Timing-dependent synergies between motor cortex and posterior spinal stimulation in humans.

Volitional movement requires descending input from the motor cortex and sensory feedback through the spinal cord. We previously developed a paired brain and spinal electrical stimulation approach in rats that relies on convergence of the descending motor and spinal sensory stimuli in the cervical cord. This approach strengthened sensorimotor circuits and improved volitional movement through associative plasticity. In humans, it is not known whether posterior epidural spinal cord stimulation targeted at the sensorimotor interface or anterior epidural spinal cord stimulation targeted within the motor system is effective at facilitating brain evoked responses. In 59 individuals undergoing elective cervical spine decompression surgery, the motor cortex was stimulated with scalp electrodes and the spinal cord was stimulated with epidural electrodes, with muscle responses being recorded in arm and leg muscles. Spinal electrodes were placed either posteriorly or anteriorly, and the interval between cortex and spinal cord stimulation was varied. Pairing stimulation between the motor cortex and spinal sensory (posterior) but not spinal motor (anterior) stimulation produced motor evoked potentials that were over five times larger than brain stimulation alone. This strong augmentation occurred only when descending motor and spinal afferent stimuli were timed to converge in the spinal cord. Paired stimulation also increased the selectivity of muscle responses relative to unpaired brain or spinal cord stimulation. Finally, clinical signs suggest that facilitation was observed in both injured and uninjured segments of the spinal cord. The large effect size of this paired stimulation makes it a promising candidate for therapeutic neuromodulation. KEY POINTS: Pairs of stimuli designed to alter nervous system function typically target the motor system, or one targets the sensory system and the other targets the motor system for convergence in cortex. In humans undergoing clinically indicated surgery, we tested paired brain and spinal cord stimulation that we developed in rats aiming to target sensorimotor convergence in the cervical cord. Arm and hand muscle responses to paired sensorimotor stimulation were more than five times larger than brain or spinal cord stimulation alone when applied to the posterior but not anterior spinal cord. Arm and hand muscle responses to paired stimulation were more selective for targeted muscles than the brain- or spinal-only conditions, especially at latencies that produced the strongest effects of paired stimulation. Measures of clinical evidence of compression were only weakly related to the paired stimulation effect, suggesting that it could be applied as therapy in people affected by disorders of the central nervous system.

Intraoperative electrical stimulation of the human dorsal spinal cord reveals a map of arm and hand muscle responses.

Although epidural stimulation of the lumbar spinal cord has emerged as a powerful modality for recovery of movement, how it should be targeted to the cervical spinal cord to activate arm and hand muscles is not well understood, particularly in humans. We sought to map muscle responses to posterior epidural cervical spinal cord stimulation in humans. We hypothesized that lateral stimulation over the dorsal root entry zone would be most effective and responses would be strongest in the muscles innervated by the stimulated segment. Twenty-six people undergoing clinically indicated cervical spine surgery consented to mapping of motor responses. During surgery, stimulation was performed in midline and lateral positions at multiple exposed segments; six arm and three leg muscles were recorded on each side of the body. Across all segments and muscles tested, lateral stimulation produced stronger muscle responses than midline despite similar latency and shape of responses. Muscles innervated at a cervical segment had the largest responses from stimulation at that segment, but responses were also observed in muscles innervated at other cervical segments and in leg muscles. The cervical responses were clustered in rostral (C4-C6) and caudal (C7-T1) cervical segments. Strong responses to lateral stimulation are likely due to the proximity of stimulation to afferent axons. Small changes in response sizes to stimulation of adjacent cervical segments argue for local circuit integration, and distant muscle responses suggest activation of long propriospinal connections. This map can help guide cervical stimulation to improve arm and hand function.NEW & NOTEWORTHY A map of muscle responses to cervical epidural stimulation during clinically indicated surgery revealed strongest activation when stimulating laterally compared to midline and revealed differences to be weaker than expected across different segments. In contrast, waveform shapes and latencies were most similar when stimulating midline and laterally, indicating activation of overlapping circuitry. Thus, a map of the cervical spinal cord reveals organization and may help guide stimulation to activate arm and hand muscles strongly and selectively.

Remote Ischemic conditioning as an emerging tool to improve corticospinal transmission in individuals with chronic spinal cord injury.

PURPOSE OF REVIEW: Remote ischemic conditioning (RIC) involves transient blood flow restriction to one limb leading to systemic tissue-protective effects. RIC shares some potential underlying mechanisms with intermittent hypoxia (IH), in which brief bouts of systemic hypoxia trigger increases in growth factor expression and neural plasticity. RIC has shown promise in acute myocardial infarction and stroke but may be applicable toward chronic neuropathology as well. Consequently, this review discusses similarities and differences between RIC and IH and presents preliminary and ongoing research findings regarding RIC. RECENT FINDINGS: Several publications demonstrated that combining RIC with motor training may enhance motor learning in adults with intact nervous systems, though the precise mechanisms were unclear. Our own preliminary data has found that RIC, in conjunction with task specific exercise, can increase corticospinal excitability in a subset of people without neurological injury and in those with chronic cervical spinal cord injury or amyotrophic lateral sclerosis. SUMMARY: RIC is a low-cost intervention easy to deliver in a clinical or home setting. Its potential application to facilitate neural plasticity and motor learning during rehabilitation training for individuals with chronic neurological disorders is a novel concept requiring further investigation to characterize mechanisms, safety, and efficacy.

The experience of a severe hypoglycaemic event from the perspective of people with diabetes and their caregivers: "What am I going to do?"

AIMS: Among people with diabetes using insulin, severe hypoglycaemia (SH) can be a life-threatening complication, if untreated. The personal experiences during an SH event from the perspectives of people with diabetes and their caregivers are not well-characterized. This study assessed the perceptions of the event and the decision making processes of people with diabetes (T1D n = 36; T2D n = 24) and their caregivers during SH events. METHODS: In-depth one-on-one telephone interviews were conducted with dyads of people with diabetes and caregivers in the United States (n = 120). An initial synopsis and inductive codebook schema were used to analyse the data with two independent coders (kappa = 0.87-0.89). Themes were developed from the codes, and codes were re-mapped to the themes. RESULTS: Four themes were formed: (1) Caregivers scramble to do the right thing and support people with diabetes in treating SH; (2) Decision making capacity is impaired during an SH event, often a panicked time; (3) People learn to manage SH events through their own experiences and frequently make lifestyle changes to prevent and treat future events; and (4) Discussion with healthcare providers about SH, and particularly SH treatment, is limited. CONCLUSIONS: SH events are stressful and often evoke emotional reactions that can impair decision making. Thus, advance treatment planning of SH events needs to occur. Much of the knowledge about SH treatment derives from prior experience rather than healthcare provider guidance, suggesting a need for healthcare providers to initiate proactive discussions about SH treatment.

Antiviral Polymers Based on N-Halamine Polyurea.

N-halamines are a commonly applied class of antimicrobial agents used for a variety of applications relating to human health. Here, we present the modulation of the common polymers polyurea and polyguanidine with the N-halamine technology. The N-H bonds in either polymer were converted to N-Cl or N-Br bonds capable of releasing Cl+ or Br+ cations to aqueous media as antiviral agents. Controlled release of the oxidizing agents was monitored for a period of 4 weeks. Antiviral activity was evaluated against the T4 bacteriophage as well as against the highly stable plant virus belonging to the Tobamovirus genus, tomato brown rugose fruit virus. The incorporation of the N-halamine technology on commonly used polymers has effectively introduced antiviral functionality for a wide variety of potential applications.

Duration and reliability of the silent period in individuals with spinal cord injury.

DESIGN: Prospective cohort study. OBJECTIVES: We aim to better understand the silent period (SP), an inhibitory counterpart to the well-known motor evoked potential (MEP) elicited by transcranial magnetic stimulation (TMS), in individuals with spinal cord injury (SCI). SETTING: Veterans Affairs Hospital in New York. METHODS: EMG responses were measured in the target abductor pollicis brevis at rest (TMS at 120% of resting motor threshold (RMT)) and during maximal effort (TMS at 110% of RMT). Participants with chronic cervical SCI (n = 9) and AB participants (n = 12) underwent between 3 and 7 sessions of testing on separate days. The primary outcomes were the magnitude and reliability of SP duration, resting and active MEP amplitudes, and RMT. RESULTS: SCI participants showed significantly lower MEP amplitudes compared to AB participants. SCI SP duration was not significantly different from AB SP duration. SP duration demonstrated reduced intra-participant variability within and across sessions compared with MEP amplitudes. SCI participants also demonstrated a higher prevalence of SP 'interruptions' compared to AB participants. CONCLUSIONS: In a small group of individuals with chronic cervical SCI, we confirmed the well-known findings that SCI individuals have lower TMS evoked potential amplitudes and a tendency toward higher TMS motor thresholds relative to able-bodied controls. We did not observe a significant difference in SP duration between individuals with versus without SCI. However, SP duration is a more reliable outcome within and across multiple sessions than MEP amplitude.

Training with Agency-Inspired Feedback from an Instrumented Glove to Improve Functional Grasp Performance.

Sensory feedback from wearables can be effective to learn better movement through enhanced information and engagement. Facilitating greater user cognition during movement practice is critical to accelerate gains in motor function during rehabilitation following brain or spinal cord trauma. This preliminary study presents an approach using an instrumented glove to leverage sense of agency, or perception of control, to provide training feedback for functional grasp. Seventeen able-bodied subjects underwent training and testing with a custom-built sensor glove prototype from our laboratory. The glove utilizes onboard force and flex sensors to provide inputs to an artificial neural network that predicts achievement of "secure" grasp. Onboard visual and audio feedback was provided during training with progressively shorter time delay to induce greater agency by intentional binding, or perceived compression in time between an action (grasp) and sensory consequence (feedback). After training, subjects demonstrated a significant reduction (p < 0.05) in movement pathlength and completion time for a functional task involving grasp-move-place of a small object. Future work will include a model-based algorithm to compute secure grasp, virtual reality immersion, and testing with clinical populations.

Impact of Telerehabilitation for Stroke-Related Deficits.

Background: Stroke is the leading cause of serious long-term disability in the United States. Barriers to rehabilitation include cost, transportation, lack of trained personnel, and equipment. Telerehabilitation (TR) has emerged as a promising modality to reduce costs, improve accessibility, and retain patient independence. TR allows providers to remotely administer therapy, potentially increasing access to underserved regions. Objectives: To describe types of stroke rehabilitation therapy delivered through TR and to evaluate whether TR is as effective as traditional in-person outpatient therapy in improving satisfaction and poststroke residual deficits such as motor function, speech, and disability. Methods: A literature search of the term "telerehabilitation and stroke" was conducted across three databases. Full-text articles with results pertaining to TR interventions were reviewed. Articles were scored for methodological quality using the PEDro scale. Results: Thirty-four articles with 1,025 patients were included. Types of TR included speech therapy, virtual reality (VR), robotic, community-based, goal setting, and motor training exercises. Frequently measured outcomes included motor function, speech, disability, and satisfaction. All 34 studies reported improvement from baseline after TR therapy. PEDro scores ranged from 2 to 8 with a mean of 4.59 ± 1.94 (on a scale of 0-10). Studies with control interventions, randomized allocation, and blinded assessment had significantly higher PEDro scores. All 15 studies that compared TR with traditional therapy showed equivalent or better functional outcomes. Home-based robotic therapy and VR were less costly than in-person therapy. Patient satisfaction with TR and in-person clinical therapy was similar. Conclusions: TR is less costly and equally as effective as clinic-based rehabilitation at improving functional outcomes in stroke patients. TR produces similar patient satisfaction. TR can be combined with other therapies, including VR, speech, and robotic assistance, or used as an adjuvant to direct in-person care.

Clinical Trial Designs for Neuromodulation in Chronic Spinal Cord Injury Using Epidural Stimulation.

STUDY DESIGN: This is a narrative review focused on specific challenges related to adequate controls that arise in neuromodulation clinical trials involving perceptible stimulation and physiological effects of stimulation activation. OBJECTIVES: 1) To present the strengths and limitations of available clinical trial research designs for the testing of epidural stimulation to improve recovery after spinal cord injury. 2) To describe how studies can control for the placebo effects that arise due to surgical implantation, the physical presence of the battery, generator, control interfaces, and rehabilitative activity aimed to promote use-dependent plasticity. 3) To mitigate Hawthorne effects that may occur in clinical trials with intensive supervised participation, including rehabilitation. MATERIALS AND METHODS: Focused literature review of neuromodulation clinical trials with integration to the specific context of epidural stimulation for persons with chronic spinal cord injury. CONCLUSIONS: Standard of care control groups fail to control for the multiple effects of knowledge of having undergone surgical procedures, having implanted stimulation systems, and being observed in a clinical trial. The irreducible effects that have been identified as "placebo" require sham controls or comparison groups in which both are implanted with potentially active devices and undergo similar rehabilitative training.

Cardiovascular Autonomic Dysfunction in Spinal Cord Injury: Epidemiology, Diagnosis, and Management.

Spinal cord injury (SCI) disrupts autonomic circuits and impairs synchronistic functioning of the autonomic nervous system, leading to inadequate cardiovascular regulation. Individuals with SCI, particularly at or above the sixth thoracic vertebral level (T6), often have impaired regulation of sympathetic vasoconstriction of the peripheral vasculature and the splanchnic circulation, and diminished control of heart rate and cardiac output. In addition, impaired descending sympathetic control results in changes in circulating levels of plasma catecholamines, which can have a profound effect on cardiovascular function. Although individuals with lesions below T6 often have normal resting blood pressures, there is evidence of increases in resting heart rate and inadequate cardiovascular response to autonomic provocations such as the head-up tilt and cold face tests. This manuscript reviews the prevalence of cardiovascular disorders given the level, duration and severity of SCI, the clinical presentation, diagnostic workup, short- and long-term consequences, and empirical evidence supporting management strategies to treat cardiovascular dysfunction following a SCI.

Asymmetric trisalkylamine cyclopropenium derivatives with antimicrobial activity.

Cationic molecules are found in abundance as antimicrobial agents with a well-defined mechanism of action and significant therapeutic benefits. Quaternary ammonium-containing compounds are frequently employed due to their facile synthesis and tunable properties. Over time, however, bacterial resistance to these compounds has become a significant obstacle. We report here a series of asymmetric trisalkylamine cyclopropenium cationic derivatives as chemical isosteres of quaternary ammonium compounds, capable of strong antimicrobial activity and overcoming microbial resistance. These small molecules were prepared by one-pot reaction of tetrachlorocyclopropene (TCC) with unhindered secondary amines in the presence of Hünig's base. In this work we describe the synthesis, purification, and characterization of five trisamino-cyclopropenium derivatives and confirm their structures by spectral analysis and mass-spectrometry. Three of the compounds displayed considerable antimalarial activity (IC50 < 0.1 µM) without demonstrating significant toxic effects in vitro (TC50 > 1 µM). This class of cyclopropenium-based compounds provides an opening for the discovery of potent and non-toxic antimicrobial agents.

Changes in bowel function following exoskeletal-assisted walking in persons with spinal cord injury: an observational pilot study.

STUDY DESIGN: Prospective, observational study. OBJECTIVE: To explore the effects of exoskeletal-assisted walking (EAW) on bowel function in persons with spinal cord injury (SCI). SETTING: Ambulatory research facility located in a tertiary care hospital. METHODS: Individuals 18-65 years of age, with thoracic vertebrae one (T1) to T11 motor-complete paraplegia of at least 12 months duration were enrolled. Pre- and post-EAW training, participants were asked to report on various aspects of their bowel function as well as on their overall quality of life (QOL) as related to their bowel function. RESULTS: Ten participants completed 25-63 sessions of EAW over a period of 12-14 weeks, one participant was lost to follow up due to early withdrawal after ten sessions. Due to the small sample size, each participant's results were presented descriptively in a case series format. At least 5/10 participants reported improvements with frequency of bowel evacuations, less time spent on bowel management per bowel day, fewer bowel accidents per month, reduced laxative and/or stool softener use, and improved overall satisfaction with their bowel program post-EAW training. Furthermore, 8/10 reported improved stool consistency and 7/10 reported improved bowel function related QOL. One participant reported worsening of bowel function post-EAW. CONCLUSION: Between 50 and 80% of the participants studied reported improvements in bowel function and/or management post-EAW training. EAW training appeared to mitigate SCI-related bowel dysfunction and the potential benefits of EAW on bowel function after SCI is worthy or further study.

Transspinal stimulation decreases corticospinal excitability and alters the function of spinal locomotor networks.

Locomotion requires the continuous integration of descending motor commands and sensory inputs from the legs by spinal central pattern generator circuits. Modulation of spinal neural circuits by transspinal stimulation is well documented, but how transspinal stimulation affects corticospinal excitability during walking in humans remains elusive. We measured the motor evoked potentials (MEPs) at multiple phases of the step cycle conditioned with transspinal stimulation delivered at sub- and suprathreshold intensities of the spinally mediated transspinal evoked potential (TEP). Transspinal stimulation was delivered before or after transcranial magnetic stimulation during which summation between MEP and TEP responses in the surface EMG was absent or present. Relationships between MEP amplitude and background EMG activity, silent period duration, and phase-dependent EMG amplitude modulation during and after stimulation were also determined. Ankle flexor and extensor MEPs were depressed by suprathreshold transspinal stimulation when descending volleys were timed to interact with transspinal stimulation-induced motoneuron depolarization at the spinal cord. MEP depression coincided with decreased MEP gain, unaltered MEP threshold, and unaltered silent period duration. Locomotor EMG activity of bilateral knee and ankle muscles was significantly depressed during the step at which transspinal stimulation was delivered but fully recovered at the subsequent step. The results support a model in which MEP depression by transspinal stimulation occurs via subcortical or spinal mechanisms. Transspinal stimulation disrupts the locomotor output of flexor and extensor motoneurons initially, but the intact nervous system has the ability to rapidly overcome this pronounced locomotor adaptation. In conclusion, transspinal stimulation directly affects spinal locomotor centers in healthy humans.NEW & NOTEWORTHY Lumbar transspinal stimulation decreases ankle flexor and extensor motor evoked potentials (MEPs) during walking. The MEP depression coincides with decreased MEP gain, unaltered MEP threshold changes, and unaltered silent period duration. These findings indicate that MEP depression is subcortical or spinal in origin. Healthy subjects could rapidly overcome the pronounced depression of muscle activity during the step at which transspinal stimulation was delivered. Thus, transspinal stimulation directly affects the function of spinal locomotor networks in healthy humans.

Injectable Pasty Biodegradable Polyesters Derived from Castor Oil and Hydroxyl-Acid Lactones.

Pasty polymers offer a platform for injectable implants for drug delivery. A library of biodegradable pasty polymers was synthesized by bulk ring-opening polymerization of lactide, glycolide, trimethylene carbonate, or caprolactone using castor oil or 12-hydroxy stearic acid as hydroxyl initiators and stannous octoate as the catalyst. Some of the polymers behaved as Newtonian liquids. Pasty polymers of poly(caprolactone) and poly(trimethylene carbonate) were stable under physiologic conditions for over 1 month in vitro, whereas polymers of poly(lactic-co-glycolic acid) degraded within 10 days. These pasty polymers offer a platform for pasty injectable biodegradable carriers for drugs and fillers. SIGNIFICANCE STATEMENT: New injectable pasty, in situ forming drug delivery systems are described and are advantageous due to their ease of administration, tunable viscosity, and biodegradability. Polyesters based on lactide, glycolide, trimethylene carbonate, and caprolactone, which are commonly used as absorbable implants and drug carriers, were conjugated onto natural hydroxyl fatty acids. These polymers have potential use as wrinkle fillers and drug carriers.

NRSF-dependent epigenetic mechanisms contribute to programming of stress-sensitive neurons by neonatal experience, promoting resilience.

Resilience to stress-related emotional disorders is governed in part by early-life experiences. Here we demonstrate experience-dependent re-programming of stress-sensitive hypothalamic neurons, which takes place through modification of neuronal gene expression via epigenetic mechanisms. Specifically, we found that augmented maternal care reduced glutamatergic synapses onto stress-sensitive hypothalamic neurons and repressed expression of the stress-responsive gene, Crh. In hypothalamus in vitro, reduced glutamatergic neurotransmission recapitulated the repressive effects of augmented maternal care on Crh, and this required recruitment of the transcriptional repressor repressor element-1 silencing transcription factor/neuron restrictive silencing factor (NRSF). Increased NRSF binding to chromatin was accompanied by sequential repressive epigenetic changes which outlasted NRSF binding. chromatin immunoprecipitation-seq analyses of NRSF targets identified gene networks that, in addition to Crh, likely contributed to the augmented care-induced phenotype, including diminished depression-like and anxiety-like behaviors. Together, we believe these findings provide the first causal link between enriched neonatal experience, synaptic refinement and induction of epigenetic processes within specific neurons. They uncover a novel mechanistic pathway from neonatal environment to emotional resilience.

Efficacy and Safety of Procalcitonin Guidance in Patients With Suspected or Confirmed Sepsis: A Systematic Review and Meta-Analysis.

OBJECTIVE: Sepsis is a leading cause of mortality in noncoronary ICUs. Although immediate start of antibiotics reduces sepsis-related mortality, antibiotics are often administered for too long, leading to suboptimal treatment and, importantly, contributes to antimicrobial resistance. Prior literature suggests that procalcitonin correlates with infection and thus may help to guide the decision on when to stop antibiotic treatment. This study was conducted as part of a regulatory submission to the U.S. Food and Drug Administration and aimed to summarize the evidence of procalcitonin guidance on efficacy and safety outcomes in adult patients with sepsis. DATA SOURCES: PubMed and the Cochrane Database of Systematic Reviews. STUDY SELECTION: English-language randomized controlled trials evaluating procalcitonin use among adult patients with suspected or confirmed sepsis published between January 2004 and May 2016. DATA EXTRACTION: Inverse-variance weighting fixed and random effects meta-analyses were performed on the following efficacy and safety endpoints: antibiotic duration, all-cause mortality, and length of ICU stay. Two reviewers independently extracted data elements from identified studies and measured risk of bias with the Cochrane Risk of Bias Tool. DATA SYNTHESIS: From a total of 369 potentially eligible articles, 10 randomized controlled trials containing 3,489 patients were used for analysis. Procalcitonin-guided patients had shorter antibiotics duration compared with controls (7.35 vs. 8.85 d; weighted mean difference, -1.49 d; 95% CI, -2.27 to -0.71; p < 0.001). Procalcitonin use had no adverse impact on mortality (risk ratio, 0.90; 95% CI, 0.79-1.03; p = 0.114) and length of ICU stay (11.09 d vs. 11.91 d; weighted mean difference, -0.84 d; 95% CI, -2.52 to 0.84; p = 0.329). CONCLUSIONS: In adult patients with suspected or confirmed sepsis, procalcitonin guidance reduces antibiotics duration with no observed adverse effects on patient outcomes.

Procalcitonin guidance in patients with lower respiratory tract infections: a systematic review and meta-analysis.

Although effective for bacterial lower respiratory tract infections (LRTIs), antibiotic treatment is often incorrectly prescribed for non-bacterial LRTIs. Procalcitonin has emerged as a promising biomarker to diagnose bacterial infections and guide antibiotic treatment decisions. As part of a regulatory submission to the U.S. Food and Drug Administration, this systematic review and meta-analysis summarizes the effects of procalcitonin-guided antibiotic stewardship on antibiotic use and clinical outcomes in adult LRTI patients. PubMed and the Cochrane Database of Systematic Reviews were searched for English-language randomized controlled trials published between January 2004 and May 2016. Random and fixed effects meta-analyses were performed to study efficacy (initiation of antibiotics, antibiotic use) and safety (mortality, length of hospital stay). Eleven trials were retained, comprising 4090 patients. Procalcitonin-guided patients had lower odds of antibiotic initiation (odds ratio: 0.26; 95% confidence interval [CI]: 0.13-0.52) and shorter mean antibiotic use (weighted mean difference: -2.15 days; 95% CI: -3.30 to -0.99) compared to patients treated with standard care. Procalcitonin use had no adverse impact on mortality (relative risk: 0.94; 95% CI: 0.69-1.28) and length of hospital stay (weighted mean difference: -0.15 days; 95% CI: -0.60 to 0.30). Procalcitonin guidance reduces antibiotic initiation and use among adults with LRTIs with no apparent adverse impact on length of hospital stay or mortality.

Methods for the effective study of collective behavior in a radial arm maze.

Collective behaviors are observed throughout nature, from bacterial colonies to human societies. Important theoretical breakthroughs have recently been made in understanding why animals produce group behaviors and how they coordinate their activities, build collective structures, and make decisions. However, standardized experimental methods to test these findings have been lacking. Notably, easily and unambiguously determining the membership of a group and the responses of an individual within that group is still a challenge. The radial arm maze is presented here as a new standardized method to investigate collective exploration and decision-making in animal groups. This paradigm gives individuals within animal groups the opportunity to make choices among a set of discrete alternatives, and these choices can easily be tracked over long periods of time. We demonstrate the usefulness of this paradigm by performing a set of refuge-site selection experiments with groups of fish. Using an open-source, robust custom image-processing algorithm, we automatically counted the number of animals in each arm of the maze to identify the majority choice. We also propose a new index to quantify the degree of group cohesion in this context. The radial arm maze paradigm provides an easy way to categorize and quantify the choices made by animals. It makes it possible to readily apply the traditional uses of the radial arm maze with single animals to the study of animal groups. Moreover, it opens up the possibility of studying questions specifically related to collective behaviors.

Assessing the economic burden of Alzheimer's disease patients first diagnosed by specialists.

BACKGROUND: It is not known if there is a differential impact on Alzheimer's disease (AD) diagnosis and outcomes if/when patients are diagnosed with cognitive decline by specialists versus non-specialists. This study examined the cost trajectories of Medicare beneficiaries initially diagnosed by specialists compared to similar patients who received their diagnosis in primary care settings. METHODS: Patients with ≥2 claims for AD were selected from de-identified administrative claims data for US Medicare beneficiaries (5 % random sample). The earliest observed diagnosis of cognitive decline served as the index date. Patients were required to have continuous Medicare coverage for ≥12 months pre-index (baseline) and ≥12 months following the first AD diagnosis, allowing for up to 3 years from index to AD diagnosis. Time from index date to AD diagnosis was compared between those diagnosed by specialists (i.e., neurologist, psychiatrist, or geriatrician) versus non-specialists using Kaplan-Meier analyses with log-rank tests. Patient demographics, Charlson Comorbidity Index (CCI) during baseline, and annual all-cause medical costs (reimbursed by Medicare) in baseline and follow-up periods were compared across propensity-score matched cohorts. RESULTS: Patients first diagnosed with cognitive decline by specialists (n = 2593) were younger (78.8 versus 80.8 years old), more likely to be male (40 % versus 34 %), and had higher CCI scores and higher medical costs at baseline than those diagnosed by non-specialists (n = 13,961). However, patients diagnosed by specialists had a significantly shorter time to AD diagnosis, both before and after matching (mean [after matching]: 3.5 versus 4.6 months, p < 0.0001). In addition, patients diagnosed by specialists had significantly lower average total all-cause medical costs in the first 12 months after their index date, a finding that persisted after matching ($19,824 versus $25,863, p < 0.0001). Total per-patient annual medical costs were similar for the two groups starting in the second year post-index. CONCLUSIONS: Before and after matching, patients diagnosed by a specialist had a shorter time to AD diagnosis and incurred lower costs in the year following the initial cognitive decline diagnosis. Differences in costs converged during subsequent years. This suggests that seeking care from specialists may yield more timely diagnosis, appropriate care and reduced costs among those with cognitive decline.

Paired Stimulation to Promote Lasting Augmentation of Corticospinal Circuits.

After injury, electrical stimulation of the nervous system can augment plasticity of spared or latent circuits through focal modulation. Pairing stimulation of two parts of a spared circuit can target modulation more specifically to the intended circuit. We discuss 3 kinds of paired stimulation in the context of the corticospinal system, because of its importance in clinical neurorehabilitation. The first uses principles of Hebbian plasticity: by altering the stimulation timing of presynaptic neurons and their postsynaptic targets, synapse function can be modulated up or down. The second form uses synchronized presynaptic inputs onto a common synaptic target. We dub this a "convergent" mechanism, because stimuli have to converge on a common target with coordinated timing. The third form induces focal modulation by tonic excitation of one region (e.g., the spinal cord) during phasic stimulation of another (e.g., motor cortex). Additionally, endogenous neural activity may be paired with exogenous electrical stimulation. This review addresses what is known about paired stimulation of the corticospinal system of both humans and animal models, emphasizes how it qualitatively differs from single-site stimulation, and discusses the gaps in knowledge that must be addressed to maximize its use and efficacy in neurorehabilitation.