Reduced Modulation of Task-Related Connectivity Mediates Age-Related Declines in Bimanual Performance.

Aging is accompanied by marked changes in motor behavior and its neural correlates. At the behavioral level, age-related declines in motor performance manifest, for example, as a reduced capacity to inhibit interference between hands during bimanual movements, particularly when task complexity increases. At the neural level, aging is associated with reduced differentiation between distinct functional systems. Functional connectivity (FC) dedifferentiation is characterized by more homogeneous connectivity patterns across various tasks or task conditions, reflecting a reduced ability of the aging adult to modulate brain activity according to changing task demands. It is currently unknown, however, how whole-brain dedifferentiation interacts with increasing task complexity. In the present study, we investigated age- and task-related FC in a group of 96 human adults across a wide age range (19.9-74.5 years of age) during the performance of a bimanual coordination task of varying complexity. Our findings indicated stronger task complexity-related differentiation between visuomotor- and nonvisuomotor-related networks, though modulation capability decreased with increasing age. Decreased FC modulation mediated larger complexity-related increases in between-hand interference, reflective of worse bimanual coordination. Thus, the ability to maintain high motor performance levels in older adults is related to the capability to properly segregate and modulate functional networks.

Quantitation of free and total N-acetylcysteine amide and its metabolite N-acetylcysteine in human plasma using derivatization and electrospray LC-MS/MS.

Studies of N-acetylcysteine amide (NACA) in nonclinical models have demonstrated various antioxidant, anti-apoptotic, anti-inflammatory and neuroprotective effects, and it is currently being developed as a treatment for retinitis pigmentosa. Sensitive LC-MS/MS methods were developed and validated to quantitate reduced and total NACA and its major metabolite, N-acetylcysteine (NAC), in human plasma to support clinical studies involving NACA. To trap and stabilize reduced NACA and NAC at the time of collection, whole blood was immediately treated with 2-chloro-1-methylpyridinium iodide (CMPI) to convert free thiols to 1-methylpyridinyl thioether derivatives. Plasma was harvested and frozen until samples were assayed using protein precipitation and an LC-MS/MS separation based on hydrophilic-interaction chromatography (HILIC). To process NACA and NAC present as disulfides, an intermediate portion of the extract was further subjected to reduction with tris(2-carboxyethyl) phosphine; the released thiols were then reacted with CMPI, extracted, and analyzed as before, to measure total thiols. The method for NACA and NAC, whether free/reduced or total, covered a range from 50 ng/mL to 50 µg/mL in human plasma and required a single 25 µL plasma sample. Up to 180 samples could be assayed in a single session. The inter-run mean bias and precision (%CV) were within ±5% for the free thiol method and within ±8.5% for the total thiol method. Benchtop, freeze/thaw, and long-term stability were evaluated and acceptable. The NAC/NACA method applied to a clinical study demonstrated incurred sample reproducibility of 95.5% for NAC and 99.1% for NACA.

Measurement of lidocaine and 2,6-dimethylaniline in minipig plasma, skin, and dermal tapes using UHPLC with electrospray MS/MS.

Sensitive LC-MS/MS methods were developed to measure lidocaine and its metabolite 2,6-dimethylaniline (2,6-DMA) with application to transdermal studies. The methods for lidocaine in minipig plasma, tissue biopsies, and dermal tapes utilized mixed mode/SCX solid phase extraction, with lower quantitation limits of 25 pg/mL in plasma, 15 ng/g tissue, and 5 ng/tape. 2,6-DMA was measured in plasma and skin tissue homogenates by ultrafiltration and (for tissue) by further derivatization with 4-methoxybenzoyl chloride to form the corresponding benzamide derivative, which extended the lower limit of quantitation to 200 pg/mL. The methods allowed local measurement of lidocaine in stratum corneum, punch biopsies, and plasma and of 2,6-DMA in plasma and biopsies obtained from minipigs dosed with experimental transdermal formulations. Quantitation limits were approximately 7-fold lower than previously reported for lidocaine and 3-fold lower for 2,6-DMA.

Relative cortico-subcortical shift in brain activity but preserved training-induced neural modulation in older adults during bimanual motor learning.

To study age-related differences in neural activation during motor learning, functional magnetic resonance imaging scans were acquired from 25 young (mean 21.5-year old) and 18 older adults (mean 68.6-year old) while performing a bimanual coordination task before (pretest) and after (posttest) a 2-week training intervention on the task. We studied whether task-related brain activity and training-induced brain activation changes differed between age groups, particularly with respect to the hyperactivation typically observed in older adults. Findings revealed that older adults showed lower performance levels than younger adults but similar learning capability. At the cerebral level, the task-related hyperactivation in parietofrontal areas and underactivation in subcortical areas observed in older adults were not differentially modulated by the training intervention. However, brain activity related to task planning and execution decreased from pretest to posttest in temporo-parieto-frontal areas and subcortical areas in both age groups, suggesting similar processes of enhanced activation efficiency with advanced skill level. Furthermore, older adults who displayed higher activity in prefrontal regions at pretest demonstrated larger training-induced performance gains. In conclusion, in spite of prominent age-related brain activation differences during movement planning and execution, the mechanisms of learning-related reduction of brain activation appear to be similar in both groups. Importantly, cerebral activity during early learning can differentially predict the amplitude of the training-induced performance benefit between young and older adults.

Ground-level falls: 9-year cumulative experience in a regionalized trauma system.

Ground-level falls (GLFs) are the leading cause of nonfatal hospitalized injuries in the US. We hypothesized that risk-adjusted mortality would not vary between levels of trauma center verification if regional triage functioned appropriately. Data were collected from our regional trauma registry for the years 2001 through 2009. A multilevel mixed-effects logistic regression model was developed to compare risk-adjusted mortality rates by trauma center level and by year. GLF patients numbered 8202 over 9 years with 2.1% mortality. Mean age was 74.5 years and mean probability of death was 0.021 (95% confidence interval [CI], 0.020-0.021). The level I center-treated patients had the highest probability of death (0.033) compared to levels II and III/IV patients (0.023 and 0.018, respectively; P < 0.001), with the highest mortality (6.0%, 3.1%, and 1.1% for levels I, II, and III/IV; P < 0.001). The adjusted odds ratio of mortality was lowest at the level I center (0.71; 95% CI, 0.56-0.91), while no difference existed between level II (1.17; 95% CI, 0.90-1.51) and level III/IV centers (1.22; 95% CI, 0.90-1.66). The 95% CIs for risk-adjusted mortality by year overlapped the 1.0 reference line for each year from 2002 to 2009. In conclusion, regional risk-adjusted mortality for GLF has varied little since 2002. More study is warranted to understand the lower risk-adjusted GLF mortality at the level I center for this growing patient population.