Directional versus ring-mode deep brain stimulation for Parkinson's disease: protocol of a multi-centre double-blind randomised crossover trial.

BACKGROUND: The effectiveness of Deep Brain Stimulation (DBS) therapy for Parkinson's disease can be limited by side-effects caused by electrical current spillover into structures adjacent to the target area. The objective of the STEEred versus RING-mode DBS for Parkinson's disease (STEERING) study is to investigate if directional DBS for Parkinson's disease results in a better clinical outcome when compared to ring-mode DBS. METHODS: The STEERING study is a prospective multi-centre double-blind randomised crossover trial. Inclusion criteria are Parkinson's disease, subthalamic nucleus DBS in a 'classic' ring-mode setting for a minimum of six months, and optimal ring-mode settings have been established. Participants are categorised into one of two subgroups according to their clinical response to the ring-mode settings as 'responders' (i.e., patient with a satisfactory effect of ring-mode DBS) or 'non-responder' (i.e., patient with a non-satisfactory effect of ring-mode DBS). A total of 64 responders and 38 non-responders will be included (total 102 patients). After an optimisation period in which an optimal directional setting is found, participants are randomised to first receive ring-mode DBS for 56 days (range 28-66) followed by directional DBS for 56 days (28-66) or vice-versa. The primary outcome is the difference between ring-mode DBS and directional DBS settings on the Movement Disorders Society Unified Parkinson's Disease Rating Scale - Motor Evaluation (MDS-UPDRS-ME) in the off-medication state. Secondary outcome measures consist of MDS-UPDRS-ME in the on-medication state, MDS-UPDRS Activities of Daily Living, MDS-UPDRS Motor Complications-Dyskinesia, disease related quality of life measured with the Parkinson's Disease Questionnaire 39, stimulation-induced side-effects, antiparkinsonian medication use, and DBS-parameters. Participants' therapy preference is measured at the end of the study. Outcomes will be analysed for both responder and non-responder groups, as well as for both groups pooled together. DISCUSSION: The STEERING trial will provide insights into whether or not directional DBS should be standardly used in all Parkinson's disease DBS patients or if directional DBS should only be used in a case-based approach. TRIAL REGISTRATION: This trial was registered on the Netherlands Trial Register, as trial NL6508 ( NTR6696 ) on June 23, 2017.

Accelerometric Classification of Resting and Postural Tremor Amplitude.

Clinical rating scales for tremors have significant limitations due to low resolution, high rater dependency, and lack of applicability in outpatient settings. Reliable, quantitative approaches for assessing tremor severity are warranted, especially evaluating treatment effects, e.g., of deep brain stimulation (DBS). We aimed to investigate how different accelerometry metrics can objectively classify tremor amplitude of Essential Tremor (ET) and tremor in Parkinson's Disease (PD). We assessed 860 resting and postural tremor trials in 16 patients with ET and 25 patients with PD under different DBS settings. Clinical ratings were compared to different metrics, based on either spectral components in the tremorband or pure acceleration, derived from simultaneous triaxial accelerometry captured at the index finger and wrist. Nonlinear regression was applied to a training dataset to determine the relationship between accelerometry and clinical ratings, which was then evaluated in a holdout dataset. All of the investigated accelerometry metrics could predict clinical tremor ratings with a high concordance (>70%) and substantial interrater reliability (Cohen's weighted Kappa > 0.7) in out-of-sample data. Finger-worn accelerometry performed slightly better than wrist-worn accelerometry. We conclude that triaxial accelerometry reliably quantifies resting and postural tremor amplitude in ET and PD patients. A full release of our dataset and software allows for implementation, development, training, and validation of novel methods.

Brain Morphometry Associated With Response to Levodopa and Deep Brain Stimulation in Parkinson Disease.

OBJECTIVES: Whether treatment response in patients with Parkinson disease depends on brain atrophy is insufficiently understood. The goal of this study is to identify specific atrophy patterns associated with response to dopaminergic therapy and deep brain stimulation. MATERIALS AND METHODS: In this study, we analyzed the association of gray matter brain atrophy patterns, as identified by voxel-based morphometry, with acute response to levodopa (N = 118) and subthalamic nucleus deep brain stimulation (N = 39). Motor status was measured as a change in points on the Unified Parkinson's Disease Rating Scale III score. Baseline values were obtained before surgery, after cessation of dopaminergic medication for at least 12 hours; response to medication was assessed after administration of a standardized dose of levodopa. Response to deep brain stimulation was measured three months after surgery in the clinical condition after withdrawal of dopaminergic medication. RESULTS: Although frontoparietal brain gray matter loss was associated with subpar response to deep brain stimulation, there was no significant link between brain atrophy and response to levodopa. CONCLUSION: We conclude that response to deep brain stimulation relies on gray matter integrity; hence, gray matter loss may present a risk factor for poor response to deep brain stimulation and may be considered when making decision regarding clinical practice.

Network Fingerprint of Stimulation-Induced Speech Impairment in Essential Tremor.

OBJECTIVE: This study was undertaken to gain insights into structural networks associated with stimulation-induced dysarthria (SID) and to predict stimulation-induced worsening of intelligibility in essential tremor patients with bilateral thalamic deep brain stimulation (DBS). METHODS: Monopolar reviews were conducted in 14 essential tremor patients. Testing included determination of SID thresholds, intelligibility ratings, and a fast syllable repetition task. Volumes of tissue activated (VTAs) were calculated to identify discriminative fibers for stimulation-induced worsening of intelligibility in a structural connectome. The resulting fiber-based atlas structure was then validated in a leave-one-out design. RESULTS: Fibers determined as discriminative for stimulation-induced worsening of intelligibility were mainly connected to the ipsilateral precentral gyrus as well as to both cerebellar hemispheres and the ipsilateral brain stem. In the thalamic area, they ran laterally to the thalamus and posteromedially to the subthalamic nucleus, in close proximity, mainly anterolaterally, to fibers beneficial for tremor control as published by Al-Fatly et al in 2019. The overlap of the respective clinical stimulation setting's VTAs with these fibers explained 62.4% (p < 0.001) of the variance of stimulation-induced change in intelligibility in a leave-one-out analysis. INTERPRETATION: This study demonstrates that SID in essential tremor patients is associated with both motor cortex and cerebellar connectivity. Furthermore, the identified fiber-based atlas structure might contribute to future postoperative programming strategies to achieve optimal tremor control without speech impairment in essential tremor patients with thalamic DBS. ANN NEUROL 2021;89:315-326.

Sweetspot Mapping in Deep Brain Stimulation: Strengths and Limitations of Current Approaches.

OBJECTIVES: Open questions remain regarding the optimal target, or sweetspot, for deep brain stimulation (DBS) in, for example, Parkinson's disease. Previous studies introduced different methods of mapping DBS effects to determine sweetspots. While having a direct impact on surgical targeting and postoperative programming in DBS, these methods so far have not been compared. MATERIALS AND METHODS: This study investigated five previously published DBS mapping approaches regarding their potential to correctly identify a predefined target. Methods were investigated in silico in eight different use-case scenarios, which incorporated different types of clinical data, noise, and differences in underlying neuroanatomy. Dice coefficients were calculated to determine the overlap between identified sweetspots and the predefined target. Additionally, out-of-sample predictive capabilities were assessed using the amount of explained variance R2. RESULTS: The five investigated methods resulted in highly variable sweetspots. Methods based on voxel-wise statistics against average outcomes showed the best performance overall. While predictive capabilities were high, even in the best of cases Dice coefficients remained limited to values around 0.5, highlighting the overall limitations of sweetspot identification. CONCLUSIONS: This study highlights the strengths and limitations of current approaches to DBS sweetspot mapping. Those limitations need to be taken into account when considering the clinical implications. All future approaches should be investigated in silico before being applied to clinical data.

Genotype-phenotype correlation in seven motor neuron disease families with novel ALS2 mutations.

Autosomal-recessive mutations in the Alsin Rho guanine nucleotide exchange factor (ALS2) gene may cause specific subtypes of childhood-onset progressive neurodegenerative motor neuron diseases (MND). These diseases can manifest with a clinical continuum from infantile ascending hereditary spastic paraplegia (IAHSP) to juvenile-onset forms with or without lower motor neuron involvement, the juvenile primary lateral sclerosis (JPLS) and the juvenile amyotrophic lateral sclerosis (JALS). We report 11 patients from seven unrelated Turkish and Yemeni families with clinical signs of IAHSP or JPLS. We performed haplotype analysis or next-generation panel sequencing followed by Sanger Sequencing to unravel the genetic disease cause. We described their clinical phenotype and analyzed the pathogenicity of the detected variants with bioinformatics tools. We further reviewed all previously reported cases with ALS2-related MND. We identified five novel homozygous pathogenic variants in ALS2 at various positions: c.275_276delAT (p.Tyr92CysfsTer11), c.1044C>G (p.Tyr348Ter), c.1718C>A (p.Ala573Glu), c.3161T>C (p.Leu1054Pro), and c.1471+1G>A (NM_020919.3, NP_065970.2). In our cohort, disease onset was in infancy or early childhood with rapid onset of motor neuron signs. Muscle weakness, spasticity, severe dysarthria, dysphagia, and facial weakness were common features in the first decade of life. Frameshift and nonsense mutations clustered in the N-terminal Alsin domains are most prevalent. We enriched the mutational spectrum of ALS2-related disorders with five novel pathogenic variants. Our study indicates a high detection rate of ALS2 mutations in patients with a clinically well-characterized early onset MND. Intrafamilial and even interfamilial diversity in patients with identical pathogenic variants suggest yet unknown modifiers for phenotypic expression.

Pallidal deep brain stimulation in a patient with nonketotic hyperglycemic hemichorea.

Background: Hyperkinetic movement disorders secondary to brain tissue damage due to hyperglycemia are a rare complication of diabetes mellitus. Nonketotic hyperglycemic hemichorea (NH-HC) is characterized by a rapid onset of involuntary movements after increased serum glucose levels. Case Description: We report on a case of a 62-year-old male patient with a 28-year history of Type II diabetes mellitus with NH-HC following an infect-associated exacerbation of blood glucose levels. Choreiform movements of the right upper extremity, face, and trunk persisted 6 months after onset. Due to failure of conservative treatments, we opted for unilateral deep brain stimulation of the globus pallidus internus, which led to complete cessation of symptoms within a week after initial programming. Symptom control was still satisfactory 12 months after surgery. No side-effects or surgery-associated complications were observed. Conclusion: Globus pallidus internus DBS is an effective and safe treatment option for hyperkinetic movement disorders secondary to brain tissue damage caused by hyperglycemia. Postoperatively, stimulation effects can be observed quickly and effects persist even after 12 months.

Patients with isolated REM-sleep behavior disorder have elevated levels of alpha-synuclein aggregates in stool.

Misfolded and aggregated α-synuclein is a neuropathological hallmark of Parkinson's disease (PD). Thus, α-synuclein aggregates are regarded as a biomarker for the development of diagnostic assays. Quantification of α-synuclein aggregates in body fluids is challenging, and requires highly sensitive and specific assays. Recent studies suggest that α-synuclein aggregates may be shed into stool. We used surface-based fluorescence intensity distribution analysis (sFIDA) to detect and quantify single particles of α-synuclein aggregates in stool of 94 PD patients, 72 isolated rapid eye movement sleep behavior disorder (iRBD) patients, and 51 healthy controls. We measured significantly elevated concentrations of α-synuclein aggregates in stool of iRBD patients versus those of controls (p = 0.024) or PD patients (p < 0.001). Our results show that α-synuclein aggregates are excreted in stool and can be measured using the sFIDA assay, which could support the diagnosis of prodromal synucleinopathies.

Nationwide Retrospective Analysis of Combinations of Advanced Therapies in Patients With Parkinson Disease.

BACKGROUND AND OBJECTIVES: Advanced therapies (ATs; deep brain stimulation [DBS] or pump therapies: continuous subcutaneous apomorphine infusion [CSAI], levodopa/carbidopa intestinal gel [LCIG]) are used in later stages of Parkinson disease (PD). However, decreasing efficacy over time and/or side effects may require an AT change or combination in individual patients. Current knowledge about changing or combining ATs is limited to mostly retrospective and small-scale studies. The nationwide case collection Combinations of Advanced Therapies in PD assessed simultaneous or sequential AT combinations in Germany since 2005 to analyze their clinical outcome, their side effects, and the reasons for AT modifications. METHODS: Data were acquired retrospectively by modular questionnaires in 22 PD centers throughout Germany based on clinical records and comprised general information about the centers/patients, clinical (Mini-Mental Status Test/Montréal Cognitive Assessment, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS], side effects, reasons for AT modification), and therapeutical (ATs with specifications, oral medication) data. Data assessment started with initiation of the second AT. RESULTS: A total of 148 AT modifications in 116 patients were associated with significantly improved objective (median decrease of MDS-UPDRS Part III 4.0 points [p < 0.001], of MDS-UPDRS Part IV 6.0 points [p < 0.001], of MDS-UPDRS Part IV-off-time item 1.0 points [p < 0.001]) and subjective clinical outcome and decreasing side effect rates. Main reasons for an AT modification were insufficient symptom control and side effects of the previous therapy. Subgroup analyses suggest addition of DBS in AT patients with leading dyskinesia, addition of LCIG for leading other cardinal motor symptoms, and addition of LCIG or CSAI for dominant off-time. The most long-lasting therapy-until requiring a modification-was DBS. DISCUSSION: Changing or combining ATs may be beneficial when 1 AT is insufficient in efficacy or side effects. The outcome of an AT combination is comparable with the clinical benefit by introducing the first AT. The added AT should be chosen dependent on dominant clinical symptoms and adverse effects. Furthermore, prospective trials are needed to confirm the results of this exploratory case collection. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, in patients with PD, changing or combining ATs is associated with an improvement in the MDS-UPDRS or subjective symptom reporting.

Local Field Potential-Guided Contact Selection Using Chronically Implanted Sensing Devices for Deep Brain Stimulation in Parkinson's Disease.

Intra- and perioperatively recorded local field potential (LFP) activity of the nucleus subthalamicus (STN) has been suggested to guide contact selection in patients undergoing deep brain stimulation (DBS) for Parkinson's disease (PD). Despite the invention of sensing capacities in chronically implanted devices, a comprehensible algorithm that enables contact selection using such recordings is still lacking. We evaluated a fully automated algorithm that uses the weighted average of bipolar recordings to determine effective monopolar contacts based on elevated activity in the beta band. LFPs from 14 hemispheres in seven PD patients with newly implanted directional DBS leads of the STN were recorded. First, the algorithm determined the stimulation level with the highest beta activity. Based on the prior determined level, the directional contact with the highest beta activity was chosen in the second step. The mean clinical efficacy of the contacts chosen using the algorithm did not statistically differ from the mean clinical efficacy of standard contact selection as performed in clinical routine. All recording sites were projected into MNI standard space to investigate the feasibility of the algorithm with respect to the anatomical boundaries of the STN. We conclude that the proposed algorithm is a first step towards LFP-based contact selection in STN-DBS for PD using chronically implanted devices.

A Randomized, Double-Blinded Crossover Trial of Short Versus Conventional Pulse Width Subthalamic Deep Brain Stimulation in Parkinson's Disease.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) is a well-established treatment for patients with Parkinson's disease. Previous acute challenge studies suggested that short pulse widths might increase the therapeutic window while maintaining motor symptom control with a decrease in energy consumption. However, only little is known about the effect of short pulse width stimulation beyond the setting of an acute challenge. OBJECTIVE: To compare 4 weeks of STN-DBS with conventional pulse width stimulation (60 µs) to 4 weeks of STN-DBS with short pulse width stimulation (30 µs) regarding motor symptom control. METHODS: This study was a monocentric, double-blinded, randomized crossover non-inferiority trial investigating whether short pulse width stimulation with 30 µs maintains equal motor control as conventional 60 µs stimulation over a period of 4 weeks (German Clinical Trials Register No. DRKS00017528). Primary outcome was the difference in motor symptom control as assessed by a motor diary. Secondary outcomes included energy consumption measures, non-motor effects, side-effects, and quality of life. RESULTS: Due to a high dropout rate, the calculated sample size of 27 patients was not met and 24 patients with Parkinson's disease and STN-DBS were included in the final analysis. However, there were no differences in any investigated outcome parameter between the two treatment conditions. CONCLUSION: This study demonstrates that short pulse width settings (30 µs) provide non-inferior motor symptom control as conventional (60 µs) stimulation without significant differences in energy consumption. Future studies are warranted to evaluate a potential benefit of short pulse width settings in patients with pronounced dyskinesia.

Structural Connectivity of Subthalamic Nucleus Stimulation for Improving Freezing of Gait.

BACKGROUND: Freezing of gait (FOG) is among the most common and disabling symptoms of Parkinson's disease (PD). Studies show that deep brain stimulation (DBS) of the subthalamic nucleus (STN) can reduce FOG severity. However, there is uncertainty about pathways that need to be modulated to improve FOG. OBJECTIVE: To investigate whether STN-DBS effectively reduces FOG postoperatively and whether structural connectivity of the stimulated tissue explains variance of outcomes. METHODS: We investigated 47 patients with PD and preoperative FOG. Freezing prevalence and severity was primarily assessed using the Freezing of Gait Questionnaire (FOG-Q). In a subset of 18 patients, provoked FOG during a standardized walking course was assessed. Using a publicly available model of basal-ganglia pathways we determined stimulation-dependent connectivity associated with postoperative changes in FOG. A region-of-interest analysis to a priori defined mesencephalic regions was performed using a disease-specific normative connectome. RESULTS: Freezing of gait significantly improved six months postoperatively, marked by reduced frequency and duration of freezing episodes. Optimal stimulation volumes for improving FOG structurally connected to motor areas, the prefrontal cortex and to the globus pallidus. Stimulation of the lenticular fasciculus was associated with worsening of FOG. This connectivity profile was robust in a leave-one-out cross-validation. Subcortically, stimulation of fibers crossing the pedunculopontine nucleus and the substantia nigra correlated with postoperative improvement. CONCLUSION: STN-DBS can alleviate FOG severity by modulating specific pathways structurally connected to prefrontal and motor cortices. More differentiated FOG assessments may allow to differentiate pathways for specific FOG subtypes in the future.

Longitudinal analysis of the contribution of 3D patella and trochlear bone shape on patellofemoral joint osteoarthritic features.

To explore bone shape features that are associated with patellofemoral joint (PFJ) osteoarthritic features. Thirty subjects with PFJ degeneration (six males, 53.2 ± 9.8 years) and 23 controls (12 males, 48.1 ± 10.6 years) were included. Magnetic resonance (MR) assessment was performed to provide bone segmentation, morpholgocial grading, and cartilage relaxation times. In addition, subject self-reported symptoms were reported. Logistic regressions were used to identify the shape features that were associated with the presence and worsening of PFJ morphological lesions over 3 years, and worsening of self-reported symptoms. Statistical parametric mapping was used to evaluate the associations between shape features and cartilage relaxation times at 3 years. Results indicated that subjects with PFJ degeneration exhibited a trochlea with longer lateral condyle and shallower trochlear groove (adjusted odds ratio [OR] = 0.30; 95% confidence interval [CI]: 0.10, 0.86; P = .025). Subjects with worsening of PFJ degeneration exhibited a patella with equally distributed facets (adjusted OR = 3.14; 95% CI: 1.05, 9.37; P = .040) and lateral bump (adjusted OR = 0.14; 95% CI: 0.02, 0.83; P = .030). No shape features were associated with worsening of self-reported symptoms. Elevated T1ρ and T2 times at 3 years were associated with a patella with a lateral hook, equally distributed facets, round and thick as well as a trochlea larger in size (R = 0.38~0.46, P = .015~.025). The study demonstrated the ability of 3D statistical shape modeling to quantify patella and trochlear bone shape features that are associated with the presence and progression of PFJ osteoarthritic features.

The impact of subthalamic deep brain stimulation on belief revision and social validation.

We investigated whether Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) influences social validation as measured by a Judge-Advisor task. In contrast to healthy controls and patients with their DBS OFF, patients with their stimulation switched on do not experience a gain of confidence after receiving competent advice.

DiODe v2: Unambiguous and Fully-Automated Detection of Directional DBS Lead Orientation.

Directional deep brain stimulation (DBS) leads are now widely used, but the orientation of directional leads needs to be taken into account when relating DBS to neuroanatomy. Methods that can reliably and unambiguously determine the orientation of directional DBS leads are needed. In this study, we provide an enhanced algorithm that determines the orientation of directional DBS leads from postoperative CT scans. To resolve the ambiguity of symmetric CT artifacts, which in the past, limited the orientation detection to two possible solutions, we retrospectively evaluated four different methods in 150 Cartesia™ directional leads, for which the true solution was known from additional X-ray images. The method based on shifts of the center of mass (COM) of the directional marker compared to its expected geometric center correctly resolved the ambiguity in 100% of cases. In conclusion, the DiODe v2 algorithm provides an open-source, fully automated solution for determining the orientation of directional DBS leads.

Correction: Petry-Schmelzer et al. Selecting the Most Effective DBS Contact in Essential Tremor Patients Based on Individual Tractography. Brain Sci. 2020, 10, 1015.

The authors wish to make the following correction to [...].

Thalamic Deep Brain Stimulation in Essential Tremor Plus Is as Effective as in Essential Tremor.

The new essential tremor (ET) classification defined ET-plus (ET-p) as an ET subgroup with additional neurological signs besides action tremor. While deep brain stimulation (DBS) is effective in ET, there are no studies specifically addressing DBS effects in ET-p. 44 patients with medication-refractory ET and thalamic/subthalamic DBS implanted at our center were postoperatively classified into ET and ET-p according to preoperative documentation. Tremor suppression with DBS (stimulation ON vs. preoperative baseline and vs. stimulation OFF), measured via the Fahn-Tolosa-Marin tremor rating scale (TRS), stimulation parameters, and the location of active contacts were compared between patients classified as ET and ET-p. TRS scores at baseline were higher in ET-p. ET-p patients showed comparable tremor reduction as patients with ET, albeit higher stimulation parameters were needed in ET-p. Active electrode contacts were located more dorsally in ET-p of uncertain reason. Our data show that DBS is similarly effective in ET-p compared to ET. TRS scores were higher in ET-p preoperatively, and higher stimulation parameters were needed for tremor reduction compared to ET. The latter may be related to a more dorsal location of active electrode contacts in the ET-p group of this cohort. Prospective studies are warranted to investigate DBS in ET-p further.

Selecting the Most Effective DBS Contact in Essential Tremor Patients Based on Individual Tractography.

Postoperative choice of the most effective deep brain stimulation (DBS) contact in patients with essential tremor (ET) so far relies on lengthy clinical testing. Previous studies showed that the postoperative effectiveness of DBS contacts depends on the distance to the dentatorubrothalamic tract (DRTT). Here, we investigated whether the most effective DBS contact could be determined from calculating stimulation overlap with the individual DRTT. Seven ET patients with bilateral thalamic deep brain stimulation were included retrospectively. Tremor control was assessed for each contact during test stimulation with 2mA. Individual DRTTs were identified from diffusion tensor imaging and contacts were ranked by their stimulation overlap with the respective DRTT in relation to their clinical effectiveness. A linear mixed-effects model was calculated to determine the influence of the DRTT overlap on tremor control. In 92.9% of investigated DBS leads, the contact with the best clinical effect was the contact with the highest or second-highest DRTT-overlap. At the group level, the DRTT-overlap explained 26.7% of the variance in the clinical outcomes (p < 0.001). Our data suggest that the overlap with the DRTT based on individual tractography may serve as a marker to determine the most effective DBS contact in ET patients and reduce burdensome clinical testing in the future.