Assessing the benefits of digital twins in neurosurgery: a systematic review.

Digital twins are virtual replicas of their physical counterparts, and can assist in delivering personalized surgical care. This PRISMA guideline-based systematic review evaluates current literature addressing the effectiveness and role of digital twins in many stages of neurosurgical management. The aim of this review is to provide a high-quality analysis of relevant, randomized controlled trials and observational studies addressing the neurosurgical applicability of a variety of digital twin technologies. Using pre-specified criteria, we evaluated 25 randomized controlled trials and observational studies on the applications of digital twins, including navigation, robotics, and image-guided neurosurgeries. All 25 studies compared these technologies against usual surgical approaches. Risk of bias analyses using the Cochrane risk of bias tool for randomized trials (Rob 2) found "low" risk of bias in the majority of studies (23/25). Overall, this systematic review shows that digital twin applications have the potential to be more effective than conventional neurosurgical approaches when applied to brain and spinal surgery. Moreover, the application of these novel technologies may also lead to fewer post-operative complications.

Gray matter volume covariance networks associated with dual-task cost during walking-while-talking.

We studied gray matter volume covariance networks associated with normal pace walking (NPW) speed and dual-task costs (DTCs) during walking-while-talking (WWT)-a mobility stress test that involves walking while reciting alternate letters of the alphabet. Using a multivariate covariance-based analytic approach, we identified gray matter networks associated with NPW speed (mean 102.1 cm/s ±22.5 cm/s) and DTC (percent difference in gait speed between NPW and WWT, mean 25.9% ± 18.8%) in 139 older adults without dementia (M = 75.3 ± 6.1 years). The gray matter network associated with NPW was primarily composed of supplementary motor area, precuneus cortex, and the middle frontal gyrus. Greater expression of this NPW network was associated with better processing speed (trail-making test A [r = -0.30, p = 0.005]) and executive function (trail-making test B - A [r = -0.43, p < 0.0001]). The gray matter network associated with DTC was primarily composed of medial prefrontal, cingulate, and thalamic regions. Greater expression of this DTC network was associated with better episodic memory performance on the free and cued selective reminding test (r = 0.30, p = 0.007). These results suggest that NPW speed and DTC are supported by different networks, and are associated with different cognitive domains.

The role of genetics in the treatment of dystonia with deep brain stimulation: Systematic review and Meta-analysis.

BACKGROUND: Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions that lead to involuntary postures or repetitive movements. Genetic mutations are being increasingly recognized as a cause of dystonia. Deep brain stimulation (DBS) is one of the limited treatment options available. However, there are varying reports on its efficacy in genetic dystonias. This systematic review of the characteristics of genetic dystonias treated with DBS and their outcomes aims to aid in the evaluation of eligibility for such treatment. METHODS: We performed a PUBMED search of all papers related to genetic dystonias and DBS up until April 2022. In addition to performing a systematic review, we also performed a meta-analysis to assess the role of the mutation on DBS response. We included cases that had a confirmed genetic mutation and DBS along with pre-and post-operative BFMDRS. RESULTS: Ninety-one reports met our inclusion criteria and from them, 235 cases were analyzed. Based on our analysis DYT-TOR1A dystonia had the best evidence for DBS response and Rapid-Onset Dystonia Parkinsonism was among the least responsive to DBS. CONCLUSION: While our report supports the role of genetics in DBS selection and response, it is limited by the rarity of the individual genetic conditions, the reliance on case reports and case series, and the limited ability to obtain genetic testing on a large scale in real-time as opposed to retrospectively as in many cases.

Pronounced toxicity differences between homobifunctional protein cross-linkers and analogous monofunctional electrophiles.

Bifunctional electrophiles have been used in various chemopreventive, chemotherapeutic, and bioconjugate applications. Many of their effects in biological systems are traceable to their reactive properties, whereby they can modify nucleophilic sites in DNA, proteins, and other cellular molecules. Previously, we found that two different bifunctional electrophiles--diethyl acetylenedicarboxylate and divinyl sulfone--exhibited a strong enhancement of toxicity when compared with analogous monofunctional electrophiles in both human colorectal carcinoma cells and baker's yeast. Here, we have compared the toxicities for a broader panel of homobifunctional electrophiles bearing diverse electrophilic centers (e.g., isothiocyanate, isocyanate, epoxide, nitrogen mustard, and aldehyde groups) to their monofunctional analogues. Each bifunctional electrophile showed at least a 3-fold enhancement of toxicity over its monofunctional counterpart, although in most cases, the differences were even more pronounced. To explain their enhanced toxicity, we tested the ability of each bifunctional electrophile to cross-link recombinant yeast thioredoxin 2 (Trx2), a known intracellular target of electrophiles. The bifunctional electrophiles were capable of cross-linking Trx2 to itself in vitro and to other proteins in cells exposed to toxic concentrations. Moreover, most cross-linkers were preferentially reactive with thiols in these experiments. Collectively, our results indicate that thiol-reactive protein cross-linkers in general are much more potent cytotoxins than analogous monofunctional electrophiles, irrespective of the electrophilic group studied.

Brain patterns of pace - but not rhythm - are associated with vascular disease in older adults.

Background: Distinct domains of gait such as pace and rhythm are linked to an increased risk for cognitive decline, falls, and dementia in aging. The brain substrates supporting these domains and underlying diseases, however, remain relatively unknown. The current study aimed to identify patterns of gray matter volume (GMV) associated with pace and rhythm, and whether these patterns vary as a function of vascular and non-vascular comorbidities. Methods: A cross-sectional sample of 297 older adults (M Age = 72.5 years ± 7.2 years, 43% women) without dementia was drawn from the Tasmanian Study of Cognition and Gait (TASCOG). Factor analyses were used to reduce eight quantitative gait variables into two domains. The "pace" domain was primarily composed of gait speed, stride length, and double support time. The "rhythm" domain was composed of swing time, stance time, and cadence. Multivariate covariance-based analyses adjusted for age, sex, education, total intracranial volume, and presence of mild cognitive impairment identified gray matter volume (GMV) patterns associated with pace and rhythm, as well as participant-specific expression (or factor) scores for each pattern. Results: Pace was positively associated with GMV in the right superior temporal sulcus, bilateral supplementary motor areas (SMA), and bilateral cerebellar regions. Rhythm was positively associated with GMV in bilateral SMA, prefrontal, cingulate, and paracingulate cortices. The GMV pattern associated with pace was less expressed in participants with any vascular disease; this association was also found independently with hypertension, diabetes, and myocardial infarction. Conclusion: Both pace and rhythm domains of gait were associated with the volume of brain structures that have been linked to controlled and automatic aspects of gait control, as well as with structures involved in multisensory integration. Only the brain structures associated with pace, however, were associated with vascular disease.

Clinical Review of Smartphone Applications in Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) is the second leading neurodegenerative disease worldwide. Important advances in monitoring and treatment have been made in recent years. This article reviews literature on utility of smartphone applications in monitoring PD symptoms that may ultimately facilitate improved patient care, and on movement modulation as a potential therapeutic. REVIEW SUMMARY: Novel mobile phone applications can provide one-time and/or continuous data to monitor PD motor symptoms in person or remotely, that may support precise therapeutic adjustments and management decisions. Apps have also been developed for medication management and treatment. CONCLUSIONS: Smartphone applications provide a wide array of platforms allowing for meaningful short-term and long-term data collection and are also being tested for intervention. However, the variability of the applications and the need to translate complicated sensor data may hinder immediate clinical applicability. Future studies should involve stake-holders early in the design process to promote usability and streamline the interface between patients, clinicians, and PD apps.

Persistent seropositivity in oophorectomy-resistant anti-NMDA receptor encephalitis.

To discuss (1) the significance of seropositivity in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and (2) clinical decision making in oophorectomy resistant disease. Patient A (a 35-year-old woman) had high CSF and serum anti-NMDA antibody titres, a complicated hospital course, little improvement with first and second-line therapies, and remained with high CSF and serum antibody titres despite unilateral oophorectomy, requiring a nearly 13-month long hospitalisation. Conversely, patient B (a 29-year-old woman) had low CSF titres, seronegative disease and quickly recovered to her baseline with first line therapies and oophorectomy. Anti-NMDAR antibodies are themselves pathological, causing signalling dysfunction and internalisation of the NMDAR. Seropositivity with anti-NMDAR antibodies likely reflects leakage from the blood-brain barrier, with high serum titres being a downstream effect of high CSF titres. Empiric bilateral oophorectomies is controversial but appropriate on a case-by-case basis in extremely treatment-resistant NMDAR encephalitis given the possibility of antigenic microteratomas, which may not be detected on imaging or even bilateral ovarian biopsies.

Effectiveness of online education for recruitment to an Alzheimer's disease prevention clinical trial.

INTRODUCTION: Low awareness of Alzheimer's disease (AD) clinical trials is a recruitment barrier. To assess whether online education may affect screening rates for AD prevention clinical trials, we conducted an initial prospective cohort study (n = 10,450) and subsequent randomized study (n = 351) using an online digital tool: AlzU.org. METHODS: A total of 10,450 participants were enrolled in an initial cohort study and asked to complete a six-lesson course on AlzU.org, as well as a baseline and 6-month follow-up questionnaire. Participants were stratified into three groups based on lesson completion at 6 months: group 1 (zero to one lesson completed), group 2 (two to four lessons), and group 3 (five or more lessons). For the subsequent randomized-controlled trial (RCT), 351 new participants were enrolled in a six-lesson course (n = 180) versus a time-neutral control (n = 171). Screening and enrollment in the Anti-Amyloid Treatment in Asymptomatic AD (A4) clinical trial were reported via the 6-month questionnaire and are the primary outcomes. RESULTS: Cohort: 3.9% of group 1, 5% of group 2, and 8.4% of group 3 screened for the A4 trial. Significant differences were found among the groups (P < 0.001). Post hoc analyses showed differences in A4 screening rates between groups 1 and 3 (P < 0.001) and groups 2 and 3 (P = 0.0194). There were no differences in enrollment among the three groups. RCT: 2.78% of the intervention group screened for A4 compared to 0% of controls (P = 0.0611). DISCUSSION: Online education via the AlzU.org digital tool may serve as an effective strategy to supplement clinical trial recruitment.

Trapping redox partnerships in oxidant-sensitive proteins with a small, thiol-reactive cross-linker.

A broad range of redox-regulated proteins undergo reversible disulfide bond formation on oxidation-prone cysteine residues. Heightened reactivity of the thiol groups in these cysteines also increases susceptibility to modification by organic electrophiles, a property that can be exploited in the study of redox networks. Here, we explored whether divinyl sulfone (DVSF), a thiol-reactive bifunctional electrophile, cross-links oxidant-sensitive proteins to their putative redox partners in cells. To test this idea, previously identified oxidant targets involved in oxidant defense (namely, peroxiredoxins, methionine sulfoxide reductases, sulfiredoxin, and glutathione peroxidases), metabolism, and proteostasis were monitored for cross-link formation following treatment of Saccharomyces cerevisiae with DVSF. Several proteins screened, including multiple oxidant defense proteins, underwent intermolecular and/or intramolecular cross-linking in response to DVSF. Specific redox-active cysteines within a subset of DVSF targets were found to influence cross-linking; in addition, DVSF-mediated cross-linking of its targets was impaired in cells first exposed to oxidants. Since cross-linking appeared to involve redox-active cysteines in these proteins, we examined whether potential redox partners became cross-linked to them upon DVSF treatment. Specifically, we found that several substrates of thioredoxins were cross-linked to the cytosolic thioredoxin Trx2 in cells treated with DVSF. However, other DVSF targets, like the peroxiredoxin Ahp1, principally formed intra-protein cross-links upon DVSF treatment. Moreover, additional protein targets, including several known to undergo S-glutathionylation, were conjugated via DVSF to glutathione. Our results indicate that DVSF is of potential use as a chemical tool for irreversibly trapping and discovering thiol-based redox partnerships within cells.