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Introduction
Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, and is characterised by cardinal motor symptoms, including tremor, rigidity, bradykinesia and postural instability. 1 However, growing evidence suggests that PD is a disease with numerous non-motor symptoms (NMS) that affect multiple, non-dopaminergic neuronal populations aside from the dopaminergic system. 2 3 Depression is a prevalent NMS in PD, with a prevalence of approximately 40-50%. 4 Although depression may be secondary to progressive and disabling symptoms, several lines of evidence support the concept that depression may be a consequence of the pathologic substrates of the disease. 5 Additionally, some studies observed that depression could be the initial symptom in PD other than motor symptoms 6 ; depression in PD is associated with a faster decline of functional and motor abilities, as well as of cognitive performance. 7 However, depression, which has been found to be one of the most important factors impairing patients' quality of life is frequently unrecognised and undertreated.
Substantial efforts have been made in the past decade to elucidate the neural basis of depression in PD. Postmortem studies indicate that pathological processes may already occur in limbic regions during the presymptomatic phase of PD, 8 thus providing insight into the pathological mechanisms of depression in PD. Through neurotransmitter imaging, abnormal serotonergic neurotransmission 9 10 and specific loss of dopamine and noradrenaline innervation in the limbic system 11 have been found in PD patients with depression. Abnormal functional activity in the prefrontal area has been characterised as a critical hallmark in previous models of depression pathophysiology. 12 In line with these models, altered metabolism or cerebellum blood flow in the frontal cortex has been associated with depression in PD. 13-16 With the aid of structural neuroimaging techniques, grey matter loss and white matter abnormalities in the prefrontal, temporal and some limbic regions, were detected in patients with PD with depression. These findings provide a structural basis for these functional changes. 17 18 Previous studies found that the abnormal brain regions in patients with PD with depression, mainly involved the prefrontal cortex and limbic regions. The outcome highlights a complex pathophysiological mechanism involving deficits in the prefrontal-limbic network in PD patients with depression.
The brain is a network of a large number...