A Computational Model of Deep Brain Stimulation for Parkinson's Disease Tremor and Bradykinesia.

Parkinson's disease (PD) is a progressive neurological disorder that is typically characterized by a range of motor dysfunctions, and its impact extends beyond physical abnormalities into emotional well-being and cognitive symptoms. The loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) leads to an array of dysfunctions in the functioning of the basal ganglia (BG) circuitry that manifests into PD. While active research is being carried out to find the root cause of SNc cell death, various therapeutic techniques are used to manage the symptoms of PD. The most common approach in managing the symptoms is replenishing the lost dopamine in the form of taking dopaminergic medications such as levodopa, despite its long-term complications. Another commonly used intervention for PD is deep brain stimulation (DBS). DBS is most commonly used when levodopa medication efficacy is reduced, and, in combination with levodopa medication, it helps reduce the required dosage of medication, prolonging the therapeutic effect. DBS is also a first choice option when motor complications such as dyskinesia emerge as a side effect of medication. Several studies have also reported that though DBS is found to be effective in suppressing severe motor symptoms such as tremors and rigidity, it has an adverse effect on cognitive capabilities. Henceforth, it is important to understand the exact mechanism of DBS in alleviating motor symptoms. A computational model of DBS stimulation for motor symptoms will offer great insights into understanding the mechanisms underlying DBS, and, along this line, in our current study, we modeled a cortico-basal ganglia circuitry of arm reaching, where we simulated healthy control (HC) and PD symptoms as well as the DBS effect on PD tremor and bradykinesia. Our modeling results reveal that PD tremors are more correlated with the theta band, while bradykinesia is more correlated with the beta band of the frequency spectrum of the local field potential (LFP) of the subthalamic nucleus (STN) neurons. With a DBS current of 220 pA, 130 Hz, and a 100 microsecond pulse-width, we could found the maximum therapeutic effect for the pathological dynamics simulated using our model using a set of parameter values. However, the exact DBS characteristics vary from patient to patient, and this can be further studied by exploring the model parameter space. This model can be extended to study different DBS targets and accommodate cognitive dynamics in the future to study the impact of DBS on cognitive symptoms and thereby optimize the parameters to produce optimal performance effects across modalities. Combining DBS with rehabilitation is another frontier where DBS can reduce symptoms such as tremors and rigidity, enabling patients to participate in their therapy. With DBS providing instant relief to patients, a combination of DBS and rehabilitation can enhance neural plasticity. One of the key motivations behind combining DBS with rehabilitation is to expect comparable results in motor performance even with milder DBS currents.

A generalized reinforcement learning based deep neural network agent model for diverse cognitive constructs.

Human cognition is characterized by a wide range of capabilities including goal-oriented selective attention, distractor suppression, decision making, response inhibition, and working memory. Much research has focused on studying these individual components of cognition in isolation, whereas in several translational applications for cognitive impairment, multiple cognitive functions are altered in a given individual. Hence it is important to study multiple cognitive abilities in the same subject or, in computational terms, model them using a single model. To this end, we propose a unified, reinforcement learning-based agent model comprising of systems for representation, memory, value computation and exploration. We successfully modeled the aforementioned cognitive tasks and show how individual performance can be mapped to model meta-parameters. This model has the potential to serve as a proxy for cognitively impaired conditions, and can be used as a clinical testbench on which therapeutic interventions can be simulated first before delivering to human subjects.

Flexible, robust, and high-performance gas sensors based on lignocellulosic nanofibrils.

Gas detection in flexible electronics demands novel materials with superior sensing performance that have high mechanically strength, are flexible, low-cost, and sustainable. We explore a composite sensing nanopaper based on lignocellulosic cellulose nanofibrils (LCNF) as a renewable and mechanically strong substrate that enables the fabrication of flexible, and highly sensitive gas sensors. In the system the hydrophobic lignin covalently bonds to cellulose in the nanofibrils, increasing the nanopaper water-resistance and limiting sensing materials response to humidity. The sensor is composed of polyaniline (PANI) grown on flexible LCNF and reduced graphene oxide (rGO) nanosheets. The proposed structure, at 10 wt% rGO, demonstrated a 10-fold improvement in sensitivity to volatile amines (i.e. ammonia detection down to 1 ppm) while maintaining an acceptable selectivity. Furthermore, we demonstrated the application of the sensing nanopaper in a microwave sensor that paves the path toward flexible, wireless, and high-performance sensing devices.

Interpreting device diagnostics for lead failure.

Implantable cardioverter-defibrillators (ICDs) incorporate automated, lead-monitoring alerts (alerts) and other diagnostics to detect defibrillation lead failure (LF) and minimize its adverse clinical consequences. Partial conductor fractures cause oversensing, but pacing or high-voltage alerts for high impedance detect only complete conductor fracture. In both pacing and high-voltage insulation breaches, low-impedance alerts require complete breach with metal-to-metal contact. Oversensing alerts for pace-sense LF also require complete breach, but not metal-to metal contact. Electrograms (EGMs) from leads with confirmed fractures have characteristics findings. In insulation breach, however, oversensed EGMs reflect characteristics of the source signal. Oversensing alerts that operate on the sensing channel analyze R-R intervals for 2 patterns typical of LF but uncommon in other conditions: a rapidly increasing count of "nonphysiological" short intervals and rapid "nonsustained tachycardias." These alerts are sensitive but nonspecific. Alerts that compare sensing and shock channels define oversensing as sensed events that do not correlate temporally with EGMs on the shock channel. Their performance depends on implementation. Specific advantages and limitations are reviewed. Most ICDs measure impedance using subthreshold pulses. Patterns in impedance trends provide diagnostic information, whether or not an alert is triggered. Gradual increases in impedance do not indicate structural LF, but they may cause failed defibrillation if shock impedance is high enough. Because impedance-threshold alerts are insensitive, normal impedance trends never exclude LF, but an abrupt increase that triggers an alert almost always indicates a header connection issue or LF. Methods for discriminating connection issues from LF are reviewed.

Curing Behavior and Thermomechanical Performance of Bioepoxy Resin Synthesized from Vanillyl Alcohol: Effects of the Curing Agent.

In order to reduce the dependency of resin synthesis on petroleum resources, vanillyl alcohol which is a renewable material that can be produced from lignin has been used to synthesize bioepoxy resin. Although it has been widely reported that the curing reaction and properties of the cured epoxies can be greatly affected by the molecular structure of the curing agents, the exact influence remains unknown for bioepoxies. In this study, four aliphatic amines with different molecular structures and amine functionalities, namely triethylenetetramine (TETA), Tris(2-aminoethyl)amine (TREN), diethylenetriamine (DETA), and ethylenediamine (EDA), were used to cure the synthesized vanillyl alcohol-based bioepoxy resin (VE). The curing reaction of VE and the physicochemical properties, especially the thermomechanical performance of the cured bioepoxies with different amine functionalities, were systematically investigated and compared using different characterization methods, such as DSC, ATR-FTIR, TGA, DMA, and tensile testing, etc. Despite a higher curing temperature needed in the VE-TETA resin system, the cured VE-TETA epoxy showed a better chemical resistance, particularly acidic resistance, as well as a lower swelling ratio than the others. The higher thermal decomposition temperature, storage modulus, and relaxation temperature of VE-TETA epoxy indicated its superior thermal stability and thermomechanical properties. Moreover, the tensile strength of VE cured by TETA was 1.4~2.6 times higher than those of other curing systems. In conclusion, TETA was shown to be the optimum epoxy curing agent for vanillyl alcohol-based bioepoxy resin.

A Multiscale, Systems-Level, Neuropharmacological Model of Cortico-Basal Ganglia System for Arm Reaching Under Normal, Parkinsonian, and Levodopa Medication Conditions.

In order to understand the link between substantia nigra pars compacta (SNc) cell loss and Parkinson's disease (PD) symptoms, we developed a multiscale computational model that can replicate the symptoms at the behavioural level by incorporating the key cellular and molecular mechanisms underlying PD pathology. There is a modelling tradition that links dopamine to reward and uses reinforcement learning (RL) concepts to model the basal ganglia. In our model, we replace the abstract representations of reward with the realistic variable of extracellular DA released by a network of SNc cells and incorporate it in the RL-based behavioural model, which simulates the arm reaching task. Our results successfully replicated the impact of SNc cell loss and levodopa (L-DOPA) medication on reaching performance. It also shows the side effects of medication, such as wearing off and peak dosage dyskinesias. The model demonstrates how differential dopaminergic axonal degeneration in basal ganglia results in various cardinal symptoms of PD. It was able to predict the optimum L-DOPA medication dosage for varying degrees of cell loss. The proposed model has a potential clinical application where drug dosage can be optimised as per patient characteristics.

Lignin Cellulose Nanofibrils as an Electrochemically Functional Component for High-Performance and Flexible Supercapacitor Electrodes.

The increasing demand for wearable electronics has driven the development of supercapacitor electrode materials toward enhanced energy density, while being mechanically strong, flexible, as well as environmentally friendly and low-cost. Taking advantage of faradaic reaction of quinone groups in natural lignin that is covalently bound to the high-strength cellulose nanofibrils, the fabrication of a novel class of mechanically strong and flexible thin film electrodes with high energy storage performance is reported. The electrodes were made by growing polyaniline (PANI) on flexible films composed of lignin-containing cellulose nanofibrils (LCNF) and reduced graphene oxide (rGO) nanosheets at various loading levels. The highest specific capacitance was observed for the LCNF/rGO/PANI electrode with 20 wt% rGO nanosheets (475 F g-1 at 10 mV s-1 and 733 F g-1 at 1 mV s-1 ), which represented a 68 % improvement as compared to a similar electrode made without lignin. In addition, the LCNF/rGO(20)/PANI electrode demonstrated high rate performance and cycle life (87 % after 5000 cycles). These results indicated that LCNF functioned as an electrochemically active multifunctional component to impart the composite electrode with mechanical strength and flexibility and enhanced overall energy storage performance. LCNF/rGO(20)/PANI electrode was further integrated in a flexible supercapacitor device, revealing the excellent promise of LCNF for fabrication of advanced flexible electrodes with reduced cost and environmental footprint and enhanced mechanical and energy storage performances.

Thermally stable, enhanced water barrier, high strength starch bio-composite reinforced with lignin containing cellulose nanofibrils.

Lignin containing cellulose nanofibrils (LCNF) were obtained by mechanically fibrillating unbleached tree bark after alkaline extraction and used as a reinforcement in thermoplastic starch (TPS) to develop novel biodegradable composite films. With the addition of 15 wt % LCNF, the tensile strength and modulus of the composites increased by 319 % and 800 % compared to neat TPS films, respectively. The crystalline property of cellulose and the high interaction between TPS and LCNF improved the mechanical property of the composite films. The composite film Tonset and Tmax were 263.1 °C and 316.5 °C, respectively, compared to 250.5 °C and 297.3 °C for neat TPS. The composite films also showed higher water barrier property. Experimental results showed that LCNF features a high lignin content. Lignin, a natural polymer, contains hydrophobic and aromatic groups and, thus, can increase the water barrier property and thermal stability of TPS/LCNF composite films.

An association between right ventricular dysfunction and sudden cardiac death.

BACKGROUND: The effectiveness of severely reduced left ventricular ejection fraction (LVEF <35%) as a predictor of sudden cardiac death (SCD) has diminished, and improvements in risk stratification await discovery of novel markers. Right ventricular (RV) abnormalities can be observed in conditions such as chronic obstructive pulmonary disease and sleep apnea, which have been linked to SCD. OBJECTIVE: The purpose of this study was to evaluate whether RV abnormalities were associated with SCD after accounting for LVEF and other patient characteristics. METHODS: In a large, prospective ongoing community-based study of SCD in the Portland, Oregon, metropolitan area, SCD cases (age ≥18 years; 2002-2014) were compared to controls with coronary artery disease but no SCD. Using a novel archive of digital echocardiograms, a standardized approach was used to evaluate RV basal diameter, RV end-diastolic area, and right ventricular fractional area change (RVFAC). RESULTS: A total of 350 subjects were studied, including 81 SCD cases (age 68.7 ± 13.6 years; 73% male) and 269 controls (age 66.5 ± 10.2 years; 69% male). In multivariate analysis, RVFAC was significantly associated with SCD (odds ratio 1.14 for each 5% decrease; 95% confidence interval 1.03-1.25; P = .01). When modeled with LVEF ≤35%, RVFAC ≤35% was significantly associated with increased risk of SCD. Individuals with both left ventricular and RV dysfunction had a 3× higher odds of SCD than those with neither (odds ratio 3.19; 95% confidence interval 1.33-7.68; P = .01). CONCLUSION: RV dysfunction was associated with a significantly increased risk of SCD independent of LVEF and, when combined with LVEF, had additive effects on SCD risk.

Highly Toughened and Transparent Biobased Epoxy Composites Reinforced with Cellulose Nanofibrils.

Biobased nanofillers, such as cellulose nanofibrils (CNFs), have been widely used as reinforcing fillers for various polymers due to their high mechanical properties and potential for sustainable production. In this study, CNF-based composites with a commercial biobased epoxy resin were prepared and characterized to determine the morphology, mechanical, thermal, and barrier properties. The addition of 18⁻23 wt % of CNFs to epoxy significantly increased the modulus, strength and strain of the resulting composites. The addition of fibrils led to an overall increase in strain energy density or modulus of toughness by almost 184 times for the composites compared to the neat epoxy. The addition of CNFs did not affect the high thermal stability of epoxy. The presence of nanofibrils had a strong reinforcing effect in both glassy and glass transition region of the composites. A significant decrease in intensity in tan δ peak for the epoxy matrix occurred with the addition of CNFs, indicating a high interaction between fibrils and epoxy during the phase transition. The presence of highly crystalline and high aspect ratio CNFs (23 wt %) decreased the water vapour permeability of the neat epoxy resin by more than 50%.

Monitoring for and Diagnosis of Lead Dysfunction.

The predominant structural mechanisms of transvenous lead dysfunction (LD) are conductor fracture and insulation breach. LD typically presents as an abnormality of electrical performance; the earliest sign usually is either oversensing or out-of-range pacing or shock impedance. Accurate diagnosis of LD requires discriminating patterns of oversensing and impedance trends that are characteristic of LD from similar patterns that occur in other conditions. Implantable cardioverter-defibrillators have advanced features to detect and mitigate the consequences of LD; these features operate both independently and in conjunction with remote monitoring networks.

Device implantation for patients on antiplatelets and anticoagulants: Use of suction drain.

BACKGROUND AND OBJECTIVES: Cardiovascular implantable electronic devices (CIED) are frequently implanted in patients on anti-thrombotic agents. Pocket hematomas are more likely to occur in these patients. The use of a sterile surgical drain in the pulse generator pocket site could prevent hematomas, but fear of infection precludes its use. The objective of the present study is to study the safety and efficacy of surgical drain in patients on antithrombotics undergoing CIED implantations. METHODS: This is a single-centre, retrospective study involving patients undergoing CIED implantations on antithrombotics (antiplatelets and anticoagulants) from August 2013 to July 2016. Patients with high risk of thromboembolism were continued on oral antithrombotics or were bridged with heparin after stopping oral antithrombotics. A sterile close wound suction drain was placed in device pockets following CIED implantations. Post procedure, pressure dressing was applied and removed after 12 h once the drain volume was less than 10 ml in 24 h. RESULTS: Sixty seven patients required surgical drain implantation. Major indications for antithrombotic use were presence of intracoronary stent, atrial fibrillation and mechanical valve replacements. The mean post-procedural hospital stay was 3 ±â€¯0.9 days and mean overall drain was 16.6 ±â€¯8.2 ml. At a mean follow up of 17.6 ±â€¯8.2 months, one patient (1.4%) had pocket hematoma. There were no infections. CONCLUSION: The use of a surgical drain in CIED implantation significantly reduces the risk of hematoma formation without increasing the risk of infection. Antithrombotic drugs can be safely continued at the time of implantation of cardiac devices.

Risk Factors of Sudden Cardiac Death in the Young: Multiple-Year Community-Wide Assessment.

BACKGROUND: Prevention of sudden cardiac arrest (SCA) in the young remains a largely unsolved public health problem, and sports activity is an established trigger. Although the presence of standard cardiovascular risk factors in the young can link to future morbidity and mortality in adulthood, the potential contribution of these risk factors to SCA in the young has not been evaluated. METHODS: We prospectively ascertained subjects who experienced SCA between the ages of 5 and 34 years in the Portland, Oregon, metropolitan area (2002-2015, catchment population ≈1 million). We assessed the circumstances, resuscitation outcomes, and clinical profile of subjects who had SCA by a detailed evaluation of emergency response records, lifetime clinical records, and autopsy examinations. We specifically evaluated the association of standard cardiovascular risk factors and SCA, and sports as a trigger for SCA in the young. RESULTS: Of 3775 SCAs in all age groups, 186 (5%) occurred in the young (mean age 25.9±6.8, 67% male). In SCA in the young, overall prevalence of warning signs before SCA was low (29%), and 26 (14%) were associated with sports as a trigger. The remainder (n=160) occurred in other settings categorized as nonsports. Sports-related SCAs accounted for 39% of SCAs in patients aged ≤18, 13% of SCAs in patients aged 19 to 25, and 7% of SCAs in patients aged 25 to 34. Sports-related SCA cases were more likely to present with shockable rhythms, and survival from cardiac arrest was 2.5-fold higher in sports-related versus nonsports SCA (28% versus 11%; P=0.05). Overall, the most common SCA-related conditions were sudden arrhythmic death syndrome (31%), coronary artery disease (22%), and hypertrophic cardiomyopathy (14%). There was an unexpectedly high overall prevalence of established cardiovascular risk factors (obesity, diabetes mellitus, hypertension, hyperlipidemia, smoking) with ≥1 risk factors in 58% of SCA cases. CONCLUSIONS: Sports was a trigger of SCA in a minority of cases, and, in most patients, SCA occurred without warning symptoms. Standard cardiovascular risk factors were found in over half of patients, suggesting the potential role of public health approaches that screen for cardiovascular risk factors at earlier ages.

Novel measure of autonomic remodeling associated with sudden cardiac arrest in diabetes.

BACKGROUND: Diabetes is independently associated with an increased risk of sudden cardiac arrest (SCA), with a need to identify novel methods for risk stratification. Diabetic patients can develop autonomic dysfunction that has been associated with an increased risk of ventricular arrhythmogenesis and manifests as reduced heart rate variability (HRV). However, previously published studies have not accounted for resting heart rate (HR), important from both pathophysiological and prognosticating standpoints. OBJECTIVE: We sought to evaluate autonomic remodeling of the sinus node response in SCA and diabetes while accounting for HR. METHODS: We performed a case-control study in SCA cases (age 35-59 years; 2002-2014) from the ongoing Oregon Sudden Unexpected Death Study (catchment population ∼1 million), and archived 12-lead electrocardiograms recorded prior to the SCA event were compared with those of geographic controls. Short-term HRV was calculated from digitized 10-second electrocardiograms by using established methods. We analyzed 313 subjects (mean age 52.0 ± 5.5 years; 216 men, 69.0%) and compared 4 groups: 111 diabetic (49 cases, 62 controls) and 202 nondiabetic (80 cases, 122 controls) subjects. RESULTS: Analysis of covariance showed an absence of the expected interaction between HRV and HR (HRV-HR) in diabetic patients with SCA (regression slope -0.008; 95% confidence interval -0.023 to 0.0071; P = .26). This finding, unique to this population of diabetic patients with SCA, was not detected using traditional HRV measures. CONCLUSION: By incorporating resting HR in this analysis, we observed that this population of diabetic patients with SCA had loss of the expected HRV-HR relationship. This potentially novel noninvasive risk measurement warrants further investigation, especially at the level of the individual patient.

A novel approach in the use of radiofrequency catheter ablation of septal hypertrophy in hypertrophic obstructive cardiomyopathy.

OBJECTIVE: Alcohol septal ablation (ASA) is a therapeutic alternative to surgical myectomy in patients with hypertrophic obstructive cardiomyopathy (HOCM). However, the anatomical variability of the septal branch, risk of complete heart block, and late onset ventricular arrhythmias are limitations to its therapeutic usage. There is recent interest in the use of radiofrequency catheter ablation (RFCA) as a therapeutic option in HOCM. We aimed to assess the safety and efficacy of RFCA in the treatment of symptomatic HOCM. METHODS: Seven patients with symptomatic HOCM (mean age 43.7±15.6 years, five males), and significant left ventricular outflow tract (LVOT) gradient despite optimal drug therapy, underwent ablation of the hypertrophied interventricular septum. These patients had unfavorable anatomy for ASA. Ablation was performed under 3D electro-anatomical system guidance using an open irrigated tip catheter. The region of maximal LV septal bulge as seen on intracardiac echocardiography was targeted. Patients were followed up at 1, 6, and 12 months post-procedure. RESULTS: The mean baseline LVOT gradient by Doppler echocardiography was 81±14.8mm of Hg which reduced to 48.5±22.6 (p=0.0004), 49.8±19.3 (p=0.0004), and 42.8±26.1mm of Hg (p=0.05) at 1, 6, and 12 months respectively. Symptoms improved at least by one NYHA class in all but one patient. One patient developed transient pulmonary edema post-RFA. There were no other complications. CONCLUSION: RFCA of the hypertrophied septum causes sustained reduction in the LVOT gradient and symptomatic improvement among patients with HOCM. Electroanatomical mapping helps to perform the procedure safely.

Prevalence of atrial fibrillation in an urban population in India: the Nagpur pilot study.

OBJECTIVES: Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice with major public health impact mainly due to the increased risk of stroke. The recent Global Burden of Disease Study reported a lack of prevalence data from India. Our goal was to conduct a pilot study to evaluate the feasibility of assessing AF prevalence and stroke prophylaxis in an urban Indian community. METHODS: A screening camp was conducted in Nagpur, India, that evaluated adults aged ≥18 years. We collected demographics, recorded blood pressure, height, weight and the 12-lead electrocardiogram (ECG). The presence of diabetes and hypertension was recorded by self-reported history. Patients diagnosed with AF were evaluated further to assess aetiology and management. RESULTS: Of the total 4077 randomly selected, community-dwelling adults studied, 0.196% (eight patients) were found to have AF. Mean age of the population was 43.9±14.8, and 44.5% were female. The mean age of the patients with AF was 60.5±15.8 years (five females). Rheumatic heart disease was found in five patients with AF. Three patients had history of stroke (37.5%) and one had peripheral arterial thrombosis. Three patients were on warfarin, but without routine international normalised ratio (INR) monitoring. One patient was on aspirin. Five patients were on ß-blockers and one on both ß-blocker and digoxin. CONCLUSIONS: The prevalence of AF was low compared with other regions of the world and stroke prophylaxis was underused. A larger study is needed to confirm these findings. This study demonstrates that larger evaluations would be feasible using the community-based techniques employed here.