Apathy and Impulse Control Disorders: Yin & Yang of Dopamine Dependent Behaviors.

Neuropsychiatric symptoms are common non-motor symptoms in Parkinson's disease (PD). Apathy and impulse control disorders (ICD) are two opposite motivational expressions of a continuous behavioural spectrum involving hypo- and hyperdopaminergia. Both syndromes share pathological (decreased vs increased) dopamine receptor stimulation states. Apathy belongs to the spectrum of hypodopaminergic symptoms together with anhedonia, anxiety and depression. Apathy is a key symptom of PD which worsens with disease progression. Animal models, imaging and pharmacological studies concur in pointing out dopaminergic denervation in the aetiology of parkinsonian apathy with a cardinal role of decreased tonic D2/D3 receptor stimulation. ICDs are part of the hyperdopaminergic behavioural spectrum, which also includes punding, and dopamine dysregulation syndrome (DDS), which are all related to non-physiological dopaminergic stimulation induced by antiparkinsonian drugs. According to clinical data tonic D2/D3 receptor stimulation can be sufficient to induce ICDs. Clinical observations in drug addiction and PD as well as data from studies in dopamine depleted rodents provide hints allowing to argue that both pulsatile D1 and D2 receptor stimulation and the severity of dopaminergic denervation are risk factors to develop punding behavior and DDS. Imaging studies have shown that the brain structures involved in drug addiction are also involved in hyperdopaminergic behaviours with increase of bottom-up appetitive drive and decrease in prefrontal top down behavioural control.

New targets for deep brain stimulation treatment of Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and the globus pallidus pars interna (GPi) has been shown to be an effective treatment for patients with Parkinson's disease. Strong clinical evidence supports the improvement of motor and non-motor complications and quality of life, with some data suggesting that GPi DBS might be less effective than STN DBS. However, neither STN nor GPi stimulation provides a satisfactory control of non-dopaminergic symptoms, such as gait and balance impairment and cognitive decline, which are frequent and disabling symptoms in advanced Parkinson's disease patients. Therefore, several efforts have been made to discover alternative and new targets to overcome these current DBS limitations. Among these new targets, the stimulation of the pedunculopontine nucleus has initially appeared encouraging. However, findings from different double-blind trials have mitigated the enthusiasm. A multi-target strategy aimed at improving symptoms with different pathogenetic mechanisms might be a promising approach in the next years.