Our results showed that, in PD patients presenting for STN DBS, wake disturbances were frequent and sleepquality was poor. Despite considerable overlap, subjective daytime sleepi- ness, fatigue, apathy, and depression were distinct and occurred also as “pure” symptom, i.e. isolated. These findings further support the notion that SWD do not occur in PD solely as part of other non-motor symptoms (e.g. depression) or as side-effects of dopaminergic medication but may represent manifestations of PD that may occur even in the drug-naïve phase worsen with disease progression. The short sleep latency in MSLT was suggestive for severe excessive daytime sleepiness whereas the scores in MWT and in the actigraphy were consistent with pre- served ability to remain alert and physical daytime activity. However, it cannot be excluded that an increased physical inactivity during the day could be masked by the increased severity in disease symptoms (e.g dyskinesias) in these patients, which cannot be distinguished by acti- graphy. The main polysomnographic findings can be summarized as followings: the disrupted sleep macroarchitecture, the reduced sleep efficiency and in about one fifth of the patients the presence of PLM in sleep and the disturbed respiration suggestive for the presence of at least a Table 4. Association of post-DBS changes in QoL with change scores of several progression variables.
Although proven safe and effective, DBS therapy is most effective when applied to the correctly selected PD patient (Bronstein et al., 2011), and nearly one-third of DBS failures are attributed to improper patient selection (Okun et al., 2005). In the most expert neurological centers, multidisciplinary teams of neurologists, neurosurgeons, neuropsychologists, and even psychiatrists evaluate a patient’s candidacy for surgery, determining their individual risk- benefit analysis. It is worth noting, however, that there is evidence that DBS interventions (for patients with non-atypical parkinsonism) may have a greater positive impact on quality of life measures when delivered in earlier stages of Parkinson’s disease progression (Schüpbach et al., 2007; Merola et al., 2015).
Akinesia and rigidity UPDRS III subscores with med “on”/stim “on” and med “off”/stim “on” show a sustained improvement up to 4 years after surgery, compared to baseline. A significant decrease in UPDRS IV is observed. This is most likely due to the reduction of the levodopa equivalent dosage administered to the patients. The dyskinesia-related pain and disability together with off-periods related with levodopa medication are critical factors affecting a patient’s everyday life, and the reduction of such complications is a major advantage in the patients’ quality of life. Thus, it is evident that the stimulation of STN makes possible a substantial reduction in the dose of dopaminergic treatment. Motor activities of daily living (UPDRS II) show a marked decrease when compared to baseline, a result consistent with the improvement shown in UPDRS III scores.
DBS is an effective treatment for many medically intractable motor symptoms of Parkinson’s disease. In recent years, signif- icant advances have been made both in the hardware and in our understanding of the benefits and limitations of DBS, allow- ing us to select patients for surgery better and provide more realistic expectations of outcomes. DBS is clearly superior to best medical management in properly selected patients but is associated with additional risks. Infection is the most common serious adverse event encountered, but most adverse events do not result in permanent disability. Recent randomized blinded studies have suggested that DBS to the globus pallidus inter- nus is equally effective in controlling motor symptoms and may be associated with fewer nonmotor side effects. Given the increased risk of neurobehavioral problems with DBS to the subthalamic nucleus, we have been selecting the globus pallidus internus as the surgical target much more frequently than the subthalamic nucleus. Although it is our opinion that the goal of DBS is to improve the patient’s quality of life and not necessarily to reduce medication dosages maximally, there are some patients for which DBS to the subthalamic nucleus is the more appropriate target. Thus, both targets should be considered and the final target selection should be based on each patient’s individual characteristics.
Purpose: The nonmotor symptoms (NMS) of Parkinson’s disease (PD) are important factors for quality of life (QoL). Few studies on NMS have been conducted in Asian PD patients. Addi- tionally, effects of anti-PD drugs on risk of NMS are still controversial. We therefore conducted this hospital-based cross-sectional study to examine the clinical factors, including concomitant anti-PD medication use, on the occurrence of NMS and QoL in Taiwanese PD patients. Patients and methods: PD patients who received long-term follow-up in the movement disorders clinics were enrolled and received NMS questionnaire (NMSQuest) and the 39-item Parkinson’s Disease Questionnaire (PDQ-39). Spearman’s rank correlation coefficient was checked for the correlation between clinical factors and NMSQT/PDQSI. Multiple linear regres- sions were applied to assess the influence of clinical factors on NMSQT/PDQSI.
Over the last decades, DeepBrainStimulation (DBS) of the subthalamic nucleus (STN) has emerged as an effective treatment for drug-resistant resting tremor and disabling drug- induced motor complications in patients with PD. Growing data show an improvement of motor symptoms and quality of life in PD patients over a period of up to five years after DBS. 5 The few available studies with longer follow-up periods (8-10 years), show a persistent
DeepBrainStimulation should be considered by patients with Parkinson’s disease who respond to levodopa therapy but have medication side effects or motor fluctuations throughout the day despite being on optimal medical treatment. DBS can improve function and quality of life by reducing dyskinesia, increasing “on” time, reducing severity of “off” symptoms, and allowing medications to be reduced.
most consistent and signiﬁcant change is seen in sleep maintenance (PDSS-3), in keeping with our study. It is possible that patients interpret this change as an improvement in their overall sleepquality (PDSS-1). In addition, we also noted substantial improvement in tremor and painful posturing after waking (PDSS-12 and 13), which is likely related to better control of motor symptoms by DBS even before the morning dose of dopaminergic medication is ingested.
A factor difficult to account for is whether STN stimula- tion also influences attention and cognitive functions. The STN receives projections involved in emotional and cog- nitive activities from the anterior cingulate, inferior frontal cortex and medial and dorsolateral pre-frontal cortices , and an integrative function has been suggested . Indeed, recent evidence suggests that DBS stimulation of the STN may have some involvement in modifying atten- tional cerebral networks . Noteworthy, attention is also important for human motor control and for oculo- motor performance [52,53]. Hence, one cannot rule out that improvements in attention and cognition partly ac- count for the improvements recorded in oculomotor per- formance with STN stimulation. However, given the revealed relationships between several oculomotor param- eters and UPDRS motor scores assessed with DBS ON, it is likely that not only is oculomotor function changed by any such attention enhancement induced by STN stimula- tion, but also motor functions assessed by the UPDRS.
of using DBS, they do not provide much guidance to the clinician trying to select stimulation parameters that bal- ance the tradeoffs between clinical effects and battery life. A more detailed understanding might help clinicians select more suitable stimulation parameters, but only a few studies have begun to investigate motor performance at intermediate stimulation settings. For example, one study investigated the effects of different combinations of contact location (rela- tive to the subthalamic nucleus) and amplitude in patients with Parkinson’s disease. Given that the main focus was speech intelligibility, movement was only examined as a composite outcome. 10 Another demonstrated that frequency
Abstract: Study Objectives: This prospective observational study was designed to systematically examine the effect of subthalamicdeepbrainstimulation (DBS) on subjective and objective sleep–wake parameters in Parkinsonpatients. Methods: In 50 consecutive Parkinsonpatients undergoing subthalamic DBS, we assessed motor symptoms, medication, the position of DBS electrodes within the subthalamic nucleus (STN), subjective sleep–wake parameters, 2-week actigraphy, video-polysomnography studies, and sleep electroencepahalogram frequency and dynamics analyses before and 6 months after surgery. Results: Subthalamic DBS improved not only motor symptoms and reduced daily intake of dopaminergic agents but also enhanced subjective sleepquality and reduced sleepiness (Epworth Sleepiness Scale: −2.1 ± 3.8, p < .001). Actigraphy recordings revealed longer bedtimes (+1:06 ± 0:51 hours, p < .001) without shifting of circadian timing. Upon polysomnography, we observed an increase in sleep eﬀiciency (+5.2 ± 17.6%, p = .005) and deepsleep (+11.2 ± 32.2 min, p = .017) and increased accumulation of slow-wave activity over the night (+41.0 ± 80.0%, p = .005). Rapid eye movement sleep features were refractory to subthalamic DBS, and the dynamics of sleep as assessed by state space analyses did not normalize. Increased sleep eﬀiciency was associated with active electrode contact localization more distant from the ventral margin of the left subthalamic nucleus. Conclusion: Subthalamic DBS deepens and consolidates nocturnal sleep and improves daytime wakefulness in Parkinsonpatients, but several outcomes suggest that it does not normalize sleep. It remains elusive whether modulated activity in the STN directly contributes to changes in sleep–wake behavior, but dorsal positioning of electrodes within the STN is linked to improved sleep–wake outcomes.
WHAT ARE THE STUDY’S MAIN FINDINGS? Most tests of thinking were not different in the 2 groups. Scores on 2 tests of thinking were better in the GPi group than the STN group. Both tests involved response speed. This means that as groups, the GPi and STN DBS patients mostly showed similar changes in mental abilities. This main finding did not answer all questions about the effects of DBS. The researchers compared groups of people, but those tested may have had important changes that were hid- den in the group results. Group findings do not express whether the changes have an important effect on quality of life. In additional analyses, the study found that those who experienced cognitive changes had a comparable quality of life to those who did not experience such cognitive changes. In fact, quality of life improved to a similar degree after DBS in both groups. Only one test score (ability to quickly say words belonging to a category) before surgery pre- dicted whether a person would have a decline, but the study could not convincingly explain why those with better scores on the test got worse. When look- ing at person characteristics, the cognitive changes tended to occur in “older” persons. However, the average ages of those showing and not showing de- clines (62 years vs 58 years) were quite similar.
two age groups and is the same as for the natural history of Parkinson's disease. Mental alterations were frequent after bilateral STN stimulation in both age groups (Tab. 2). These complaints were independent of stimulation. There were retrospectively more related to withdrawal of medication and operative stress. Further prospective eval- uation was started to systematically analyze these symp- toms. Reports in the literature again present a fairly heterogeneous picture. Major differences existed between both age groups with regard to the complications that occurred: Infections were significantly more frequent in the older age group than in the younger patients (p < 0.05). A total of 7 patients died during the 2-year follow- up period. In 6 patients deaths were unrelated to surgery (2 pneumonia, 1 suspected pulmonary embolism, 3 patients with cardiac failure, all deaths >6 months postop- eratively). One suicide was determined to be related to surgery. This particular patient suffered from a young onset tremordominant Parkinson's disease and has had no significant history of psychiatric disorders. After sur- gery he developed transient manic-depressive state, which were stimulation dependend, i.e. especially stimulation of the lower two contacts led to a worsening of manic symp- toms. Although motoric improvement was significant under stimulation, psychic deteriorations limited the out- come of the patient. With maximum stimulation of 1.5 V, 90 μ s and 130 Hz, tremor was only partially influenced, however without psychic symptoms. These symptoms led also to a worsening of his however previously disturbed social interactions of the patient. He got finally divorced and he committed suicide 15 months after surgery. Not counting the suicide, significantly more elderly patients died (p < 0.05) compared with the younger age group. This is not surprising if one takes into account natural life expectancy. However, as shown by the results presented here, the effectiveness of DBS is independent of patient age. This is a supporting argument against an age limit for DBS. Nevertheless, DBS should be contemplated as a ther- apeutic option already in younger patients and in patients with earlier stages of Parkinson's disease, for example, at the time when complications of long-term levodopa ther- apy first manifest themselves. With such an approach, patients can benefit from STN stimulation for a much longer period of time.
From a physiological perspective, the pathogenesis of PD is closely related to the developing mechanisms of urinary dysfunctions. 13 The most prominent pathological changes in patients with PD are the degeneration or loss of pigmented neurons localized in the basal ganglia and brainstem, with the most signi ﬁ cant loss of the dopaminer- gic neurons occurring in the pars compacta of the substantia nigra. Urinary functions are controlled and regulated to various degrees by a series of structures in the central nervous system, including the cerebral cortex, basal gang- lia, hypothalamus and the reticular formation of the brain- stem. Thus, the degeneration and loss of neurons in these structures may lead to urinary dysfunctions in PD patients. The DBS procedure consists of implanting neuron- stimulating electrodes at speci ﬁ cally targeted locations in patients ’ brains through precise stereotactic positioning and performing high-frequency electrical stimulation of the hypothalamic nuclei of the patients to excite the nuclei, thereby improving motility, controlling seizures, and relieving pain in PD patients. 14 The nuclei of the brain, such as the subthalamic nucleus, are involved in the reg- ulation of urinary functions. DBS treatments stimulate these nuclei to also improve urinary functions, offering one of the possible reasons for the relief of urinary symp- toms in the group of PD patients who received DBS. 15 Additionally, the stimulation of the hypothalamic nuclei can increase the release of vasopressin through the hypothalamic-neuronal pituitary system, which in turn promotes the reabsorption of water molecules in the renal collecting duct and in the distal convoluted tubule, consequently reducing the quantity of urine production. 16 The regulatory control of urination, together with the reduction in urine production, can result in signi ﬁ cant improvements in urinary frequency in male PD patients.
reasoning (Levy et al., 2002), picture completion (Mahieux et al., 1998) and Stroop performance (Janvin, Aarsland & Larsen, 2005; Mahieux et al., 1998) are predictors for PD-D. However, the extent to which these executive deficits relate to PD-D may be dependent on how long they precede the development of PD-D. For instance, the association between perseveration on the Wisconsin card sorting test (WCST) and the consequent development of PD-D was reported within one year of dementia onset (Woods & Troster, 2003), which does not provide information about the association between early executive deficits and PD-D. Further research indicated that the early cognitive profile in PD patients who eventually develop dementia is different to the typical early executive dysfunction (Williams-Gray, Foltynie, Robbins & Barker, 2007). Williams-Gray et al. (2007) suggested that visuospatial and language deficits may be good predictors of dementia in PD. Further evidence suggested that the pentagon copying on the mini mental state examination (Folstein, Folstein & McHugh, 1975) and semantic fluency are good predictors of PD-D at three and five year follow-up (Williams-Gray et al., 2007; Williams-Gray et al., 2009). Third, the dominant motor symptoms in PD patients may also relate to the development of dementia. PD patients who have axial symptoms such as gait disturbance and postural instability, are more likely to develop dementia early on in the course of the disease (Burn et al., 2006; Foltynie, Brayne, Robbins, & Barker, 2004; Lewis et al., 2005; Williams-Gray et al., 2007), whereas patients with tremor-dominant PD are less likely to develop dementia (Alves, Larsen, Emre, Wentzel- Larsen & Aarsland, 2006). Depression, hallucinations and REM sleep behaviour disorder have been identified as other risk factors for the development of dementia in PD (Williams-Gray et al, 2007; Postuma et al, 2012).
The capability to direct current offers many potential benefits, allowing clinicians the ability to drive stimulation away from neighboring areas that are causing stimulation- limiting side effects, particularly when the electrodes are not ideally placed. Presently, clinicians have the ability to change active contact configurations from simple monopolar settings to bipolar and to employ interleaving, a technique that allows two different programs to run alternatively. Impending new DBS lead technology will allow some degree of “current steering” or the ability to apply current in other than a concentric ring around the activated contact(s) as is the case with the current four-contact lead. 75,90 Most future
Under local anesthesia, implantation of the DBS electrodes was performed bilaterally in all patients using a Leksell stereotactic frame and magnetic resonance imaging (MRI; Philips MR System Achieva, Eindhoven, the Netherlands)-guided target- ing with Surgiplan (Elekta, Stockholm, Sweden). Initial values for STN localization were 12 mm lateral, 2 mm posterior, and 4 mm inferior to the mid-point between the anterior and posteri- or commissures. Single-track microelectrode recording (MER) using the Microdrive System (Medtronic, Inc., Minneapolis, MN, USA) was performed, and cell activity was recorded start- ing from 15 mm above the STN target. After the precise localiz- ation of the target point, DBS electrodes (Medtronic 3387; Min- neapolis, MN, USA) with four contact points were placed in such a way that the tip of the electrode was located on the ven- tral boundary of the STN, passing through the center of the STN. Each contact of the DBS electrode was 1.5 mm long, and the contacts were 1.5 mm apart from each other. Based on the MER results, electrodes were positioned and labeled as follows: 0 and 1, STN; 2 and 3, the area above the STN (Fig. 1). After satis- factory outcomes during test stimulations, the position of each electrode was verified by postoperative MRI or computed to- mography that was merged with the preoperatively planned target and trajectory. If the actual electrode position was ac- ceptable, the DBS electrodes were connected to an implant- able pulse generator (IPG) placed in the subclavicular area un- der general anesthesia. The patients underwent a single-stage operation in which both DBS electrode insertion and IPG im- plantation were performed on the same day. An efficacy test was performed about 1 month after surgery. Over the next 1–2 months, the contact and stimulation parameters were optimiz- ed to obtain maximum clinical benefit and minimal side effects.
SureTune ® (Medtronic Inc. Minnesota), a DBS therapy planning platform was used to model VTAs around individual contacts and to manually delineate STN volume meshes. The VTAs were created based on homogeneous finite element simulations of the distribution of the electric potential together with coupled axon cable models. Axon models were composed of 21 nodes, with a diameter of 2.5 µm and oriented in the vicinity of the lead in a perpendicular orientation. Specific VTA thresholds were calculated for every electrical setting taking in consideration the specific stimulation configuration, amplitude and pulse width as described by Åström and colleagues in order to generate DBS therapy VTA (Åström et al., 2015). Patient-specific tissue conductivity and patient-specific axon orientations were not considered. Intraoperative (pre- and post-implantation) stereotactic scans were co-registered. Scans were first manually aligned to pre-implantation MPRAGE scan before running automated co-registration with a restricted volume of fusion centred around the diencephalon/ mesencephalon. This was carried out to minimise registration error resulting from eventual brain shift incurred during surgery, despite minimal brain shift with our surgical technique (Petersen et al., 2010). Registration accuracy was carefully inspected and the process iterated if necessary.
Atlas coordinate-based DBS targeting has a long history in the clinic. It assumes that the relative positions and sizes of DBS surgical targets, such as the STN, are consistent across subjects, and can tolerate minimum or lower quality imaging data. Meanwhile, non-negligible anatomical variability across subjects [52, 99, 100] has also been reported for the surgical target. The choice between the coordinate-based technique and direct targeting has been actively debated, largely for localizing the STN. While the earlier reports favored the first , more recent evidence [52, 100] prefer the latter. This discrepancy may likely be attributed to the improved image quality of MRI scanners, especially in terms of signal-to-noise ratio, image resolution, and newer scanning sequences, but unfortunately most studies  only reported results with fairly limited patients, or even healthy cohorts. Notably, the initial stimulation locations derived from coordinate-based methods and anatomical MRI are usually the estimated centroid or geometric center of the nucleus, which is often different from the therapeutic target. Inputs from functional information at the planning stage can therefore be important. Such insights can be made available through brain atlases that contain connectivity-based sub-divisions of the nucleus , probabilistic representation of effective stimulation loci [61, 65], and group-averaged connectomes . With physiological recording , we have observed that therapeutic regions are not necessarily bounded by the borders of a particular anatomy. To push this notion further, functional
screening process is required to determine those who are good candidates [69,70]. In the current context of re- ducing unnecessary expenses, this screening process can be staged to help reduce costs and improve its efficiency. Patients should first undergo a thorough clinical evalu- ation from the neurologist to ascertain the diagnosis and exclude other causes of parkinsonism, such as vascular parkinsonism or Parkinson Plus Syndromes that are re- fractory to DBS. The neurologist should optimize med- ical management before offering DBS. Patients should then discuss at length with the neurologist and neuro- surgeon to assess their understanding of the risk/benefits ratio of the surgery. If the patients then clearly under- stand this commitment and wish to proceed, the ON levodopa/OFF levodopa motor testing can be performed. In the ON/OFF testing, the patient is asked to withhold all PD medications for 12 hours before undergoing examination with the UPDRS. The patient is then given his regular dose of levodopa and the UPDRS is adminis- tered again after the patient reports feeling the full effect of this dose. ON and OFF UPDRS scores are compared and an improvement of at least 30% after medication intake is typically recommended to proceed to the next step. Indeed, only the symptoms that improve with levodopa are expected to improve with DBS, with the notable exception of medication refractory tremor that can still improve after surgery. DBS should thus be offered to patients with levodopa-responsive symp- toms . At that point, if the patient is still considered a good candidate for surgery, brain MRI, neuropsycho- logical testing and psychiatry evaluation would be pursued.