INTRODUCTION
Parkinson’s disease (PD) has been recognized as the second most prevalent neurodegenerative disease in the U.S., with incidence of disease increasing with both age and life-span (Chen, 2010). PD is characterized as a progressive and systemic disease involving several motor and non-motor symptoms, of which include the following: tremors, bradykinesia, rigidity, olfactory dysfunction, cognitive decline, sleep disorders, and many others (Jankovic and Aguilar, 2008). Markers of early-stage onset in PD, that can be assessed well before the onset of the more commonly associated motor symptoms of the disease, could be the key to early diagnosis, treatment, and therefore, better patient outcome. Currently, many efforts are underway to identify such markers. Of these efforts, olfactory dysfunction, which occurs in 90% of PD patients before the onset of motor symptoms, has been shown to serve as an early diagnostic marker to estimate the progression of PD, as well as differentiate PD from other similarly presenting movement disorders such as progressive supranuclear palsy (PSP) and essential tremor (ET) (Haehner et al., 2009).
Despite serving as an early diagnostic marker and being present in 90% of the PD population, olfactory dysfunction is an overlooked symptom of PD. The importance of this sensory system cannot be understated. It drives both nutrient perception (flavor), avoidance of potentially dangerous solvents, and detects human aromas, such as pheromones, aiding social interactions (Chen, 2010). Considering its importance to survival and quality of life, it is not surprising that olfactory dysfunction has been linked to decreases in appetite, increases in contact with hazardous events, disturbances in social communication, and depression (Croy et al., 2012; Miwa et al., 2001). Therefore, recognizing and understanding the role of olfactory dysfunction as not only a marker, but also a symptom of PD is paramount to improving patient quality of life and therefore patient outcome. The current treatments available for advanced idiopathic PD patients includes dopamine pre-cursors such as L-Dopa, and subthalamic nucleus (STN) deep brain stimulation (DBS). Although these treatment modalities have shown improvement in managing the motor symptoms of PD, only DBS has been shown to induce positive observable changes in olfaction (Fabbri et al., 2015). However, little is known about recovery of olfactory function in PD and the underlying neuroanatomical changes that mediate recovery.
In most cases, recovery of olfactory function in PD, following DBS, is associated with either odor discrimination (OD) or odor identification (OI), but not odor threshold (OT) (Hummel et al., 2005; Fabbri et al., 2015; Guo et al., 2008). A study conducted on eleven PD patients that underwent a range of two to thirty-one months of stimulation showed improvement in odor discrimination (OD), but no significant differences in OT (Hummel et al., 2005). A similar study was done on forty-five PD patients that showed significant improvement in olfaction in nine of the patients that received bilateral STN stimulation in conjunction with dopamine agonists, compared to no improvement in the group that received standard medical care (Peters et al., 2010). These studies support the hypothesis that improvements seen in OD or OI are likely due to higher olfactory processing, rather than peripheral olfactory sensory neurons.
Across the olfactory processing network, in humans, studies have shown that OB volume will fluctuate as a function of olfactory impairment (Haehner et al., 2009). Specifically, OB volume was directly correlated with duration of olfactory function loss in a cohort of non-PD patients that suffered post-traumatic or post-infectious olfactory deficits (Haehner et al., 2009). The ability to regain olfactory function implies the plasticity could arise in the OB, but also further extend to plasticity in cortical and sub-cortical structures involved in the olfactory processing pathway, including the olfactory epithelium, and possibly the amygdala, piriform cortex (primary olfactory cortex), lateral orbitofrontal cortex (OFC) and hippocampus (Ham et al., 2016). Odor-evoked memory is a critical component of higher olfactory functioning that involves the hippocampus (Herz, 2003). On a study done that examined functional magnetic resonance imaging (fMRI) of participants smelling a control odorant (CO) vs the experimental odorant (EO) of their choice, test subjects showed greater activation in brain regions such as the amygdala and hippocampus, suggesting that odor is strongly linked to both emotion and memory (Herz, 2003).The OFC is also thought to be involved in both memory and decision making (Courtiol and Wilson, 2016). The OFC serves as a sensory integration center for several senses, and is also thought to have reciprocal communication with structures such as the primary olfactory cortex and the mediodorsal thalamus (Courtiol and Wilson, 2016). In addition, the convergence of the gustatory and olfactory system is thought to take place here in the OFC, which contributes to modern day interpretation of ‘flavor’ (Kringelbach, 2004). The complex and integrated circuitry of the olfactory system could help explain why we could possibly see induced changes in cortical structures due to the indirect effects of DBS.
Previous studies have suggested that STN-DBS in PD leads to improvements in olfactory function; however, there is a gap in our understanding of the underlying anatomical changes that might accompany not only olfactory structures, but also olfactory processing brain regions following STN-DBS. The purpose of this study was to investigate whether duration of STN stimulation via DBS correlates with measurable changes in OB volume in PD patients, as well as cortical structures of the hippocampus and the lateral orbitofrontal cortex that are involved in this sensory pathway. We hypothesize that PD patients who have undergone longer periods of STN stimulation may exhibit greater relative change in OB volumes compared to not only the hemisphere that received no stimulation, but also to other PD patient cohorts who had shorter stimulation. Additionally, we expect to see no change in OB volumes in ET patients compared to PD patients regardless of length of STN stimulation. Furthermore, we believe that STN-DBS might indirectly induce changes in several other brain areas involved in olfactory processing such as the thalamus, lateral orbitofrontal cortex, and hippocampus. This study will complement previous studies that have examined olfactory recovery following STN-DBS. In addition, our method for measuring OB volume may provide a clinometric marker for olfactory recovery following STN-DBS in PD patients.
METHODS
Experimental Design
We compared changes in anatomical structure between patients that recevied STN-DBS stimulation vs patietns that were implanted but unstimluated.
Patient information
This investigation was approved by the Colorado Multiple Institution Review Board (COMIRB). All medical imaging analyses were conducted on de-identified data collected during the standard-of-care procedures for routine STN-DBS implantation surgery in patients with idiopathic PD, using a retrospective chart-review IRB-approved protocol. Patient information was organized with respect to sex ratio, age distribution, and length of stimulation.
a. Total patients: 30 PD patients, and 3 ET patients.
b. Male to Female ratio: 19:14.
c. Age range: 46-80 with a mean of 63.30 (± SD 7.76)
d. Length of stimulation in days: short = 0-55; medium = 55-306; long = >306.
Following approval by Colorado Multi Institutional Review Board (COMIRB), 30 subjects with idiopathic PD and 3 subjects with ET were recruited for the study. All subjects demonstrated typical parkinsonian motor symptoms, including tremor, akinesia, and rigidity or classic ET with upper limb kinetic tremors. PD inclusion criteria for the study included the diagnosis of idiopathic PD and a positive response to anti-Parkinson medication, amounting to a greater than 30% improvement on the motor subscale of the Unified Parkinson’s Disease Rating Scale (mUPDRS) in the on- vs off-state, a brain MRI scan lacking significant abnormalities, and medical clearance for surgery. All study subjects provided written consent for participation. Patients over the age of 75 or under the age of 18, those at increased risk of infection (e.g., comorbid diabetes or history of recurrent infections), and patients with significant cognitive deficits or untreated psychiatric disorders (e.g., depression) detected on neuropsychological testing were excluded from this study.