Spectral Topography of the Subthalamic Nucleus to Inform Next-Generation Deep Brain Stimulation.

BACKGROUND: The landscape of neurophysiological symptoms and behavioral biomarkers in basal ganglia signals for movement disorders is expanding. The clinical translation of sensing-based deep brain stimulation (DBS) also requires a thorough understanding of the anatomical organization of spectral biomarkers within the subthalamic nucleus (STN). OBJECTIVES: The aims were to systematically investigate the spectral topography, including a wide range of sub-bands in STN local field potentials (LFP) of Parkinson's disease (PD) patients, and to evaluate its predictive performance for clinical response to DBS. METHODS: STN-LFPs were recorded from 70 PD patients (130 hemispheres) awake and at rest using multicontact DBS electrodes. A comprehensive spatial characterization, including hot spot localization and focality estimation, was performed for multiple sub-bands (delta, theta, alpha, low-beta, high-beta, low-gamma, high-gamma, and fast-gamma (FG) as well as low- and fast high-frequency oscillations [HFO]) and compared to the clinical hot spot for rigidity response to DBS. A spectral biomarker map was established and used to predict the clinical response to DBS. RESULTS: The STN shows a heterogeneous topographic distribution of different spectral biomarkers, with the strongest segregation in the inferior-superior axis. Relative to the superiorly localized beta hot spot, HFOs (FG, slow HFO) were localized up to 2 mm more inferiorly. Beta oscillations are spatially more spread compared to other sub-bands. Both the spatial proximity of contacts to the beta hot spot and the distance to higher-frequency hot spots were predictive for the best rigidity response to DBS. CONCLUSIONS: The spatial segregation and properties of spectral biomarkers within the DBS target structure can additionally be informative for the implementation of next-generation sensing-based DBS. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Deep Brain Stimulation: When to Test Directional?

Background: Directional deep brain stimulation (DBS) allows for steering of the stimulation field, but extensive and time-consuming testing of all segmented contacts is necessary to identify the possible benefit of steering. It is therefore important to determine under which circumstances directional current steering is advantageous. Methods: Fifty two Parkinson's disease patients implanted in the STN with a directional DBS system underwent a standardized monopolar programming session 5 to 9 months after implantation. Individual contacts were tested for a potential advantage of directional stimulation. Results were used to build a prediction model for the selection of ring levels that would benefit from directional stimulation. Results: On average, there was no significant difference in therapeutic window between ring-level contact and best directional contact. However, according to our standardized protocol, 35% of the contacts and 66% of patients had a larger therapeutic window under directional stimulation compared to ring-mode. The segmented contacts warranting directional current steering could be predicted with a sensitivity of 79% and a specificity of 57%. Conclusion: To reduce time required for DBS programming, we recommend additional directional contact testing initially only on ring-level contacts with a therapeutic window of less than 2.0 mA.

The Contribution of Subthalamic Nucleus Deep Brain Stimulation to the Improvement in Motor Functions and Quality of Life.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) effectively treats motor symptoms and quality of life (QoL) of advanced and fluctuating early Parkinson's disease. Little is known about the relation between electrode position and changes in symptom control and ultimately QoL. OBJECTIVES: The relation between the stimulated part of the STN and clinical outcomes, including the motor score of the Unified Parkinson's Disease Rating Scale (UPDRS) and the quality-of-life questionnaire, was assessed in a subcohort of the EARLYSTIM study. METHODS: Sixty-nine patients from the EARLYSTIM cohort who underwent DBS, with a comprehensive clinical characterization before and 24 months after surgery, were included. Intercorrelations of clinical outcome changes, correlation between the affected functional parts of the STN, and changes in clinical outcomes were investigated. We further calculated sweet spots for different clinical parameters. RESULTS: Improvements in the UPDRS III and Parkinson's Disease Questionnaire (PDQ-39) correlated positively with the extent of the overlap with the sensorimotor STN. The sweet spots for the UPDRS III (x = 11.6, y = -13.1, z = -6.3) and the PDQ-39 differed (x = 14.8, y = -12.4, z = -4.3) ~3.8 mm. CONCLUSIONS: The main influence of DBS on QoL is likely mediated through the sensory-motor basal ganglia loop. The PDQ sweet spot is located in a posteroventral spatial location in the STN territory. For aspects of QoL, however, there was also evidence of improvement through stimulation of the other STN subnuclei. More research is necessary to customize the DBS target to individual symptoms of each patient. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A prospective international multi-center study on safety and efficacy of deep brain stimulation for resistant obsessive-compulsive disorder.

Deep brain stimulation (DBS) has been proposed for severe, chronic, treatment-refractory obsessive-compulsive disorder (OCD) patients. Although serious adverse events can occur, only a few studies report on the safety profile of DBS for psychiatric disorders. In a prospective, open-label, interventional multi-center study, we examined the safety and efficacy of electrical stimulation in 30 patients with DBS electrodes bilaterally implanted in the anterior limb of the internal capsule. Safety, efficacy, and functionality assessments were performed at 3, 6, and 12 months post implant. An independent Clinical Events Committee classified and coded all adverse events (AEs) according to EN ISO14155:2011. All patients experienced AEs (195 in total), with the majority of these being mild (52% of all AEs) or moderate (37%). Median time to resolution was 22 days for all AEs and the etiology with the highest AE incidence was 'programming/stimulation' (in 26 patients), followed by 'New illness, injury, condition' (13 patients) and 'pre-existing condition, worsening or exacerbation' (11 patients). Sixteen patients reported a total of 36 serious AEs (eight of them in one single patient), mainly transient anxiety and affective symptoms worsening (20 SAEs). Regarding efficacy measures, Y-BOCS reduction was 42% at 12 months and the responder rate was 60%. Improvements in GAF, CGI, and EuroQol-5D index scores were also observed. In sum, although some severe AEs occurred, most AEs were mild or moderate, transient and related to programming/stimulation and tended to resolve by adjustment of stimulation. In a severely treatment-resistant population, this open-label study supports that the potential benefits outweigh the potential risks of DBS.

Subthalamic nucleus activity dynamics and limb movement prediction in Parkinson's disease.

Whilst exaggerated bursts of beta frequency band oscillatory synchronization in the subthalamic nucleus have been associated with motor impairment in Parkinson's disease, a plausible mechanism linking the two phenomena has been lacking. Here we test the hypothesis that increased synchronization denoted by beta bursting might compromise information coding capacity in basal ganglia networks. To this end we recorded local field potential activity in the subthalamic nucleus of 18 patients with Parkinson's disease as they executed cued upper and lower limb movements. We used the accuracy of local field potential-based classification of the limb to be moved on each trial as an index of the information held by the system with respect to intended action. Machine learning using the naïve Bayes conditional probability model was used for classification. Local field potential dynamics allowed accurate prediction of intended movements well ahead of their execution, with an area under the receiver operator characteristic curve of 0.80 ± 0.04 before imperative cues when the demanded action was known ahead of time. The presence of bursts of local field potential activity in the alpha, and even more so, in the beta frequency band significantly compromised the prediction of the limb to be moved. We conclude that low frequency bursts, particularly those in the beta band, restrict the capacity of the basal ganglia system to encode physiologically relevant information about intended actions. The current findings are also important as they suggest that local subthalamic activity may potentially be decoded to enable effector selection, in addition to force control in restorative brain-machine interface applications.

Axial symptoms predict mortality in patients with Parkinson disease and subthalamic stimulation.

OBJECTIVE: To characterize how disease progression is associated with mortality in a large cohort of patients with Parkinson disease (PD) with long-term follow-up after subthalamic nucleus deep brain stimulation (STN-DBS). METHODS: Motor and cognitive disabilities were assessed before and 1, 2, 5, and 10 years after STN-DBS in 143 consecutive patients with PD. We measured motor symptoms "off" and "on" levodopa and STN-DBS and recorded causes of death. We used linear mixed models to characterize symptom progression, including interactions between treatment conditions and time to determine how treatments changed efficacy. We used joint models to link symptom progression to mortality. RESULTS: Median observation time was 12 years after surgery, during which akinesia, rigidity, and axial symptoms worsened, with mean increases of 8.8 (SD 6.5), 1.8 (3.1), and 5.4 (4.1) points from year 1-10 after surgery ("on" dopamine/"on" STN-DBS), respectively. Responses to dopaminergic medication and STN-DBS were attenuated with time, but remained effective for all except axial symptoms, for which both treatments and their combination were predicted to be ineffective 20 years after surgery. Cognitive status significantly declined. Forty-one patients died, with a median time to death of 9 years after surgery. The current level of axial disability was the only symptom that significantly predicted death (hazard ratio 4.30 [SE 1.50] per unit of square-root transformed axial score). CONCLUSIONS: We quantified long-term symptom progression and attenuation of dopaminergic medication and STN-DBS treatment efficacy in patients with PD and linked symptom progression to mortality. Axial disability significantly predicts individual risk of death after surgery, which may be useful for planning therapeutic strategies in PD.

Electrophysiological differences between upper and lower limb movements in the human subthalamic nucleus.

OBJECTIVE: Functional processes in the brain are segregated in both the spatial and spectral domain. Motivated by findings reported at the cortical level in healthy participants we test the hypothesis in the basal ganglia of Parkinson's disease patients that lower frequency beta band activity relates to motor circuits associated with the upper limb and higher beta frequencies with lower limb movements. METHODS: We recorded local field potentials (LFPs) from the subthalamic nucleus using segmented "directional" DBS leads, during which patients performed repetitive upper and lower limb movements. Movement-related spectral changes in the beta and gamma frequency-ranges and their spatial distributions were compared between limbs. RESULTS: We found that the beta desynchronization during leg movements is characterised by a strikingly greater involvement of higher beta frequencies (24-31 Hz), regardless of whether this was contralateral or ipsilateral to the limb moved. The spatial distribution of limb-specific movement-related changes was evident at higher gamma frequencies. CONCLUSION: Limb processing in the basal ganglia is differentially organised in the spectral and spatial domain and can be captured by directional DBS leads. SIGNIFICANCE: These findings may help to refine the use of the subthalamic LFPs as a control signal for adaptive DBS and neuroprosthetic devices.

Directional local field potentials: A tool to optimize deep brain stimulation.

BACKGROUND: Although recently introduced directional DBS leads provide control of the stimulation field, programing is time-consuming. OBJECTIVES: Here, we validate local field potentials recorded from directional contacts as a predictor of the most efficient contacts for stimulation in patients with PD. METHODS: Intraoperative local field potentials were recorded from directional contacts in the STN of 12 patients and beta activity compared with the results of the clinical contact review performed after 4 to 7 months. RESULTS: Normalized beta activity was positively correlated with the contact's clinical efficacy. The two contacts with the highest beta activity included the most efficient stimulation contact in up to 92% and that with the widest therapeutic window in 74% of cases. CONCLUSION: Local field potentials predict the most efficient stimulation contacts and may provide a useful tool to expedite the selection of the optimal contact for directional DBS. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Sleep-wake disturbances in the premotor and early stage of Parkinson's disease.

PURPOSE OF REVIEW: Review of recent literature pertaining to frequency, associations, mechanisms, and overall significance of sleep--wake disturbances (SWD) in the premotor and early phase of Parkinson's disease. RECENT FINDINGS: SWD are frequent in Parkinson's disease and their prevalence increases with disease progression. Recent studies confirm previous findings that SWD can appear as initial manifestation of Parkinson's disease even decades before motor signs appear and highlight their clinical associations in these early stages. More intriguingly, new evidence underpins their role as risk factors, predictors, or even as driving force for the neurodegenerative process. As our understanding of sleep--wake neurobiology increases, new hypotheses emerge concerning the pathophysiology of SWD in early Parkinson's disease stages involving dopaminergic and nondopaminergic mechanisms. SUMMARY: SWD are predictors for the development of parkinsonian syndromes including Parkinson's disease. This may offer the opportunity of developing new preventive strategies and interventions at an early stage of this neurodegenerative disease.

Older Candidates for Subthalamic Deep Brain Stimulation in Parkinson's Disease Have a Higher Incidence of Psychiatric Serious Adverse Events.

OBJECTIVE: To investigate the incidence of serious adverse events (SAE) of subthalamic deep brain stimulation (STN-DBS) in elderly patients with Parkinson's disease (PD). METHODS: We investigated a group of 26 patients with PD who underwent STN-DBS at mean age 63.2 ± 3.3 years. The operated patients from the EARLYSTIM study (mean age 52.9 ± 6.6) were used as a comparison group. Incidences of SAE were compared between these groups. RESULTS: A higher incidence of psychosis and hallucinations was found in these elderly patients compared to the younger patients in the EARLYSTIM study (p < 0.01). CONCLUSIONS: The higher incidence of STN-DBS-related psychiatric complications underscores the need for comprehensive psychiatric pre- and postoperative assessment in older DBS candidates. However, these psychiatric SAE were transient, and the benefits of DBS clearly outweighed its adverse effects.

Dopaminergic denervation severity depends on COMT Val158Met polymorphism in Parkinson's disease.

BACKGROUND: Catecholamine-O-methyl-tranferase (COMT) initiates dopamine degradation. Its activity is mainly determined by a single nucleotide polymorphism in the COMT gene (Val158Met, rs4680) separating high (Val/Val, COMT(HH)), intermediate (Val/Met, COMT(HL)) and low metabolizers (Met/Met, COMT(LL)). We investigated dopaminergic denervation in the striatum in PD patients according to COMT rs4680 genotype. METHODS: Patients with idiopathic PD were assessed for motor severity (UPDRS-III rating scale in OFF-state), dopaminergic denervation using [123I]-FP-CIT SPECT imaging, and genotyped for the COMT rs4680 enzyme. [123I]-FP-CIT binding potential (BP) for each voxel was defined by the ratio of tracer-binding in the region of interest (striatum, caudate nucleus and putamen) to that in a region of non-specific activity. Genotyping was performed using TaqMan(®) SNP genotyping assay. We used a regression model to evaluate the effect of COMT genotype on the BP in the striatum and its sub-regions. RESULTS: Genotype distribution was: 11 (27.5%) COMT(HH), 26 (65%) COMT(HL) and 3 (7.5%) COMT(LL). There were no significant differences in disease severity, treatments, or motor scores between genotypes. When adjusted to clinical severity, gender and age, low and intermediate metabolizers showed significantly higher rates of striatal denervation (COMT(HL+LL) BP = 1.32 ± 0.04) than high metabolizers (COMT(HH), BP = 1.6 ± 0.08; F(1.34) = 9.0, p = 0.005). Striatal sub-regions showed similar results. BP and UPDRS-III motor scores (r = 0.44, p = 0.04) (p < 0.001) were highly correlated. There was a gender effect, but no gender-genotype interaction. CONCLUSIONS: Striatal denervation differs according to COMT-Val158Met polymorphism. COMT activity may play a role as a compensatory mechanism in PD motor symptoms.

Electrocardiologic and related methods of non-invasive detection and risk stratification in myocardial ischemia: state of the art and perspectives.

BACKGROUND: Electrocardiographic methods still provide the bulk of cardiovascular diagnostics. Cardiac ischemia is associated with typical alterations in cardiac biosignals that have to be measured, analyzed by mathematical algorithms and allegorized for further clinical diagnostics. The fast growing fields of biomedical engineering and applied sciences are intensely focused on generating new approaches to cardiac biosignal analysis for diagnosis and risk stratification in myocardial ischemia. OBJECTIVES: To present and review the state of the art in and new approaches to electrocardiologic methods for non-invasive detection and risk stratification in coronary artery disease (CAD) and myocardial ischemia; secondarily, to explore the future perspectives of these methods. METHODS: In follow-up to the Expert Discussion at the 2008 Workshop on "Biosignal Analysis" of the German Society of Biomedical Engineering in Potsdam, Germany, we comprehensively searched the pertinent literature and databases and compiled the results into this review. Then, we categorized the state-of-the-art methods and selected new approaches based on their applications in detection and risk stratification of myocardial ischemia. Finally, we compared the pros and cons of the methods and explored their future potentials for cardiology. RESULTS: Resting ECG, particularly suited for detecting ST-elevation myocardial infarctions, and exercise ECG, for the diagnosis of stable CAD, are state-of-the-art methods. New exercise-free methods for detecting stable CAD include cardiogoniometry (CGM); methods for detecting acute coronary syndrome without ST elevation are Body Surface Potential Mapping, functional imaging and CGM. Heart rate variability and blood pressure variability analyses, microvolt T-wave alternans and signal-averaged ECG mainly serve in detecting and stratifying the risk for lethal arrythmias in patients with myocardial ischemia or previous myocardial infarctions. Telemedicine and ambient-assisted living support the electrocardiological monitoring of at-risk patients. CONCLUSIONS: There are many promising methods for the exercise-free, non-invasive detection of CAD and myocardial ischemia in the stable and acute phases. In the coming years, these new methods will help enhance state-of-the-art procedures in routine diagnostics. The future can expect that equally novel methods for risk stratification and telemedicine will transition into clinical routine.