During the last 20 years of neuroscience research, we have witnessed a fundamental shift in the conceptualization of psychiatric disorders, with the dominant psychological and neurochemical theories ...of the past now complemented by a growing emphasis on developmental, genetic, molecular, and brain circuit models. Facilitating this evolving paradigm shift has been the growing contribution of functional neuroimaging, which provides a versatile platform to characterize brain circuit dysfunction underlying specific syndromes as well as changes associated with their successful treatment. Discussed here are converging imaging findings that established a rationale for testing a targeted neuromodulation strategy, deep brain stimulation, for treatment-resistant major depression.
The link between dysregulated serotonergic activity and depression and anxiety disorders is well established, yet the molecular mechanisms underlying these psychopathologies are not fully understood. ...Here, we explore the role of microRNAs in regulating serotonergic (5HT) neuron activity. To this end, we determined the specific microRNA “fingerprint” of 5HT neurons and identified a strong microRNA-target interaction between microRNA 135 (miR135), and both serotonin transporter and serotonin receptor-1a transcripts. Intriguingly, miR135a levels were upregulated after administration of antidepressants. Genetically modified mouse models, expressing higher or lower levels of miR135, demonstrated major alterations in anxiety- and depression-like behaviors, 5HT levels, and behavioral response to antidepressant treatment. Finally, miR135a levels in blood and brain of depressed human patients were significantly lower. The current results suggest a potential role for miR135 as an endogenous antidepressant and provide a venue for potential treatment and insights into the onset, susceptibility, and heterogeneity of stress-related psychopathologies.
•miRs “fingerprint” of 5HT neurons position miR135 as potent regulator of 5HT system•miR135a levels are upregulated following 5HT-linked antidepressants treatment•miR135 levels in vivo influence behavior, 5HT levels, and antidepressant treatment•Lower levels of miR135a in blood and brain of depressed human patients
Issler et al. identify microRNA135 as potent regulator of serotonergic activity known to be associated with depression and anxiety disorders and suggest a role for miR135 as an endogenous antidepressant and provide a venue for potential treatment and insights into stress-related psychopathologies.
The current definition of major depressive disorder (MDD) emerged from efforts to create reliable diagnostic criteria for clinical and research use. However, despite decades of research, the ...neurobiology of MDD is largely unknown, and treatments are no more effective today than they were 50–70 years ago. Here, we propose that the current conception of depression is misguiding basic and clinical research. Redefinition is necessary and could include a focus on a more narrowly defined set of core symptoms. However, we conclude that depression is better defined as the tendency to enter into, and inability to disengage from, a negative mood state rather than the mood state per se . We also discuss the implications of this revised definition for future clinical and basic research.
...depression is a heterogeneous entity experienced with various combinations of signs and symptoms, severity levels, and longitudinal trajectories. ...core features of the condition have been ...described over thousands of years, long before the advent of contemporary classifications, and in diverse communities and cultures. More efficient prevention of depression is likely to have powerful impacts on the Sustainable Development Goals for a country and the health of individuals and families. 5 The experiences of depression and recovery are unique for each individual Depression is the result of a set of factors, typically the interaction of proximal adversities with genetic, social, environmental, and developmental risk and resilience factors. Empowering individuals, families, and communities to work with professionals who can learn from their experiences and help demand the implementation of known preventive and therapeutic strategies and to hold health-care systems and decision makers accountable is vital. 7 A formulation is needed to personalise care Detection and diagnosis of depression on the basis of symptoms, function, and duration should be accompanied by a clinical review or formulation for each person, which takes into account individual values and preferences, life stories, and circumstances.
Recent decades have witnessed tremendous advances in the neuroscience of emotion, learning and memory, and in animal models for understanding depression and anxiety. This review focuses on new ...rationally designed psychiatric treatments derived from preclinical human and animal studies. Nonpharmacological treatments that affect disrupted emotion circuits include vagal nerve stimulation, rapid transcranial magnetic stimulation and deep brain stimulation, all borrowed from neurological interventions that attempt to target known pathological foci. Other approaches include drugs that are given in relation to specific learning events to enhance or disrupt endogenous emotional learning processes. Imaging data suggest that common regions of brain activation are targeted with pharmacological and somatic treatments as well as with the emotional learning in psychotherapy. Although many of these approaches are experimental, the rapidly developing understanding of emotional circuit regulation is likely to provide exciting and powerful future treatments for debilitating mood and anxiety disorders.
Medications, psychotherapy, and other treatments are effective for many patients with psychiatric disorders. However, with currently available interventions, a substantial number of patients ...experience incomplete resolution of symptoms, and relapse rates are high. In the search for better treatments, increasing interest has focused on focal neuromodulation. This focus has been driven by improved neuroanatomical models of mood, thought, and behavior regulation, as well as by more advanced strategies for directly and focally altering neural activity. Deep brain stimulation (DBS) is one of the most invasive focal neuromodulation techniques available; data have supported its safety and efficacy in a number of movement disorders. Investigators have produced preliminary data on the safety and efficacy of DBS for several psychiatric disorders, as well. In this review, we describe the development and justification for testing DBS for various psychiatric disorders, carefully consider the available clinical data, and briefly discuss potential mechanisms of action.
Biomarkers have transformed modern medicine but remain largely elusive in psychiatry, partly because there is a weak correspondence between diagnostic labels and their neurobiological substrates. ...Like other neuropsychiatric disorders, depression is not a unitary disease, but rather a heterogeneous syndrome that encompasses varied, co-occurring symptoms and divergent responses to treatment. By using functional magnetic resonance imaging (fMRI) in a large multisite sample (n = 1,188), we show here that patients with depression can be subdivided into four neurophysiological subtypes ('biotypes') defined by distinct patterns of dysfunctional connectivity in limbic and frontostriatal networks. Clustering patients on this basis enabled the development of diagnostic classifiers (biomarkers) with high (82-93%) sensitivity and specificity for depression subtypes in multisite validation (n = 711) and out-of-sample replication (n = 477) data sets. These biotypes cannot be differentiated solely on the basis of clinical features, but they are associated with differing clinical-symptom profiles. They also predict responsiveness to transcranial magnetic stimulation therapy (n = 154). Our results define novel subtypes of depression that transcend current diagnostic boundaries and may be useful for identifying the individuals who are most likely to benefit from targeted neurostimulation therapies.
Background Subcallosal cingulate white matter (SCC) deep brain stimulation (DBS) is an evolving investigational treatment for depression. Mechanisms of action are hypothesized to involve modulation ...of activity within a structurally defined network of brain regions involved in mood regulation. Diffusion tensor imaging was used to model white matter connections within this network to identify those critical for successful antidepressant response. Methods Preoperative high-resolution magnetic resonance imaging data, including diffusion tensor imaging, were acquired in 16 patients with treatment-resistant depression, who then received SCC DBS. Computerized tomography was used postoperatively to locate DBS contacts. The activation volume around the contacts used for chronic stimulation was modeled for each patient retrospectively. Probabilistic tractography was used to delineate the white matter tracts traveling through each activation volume. Patient-specific tract maps were calculated using whole-brain analysis. Clinical evaluations of therapeutic outcome from SCC DBS were defined at 6 months and 2 years. Results Whole-brain activation volume tractography demonstrated that all DBS responders at 6 months ( n = 6) and 2 years ( n = 12) shared bilateral pathways from their activation volumes to 1) medial frontal cortex via forceps minor and uncinate fasciculus; 2) rostral and dorsal cingulate cortex via the cingulum bundle; and 3) subcortical nuclei. Nonresponders did not consistently show these connections. Specific anatomical coordinates of the active contacts did not discriminate responders from nonresponders. Conclusions Patient-specific activation volume tractography modeling may identify critical tracts that mediate SCC DBS antidepressant response. This suggests a novel method for patient-specific target and stimulation parameter selection.
Sexual dysfunction is a common clinical symptom in women who were victims of childhood sexual abuse. The precise mechanism that mediates this association remains poorly understood. The authors ...evaluated the relationship between the experience of childhood abuse and neuroplastic thinning of cortical fields, depending on the nature of the abusive experience.
The authors used MRI-based cortical thickness analysis in 51 medically healthy adult women to test whether different forms of childhood abuse were associated with cortical thinning in areas critical to the perception and processing of specific behavior implicated in the type of abuse.
Exposure to childhood sexual abuse was specifically associated with pronounced cortical thinning in the genital representation field of the primary somatosensory cortex. In contrast, emotional abuse was associated with cortical thinning in regions relevant to self-awareness and self-evaluation.
Neural plasticity during development appears to result in cortical adaptation that may shield a child from the sensory processing of the specific abusive experience by altering cortical representation fields in a regionally highly specific manner. Such plastic reorganization may be protective for the child living under abusive conditions, but it may underlie the development of behavioral problems, such as sexual dysfunction, later in life.
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