Rhythms and blues: modulation of oscillatory synchrony and the mechanism of action of antidepressant treatments

Abstract

Treatments for major depressive disorder (MDD) act at different hierarchical levels of biological complexity, ranging from the individual synapse to the brain as a whole. Theories of antidepressant medication action traditionally have focused on the level of cell-to-cell interaction and synaptic neurotransmission. However, recent evidence suggests that modulation of synchronized electrical activity in neuronal networks is a common effect of antidepressant treatments, including not only medications, but also neuromodulatory treatments such as repetitive transcranial magnetic stimulation. Synchronization of oscillatory network activity in particular frequency bands has been proposed to underlie neurodevelopmental and learning processes, and also may be important in the mechanism of action of antidepressant treatments. Here, we review current research on the relationship between neuroplasticity and oscillatory synchrony, which suggests that oscillatory synchrony may help mediate neuroplastic changes related to neurodevelopment, learning, and memory, as well as medication and neuromodulatory treatment for MDD. We hypothesize that medication and neuromodulation treatments may have related effects on the rate and pattern of neuronal firing, and that these effects underlie antidepressant efficacy. Elucidating the mechanisms through which oscillatory synchrony may be related to neuroplasticity could lead to enhanced treatment strategies for MDD.

Keywords: antidepressant medication; antidepressant treatment; biomarkers; biosignatures; intermediate phenotype; major depressive disorder; mechanism of action; neuromodulation; oscillations; oscillatory synchrony; quantitative electroencephalography; thalamocortical dysrhythmia.

© 2015 New York Academy of Sciences.

Figures

Figure 1

Spectrum of factors that influence expression of the depressive phenotype in MDD. A continuum of factors contributes to the depressive phenotype in MDD, ranging from genetic polymorphisms through function in brain networks. The multiple levels of biological structures, ranging from the genome to brain networks and ultimately culminating in the phenotype(s) of MDD, represent a spectrum of increasing biological complexity (shown in the center of the diagram from bottom left to top right). These structures can be grouped into three general categories of organization: those existing at the level of the single cell, those involving cell-to-cell communication, and those involving ensembles of cells that form circuits and networks. Each of these categories of structural organization is characterized by certain physiologic functions, shown on the right. The three levels of structural and functional organization are not entirely autonomous: the effects of genetic and molecular factors are translated bottom up to influence the clinical phenotype of MDD, whereas the influence of brain functional networks are translated top down to influence cellular communication and intracellular processes. The spectrum of structures and functions presented here are intended to be illustrative of general physiologic principles and are not an exhaustive list of structural and functional features of interest in MDD. Reproduced from www.brain.ucla.edu. © 2015 UCLA Laboratory of Brain, Behavior, and Pharmacology.

Figure 2

Central role of rhythmic oscillations in regulating brain processes. Oscillatory synchrony integrates the activity of individual neurons into microcircuits and larger-scale functional networks. Modulation of activity in these networks helps regulate information processing, cerebral blood flow and metabolism, and autonomic functions.

Figure 3

Hypothesized action of antidepressant treatments at different levels of biological complexity in the brain. Antidepressant treatments act along a continuum of structures and processes ranging from the level of a single cell to ensembles of neurons in brain networks. Neuromodulatory and medication treatments for MDD are shown graphically in relation to the hypothesized level of action along this continuum. Neuromodulatory treatments (such as rTMS) may modulate oscillations in higher-order brain networks (arrow at top left), whereas medication treatments may affect synaptic neurotransmission or neuroelectric communication at the level of cell-to-cell communication (arrow at middle left). Treatments acting at any level along this continuum may increase neuroplasticity and exert physiologic effects in a bidirectional manner. Treatments acting on intracellular processes or intercellular communication may transmit their effects bottom up to affect brain functional networks, whereas treatments that directly modulate function in brain networks or microcircuits may transmit their effects top down to influence cellular processes or intercellular communication. Evidence indicates that, in addition to synaptic neurotransmission, neuroelectric communication plays a central role in mediating top-down and bottom-up effects across multiple levels of biological complexity in the brain. Modulation of neuronal firing rates and patterns and oscillatory synchrony may represent a mechanism through which treatment effects are transduced across multiple levels of physiologic action to increase neuroplasticity. We hypothesize that modulation of oscillatory synchrony plays an important role in the MOA of antidepressant treatments. Reproduced from www.brain.ucla.edu. © 2015 UCLA Laboratory of Brain, Behavior, and Pharmacology.