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Issue 4 (2017) – Supplement 3


Special Issue on the Neurobiology of Mental Illness

This special issue on the Neurobiology of Mental Illness provides an overview of a wide range of topics on the role of the biological factors and mechanisms that influence the etiopathogeny, the course and treatment of psychiatric disorders. From biomarkers, such as genetics, proteomics, metabolomics and imaging, and research methodologies to new therapeutic modalities such as neuromodulation, this supplement presents a set of current and relevant subjects.

Guest editor:
António Ferreira Macedo, MD, PhD

Issue Nr:

4

|    Issue date: 2017-11-15

Guest Editorial


Neurobiology of mental illness: from reductionism to integration - read full article

By: António Ferreira de Macedo

From its inception until now, psychiatry has continually searched for knowledge of brain-behavior relationships and the neurobiological underpinnings of psychopathology. The tendency to view mental illnesses as brain diseases is not new and goes back to Hippocrates, being dominant in the nineteenth century. This theoretical tradition was interrupted during the first decades of the twentieth century by a predominant psychological vision, embodied in different theories such as psychoanalysis, and a range of behavioural, humanistic and cognitive perspectives. However, in the last forty years the tendency to view psychiatric patients as individuals who have some kind of brain disorder has grown to the point of being an almost indisputable truth. In the second edition of Biological Psychiatry, Michael Trimble [1] said that biological psychiatry has a long past—which establishes its respectability—but a short history—which establishes its scientificity. Indeed, this part of the story is relatively short and researchers all over the world continue to struggle for discovering the neuronal and neurochemical bases of psychiatric symptoms. The corollary of this brain-centered vision, which is now firmly rooted in the mind of most psychiatrists, and is at the core of the contemporary neuroscience thinking, is that the mind is simply what the brain does. Consequently, mental pathology is merely the behavioral consequence of identifiable neuromolecular abnormalities. However, we must dispute this kind of simplistic brain-centered reductionisms, emphasizing that this view must be tempered with the notion that mental illness is multidetermined. This awareness should reminds us the great density of causal factors involved in mental illness and prevent us from falling into a simplistic and linear causal thinking. The explanation of this complex causality, including inside and outside-the skin factors is now well addressed within disciplines such as critical neuroscience and social neuroscience.

Special Issue on the Neurobiology of Mental Illness

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 3):S01
DOI: https://doi.org/10.21035/ijcnmh.2017.4(Suppl.3).S01

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Review Article


Neural connectivity in youth at-risk for bipolar disorder: a review of functional magnetic resonance imaging studies - read full article

By: Vítor Santos, Manuel Coroa, Salomé Caldeira, Miguel Bajouco, and Nuno Madeira

Background: Delayed diagnosis of bipolar disorder (BD) is common in adolescents and young adults and the search for biomarkers to help in early diagnosis in BD at-risk populations is an important goal of neuroimaging research. Functional connectivity studies in BD patients suggests that anomalous connectivity between prefrontal and limbic regions could be risk biomarkers for BD. The aim of this review is to provide an overview of the neuroimaging literature that employed functional connectivity techniques in adolescents and young adults at-risk for BD. 
Methods: A literature search was conducted using PubMed and EMBASE databases, to identify fMRI studies that employed a measure of functional or effective connectivity or network based statistics and included individuals at-risk for BD who were in the age range of early-mid adolescence (13–18 years old) and/or young adulthood (19–25 years old). 
Results: Ten studies focusing on 4 functional imaging domains were identified, namely emotion processing, affective cognition, reward processing and resting-state. Altered functional connectivity between amygdala and ventrolateral prefrontal cortex (PFC); amygdala and anterior cingulate cortex and between anterior cingulate cortex, ventrolateral PFC and dorsolateral PFC emerged as putative risk biomarkers. Heterogeneity in BD at-risk samples, tasks and connectivity analysis methods has been identified. 
Conclusions: Youth at-risk for BD have altered functional connectivity in prefrontal-limbic networks supporting emotion regulation that might underlie emotion lability and mood dysregulation predisposing to BD. Future longitudinal studies in adolescents and young adults with Bipolar At-Risk criteria are important to establish functional connectivity measures as risk biomarkers.

Keywords: Bipolar Disorder, At-Risk, Functional Connectivity, fMRI.

Special Issue on the Neurobiology of Mental Illness

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 3):S02
DOI: https://doi.org/10.21035/ijcnmh.2017.4(Suppl.3).S02

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Review Article


The quest for biomarkers in Schizophrenia: from neuroimaging to machine learning - read full article

By: Miguel Bajouco, David Mota, Manuel Coroa, Salomé Caldeira, Vitor Santos, and Nuno Madeira

Schizophrenia is a severe mental disorder and one of the leading causes of disease burden worldwide. It represents a source of significant suffering and disability to the affected individuals, and is associated with substantial societal and economical costs. The diagnosis of schizophrenia still depends exclusively on the detection of symptoms that are also present in other mental disorders. This situation causes overlapping of the boundaries of the diagnostic categories and constitutes a source of diagnostic errors. Moreover, current treatment algorithms do not take into account the substantial interindividual variability in response to antipsychotic drugs. As a result, around one-third of patients are treatment-resistant to first line antipsychotic drugs. This deleterious consequence is associated with poor individual outcomes and elevated healthcare costs. Neuroimaging research in schizophrenia has shed some light in a vast array of structural and functional connectivity abnormalities and neurochemical (dopamine and glutamate) imbalances, which may constitute ‘organic surrogates’ of this disorder. However, the neuroimaging field, so far, has not been able to identify biomarkers that could facilitate early detection and allow individualised treatment management. This paper reviews neuroimaging studies from different modalities that may provide relevant biomarkers for schizophrenia. We discuss how the current application of novel Machine Learning methods to the analyses of imaging data is allowing the translation of such findings into potential biomarkers enabling the prediction of clinical outcomes at the individual level, towards the development of innovative and personalised treatment strategies.

Keywords: Schizophrenia, Biomarkers, Neuroimaging, Machine-Learning.

Special Issue on the Neurobiology of Mental Illness

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 3):S03
DOI: https://doi.org/10.21035/ijcnmh.2017.4(Suppl.3).S03

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Review Article


The ups and downs of cellular stress: the “MAM hypothesis” for Bipolar disorder pathophysiology - read full article

By: Ana Catarina Pereira, Rosa Resende, Sofia Morais, Nuno Madeira, and Claudia Fragão Pereira

Mental health problems constitute the largest single source of world economic burden, with an estimated global cost greater than cardiovascular disease, cancer or diabetes individually. In the European Union mental disorders affect millions of people and these numbers are expected to rise as result of Europe's ageing population. Given the biological causes of many of these disorders, most studies focus on their molecular basis. Bipolar disorder (BD) is characterized by mood swings between depression and mania resulting in cognitive and functional impairments that require lifetime treatment. Recurrent mood episodes, residual symptoms, functional impairment, psychosocial disability with high rates of divorce, unemployment, drug abuse and suicide attempting, and significant medical comorbidities such as metabolic and cardiovascular diseases cannot be efficiently controlled even with proper use of current treatments. Moreover, delayed diagnosis/misdiagnosis is frequent because reliable biomarkers are absent. Therefore, a better understanding of BD pathophysiology is a prerequisite for the design of new drugs and their implementation in clinical practice as well as to develop biomarkers for a more accurate and earlier diagnosis and/or evaluation of therapeutic response. This review summarises the association between decreased cellular resilience towards stress and BD. Since the key stress-response mediator Mitochondria-Associated Membranes (MAMs) modulate several BD relevant processes such as mitochondrial dysfunction and oxidative stress, Ca2+ deregulation and cytoskeleton abnormalities, endoplasmic reticulum stress responses, loss of proteostasis and inflammasome activation, we propose the “MAM hypothesis” for BD pathophysiology. Targeting MAM-associated signaling pathways can be a promising investigation avenue to identify novel therapeutic strategies.

Keywords: Bipolar disorder, Endoplasmic reticulum, Mitochondria, Mitochondria-associated membranes, Cellular resilience, Cellular stress, Plasticity.

Special Issue on the Neurobiology of Mental Illness

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 3):S04
DOI: https://doi.org/10.21035/ijcnmh.2017.4(Suppl.3).S04

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Review Article


Circulating biomarkers in schizophrenia: a proteomics perspective - read full article

By: Cátia Santa, Joana F. Coelho, Nuno Madeira and Bruno Manadas

Schizophrenia (SCZ) is one of the most severe and devastating major mental disorders, with an onset typically in late adolescence or early adulthood affecting about 0.5–1.2% of the population worldwide. It is one of the most debilitating medical conditions, with striking socio-economic burden to society due to lost employment and social support that largely surpass direct costs of treatment. SCZ is listed by the World Health Organization (WHO) among the top 20 leading causes of disability worldwide. Its diagnosis is syndromic, based in clinical interviewing and anamnesis, as there is to date no biochemical test to aid in this diagnosis. On the other hand, SCZ treatment is mostly based in antipsychotic drugs which are in several aspects somehow ineffective, and some of these medications have low tolerability with severe side effects. For all these reasons, the current search for new panels of biomarkers is of the utmost importance to aid in the correct diagnosis and stratification of the patients, prognosis, and prediction of treatment effectiveness. In this review, a total of 25 publications on peripheral SCZ biomarkers are presented from proteomics studies performed in body fluids of patients searching for protein markers, and using mass spectrometry. To date such proteomics studies have already been achieved in cerebrospinal fluid (CSF), serum, plasma, peripheral blood cells (namely, mononuclear cells, T-cells and red blood cells), saliva, and sweat, being of paramount importance in the schizophrenia research field, but still lacking validation and clinical translation. In summary, a general overview of the results from these 25 studies, as well as the challenges and future perspectives of the field, are presented and discussed.

Keywords: Schizophrenia, Biomarkers, Proteomics, Mass Spectrometry.

Special Issue on the Neurobiology of Mental Illness

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 3):S05
DOI: https://doi.org/10.21035/ijcnmh.2017.4(Suppl.3).S05

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Review Article


Facial emotion processing in schizophrenia: a review of behavioural and neural correlates - read full article

By: Joana Grave, Sandra C. Soares, Maria João Martins, and Nuno Madeira

Schizophrenia is one of the most severe psychiatric conditions, often associated with deficits in social cognition. Social cognition deficits are predictors of functionality in patients and involve theory of mind, attributional style, social perception, and emotional processing. In particular, facial emotion processing (an important domain of emotional processing) seems to be particularly related to cognitive and social functioning, and to positive and negative symptoms. Patients with schizophrenia have difficulties in processing emotional faces; however, those impairments are still far from fully understood. In this review, we addressed the behavioural and neural correlates of facial emotion processing in schizophrenia. Despite studies showing impairments in both positive and negative faces, the most consistent findings involved negative faces. Moreover, patients with schizophrenia showed abnormalities in the social brain neural circuit during facial emotion processing. While some studies described hypoactivation of brain areas related to emotional processing, such as the amygdala, others reported hyperactivation, leading to a high number of inconsistencies. The findings are limited by the experimental designs used, and the clinical and demographic characteristics of patients. Despite such variable findings, there has been growing interest in developing psychosocial interventions focused directly on social cognitive impairments in schizophrenia, with potential impact on patient’s ability to perceive emotional faces. We provide a critical perspective on current evidence and suggest new pathways of research. The understanding of the mechanisms underlying facial emotion processing in schizophrenia could enhance functionality and quality of life by providing innovative approaches to the interpersonal difficulties patients frequently experience.

Keywords: Schizophrenia, Facial Emotion Processing, Social Cognition.

Special Issue on the Neurobiology of Mental Illness

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 3):S06
DOI: https://doi.org/10.21035/ijcnmh.2017.4(Suppl.3).S06

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Review Article


Neuromodulation in Psychiatric disorders: recent findings and clinical implications - read full article

By: Joana Andrade, David Mota, Sofia Ferreira, and Ana Araújo

The potential therapeutic value of electricity to treat neuropsychiatric disorders has been known for a long time. However, it is only recently that it has been successfully applied to these clinical conditions. Two of the most promising neuromodulation techniques are the deep brain stimulation (DBS) and the transcranial magnetic stimulation (TMS). DBS uses a high-frequency stimulation that causes a “reversible lesion” and is increasingly becoming an alternative for lesional surgery for its better balance between efficacy, tolerability and safety, and has consistently been shown to improve depressive and obsessive symptoms. TMS is a non-invasive and safe approach that has been approved for the treatment of major depressive disorder and for auditory-verbal hallucinations in schizophrenia and is being studied in several other psychiatric disorders, such as obsessive-compulsive disorder, eating disorders and negative symptoms of schizophrenia. In the current paper, we will review recent evidence of these two neuromodulation techniques, its main psychiatric indications and present two brief case reports to further illustrate its clinical applicability.

Keywords: Neuromodulation, Deep brain stimulation, Transcranial magnetic stimulation, Depression, Obsessive-compulsive disorder, Schizophrenia.

Special Issue on the Neurobiology of Mental Illness

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 3):S07
DOI: https://doi.org/10.21035/ijcnmh.2017.4(Suppl.3).S07

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Review Article


Psychological risk factors, cognitive-contextual approaches and neural correlates in eating disorders: an integrative review - read full article

By: Cristiana Marques, Inês Almeida, Sara Santos, Paula Castilho, Ana Telma Pereira, and Miguel Castelo-Branco

Eating disorders (ED) are a significant source of physical and psychosocial impairment, mainly amongst women in adolescence and early adulthood. The development and progression of ED are influenced by a large set of environmental and social factors, but it has also been recognized that ED have important biological and psychological determinants. This article reviews the literature on ED concerning defensive emotion and psychological processes involved in the development and maintenance of ED, but also their neuroimaging/electrophysiological correlates. Furthermore, it also reviews treatment approaches that focused on the improvement of ED patients’ symptomatology. An extensive literature exists regarding neuroimaging/electrophysiological studies associated with clinical features of ED patients in terms of body image and food processing and reward/inhibition processes. However, studies addressing the neural correlates of psychological processes, such as rumination, experiential avoidance, cognitive fusion and self-criticism, and the defensive emotion of shame, which are key components for the development and maintenance of ED, are still scarce if not lacking. In the context of this cognitive set, cognitive-contextual approaches for ED patients, such as mindfulness, acceptance- and compassion-based interventions are promising to change the way individuals relate to their aversive experiences, but still requires a deeper understanding of the mechanisms by which it operates and further testing of its therapeutic efficacy. This review highlights the lack of neuroimaging/electrophysiological studies in ED patients in which concerns shame and other relevant psychological processes, but also the scarce evidence in terms of brain modifications associated with therapeutic efficacy of cognitive-contextual approaches that help to change the way individuals relate to their body, weight and food concerns, reduce maladaptive emotion regulation strategies and improve well-being in patients suffering from ED.

Keywords: Eating disorders, Neural correlates, Psychological processes, Cognitive-contextual approaches.

Special Issue on the Neurobiology of Mental Illness

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 3):S08
DOI: https://doi.org/10.21035/ijcnmh.2017.4(Suppl.3).S08

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Review Article


A relationship between early life stress and depression: the role of the serotonin transporter gene polymorphism (5-HTTLPR) - read full article

By: Jorge Valderrama, Carlos N. Pato, and Michele T. Pato

Early life stress has been associated with many different negative outcomes including adulthood depression. Studies have suggested a role of the serotonin transporter gene polymorphism (5-HTTLPR) in explaining this relationship. However, consistent replication of this gene-environment interaction have proven difficult. This paper will review contrasting evidence assessing this interaction. Previous research has revealed a complex interplay of factors that might explain how certain 5-HTTLPR genotypes interact with early life stress to produce sensitivity to stress and adulthood depression. Maladaptive cognitive and behavioral patterns will be reviewed in light of 5-HTTLPR’s impact on brain regions associated with mood regulation. Future research directions and clinical interventions will also be discussed.

Keywords: Early life stress, Childhood abuse, 5-HTTLPR, Depression.

Special Issue on the Neurobiology of Mental Illness

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 3):S09
DOI: https://doi.org/10.21035/ijcnmh.2017.4(Suppl.3).S09

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Review Article


Estrogen and schizophrenia in women: animal models lend a hand in understanding cognition - read full article

By: Saranna Belgrave, Carlos N. Pato, and Michele T. Pato

Women experience a differential onset of schizophrenia symptoms and a bi-modal peak of onset in the early years of adulthood and in the post-menopausal period. Cognitive deficits that accompany schizophrenia are some of the more severe symptoms associated with the disease. The understanding of the mechanisms underlying cognitive dysfunction is still very limited and its understanding can bring important contributions to the adequate clinical management of the disease. Using rodent research to explore cognition, and how female hormones may affect cognitive decline with age in the context of schizophrenia can expand our understanding and perhaps offer more treatment options.

Keywords: Estrogen, Schizophrenia, Animal model, Cognition.

Special Issue on the Neurobiology of Mental Illness

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 3):S10
DOI: https://doi.org/10.21035/ijcnmh.2017.4(Suppl.3).S10

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Review Article


Toxoplasmosis and psychosis: environment makes a difference - read full article

By: Penelope Georgakopoulos, Carlos N. Pato, Michele T. Pato

Psychotic symptoms are the hallmark of one of the most debilitating serious mental illnesses, schizophrenia. They are also evident in certain forms of depression, bipolar disorder, delirium, and other neuropsychiatric disorders. Thus, differential diagnosis can sometimes be difficult to perform. Further, schizophrenia is believed to be, in part, related to genomic risk, with many variants already identified to contributing to genomic risk. However, most models include a likely role for environmental risk factors as well. We will explore the relationship between Toxoplasmosis, as one such environmental risk and schizophrenia.

Keywords: Toxoplasmosis gondii, Psychosis, Schizophrenia, Dopamine, Cats, Feline.

Special Issue on the Neurobiology of Mental Illness

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 3):S11
DOI: https://doi.org/10.21035/ijcnmh.2017.4(Suppl.3).S11

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Original Article


Association of p.Val158Met COMT polymorphism with paranoid ideation in drug addicts - read full article

By: Carolina Ribeiro, João Curto, Graça Areias, Adriana Belo, João Balhau, José Rocha Almeida, and Manuela Grazina

Introduction: Drug addiction is one of the most devastating brain disorders, involving the impairment of brain reward pathway. The enzyme catechol-O-methyltransferase (COMT) metabolizes dopamine and influences the reward pathway functioning. COMT activity is influenced by genetic variations, particularly the p.Val158Met (rs4680); the Met/Met genotype has been associated with a 40% reduction in enzyme activity. The aim of this study was to determine p.Val158Met COMT polymorphism in a Portuguese population of drugs addicts seeking treatment and its association with paranoid ideation. 
Methods: A group of 106 drug addicts seeking treatment were evaluated, upon written informed consent, taking into account their clinical history. Sixty patients were submitted to an evaluation protocol for neuropsychological assessment. Genetic screening for the COMT polymorphism p.Val158Met was performed. Control subjects (n=77) without clinical history of addiction were included, matching for age and socioeconomic status. Statistical analysis was performed (SPSS 19.0®) and significance was considered if p<0.05. 
Results: Significant differences were observed in genotype and allele frequencies between drug abusers and controls (p-value = 0.0068 and 0.0033, respectively). Moreover, paranoid ideation was associated with Met/Met genotype (p-value = 0.046). 
Conclusions: Drug addicts have a higher frequency of Val allele. The Met/Met genotype is associated with higher risk of developing paranoid ideation, probably due to the lower enzyme activity that leads to higher synaptic dopamine levels. The results are preliminary but significant for the study of genetic variability influencing drug addiction and are a relevant contribution for therapeutic strategies.

Keywords: Drug Addiction, COMT, Dopamine, Paranoid Ideation, Reward Pathway.

Special Issue on the Neurobiology of Mental Illness

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 3):S12
DOI: https://doi.org/10.21035/ijcnmh.2017.4(Suppl.3).S12

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