Personalised profiling to identify clinically relevant changes in tremor due to multiple sclerosis.

BACKGROUND: There is growing interest in sensor-based assessment of upper limb tremor in multiple sclerosis and other movement disorders. However, previously such assessments have not been found to offer any improvement over conventional clinical observation in identifying clinically relevant changes in an individual's tremor symptoms, due to poor test-retest repeatability. METHOD: We hypothesised that this barrier could be overcome by constructing a tremor change metric that is customised to each individual's tremor characteristics, such that random variability can be distinguished from clinically relevant changes in symptoms. In a cohort of 24 people with tremor due to multiple sclerosis, the newly proposed metrics were compared against conventional clinical and sensor-based metrics. Each metric was evaluated based on Spearman rank correlation with two reference metrics extracted from the Fahn-Tolosa-Marin Tremor Rating Scale: a task-based measure of functional disability (FTMTRS B) and the subject's self-assessment of the impact of tremor on their activities of daily living (FTMTRS C). RESULTS: Unlike the conventional sensor-based and clinical metrics, the newly proposed 'change in scale' metrics presented statistically significant correlations with changes in self-assessed impact of tremor (max R2>0.5,p<0.05 after correction for false discovery rate control). They also outperformed all other metrics in terms of correlations with changes in task-based functional performance (R2=0.25 vs. R2=0.15 for conventional clinical observation, both p<0.05). CONCLUSIONS: The proposed metrics achieve an elusive goal of sensor-based tremor assessment: improving on conventional visual observation in terms of sensitivity to change. Further refinement and evaluation of the proposed techniques is required, but our core findings imply that the main barrier to translational impact for this application can be overcome. Sensor-based tremor assessments may improve personalised treatment selection and the efficiency of clinical trials for new treatments by enabling greater standardisation and sensitivity to clinically relevant changes in symptoms.

Measurement bias in activation-recovery intervals from unipolar electrograms.

The activation-recovery interval (ARI) calculated from unipolar electrograms is regularly used as a convenient surrogate measure of local cardiac action potential durations (APD). This method enables important research bridging between computational studies and in vitro and in vivo human studies. The Wyatt method is well established as a theoretically sound method for calculating ARIs; however, some studies have observed that it is prone to a bias error in measurement when applied to positive T waves. This article demonstrates that recent theoretical and computational studies supporting the use of the Wyatt method are likely to have underestimated the extent of this bias in many practical experimental recording scenarios. This work addresses these situations and explains the measurement bias by adapting existing theoretical expressions of the electrogram to represent practical experimental recording configurations. A new analytic expression for the electrogram's local component is derived, which identifies the source of measurement bias for positive T waves. A computer implementation of the new analytic model confirms our hypothesis that the bias is systematically dependent on the electrode configuration. These results provide an aid to electrogram interpretation in general, and this work's outcomes are used to make recommendations on how to minimize measurement error.

Increased ecological resource variability during a critical transition in hominin evolution.

Although climate change is considered to have been a large-scale driver of African human evolution, landscape-scale shifts in ecological resources that may have shaped novel hominin adaptations are rarely investigated. We use well-dated, high-resolution, drill-core datasets to understand ecological dynamics associated with a major adaptive transition in the archeological record ~24 km from the coring site. Outcrops preserve evidence of the replacement of Acheulean by Middle Stone Age (MSA) technological, cognitive, and social innovations between 500 and 300 thousand years (ka) ago, contemporaneous with large-scale taxonomic and adaptive turnover in mammal herbivores. Beginning ~400 ka ago, tectonic, hydrological, and ecological changes combined to disrupt a relatively stable resource base, prompting fluctuations of increasing magnitude in freshwater availability, grassland communities, and woody plant cover. Interaction of these factors offers a resource-oriented hypothesis for the evolutionary success of MSA adaptations, which likely contributed to the ecological flexibility typical of Homo sapiens foragers.

Grasslands, people, and conservation: over-the-horizon learning exchanges between African and American pastoralists.

The world's grasslands and large migratory populations of wildlife have been disproportionately lost or disrupted by human activities, yet are poorly represented in protected areas. The major threats they face are land subdivision and the loss of large-scale dynamic processes such as wildlife migrations and fire. The large-scale dynamical processes and ubiquity of livestock economies and cultures across the grasslands calls for an integrated ecosystem approach to conservation to make up the shortfall in protected-area coverage. Ranchers and pastoralists will be more inclined to adopt an integrated landscape approach to conservation if they also see the threats to wildlife and grassland ecosystems as affecting their livelihoods and way of life. We arranged a series of learning exchanges between African and American pastoralists, ranchers, scientists, and conservationists aimed at building the collaboration and consensus needed to conserve grasslands at a landscape level. There was broad agreement on the threat of land fragmentation to livelihoods, wildlife, and grasslands. The exchanges also identified weaknesses in prevailing public, private, and community modes of ownership in halting fragmentation. New collaborative approaches were explored to attain the benefits of privatization while keeping the landscape open. The African-U.S. exchanges showed that learning exchanges can anticipate over-the-horizon problems and speed up the feedback loops that underlie adaptive management and build social and ecological resilience.

Predicting Extreme Droughts in Savannah Africa: A Comparison of Proxy and Direct Measures in Detecting Biomass Fluctuations, Trends and Their Causes.

We monitored pasture biomass on 20 permanent plots over 35 years to gauge the reliability of rainfall and NDVI as proxy measures of forage shortfalls in a savannah ecosystem. Both proxies are reliable indicators of pasture biomass at the onset of dry periods but fail to predict shortfalls in prolonged dry spells. In contrast, grazing pressure predicts pasture deficits with a high degree of accuracy. Large herbivores play a primary role in determining the severity of pasture deficits and variation across habitats. Grazing pressure also explains oscillations in plant biomass unrelated to rainfall. Plant biomass has declined steadily and biomass per unit of rainfall has fallen by a third, corresponding to a doubling in grazing intensity over the study period. The rising probability of forage deficits fits local pastoral perceptions of an increasing frequency of extreme shortfalls. The decline in forage is linked to sedentarization, range loss and herbivore compression into drought refuges, rather than climate change. The results show that the decline in rangeland productivity and increasing frequency of pasture shortfalls can be ameliorated by better husbandry practices and reinforces the need for ground monitoring to complement remote sensing in forecasting pasture shortfalls.

Production, reproduction and size in mammals.

It is argued that birth rate, turnover rate and production/biomass ratios (P/B) are equivalent in stable populations. It is then shown from field data on 21 mammal species that production scales as a 2/3 power of body mass, suggesting that size rather than life history characteristics explain most interspecific variation. The relationship simolifies calculations of annual production in populations and energy flow through communities.

Life history patterns in birds and mammals and their evolutionary interpretation.

It is argued that allometric principles account for most of the observed variation in the life history patterns amongst birds. To test this contention it is shown that traits such as incubation time, growth rates, age at first reproduction, lifespan, clutch weight and egg weight all scale to body weight with exponents similar to those found for analogous traits in mammals. It is then shown that most of the variation amongst bird taxa and between birds and mammals based on body weight allometry can be explained by variations in brain size, body temperature and metabolic rate, consistent with theories of growth and ageing derived from mammalian studies. Finally, it is suggested that the evidence for life histostory allometry is sufficiently strong that it argues for a more epigenetic view of life history patterns and their evolution than is generally conceded in most adaptation theories.

Ecological conditions that determine when grazing stimulates grass production.

We report the results of a pot experiment that examined the effects of three ecologically important factors controlling plant growth rates in savanna grasslands: defoliation, soil nitrogen and soil water availability. The experiment was conducted in the Amboseli region in east Africa, and was designed to simulate natural conditions as far as possible, using local soils and a grass species that is heavily grazed by abundant large herbivores. Productivity by different plant components was reduced, stimulated or unchanged by defoliation, depending on specific watering and fertilization treatments. Total above-ground production was stimulated by defoliation and was maximized at moderate clipping intensities, but this was statistically significant only when plants were watered infrequently (every 8 days), and most important, periods between clipping events were extended (at least 24 days). Under these conditions, plant growth rates were limited by water availability at the time of clipping, and soil water conserved in clipped, compared to unclipped plants. Within a given fertilization treatment, whole-plant production was never stimulated by defoliation because root growth was unaffected or inhibited by clipping. However, when fertilization was coupled to defoliation, as they are in the field, whole-plant production by fertilized and moderately clipped plants exceeded production by infertilized, unclipped plants. Under this interpretation, maximum whole-plant production coincided with optimum conditions for herbivores (maximum nitrogen concentration in grass leaves) when watering was frequent, and plants were moderately defoliated. However, these conditions were not the same as those that maximized relative above-ground stimulation of growth (infrequent watering and clipping).The results indicate that above-ground grass production can be stimulated by grazing, and when that is likely to occur. However, the results emphasize that plant production responses to defoliation can vary widely, contigent upon a complex interaction of ecological factors.

Inverse dynamics modelling of upper-limb tremor, with cross-correlation analysis.

A method to characterise upper-limb tremor using inverse dynamics modelling in combination with cross-correlation analyses is presented. A 15 degree-of-freedom inverse dynamics model is used to estimate the joint torques required to produce the measured limb motion, given a set of estimated inertial properties for the body segments. The magnitudes of the estimated torques are useful when assessing patients or evaluating possible intervention methods. The cross-correlation of the estimated joint torques is proposed to gain insight into how tremor in one limb segment interacts with tremor in another. The method is demonstrated using data from a single patient presenting intention tremor because of multiple sclerosis. It is shown that the inertial properties of the body segments can be estimated with sufficient accuracy using only the patient's height and weight as a priori knowledge, which ensures the method's practicality and transferability to clinical use. By providing a more detailed, objective characterisation of patient-specific tremor properties, the method is expected to improve the selection, design and assessment of treatment options on an individual basis.

Effect of mental challenge induced by movie clips on action potential duration in normal human subjects independent of heart rate.

BACKGROUND: Mental stress and emotion have long been associated with ventricular arrhythmias and sudden death in animal models and humans. The effect of mental challenge on ventricular action potential duration (APD) in conscious healthy humans has not been reported. METHODS AND RESULTS: Activation recovery intervals measured from unipolar electrograms as a surrogate for APD (n=19) were recorded from right and left ventricular endocardium during steady-state pacing, whilst subjects watched an emotionally charged film clip. To assess the possible modulating role of altered respiration on APD, the subjects then repeated the same breathing pattern they had during the stress, but without the movie clip. Hemodynamic parameters (mean, systolic, and diastolic blood pressure, and rate of pressure increase) and respiration rate increased during the stressful part of the film clip (P=0.001). APD decreased during the stressful parts of the film clip, for example, for global right ventricular activation recovery interval at end of film clip 193.8 ms (SD, 14) versus 198.0 ms (SD, 13) during the matched breathing control (end film left ventricle 199.8 ms [SD, 16] versus control 201.6 ms [SD, 15]; P=0.004). Respiration rate increased during the stressful part of the film clip (by 2 breaths per minute) and was well matched in the respective control period without any hemodynamic or activation recovery interval changes. CONCLUSIONS: Our results document for the first time direct recordings of the effect of a mental challenge protocol on ventricular APD in conscious humans. The effect of mental challenge on APD was not secondary to emotionally induced altered respiration or heart rate.

Identifying source populations and genetic structure for savannah elephants in human-dominated landscapes and protected areas in the Kenya-Tanzania borderlands.

We investigated the genetic metapopulation structure of elephants across the trans Rift Valley region of Kenya and Tanzania, one of the remaining strongholds for savannah elephants (Loxodonata africana) in East Africa, using microsatellite and mitochondrial DNA (mtDNA) markers. We then examined this population structure to determine the source population for a recent colonization event of savannah elephants on community-owned land within the trans rift valley region. Four of the five sampled populations showed significant genetic differentiation (p<0.05) as measured with both mtDNA haplotypes and microsatellites. Only the samples from the adjacent Maasai Mara and Serengeti ecosystems showed no significant differentiation. A phylogenetic neighbour-joining tree constructed from mtDNA haplotypes detected four clades. Clade four corresponds to the F clade of previous mtDNA studies that reported to have originated in forest elephants (Loxodonta cyclotis) but to also be present in some savannah elephant populations. The split between clade four and the other three clades corresponded strongly to the geographic distribution of mtDNA haplotypes across the rift valley in the study area. Clade four was the dominant clade detected on the west side of the rift valley with rare occurrences on the east side. Finally, the strong patterns of population differentiation clearly indicated that the recent colonists to the community-owned land in Kenya came from the west side of the rift valley. Our results indicate strong female philopatry within the isolated populations of the trans rift valley region, with gene flow primarily mediated via male movements. The recent colonization event from Maasai Mara or Serengeti suggests there is hope for maintaining connectivity and population viability outside formal protected areas in the region.

Cyclical modulation of human ventricular repolarization by respiration.

BACKGROUND: Respiratory modulation of autonomic input to the sinus node results in cyclical modulation of heart rate, known as respiratory sinus arrhythmia (RSA). We hypothesized that the respiratory cycle may also exert cyclical modulation on ventricular repolarization, which may be separately measurable using local endocardial recordings. METHODS AND RESULTS: The study included 16 subjects with normal ventricles undergoing routine clinical electrophysiological procedures for supraventricular arrhythmias. Unipolar electrograms were recorded from 10 right and 10 left ventricular endocardial sites. Breathing was voluntarily regulated at 5 fixed frequencies (6, 9, 12, 15, and 30 breaths per min) and heart rate was clamped by RV pacing. Activation-recovery intervals (ARI: a surrogate for APD) exhibited significant (p < 0.025) cyclical variation at the respiratory frequency in all subjects; ARI shortened with inspiration and lengthened with expiration. Peak-to-peak ARI variation ranged from 0-26 ms; the spatial pattern varied with subject. Arterial blood pressure also oscillated at the respiratory frequency (p < 0.025) and lagged behind respiration by between 1.5 s and 0.65 s from slowest to fastest breathing rates respectively. Systolic oscillation amplitude was significantly greater than diastolic (14 ± 5 vs. 8 ± 4 mm Hg ± SD, p < 0.001). CONCLUSIONS: Observations in humans with healthy ventricles using multiple left and right ventricular endocardial recordings showed that ARI action potential duration (APD) varied cyclically with respiration.

Oscillatory patterns of respiration: consequences for the stability and control of cardiac electrophysiology.

Periodic breathing patterns known as Central Sleep Apnea (CSA) are often observed in congestive heart failure. This phenomenon is associated with increased risk of sudden cardiac death, but the mechanism for that outcome has not been exposed. Endocardial electrograms were recorded during spontaneous episodes of CSR and PB in patients in conscious and unconscious states. Analysis exposed a regular bidirectional phase-walk in the relationship between respiration and arterial blood pressure. Recently developed signal processing techniques revealed that respiration also modulates cardiac repolarization properties at multiple simultaneous frequencies, and the effect was heterogeneous across measurement sites in both ventricles. These measurements offer unique evidence of the electro-physiological manifestations of these breathing patterns. Analysis of phase relationships suggested a mechanism by which the behavior may predispose patients to cardiac arrhythmias. Such predisposition would be easily measured to direct treatment priorities and improve risk stratification.

Real-time feedback of dynamic cardiac repolarization properties.

Arrhythmia is a major health problem and is the subject of much research and computational modeling. The impact of this research has been limited by the availability of human data and by difficulties in its translation to clinical practice. This paper describes an expert system for analysis of cardiac electrogram signals, detecting local activation and repolarization times using heuristic algorithms that incorporate automatic rejection of measurements that are deemed to be unreliable. The fully-automated system operates in real-time to provide feedback to cardiologists of derived dynamic repolarization models, which could dramatically enhance research capabilities and produce novel diagnostic techniques and therapies.

Bone assemblages track animal community structure over 40 years in an African savanna ecosystem.

Reconstructing ancient communities depends on how accurately fossil assemblages retain information about living populations. We report a high level of fidelity between modern bone assemblages and living populations based on a 40-year study of the Amboseli ecosystem in southern Kenya. Relative abundance of 15 herbivorous species recorded in the bone assemblage accurately tracks the living populations through major changes in community composition and habitat over intervals as short as 5 years. The aggregated bone sample provides an accurate record of community structure time-averaged over four decades. These results lay the groundwork for integrating paleobiological and contemporary ecological studies across evolutionary and ecological time scales. Bone surveys also provide a useful method of assessing population changes and community structure for modern vertebrates.

The status of wildlife in protected areas compared to non-protected areas of Kenya.

We compile over 270 wildlife counts of Kenya's wildlife populations conducted over the last 30 years to compare trends in national parks and reserves with adjacent ecosystems and country-wide trends. The study shows the importance of discriminating human-induced changes from natural population oscillations related to rainfall and ecological factors. National park and reserve populations have declined sharply over the last 30 years, at a rate similar to non-protected areas and country-wide trends. The protected area losses reflect in part their poor coverage of seasonal ungulate migrations. The losses vary among parks. The largest parks, Tsavo East, Tsavo West and Meru, account for a disproportionate share of the losses due to habitat change and the difficulty of protecting large remote parks. The losses in Kenya's parks add to growing evidence for wildlife declines inside as well as outside African parks. The losses point to the need to quantify the performance of conservation policies and promote integrated landscape practices that combine parks with private and community-based measures.