VC/VS for Apathy in PD

Apathy is a significant mental health condition. Apathy was originally defined as a disorder of motivation and is now operationalized as a reduction in goal-directed behavior. It manifests with diminished interest, goal setting, emotional expression, and social connection. Although not named as a formal diagnosis in the DSM-V, apathy is highly prevalent and co-morbid with several neuropsychiatric disorders. Apathy impacts ~40% of patients with Parkinson's Disease (PD), ~60% of patients with Alzheimer's Disease, ~40% of patients with major depressive disorder, ~50% of patients with schizophrenia and more than 30% of individuals after stroke. Its presence conveys greater caregiver burden, poorer engagement in activities of daily living, higher risk of cognitive decline, and generally lower quality of life. These factors impose a profound clinical, social, and economic burden, not only by exacerbating the challenges faced by individuals with apathy but also by straining caregivers, healthcare, and societal resources.

In the US alone, PD impacts over 680,000 individuals today and is anticipated to impact 1,238,000 individuals by 2030. PD is a neuropsychiatric disorder characterized by a combination of motor symptoms including bradykinesia (100%), tremor (70-90%), and rigidity (90%) and non-motor symptoms, including psychiatric issues such as depression (50%), anxiety (40%) and apathy (40%). Apathy is now recognized as one of the most debilitating nonmotor symptoms. It is associated with decreased participation in everyday activities, decreased functional capabilities, and increased caregiver burden. Remarkably, apathetic PD patients have a nearly 3X increased risk of mortality compared to their non-apathetic counterparts.

Dopaminergic medications and deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the globus pallidus internus (GPi) are effective treatments for the motor complications of PD. However, apathy symptoms commonly persist and may even worsen after DBS, with most patients continuing to deteriorate over time with significant implications on their quality of life and overall morbidity and mortality. Furthermore, although dopamine agonists (e.g., Pramipexole, Ropinirole, Rotigotine), may reduce apathy severity in PD, they commonly lead to side effects including psychosis and impulse control disorders that limit their prolonged use. Therefore, there are no effective and practically usable treatments for apathy in PD. Importantly, other neuropsychiatric symptoms such as depression and cognitive decline often co-occur in PD patients with apathy. In cases of co-morbid depression, apathy may be clinically distinguished, and treatment options for depression may be attempted (e.g., selective serotonin reuptake inhibitors, SSRIs). However, the use of SSRI antidepressants has been associated with greater apathy in PD and are not indicated specifically for the treatment of apathy. Similarly, cholinesterase inhibitors (e.g., rivastigmine, galantamine) may be attempted in patients with apathy and associated cognitive impairment. However, common side effects (i.e., psychosis, confusion, anxiety) are frequently prohibitive in PD and limit their use. Thus, in light of the lack of specific treatments for apathy in PD, the detrimental impact of apathy on quality of life, morbidity, and mortality in PD represents a critical treatment gap.

The success of DBS for the treatment of motor symptoms in PD derives from the well understood pathophysiology within the underlying circuit. Analogously, the investigators propose to leverage our understanding of the circuitry underlying apathy as a disruption of goal-directed behavior to rationally target the treatment of apathy. In humans, tasks studying goal-directed behavior consistently implicate the region of the ventral striatum (VS) and adjacent white matter of the ventral portion of the anterior limb of the internal capsule (ventral capsule, VC), which carries axons from prefrontal cortex (PFC). DBS of this region is used to treat refractory OCD (under US FDA humanitarian device exemption status), as well as depression, addiction, and other disorders (as investigational indications). The emerging success of neuromodulation of this region for such a diversity of disorders strongly suggests common underlying mechanisms. Two prominent mechanisms likely playing important roles are reward sensitivity and cognitive control. Deficits in reward sensitivity may manifest as anhedonia or avoidance, and deficits in cognitive control may produce inattention or effort intolerance. Aspects of these deficits appear in various combinations in OCD, depression, addiction, and other disorders treated by VC/VS DBS. Stimulation in this region likely enhances reward sensitivity via fibers from the orbitofrontal and ventral anterior cingulate cortices and the VS and likely exerts influence on cognitive control via stimulation of fibers from dorsal PFC and the dorsal anterior cingulate cortex. Deficits in goal-directed behavior may be attributable to either/both of these dimensions of dysfunction, motivating our hypothesis that VC/VS of this region will ameliorate apathy.

Indeed, further evidence for this therapeutic strategy comes from a case report in which a single patient was implanted bilaterally in both the STN and VC/VS for treatment of motor symptoms in PD and treatment-resistant OCD, respectively. In addition to achieving improvement in motor and OCD symptoms, VC/VS DBS also led to a significant reduction in apathy severity. During an unplanned discontinuation of stimulation due to battery depletion, OCD symptoms and apathy abruptly worsened. When VC/VS stimulation resumed, OCD and apathy once again improved. Even though this is a single case study, it suggests that 1) a dual implant (VC/VS + motor target) is safe and tolerable in PD; 2) VC/VS DBS in PD does not worsen motor symptoms; 3) VC/VS DBS shows promise for improving apathy in PD.

This protocol aims to address apathy/loss of motivation, one of the most disabling and largely undertreated symptoms of PD, with VC/VS DBS.