the aftermath of prolonged and severe CM is often associated with clinical features that extend beyond classic PTSD symptoms such as affective dysregulation, negative self-concept and disturbances in relationships. This complex form of PTSD (cPTSD) has therefore been included in the 11th revision of the World Health Organization’s International Classification of Diseases (ICD-11). Numerous studies in PTSD patients related to various trauma types have already provided evidence for neurocognitive alterations. However, the empirical database on neurocognitive correlates of cPTSD is quite limited at this time. Understanding alterations in cognitive and neural processes could optimize treatments in order to improve long-term outcomes of individuals with cPTSD. Several psychotherapeutic approaches have been developed for PTSD treatment and have been shown to be successful in treating PTSD symptoms as well as neurocognitive alterations. However, those treatments have mostly been developed for survivors of adult-trauma PTSD. Meta-analyses demonstrated substantially lower effect sizes of psychotherapeutic treatments in CM-related cPTSD indicating poorer treatment response. Even though preliminary data point to the effectiveness of psychotherapy on normalizing neurocognitive correlates in cPTSD patients, these data are in clear need of replication. To fill this gap, the aim of the doctoral thesis was to examine the long-term sequelea of CM with an emphasis on neurocognitive correlates of CM-related PTSD and cPTSD and the impact of psychotherapy on these measures. For this purpose, three experimental studies were conducted. Two studies investigated the role of cPTSD and CM history on neurocognitive correlates. Study I investigated the role of psychopathology and CM history on functional correlates of cognitive control and emotional interference. Study II focused on the effects of CM on structural brain correlates with an emphasis on type and timing of traumatization. The third study aimed to examine whether 12 months of psychotherapy (DBT-PTSD or CPT) lead to an improvement of neurocognitive alterations in patients with cPTSD. In study I, patients with cPTSD showed poorer behavioral outcome and an increased need for activation within prefrontal cognitive control networks, while confronted with trauma-related stimuli as compared to healthy controls with and without CM history. After 12 months of psychotherapy (study III), the pathologically increased emotional interference in cPTSD patients was found to be “normalized” on both neuronal and behavioral measures (reflected in faster reaction times, less errors and decreased activation within limbic and prefrontal brain regions). It can be concluded that psychotherapy helped patients by working with trauma-related memories, cognitions and emotions to integrate new adaptive information to distinguish between threat and safety to habituate towards trauma-related material. Regarding structural brain correlates of CM, study II demonstrated a negative correlation between global CM severity and bilateral amygdala volume. Interestingly, this effect was driven by the severity of neglect. Moreover, results point to an effect of timing of CM exposure at 10-11 years of age and 13 years of age, for both bilateral amygdala and hippocampal volume. Regarding type x timing analyses, results revealed sensitive periods during 10-12 years of age and 13-14 years of age for the severity of neglect, affecting right amygdala volume. Moreover, results point to a sensitive period during 14 - 16 years of age for the severity of neglect affecting left amygdala volume. Likewise, a sensitive time window for the severity of neglect were identified during 9-13 years of age, affecting bilateral hippocampal volume. The results of the present thesis provide further support that exposure to CM lead to long-term stress-induced cumulative changes in the neurobiological system. Moreover, the results provide further evidence for a type and timing model of CM, as a complementary approach in the understanding of the impact of CM across the entire lifespan on neurocognitive correlates. Longitudinal studies, however, are needed to get insight on causal relationships.

Emotional Reactivity in Posttraumatic Stress Disorder:Behavioural and Neurobiological Correlates of Underlying Mechanisms and the Role of Emotional Memory Modification

Revisiting melancholic depression: Review of the concept and clinical implications

This thesis examines the influence of culture on the relationship between social support and posttraumatic stress disorder (PTSD). A review considers the intersections, theoretical, and clinical implications, of integrating these fields. Empirical research found that for highly interdependent people, greater social support reduced the impact of trauma on PTSD symptoms. An indirect relationship between social support and PTSD symptoms, through negative cognitive appraisals and maladaptive coping strategies was found. Through exploring the impact of culture, maladaptive thinking and coping, on the association between social support and PTSD, we can better understand the processes through which social support influences PTSD symptoms.

Emotional dysregulation is a core feature of Major Depressive Disorder (MDD), manifested by perceptual biases in processing positive and negative emotional stimuli. In support, a constellation of neuroimaging studies have consistently reported abnormalities in brain areas during the processing of negative and positive emotional stimuli in acutely depressed patients during a major depressive episode. These areas, which are pivotal for bottom-up emotion generation processes and top-down cognitive control of emotion through reciprocal connections, include lateral prefrontal cortical (PFC) regions (dorsolateral PFC, ventrolateral PFC), medial PFC regions (orbitofrontal cortex) and subcortical regions (amygdala, ventral striatum). However despite considerable progress into identifying the neural circuitry involved in MDD, a neural circuitry marker for the MDD trait has not yet been defined. Studying individuals in remission from MDD who are euthymic and medication-free, allows for the examination of enduring abnormalities in the neural circuitry supporting emotion processing and its regulation that may represent trait markers of the illness. Therefore the aims of this thesis were to examine, by means of two functional magnetic resonance imaging (fMRI) studies, neural activation in key areas subserving emotion processing and higher-order cognitive control processes, to determine whether abnormalities in the circuit persist into remission and thus represent trait-like markers of MDD. Using blood oxygen level dependent (BOLD) fMRI, 19 remitted medication-free individuals with recurrent MDD (rMDD) (mean age 33.6 ± 13.64) and 20 healthy controls (HC) (mean age 35.8 ± 12.10) completed an implicit gender-labelling emotion processing task (study 1), and a working memory task with emotional distracter stimuli (study 2). In each study faces depicting negative (fearful), positive (happy) and neutral emotions were used. Brain imaging data were analyzed in SPM2 using a whole-brain and region-of-interest approach corrected for multiple comparisons using AlphaSim (PFWE

Theoretical and practical insights for anorexia nervosa and major depression: novel neurobiological targets for pharmacology and brain stimulation therapies

Schizophrenia is characterized as one of the most serious mental illnesses, occurs in 1% of general population and affects the individual in thought, perception, behavior and emotion. The disorder’s onset is located at the end of adolescence and early adulthood, however there is also a more infrequent onset during childhood. Its symptoms are divided into positive and negative. Positive symptoms refer to distortions of reality, through strange beliefs and illusions, while negative symptoms refer to behavioral deficits. Deficiencies also occur in cognitive areas, such as attention, working memory and executive functions. Schizophrenia’s diagnosis is based on the criteria of the International Classification of Diseases - 10th Revision (ICD-10) and the Diagnostic and Statistical Manual of Mental Disorders - 5th Edition (DSM-V), depending on the presence and duration of symptoms. The causative disorder’s factors are genetic, neurobiological, environmental and psychosocial. Research supports the genetic background and neurobiological basis of schizophrenia, by twin studies on the genetic predisposition of the disease and neuroimaging and neuroanatomical studies showing structural brains’ abnormalities of people with schizophrenia. Various neurotransmitters are also considered to be responsible for the etiology, mainly dopamine and glutamate. The course of the disease is characterized by specific stages, which are the premorbid phase, the onset of the disease and the outcome. When the onset is early and insidious, the outcome is worse than the acute one. The treatment of schizophrenia includes taking antipsychotic drugs and utilizing educational and psychosocial interventions, in collaboration with the community, family and school to improve patients' daily living.

Children and adolescents whose make the street as their surviving place, reflects the social vulnerability process experienced by a lot of Brazilian families living in misery, abandonment and violence situation. For groups similar to that, Castel (2005) identifies an increasing rupture process to their insertion in the working world and social relationship that supports daily life, which could culminate in disaffiliation conditions, becoming them an extra-number, because they float in social structure where they don’ find a designated location. In this context, many adolescent live their sexuality and the possibility or the experience to become fathers or mothers, based on individual values, but also related to the limitations and subjacent possibilities to these processes. The aim of this study was to analyze the meanings of maternity and paternity by adolescents with life experience in streets, relating it to the vulnerability and disaffiliation process by Castel. It was a strategic social research developed on two non-governmental institutions in Goiania, where adolescents that lives in streets are assisted. The subjects of this study was adolescents in age among 12 and 17 years old, whose were living in street by 6 months at least. Data were collected by semi-structured interviews and participant observation, and analyzed by the Senses Interpretation Method, through the themes “Damned Street” and “Father Supports; Mother is 24 Hours”. It was possible to identify how the vulnerability and disaffiliation process is characterized and determines the life trajectory of these adolescents. Moreover, that the signification processes of maternity and paternity are impregnated as by living context as by related values with genre relationship considered traditional in the contemporary society. Thus, it was possible to identify a large potential of maternity as a factor that motivates the adolescent girl to search for alternatives beyond the street life, reverting the social disaffiliation to the vulnerability situation, in opposition to the observed in paternity meaning for adolescent boys of this study. Key words: Social vulnerability; Homeless youth; Pregnancy in adolescence.

The impact of global societal trends regarding product reliability provides society with great benefits and yet comes with the consequence of increased organizational vulnerability. The goal of this research was to examine these issues and develop the means for organizations to mitigate the potential negative effects of disturbances from within and external to the organization for the purpose of sustaining organizational resilience. As a result of this research the Highly Reliable Resilient Organization (HRRO) methodology was developed to provide a consistent and customizable methodology to assess organizational vulnerability. The purpose of this methodology is to determine current and potential levels of vulnerability and to select and prioritize vulnerability elimination and mitigation initiatives and projects using pre-established monetary and non-monetary factors. Moreover, the HRRO methodology provides the means to identify, define, and assess the prerequisite criteria of an organization that enable it to be resilient. These prerequisite criteria are the foundation for the organization’s core function; its culture, its ability to manage risk, and its governing processes, i.e. its ability to be resilient, or at the very least available to fulfill monetary and non-monetary goals and enjoy a better chance for sustained viability. The HRRO methodology is a generalizable analytic-deliberative process that was validated by stakeholders, nine well known organizational models, a prioritization methodology that has been in use for several years, independent case studies, and an independent and widely used location risk quality benchmarking algorithm. To foster sustained use, the HRRO methodology strikes a balance between complexity and simplicity, i.e. the model is sufficiently comprehensive to reflect reality and sufficiently simple to be manageable. The methodology used in this dissertation is based upon transformative-reflective design processes. The first step in this process was, in this case, the creation of a construct that was analyzed, validated and adapted during subsequent steps.

Bone drilling process is one the most common processes in orthopedic surgeries and bone breakages treatment. It is also very frequent in dentistry and bone sampling operations. Bone is a complex material and the machining process itself is sensitive so bone drilling is one of the most important, common and sensitive processes in Biomedical Engineering field. Orthopedic surgeries can be improved using robotic bone drilling systems and mechatronic bone drilling tools. In the present study, multi-objective optimization is performed on the temperature and trust force at two steps. At the first step, two regression models are developed for modeling the temperature and force in bone drilling process considering three design variables namely tool’s rotational speed (V), feed rate (f) and tool diameter (D). At the second step, by using regression models, multi-objective genetic algorithm is used for Pareto based optimization of bone drilling process considering two conflicting objectives: temperature and force. It has been found out that there are considerable connections and feasible principles for an optimal design of the process in case of applying Pareto-based multi-objective optimization; otherwise these interesting results would not be discernible.