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Abstract Background Unfettered movement among habitats is crucial for fish to access patchily distributed resources and complete their life cycle, but many riverscapes in the American Southwest are fragmented by dams and dewatering. The endangered Rio Grande silvery minnow (Hybognathus amarus, RGSM) persists in a fragmented remnant of its former range (ca. 5%), and its movement ecology is understudied. Methods We tracked movements of hatchery-reared RGSM, tagged with passive integrated transponder tags, using stationary and mobile antennas from 2019 to 2022. We quantified probability of movement and total distance moved by RGSM released above and below a dam. We then assessed how well two prevailing riverine movement theories (i.e., restricted movement paradigm [RMP] and colonization cycle hypothesis [CCH]) explained RGSM movement patterns. Results We detected 36.8% of released RGSM (n = 37,215) making at least one movement. Movements were leptokurtic and substantially greater than expected based on the RMP for both stationary (1.7–5.9 m) and mobile (30.3–77.8 m) individuals. On average, RGSM were detected at large for 75 days and moved a total of 12.2 rkm within a year. The maximum total distance moved by RGSM was 103 rkm. Similarly, we observed a multimodal distribution of detected range sizes with a mean detected range of 2.4 rkm and a maximum detected range of 78.2 rkm. We found little support for an upstream movement bias, as expected under the CCH, and most movements (74%) were directed downstream. Conclusions Our data suggest RGSM are highly mobile, with the ability to make long-distance movements. Neither movement theory adequately described movement patterns of RGSM; instead, our findings support a nomadic movement pattern and an apparent drift paradox matching recent studies of other pelagic-broadcast spawning minnows where populations persist upstream despite experiencing downstream drift as larvae. Resolution of the drift paradox may be achieved through further, targeted studies into different aspects of the species’ life history. Quantification of RGSM movement provides crucial insights into the species’ movement ecology and may help define the appropriate scale of recovery efforts.

Increasing evidence suggests slow-wave sleep (SWS) dysfunction in Parkinson’s disease (PD) is associated with faster disease progression, cognitive impairment, and excessive daytime sleepiness. Beta oscillations (8–35 Hz) in the basal ganglia thalamocortical (BGTC) network are thought to play a role in the development of cardinal motor signs of PD. The role cortical beta oscillations play in SWS dysfunction in the early stage of parkinsonism is not understood, however. To address this question, we used a within-subject design in a nonhuman primate (NHP) model of PD to record local field potentials from the primary motor cortex (MC) during sleep across normal and mild parkinsonian states. The MC is a critical node in the BGTC network, exhibits pathological oscillations with depletion in dopamine tone, and displays high amplitude slow oscillations during SWS. The MC is therefore an appropriate recording site to understand the neurophysiology of SWS dysfunction in parkinsonism. We observed a reduction in SWS quantity (p = 0.027) in the parkinsonian state compared to normal. The cortical delta (0.5–3 Hz) power was reduced (p = 0.038) whereas beta (8–35 Hz) power was elevated (p = 0.001) during SWS in the parkinsonian state compared to normal. Furthermore, SWS quantity positively correlated with delta power (r = 0.43, p = 0.037) and negatively correlated with beta power (r = −0.65, p

Abstract 7 Tesla-field-strength (7 T) Magnetic Resonance Imaging allows the small perforating arteries in the brain to be visualised, and this modality may allow visualisation of the arterial pathology in cerebral small vessel disease. Most studies have used standard Time-of-Flight (ToF) Magnetic Resonance Angiography (MRA). Whether the use of contrast enhancement improves perforating artery visualisation at 7 T remains unclear. In a prospective study, we compared standard ToF MRA with contrast-enhanced (CE) ToF MRA at 7 T for the visualisation of the lenticulostriate arteries (LSAs). Ten patients with symptomatic lacunar stroke were recruited (mean age, SD, 64 ± 9.9 years). Visualisation was assessed using a visual rating scale administered by two independent expert readers and length of the LSAs visible. Visualisation of the LSAs was improved with CE ToF MRA. The mean Visibility and Sharpness Score was higher for CE ToF MRA over standard ToF MRA (2.55 ± 0.64 vs. 1.75 ± 0.68; P = 0.0008). The mean length of LSA visualised was significantly longer with CE ToF MRA compared to standard ToF MRA (24.4 ± 4.5 vs. 21.9 ± 4.0 mm; P = 0.01). CE ToF MRA offers improved visualisation of the LSAs over standard ToF MRA. The addition of contrast may improve the ability to visualise cerebral small vessel disease arterial pathology.

IntroductionEvidence suggests that spontaneous beta band (11–35 Hz) oscillations in the basal ganglia thalamocortical (BGTC) circuit are linked to Parkinson’s disease (PD) pathophysiology. Previous studies on neural responses in the motor cortex evoked by electrical stimulation in the subthalamic nucleus have suggested that circuit resonance may underlie the generation of spontaneous and stimulation-evoked beta oscillations in PD. Whether these stimulation-evoked, resonant oscillations are present across PD patients in the internal segment of the globus pallidus (GPi), a primary output nucleus in the BGTC circuit, is yet to be determined.MethodsWe characterized spontaneous and stimulation-evoked local field potentials (LFPs) in the GPi of four PD patients (five hemispheres) using deep brain stimulation (DBS) leads externalized after DBS implantation surgery.ResultsOur analyses show that low-frequency (2–4 Hz) stimulation in the GPi evoked long-latency (>50 ms) beta-band neural responses in the GPi in 4/5 hemispheres. We demonstrated that neural sources generating both stimulation-evoked and spontaneous beta oscillations were correlated in their frequency content and spatial localization.DiscussionOur results support the hypothesis that the same neuronal population and resonance phenomenon in the BGTC circuit generates both spontaneous and evoked pallidal beta oscillations. These data also support the development of closed-loop control systems that modulate the GPi spontaneous oscillations across PD patients using beta band stimulation-evoked responses.

Abstract To elucidate the role of the basal ganglia during REM sleep movements in Parkinson’s disease (PD) we recorded pallidal neural activity from four PD patients. Unlike desynchronization commonly observed during wakeful movements, beta oscillations (13–35 Hz) synchronized during REM sleep movements; furthermore, high-frequency oscillations (150–350 Hz) synchronized during movement irrespective of sleep-wake states. Our results demonstrate differential engagement of the basal ganglia during REM sleep and awake movements.

Approaches to control basal ganglia neural activity in real-time are needed to clarify the causal role of 13–35 Hz (“beta band”) oscillatory dynamics in the manifestation of Parkinson's disease (PD) motor signs. Here, we show that resonant beta oscillations evoked by electrical pulses with precise amplitude and timing can be used to predictably suppress or amplify spontaneous beta band activity in the internal segment of the globus pallidus (GPi) in the human. Using this approach, referred to as closed-loop evoked interference deep brain stimulation (eiDBS), we could suppress or amplify frequency-specific (16–22 Hz) neural activity in a PD patient. Our results highlight the utility of eiDBS to characterize the role of oscillatory dynamics in PD and other brain conditions, and to develop personalized neuromodulation systems.

Excessive daytime sleepiness is a recognized non-motor symptom that adversely impacts the quality of life of people with Parkinson's disease (PD), yet effective treatment options remain limited. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for PD motor signs. Reliable daytime sleep-wake classification using local field potentials (LFPs) recorded from DBS leads implanted in STN can inform the development of closed-loop DBS approaches for prompt detection and disruption of sleep-related neural oscillations. We performed STN DBS lead recordings in three nonhuman primates rendered parkinsonian by administrating neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Reference sleep-wake states were determined on a second-by-second basis by video monitoring of eyes (eyes-open, wake and eyes-closed, sleep). The spectral power in delta (1–4 Hz), theta (4–8 Hz), low-beta (8–20 Hz), high-beta (20–35 Hz), gamma (35–90 Hz), and high-frequency (200–400 Hz) bands were extracted from each wake and sleep epochs for training (70% data) and testing (30% data) a support vector machines classifier for each subject independently. The spectral features yielded reasonable daytime sleep-wake classification (sensitivity: 90.68 ± 1.28; specificity: 88.16 ± 1.08; accuracy: 89.42 ± 0.68; positive predictive value; 88.70 ± 0.89, n = 3). Our findings support the plausibility of monitoring daytime sleep-wake states using DBS lead recordings. These results could have future clinical implications in informing the development of closed-loop DBS approaches for automatic detection and disruption of sleep-related neural oscillations in people with PD to promote wakefulness.

Vaccine coverage is below desired levels in Canada, despite National Advisory Committee on Immunization recommendations. One solution to improve coverage is to offer vaccines in pharmacies. We explore the awareness, attitudes, beliefs, and behaviors of the general public in four communities in Nova Scotia (NS) and New Brunswick (NB) about the changing role of pharmacists as immunizers. Adult members of the public were invited to complete an online survey through advertisements in print and online, and through e-mail lists at local universities. Immunization status among participants (n = 985) varied across vaccines with slightly more than one-half of the participants (51.8%) reporting receipt of a seasonal influenza vaccine last year, 38.0% reporting receipt of the meningococcal C or ACWY vaccine, and 77.7% reporting receipt of the pertussis vaccine. Despite variable self-reported receipt of vaccines, the pervasive belief that participants were not at risk of getting vaccine-preventable diseases, and a lack of awareness about which vaccines are recommended for adults, participants in this study held vaccine-positive beliefs. Participants, especially those who had previously been vaccinated in a pharmacy (39.0%), were supportive of the inclusion of pharmacists as immunizers although nearly one-half of the participants would feel more comfortable getting vaccinated by a pharmacist if another practitioner recommended it to them. While cost threatens to be a barrier to pharmacists as immunizers, this study suggests that they are well-positioned to improve vaccine coverage and to communicate recommendations and other vaccine-related information to the public.

Abstract Background Deep brain stimulation (DBS) is a treatment option for Parkinson’s disease patients when medication does not sufficiently manage their symptoms. DBS can be a highly effect therapy, but only after a time-consuming trial-and-error stimulation parameter adjustment process that is susceptible to clinician bias. This trial-and-error process will be further prolonged with the introduction of segmented electrodes that are now commercially available. New approaches to optimizing a patient’s stimulation parameters, that can also handle the increasing complexity of new electrode and stimulator designs, is needed. Methods To improve DBS parameter programming, we explored two semi-automated optimization approaches: a Bayesian optimization (BayesOpt) algorithm to efficiently determine a patient’s optimal stimulation parameter for minimizing rigidity, and a probit Gaussian process (pGP) to assess patient’s preference. Quantified rigidity measurements were obtained using a robotic manipulandum in two participants over two visits. Rigidity was measured, in 5Hz increments, between 10–185Hz (total 30–36 frequencies) on the first visit and at eight BayesOpt algorithm-selected frequencies on the second visit. The participant was also asked their preference between the current and previous stimulation frequency. First, we compared the optimal frequency between visits with the participant’s preferred frequency. Next, we evaluated the efficiency of the BayesOpt algorithm, comparing it to random and equal interval selection of frequency. Results The BayesOpt algorithm estimated the optimal frequency to be the highest tolerable frequency, matching the optimal frequency found during the first visit. However, the participants’ pGP models indicate a preference at frequencies between 70–110 Hz. Here the stimulation frequency is lowest that achieves nearly maximal suppression of rigidity. BayesOpt was efficient, estimating the rigidity response curve to stimulation that was almost indistinguishable when compared to the longer brute force method. Conclusions These results provide preliminary evidence of the feasibility to use BayesOpt for determining the optimal frequency, while pGP patient’s preferences include more difficult to measure outcomes. Both novel approaches can shorten DBS programming and can be expanded to include multiple symptoms and parameters.

Freezing of gait (FOG) is a particularly debilitating symptom of Parkinson’s disease (PD) and is often refractory to treatment. A striking feature of FOG is that external sensory cues can be used to overcome freezing and improve gait. Local field potentials (LFPs) recorded from the subthalamic nucleus (STN) and globus pallidus (GP) show that beta-band power modulates with gait phase. In the STN, beta-band oscillations are modulated by external cues, but it is unknown if this relationship holds in the globus pallidus (GP). Here we report LFP data recorded from the left GP, using a Medtronic PC + S device, in a 68-year-old man with PD and FOG during treadmill walking. A “stepping stone” task was used during which stepping was cued using visual targets of constant color or targets that unpredictably changed color, requiring a step length adjustment. Gait performance was quantified using measures of treadmill ground reaction forces and center of pressure and body kinematics from video monitoring. Beta-band power (12–30 Hz) and number of freezing episodes were measured. Cues which unpredictably changed color improved FOG more than conventional cues and were associated with greater modulation of beta-band power in phase with gait. This preliminary finding suggests that cueing-induced improvement of FOG may relate to beta-band modulation.

This paper assesses the ability of a recently installed 55 MHz multistatic meteor radar to measure gravity-wave-driven momentum fluxes around the mesopause and applies it in a case study of measuring gravity wave forcing on the diurnal tide during a period following the autumnal equinox of 2018. The radar considered is in the vicinity of Adelaide, South Australia (34.9∘ S, 138.6∘ E), and consists of a monostatic radar and bistatic receiver separated by approximately 55 km. The assessment shows that the inclusion of the bistatic receiver reduces the relative uncertainty of the momentum flux estimate from about 75 % to 65 % (for a flux magnitude of ∼20 m2 s−2, 1 d's worth of integration, and for a gravity wave field synthesized from a realistic spectral model). This increase in precision appears to be entirely attributable to the increased number of meteor detections associated with the combined monostatic and bistatic receivers rather than changes in the meteors' spatial distribution. The case study reveals large modulations in the diurnal tidal amplitudes, with a maximum tidal amplitude of ∼50 m s−1 and an associated maximum zonal wind velocity of around 140 m s−1. While the observed gravity wave forcing exhibits a complex relationship with the tidal winds during this period, the components of the forcing are seen to be approximately out of phase with the tidal winds above 88 km. No clear phase relationship has been observed below 88 km.

The goal of this study was to characterize the spectral characteristics and spatial topography of local field potential (LFP) activity in the internal segment of the globus pallidus (GPi) in patients with Parkinson's disease utilizing directional (segmented) deep brain stimulation (dDBS) leads. Data were collected from externalized dDBS leads of three patients with idiopathic Parkinson's disease after overnight withdrawal of parkinsonian medication at rest and during a cued reach-to-target task. Oscillatory activity across lead contacts/segments was examined in the context of lead locations and contact orientations determined using co-registered preoperative 7 Tesla (T) MRI and postoperative CT scans. Each of the three patients displayed a unique frequency spectrum of oscillatory activity in the pallidum, with prominent peaks ranging from 5 to 35 Hz, that modulated variably across subjects during volitional movement. Despite subject-specific spectral profiles, a consistent finding across patients was that oscillatory power was strongest and had the largest magnitude of modulation during movement in LFPs recorded from segments facing the postero-lateral “sensorimotor” region of GPi, whereas antero-medially-directed segmented contacts facing the internal capsule and/or anterior GPi, had relatively weaker LFP power and less modulation in the 5 to 35 Hz. In each subject, contact configurations chosen for clinically therapeutic stimulation (following data collection and blinded to physiology recordings), were in concordance with the contact pairs showing the largest amplitude of LFP oscillations in the 5–35 Hz range. Although limited to three subjects, these findings provide support for the hypothesis that the sensorimotor territory of the GPi corresponds to the site of maximal power of oscillatory activity in the 5 to 35 Hz and provides the greatest benefit in motor signs during stimulation in the GPi. Variability in oscillatory activity across patients is likely related to Parkinson's disease phenotype as well as small differences in recording location (i.e. lead location), highlighting the importance of lead location for optimizing stimulation efficacy. These data also provide compelling evidence for the use of LFP activity for the development of predictive stimulation models that may optimize patient benefits while reducing clinic time needed for programming.

Individuals with Parkinson's disease (PD) demonstrate deficits in muscle activation such as decreased amplitude and inappropriate bursting. There is evidence that some of these disturbances are more pronounced in extensor vs. flexor muscles. Surface EMG has been used widely to quantify muscle activation deficits in PD, but analysis of discharge of the underlying motor units may provide greater insight and be more sensitive to changes early in the disease. Of the few studies that have examined motor unit discharge in PD, the majority were conducted in the first dorsal interosseous, and no studies have measured motor units from extensor and flexor muscles within the same cohort. The objective of this study was to characterize the firing behavior of single motor units in the elbow flexor and extensor muscles during isometric contractions in people with mild-to-moderate PD. Ten individuals with PD (off-medication) and nine healthy controls were tested. Motor unit spike times were recorded via intramuscular EMG from the biceps and triceps brachii muscles during 30-s isometric contractions at 10% maximum voluntary elbow flexion and elbow extension torque, respectively. We selected variables of mean motor unit discharge rate, discharge variability, and torque variability to evaluate motor abnormalities in the PD group. The effects of group, muscle, and group-by-muscle on each variable were determined using separate linear mixed models. Discharge rate and torque variability were not different between groups, but discharge variability was significantly higher in the PD group for both muscles combined (p < 0.0001). We also evaluated the asymmetry in these motor variables between the triceps and biceps for each individual participant with PD to evaluate whether there was an association with disease severity. The difference in torque variability between elbow flexion and extension was significantly correlated with both the Hoehn and Yahr scale (rho = 0.71) and UPDRS (rho = 0.62). Our findings demonstrate that variability in motor output, rather than decreased discharge rates, may contribute to motor dysfunction in people with mild-to-moderate PD. Our findings provide insight into altered neural control of movement in PD and demonstrate the importance of measuring from multiple muscles within the same cohort.

Acute stroke is often superimposed on chronic damage from previous cerebrovascular events. This background will inevitably modulate the impact of acute injury on clinical outcomes to an extent that will depend on the precise anatomical pattern of damage. Previous attempts to quantify such modulation have employed only reductive models that ignore anatomical detail. The combination of automated image processing, large-scale data, and machine learning now enables us to quantify the impact of this with high-dimensional multivariate models sensitive to individual variations in the detailed anatomical pattern. We introduce and validate a new automated chronic lesion segmentation routine for use with non-contrast CT brain scans, combining non-parametric outlier-detection score, Zeta, with an unsupervised 3-dimensional maximum-flow, minimum-cut algorithm. The routine was then applied to a dataset of 1,704 stroke patient scans, obtained at their presentation to a hyper-acute stroke unit (St George's Hospital, London, UK), and used to train a support vector machine (SVM) model to predict between low (0–2) and high (3–6) pre-admission and discharge modified Rankin Scale (mRS) scores, quantifying performance by the area under the receiver operating curve (AUROC). In this single center retrospective observational study, our SVM models were able to differentiate between low (0–2) and high (3–6) pre-admission and discharge mRS scores with an AUROC of 0.77 (95% confidence interval of 0.74–0.79), and 0.76 (0.74–0.78), respectively. The chronic lesion segmentation routine achieved a mean (standard deviation) sensitivity, specificity and Dice similarity coefficient of 0.746 (0.069), 0.999 (0.001), and 0.717 (0.091), respectively. We have demonstrated that machine learning models capable of capturing the high-dimensional features of chronic injuries are able to stratify patients—at the time of presentation—by pre-admission and discharge mRS scores. Our fully automated chronic stroke lesion segmentation routine simplifies this process, and utilizes routinely collected CT head scans, thereby facilitating future large-scale studies to develop supportive clinical decision tools.

Sporadic cerebral small vessel disease is an important cause of vascular dementia, a syndrome of cognitive impairment together with vascular brain damage. At post-mortem pure vascular dementia is rare, with evidence of co-existing Alzheimer's disease pathology in 95% of cases. This work used MRI to characterize structural abnormalities during the preclinical phase of vascular dementia in symptomatic small vessel disease.121 subjects were recruited into the St George's Cognition and Neuroimaging in Stroke study and followed up longitudinally for five years. Over this period 22 individuals converted to dementia. Using voxel-based morphometry, we found structural abnormalities present at baseline in those with preclinical dementia, with reduced grey matter density in the left striatum and hippocampus, and more white matter hyperintensities in the frontal white-matter. The lacunar data revealed that some of these abnormalities may be due to lesions within the striatum and centrum semiovale.Using support vector machines, future dementia could be best predicted using hippocampal and striatal Jacobian determinant data, achieving a balanced classification accuracy of 73%. Using cluster ward linkage we identified four anatomical subtypes. Successful predictions were restricted to groups with lower levels of vascular damage. The subgroup that could not be predicted were younger, further from conversion, had the highest levels of vascular damage, with milder cognitive impairment at baseline but more rapid deterioration in processing speed and executive function, consistent with a primary vascular dementia. In contrast, the remaining groups had decreasing levels of vascular damage and increasing memory impairment consistent with progressively more Alzheimer's-like pathology. Voxel-wise rates of hippocampal atrophy supported these distinctions, with the vascular group closely resembling the non-dementing cohort, whereas the Alzheimer's like group demonstrated global hippocampal atrophy.This work reveals distinct anatomical endophenotypes in preclinical vascular dementia, forming a spectrum between vascular and Alzheimer's like pathology. The latter group can be identified using baseline MRI, with 73% converting within 5 years. It was not possible to predict the vascular dominant dementia subgroup, however 19% of negative predictions with high levels of vascular disease would ultimately develop dementia. It may be that techniques more sensitive to white matter damage, such as diffusion weighted imaging, may prove more useful for this vascular dominant subgroup in the future.This work provides a way to accurately stratify patients using a baseline MRI scan, and has utility in future clinical trials designed to slow or prevent the onset of dementia in these high-risk cohorts. Keywords: Structural MRI, Voxel-based morphometry, Vascular dementia, Preclinical dementia, Cerebral small vessel disease

Mesospheric gravity wave (GW) momentum flux estimates using data from multibeam Buckland Park MF radar (34.6° S, 138.5° E) experiments (conducted from July 1997 to June 1998) are presented. On transmission, five Doppler beams were symmetrically steered about the zenith (one zenith beam and four off-zenith beams in the cardinal directions). The received beams were analysed with hybrid Doppler interferometry (HDI) (Holdsworth and Reid, 1998), principally to determine the radial velocities of the effective scattering centres illuminated by the radar. The methodology of Thorsen et al. (1997), later re-introduced by Hocking (2005) and since extensively applied to meteor radar returns, was used to estimate components of Reynolds stress due to propagating GWs and/or turbulence in the radar resolution volume. Physically reasonable momentum flux estimates are derived from the Reynolds stress components, which are also verified using a simple radar model incorporating GW-induced wind perturbations. On the basis of these results, we recommend the intercomparison of momentum flux estimates between co-located meteor radars and vertical-beam interferometric MF radars. It is envisaged that such intercomparisons will assist with the clarification of recent concerns (e.g. Vincent et al., 2010) of the accuracy of the meteor radar technique.

Cerebral small vessel disease (SVD) is the primary cause of vascular cognitive impairment and is associated with decline in executive function (EF) and information processing speed (IPS). Imaging biomarkers are needed that can monitor and identify individuals at risk of severe cognitive decline. Recently there has been interest in combining several magnetic resonance imaging (MRI) markers of SVD into a unitary score to describe disease severity. Here we apply a diffusion tensor image (DTI) segmentation technique (DSEG) to describe SVD related changes in a single unitary score across the whole cerebrum, to investigate its relationship with cognitive change over a three-year period.98 patients (aged 43–89) with SVD underwent annual MRI scanning and cognitive testing for up to three years. DSEG provides a vector of 16 discrete segments describing brain microstructure of healthy and/or damaged tissue. By calculating the scalar product of each DSEG vector in reference to that of a healthy ageing control we generate an angular measure (DSEG θ) describing the patients' brain tissue microstructural similarity to a disease free model of a healthy ageing brain. Conventional MRI markers of SVD brain change were also assessed including white matter hyperintensities, cerebral atrophy, incident lacunes, cerebral-microbleeds, and white matter microstructural damage measured by DTI histogram parameters. The impact of brain change on cognition was explored using linear mixed-effects models. Post-hoc sample size analysis was used to assess the viability of DSEG θ as a tool for clinical trials.Changes in brain structure described by DSEG θ were related to change in EF and IPS (p

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation method commonly used in the disciplines of neuroscience, neurology, and neuropsychiatry to examine or modulate brain function. Low frequency rTMS (e.g., 1 Hz) is associated with a net suppression of cortical excitability, whereas higher frequencies (e.g., 5 Hz) purportedly increase excitability. Magnetic resonance spectroscopy (MRS) and resting-state functional MRI (rsfMRI) allow investigation of neurochemistry and functional connectivity, respectively, and can assess the influence of rTMS in these domains. This pilot study investigated the effects of rTMS on the primary motor cortex using pre and post MRS and rsfMRI assessments at 7 T. Seven right-handed males (age 27 ± 7 y.o.) underwent single-voxel MRS and rsfMRI before and about 30-min after rTMS was administered outside the scanner for 20-min over the primary motor cortex of the left (dominant) hemisphere. All participants received 1-Hz rTMS; one participant additionally received 5-Hz rTMS in a separate session. Concentrations of 17 neurochemicals were quantified in left and right motor cortices. Connectivity metrics included fractional amplitude of low-frequency fluctuations (fALFF) and regional homogeneity (ReHo) of both motor cortices, strength of related brain networks, and inter-hemispheric connectivity. The group-analysis revealed few trends (i.e., uncorrected for multiple comparisons), including a mean increase in the concentration of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) after the inhibitory rTMS protocol as compared to baseline in the stimulated (left) motor cortex (+8%, p = 0.043), along with a slight increase of total creatine (+2%, p = 0.018), and decrease of aspartate (−18%, p = 0.016). Additionally, GABA tended to decrease in the contralateral hemisphere (−6%, p = 0.033). No other changes of metabolite concentrations were found. Whereas functional connectivity outcomes did not exhibit trends of significant changes induced by rTMS, the percent changes of few connectivity metrics in both hemispheres were negatively correlated with GABA changes in the contralateral hemisphere. While studies in larger cohorts are needed to confirm these preliminary findings, our results indicate the safety and feasibility of detecting changes in key metabolites associated with neurotransmission after a single 1-Hz rTMS session, establishing the construct for future exploration of the neurochemical, and connectivity mechanisms of cortical responses to neuromodulation.

Falls often occur due to spontaneous loss of balance, but tripping over an obstacle during gait is also a frequent cause of falls (Sheldon, 1960; Stolze et al., 2004). Obstacle avoidance requires that appropriate modifications of the ongoing cyclical movement be initiated and completed in time. We evaluated the available response time to avoid a virtual obstacle in 26 Parkinson’s disease (PD) patients (in the off-medication state) and 26 controls (18 elderly and 8 young), using a virtual obstacle avoidance task during visually cued treadmill walking. To maintain a stable baseline of stride length and visual attention, participants stepped on virtual “stepping stones” projected onto a treadmill belt. Treadmill speed and stepping stone spacing were matched to overground walking (speed and stride length) for each individual. Unpredictably, a stepping stone changed color, indicating that it was an obstacle. Participants were instructed to try to step short to avoid the obstacle. By using an obstacle that appeared at a precise instant, this task probed the time interval required for processing new information and implementing gait cycle modifications. Probability of successful avoidance of an obstacle was strongly associated with the time of obstacle appearance, with earlier-appearing obstacles being more easily avoided. Age was positively correlated (p < 0.001) with the time required to successfully avoid obstacles. Nonetheless, the PD group required significantly more time than controls (p = 0.001) to achieve equivalent obstacle-avoidance success rates after accounting for the effect of age. Slowing of gait adaptability could contribute to high fall risk in elderly and PD. Possible mechanisms may include disturbances in motor planning, movement execution, or disordered response inhibition.

This article offers an academic and practical overview for the drafting of international arbitration clauses, from an international Latin American approach and with special emphasis on the energy and construction industries. The authors begin by analyzing the elements of the existence of the arbitral clause and putting forward certain fundamental and general cautionary notes. Then they go on to analyze key elements to include in an arbitral clause, the elements which inclusion is recommended, the elements that might be convenient to include, and others that is best to leave out. The article ends with a conclusion regarding the mindset that parties should have when drafting arbitration clauses.

The Calbuco volcano in southern Chile (41.3° S, 72.6° W) underwent three separate eruptions on 22−23 April 2015. Following the eruptions, distinct layers of enhanced lidar backscatter at 532 nm were observed in the lower stratosphere above Buckland Park, South Australia (34.6° S, 138.5° E), and Kingston, Tasmania (43.0° S, 147.3° E), during a small set of observations in April−May 2015. Using atmospheric trajectory modelling and measurements from the Cloud-Aerosol Lidar with Orthogonal Polarization (CALIOP) space-borne lidar and the Ozone Mapping Profiler Suite (OMPS) instrument on the Suomi National Polar-orbiting Partnership (NPP) satellite, we show that these layers were associated with the Calbuco eruptions. Buckland Park measurements on 30 April and 3 May detected discrete aerosol layers at and slightly above the tropopause, where the relative humidity was well below saturation. Stratospheric aerosol layers likely associated with the eruptions were observed at Kingston on 17 and 22 May in narrow discrete layers accompanied by weaker and more vertically extended backscatter. The measurements on 22 May provided a mean value of the particle linear depolarisation ratio within the main observed volcanic aerosol layer of 18.0 ± 3.0%, which was consistent with contemporaneous CALIOP measurements. The depolarisation measurements indicated that this layer consisted of a filament dominated by ash backscatter residing above a main region having likely more sulfate backscatter. Layer-average optical depths were estimated from the measurements. The mean lidar ratio for the volcanic aerosols on 22 May of 86 ± 37 sr is consistent with but generally higher than the mean for ground-based measurements for other volcanic events. The inferred optical depth for the main volcanic layer on 17 May was consistent with a value obtained from OMPS measurements, but a large difference on 22 May likely reflected the spatial inhomogeneity of the volcanic plume. Short-lived enhancements of backscatter near the tropopause of 17 May likely represented the formation cirrus that was aided by the presence of associated volcanic aerosols. We also provide evidence that gravity waves potentially influenced the layers, particularly in regard to the vertical motion observed in the strong layer on 22 May. Overall, these observations provide additional information on the dispersal and characteristics of the Calbuco aerosol plumes at higher southern latitudes than previously reported for ground-based lidar measurements.

The frequency, clinical correlates, and risk factors of cerebral microbleeds (CMB) in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) are still poorly known. We aimed at determining the location and number of CMB and their relationship with clinical manifestations, vascular risk factors, drugs, and other neuroimaging features in CADASIL patients.We collected clinical data by means of a structured proforma and centrally evaluated CMB on magnetic resonance gradient echo sequences applying the Microbleed Anatomical Rating Scale in CADASIL patients seen in 2 referral centers in Italy and United Kingdom.We evaluated 125 patients. CMB were present in 34% of patients and their presence was strongly influenced by the age. Twenty-nine percent of the patients had CMB in deep subcortical location, 22% in a lobar location, and 18% in infratentorial regions. After adjustment for age, factors significantly associated with a higher total number of CMB were hemorrhagic stroke, dementia, urge incontinence, and statins use (this latter not confirmed by multivariate analysis). Infratentorial and deep CMB were associated with dementia and urge incontinence, lobar CMB with hemorrhagic stroke, dementia, and statins use. Unexpectedly, patients with migraine, with or without aura, had a lower total, deep, and lobar number of CMB than patients without migraine.CMB formation in CADASIL seems to increase with age. History of hemorrhagic stroke, dementia, urge incontinence, and statins use are associated with a higher number of CMB. However, these findings need to be confirmed by longitudinal studies.

Objectives: Lacunes are an important disease feature of cerebral small vessel disease (SVD) but their relationship to cognitive impairment is not fully understood. To investigate this we determined (1) the relationship between lacune count and total lacune volume with cognition, (2) the spatial distribution of lacunes and the cognitive impact of lacune location, and (3) the whole brain anatomical covariance associated with these strategically located regions of lacune damage. Methods: One hundred and twenty one patients with symptomatic lacunar stroke and radiological leukoaraiosis were recruited and multimodal MRI and neuropsychological data acquired. Lacunes were mapped semi-automatically and their volume calculated. Lacune location was automatically determined by projection onto atlases, including an atlas which segments the thalamus based on its connectivity to the cortex. Lacune locations were correlated with neuropsychological results. Voxel based morphometry was used to create anatomical covariance maps for these ‘strategic’ regions. Results: Lacune number and lacune volume were positively associated with worse executive function (number p

Chaparral is the most abundant vegetation type in California and current climate change models predict more frequent and severe droughts that could impact plant community structure. Understanding the factors related to species-specific drought mortality is essential to predict such changes. We predicted that life history type, hydraulic traits, and plant size would be related to the ability of species to survive drought. We evaluated the impact of these factors in a mature chaparral stand during the drought of 2014, which has been reported as the most severe in California in the last 1,200 years. We measured tissue water potential, native xylem specific conductivity, leaf specific conductivity, percentage loss in conductivity, and chlorophyll fluorescence for 11 species in February 2014, which was exceptionally dry following protracted drought. Mortality among the 11 dominant species ranged from 0 to 93%. Total stand density was reduced 63.4% and relative dominance of species shifted after the drought. Mortality was negatively correlated with water potential, native xylem specific conductivity, and chlorophyll fluorescence, but not with percent loss in hydraulic conductivity and leaf specific conductivity. The model that best explained mortality included species and plant size as main factors and indicated that larger plants had greater survival for 2 of the species. In general, species with greater resistance to water-stress induced cavitation showed greater mortality levels. Despite adult resprouters typically being more vulnerable to cavitation, results suggest that their more extensive root systems enable them to better access soil moisture and avoid harmful levels of dehydration. These results are consistent with the hypothesis that short-term high intensity droughts have the strongest effect on mature plants of shallow-rooted dehydration tolerant species, whereas deep-rooted dehydration avoiding species fare better in the short-term. Severe droughts can drive changes in chaparral structure as a result of the differential mortality among species.

Cerebral small vessel disease (SVD) is a common cause of vascular cognitive impairment. A number of disease features can be assessed on MRI including lacunar infarcts, T2 lesion volume, brain atrophy, and cerebral microbleeds. In addition, diffusion tensor imaging (DTI) is sensitive to disruption of white matter ultrastructure, and recently it has been suggested that additional information on the pattern of damage may be obtained from axial diffusivity, a proposed marker of axonal damage, and radial diffusivity, an indicator of demyelination. We determined the contribution of these whole brain MRI markers to cognitive impairment in SVD. Consecutive patients with lacunar stroke and confluent leukoaraiosis were recruited into the ongoing SCANS study of cognitive impairment in SVD (n = 115), and underwent neuropsychological assessment and multimodal MRI. SVD subjects displayed poor performance on tests of executive function and processing speed. In the SVD group brain volume was lower, white matter hyperintensity volume higher and all diffusion characteristics differed significantly from control subjects (n = 50). On multi-predictor analysis independent predictors of executive function in SVD were lacunar infarct count and diffusivity of normal appearing white matter on DTI. Independent predictors of processing speed were lacunar infarct count and brain atrophy. Radial diffusivity was a stronger DTI predictor than axial diffusivity, suggesting ischaemic demyelination, seen neuropathologically in SVD, may be an important predictor of cognitive impairment in SVD. Our study provides information on the mechanism of cognitive impairment in SVD.

Voluntary movements are often preceded by a movement-related potential beginning as much as two seconds prior to the onset of movement. In light of evidence that motor actions can be prepared and initiated in less than 200 ms, the function of this early activity has remained enigmatic. We hypothesized that the movement-related potential reflects the state of preparation of the planned movement. This was tested by delivering a startling acoustic stimulus during the preparation phase of a load-release task. The cue to release the load was presented either 3.5 seconds after a warning cue (PREDICT condition) or randomly between 4-12 seconds (REACT condition). Electroencephalographic, electromyographic and limb and load kinematic signals were recorded. In a subset of trials, a startle stimulus was delivered at -1500, -1000, -500, -250, -100 or 0 ms before the release cue. A contingent-negative variation (CNV) waveform, with a late phase of slow-rising negativity beginning an average of 1459 ms prior to movement, was observed for the PREDICT condition but not the REACT condition. For both conditions, the startle stimulus frequently evoked the early and unintentional release of the load-release sequence. The incidence of release was significantly (p

Disorders of posture, balance, and gait are debilitating motor manifestations of advancing Parkinson's disease requiring rehabilitation intervention. These problems often reflect difficulties with coupling or sequencing posture and locomotion during complex whole body movements linked with falls. Considerable progress has been made with demonstrating the effectiveness of exercise interventions for individuals with Parkinson's disease. However, gaps remain in the evidence base for specific interventions and the optimal content of exercise interventions. Using a conceptual theoretical framework and experimental findings, this perspective and review advances the viewpoint that rehabilitation interventions focused on separate or isolated components of posture, balance, or gait may limit the effectiveness of current clinical practices. It is argued that treatment effectiveness may be improved by directly targeting posture and locomotion coupling problems as causal factors contributing to balance and gait dysfunction. This approach may help advance current clinical practice and improve outcomes in rehabilitation for persons with Parkinson's disease.

Thiol mimics are molecules that are less chemically reactive than thiols but that also attach to a metal surface through a metal–thiolate bond; thus, they give an alternative method of attaching organic semiconductors to a surface. The synthesis and molecular characterization of substituted bithiophenes and terthiophenes containing at least one thionitrile substituent (a “protected thiol”) are presented. Photoluminescence spectroscopy shows that the nitrile groups are not in conjugation with the oligothiophene core. Single-crystal X-ray structures of two bithiophenes (T2SCN2and BrT2SCN, where T = 2,5-thienylene) show that the thionitriles have extended intermolecular contacts and π-stacking in the solid state. All the synthesized compounds form thin films on gold substrates, as shown by electrochemical capacitance measurements. Atomic force microscopy demonstrates uniform coverage and shows good crystallite overlap in the films, with crystallite size dependent on the number of intermolecular contacts in the solid-state structure. [ABSTRACT FROM AUTHOR]

The two ligands 3,3′-dicyanobiphenyl (3) and 5,5′-dicyano-2,2′-bithiophene (4) are geometrically similar but give rise to different coordination compounds when reacted with silver(I) salts. The crystal structures of 3·AgClO4and 3·AgBF4have 1 : 1 ligand : cation ratios, while 42·ClO4and 42·BF4have 2 : 1 ligand : cation ratios. These ratios for the solid-state materials were constant, even when different stoichiometric ratios were used in the reaction vessels. The structures of these four coordination compounds are presented and the reasons for the difference in the coordination environments discussed with reference to IR spectroscopic and DFT computational results. [ABSTRACT FROM AUTHOR]

Step initiation involves anticipatory postural adjustments (APAs) that propel the body mass forward and laterally before the first step. This study used a startle-like acoustic stimulus (SAS) and transcranial magnetic stimulation (TMS) to examine the preparation of APAs before forward stepping. After an instructed delay period, subjects initiated forward steps in reaction to a visual "go" cue. TMS or SAS was delivered before (–1,400 or –100 ms), on (0 ms), or after (+100 ms for TMS, +200 ms for SAS) the imperative "go" cue. Ground reaction forces and electromyographic activity were recorded. In control trials, the mean reaction time was 217 ± 38 ms. In contrast, the SAS evoked APAs that had an average onset of 110 ± 54 ms, whereas the incidence, magnitude, and duration of the APA increased as the stimulus timing approached the "go" cue. A facilitation of motor-evoked potentials in the initial agonist muscle was observed only when TMS was applied at +100 ms. These findings indicate that there was an initial phase of movement preparation during which the APA-stepping sequence was progressively assembled, and that this early preparation did not involve the corticomotor pathways activated by TMS. The subsequent increase in corticomotor excitability between the imperative stimulus and onset of the APA suggests that corticospinal pathways contribute to the voluntary initiation of the prepared APA-stepping sequence. These findings are consistent with a feedforward mode of neural control whereby the motor sequence, including the associated postural adjustments, is prepared before voluntary movement. [ABSTRACT FROM AUTHOR]

Current models of basal ganglia dysfunction in primary dystonia propose that the excessive muscle activity results from an increase in the excitability of the primary motor cortex. Neurophysiological and neuroimaging studies, however, have shown consistently reduced movement-related sensorimotor cortical activity. To explore this paradox, we used transcranial magnetic stimulation (TMS) to examine changes in corticospinal excitability preceding and during ballistic movements of the wrist in 9 patients with primary dystonia affecting the arm and 9 matched control subjects. The onset time, rate of rise, and duration of changes in the excitability of corticospinal projections to the agonist muscle were normal in the patients with dystonia. Increases in excitability were selective to the initial agonist muscle, suggesting that the spatial recruitment of corticospinal neurons was normal. Nonetheless, movements were slower in the patients by an average of 26%. The onset of the first agonist muscle burst was normal in magnitude and timing but the activity in this muscle subsequently became attenuated as movement progressed. Muscle activity in antagonist and proximal muscles of the upper arm was reduced significantly in the dystonia patients. These findings support the view that movement preparation and initiation at the level of the primary motor cortex is normal in patients with dystonia. Bradykinesia could not be attributed to co-contraction or overflow of activity and was associated with reduced rather than excessive muscle activity. © 2004 Movement Disorder Society [ABSTRACT FROM AUTHOR]