Neurobiological mechanisms of repetitive transcranial magnetic stimulation on the underlying neurocircuitry in unipolar depression

Abstract

For nearly two decades now, transcranial magnetic stimulation (TMS) has been available as a noninvasive clinical tool to treat patients suffering from major depression. In this period, a bulk of animal and human studies examined TMS parameters to improve clinical outcome. However, the neurobiological mechanisms underlying mood changes remain an important focus of research. In addition to having an effect on neuroendocrinological processes, neurotransmitter systems, and neurotrophic factors, TMS may not only affect the stimulated cortical regions, but also those connected to them. Therefore, we will review current human data on possible neurobiological mechanisms of repetitive (r) TMS implicated in the deregulated neurocircuitry present in unipolar depression. Furthermore, as the rTMS application can be considered as a "top-down" neuronal intervention, we will focus on the neuronal pathways linked with the stimulated area and we will present an integrative model of action.

Figure 1.. Theoretical framework of deregulated cortico-thalamiclimbic pathways in unipolar major depression. In major depression there is a pronounced shift in the homeostasis with diminished activity in the prefrontal cortex (DLPFC and dorsal ACC - blue), enhanced activity in the amygdala (red) and activation of the core stress system. Hyperactivity in limbic areas results in higher neural activities at the hypothalamic level, evoking higher corticotrophin-releasing hormone (CRH) secretions, resulting in elevations of cortisol levels. Hippocampal dysfunction may also result in reduction of the inhibitory regulation of the HPA axis, which could then lead to hypercortisolemia. The failing negative feedback system results in chronic hypercortisolemia. In long-term depressive episodes, chronically elevated levels of cortisol contribute to hippocampal and cortical atrophy and reducing hippocampal ability to inhibit amygdala hyperactivity. Abnormal modulation of cortical-hippocampal-amygdala pathways may contribute to chronically hypersensitive stress responses, mediating features of anxiety, anhedonia, and affective dyscontrol. Additionally, the dysfunctional ACC fails to serve its inhibitory role in emotional regulation on the amygdala, resulting in further motivational and affective disruption. DLPFC, dorsolateral prefrontal cortex; ACC, anterior cingulate cortex; ACTH, adenocorticotropic hormone; HPA, hypothalamic-pituitaryadrena

Figure2.. Visualization of a theoretical working mechanism of HF-rTMS applied to the DLPFC on the HPA-system in unipolar major depression. In the left hand corner a figure-of-eight shaped repetitive transcranial magnetic stimulation (rTMS) coil is depicted. rTMS treatment results in increased neuronal activity in the (dorsolateral) prefrontal cortex, which through cortico-subcortical trans-synaptic connections (presumably through frontocingulate networks) suppresses hypothalamic and/or indirectly amygdala overactivity, resulting in CRH decreases and ultimately in decreased salivary cortisol concentrations. In line with successful pharmacological interventions, successful rTMS treatment results in normalization of the negative feedback system. The areas in red represent an elevated neuronal activity. The blue areas represent the reverse, a diminished level of neuronal activity. ACTH, adenocorticotropic hormone DLPFC, dorsolateral prefrontal cortex; ACC, anterior cingulate cortex; GR, glucocorticoid receptors; MR, mineral-corticoid receptor; CRH, corticotrophin-releasing hormone; ACTH: adenocorticotrope hormone; H, Hypothalamus; P, Pituitary gland; A, Adrenal cortex; (-), inhibitory; (+) ,excitatory