This study used latent growth curve modeling to examine longitudinal data from 48 PD patients who underwent unilateral STN or GPi DBS surgery. Further, we also examined a matched control group of 48 non-surgical PD patients and hypothesized that apathy would increase in the DBS group, but not in the control group. This hypothesis was supported. Apathy scores in the DBS group increased by .66 points every 2 months while scores in the non-surgical group did not change. Next, we hypothesized a positive relationship between apathy and age, motor severity, and depression. This was only partially supported. Higher pre-surgical depression was related to higher pre-surgical apathy, but not to change in apathy. Contrary to our prediction, middle-aged adults had a steeper rise in apathy after DBS than older adults. Motor severity was not related to baseline apathy or change in apathy after DBS. STN (versus GPi) implantation, laterality, and change in levodopa equivalent dose were not related to change in apathy.
Our finding of increased apathy is consistent with the current literature. Thirteen prior studies have investigated apathy after DBS. Ten studies report an increase in chronic apathy after DBS [4
], two report no change in apathy after DBS[15
], and one reports a reduction in acute apathy when stimulators were turned from OFF to ON, but did not examine chronic apathy [17
]. See for a review. No studies found improvement in chronic apathy following DBS. This is the first study to investigate unilateral STN and GPi found DBS whereas other studies have all been bilateral STN DBS. Importantly, we found a longitudinal trajectory of increased apathy as a result of unilateral surgery.
Table 3 Apathy outcome following chronic deep brain stimulation reported by study, surgical treatment, sample size (n), evaluation period, apathy measures, and outcome. Note: Abbreviations used: AS = Apathy Scale, FRSBE = Frontal Systems of Behavior Scale UPDRS (more ...)
In terms of predictors of apathy, older age and motor severity did not predict baseline apathy score. Higher baseline depression scores predicted higher baseline apathy scores, which is consistent with studies in PD and other neurological disease groups that report a positive correlation between apathy and depression [14
]. Higher baseline depression score was not related to change in apathy after surgery. In our study, the only significant predictor of apathy was being a middle-aged (versus older) adult. To further investigate this, we performed a post-hoc t
-test examining apathy scores at baseline between older and younger adults. While older adult status was not a significant predictor of baseline apathy in our SEM due perhaps to power and/or multi-collinearity with baseline BDI scores, we found a trend for apathy scores at baseline to be lower in middle aged adults (M
= 9.03, SD = 5.6), than in older adults (M
= 11.95, SD = 5.14), t
(46) = −1.81, p
= .077. Apathy scores may have increased faster because they started out lower (i.e. return to the mean). Future studies should confirm the relationship between change in apathy and age.
Per site of electrode implantation, we found no relationship between change in apathy and laterality or STN versus GPi implantation. Studies in other disorders have broadly suggested right hemispheric lateralization for apathy, but we found no difference between right and left lateralization in the development of apathy after DBS. No other study has examined this in PD. Per STN versus GPi, the STN has a smaller and more difficult to target sensorimotor region than the GPi. Thus, we hypothesized that either the lesion itself or stimulation effects of STN would be more likely to affect non-motor pathways potentially involved in apathy than would the GPi. This was not supported and both targets were equally likely to lead to apathy. Consistent with this, some authors have argued against the idea that apathy is a specific side effect of stimulation of the limbic part of the STN [5
]. They base this on the psycho-stimulating effects of acute bilateral STN stimulation [30
]. Further, acute bilateral STN has been shown to reduce acute apathy scores [17
]. Also, apathetic versus non-apathetic groups often have similar improvements in motor symptoms (i.e. also found in the present study), suggesting they were accurately targeting the sensorimotor versus non-motor regions of the STN.
Turning to apathy and levodopa, we found no relationship between apathy and change in levodopa equivalent dose (LED) after surgery. Several studies did not find a relationship between apathy and reduction in levodopa, despite substantial reductions in overall LED (see ) [4
]. Furthermore, one study found increased apathy scores were associated with less reduction (i.e. rather than more reduction) in levodopa [14
]. In our study, overall LED change was a slight increase (i.e. 5%), yet apathy still increased after surgery. Taken together, results from previous studies and our own study suggest levodopa reduction alone is not sufficient for the development of apathy.
Instead, Thobois and coworkers [5
] recently suggested a more complex interaction between medication changes and underlying neuropathology. They examined 63 bilateral STN patients with self-report inventories, motor testing, and PET imaging (i.e. subgroup of 25 for PET) and found that baseline non-motor fluctuations were predictive of change in apathy after DBS. Post-operative reduction in overall dopaminergic treatment per se did not predict the occurrence of apathy. However, they suggest that underlying individual variations in denervation of the mesolimbic system are the substrate for “unmasking” hypodopaminergic behaviors such as apathy when medications are reduced after surgery. PET imaging suggested a relationship between apathy and the left orbitofrontal cortex, dorsolateral prefrontal cortex, thalamus, internal globus pallidus, and bilaterally in anterior and posterior cingulate cortices. Authors hypothesized that based on this, certain individuals with PD have a lower dopaminergic tone at baseline within the mesocorticolimbic pathways, and these patients are the ones at risk for developing post-operative apathy.