Background

Peripheral levels of pro-inflammatory biomarkers have been shown to be altered in schizophrenia (SZ) and associated with cognitive impairments, but their relevance to specific cognitive domains remains unclear.

Methods

Plasma levels of cytokines, chemokines, and vascular biomarkers were quantified and compared between SZ and healthy comparison (HC) groups. Cognition was assessed using the Delis-Kaplan Executive Function System Trail Making (TM) and Color Word Interference (CWI) tests. Linear regression analyses examined differential relationships of inflammatory biomarkers with executive function between groups.

Results

Plasma levels of TNFα, ICAM1, and MCP1 were higher in individuals with SZ compared to HCs. Higher level of MCP1 was associated with increased CWI Inhibition Switching Errors in SZ but not HCs.

Conclusion

Like other studies, we found evidence for increased peripheral inflammation in SZ. We also showed that SZ with particularly high MCP1 levels had poor cognitive flexibility. Interventions to reduce chemokine elevations might prove beneficial for cognitive performance.

Background

Blepharospasm can be present as an isolated dystonia or in conjunction with other forms of cranial dystonia, causing significant disability.

Case report

We report a case of a 69-year-old male with craniocervical dystonia, manifesting primarily as incapacitating blepharospasm refractory to medical treatments. He underwent bilateral globus pallidus (GP) deep brain stimulation (DBS) with complete resolution of his blepharospasm and sustained benefit at 12 months postoperatively.

Discussion

This case illustrates successful treatment of blepharospasm with pallidal stimulation. GP-DBS should be considered a reasonable therapeutic option for intractable blepharospasm.

Abnormalities in nonverbal communication are a hallmark of schizophrenia. Results from studies using symptom rating scales suggest that these abnormalities are profound (i.e., 3-5 SDs) and occur across virtually every channel of vocal expression. Computerized acoustic analytic technologies, used to overcome practical and psychometric limitations with symptom rating scales, have found much more benign and isolated abnormalities. To better understand vocal deficits in schizophrenia and to advance acoustic analytic technologies for clinical and research applications, we examined archived speech samples from 5 separate studies, each using different speaking tasks (patient N = 309; control N = 117). We sought to: (a) use Principal Component Analysis (PCA) to identify independent vocal expression measures from a large set of variables, (b) quantify how patients with schizophrenia are abnormal with respect to these variables, (c) evaluate the impact of demographic and contextual factors (e.g., study site, speaking task), and (d) examine the relationship between clinically-rated psychiatric symptoms and vocal variables. PCA identified 7 independent markers of vocal expression. Most of these vocal variables varied considerably as a function of context and many were associated with demographic factors. After controlling for context and demographics, there were no meaningful differences in vocal expression between patients and controls. Within patients, vocal variables were associated with a range of psychiatric symptoms-though only pause length was significantly associated with clinically rated negative symptoms. The discussion centers on explaining the apparent discordance between clinical and computerized speech measures.

Objective.Deep brain stimulation (DBS) programming for movement disorders requires systematic fine tuning of stimulation parameters to ameliorate tremor and other symptoms while avoiding side effects. DBS programming can be a time-consuming process and requires clinical expertise to assess response to DBS to optimize therapy for each patient. In this study, we describe and evaluate an automated, closed-loop, and patient-specific framework for DBS programming that measures tremor using a smartwatch and automatically changes DBS parameters based on the recommendations from a closed-loop optimization algorithm thus eliminating the need for an expert clinician.Approach.Bayesian optimization which is a sample-efficient global optimization method was used as the core of this DBS programming framework to adaptively learn each patient's response to DBS and suggest the next best settings to be evaluated. Input from a clinician was used initially to define a maximum safe amplitude, but we also implemented 'safe Bayesian optimization' to automatically discover tolerable exploration boundaries.Main results.We tested the system in 15 patients (nine with Parkinson's disease and six with essential tremor). Tremor suppression at best automated settings was statistically comparable to previously established clinical settings. The optimization algorithm converged after testing15.1±0.7settings when maximum safe exploration boundaries were predefined, and17.7±4.9when the algorithm itself determined safe exploration boundaries.Significance.We demonstrate that fully automated DBS programming framework for treatment of tremor is efficient and safe while providing outcomes comparable to that achieved by expert clinicians.

Brain structural abnormalities have been demonstrated in schizophrenia (SZ); these resemble those seen in typical aging, but are seen at younger ages. Furthermore, SZ is associated with accelerated global brain aging, as measured by brain structure-based brain predicted age difference (Brain-PAD). High heterogeneity exists in the degree of brain abnormalities in SZ, and individual differences may be related to levels of peripheral inflammation and may relate to cognitive deficits and negative symptoms. The goal of our study was to investigate the relationship between brain aging, peripheral inflammation, and symptoms of SZ. We hypothesized older brain-PAD in SZ vs. healthy comparison (HC) participants, as well as positive relationships of brain-PAD with peripheral inflammation markers and symptoms in SZ. We analyzed data from two cross-sectional studies in SZ (n = 26; M/F: 21/5) and HC (n = 28; 20/8) (22-64 years). Brain-PAD was calculated using a previously validated Gaussian process regression model applied to raw T1-weighted MRI data. Plasma levels of inflammatory biomarkers (CRP, Eotaxin, Fractalkine, IP10, IL6, IL10, ICAM1, IFNγ, MCP1, MIP1β, SAA, TNFα, VEGF, VCAM1) and cognitive and negative symptoms were assessed. We observed a higher brain-PAD in SZ vs. HC, and advanced brain age relative to chronological age was related to higher peripheral levels of TNFα in the overall group and in the SZ group; other inflammatory markers were not related to brain-PAD. Within the SZ group, we observed no association between cognitive or negative symptoms and brain-PAD. These results support our hypothesis of advanced brain aging in SZ. Furthermore, our findings on the relationship of the pro-inflammatory cytokine TNFα with higher brain-PAD of SZ are relevant to explain heterogeneity of brain ages in SZ, but we did not find strong evidence for cognitive or negative symptom relationships with brain-PAD.

Background/aims

Nonrechargeable deep brain stimulation implantable pulse generators (IPGs) for movement disorders require surgical replacement every few years due to battery depletion. Rechargeable IPGs reduce frequency of replacement surgeries and inherent risks of complications but require frequent recharging. Here, we evaluate patient experience with rechargeable IPGs and define predictive characteristics for higher satisfaction.

Methods

We contacted all patients implanted with rechargeable IPGs at a single center in a survey-based study. We analyzed patient satisfaction with respect to age, diagnosis, target, charging duration, and body mass index. We tabulated hardware-related adverse events.

Results

Dystonia patients had significantly higher satisfaction than Parkinson's disease patients in recharging, display, programmer, and training domains. Common positive responses were "fewer surgeries" and "small size." Common negative responses were "difficulty finding the right position to recharge" and "need to recharge every day." Hardware-related adverse events occurred in 21 of 59 participants.

Conclusion

Patient experience with rechargeable IPGs was largely positive; however, frustrations with recharging and adverse events were common. Dystonia diagnosis was most predictive of high satisfaction across multiple categories, potentially related to expected long disease duration with need for numerous IPG replacements.

Background

Despite over 30 years of clinical experience, high-quality studies on the efficacy of bilateral versus unilateral deep brain stimulation (DBS) of the ventral intermediate (VIM) nucleus of the thalamus for medically refractory essential tremor (ET) remain limited.

Objectives

To compare benefits and risks of bilateral versus unilateral VIM DBS using the largest ET DBS clinical trial dataset available to date.

Methods

Participants from the US St. Jude/Abbott pivotal ET DBS trial who underwent staged-bilateral VIM implantation constituted the primary cohort in this sub-analysis. Their assessments "on" DBS at six months after second-side VIM DBS implantation were compared to the assessments six months after unilateral implantation. Two control cohorts of participants with unilateral implantation only were also used for between-group comparisons.

Results

The primary cohort consisted of n = 38 ET patients (22M/16F; age of 65.3 ± 9.5 years). The second side VIM-DBS resulted in a 29.6% additional improvement in the total motor CRST score (P < 0.001), with a 64.1% CRST improvement in the contralateral side (P < 0.001). An added improvement was observed in the axial tremor score (21.4%, P = 0.005), and CRST part B (24.8%, P < 0.001) score. Rate of adverse events was slightly higher after bilateral stimulation.

Conclusions

In the largest ET DBS study to date, staged-bilateral VIM DBS was a highly effective treatment for ET with bilateral implantation resulting in greater reduction in total motor tremor scores when compared to unilateral stimulation alone.

The Trial of Parkinson's And Zoledronic acid (TOPAZ, https://clinicaltrials.gov/ct2/show/NCT03924414 ) is a unique collaboration between experts in movement disorders and osteoporosis to test the efficacy of zoledronic acid, an FDA-approved parenteral treatment for osteoporosis, for fracture prevention in people with neurodegenerative parkinsonism. Aiming to enroll 3,500 participants age 65 years or older, TOPAZ is one of the largest randomized, placebo-controlled clinical trials ever attempted in parkinsonism. The feasibility of TOPAZ is enhanced by its design as a U.S.- wide home-based trial without geographical limits. Participants receive information from multiple sources, including specialty practices, support groups and websites. Conducting TOPAZ in participants' homes takes advantage of online consent technology, the capacity to confirm diagnosis using telemedicine and the availability of research nursing to provide screening and parenteral therapy in homes. Home-based clinical research may provide an efficient, convenient, less expensive method that opens participation in clinical trials to almost anyone with parkinsonism.

Adaptive deep brain stimulation (aDBS) is an emerging advancement in DBS technology; however, local field potential (LFP) signal rate detection sufficient for aDBS algorithms and the methods to set-up aDBS have yet to be defined. Here we summarize sensing data and aDBS programming steps associated with the ongoing Adaptive DBS Algorithm for Personalized Therapy in Parkinsons Disease (ADAPT-PD) pivotal trial (NCT04547712). Sixty-eight patients were enrolled with either subthalamic nucleus or globus pallidus internus DBS leads connected to a Medtronic PerceptTM PC neurostimulator. During the enrollment and screening procedures, a LFP (8-30 Hz, ≥1.2 µVp) control signal was identified by clinicians in 84.8% of patients on medication (65% bilateral signal), and in 92% of patients off medication (78% bilateral signal). The ADAPT-PD trial sensing data indicate a high LFP signal presence in both on and off medication states of these patients, with bilateral signal in the majority, regardless of PD phenotype.