Systems Neuroscience in Depression

Systems Neuroscience in Depression

Editor

Thomas Frodl

Department of Psychiatry and Psychotherapy, Otto von Guericke University, Magdeburg, Germany

Department of Psychiatry, Trinity College Dublin, Ireland

Table of Contents

Cover image

Title page

Copyright

Contributors

The Systems Neuroscience Approach

Part I. Developmental Aspects

Chapter 1. A Multilevel Developmental Psychopathology Systems Perspective on Depression

What is Developmental Psychopathology?

Developmental Analysis

Normal and Abnormal Development

Research Approaches within Developmental Psychopathology

Principles of Developmental Psychopathology

Conclusion and Future Directions

Chapter 2. Early Life Adversity and Risk for Depression: Alterations in Cortisol and Brain Structure and Function as Mediating Mechanisms

Linking Stress Exposure and Depression

Complexities in the Relationship of Stress to Depression

Mediators of the Relationship between Stress and Mood Pathology

Changes in Brain Structure and Function as a Mediator between Stress and Depression

Direct Tests of the ELS-Cortisol-Brain-Depression Mechanism

Summary and Pointers to the Future

Part II. Experimental Systems Neuroscience

Chapter 3. Novel Targets in the Glutamate and Nitric Oxide Neurotransmitter Systems for the Treatment of Depression

Introduction

Overview of Glutamate Neurotransmission in the Brain

Overview of the Functional Role and Regulation of nNOS in the Brain

nNOS Regulation by PDZ-Binding Proteins

NO Signaling: cGMP-Dependent and cGMP-Independent Pathways

Biological Mechanisms Underlying the Pathophysiology of Depression

Evidence Linking Glutamate to Depression

Evidence Linking NO to Depression

Inhibition of NMDA-R/PSD-95/nNOS Protein Interactions

Downstream of NO: A Role for sGC, cGMP, and PDE in Depression

NMDA-R/NO Pathway in Neuronal Plasticity: A Mechanism for Producing Antidepressant Effects

Conclusions

Chapter 4. Anti-Inflammatory and Immune-Modulatory Therapeutic Approaches in Major Depression

Introduction

The Cellular Basis of Inflammation in the Central Nervous System

BBB Disturbance in Major Depression

The Model of Sickness Behavior for Depression

The Proinflammatory Immune State in Major Depression

The Role of Cytokines and the Hormones of the Hypothalamus-Pituitary-Adrenal Axis

The Influence of Stress on the Immune System

Kindling and Sensitization of the Immune Response: Basis for the Stress-Induced Inflammatory Response in Psychiatric Disorders

The Vulnerability-Stress-Inflammation Model of Depression

Infections and Autoimmune Disorders as Risk Factors for MD

Inflammation Influences the Metabolism of Serotonin and Noradrenalin in Depression

Effects of the Proinflammatory Immune Activation on the Kynurenine Metabolism in Depression

CNS Volume Loss in Neuroimaging Studies: A Consequence of an Inflammatory Process?

CNS Inflammation in MD: Findings from Positron Emission Tomography Scans

COX-2 Inhibition as an Example of an Anti-Inflammatory Therapeutic Approach in MD

Anti-Inflammatory Compounds Other than NSAIDs

Inflammatory Pathogenesis in MD and Schizophrenia: The End of the Kraepelinian Dichotomy?

Chapter 5. Molecular Mechanisms of Depression

Introduction

Regulation of Synaptic Plasticity During Depression

Molecular Signaling at the Synapse That is Relevant to Depression

BDNF in Synaptic Plasticity and Depression

Protein Kinases Implicated in Depression

Part III. Systems Neuroscience

Chapter 6. Epigenetic Mechanisms in Depression

Diathesis-Stress Model

Epigenetics as a Potential Mechanism Underlying Diathesis-Stress

DNA Methylation

Early Environment and DNA Methylation

Confounds: Genetics

Specific Systems Involved in Depression

Stability of DNA Methylation Patterns

Methodological Issues and Limitations

Conclusion

Chapter 7. Identifying Large-Scale Neural Networks Using fMRI

Introduction

Methods

Changes in Large-Scale Networks in Depression

Discussion

Conclusion

Chapter 8. Imaging Functional Systems in Depression

Mood-Congruent Processing in Depression

Biased Attention Toward Negative Stimuli

Memory Biases for Negative Information

Long-Term Memory Deficits

Functional Correlates of Rumination

Functional Correlates of Anhedonia

Conclusions

Chapter 9. Integrating the Stress Systems and Neuroimaging in Depression

Introduction

Does the Hypothalamus-Pituitary-Adrenal (HPA) Axis Stress System Mediate the Morphological and Functional Brain Changes?

Immune System

Neurotrophic System

Serotonin and Genetics

Epigenetics

Overall Considerations

Chapter 10. Depression in Children and Adolescents

Background

Normal Brain Structural and Functional Development

Neuroendocrine Studies

Structural Brain Changes

Functional Brain Changes

Genetics

Final Remarks

Chapter 11. Systems Neuroscience in Late-Life Depression

Introduction

Functional Neuroanatomy Relevant to Late-Life Depression

Contributions Specific to Depression in Late-Life: Vascular Disease

Systems Neuroscience in Late-Life Depression

Simultaneous Network Activity

Functional Connectivity Underlying Behavior in Late-Life Depression

Apathy

Anxious-Depression

Suicidality

Conclusion

Chapter 12. Arousal Regulation in Affective Disorders

Introduction

Disturbed Arousal Regulation in Affective Disorders

Models of Arousal, Sleep, and Wakefulness Regulation

Assessment of Wakefulness Level and Sleepiness

EEG Vigilance as a Marker of Brain Arousal

The VIGALL

The Arousal Regulation Model of Affective Disorders

Conclusion

Index

Copyright

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Contributors

Deanna M. Barch

Program in Neuroscience, Washington University, St. Louis, MO, USA

Department of Psychiatry, Washington University, St. Louis, MO, USA

Department of Psychology, Washington University, St. Louis, MO, USA

Department of Radiology, Washington University, St. Louis, MO, USA

Christian F. Beckmann

Department of Cognitive Neuroscience, Radboud University Medical Centre, Nijmegen, The Netherlands

Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Nijmegen, The Netherlands

Oxford University Centre for Functional MRI of the Brain (FMRIB), Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK

Linda Booij

Department of Psychology, Concordia University, Montreal, QC, Canada

Sainte-Justine Hospital Research Centre, University of Montreal, Montreal, QC, Canada

Department of Psychiatry, McGill University, Montreal, QC, Canada

Dante Cicchetti,      Institute of Child Development, University of Minnesota, Minneapolis, MN, USA

Eleanor T. Coffey,      Turku Centre for Biotechnology, Åbo Akademi University and the University of Turku, Turku, Finland

Marika V. Doucet,      Neuropsychopharmacology Research Group, School of Pharmacy and Pharmaceutical Sciences, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland

Thomas Frodl

Department of Psychiatry and Psychotherapy, Otto von Guericke University, Magdeburg, Germany

Department of Psychiatry, Trinity College Dublin, Ireland

Andrew Harkin,      Neuropsychopharmacology Research Group, School of Pharmacy and Pharmaceutical Sciences, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland

Ulrich Hegerl

Department of Psychiatry and Psychotherapy, University of Leipzig, Leipzig, Germany

Research Centre of the German Depression Foundation, Leipzig, Germany

Tilman Hensch,      Department of Psychiatry and Psychotherapy, University of Leipzig, Leipzig, Germany

Tomoya Hirota,      Department of Psychiatry, Division of Child and Adolescent Psychiatry, University of California San Francisco, San Francisco, CA, USA

Melissa L. Levesque,      Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada

Kevin J. Manning,      Department of Psychiatry, University of Connecticut Health Center, Farmington, CT, USA

Fiona McNicholas

Department of Psychiatry, University College Dublin, Dublin, Ireland

Lucena Clinic, Dublin, Ireland

Department of Child Psychiatry, Our Lady's Children Hospital Crumlin, Dublin, Ireland

Gordana Milavić,      National and Specialist Services, Michael Rutter Centre, Maudsley Hospital, London, UK

Hasan Mohammad,      Turku Centre for Biotechnology, Åbo Akademi University and the University of Turku, Turku, Finland

Bernhard Mueller,      Department of Psychiatry and Psychotherapy, University Hospital Essen, Essen, Germany

Peter C. Mulders

Department of Psychiatry, Radboud University Medical Centre, Nijmegen, The Netherlands

Department of Cognitive Neuroscience, Radboud University Medical Centre, Nijmegen, The Netherlands

Norbert Müller,      Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University of Munich, Munich, Germany

Veronica O'Keane,      Department of Psychiatry, Trinity College, Dublin, Ireland

Eileen O'Toole,      Neuropsychopharmacology Research Group, School of Pharmacy and Pharmaceutical Sciences, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland

David Pagliaccio,      Program in Neuroscience, Washington University, St. Louis, MO, USA

Christian Sander

Department of Psychiatry and Psychotherapy, University of Leipzig, Leipzig, Germany

Research Centre of the German Depression Foundation, Leipzig, Germany

Eoin Sherwin,      Neuropsychopharmacology Research Group, School of Pharmacy and Pharmaceutical Sciences, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland

Norbert Skokauskas

Department of Psychiatry, Trinity College, Dublin, Ireland

Centre for Child and Adolescent Mental Health and Child Protection, Department of Neuroscience, Norges teknisk-naturvitenskapelige universitet NTNU, Trondheim, Norway

David C. Steffens,      Department of Psychiatry, University of Connecticut Health Center, Farmington, CT, USA

Moshe Szyf,      Department of Pharmacology, McGill University, Montreal, QC, Canada

Indira Tendolkar

Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands

Department of Psychiatry, Radboud University Medical Centre, Nijmegen, The Netherlands

Department of Psychiatry and Psychotherapy, University Hospital Essen, Essen, Germany

Philip F. van Eijndhoven

Department of Psychiatry, Radboud University Medical Centre, Nijmegen, The Netherlands

Department of Cognitive Neuroscience, Radboud University Medical Centre, Nijmegen, The Netherlands

Artemis Varidaki,      Turku Centre for Biotechnology, Åbo Akademi University and the University of Turku, Turku, Finland

Christina B. Young

Department of Psychology, Northwestern University, Evanston, IL, USA

Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands

Department of Psychiatry, Radboud University Medical Centre, Nijmegen, The Netherlands

The Systems Neuroscience Approach

Thomas Frodl ¹ , ² ,      ¹ Department of Psychiatry and Psychotherapy, Otto von Guericke University, Magdeburg, Germany,      ² Department of Psychiatry, Trinity College Dublin, Ireland

The current book gives an overview about the state in the field with regard to MDD. It reviews the literature from molecular and biological viewpoints and translates it in human experimental and clinical research.

Development of the systems perspective

Chronic social stress has been shown to induce glucocorticoid-mediated pyramidal dendrite retraction in the hippocampus and changes in dendrite arborization in the prefrontal cortex (Kole, Czeh, & Fuchs, 2004; Magarinos, McEwen, Flugge, & Fuchs, 1996; Wellman, 2001; Woolley, Gould, Frankfurt, & McEwen, 1990). Experimental studies have further shown that stress or cortisol administration may lead to atrophy of neurons in the hippocampus and to depressive-like states, (Duman, 2002) and therapy with antidepressants might reverse these changes (Santarelli et al., 2003).

Since the hippocampal structure was also found to be altered in depression, these stress-related changes seem to be associated with stress-related disorders like major depression (MacQueen & Frodl, 2011). Nowadays, we believe that depression is not associated with changes in single brain areas, but rather with changes in brain networks. Thus, there is evidence that specific neuronal circuits, particularly in the developing brain, are damaged by environmental stress-inducing changes in the hypothalamic-pituitary-adrenal (HPA) axis, inflammatory pathways, and affective and salience networks (Krishnan & Nestler, 2008).

Introduction to Major Depressive Disorder

Major depressive disorder (MDD) is one of the most prevalent and burdensome of all psychiatric illnesses associated with early stressors (Goetzel, Hawkins, Ozminkowski, & Wang, 2003; Murray & Lopez, 1996). The morbidity and mortality associated with MDD has a significant impact on individuals suffering from the illness as well as their families and society. The economic costs, which include reduced work productivity and lost leisure opportunities, are estimated to be €15.5   billion in the United Kingdom and €100   billion in the United States (Greenberg et al., 2003; Thomas & Morris, 2003). About 15% of patients with depression commit suicide (Jamison, 2000). The World Health Organization's World Health Report (2001, http://www.who.int/whr/2001/en/) expects that depression will lead to the second highest health burden internationally and will be the primary cause of disability and death in developed countries by the year 2020.

The diagnosis is based on clinical observations and reports by patients, caregivers, parents, and teachers. This approach has served to improve diagnostic reliability in clinical practice and research. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and the International Classification of Diseases-10 (ICD-10), which include the main diagnostic categories, are the main classification systems used for the diagnosis of mental disorders. Thus, diagnostics in psychiatry are not following an etiological viewpoint like many other medical disciplines. Instead, they are following phenomenological viewpoints, which are based on symptoms, syndromes, and disease courses.

Unfortunately, the diagnostic schemes have not assimilated breakthroughs in neuroscience. For example, most genetic and neural circuit anomalies are associated with symptoms that are common to multiple DSM diagnostic categories. Diagnoses made of self-reported and observer-rated symptoms might therefore constrain advances in research on the biology of mental illness. Notwithstanding these difficulties, there is a general consensus that the biology of mental illness is insufficiently developed to support a classification scheme based on the integration of genetics, neuroscience, and psychopathology (see http://www.nimh.nih.gov/research-priorities/rdoc/index.shtml).

Therapy

Psychological and pharmacological therapies are the most common forms of treatment. The most frequently applied form of psychotherapy is cognitive behavioral therapy (CBT), which is an effective therapy against depression. Here, the assumption that a person's mood is directly related to his or her patterns of thought is the basis for therapy. Negative, dysfunctional thinking affects a person's mood, behavior, and physical state. The goal of CBT is to help a person learn to recognize negative patterns of thought, evaluate their validity, and replace them with healthier ways of thinking and to change patterns of behavior.

Moreover, cognitive behavioral activation therapy is widely used and combines cognitive methods with positive activities and exercise, since exercise was found to have antidepressant effects on its own. Many other psychotherapy modules have been described as effective, including the Cognitive Behavioral Analysis System of Psychotherapy, interpersonal psychotherapy, and strategic short-term psychotherapy. In particular, when trauma-related interpersonal and personality development problems exist, more attention needs to be paid to these issues during psychotherapy. Understanding of the brain systems involved in depression is helpful not only for developing new antidepressant targets but also for the development of psychotherapies, e.g., those involving the interplay between body and mind.

Antidepressant medications improve depressive symptoms by modulating the monoamine neurotransmitter systems. The selective serotonin reuptake inhibitors (SSRI) class has become the most commonly prescribed (Ilyas & Moncrieff, 2012). Systems relevant for MDD are the serotonergic, noradrenergic, and dopaminergic systems as well as the glutamatergic and GABAergic system with known effects on depressive behavior.

There is evidence that the pathophysiology of depression involves low levels of serotonin, noradrenaline, and/or dopamine levels in the central nervous system (Carlsson, Corrodi, Fuxe, & Hokfelt, 1969). Depression involves dysfunctional glutamate signaling in the brain, which leads to impaired neuroplasticity (Duman, 2014). Moreover, depression is associated with hyperactivation of the cholinergic system and as a consequence decreased activity in the noradrenergic system (Drevets, Zarate, & Furey, 2013). Furthermore, reduced GABA neurotransmission in cortical circuits was also detected (Pehrson & Sanchez, 2015).

Tricyclic antidepressants (TCA) and monoamine oxidase (MAO) inhibitors were discovered first. SSRIs and serotonin and noradrenaline reuptake inhibitors (SNRIs) were later conceived mainly to improve the tolerability of TCAs. Since the discovery of SSRIs and serotonin and noradrenaline reuptake inhibitors (SNRIs), one strategy in antidepressant research has been to expand on the monoaminergic mechanisms by targeting monoaminergic receptors or additional transporters in one molecule. The main objectives have been to improve efficacy and/or reduce the time to onset the therapeutic effect of SSRIs and SNRIs. The interest in glutamate targets precipitated from the spectacular clinical finding that intravenous infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine can produce an immediate antidepressant effect in patients with treatment-resistant depression (Berman et al., 2000). Several other glutamate targets have been defined, some of which have been tested in the clinic.

Brain stimulation therapies involve activating the brain directly with electricity, magnets, or implants to treat depression and other disorders. Electroconvulsive therapy is the most researched stimulation therapy, has the longest history of use, and has strong evidence for therapy-resistant depression. Other stimulation therapies like vagus nerve stimulation, repetitive transcranial magnetic stimulation (rTMS), and magnetic seizure therapy have more regional and local effects and are thought to have less side effects, e.g., on cognitive functioning. The US Food and Drug Administration approved rTMS as a therapy for treatment-resistant depression and vagus nerve stimulation for use in treating major depression in certain circumstances—if the illness has lasted 2 years or more, if it is severe or recurrent, and if the depression has not eased after trying at least four other treatments. Within a systems neuroscience perspective it is thought that when one key area in a brain system is influenced it has effects on the whole system as well as other interrelated brain systems.

Deep brain stimulation (DBS), which was first developed as a treatment for Parkinson disease to reduce tremors, stiffness, walking problems, and uncontrollable movements, has been studied as a treatment for depression. DBS is available on an experimental basis only.

Involved Systems

HPA Axis and the Immune System

Many research studies in the field of immunology and psychiatry have reported the association between immune system changes detected in the peripheral blood or tissue or in cerebrospinal fluid and related changes in the brain in terms of imaging findings or postmortem findings. Several findings have been reported regarding the link between immune system changes, psychological abnormalities, and impairment in other systems such as energy metabolism (Myint & Kim, 2014). Moreover, changes to immune molecules in the brain are also reported to be associated with other neurochemical changes, such as serotonergic, noradrenergic, GABAergic, glutamatergic neurotransmissions, and stress hormones. Some studies have reported metabolisms such as tryptophan/kynurenine metabolism and tyrosine metabolism as the link between changes in the immune system and other neurochemicals. These results have provided the missing links between the glial–neuronal network and opportunities to develop new therapeutics and biomarkers in the field of psychiatry (Myint & Kim, 2014).

Furthermore, it was shown that both physiological and psychological stress can induce an increased production of proinflammatory mediators that can stimulate tryptophan catabolism in the brain (Myint, Schwarz, & Muller, 2012). Cytokines modulate the balance between humoral and cell-based immune responses and regulate the maturation, growth, and responsiveness of cells. They are known to have central effects, either crossing the blood–brain barrier or through the transmission of signals across the vagus nerve (Dantzer, O'connor, Freund, Johnson, & Kelley, 2008). In this regard, it has been suggested that cytokines could influence reward processing and promote the increase of depressive symptoms through altered activity of dopaminergic and serotonergic systems (Ikemoto & Panksepp, 1999; Ressler & Nemeroff, 2000). Interestingly, proinflammatory cytokines can contribute to glutamate toxicity, also stimulating microglial cells to release interleukin (IL)-1 and tumor necrosis factor alpha (TNF-α) (reviewed in McNally, Bhagwagar, & Hannestad, 2008).

In MDD, activity of the tryptophan/kynurenine pathway has been shown to modulate inflammatory processes, with kynurenine being directly associated with depressive symptoms and/or cognitive loss (Oxenkrug, 2007). Products of the kynurenine pathway include NMDA agonists (e.g., quinolinic and picolinic acids) (Jhamandas, Boegman, Beninger, Miranda, & Lipic, 2000) and antagonists as well as free radical generators, e.g., 3-hydroxykynurenine and 3-hydroxyanthranilic acids (Forrest et al., 2004; Thomas & Stocker, 1999).

Neuroimaging and Neuroimaging Genetics in MDD

Neuroimaging techniques are important in order to characterize neural circuits built from different areas in the brain and relevant for certain brain functions. Here structural, functional, and diffusion imaging in MDD will be briefly reviewed.

Structural Imaging in MDD

Studies in humans strengthen the evidence that MDD is associated with structural changes. Many structural imaging studies have reported that the hippocampus is small in patients with MDD. A recent meta-analysis of hippocampal volumes in patients with MDD confirmed that patients had hippocampal volumes that were approximately 4–6% smaller than matched control subjects in the left and right hippocampus. The analysis included 1167 patients and 1088 control subjects across a wide range of ages from pediatric to geriatric populations (McKinnon, Yucel, Nazarov, & MacQueen, 2009). Conclusions from this meta-analysis were consistent with the findings of earlier meta-analyses of hippocampal volume in patients with MDD (Campbell, Marriott, Nahmias, & MacQueen, 2004; Videbech & Ravnkilde, 2004). A meta-analysis over 226 studies found areas affected in MDD to be the hippocampus, basal ganglia, and orbitofrontal cortex, in particular the gyrus rectus (Kempton et al., 2011). The above-mentioned associations between glucocorticoids and stress and neuronal damage in the hippocampus indicate that the neurotoxic effects of glucocorticoids on the hippocampus can be visualized in terms of overall volume changes. Evidence from neuroimaging, neuropathological, and lesion analysis studies further implicates limbic-cortical-striatal-pallidal-thalamic circuits, including orbitomedial prefrontal cortex, amygdala, ventromedial striatum, mediodorsal, and midline thalamic nuclei and ventral pallidum in the pathophysiology of mood disorders (Miller, SaintMarie, Breier, & Swerdlow, 2010).

In line with the glucocorticoid cascade theory are some longitudinal imaging studies. In a longitudinal study on 30 patients with MDD and 30 healthy controls it was demonstrated that a negative clinical outcome with more relapses and a chronic course during a 3-year follow-up was associated with hippocampal, amygdala, anterior cingulate cortex, and dorsomedial prefrontal cortex volume decline (Frodl, Koutsouleris, et al., 2008). In a long-term follow-up study it was evaluated whether any possible difference in hippocampal volume and brain structure between depressed in-patients and healthy controls at inclusion disappeared over an 11-year period when the patients were in remission. At baseline, patients had smaller volumes in the right and left superior and middle temporal gyri, medulla, and body of the right hippocampus. At follow-up, there were no significant local brain differences between patients and controls. In a group of 19 patients and 19 controls who were investigated at baseline and follow-up, no significant hippocampal volume differences were detected (Ahdidan et al., 2011). While the cross-sectional parts of the study are well powered, for the longitudinal part of the study a larger sample would have been desirable, since a sample of 19 seems to not have enough power to detect small changes in brain structure. Moreover, during successful treatment brain structures like the left inferior frontal cortex, right fusiform gyrus, and right cerebellum increased in size (Lai & Hsu, 2011). On the other hand, smaller hippocampal volumes were also found to be predictive of a poor clinical outcome in 1- and 3-year follow-up studies and also for response to a course of antidepressant therapy (Frodl et al., 2004; MacQueen & Frodl, 2011). Therefore, a predisposition to depression might be associated with smaller hippocampal volumes, which might further decline during the course of a chronic depression but normalize during remission. However, this is speculative at this stage and needs to be investigated in studies with longitudinal designs.

Functional Neuroimaging

Functional magnetic resonance imaging (fMRI) studies examining neural responses to emotional stimuli in patients with major depression indicated increased responses in the amygdala, anterior cingulum (ACC), fusiform gyrus, putamen, and prefrontal cortical regions (Frodl et al., 2007; Fu et al., 2004; Surguladze et al., 2005). Since many researchers assume that the depressive syndrome might arise from abnormal interactions between brain regions, functional neuroimaging studies have examined the connectivity of the neural network. With respect to connectivity, a study in 15 unmedicated patients with major depression and 15 healthy volunteers found decreased correlations between ACC and limbic regions, which is consistent with the hypothesis that decreased cortical regulation of limbic activation in response to negative stimuli may be present in depression (Anand et al., 2005). Again the amygdala was not only negatively coupled with the ACC but also positively coupled bilaterally with medial temporal and ventral occipital regions in 19 unmedicated patients with major depression and 19 healthy volunteers (Chen et al., 2008). Studies on functional connectivity in patients with major depression receiving antidepressant medication achieved varied results. The results indicated that a neural network consisting of the cingulate region, prefrontal cortical regions, amygdala, and subcortical regions may play key roles in MDD: compared to healthy controls, patients with depression showed increased functional connectivity between the amygdala, hippocampus, and caudate–putamen regions during emotion processing (Hamilton & Gotlib, 2008) but significantly reduced amygdala–prefrontal connectivity (Dannlowski et al., 2009). Uncoupling of the prefrontal cortex and gyrus cinguli was found in 14 patients with MDD and 14 healthy controls during a verbal working memory task (Vasic, Walter, Sambataro, & Wolf, 2008).

In 25 drug-free patients with MDD as compared to 15 healthy controls, dorsal anterior cingulate cortex, precuneus, and cerebellum activity showed less connectivity with the orbitofrontal cortex (OFC) in patients than in controls, while functional connectivity between the OFC and the right dorsolateral prefrontal cortex, right inferior frontal operculum, and left motor areas was increased in patients as compared to healthy controls (Frodl, Bokde, et al., 2010).

Interest is growing in the use of resting state fMRI, which does not require the use of a task and which has become a popular means of complementing the results of task-based fMRI studies. Resting state fMRI allows for the examination of large-scale neural systems that exhibit spontaneous synchronous fluctuations during goal-directed and nongoal-directed behavior (Castellanos & Proal, 2012). These low-frequency (<0.1 Hz) spontaneous fluctuations in blood oxygenated level-dependent (BOLD) signals correlate with interactions between adjacent and nonadjacent brain areas that form spatially distributed networks of brain function (Raichle et al., 2001). Functional connectivity is the observed correlation in spontaneous neural activity between brain areas at rest (Deco & Corbetta, 2011). Several resting state studies have found increased resting state functional connectivity in the cognitive control network (Sheline et al., 2009; Zhou et al., 2010), increased connectivity in the default mode network (Grimm et al., 2009; Sheline et al., 2010; Zhou et al., 2010), and increased functional connectivity in the affective network (Sheline et al., 2010).

Resting state fMRI demonstrated that subgenual cingulate and thalamic functional connectivity were significantly increased in 20 patients with MDD as compared to 20 healthy controls (Greicius, Supekar, Menon, & Dougherty, 2009).

Diffusion Imaging in MDD

Structural neuroimaging studies in MDD show volume reductions, and functional imaging studies indicate disconnectivity in the limbic and frontal brain regions. Whether or not white matter fiber bundles between limbic and frontal brain regions are altered can be investigated with diffusion tensor imaging (DTI).

Magnetic resonance DTI is a novel neuroimaging technique that can evaluate both the orientation and the diffusion characteristics of white matter tracts in vivo (Sexton, Mackay, & Ebmeier, 2009). DTI represents the forefront of neuroimaging techniques in the characterization of microstructural alterations (Frodl, Carballedo, et al., 2012). These findings appear to be heterogeneous, and therefore we conducted a meta-analysis of seven available studies, including 188 patients with MDD and 221 healthy controls. Patients with depression showed decreased white matter fractional anisotropy (FA) values in the superior longitudinal fasciculus (SLF) and increased FA values in the fronto-occipital fasciculus as compared to controls. In conclusion, the meta-analysis revealed a significant reduction in FA values in the left SLF, which may ultimately play an important role in the pathology of depression. More research in larger samples is needed to track changes during the disease course using DTI (Murphy & Frodl, 2011). Another meta-analysis of DTI studies of patients with MDD consistently identified decreased fractional anisotropy in the white matter fascicles connecting the prefrontal cortex within the frontal, temporal, and occipital lobes as well as the amygdala and hippocampus (Liao et al., 2013).

Some studies were carried out to investigate certain clinical characteristics. With respect to remission status in MDD, findings are inconclusive. Interestingly, remitted MDD patients revealed decreased mean diffusivity and increased fractional anisotropy within the left amygdala, which may be interpreted as a greater cell density and increased number of fibers, respectively. This last notion was supported by probabilistic tractography results, which revealed increased connectivity from the left amygdala to the hippocampus, cerebellum, and brain stem in remitted as compared to nonremitted patients (Arnold et al., 2012). A study comparing 13 patients with late-life depression to matched healthy controls found a reduction in FA in both the frontal and temporal lobes of depressed patients (Nobuhara et al., 2006). In addition, an inverse relationship was established between FA values and symptom severity (Nobuhara et al., 2006).

Importantly, reductions in FA have also been associated with early life adversity in the form of disrupted maternal–infant attachment and correlate with an increased risk of both anxiety and depression (Coplan et al., 2010). A study comparing 12 maternally deprived adult male macaques to nine normally reared controls found significant reductions in FA in the anterior limb of the internal capsule in the maternally deprived macaques (Coplan et al., 2010). This is another brain region that is important in emotional regulation and is involved in the medial and the basolateral limbic circuits (Coplan et al., 2010). Thus, disruption of this region may alter functional connectivity between the frontal and temporal lobes, conferring an increased risk of MDD (Coplan et al., 2010). Another study demonstrating the microstructural implications of early life adversity found significantly reduced FA within the genu of the corpus callosum among those exposed to high levels of early life stress (Paul et al., 2008). We have demonstrated that first-degree relatives of patients with MDD who managed to stay healthy showed greater fractional anisotropy than controls in the body and splenium of the corpus callosum, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, and fornix, suggesting adaptive and protective mechanisms (Frodl et al., 2012).

Imaging Genetics

In functional models of MDD, overactivity in limbic areas like the amygdala, anterior cingulate cortex, and hippocampus is not adequately controlled by prefrontal areas (Mayberg et al., 1999). A meta-analysis of functional MRI studies support the involvement of these brain regions in MDD (Graham et al., 2013). A review about the impact of genetic variations on brain function concluded that genetic variants are associated with brain function in MDD (Scharinger, Rabl, Sitte, & Pezawas, 2010). Most evidence comes from genes involved in the regulation of the 5-HT system, especially with regard to the 5-HT transporter gene (SLC6A4). For instance, short allele carriers of the promoter polymorphism of the serotonin transporter gene commonly known as 5-HTTLPR have increased amygdala reactivity to masked emotional faces in 35 patients with MDD (Dannlowski et al., 2007).

Vulnerability models suggest that within the etiology of depression, environmental (e.g., stress) factors and genetic factors are supposed to interact, thereby altering the brain structure and function. In a first step it has been shown that genetic polymorphisms of the serotonin transporter gene affect hippocampal structure (Frodl, Zill, et al., 2008) and amygdala brain function (Hariri et al., 2002). We demonstrated that a genetic polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) interacts and influences hippocampal volumes measured with MRI (Frodl, Reinhold, Koutsouleris, Donohoe, et al., 2010). Moreover, in an independent sample, hippocampal volume changes, which are related to a depressive vulnerability due to changes in neurocognitive processes (Gerritsen et al., 2012) and plasticity (MacQueen & Frodl, 2011), are caused by interactive effects of childhood adversity and genetic variation (Everaerd et al., 2012). It was further demonstrated—on top of the well-known finding of an increased risk of developing disorders like MDD due to childhood maltreatment—that childhood maltreatment affects the brain structure with respect to regional gray matter volume (Chaney et al., 2014; Frodl, Reinhold, Koutsouleris, Reiser, & Meisenzahl, 2010) and white matter tractography (Ugwu, Amico, Carballedo, Fagan, & Frodl, 2014). As variations in the mineralocorticoid receptor gene (NR3C2) have been related to a higher risk for depression, it was investigated whether NR3C2 variance is related to negative memory bias, an established endophenotype for depression, in healthy participants (Vogel et al., 2014). Furthermore, the influence of life adversity on the association between NR3C2 and negative memory bias was demonstrated. A set-based analysis was used to simultaneously test all measured variations in NR3C2 for an association with negative memory bias in 483 participants and an interaction with life adversity. To further specify this interaction, the sample was split into low and high live adversity groups and the analyses was repeated separately in both groups. NR3C2 variance was associated with negative memory bias, especially in the high life adversity group. Additionally, a functional polymorphism (rs5534) related to negative memory bias demonstrated a gene by life adversity interaction. Variations in NR3C2 are associated with negative memory bias, and this relationship appears to be influenced by life adversity (Vogel et al., 2014).

Studies showed that genes relevant for depression, like the serotonin transporter and glucocorticoid genes, and early life stress interact and influence the development of depression and affect brain structure and function (Bermingham et al., 2012; Frodl, Reinhold, Koutsouleris, Donohoe, et al., 2010). The mechanisms through which these interactive effects seem to be mediated seem to be epigenetics like methylation of DNA. The study of epigenetics in depression is at its start. In healthy subjects, an association was found between methylation of the serotonin transporter polymorphism and brain serotonin synthesis measured with positron emission tomography (Wang et al., 2012). Subjects committing suicide and having a history of early life adversity had higher methylation of glucocorticoid receptor genes as compared to subjects committing suicide without a history of early life adversity. Interestingly, this higher methylation was associated with a decreased expression of glucocorticoid receptor proteins in the hippocampus (McGowan et al., 2009).

Longitudinal Imaging Changes

It is well established from cross-sectional studies that patients with MDD have impaired glucocorticoid receptor functioning, increased circulating concentrations of inflammatory cytokines and C-reactive protein (CRP), and reduced hippocampal volumes, in particular in the hippocampal subfields CA1, CA2-CA3, and subiculum (Frodl & O'Keane, 2013; MacQueen & Frodl, 2011). Experimental studies in animals demonstrate that neuroplastic changes occur during the onset of depressive-like states, indicating that dysfunction of neuronal plasticity might potentially contribute to the pathophysiology of MDD (Duman, 2002). In animal models, glucocorticoid administration induces increases in neural cell death, reductions in brain-derived neurotrophic factor (BDNF), atrophy of neuronal processes, a reduction of hippocampal neurogenesis, and ultimately a reduction in hippocampal volume (Sapolsky, 2002). On the other hand, antidepressant therapy seems to increase hippocampal neurogenesis in rats (Santarelli et al., 2003) and restore homeostasis of the inflammatory and HPA axis systems. Glucocorticoids, via a process of repression of gene transcription, inhibit the key target genes in the inflammatory system such as IL-1β, IL-6, TNF α, and cyclo-oxygenase-2 (COX-2) (De Bosscher & Haegeman, 2009).

These experimental findings are being translated into clinical investigations. The first longitudinal long-term structural neuroimaging studies in humans with MDD found that the hippocampus, prefrontal cortex, and anterior cortex cinguli decline in patients developing a chronic depression (Frodl, Koutsouleris, et al., 2008), which seems to be related to neuroplastic processes. Moreover, we demonstrated that a smaller total hippocampal volume was related to a poor clinical outcome and that hippocampal volumes increased in patients with MDD under continuous therapy with antidepressants (Frodl et al., 2004). In a pilot study, 27 patients with treatment-resistant MDD were investigated at baseline and at follow-up, when they either achieved 6   months of sustained remission or 12   months of failure to remit. The 12 patients who achieved sustained 6-month remission demonstrated a significant mean increase in whole-brain volume in the right orbitofrontal cortex and the right inferior temporal gyrus as compared to nonremitted patients (Phillips, Batten, Aldosary, Tremblay, & Blier, 2012). Similar to our longitudinal study (Frodl, Koutsouleris, et al., 2008) nonremitters showed decreased brain volumes, although here in the white matter volume in the left anterior limb of the internal capsule. However, these previous studies only investigated brain structure and had limitations of a small sample size, so novel studies are necessary that also investigate brain function and structural connectivity using DTI and explore relationships to the stress hormone system and inflammation.

A few longitudinal antidepressant trials have previously investigated BOLD-responses due to emotional stimuli processing using fMRI. We found a significant decrease of BOLD-responses in the hippocampus, basal ganglia, thalamus, and cerebellum of venlafaxine (serotonin and noradrenaline reuptake inhibitor)-treated patients and a significant increase in BOLD-responses in the middle gyrus cinguli and supplementary motor area of mirtazapine (selective serotonin and norepinephrine reuptake inhibitor)-treated patients, indicating different locations of actions for different treatment strategies (Frodl, Scheuerecker, et al., 2011). A meta-analysis summarized the results of nine fMRI studies and showed that antidepressant treatment resulted in an increase of BOLD-responses of dorsolateral, dorsomedial, and ventrolateral prefrontal cortices, whereas subcortical regions and those related to emotion processing like amygdala, hippocampus, parahippocampus, cingulate cortex, orbitofrontal cortex, insula, and precuneus decreased in BOLD-responses (Delaveau et al., 2011). However, to our knowledge longitudinal studies using fMRI investigating the long-term effects of MDD are missing.

Outline of Systems Neuroscience in Depression

The book starts with brain development, early life changes, and how early life stressors alter brain function and structure. In the first chapter, D. Cichetti and colleagues examine how the principles of a multilevel developmental psychopathology systems perspective provide insight into understanding the etiology, course, and sequelae of depressive disorders. Here depression is of particular interest to developmental psychopathologists because of the complex interplay of psychological (affective, cognitive, interpersonal) and biological (genetic, neurobiological, neurophysiological) systems that are involved. The knowledge about normative development and functioning will provide a background to characterize deviations evident among those with depression. In addition, pathways to resilience are discussed that represent competent adaptation despite the experience of significant adversity, and approaches for prevention are examined.

In the second chapter, D. Pagliaccio and D. Barch focus on the role of stress in the development of major depression and highlight within an integrated view other possible factors influencing the association between stress and depression. It is well known that the experience of stressful life events, comorbidity, genetic risk, and low social support can all contribute to ineffective treatment and treatment resistance. As such, understanding the role of factors such as stress in the etiological mechanisms underlying depression may be key to improved treatment and diagnostics. In the chapter, literature on the link between stressors and depression as well as potential mediators of this relationship is reviewed. The authors discuss a mechanism implicit in much of the literature, namely that childhood stress leads to alterations in cortisol function, which in turn leads to alterations in the brain that contribute to the risk for MDD.

Ultimately this leads to a chapter (T. Hirota, G. Milavić, F. McNicholas, T. Frodl, and N. Skokauskas) reviewing knowledge about child and youth depression and the current state of system neuroscience within the discipline. The development timeline of brain regions is discussed in terms of structural and functional brain changes in children and youth with depression. There is a clear trend that despite a growing body of research into the neurobiological correlates of depression, the evidence in children and adolescents is limited to the extent that no firm conclusions may yet be drawn.

Three chapters explore the underlying molecular backgrounds including genetics and epigenetics of depression. It is well investigated that long-term stress exposure leads to dendritic atrophy and atypical synaptic connections in regions controlling emotions, like the amygdala, prefrontal cortex, and hippocampus, and contributes to the development of depression.

A. Varidaki, H. Mohammad, and E.T. Coffey describe important findings from animal models of depression and postmortem tissues of subjects with mood disorders. They highlight how deregulated BDNF and NMDA disturb cellular signaling and dendritic spine plasticity in depression. Downstream effectors, including small GTPases and synaptic proteins, and the mechanisms whereby they regulate spine plasticity are reviewed. Also, the function of protein kinases LIMK, mTOR, MAPK, CamKII, SGK1, and GSK-3 in the pathophysiology of depression is discussed.

The book then moves toward an understanding of molecular and biological alterations affecting neural systems in depression and its rational toward developing new targets for antidepressant treatment. Here, E. O'Toole, M.V. Doucet, E. Sherwin, and A. Harkin review the glutamatergic system and its relevance for MDD. The NMDA-R antagonist ketamine has repeatedly shown rapid and sustained antidepressant effects following a single dose in a number of clinical studies. Since the adverse effects associated with ketamine limit its wider use in the clinic, investigations are instead aimed at developing cleaner ketamine compounds that could demonstrate a fast onset of action and sustained efficacy, without incurring adverse effects. In this regard, targets located downstream of the NMDA-R, such as nitric oxide synthase, may represent novel avenues for treating neuropsychiatric disorders. Here, the authors review the rationale for the development of glutamate and nitric oxide-modulating drugs for treating depression and highlight findings in the field, which provide a basis for ongoing drug development.

Since MDD is a heterogeneous disorder, in which many neurobiological systems have been shown to be involved, it is important to also consider genetic and environmental factors together that are underlying physiological mechanisms. In the chapter by M. Levesque, M. Szyf, and L. Booij, the gene by environment interaction model is described, and evidence that early adverse exposures are associated with epigenetic alterations in specific physiological systems relevant to MDD, including the serotonin system, the HPA axis, BDNF, and the immune system, is outlined. The authors also discuss the stability of epigenetic mechanisms and the methodological challenges encountered when studying epigenetic mechanisms in humans.

The inflammatory system was also found to be altered in patients with MDD as compared to healthy controls. So, high levels of several proinflammatory components of the immune system such as IL-6, CRP, TNF-α, or neopterin in patients suffering from MDD point to the involvement of an inflammatory process