Neuropsychological and social predictors of participation in a deep brain stimulation study of Parkinson's disease and dystonia.

Objectives: Participation is essential to DBS research, yet circumstances that affect diverse participation remain unclear. Here we evaluate factors impacting participation in an adaptive DBS study of Parkinson's disease (PD) and dystonia. Methods: Twenty participants were implanted with a sensing-enabled DBS device (Medtronic Summit RC+S) that allows neural data streaming in naturalistic settings and encouraged to stream as much as possible for the first five months after surgery. Using standardized baseline data obtained through neuropsychological evaluation, we compared neuropsychological and social variables to streaming hours. Results: Marital status and irritability significantly impacted streaming hours (estimate=136.7, bootstrapped ( b ) CI b =45.0 to 249.0, p b =0.016, and estimate=-95.1, CI b =-159.9 to -49.2, p b =0.027, respectively). These variables remained significant after multivariable analysis. Composite scores on verbal memory evaluations predicted the number of hours of data streamed (R 2 =0.284, estimate=67.7, CI b =20.1 to 119.9, p b =0.019). Discussion: Verbal memory impairment, irritability, and lack of a caregiver may be associated with decreased participation. Further study of factors that impact research participation is critical to the sustained inclusion of diverse participants.

Short term cardiovascular symptoms improvement after deep brain stimulation in patients with Parkinson's disease: a systematic review.

BACKGROUND: Autonomic dysfunction is common and disabling in Parkinson's disease (PD). The effects of deep brain stimulation (DBS) on the cardiovascular system in PD remain poorly understood. We aimed to assess the effect of DBS on cardiovascular symptoms and objective measures in PD patients. METHODS: We conducted a systematic literature search in PubMed/MEDLINE. RESULTS: 36 out of 472 studies were included, mostly involving DBS of the subthalamic nucleus, and to a lesser extent the globus pallidus pars interna and pedunculopontine nucleus. Seventeen studies evaluated the effect of DBS on patient-reported or clinician-rated cardiovascular symptoms, showing an improvement in the first year after surgery but not with longer-term follow-up. DBS has no clear direct effects on blood pressure during an orthostatic challenge (n = 10 studies). DBS has inconsistent effects on heart rate variability (n = 10 studies). CONCLUSION: Current evidence on the impact of DBS on cardiovascular functions in PD is inconclusive. DBS may offer short-term improvement of cardiovascular symptoms in PD, particularly orthostatic hypotension, which may be attributed to dopaminergic medication reduction after surgery. There is insufficient evidence to draw conclusions on the direct effect of DBS on blood pressure and heart rate variability.

Artifact Characterization and a Multipurpose Template-Based Offline Removal Solution for a Sensing-Enabled Deep Brain Stimulation Device.

BACKGROUND: The Medtronic "Percept" is the first FDA-approved deep brain stimulation (DBS) device with sensing capabilities during active stimulation. Its real-world signal-recording properties have yet to be fully described. OBJECTIVE: This study details three sources of artifact (and potential mitigations) in local field potential (LFP) signals collected by the Percept and assesses the potential impact of artifact on the future development of adaptive DBS (aDBS) using this device. METHODS: LFP signals were collected from 7 subjects in both experimental and clinical settings. The presence of artifacts and their effect on the spectral content of neural signals were evaluated in both the stimulation ON and OFF states using three distinct offline artifact removal techniques. RESULTS: Template subtraction successfully removed multiple sources of artifact, including (1) electrocardiogram (ECG), (2) nonphysiologic polyphasic artifacts, and (3) ramping-related artifacts seen when changing stimulation amplitudes. ECG removal from stimulation ON (at 0 mA) signals resulted in spectral shapes similar to OFF stimulation spectra (averaged difference in normalized power in theta, alpha, and beta bands ≤3.5%). ECG removal using singular value decomposition was similarly successful, though required subjective researcher input. QRS interpolation produced similar recovery of beta-band signal but resulted in residual low-frequency artifact. CONCLUSIONS: Artifacts present when stimulation is enabled notably affected the spectral properties of sensed signals using the Percept. Multiple discrete artifacts could be successfully removed offline using an automated template subtraction method. The presence of unrejected artifact likely influences online power estimates, with the potential to affect aDBS algorithm performance.

Alternating Modulation of Subthalamic Nucleus Beta Oscillations during Stepping.

Gait disturbances in Parkinson's disease are commonly refractory to current treatment options and majorly impair patient's quality of life. Auditory cues facilitate gait and prevent motor blocks. We investigated how neural dynamics in the human subthalamic nucleus of Parkinsons's disease patients (14 male, 2 female) vary during stepping and whether rhythmic auditory cues enhance the observed modulation. Oscillations in the beta band were suppressed after ipsilateral heel strikes, when the contralateral foot had to be raised, and reappeared after contralateral heel strikes, when the contralateral foot rested on the floor. The timing of this 20-30 Hz beta modulation was clearly distinct between the left and right subthalamic nucleus, and was alternating within each stepping cycle. This modulation was similar, whether stepping movements were made while sitting, standing, or during gait, confirming the utility of the stepping in place paradigm. During stepping in place, beta modulation increased with auditory cues that assisted patients in timing their steps more regularly. Our results suggest a link between the degree of power modulation within high beta frequency bands and stepping performance. These findings raise the possibility that alternating deep brain stimulation patterns may be superior to constant stimulation for improving parkinsonian gait.SIGNIFICANCE STATEMENT Gait disturbances in Parkinson's disease majorly reduce patients' quality of life and are often refractory to current treatment options. We investigated how neural activity in the subthalamic nucleus of patients who received deep brain stimulation surgery covaries with the stepping cycle. 20-30 Hz beta activity was modulated relative to each step, alternating between the left and right STN. The stepping performance of patients improved when auditory cues were provided, which went along with enhanced beta modulation. This raises the possibility that alternating stimulation patterns may also enhance beta modulation and may be more beneficial for gait control than continuous stimulation, which needs to be tested in future studies.

Adaptive Brain Stimulation for Movement Disorders.

Deep brain stimulation (DBS) has markedly changed how we treat movement disorders including Parkinson's disease (PD), dystonia, and essential tremor (ET). However, despite its demonstrable clinical benefit, DBS is often limited by side effects and partial efficacy. These limitations may be due in part to the fact that DBS interferes with both pathological and physiological neural activities. DBS could, therefore, be potentially improved were it applied selectively and only at times of enhanced pathological activity. This form of stimulation is known as closed-loop or adaptive DBS (aDBS). An aDBS approach has been shown to be superior to conventional DBS in PD in primates using cortical neuronal spike triggering and in humans employing local field potential biomarkers. Likewise, aDBS studies for essential and Parkinsonian tremor are advancing and show great promise, using both peripheral or central sensing and stimulation. aDBS has not yet been trialed in dystonia and yet exciting and promising biomarkers suggest it could be beneficial here too. In this chapter, we will review the existing literature on aDBS in movement disorders and explore potential biomarkers and stimulation algorithms for applying aDBS in PD, ET, and dystonia.

Plasmatic isoforms of cytokeratin 18 and RAGE after severe trauma: a longitudinal cohort study.

BACKGROUND: Life-threatening traumatic injuries lead to a complex inflammation-driven pathophysiology. Receptor of advanced glycation end product (RAGE) is a multiligand receptor of several endogenous alarmins, while cytokeratin 18 is a structural component of the filament of epithelial cells. Both proteins can be frequently found in plasma of patients with different diseases, whereby they have distinct underlying mechanism of formation. In this prospective observational study, we wanted to shed light on the kinetic of plasmatic RAGE and cytokeratin 18 isoforms after severe trauma, thereby also addressing the association of these markers with inflammation and their potential use as biomarkers. METHODS: Plasma samples of 77 patients with severe multiple trauma as defined by an Injury Severity Score (ISS) 16 or greater were obtained from a local repository and levels of soluble RAGE, endogenous secretory RAGE, cytokeratin 18, cleaved cytokeratin 18, and interleukin 6 by enzyme-linked immunosorbent assay. Demographic and routine parameters of the cohort were extracted from an electronic patient data management system. RESULTS: Both RAGE isoforms were transiently increased in plasma within 24 hours after trauma, while cytokeratin 18 levels were unchanged. Moreover, soluble RAGE concentrations in patients with thoracic injuries were higher compared with patients without injury, and both isoforms of RAGE discriminated between patients with most severe adult respiratory distress syndrome and patients with milder forms. In addition, cleaved and total cytokeratin 18 levels differ between patients with hepatic dysfunction and normal function, without possessing discriminatory power. RAGE and cytokeratin 18 isoforms correlated significantly but to a low extent with interleukin 6, while the isoforms of both parameters correlated to a high extent with one another. CONCLUSION: The release of RAGE (but not cytokeratin 18) isoforms occurs early and transiently after trauma and is associated with the extent of injury and inflammatory response. RAGE and cytokeratin 18 isoforms have the potential to act as diagnostic or prognostic biomarkers of lung and hepatic dysfunction. LEVEL OF EVIDENCE: Epidemiologic/prognostic study, level IV.

Sepsis syndrome and death in trauma patients are associated with variation in the gene encoding tumor necrosis factor.

OBJECTIVE: Patients encountering severe trauma are at risk of developing sepsis syndrome and subsequent multiple organ failure. This is often associated with fatal outcome despite survival of the initial injury. We postulate that variation of the gene coding for tumor necrosis factor (TNF)-alpha is associated with increased occurrence of sepsis syndrome and mortality in trauma patients. DESIGN: Prospective cohort study; validation in an external replication sample. SETTING: Tertiary academic medical center. PATIENTS: We included 159 severely traumatized patients from a single center. Serial blood samples were analyzed for serum concentrations of TNF-alpha and lymphotoxin-alpha (LTA). We genotyped nine polymorphisms in the TNF gene and tested for an association with sepsis syndrome and outcome. Genetic associations were validated in an external replication sample (n = 76). We examined the peripheral blood transcriptome in 28 patients by whole genome-based profiling and validated the results. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Carriage of the TNF rs1800629 A allele was associated with higher TNF-alpha serum concentrations on the first day after trauma and during follow-up (two-sided p = 5.0 x 10(-5)), with development of sepsis syndrome (odds ratio 7.14, two-sided p = 1.2 x 10(-6); external validation sample [n = 76]: odds ratio 3.3, one-sided p = .03), and with fatal outcome (odds ratio 7.65, two-sided p = 1.9 x 10(-6)). Carriage of the TNF rs1800629 A allele was associated with differential expression of genes representing stronger proinflammatory and apoptotic responses compared with carriage of the wild-type allele. CONCLUSIONS: Common TNF gene variants are associated with sepsis syndrome and death after severe injury. These findings are strongly supported by functional data and may be important for developing preemptive anti-inflammatory interventions in carriers of the risk-associated allele.

Performance and customization of 4 prognostic models for postoperative onset of nausea and vomiting in ear, nose, and throat surgery.

OBJECTIVE: To evaluate the performance of 4 published prognostic models for postoperative onset of nausea and vomiting (PONV) by means of discrimination and calibration and the possible impact of customization on these models. DESIGN: Prospective, observational study. SETTING: Tertiary care university hospital. PATIENTS: 748 adult patients (>18 years old) enrolled in this study. Severe obesity (weight > 150 kg or body mass index > 40 kg/m) was an exclusion criterion. INTERVENTIONS: All perioperative data were recorded with an anesthesia information management system. A standardized patient interview was performed on the postoperative morning and afternoon. MEASUREMENTS: Individual PONV risk was calculated using 4 original regression equations by Koivuranta et al, Apfel et al, Sinclair et al, and Junger et al Discrimination was assessed using receiver operating characteristic (ROC) curves. Calibration was tested using Hosmer-Lemeshow goodness-of-fit statistics. New predictive equations for the 4 models were derived by means of logistic regression (customization). The prognostic performance of the customized models was validated using the "leaving-one-out" technique. MAIN RESULTS: Postoperative onset of nausea and vomiting was observed in 11.2% of the specialized patient population. Discrimination could be demonstrated as shown by areas under the receiver operating characteristic curve of 0.62 for the Koivuranta et al model, 0.63 for the Apfel et al model, 0.70 for the Sinclair et al model, and 0.70 for the Junger et al model. Calibration was poor for all 4 original models, indicated by a P value lower than 0.01 in the C and H statistics. Customization improved the accuracy of the prediction for all 4 models. However, the simplified risk scores of the Koivuranta et al model and the Apfel et al model did not show the same efficiency as those of the Sinclair et al model and the Junger et al model. This is possibly a result of having relatively few patients at high risk for PONV in combination with an information loss caused by too few dichotomous variables in the simplified scores. CONCLUSIONS: The original models were not well validated in our study. An antiemetic therapy based on the results of these scores seems therefore unsatisfactory. Customization improved the accuracy of the prediction in our specialized patient population, more so for the Sinclair et al model and the Junger et al model than for the Koivuranta et al model and the Apfel et al model.