The impact of deep brain stimulation on the nonmotor symptoms of Parkinson’s disease

Deep brain stimulation (DBS) is a well-established therapy for patients with advanced Parkinson’s disease (PD) with clear benefits on many of the motor symptoms. The effects of DBS on the nonmotor symptoms are less well examined. Emergence of tools to measure the nonmotor burden in PD is now allowing a more objective assessment of impact of DBS on such symptoms. Here we review the pertinent evidence and conclude that, as a therapy, DBS has a major potential to contribute towards the holistic care of PD patients.     

Olfactory function in patients with idiopathic Parkinson’s disease: effects of deep brain stimulation in the subthalamic nucleus

Summary. Decrease of olfactory function in patients with Parkinsons disease (PD) is a well-investigated fact. The present study aimed to investigate olfaction in PD patients with a specific focus on the effects of deep brain stimulation in the subthalamic nucleus. Eleven patients (age 42–67 years) participated in this study. Using the Sniffin Sticks, olfactory function was assessed based on butanol odor thresholds and the patients ability to discriminate odors. Measures were taken with the stimulator being switched ON and OFF, respectively. While deep brain stimulation had no effect on odor thresholds, in hyposmic PD patients odor discrimination was found to be significantly higher during the ON period. This may indicate that deep brain stimulation has a positive effect on the cognitive processing of olfactory information in PD patients.     

Low-frequency subthalamic nucleus deep brain stimulation for axial symptoms in advanced Parkinson’s disease

Axial symptoms such as freezing of gait and falls are common manifestations of advanced Parkinson’s disease (PD) and are partially responsive to medical treatment. High-frequency (≥130 Hz) deep brain stimulation (DBS) of the subthalamic nucleus (STN) is highly efficacious in ameliorating appendicular symptoms in PD. However, it is typically less effective in improving axial symptomatology, especially in the long term. We have studied the effects of low-frequency stimulation (LFS) (≤80 Hz) for improving speech, gait and balance dysfunction in the largest patient population to date. PD patients with bilateral STN-DBS and resistant axial symptoms were switched from chronic 130 Hz stimulation to LFS and followed up to 4 years. Primary outcome measures were total motor UPDRS scores, and axial and gait subscores before and after LFS. Bivariate analyses and correlation coefficients were calculated for the different conditions. Potential predictors of therapeutic response were also investigated. Forty-five advanced PD patients who had high frequency stimulation (HFS) for 39.5 ± 27.8 consecutive months were switched to LFS. LFS was kept on for a median period of 111.5 days before the assessment. There was no significant improvement in any of the primary outcomes between HFS and LFS, although a minority of patients preferred to be maintained on LFS for longer periods of time. No predictive factors of response could be identified. There was overall no improvement from LFS in axial symptoms. This could be partly due to some study limitations. Larger prospective trials are warranted to better clarify the impact of stimulation frequency on axial signs.     

The potential neuromodulatory impact of subthalamic nucleus deep brain stimulation on Parkinson’s disease progression

IntroductionSTN-DBS has been claimed to change progression symptoms in animal models of PD, but information is lacking about the possible neuromodulatory role of STN-DBS in humans. The aim of this prospective controlled study was to evaluate the long-term impact of STN-DBS on motor disabilities and cognitive impairment in PD patients in comparison to Best-Medical-Therapy (BMT) and Long-term-Post-Operative (POP) groups.Material and methodsPatients were divided into 3 groups: the BMT-group consisted of 20 patients treated only with pharmacotherapy, the DBS-group consisted of 20 PD patients who underwent bilateral STN-DBS (examined pre- and postoperatively) and the POP-group consisted of 14 long-term postoperative patients in median 30 month-time after DBS. UPDRS III scale was measured during 3 visits in 9 ± 2 months periods (V1, V2, V3) in total-OFF phase. Cognitive assessment was performed during each visit in total-ON phase.ResultsThe comparable UPDRS III OFF gain was observed in both BMT-group and POP-group evaluations (p < 0.05). UPDRS III OFF results in DBS-group revealed significant UPDRS III OFF increase in ΔV2-V1 assessment (p < 0.05) with no significant UPDRS III OFF alteration in ΔV3-V2 DBS-group evaluation (p > 0.05). Cognitive assessment revealed significant alterations between DBS-group and BMT-group in working memory, executive functions and learning abilities (p < 0.05).ConclusionsThe impact of STN-DBS on UPDRS III OFF score and cognitive alterations suggest its neuromodulatory role, mainly during the first 9–18 months after surgery.     

Influence of deep brain stimulation of the subthalamic nucleus on cognitive function in patients with Parkinson’s disease

Deep brain stimulation (DBS) is an effective technique for treating Parkinson’s disease (PD) in the middle and advanced stages. The subthalamic nucleus (STN) is the most common target for clinical treatment using DBS. While STN-DBS can significantly improve motor symptoms in PD patients, adverse cognitive effects have also been reported. The specific effects of STN-DBS on cognitive function and the related mechanisms remain unclear. Thus, it is imperative to identify the influence of STN-DBS on cognition and investigate the potential mechanisms to provide a clearer view of the various cognitive sequelae in PD patients. For this review, a literature search was performed using the following inclusion criteria: (1) at least 10 patients followed for a mean of at least 6 months after surgery since the year 2006; (2) pre- and postoperative cognitive data using at least one standardized neuropsychological scale; and (3) adequate reporting of study results using means and standard deviations. Of ～170 clinical studies identified, 25 cohort studies (including 15 self-controlled studies, nine intergroup controlled studies, and one multi-center, randomized control experiment) and one metaanalysis were eligible for inclusion. The results suggest that the precise mechanism of the changes in cognitive function after STN-DBS remains obscure, but STN-DBS certainly has effects on cognition. In particular, a progressive decrease in verbal fluency after STN-DBS is consistently reported and although executive function is unchanged in the intermediate stage postoperatively, it tends to decline in the early and later stages. However, these changes do not affect the improvements in quality of life. STN-DBS seems to be safe with respect to cognitive effects in carefully-selected patients during a follow-up period from 6 months to 9 years.     

Influence of deep brain stimulation of the subthalamic nucleus on cognitive function in patients with Parkinson＇s disease

Deep brain stimulation （DBS） is an effective technique for treating Parkinson＇s disease （PD） in the middle and advanced stages. The subthalamic nucleus （STN） is the most common target for clinical treatment using DBS. While STN-DBS can significantly improve motor symptoms in PD patients, adverse cognitive effects have also been reported. The specific effects of STN-DBS on cognitive function and the related mechanisms remain unclear. Thus, it is imperative to identify the influence of STN-DBS on cognition and investigate the potential mechanisms to provide a clearer view of the various cognitive sequelae in PD patients. For this review, a literature search was performed using the following inclusion criteria： （1） at least 10 patients followed for a mean of at least 6 months after surgery since the year 2006; （2） pre- and postoperative cognitive data using at least one standardized neuropsychological scale; and （3） adequate reporting of study results using means and standard deviations. Of -170 clinical studies identified, 25 cohort studies （including 15 self-controlled studies, nine intergroup controlled studies, and one multi-center, randomized control experiment） and one meta- analysis were eligible for inclusion. The results suggest that the precise mechanism of the changes in cognitive function after STN-DBS remains obscure, but STN-DBS certainly has effects on cognition. In particular, a progressive decrease in verbal fluency after STN-DBS is consistently reported and although executive function is unchanged in the intermediate stage postoperatively, it tends to decline in the early and later stages. However, these changes do not affect the improvements in quality of life. STN-DBS seems to be safe with respect to cognitive effects in carefully-selected patients during a follow-up period from 6 months to 9 years.     

Pathological crying induced by deep brain stimulation of the subthalamic nucleus in Parkinson’s disease

We report on a patient with deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson’s disease (PD) who developed pathologic crying (PC) immediately postoperatively. A spread of DBS current to adjacent cortico-ponto-cerebellar pathways might be responsible. In contrast to the few cases published previously, there was no pre-existing additional lesion that would have favoured occurrence of PC. Treating physicians should be aware of DBS-induced PC.     

Does bilateral stimulation of the subthalamic nucleus aggravate apathy in Parkinson's disease?

OBJECTIVE: High frequency stimulation of the subthalamic nucleus (STN) dramatically decreases motor disability in patients with Parkinson"s disease (PD), but has been reported to aggravate apathy. The aim of this study was to analyse the effect of STN stimulation on motivation and reward sensitivity in a consecutive series of PD patients. METHODS: Apathy and reward sensitivity (Apathy Scale, Stimulus-Reward Learning, Reversal, Extinction, and Gambling tasks) were assessed in 18 PD patients treated by bilateral STN stimulation ("on" and "off" conditions) compared with 23 matched patients undergoing long term treatment with levodopa ("on" and "off" conditions). RESULTS: Apathy decreased under both STN stimulation and levodopa treatment, whereas explicit and implicit stimulus reward learning was unchanged. CONCLUSIONS: Bilateral STN stimulation in PD patients does not necessarily have a negative effect on motivation and reward sensitivity and can even improve apathy provided patients have been appropriately selected for neurosurgery.     

Neuroleptic malignant syndrome (parkinsonism–hyperpyrexia syndrome) after deep brain stimulation of the subthalamic nucleus

Neuroleptic malignant syndrome (NMS), also called parkinsonism–hyperpyrexia syndrome (PHS), is a severe, general, sometimes fatal, physical reaction, induced by sudden and strong blockade of dopamine receptors. When subthalamic nucleus (STN)–deep brain stimulation (DBS) is used on patients with Parkinson disease (PD), dopaminergic medications are transiently stopped prior to the procedure, and a reduction in the use of drugs is routinely attempted after the procedure. Although a sudden stop or abrupt reduction of dopaminergic medications may set the stage for NMS/PHS, only three cases have been reported after STN–DBS surgery. Here, we describe a 75-year-old woman with PD who experienced delayed onset, yet fatal, PHS after STN–DBS. Although STN–DBS might prevent or suppress PHS, its protective effect is not always complete. We must be aware that fatal PHS can occur when the use of medication for PD is reduced or altered, even when patients are under continuous STN stimulation.     

Is a computational model useful to understand the effect of deep brain stimulation in Parkinson's disease?

A growing number of computational models have been proposed over the last few years to help explain the therapeutic effect of deep brain stimulation (DBS) on motor disorders in Parkinson's disease (PD). However, none of these has been able to explain in a convincing manner the physiological mechanisms underlying DBS. Can these models really contribute to improving our understanding? The model by Rubin and Terman [31] represents one of the most comprehensive and biologically plausible models of DBS published recently. We examined the validity of the model, replicated its simulations and tested its robustness. While our simulations partially reproduced the results presented by Rubin and Terman [31], several issues were raised including the high complexity of the model in its non simplified form, the lack of robustness of the model with respect to small perturbations, the nonrealistic representation of the thalamus and the absence of time delays. Computational models are indeed necessary, but they may not be sufficient in their current forms to explain the effect of chronic electrical stimulation on the activity of the basal ganglia (BG) network in PD.     

Brain flow changes before and after deep brain stimulation of the subthalamic nucleus in Parkinson’s disease

Abstract. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) markedly improves motor symptoms and reduces medication needs in Parkinsons disease (PD) patients. However, its effect on brain function has remained unclear. We used SPECT and the tracer ECD to measure regional cerebral blood flow before and 6 months after DBS of the STN in 22 PD patients and 13 healthy controls. PD patients were divided into good and poor responders to DBS, if changes in off UPDRS motor scores after surgery were >60% or <40%, respectively. Statistical analysis was performed using the SPM99 software. At baseline, all PD patients showed significant perfusion reductions in cortical areas (premotor frontal, parietal, and occipital). After DBS, changes were normalized only in the good responders, while cortical defects in the poor responders were unchanged. No flow decrements were detected in basal ganglia and thalamus in both groups, suggesting that DBS does not have a lesion-like effect. We conclude that good surgery outcome is associated with normalization of cortical flow abnormalities in PD.