Therapeutic high-frequency stimulation of the subthalamic nucleus in Parkinson's disease produces global increases in cerebral blood flow

Chronic, high-frequency electrical stimulation of the subthalamic nuclei (STNs) has become an effective and widely used therapy in Parkinson's disease (PD), but the therapeutic mechanism is not understood. Stimulation of the STN is believed to reorganize neurophysiological activity patterns within the basal ganglia, whereas local field effects extending to tracts adjacent to the STN are viewed as sources of nontherapeutic side effects. This study is part of a larger project investigating the effects of STN stimulation on speech and regional cerebral blood flow (CBF) in human subjects with PD. While generating measures of global CBF (gCBF) to normalize regional CBF values for a subsequent combined analysis of regional CBF and speech data, we observed a third effect of this therapy: a gCBF increase. This effect was present across three estimates of gCBF ranging from values based on the highest activity voxels to those based on all voxels. The magnitude of the gCBF increase was related to the subject's duration of PD. It is not clear whether this CBF effect has a therapeutic role, but the impact of deep brain stimulation on cerebrovascular control warrants study from neuroscience, pathophysiological, and therapeutic perspectives.     

Deep brain stimulation of the subthalamic nucleus does not increase the striatal dopamine concentration in parkinsonian humans.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) has become an effective treatment option in advanced Parkinson's disease (PD). Recent animal studies showed an increase of neuronal firing in dopaminergic neurons under effective STN-DBS. Increased striatal dopamine levels may also contribute to the stimulation's mechanism of action in humans. We investigated the striatal dopamine release in 6 patients with advanced PD under effective bilateral STN-DBS with positron emission tomography (PET) of the reversible dopamine-D2/3-receptor ligand [(11)C]raclopride (RACLO). Although STN-DBS proved to be a highly effective treatment in these subjects, we found no significant difference of the striatal RACLO binding between the STN-DBS-on and -off condition. The changes of radioligand binding did not correlate with the patients' improvement in clinical rating scales or with the stimulation amplitudes. Therefore, our PET data in living parkinsonian humans do not provide evidence for an increased striatal dopamine concentration under effective STN-DBS. We conclude that the modulation of dopaminergic activity does not seem to play a crucial role for the stimulation's mechanisms of action in parkinsonian humans.     

Replacement of dopaminergic medication with subthalamic nucleus stimulation in Parkinson's disease: Long‐term observation

Stimulation of the subthalamic nucleus (STN) is an effective treatment for advanced Parkinson's disease (PD), but the medication requirements after implant are poorly known. We performed a long‐term prospective evaluation of 20 patients maintained at stable dopaminergic therapy for 5 years after bilateral STN implants, who were evaluated 6 months, 1 year, 3 years, and 5 years after surgery. We measured, during the entire observation period, the effect of deep brain stimulation on motor and functional outcome measures, the levodopa equivalent daily dose and the total electrical energy delivered. At 5 years, the UPDRS motor score had improved by 54.2% and levodopa equivalent dose was reduced by 61.9%, compared with preimplant. Dopaminergic medication remained stable during the observation period, but energy was progressively increased over time. Rest tremor, rigidity, gait, lower and upper limb akinesia, and total axial score were improved in decreasing order. Postural stability and speech improved transiently, whereas on‐period freezing of gait, motor fluctuations and dyskinesias recovered durably. Functional measures did not show improvement in autonomy and daily living activities after STN implant. Chronic STN stimulation allows to replace for dopaminergic medications in the long‐term at the expense of an increase of the total energy delivered. This is associated with marked improvement of motor features without a matching benefit in functional measures. © 2008 Movement Disorder Society     

Pathological gambling in Parkinson's disease improves on chronic subthalamic nucleus stimulation.

Pathological gambling (PG) related to dopaminergic treatment in Parkinson's disease (PD) is part of a spectrum of behavioral disorders called the dopamine dysregulation syndrome (DDS). We describe a series of PD patients with preoperative active PG due to dopaminergic treatment from a total of 598 patients who have undergone surgery for subthalamic nucleus stimulation for disabling motor fluctuations. The patients had systematic open assessment of behavioral symptoms and standardized assessments of motor symptoms, mood, and apathy. Seven patients (6 men, 1 woman; age, 54 +/- 9 years; levodopa equivalent dose, 1,390 +/- 350 mg/day) had preoperative PG over a mean of 7 years, intolerant to reduction in medication. Six had nonmotor fluctuations and four had other behavioral symptoms consistent with a diagnosis of the DDS. After surgery, motor symptoms improved, allowing for 74% reduction of dopaminergic treatment, below the dosage of gambling onset. In all patients, PG resolved postoperatively after 18 months on average (range, 0-48), although transient worsening occurred in two. Improvement paralleled the time course and degree of reduction in dopaminergic treatment. Nonmotor fluctuations, off period dysphoria, and other symptoms of the DDS improved. Two patients developed persistent apathy. In conclusion, PG and other symptoms of the DDS-associated dopaminergic treatment improved in our patients following surgery. Dopaminergic dysregulation commonly attributed to pulsatile overstimulation of the limbic dopaminergic system may be subject to desensitization on chronic subthalamic stimulation, which has a relative motor selectivity and allows for decrease in dopaminergic treatment.     

Clinical and economic results of bilateral subthalamic nucleus stimulation in Parkinson's disease

BACKGROUND: High frequency stimulation of the subthalamic nucleus (STN) is an alternative but expensive neurosurgical treatment for parkinsonian patients with levodopa induced motor complications. OBJECTIVE: To assess the safety, clinical effects, quality of life, and economic cost of STN stimulation. METHODS: We conducted a prospective multicentre study in 95 consecutive Parkinson's disease (PD) patients receiving bilateral STN stimulation and assessed its effects over 12 months. A double blind randomised motor evaluation was carried out at 3 month follow up, and quality of life, self care ability, and predictive factors of outcome following surgery were assessed. The cost of PD was estimated over 6 months before and after surgery. RESULTS: The Unified Parkinson's Disease Rating Scale (UPDRS) motor score improved by 57% (p<0.0001) and activities of daily living improved by 48% (p<0.0001) at 12 month follow up. Double blind motor scoring improved by 51% at 3 month follow up (p<0.0001). The total PD Quality of Life Questionnaire (PDQL-37) score improved by 28% (p<0.001). The better the preoperative motor score after a levodopa challenge, the better the outcome after STN stimulation. Five patients developed an intracerebral haematoma during electrode implantation with permanent after effects in two. The 6 month costs of PD decreased from 10,087 euros before surgery to 1673 euros after surgery (p<0.0001) mainly because of the decrease in medication. These savings allowed a return on the procedure investment, estimated at 36,904 euros over 2.2 years. CONCLUSIONS: STN stimulation has good outcomes with relatively low risk and little cost burden in PD patients with levodopa induced motor complications.     

Evolution of Parkinson's disease during 4 years of bilateral deep brain stimulation of the subthalamic nucleus.

Patients with advanced Parkinson's disease (PD) and motor complications can obtain significant symptom improvement by deep brain stimulation (DBS) of the subthalamic nucleus (STN). Very little is published, however, about long-term effect and disease evolution during DBS. We performed a 4-year prospective study of the first 22 consecutive patients treated with STN DBS. The patients were evaluated with Unified Parkinson's Disease Rating Scale Part II to VI and a patient diary concerning on-off periods and dyskinesia. Patients were scored before surgery on medication and off medication for 10 to 12 hours and in four conditions 1 and 4 years after surgery: off medication+/-stimulation and on medication+/-stimulation. In advanced PD, a significant reduction of dyskinesia and off periods was present 4 years (90%/67%) after the operation. Total motor function on stimulation alone improved 55% at 4 years, compared with baseline and activities of daily living (42%). On stimulation, significant worsening of axial symptoms and speech was present from 1 to 4 years. To evaluate disease evolution, motor symptoms were assessed off stimulation and medication for 12 hours and were found not to worsen compared with baseline, which is remarkable in an otherwise progressive disorder. Five patients developed dementia. Severe adverse events were not observed.     

Mortality in patients with Parkinson's disease treated by stimulation of the subthalamic nucleus.

Subthalamic nucleus (STN) stimulation improves motor disability and quality of life in patients with advanced Parkinson's disease (PD). Short-term mortality is low, but little is known about long-term mortality. We assessed mortality and causes of death in 171 consecutive PD patients treated by STN stimulation. Surgery was performed after a median lagtime of 13 years from PD onset at a median age of 57 years. The median follow-up after surgery was 41 months. Sixteen patients died 8 to 83 months after neurosurgery. Poorer cognitive function was the only predictive factor for mortality (standardized mortality ratio = 2.9; 95% confidence interval [CI], 1.6-4.7; P < 0.0001). Based on a historical comparison of 118 operated patients with 39 nonoperated patients from a different population, survival among operated patients was not better (hazard ratio = 1.2; 95% CI, 0.7-2.1).     

Lifetime of Itrel II pulse generators for subthalamic nucleus stimulation in Parkinson's disease.

The efficacy of bilateral subthalamic nucleus (STN) stimulation in Parkinson's disease (PD) is well-established but little is known about the lifetime of implanted pulse generators (IPG). To investigate the lifetime of the bilaterally implanted Itrel II(R) (Medtronic, Minneapolis) pulse generator, the first 49 consecutive patients with PD having been operated on at our center for bilateral STN chronic stimulation were reviewed with noting of the stimulation parameters in use prior to IPG replacement. The mean electrical voltage was 3.2 +/- 0.3 V, mean pulse width was 65 +/- 10 mus, and mean frequency was 145 +/- 16 Hz. Replacement of an IPG was anticipated in 25% due to unilateral low-battery signaling, or end of life. In either case, replacement of the contralateral IPG was undertaken simultaneously. The mean IPG lifetime was 83 +/- 14 [40-113] months. The IPG lifetime correlated with the total electrical energy delivered (P = 0.002, r = -0.496). Unilateral IPG end-of-life generally led to subacute worsening of contralateral parkinsonism. In 25% of patients, there was also a worsening of axial symptoms leading to potential medical emergencies such as falls (10%), aspiration pneumonia (10%), or psychosis (5%). A close monitoring of patients and an anticipation of IPG replacement in the case of a low-battery signal are recommended.     

Effect of levodopa on pain threshold in Parkinson's disease: a clinical and positron emission tomography study.

Patients suffering from Parkinson's disease (PD) frequently experienced painful sensations that could be in part due to central modification of nociception. We compared pain threshold before and after administration of levodopa in PD patients and in controls, and investigated cerebral activity with positron emission tomography (PET) during experimental nociceptive stimulation. Pain threshold was determined using thermal stimulation during two randomized conditions: off and on. We performed H(2) (15)O PET analysis of regional cerebral blood flow on subjects while they received alternate randomized noxious and innocuous stimuli during off and on conditions. In off condition, pain threshold in nine PD patients was significantly lower than in nine controls. Administration of levodopa significantly raised pain threshold in PD patients but not in controls. During off condition, there was a significant increase in pain-induced activation in right insula and prefrontal and left anterior cingulate cortices in PD compared to control group. Levodopa significantly reduced pain-induced activation in these areas in PD. This study shows that pain threshold is lower in PD patients but returns to normal ranges after levodopa administration. Moreover, PD patients have higher pain-induced activation in nociceptive pathways, which can be reduced by levodopa.     

Does subthalamic nucleus deep brain stimulation really improve quality of life in Parkinson's disease?

We investigated the impact of subthalamic nucleus (STN) deep brain stimulation (DBS) on quality of life (QOL) in patients with advanced Parkinson's disease, as self-assessed before and after surgery by completing the Parkinson's Disease Questionnaire (PDQ39). In addition to this prospective evaluation, we asked patients postoperatively to evaluate their preoperative QOL. In the prospective assessment, results showed that patients perceived a general improvement of QOL after the STN DBS. However, when evaluated retrospectively, they tended to overestimate their preoperative functioning, therefore obscuring the improvement found prospectively. This observation highlights the impact of the method used on obtained results when assessing the effects of STN DBS.     

Brain energization in response to deep brain stimulation of subthalamic nuclei in Parkinson's disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment in a subgroup of medically refractory patients with Parkinson''s disease (PD). Here, we compared resting-state ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography images in the stimulator off (DBS_OFF) and on (DBS_ON) conditions in eight PD patients in an unmedicated state, on average 2 years after bilateral electrode implantation. Global standardized uptake value (SUV) significantly increased by ∼11% in response to STN-DBS. To avoid any bias in the voxel-based analysis comparing DBS_ON and DBS_OFF conditions, individual scan intensity was scaled to a region where FDG-SUV did not differ significantly between conditions. The resulting FDG-SUV ratio (FDG-SUVR) was found to increase in many regions in response to STN-DBS including the target area of surgery, caudate nuclei, primary sensorimotor, and associative cortices. Contrary to previous studies, we could not find any regional decrease in FDG-SUVR. These findings were indirectly supported by comparing the extent of areas with depressed FDG-SUVR in DBS_OFF and DBS_ON relatively to 10 normal controls. Altogether, these novel results support the prediction that the effect of STN-DBS on brain activity in PD is unidirectional and consists in an increase in many subcortical and cortical regions.     

Risk factors for executive dysfunction after subthalamic nucleus stimulation in Parkinson's disease

A slight decline in cognitive functions and especially in executive functioning after deep brain stimulation (DBS) of the nucleus subthalamicus (STN) in patients with Parkinson's disease (PD) has been described. This study evaluated baseline parameters that contribute to a deterioration of cognitive functioning after DBS. We analyzed data from the neuropsychological protocol in a randomized controlled study comparing DBS with best medical treatment (BMT). Change scores were calculated for the cognitive domains “global cognitive functioning,” “memory,” “working memory,” “attention,” and “executive function.” These domain‐specific change scores were correlated with previously defined preoperative parameters. Compared with the BMT group (63 patients), the STN‐DBS group (60 patients) showed a significant decline only in the domain executive function 6 months after DBS, which was significantly correlated with age, levodopa‐equivalence dosage (LED) and axial subscore of the UPDRS in the off‐medication state at baseline. Multiple regression analysis showed that these three factors explained, however, only about 23% of the variance. Patients with higher age, higher baseline LED, and/or higher axial subscore of the UPDRS at baseline have an increased risk for worsening of executive function after STN‐DBS. High scores of these factors might reflect an advanced stage of disease progression. As these baseline factors explained the variance of the change score executive function only to a minor proportion, other factors including the surgical procedure, the exact placement of the electrode or postsurgical management might be more relevant for a decline in executive functioning after STN‐DBS. © 2010 Movement Disorder Society     

Apomorphine effect on pain threshold in Parkinson's disease: A clinical and positron emission tomography study

Patients with Parkinson's disease (PD) frequently experience pain that could be in part due to central modification of nociception. In this randomized controlled double blind study, we compared the effect of apomorphine versus placebo on pain thresholds and pain‐induced cerebral activity in 25 patients with PD. Subjective pain threshold (using thermal stimulation, thermotest), objective pain threshold (nociceptive flexion reflex), and cerebral activity (HO PET) during noxious and innocuous stimulations were performed. Neither subjective nor objective pain thresholds nor pain activation profile were modified by apomorphine compared with placebo in 25 PD patients. Apomorphine has no effect on pain processing in PD. We suggest that other monoamine systems than dopaminergic system could be involved. © 2010 Movement Disorder Society.     

Transient mania with hypersexuality after surgery for high frequency stimulation of the subthalamic nucleus in Parkinson's disease.

Among 30 Parkinson's disease patients who received high frequency stimulation of the subthalamic nucleus, 5 developed remarkable disorders of mood or sexual behavior after the implant. We describe 2 men who developed mania and hypersexuality a few days after the implant that lasted for some months and then gradually disappeared spontaneously.     

Functional imaging of subthalamic nucleus deep brain stimulation in Parkinson's disease

Deep brain stimulation of the subthalamic nucleus is an accepted treatment for the motor complications of Parkinson's disease. The therapeutic mechanism of action remains incompletely understood. Although the results of deep brain stimulation are similar to the results that can be obtained by lesional surgery, accumulating evidence from functional imaging and clinical neurophysiology suggests that the effects of subthalamic nucleus‐deep brain stimulation are not simply the result of inhibition of subthalamic nucleus activity. Positron emission tomography/single‐photon emission computed tomography has consistently demonstrated changes in cortical activation in response to subthalamic nucleus‐deep brain stimulation. However, the technique has limited spatial and temporal resolution, and therefore the changes in activity of subcortical projection sites of the subthalamic nucleus (such as the globus pallidus, substantia nigra, and thalamus) are not as clear. Clarifying whether clinically relevant effects from subthalamic nucleus‐deep brain stimulation in humans are mediated through inhibition or excitation of orthodromic or antidromic pathways (or both) would contribute to our understanding of the precise mechanism of action of deep brain stimulation and may allow improvements in safety and efficacy of the technique. In this review we discuss the published evidence from functional imaging studies of patients with subthalamic nucleus‐deep brain stimulation to date, together with how these data inform the mechanism of action of deep brain stimulation. © 2011 Movement Disorder Society     

Expectation and the placebo effect in Parkinson's disease patients with subthalamic nucleus deep brain stimulation.

To determine whether the degree to which a patient with Parkinson's disease expects therapeutic benefit from subthalamic nucleus-deep brain stimulation (STN-DBS) influences the magnitude of his or her improved motor response, 10 patients with idiopathic Parkinson's and bilateral STN-DBS were tested after a 12-hour period off medication and stimulation. Four consecutive UPDRS III scores were performed in the following conditions: (a) stimulation OFF, patient aware; (b) stimulation OFF, patient blind; (c) stimulation ON, patient aware; and (d) stimulation ON, patient blind. Statistical significance (P = 0.0001) was observed when comparing main effect ON versus OFF (mean ON: 32.55; mean OFF: 49.15). When the stimulation was OFF, patients aware of this condition had higher UPDRS motor scores than when they were blinded (mean: 50.7 vs. 47.6). With the stimulation ON, UPDRS motor scores were lower when the patients were aware of the stimulation compared with when they were blinded (mean: 30.6 vs. 34.5). The interaction between these levels was significant (P = 0.049). This variation was important for bradykinesia and was not significant for tremor and rigidity. The authors conclude that the information about the condition of the stimulation enhanced the final clinical effect in opposite directions. The results presented support the role of expectation and placebo effects in STN-DBS in Parkinson's disease patients.