Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression

The neural networks that putatively modulate aspects of normal emotional behavior have been implicated in the pathophysiology of mood disorders by converging evidence from neuroimaging, neuropathological and lesion analysis studies. These networks involve the medial prefrontal cortex (MPFC) and closely related areas in the medial and caudolateral orbital cortex (medial prefrontal network), amygdala, hippocampus, and ventromedial parts of the basal ganglia, where alterations in grey matter volume and neurophysiological activity are found in cases with recurrent depressive episodes. Such findings hold major implications for models of the neurocircuits that underlie depression. In particular evidence from lesion analysis studies suggests that the MPFC and related limbic and striato-pallido-thalamic structures organize emotional expression. The MPFC is part of a larger “default system” of cortical areas that include the dorsal PFC, mid- and posterior cingulate cortex, anterior temporal cortex, and entorhinal and parahippocampal cortex, which has been implicated in self-referential functions. Dysfunction within and between structures in this circuit may induce disturbances in emotional behavior and other cognitive aspects of depressive syndromes in humans. Further, because the MPFC and related limbic structures provide forebrain modulation over visceral control structures in the hypothalamus and brainstem, their dysfunction can account for the disturbances in autonomic regulation and neuroendocrine responses that are associated with mood disorders. This paper discusses these systems together with the neurochemical systems that impinge on them and form the basis for most pharmacological therapies

Динаміка змін структури гіпокампу в умовах міокардіальної дисфункції

З метою вивчення динаміки патоморфологічних змін нейронів гіпокампу при міокардіальній дисфункції, щурам дослідної групи вводили доксорубіцин. Щурам контрольної групи - 0,9% NaCl. У евтаназованих тварин вилучали головний мозок та готували гістологічні препарати. Аналіз цитоархітектоніки гіпокампу між 2 групами щурів виявив достовірні відмінності в кількісному складі нейронів гіпокампу. Тож, вплив міокардіальної дисфункції призвів до скорочення кількості нейронів в усіх функціональних полях гіпокампу, порушенню їх впорядкованості за рахунок зменшення кількості рядів пірамідальних нейронів

Evolving Refractory Major Depressive Disorder Diagnostic and Treatment Paradigms: Toward Closed-Loop Therapeutics

Current antidepressant therapies do not effectively control or cure depressive symptoms. Pharmaceutical therapies altogether fail to address an estimated 4 million Americans who suffer from a recurrent and severe treatment-resistant form of depression known as refractory major depressive disorder. Subjective diagnostic schemes, differing manifestations of the disorder, and antidepressant treatments with limited theoretical bases each contribute to the general lack of therapeutic efficacy and differing levels of treatment resistance in the refractory population. Stimulation-based therapies, such as vagus nerve stimulation, transcranial magnetic stimulation, and deep brain stimulation, are promising treatment alternatives for this treatment-resistant subset of patients, but are plagued with inconsistent reports of efficacy and variable side effects. Many of these problems stem from the unknown mechanisms of depressive disorder pathogenesis, which prevents the development of treatments that target the specific underlying causes of the disorder. Other problems likely arise due to the non-specific stimulation of various limbic and paralimbic structures in an open-loop configuration. This review critically assesses current literature on depressive disorder diagnostic methodologies, treatment schemes, and pathogenesis in order to emphasize the need for more stringent depressive disorder classifications, quantifiable biological markers that are suitable for objective diagnoses, and alternative closed-loop treatment options tailored to well-defined forms of the disorder. A closed-loop neurostimulation device design framework is proposed, utilizing symptom-linked biomarker abnormalities as control points for initiating and terminating a corrective electrical stimulus which is autonomously optimized for correcting the magnitude and direction of observed biomarker abnormality

Mitochondrial Impairment: A Common Motif in Neuropsychiatric Presentation? The Link to the Tryptophan–Kynurenine Metabolic System

Nearly half a century has passed since the discovery of cytoplasmic inheritance of human chloramphenicol resistance. The inheritance was then revealed to take place maternally by mitochondrial DNA (mtDNA). Later, a number of mutations in mtDNA were identified as a cause of severe inheritable metabolic diseases with neurological manifestation, and the impairment of mitochondrial functions has been probed in the pathogenesis of a wide range of illnesses including neurodegenerative diseases. Recently, a growing number of preclinical studies have revealed that animal behaviors are influenced by the impairment of mitochondrial functions and possibly by the loss of mitochondrial stress resilience. Indeed, as high as 54% of patients with one of the most common primary mitochondrial diseases, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, present psychiatric symptoms including cognitive impairment, mood disorder, anxiety, and psychosis. Mitochondria are multifunctional organelles which produce cellular energy and play a major role in other cellular functions including homeostasis, cellular signaling, and gene expression, among others. Mitochondrial functions are observed to be compromised and to become less resilient under continuous stress. Meanwhile, stress and inflammation have been linked to the activation of the tryptophan (Trp)-kynurenine (KYN) metabolic system, which observably contributes to the development of pathological conditions including neurological and psychiatric disorders. This review discusses the functions of mitochondria and the Trp-KYN system, the interaction of the Trp-KYN system with mitochondria, and the current understanding of the involvement of mitochondria and the Trp-KYN system in preclinical and clinical studies of major neurological and psychiatric diseases

Novel mechanisms in depression: focus on telomere biology and epigenetic regulation

Depression is a complex disorder with an average lifetime prevalence from 11.1% to 14.6%. It causes serious disability and is a significant public health problem worldwide. The etiology of depression is heterogeneous and multifactorial. Traditionally, researchers have tried to investigate depression from biochemical, genetic, environmental and behavioral perspectives. Since few biomarkers are available, diagnosis and treatment are still based on clinical assessment and are far from satisfactory. In recent years, depression has been proposed to be a state of “accelerated biological aging”, with an increased risk of comorbidity with other ageing-related conditions such as diabetes, cardiovascular disease and dementia. There is accumulating evidence to support that depression itself is in fact a state that involves telomere dysfunction, a prominent feature in the ageing process. Epigenetic regulation, with an emerging role in a number of complex disorders, constitutes a fusion between the results of genetic, biochemical and environmental factors. The aim of this thesis was to investigate the pathophysiology of depression with a focus on mechanisms that are perturbed in telomere biology and epigenetic regulation. Specifically, in paper I and III: telomere length and the genetic variation in the hTERT gene were examined in relation to lithium treatment, to depression disorder and depressive episodes in bipolar disorder in human cohorts. In paper II, we used a genetic rat model of depression (FSL) to study hippocampal telomere length and telomerase activity, and investigated the mechanism of how lithium affects telomere length. The epigenetic mechanisms potentially involved in depression, specifically DNA methylation/hydroxymethylation and miRNAs were investigated in the prefrontal cortex region of the FSL rats in paper IV and V, respectively. The major finding from the thesis work includes 1) telomere lengths were decreased in saliva DNA from patients with adult depression 2) genetic variation in hTERT may influence the susceptibility to depression 3) telomeres and telomerase activity are dysfunctional in the hippocampus of the depressed FSL rats 4) long-term lithium treatment is associated with longer telomeres in bipolar disorder especially when therapeutically efficacious 5) lithium treatment may normalize hippocampal telomerase dysfunction through activation of β-catenin in the rat 6) sodium butyrate exerts antidepressant-like effect and the suggestive epigenetic effects may include DNA methylation changes that are mediated by the demethylation-facilitating enzyme TET1 in the rat 7) elevation of cytokine Il6 in the prefrontal cortex is associated with depression-like states and may involve disturbance in let-7 biogenesis in the rat 8) physical exercise appears to normalize Il6 and let-7 levels through regulatory processes upstream of primary miRNA transcription in the rat

Associations Between Peripheral Immune Markers, Neural Response to Stress, and Depressive Symptoms During Adolescence: The Role of Daily Stressors, Affect, and Sleep Habits

Adolescence is characterized by marked development in neurobiological, neuroendocrine, and psychosocial domains that are posited to contribute to the increased onset and prevalence of depression and other psychiatric disorders. Emerging research also suggests an association between inflammation and affective symptoms in adolescents; however, the neural correlates that link immune functioning and affective symptoms in adolescents have been relatively understudied. The current dissertation utilized a multi-method approach (daily diary, fMRI, venipuncture samples) to investigate the role of inflammation in modulating neural function of stress/affective circuitry in a sample of adolescents (14-15 years). Results revealed that negative affect and poor sleep (short sleep duration and high sleep variability) moderated the associations between peripheral inflammatory markers and neural activation in stress-related circuitry. Specifically, among adolescents who reported high negative affect and short sleep duration, greater levels of the pro-inflammatory tumor necrosis factor (TNF)-alpha were associated with heightened activation in frontolimbic regions (e.g., amygdala, medial prefrontal cortex [MPFC]) on an fMRI stressor task, which was associated with greater stress-related anxiety and negative appraisals. Among adolescents who exhibited high sleep variability, greater levels of interferon (IFN) gamma were associated with lower activation in lateral PFC regions during stress, which was associated with poorer cognitive performance on the stress task. These immune-brain associations were attenuated among those who reported low negative affect, long sleep duration, and low sleep variability, suggesting that negative affect and poor sleep habits may sensitize the brain to peripheral immune signaling. When homeostasis is imbalanced (e.g., insufficient sleep), higher levels of TNF-alpha and IFN gamma may reflect a homeostatic drive to induce sickness-type behaviors/states (e.g., negative affect, increased anxiety, poorer cognition) to restore homeostasis (e.g., promote sleep) via modulation of respective neurocircuitry in adolescents

Neuronal and peripheral damages induced by synthetic psychoactive substances: an update of recent findings from human and animal studies

Preclinical and clinical studies indicate that synthetic psychoactive substances, in addition to having abuse potential, may elicit toxic effects of varying severity at the peripheral and central levels. Nowadays, toxicity induced by synthetic psychoactive substances poses a serious harm for health, since recreational use of these substances is on the rise among young and adult people. The present review summarizes recent findings on the peripheral and central toxicity elicited by "old" and "new" synthetic psychoactive substances in humans and experimental animals, focusing on amphetamine derivatives, hallucinogen and dissociative drugs and synthetic cannabinoids