WarpDrive: Improving spatial normalization using manual refinements.

Spatial normalization-the process of mapping subject brain images to an average template brain-has evolved over the last 20+ years into a reliable method that facilitates the comparison of brain imaging results across patients, centers & modalities. While overall successful, sometimes, this automatic process yields suboptimal results, especially when dealing with brains with extensive neurodegeneration and atrophy patterns, or when high accuracy in specific regions is needed. Here we introduce WarpDrive, a novel tool for manual refinements of image alignment after automated registration. We show that the tool applied in a cohort of patients with Alzheimer's disease who underwent deep brain stimulation surgery helps create more accurate representations of the data as well as meaningful models to explain patient outcomes. The tool is built to handle any type of 3D imaging data, also allowing refinements in high-resolution imaging, including histology and multiple modalities to precisely aggregate multiple data sources together.

Deep brain stimulation in PD: risk of complications, morbidity, and hospitalizations: a systematic review.

Introduction: Parkinson's disease (PD) is a progressive and debilitating neurological disorder. While dopaminergic medication improves PD symptoms, continued management is complicated by continued symptom progression, increasing medication fluctuations, and medication-related dyskinesia. Deep brain stimulation (DBS) surgery is a well-accepted and widespread treatment often utilized to address these symptoms in advanced PD. However, DBS may also lead to complications requiring hospitalization. In addition, patients with PD and DBS may have specialized care needs during hospitalization. Methods: This systematic review seeks to characterize the complications and risk of hospitalization following DBS surgery. Patient risk factors and modifications to DBS surgical techniques that may affect surgical risk are also discussed. Results: It is found that, when candidates are carefully screened, DBS is a relatively low-risk procedure, but rate of hospitalization is somewhat increased for DBS patients. Discussion: More research is needed to determine the relative influence of more advanced disease vs. DBS itself in increased rate of hospitalization, but education about DBS and PD is important to insure effective patient care within the hospital.

Robotic-Assisted Navigation for Stereotactic Neurosurgery: A Cadaveric Investigation of Accuracy, Time, and Radiation.

BACKGROUND AND OBJECTIVES: Despite frequent use, stereotactic head frames require manual coordinate calculations and manual frame settings that are associated with human error. This study examines freestanding robot-assisted navigation (RAN) as a means to reduce the drawbacks of traditional cranial stereotaxy and improve targeting accuracy. METHODS: Seven cadaveric human torsos with heads were tested with 8 anatomic coordinates selected for lead placement mirrored in each hemisphere. Right and left hemispheres of the brain were randomly assigned to either the traditional stereotactic arc-based (ARC) group or the RAN group. Both target accuracy and trajectory accuracy were measured. Procedural time and the radiation required for registration were also measured. RESULTS: The accuracy of the RAN group was significantly greater than that of the ARC group in both target (1.2 ± 0.5 mm vs 1.7 ± 1.2 mm, P = .005) and trajectory (0.9 ± 0.6 mm vs 1.3 ± 0.9 mm, P = .004) measurements. Total procedural time was also significantly faster for the RAN group than for the ARC group (44.6 ± 7.7 minutes vs 86.0 ± 12.5 minutes, P < .001). The RAN group had significantly reduced time per electrode placement (2.9 ± 0.9 minutes vs 5.8 ± 2.0 minutes, P < .001) and significantly reduced radiation during registration (1.9 ± 1.1 mGy vs 76.2 ± 5.0 mGy, P < .001) compared with the ARC group. CONCLUSION: In this cadaveric study, cranial leads were placed faster and with greater accuracy using RAN than those placed with conventional stereotactic arc-based technique. RAN also required significantly less radiation to register the specimen's coordinate system to the planned trajectories. Clinical testing should be performed to further investigate RAN for stereotactic cranial surgery.

What eyes do not see the heart does not grieve over? The role of intracoronary imaging in acute myocardial infarction: a case report.

Background: The evaluation of a three-dimensional structure with a two-dimensional imaging technique makes intracoronary diagnostic techniques essential, especially in the setting of acute myocardial infarction (AMI) when no apparent coronary lesions are detected. Expert consensus recommend their use in certain scenarios such as angiographically ambiguous disease and identification of the culprit lesion. Although both intravascular ultrasound and optical coherence tomography (OCT) allow the characterization of the atherosclerotic plaque and assess the immediate and long-term results of stent implantation, they have their own benefits and limitations that make them ideal for different types of coronary lesions. Case summary: We present the case of a lateral ST-elevation myocardial infarction with no evident coronary lesions in angiography, in which OCT not only allowed us to confirm a diagonal branch occlusion, but it also became crucial to locate the occlusion point and to guide the procedure, allowing complete revascularization of the culprit lesion that otherwise could have been missed. Discussion: To know the actual limitations of conventional coronary angiography to adequately assess coronary disease, intracoronary diagnostic techniques are key to evaluate the underlying mechanisms of the event, especially in the setting of AMI when no clear culprit lesion has been identified. They can be of great value to locate and revascularize acute occlusions that could go unnoticed on the angiogram, guiding the revascularization and stent implantation and, therefore, preventing myocardial injury that could become irreversible when coronary disease is not treated promptly.

Management of hangman's fractures using anchored anterior cervical cages.

Background: Hangman's fractures comprise approximately 20% of C2 fractures and often require surgery to correct significant angulation and/or subluxation. Recently, anchored anterior cervical cages (ACCs) have been used to fuse C2-3 as they reduce the risks of soft-tissue dissection, bone drilling, operative time, and postoperative dysphagia. Methods: This single-center and retrospective study (2012-2019) included 12 patients (3 type I, 6 type II, and 3 type IIa fractures) undergoing C2-3 ACCs (zero profile, half plate, full plate). Preoperative and postoperative radiographic and clinical data were analyzed. Results: The 12 patients demonstrated the following findings: a mean operative time of 106 ± 21 min, blood loss averaging 67 ± 58 mL, and mean length of stay of 9.8 ± 7.7 days (6.4 ± 5.5 days in intensive care). The mean differences in preoperative versus postoperative radiographs showed an increase in disc angle (9.0° ± 9.4° vs. 14.0° ± 7.2°), reduction of subluxation (18.5% ± 13.6% vs. 2.6% ± 6.2%), and maintenance of C2-7 lordosis (14.3° ± 9.5° vs. 14.4° ± 9.5°). All patients demonstrated fusion on dynamic films obtained >6 months postoperatively. In addition, only one patient had Grade 0 subsidence, three had transient postoperative dysphagia, whereas none had either intraoperative complications or 90-day readmissions. Conclusion: ACCs proved to be a viable alternative to traditional anterior cervical discectomy/fusion to treat 12 patients with C2-3 hangman's fractures in this preliminary study.

Maternal obesity and gestational diabetes reprogram the methylome of offspring beyond birth by inducing epigenetic signatures in metabolic and developmental pathways.

BACKGROUND: Obesity is a negative chronic metabolic health condition that represents an additional risk for the development of multiple pathologies. Epidemiological studies have shown how maternal obesity or gestational diabetes mellitus during pregnancy constitute serious risk factors in relation to the appearance of cardiometabolic diseases in the offspring. Furthermore, epigenetic remodelling may help explain the molecular mechanisms that underlie these epidemiological findings. Thus, in this study we explored the DNA methylation landscape of children born to mothers with obesity and gestational diabetes during their first year of life. METHODS: We used Illumina Infinium MethylationEPIC BeadChip arrays to profile more than 770,000 genome-wide CpG sites in blood samples from a paediatric longitudinal cohort consisting of 26 children born to mothers who suffered from obesity or obesity with gestational diabetes mellitus during pregnancy and 13 healthy controls (measurements taken at 0, 6 and 12 month; total N = 90). We carried out cross-sectional and longitudinal analyses to derive DNA methylation alterations associated with developmental and pathology-related epigenomics. RESULTS: We identified abundant DNA methylation changes during child development from birth to 6 months and, to a lesser extent, up to 12 months of age. Using cross-sectional analyses, we discovered DNA methylation biomarkers maintained across the first year of life that could discriminate children born to mothers who suffered from obesity or obesity with gestational diabetes. Importantly, enrichment analyses suggested that these alterations constitute epigenetic signatures that affect genes and pathways involved in the metabolism of fatty acids, postnatal developmental processes and mitochondrial bioenergetics, such as CPT1B, SLC38A4, SLC35F3 and FN3K. Finally, we observed evidence of an interaction between developmental DNA methylation changes and maternal metabolic condition alterations. CONCLUSIONS: Our observations highlight the first six months of development as being the most crucial for epigenetic remodelling. Furthermore, our results support the existence of systemic intrauterine foetal programming linked to obesity and gestational diabetes that affects the childhood methylome beyond birth, which involves alterations related to metabolic pathways, and which may interact with ordinary postnatal development programmes.

Advances in Technical Aspects of Deep Brain Stimulation Surgery.

BACKGROUND: Deep brain stimulation has become an established technology for the treatment of patients with a wide variety of conditions, including movement disorders, psychiatric disorders, epilepsy, and pain. Surgery for implantation of DBS devices has enhanced our understanding of human physiology, which in turn has led to advances in DBS technology. Our group has previously published on these advances, proposed future developments, and examined evolving indications for DBS. SUMMARY: The crucial roles of structural MR imaging pre-, intra-, and post-DBS procedure in target visualization and confirmation of targeting are described, with discussion of new MR sequences and higher field strength MRI enabling direct visualization of brain targets. The incorporation of functional and connectivity imaging in procedural workup and their contribution to anatomical modelling is reviewed. Various tools for targeting and implanting electrodes, including frame-based, frameless, and robot-assisted, are surveyed, and their pros and cons are described. Updates on brain atlases and various software used for planning target coordinates and trajectories are presented. The pros and cons of asleep versus awake surgery are discussed. The role and value of microelectrode recording and local field potentials are described, as well as the role of intraoperative stimulation. Technical aspects of novel electrode designs and implantable pulse generators are presented and compared.

Optimal deep brain stimulation sites and networks for stimulation of the fornix in Alzheimer's disease.

Deep brain stimulation (DBS) to the fornix is an investigational treatment for patients with mild Alzheimer's Disease. Outcomes from randomized clinical trials have shown that cognitive function improved in some patients but deteriorated in others. This could be explained by variance in electrode placement leading to differential engagement of neural circuits. To investigate this, we performed a post-hoc analysis on a multi-center cohort of 46 patients with DBS to the fornix (NCT00658125, NCT01608061). Using normative structural and functional connectivity data, we found that stimulation of the circuit of Papez and stria terminalis robustly associated with cognitive improvement (R = 0.53, p < 0.001). On a local level, the optimal stimulation site resided at the direct interface between these structures (R = 0.48, p < 0.001). Finally, modulating specific distributed brain networks related to memory accounted for optimal outcomes (R = 0.48, p < 0.001). Findings were robust to multiple cross-validation designs and may define an optimal network target that could refine DBS surgery and programming.

Instantaneous Wave-Free Ratio for the Assessment of Intermediate Left Main Coronary Artery Stenosis: Correlations With Fractional Flow Reserve/Intravascular Ultrasound and Prognostic Implications: The iLITRO-EPIC07 Study.

BACKGROUND: There is little information available on agreement between fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) in left main coronary artery (LMCA) intermediate stenosis. Besides, several meta-analyses support the use of FFR to guide LMCA revascularization, but limited information is available on iFR in this setting. Our aims were to establish the concordance between FFR and iFR in intermediate LMCA lesions, to evaluate with intravascular ultrasound (IVUS) in cases of FFR/iFR discordance, and to prospectively validate the safety of deferring revascularization based on a hybrid decision-making strategy combining iFR and IVUS. METHODS: Prospective, observational, multicenter registry with 300 consecutive patients with intermediate LMCA stenosis who underwent FFR and iFR and, in case of discordance, IVUS and minimal lumen area measurements. Primary clinical end point was a composite of cardiovascular death, LMCA lesion-related nonfatal myocardial infarction, or unplanned LMCA revascularization. RESULTS: FFR and iFR had an agreement of 80% (both positive in 67 and both negative in 167 patients); in case of disagreement (31 FFR+/iFR- and 29 FFR-/iFR+) minimal lumen area was ≥6 mm2 in 8.7% of patients with FFR+ and 14.6% with iFR+. Among the 300 patients, 105 (35%) underwent revascularization and 181 (60%) were deferred according to iFR and IVUS. At a median follow-up of 20 months, major adverse cardiac events incidence was 8.3% in the defer group and 13.3% in the revascularization group (hazard ratio, 0.71 [95% CI 0.30-1.72]; P=0.45). CONCLUSIONS: In patients with intermediate LMCA stenosis, a physiology-guided treatment decision is feasible either with FFR or iFR with moderate concordance between both indices. In case of disagreement, the use of IVUS may be useful to indicate revascularization. Deferral of revascularization based on iFR appears to be safe in terms of major adverse cardiac events. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03767621.

Microscale electrophysiological functional connectivity in human cortico-basal ganglia network.

OBJECTIVE: We investigated the electrophysiological relationships in the cortico-basal ganglia network on a sub-centimeter scale to increase our understanding of neural functional relationships in Parkinson's disease (PD). METHODS: Data was intraoperatively recorded from 2 sources in the human brain-a microelectrode in the subthalamic nucleus (STN) and a micro-electrocorticography grid on the motor association cortex-during bilateral deep brain stimulation (DBS) electrode placement. STN neurons and local field potential (LFP) were defined as functionally connected when the 99.7% confidence intervals of the action potential (AP)-aligned average LFP and control did not overlap. RESULTS: APs from STN neurons were functionally connected to the STN LFP for 18/46 STN neurons. This functional connection was observed between STN neuron APs and cortical LFP for 25/46 STN neurons. The cortical patterns of electrophysiological functional connectivity differed for each neuron. CONCLUSIONS: A subset of single neurons in the STN exhibited functional connectivity with electrophysiological activity in the STN and at a distance with the motor association cortex surveyed on a sub-centimeter spatial scale. These connections show a per neuron differential topography on the cortex. SIGNIFICANCE: The cortico-basal ganglia circuit is organized on a sub-centimeter scale, and plays an important role in the mechanisms of PD and DBS.

Bioactive or Drug-Eluting Stents in 75 Years or Older Patients: The BIODES-75 Registry.

BACKGROUND: TiNO-coated BAS have demonstrated competitive outcomes compared to drug-eluting stents (DES). These devices allow short antiplatelet regimens and may be a good option for the growing elderly population undergoing percutaneous coronary intervention (PCI). METHODS: Multicenter observational trial in routine clinical practice. A propensity-score matched analysis compared a prospective cohort of patients ≥ 75 years undergoing PCI with BAS, with a contemporary and retrospective cohort treated with last-generation DES. The co-primary endpoints of the study were the Target-Lesion-Failure (Cardiac death, non-fatal myocardial infarction, or target lesion revascularization) and Major Adverse Cardiovascular Events (total death, non-fatal myocardial infarction, stroke, or new revascularization) at 1 year. RESULTS: Whole population included 1000 patients, and 326 patients in each group were matched for analysis. No differences in primary endpoints were found: TLF 10.4% vs. 11% (HR 0.96 (Confidence Interval 95%, 0.36-1.7; p = 0.87)) and MACE 16.3% vs. 17.2% (HR 0.98 (Confidence Interval 95%; 0.3-1.5, p = 0.93)). Patients treated with BAS received shorter antiplatelets regimens (dual antiplatelet therapy at 1 year, 25.7% vs. 70.6%, p = 0.0001), and they presented lower incidence of bleeding (3.7% vs. 11.7%, HR 0.3 (IC 95% 0.16-0.6, p = 0.001)). CONCLUSION: In this real-life registry of patients ≥ 75 years, BAS were similar to the latest-generation DES in terms of efficacy and reduced the duration of the antithrombotic therapy, lowering bleeding events.

Are Peripheral Biomarkers Determinants of Eating Styles in Childhood and Adolescence Obesity? A Cross-Sectional Study.

Disturbances in eating behaviors have been widely related to obesity. However, little is known about the role of obesity-related biomarkers in shaping habitual patterns of eating behaviors (i.e., eating styles) in childhood. The objective of the present study was to explore the relationships between several biomarkers crucially involved in obesity (ghrelin, insulin resistance, and leptin/adiponectin ratio) and eating styles in children and adolescents with obesity. Seventy participants aged between 8 and 16 (56.2% men) fulfilled the Spanish version of the Dutch Eating Behavior Questionnaire for Children to measure external, emotional, and restrained eating styles. In addition, concentrations of ghrelin, leptin, adiponectin, insulin, and glucose were obtained through a blood test. Hierarchical multiple regression analyses controlling for age and sex were computed for each eating style. Results indicated that individuals with higher ghrelin concentration levels showed lower scores in restrained eating (ß = -0.61, p < 0.001). The total model explained 32% of the variance of the restrained pattern. No other relationships between obesity-related biomarkers and eating behaviors were found. This study highlights that one of the obesity-risk factors, namely lower plasma ghrelin levels, is substantially involved in a well-known maladaptive eating style, restraint eating, in childhood obesity.

Factors Contributing to Spinal Cord Stimulation Outcomes for Chronic Pain.

OBJECTIVE: Spinal cord stimulation (SCS) has been shown to be a safe and effective therapy for patients with chronic pain. However, some patients do not obtain or maintain adequate pain relief after SCS. The goal of this study was to identify factors that affect patient outcome with regard to SCS. MATERIALS AND METHODS: A retrospective analysis of electronic medical records at a single site was performed. Records for 181 patients who received SCS implants from 2014 through 2016 were collected with follow-up data captured up to August 2019. Patient outcome was measured by device explantation and patient benefit from the SCS. Study parameters included demographic characteristics, history of pain, SCS implant characteristics, and postimplantation events. RESULTS: An earlier diagnosis of radiculopathy was associated with an increased risk of poor benefit (relative risk [RR], 1.81; 95% CI, 1.19-2.74; p = 0.008). Postimplantation falls were associated with an increased risk of poor benefit (RR, 2.17; 95% CI, 1.48-3.17; p = 0.009). Device manufacturer was associated with both patient benefit and explantation. Device 2 was associated with a reduced risk of poor benefit (RR, 0.52; 95% CI, 0.32-0.85; p = 0.009). Device 4 was associated with an increased risk of poor benefit (RR, 1.71; 95% CI, 1.14-2.55; p = 0.02) and increased risk of device explantation (RR, 2.69; 95% CI, 1.2-6.02; p = 0.03). CONCLUSIONS: Patient outcome was associated with diagnosis, postimplantation falls, and device manufacturer. Further investigation is recommended to confirm associations through prospective studies that can more accurately quantify patient outcome over longer periods.

Direct targeting of the ventral intermediate nucleus of the thalamus in deep brain stimulation for essential tremor: a prospective study with comparison to a historical cohort.

OBJECTIVE: The ventral intermediate nucleus of the thalamus (VIM) is an effective target for deep brain stimulation (DBS) to control symptoms related to essential tremor. The VIM is typically targeted using indirect methods, although studies have reported visualization of the VIM on proton density-weighted MRI. This study compares the outcomes between patients who underwent VIM DBS with direct and indirect targeting. METHODS: Between August 2013 and December 2019, 230 patients underwent VIM DBS at the senior author's institution. Of these patients, 92 had direct targeting (direct visualization on proton density 3-T MRI). The remaining 138 patients had indirect targeting (relative to the third ventricle and anterior commissure-posterior commissure line). RESULTS: Coordinates of electrodes placed with direct targeting were significantly more lateral (p < 0.001) and anterior (p < 0.001) than those placed with indirect targeting. The optimal stimulation amplitude for devices measured in voltage was lower for those who underwent direct targeting than for those who underwent indirect targeting (p < 0.001). Patients undergoing direct targeting had a greater improvement only in their Quality of Life in Essential Tremor Questionnaire hobby score versus those undergoing indirect targeting (p = 0.04). The direct targeting group had substantially more symptomatic hemorrhages than the indirect targeting group (p = 0.04). All patients who experienced a postoperative hemorrhage after DBS recovered without intervention. CONCLUSIONS: Patients who underwent direct VIM targeting for DBS treatment of essential tremor had similar clinical outcomes to those who underwent indirect targeting. Direct VIM targeting is safe and effective.

A novel CDC25A/DYRK2 regulatory switch modulates cell cycle and survival.

The cell division cycle 25A (CDC25A) phosphatase is a key regulator of cell cycle progression that acts on the phosphorylation status of Cyclin-Cyclin-dependent kinase complexes, with an emergent role in the DNA damage response and cell survival control. The regulation of CDC25A activity and its protein level is essential to control the cell cycle and maintain genomic integrity. Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases. CDC25A in turn is able to control the phosphorylation of DYRK2 at several residues outside from its activation loop, thus affecting DYRK2 localization and activity. An inverse correlation between DYRK2 and CDC25A protein amounts was observed during cell cycle progression and in response to DNA damage, with CDC25A accumulation responding to the manipulation of DYRK2 levels or activity in either physiological scenario. Functional data show that the pro-survival activity of CDC25A and the pro-apoptotic activity of DYRK2 could be partly explained by the mutual regulation between both proteins. Moreover, DYRK2 modulation of CDC25A expression and/or activity contributes to the DYRK2 role in cell cycle regulation. Altogether, we provide evidence suggesting that DYRK2 and CDC25A mutually control their activity and stability by a feedback regulatory loop, with a relevant effect on the genotoxic stress pathway, apoptosis, and cell cycle regulation.

Thalamic Deep Brain Stimulation May Improve Restless Legs Syndrome in Patients With Essential Tremor.

OBJECTIVES: To determine change in restless legs syndrome (RLS) symptoms in essential tremor (ET) patients undergoing bilateral thalamic ventral intermedius (VIM) deep brain stimulation (DBS) surgery. MATERIALS AND METHODS: We retrospectively reviewed our database of ET patients with RLS who had undergone VIM DBS for tremor from 2012 to 2020. We reviewed the patients with available International Restless Leg Syndrome Study Group RLS scale scores before and after DBS. Percentage of responders, defined as proportion of patients experiencing three or more point improvement of RLS scores post-DBS, was calculated. We performed two-tailed t-test of pre-DBS and post-DBS RLS scores. RESULTS: We identified 13 patients with ET and RLS who had undergone bilateral VIM DBS, of whom nine (69%) were responders post-DBS. Five of 13 patients (38%) had complete resolution of RLS post-DBS. For all patients, mean pre-DBS RLS score was 15.8 ± 7.9 which improved by 46% post-DBS to a mean of 8.5 ± 8.8 (p = 0.007). Four patients rated their RLS scale one night with the stimulator OFF and another night with the stimulator ON. The mean RLS score with stimulator ON was 15.5 ± 7.6 which improved by 53% to a mean of 6.25 ± 7.8 (p = 0.008), with two having complete resolution of RLS with stimulator ON. Of the nine responders, six preferred to keep their stimulator ON at night due to relief of RLS and better subjective quality of sleep. CONCLUSIONS: We report for the first time improvement of RLS in patients with ET after bilateral thalamic DBS. Although many ET patients with nonrechargeable DBS systems switch off their stimulator at night to conserve battery life, those with RLS may potentially benefit from keeping their stimulator ON at night to relieve their RLS.