Emotional manifestations of PD: Neurobiological basis

Abstract

Neuropsychiatric symptoms are common and disabling in PD. Their neurobiological bases are complex, partly because of the disease itself and partly because of the dopaminergic treatment. The aim of this review is to focus on the emotional manifestations stemming from the neurodegenerative process itself. We focus on depression, anxiety, apathy, and fatigue, which can all be part of the clinical spectrum of premotor disease and may be improved or masked by medications targeting parkinsonian motor signs or psychiatric symptoms as the disease progresses. Findings from clinical, neuroimaging, and animal studies are reviewed, showing a major contribution of the dopaminergic system to the pathophysiology of these disabling symptoms. Degeneration of noradrenergic and serotonergic projection systems also has an impact on psychiatric symptoms of PD. The available literature is reviewed, but at present there is a lack of studies that would allow disentangling the separate contribution of each of the monoaminergic systems. The use of a pragmatic classification of all these symptoms under the umbrella of hypodopaminergic behavioral syndrome seems clinically useful, as it emphasizes the crucial, although not exclusive, nature of their dopaminergic neurobiological basis, which has important implications in the clinical management of PD. Psychiatric symptoms are so common in Parkinson's disease (PD) that it has been defined as a neuropsychiatric disorder.1 Neuropsychiatric symptoms, that is, emotional and cognitive symptoms, constitute a major source of disability and can be socially disruptive. [2][3][4] Some of these symptoms are a side effect of dopaminergic treatment (behavioral and dopaminergic replacement treatment addiction, nocturnal hyperactivity, hypomania, and punding).3-5 Others, like apathy, depression, and anxiety, seem more related to the disease itself, already presenting in the early stages of the disease and potentially preceding the first motor symptoms. As such, apathy, depression, and anxiety might at least in part be associated with insufficient dopaminergic drive. [4][5][6][7][8] Fluctuating patients might experience apathy, depression, and anxiety in the offperiods, with euphoria, well-being, self-confidence, and hypomania characterizing the on-drug condition. 9 The management of neuropsychiatric symptoms remains a challenge, also because it is not always easy to weight the relative contribution of medications, disease, and emotional response. The neurobiological bases of these symptoms are complex and not yet fully understood. The relative contribution of dopaminergic deficit and of other nondopaminergic systems is still under investigation. The objective of this review is to focus on the neuropsychiatric symptoms, which are most likely related to the disease itself, and to analyze ------------------------------------------------------------ N O N M O T O R S E R I E S : R E V I E WMovement Disorders, Vol. 31, No. 8, 2016 1103 the literature relating to their underlying mechanisms. We will...

Axonal damage and loss of connectivity in nigrostriatal and mesolimbic dopamine pathways in early Parkinson's disease

“…In PD, impairment in the mesolimbic dopaminergic system has been associated with non-motor symptoms, in particular mood disorders, which may affect patients since or even before the initial clinical phase of PD (see (Castrioto et al, 2016) for a recent review). A recent review on previous neuropathological studies that directly quantified dopamine neurons in both the SN and VTA in PD patients suggests that the high VTA variability can explain the PD clinical non-motor heterogeneity, such as the occurrence of mood, cognition, and sleep disturbances (Alberico et al, 2015).…”

“…This system, however, has been associated to a series of psychopathological states, which often occur in PD and may precede motor disturbances by many years (Gustafsson et al, 2015). A damage to the dopaminergic mesolimbic system is considered the leading cause of the neuropsychiatric symptoms occurring in PD (see (Castrioto et al, 2016) for a recent review).…”

Antiarrhythmics cure brain arrhythmia: The imperativeness of subthalamic ERG K + channels in parkinsonian discharges

“…That is, when burst discharges become more prevalent because of more hyperpolarized resting membrane potentials ( 56 ), the cortical input may be less faithfully followed by the STN neuronal responses. In addition to motor control, the function of the STN involves emotion, motivation, and cognition ( 12 , 13 ). In this regard, it is notable that PD is not only a motor disease.…”

“…That is, burst discharges in the STN may act as a brake of not only motor but also nonmotor loops, interfering with corticosubthalamic information flow. DBS at the STN may release this brake and result in disinhibition of motor, cognitive, and emotional behaviors ( 12 , 13 ), and thus lead to an improvement of motor deficits and obsessions/compulsions or acceleration of necessary slow processes for decision-making (a potential cause of impulse control disorders) ( 8 , 9 , 12 – 15 , 84 , 88 ). These attributes are very much analogous to the cases of thalamic relay neurons and the corticothalamic network ( 81 , 89 ).…”

The prominent role of serotonergic degeneration in apathy, anxiety and depression inde novoParkinson’s disease

“…Beyond the well-known role of nigrostriatal dopaminergic dysfunction in the pathophysiology of Parkinson's disease motor symptoms (Brooks et al, 1990;Boileau et al, 2009), dopaminergic disruption of the mesolimbic and mesostriatal pathways is involved in the occurrence of several non-motor manifestations, such as apathy, depression, anxiety, fatigue, or impulse control disorders (Remy et al, 2005;Weintraub et al, 2005Weintraub et al, , 2015aAarsland et al, 2009;Boileau et al, 2009;Chaudhuri et al, 2009;Pavese et al, 2010;Thobois et al, 2010;Pagonabarraga et al, 2015;Castrioto et al, 2016). In addition, increasing lines of evidence support a specific causal role of serotonergic dysfunction in the pathogenesis of several parkinsonian signs, such as tremor and dyskinesia, but also depression, fatigue, cognitive decline and hallucinations, at moderate-toadvanced stages of the disease (Doder et al, 2003;Boileau et al, 2008;Pavese et al, 2010;Politis et al, 2010b;Ballanger et al, 2012).…”