Deep brain stimulation (DBS) is an effective treatment for motor symptoms in advanced Parkinson’s disease (4). Most commonly, DBS electrodes are placed in the subthalamic nucleus (STN) but can also be placed in the globus pallidus pars interna (GPi). The STN comprises three main functional subterritories. The dorsolateral region is the motor territory, the ventromedial portion is the associative territory, and the anteromedial region subserves limbic function (5, 6).
Adverse Behavioral Effects Associated With DBS for Parkinson’s Disease.
Adverse behavioral effects of DBS in Parkinson’s patients are recognized but not well understood. In a systematic review of 82 published reports (1,398 patients), Temel et al. (7) noted impaired cognition (41%), depression (8%), hypomania (4%), anxiety disorders (2%), attempted suicide (0.4%), and personality changes, hypersexuality, apathy, and aggression (<0.5%). In another study (8), 17 Parkinson’s patients treated with STN DBS were compared with 22 Parkinson’s patients treated with medical therapy. At baseline, the only statistically significant between-group difference was that the DBS group had a higher rate of depression. After implantation, there were no significant between-group differences in the physical symptoms of depression, but the DBS group experienced increased cognitive-emotional symptoms of depression. There was one suicide in the DBS group and none in the non-DBS group. Case reports suggest that stimulation of the ventromedial aspect of the STN (5, 9, 10) and of the underlying substantia nigra may result in manic behavior (11, 12) or acute depression (13). York et al. (14) reported an association between decline in mood and placement of the leads inferiorly and laterally to the STN.
Stimulation of the STN or GPi has comparable benefit for motor symptoms, although behavioral side effects vary (15–18). A prospective 4-year study (15) of 49 patients found that adverse behavioral effects were more common in patients treated with STN DBS (53%) than in those treated with GPi DBS (35%). The patients who developed behavioral effects had, on average, a longer illness duration, more gait disturbance, and more psychiatric symptoms at baseline. In contrast, a randomized controlled trial (16) across five centers in the Netherlands (65 patients with GPi DBS and 63 with STN DBS) found no differences between groups in cognition, mood, or behavior after 1 year. Likewise, in a prospective blind trial, Okun et al. (17) found no differences in mood or cognition between STN and GPi with optimized DBS stimulation parameters. However, a meta-analysis of six trials (563 patients) comparing STN and GPi DBS (18) found equal improvement in motor symptoms at 1 year and a significantly greater improvement in depression symptoms in the GPi DBS group, as measured by the Beck Depression Inventory. Additionally, STN DBS was significantly more effective in reducing dopaminergic medication, which can have the additional benefit of improving impulse control.
Impulsive behaviors are present in almost one-third of patients with Parkinson’s disease (19), and they are also reported as adverse behavioral effects of STN DBS (20). However, the data are inconclusive, with studies showing that preoperative impulse control disorders may resolve, improve, worsen, or show no change after STN DBS (21).
Mood changes, such as increased anger, have also been reported. In a prospective open-label study, Burdick et al. (22) compared the anger subscore of the Visual Analog Mood Scales in patients undergoing unilateral DBS of the STN (N=195) or GPi (N=56) for Parkinson’s disease and of the ventral intermediate nucleus of the thalamus (N=71) for essential tremor. At 1 to 3 months after stimulation, both the STN and GPi DBS groups exhibited significantly more anger. For every year of illness duration, the anger subscore increased by 0.24. A higher number of electrode passes during surgery was associated with increased anger scores, and anger subscores did not change when the DBS was turned off, supporting a lesion effect rather than a stimulation-induced effect.
Premorbid psychiatric conditions increase the risk of psychiatric adverse effects. Significant active residual symptoms are a contraindication to DBS (23–25). Dementia is also a contraindication. A decrease greater than one standard deviation from the premorbid IQ suggests a neurodegenerative process and high susceptibility for further decline after surgery (26).
Stimulation parameters and electrode configuration can contribute to adverse behavioral effects. The goals of DBS programming are to select contact(s) for stimulation and to determine optimal stimulation parameters. This is accomplished by adjusting amplitude, pulse width, and frequency (3). Use of higher amplitudes (>3 V) has been associated with an increased risk of mania (27). The amount of the applied stimulation can be calculated using the total electrical energy delivered (TEED) formula (28):
The mode of stimulation can be either monopolar or bipolar. In monopolar mode, the implantable pulse generator is selected as the anode, and one or several contacts are chosen as the cathode; in bipolar mode, both anode(s) and cathode(s) are within the DBS electrode (3). Monopolar configurations generate a weaker electrical field but the largest volume of stimulation. Bipolar configurations are therefore often used to minimize side effects. Changes in the active contact (or contacts) that shift electrical field away from limbic and associative circuits within the STN and underlying substantia nigra, as with the selection of a more dorsal contact, can reduce adverse behavioral effects.
In summary, behavioral changes after DBS are associated with several factors: the trajectory of electrodes during placement, the number of electrode passes, the specific target chosen, the stimulation parameters used, the electrode configuration, concurrent dopaminergic medication use, premorbid psychiatric illness, and the natural course of Parkinson’s disease.
Our Patient.
Mr. R’s mood and behavioral changes did not consistently correlate with DBS programming parameter changes. The psychiatric examination revealed an adjustment disorder, alcohol misuse in the context of multiple stressors, and increased cognitive decline, all of which can cause mood and behavioral changes. Although adverse behavioral effects are common after DBS, not all behavioral and mood changes are related to DBS. The differential diagnosis for mood and behavior changes in the context of DBS includes complications of DBS, mood and behavioral changes due to Parkinson’s disease, substance use disorders, medication side effects, dementia, a primary mood or psychotic disorder, and psychosocial conflict.
Conclusions
DBS surgery is a dramatic and effective treatment for Parkinson’s disease–related motor symptoms. DBS does not improve cognition or other nonmotor symptoms of Parkinson’s disease, and it has been associated with significant adverse behavioral effects in some patients. In Mr. R’s case, adjustment of DBS programming parameters seemed directly related to symptom improvement after his first episode of behavior changes. Total electrical energy delivered (TEED) actually increased, but the left STN contact had been changed to a more dorsal contact, likely pulling stimulation away from the substantia nigra as well as from limbic and associative circuits. However, his second episode of increased anger, impulsivity, and irritability did not correspond to programming changes. A careful consideration of the location of active contacts and TEED did not explain the patient’s sudden change in mood and behavior or the resolution of his mood and behavior symptoms. During Mr. R’s second episode of increased irritability, depression, and mood lability, he had been drinking alcohol excessively in the context of marital conflict and life stress. These factors contributed to his mood and behavior changes, in the context of a progressive neurodegenerative disease. In our opinion, these psychiatric symptoms cannot be directly attributed to DBS. The preponderance of the evidence suggests that the patient’s progressive neurocognitive disorder, his alcohol use, and his diagnosis of adjustment disorder with disturbance of emotions and conduct contributed to his behavioral changes. This case highlights the crucial role of the psychiatrist in the assessment and treatment of patients with Parkinson’s disease undergoing DBS.
Acknowledgments
The authors thank Steven J. Pollock, Ph.D., at the University of Colorado Boulder, for his help understanding the physics of deep brain stimulation.
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Dr. Klepitskaya has served as a consultant for Acadia Pharmaceuticals and Cynapsus Therapeutics and is conducting clinical trials for U.S. WorldMeds. Dr. Ojemann has served as a consultant for Medtronic and as a data safety monitoring board member for Voyager Therapeutics. Dr. Abosch has served as a consultant for Medtronic. The other authors report no financial relationships with commercial interests.
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