Physiological, Anatomical and Metabolic Correlates of Aerobic Fitness in Human Primary Motor Cortex: A Multimodal Study.

Physical activity (PA) has been shown to benefit various cognitive functions and promote neuroplasticity. Whereas the effects of PA on brain anatomy and function have been well documented in older individuals, data are scarce in young adults. Whether high levels of cardiorespiratory fitness (CRF) achieved through regular PA are associated with significant structural and functional changes in this age group remains largely unknown. In the present study, twenty young adults that engaged in at least 8 hours per week of aerobic exercise during the last 5 years were compared to twenty sedentary controls on measures of cortical excitability, white matter microstructure, cortical thickness and metabolite concentration. All measures were taken in the left primary motor cortex and CRF was assessed with VO2max. Transcranial magnetic stimulation (TMS) revealed higher corticospinal excitability in high- compared to low-fit individuals reflected by greater input/output curve amplitude and slope. No group differences were found for other TMS (short-interval intracortical inhibition and intracortical facilitation), diffusion MRI (fractional anisotropy and apparent fiber density), structural MRI (cortical thickness) and magnetic resonance spectroscopy (NAA, GABA, Glx) measures. Taken together, the present data suggest that brain changes associated with increased CRF are relatively limited, at least in primary motor cortex, in contrast to what has been observed in older adults.

The neurophysiological aftereffects of brain stimulation in human primary motor cortex: a Sham-controlled comparison of three protocols.

Paired associative stimulation (PAS), transcranial direct current stimulation (tDCS), and transcranial alternating current stimulation (tACS) are non-invasive brain stimulation methods that are used to modulate cortical excitability. Whether one technique is superior to the others in achieving this outcome and whether individuals that respond to one intervention are more likely to respond to another remains largely unknown. In the present study, the neurophysiological aftereffects of three excitatory neurostimulation protocols were measured with transcranial magnetic stimulation (TMS). Twenty minutes of PAS at an ISI of 25 ms, anodal tDCS, 20-Hz tACS, and Sham stimulation were administered to 31 healthy adults in a repeated measures design. Compared with Sham, none of the stimulation protocols significantly modulated corticospinal excitability (input/ouput curve and slope, TMS stimulator intensity required to elicit MEPs of 1-mV amplitude) or intracortical excitability (short- and long-interval intracortical inhibition, intracortical facilitation, cortical silent period). Sham-corrected responder analysis estimates showed that an average of 41 (PAS), 39 (tDCS), and 39% (tACS) of participants responded to the interventions with an increase in corticospinal excitability. The present data show that three stimulation protocols believed to increase cortical excitability are associated with highly heterogenous and variable aftereffects that may explain a lack of significant group effects.

Stability and test-retest reliability of neuronavigated TMS measures of corticospinal and intracortical excitability.

The present study aimed at investigating the long-term stability and test-retest reliability of neuronavigated transcranial magnetic stimulation (nTMS) measures of cortical excitability, inhibition, and facilitation in the primary motor cortex. To fulfill these aims, thirty-one healthy adults underwent four nTMS sessions, over an average one-month period. Stability and test-retest reliability statistics were computed and analyzed to produce smallest real difference statistics, which indicate the absolute variation in a measurement that is likely to be the result of error (randomness). Excellent reliability was found for resting motor thresholds, which reflect baseline neuronal excitability. Good reliability statistics were found for input/output curve measurements, which reflect the excitability of a highly plastic neuronal population. Using the slope of mean amplitudes throughout the input/output curve or the stimulator intensity required to elicit motor evoked potentials of 1 mV presented good to excellent measurement reliability for global cortical excitability indexing, compared to mean MEP at a given intensity. Overall, this methodological study provides useful and novel information on transcranial magnetic stimulation interventions by providing smallest real difference statistics that inform on potential response thresholds across time, contributing to the validation of these measurements as clinical monitoring tools across time.

Transcranial Magnetic Stimulation and H1-Magnetic Resonance Spectroscopy Measures of Excitation and Inhibition Following Lorazepam Administration.

This study aimed at better understanding the neurochemistry underlying transcranial magnetic stimulation (TMS) and magnetic resonance spectroscopy (MRS) measurements as it pertains to GABAergic activity following administration of allosteric GABAA receptor agonist lorazepam. Seventeen healthy adults (8 females, 26.0 ±â€¯5.4 years old) participated in a double-blind, crossover, placebo-controlled study, where participants underwent TMS and MRS two hours after drug intake (placebo or lorazepam; 2.5 mg). Neuronavigated TMS measures reflecting cortical inhibition and excitation were obtained in the left primary motor cortex. Sensorimotor cortex and occipital cortex MRS data were acquired using a 3T scanner with a MEGA-PRESS sequence, allowing water-referenced [GABA] and [Glx] (glutamate + glutamine) quantification. Lorazepam administration decreased occipital [GABA], decreased motor cortex excitability and increased GABAA-receptor mediated motor cortex inhibition (short intracortical inhibition (SICI)). Lorazepam intake did not modulate sensorimotor [GABA] and TMS measures of intra-cortical facilitation, long-interval cortical inhibition, cortical silent period, and resting motor threshold. Furthermore, higher sensorimotor [GABA] was associated with higher cortical inhibition (SICI) following lorazepam administration, suggesting that baseline sensorimotor [GABA] may be valuable in predicting pharmacological or neuromodulatory treatment response. Finally, the differential effects of lorazepam on MRS and TMS measures, with respect to GABA, support the idea that TMS measures of cortical inhibition reflect synaptic GABAergic phasic inhibitory activity while MRS reflects extrasynaptic GABA.

Ant Foragers Compensate for the Nutritional Deficiencies in the Colony.

Achieving nutritional homeostasis is crucial for the fitness of all living organisms [1]. Using "collective wisdom," ants have been shown to excel at making rapid and appropriate decisions under various contexts [2, 3], including foraging [4-7]. Ants often use pheromone trails to share information about food resources [8-10], a process allowing them to focus their foraging activity on the best food source available [7, 11-14]. However, what constitutes the best food source depends on the nutritional context of the colony in relation to its food environment [15]. In this study, we exposed ant colonies to various nutrient deficiencies and observed their compensatory nutritional responses. Ants were deprived of carbohydrate, sterol, protein, a subset of amino acids, or a single amino acid. We found that ants were rapidly able to match their foraging decisions to their nutritional needs, even if the deficiency concerned a single amino acid. An individual-based model demonstrates that these impressive feats of nutritional compensation can emerge from the iterative process of trail-laying behavior, which relies on a simple individual decision: to eat or not to eat. Our results show that, by adjusting their feeding behavior at the individual level, ants sustain homeostasis at the colony level.

Longitudinal assessment of 1H-MRS (GABA and Glx) and TMS measures of cortical inhibition and facilitation in the sensorimotor cortex.

The purpose of the present study was to investigate the long-term stability of water-referenced GABA and Glx neurometabolite concentrations in the sensorimotor cortex using MRS and to assess the long-term stability of GABA- and glutamate-related intracortical excitability using transcranial magnetic stimulation (TMS). Healthy individuals underwent two sessions of MRS and TMS at a 3-month interval. A MEGA-PRESS sequence was used at 3 T to acquire MRS signals in the sensorimotor cortex. Metabolites were quantified by basis spectra fitting and metabolite concentrations were derived using unsuppressed water reference scans accounting for relaxation and partial volume effects. TMS was performed using published standards. After performing stability and reliability analyses for MRS and TMS, reliable change indexes were computed for all measures with a statistically significant test-retest correlation. No significant effect of time was found for GABA, Glx and TMS measures. There was an excellent ICC and a strong correlation across time for GABA and Glx. Analysis of TMS measure stability revealed an excellent ICC for rMT CSP and %MSO and a fair ICC for 2 ms SICI. There was no significant correlation between MRS and TMS measures at any time point. This study shows that MRS-GABA and MRS-Glx of the sensorimotor cortex have good stability over a 3-month period, with variability across time comparable to that reported in other brain areas. While resting motor threshold, %MSO and CSP were found to be stable and reliable, other TMS measures had greater variability and lesser reliability.

Spatial modeling of daily concentrations of ground-level ozone in Montreal, Canada: A comparison of geostatistical approaches.

Ground-level ozone (O3) is a powerful oxidizing agent and a harmful pollutant affecting human health, forests and crops. Estimating O3 exposure is a challenge because it exhibits complex spatiotemporal patterns. The aim in this study was to provide high-resolution maps (100 × 100 m) of O3 for the metropolitan area of Montreal, Canada. We assessed the kriging with external drift (KED) model to estimate O3 concentration by synoptic weather classes for 2010. We compared these results with ordinary kriging (OK), and a simple average of 12 monitoring stations. We also compared the estimates obtained for the 2010 summer with those from a Bayesian maximum entropy (BME) model reported in the literature (Adam-Poupart et al., 2014). The KED model with road and vegetation density as covariates showed good performance for all six synoptic classes (daily R2 estimates ranging from 0.77 to 0.92 and RMSE from 2.79 to 3.37 ppb). For the summer of 2010, the model using KED demonstrated the best results (R2 = 0.92; RMSE = 3.14 ppb), followed by the OK model (R2 = 0.85, RMSE = 4 ppb). Our results showed that errors appear to be substantially reduced with the KED model. This may increase our capacity of linking O3 levels to health problems by means of improved assessments of ambient exposures. However, future work integrating the temporal dependency in the data is needed to not overstate the performance of the KED model.

BDNF Val66Met polymorphism is associated with altered activity-dependent modulation of short-interval intracortical inhibition in bilateral M1.

The BDNF Val66Met polymorphism is associated with impaired short-term plasticity in the motor cortex, short-term motor learning, and intermanual transfer of a procedural motor skill. Here, we investigated the impact of the Val66Met polymorphism on the modulation of cortical excitability and interhemispheric inhibition through sensorimotor practice of simple dynamic skills with the right and left first dorsal interosseous (FDI) muscles. To that end, we compared motor evoked potentials (MEP) amplitudes and short-interval intracortical inhibition (SICI) in the bilateral representations of the FDI muscle in the primary motor cortex (M1), and interhemispheric inhibition (IHI) from the left to right M1, before and after right and left FDI muscle training in an alternated sequence. Val66Met participants did not differ from their Val66Val counterparts on motor performance at baseline and following motor training, or on measures of MEP amplitude and IHI. However, while the Val66Val group displayed significant SICI reduction in the bilateral M1 in response to motor training, SICI remained unchanged in the Val66Met group. Further, Val66Val group's SICI decrease in the left M1, which was also observed following unimanual training with the right hand in the Control Right group, was correlated with motor improvement with the left hand. The potential interaction between left and right M1 activity during bimanual training and the implications of altered activity-dependent cortical excitability on short-term motor learning in Val66Met carriers are discussed.

Actinic keratosis modelling in mice: A translational study.

BACKGROUND: Actinic keratoses (AK) are pre-malignant cutaneous lesions caused by prolonged exposure to ultraviolet radiation. As AKs lesions are generally accepted to be the initial lesions in a disease continuum that progresses to squamous cell carcinoma (SCC), AK lesions have to be treated. They are also the second most common reason for visits to the dermatologist. Several treatments are available but their efficacy still needs to be improved. The UV-B-induced KA lesion mouse model is used in preclinical studies to assess the efficacy of novel molecules, even though it is often more representative of advanced AK or SCC. OBJECTIVES: Here we report on a translational study, comparing the various stages of AK development in humans and in the UV-B irradiated mouse model, as well as the optimization of photograph acquisition of AK lesions on mouse skin. METHODS: Human and mouse skin lesions were analysed by histology and immunohistochemistry. Mouse lesions were also assessed using a digital dermatoscope. RESULTS: An histological and phenotypic analysis, including p53, Ki67 and CD3 expression detection, performed on human and mouse AK lesions, shows that overall AK modelling in mice is relevant in the clinical situation. Some differences are observed, such as disorganization of keratinocytes of the basal layer and a number of atypical nuclei which are more numerous in human AK, whereas much more pronounced acanthosis is observed in skin lesion in mice. Thanks to this translational study, we are able to select appropriate experimental conditions for establishing either early or advanced stage AK or an SCC model. Furthermore, we optimized photograph acquisition of AK lesions on mouse skin by using a digital dermatoscope which is also used in clinics and allows reproducible photograph acquisition for further reliable assessment of mouse lesions. Use of this camera is illustrated through a pharmacological study assessing the activity of CARAC®. CONCLUSION: These data demonstrate that this mouse model of UV-B-induced skin lesions is predictive for the identification of novel therapeutic treatments for both early and advanced stages of the disease.

Action Video Game Playing Is Reflected In Enhanced Visuomotor Performance and Increased Corticospinal Excitability.

Action video game playing is associated with improved visuomotor performance; however, the underlying neural mechanisms associated with this increased performance are not well understood. Using the Serial Reaction Time Task in conjunction with Transcranial Magnetic Stimulation, we investigated if improved visuomotor performance displayed in action video game players (actionVGPs) was associated with increased corticospinal plasticity in primary motor cortex (M1) compared to non-video game players (nonVGPs). Further, we assessed if actionVGPs and nonVGPs displayed differences in procedural motor learning as measured by the SRTT. We found that at the behavioral level, both the actionVGPs and nonVGPs showed evidence of procedural learning with no significant difference between groups. However, the actionVGPs displayed higher visuomotor performance as evidenced by faster reaction times in the SRTT. This observed enhancement in visuomotor performance amongst actionVGPs was associated with increased corticospinal plasticity in M1, as measured by corticospinal excitability changes pre- and post- SRTT and corticospinal excitability at rest before motor practice. Our results show that aVGPs, who are known to have better performance on visual and motor tasks, also display increased corticospinal excitability after completing a novel visuomotor task.

The percentage of prostate-specific antigen (PSA) isoform [-2]proPSA and the Prostate Health Index improve the diagnostic accuracy for clinically relevant prostate cancer at initial and repeat biopsy compared with total PSA and percentage free PSA in men aged ≤65 years.

OBJECTIVES: To prospectively test the diagnostic accuracy of the percentage of prostate specific antigen (PSA) isoform [-2]proPSA (%p2PSA) and the Prostate Health Index (PHI), and to determine their role for discrimination between significant and insignificant prostate cancer at initial and repeat prostate biopsy in men aged ≤65 years. PATIENTS AND METHODS: The diagnostic performance of %p2PSA and PHI were evaluated in a multicentre study. In all, 769 men aged ≤65 years scheduled for initial or repeat prostate biopsy were recruited in four sites based on a total PSA (t-PSA) level of 1.6-8.0 ng/mL World Health Organization (WHO) calibrated (2-10 ng/mL Hybritech-calibrated). Serum samples were measured for the concentration of t-PSA, free PSA (f-PSA) and p2PSA with Beckman Coulter immunoassays on Access-2 or DxI800 instruments. PHI was calculated as (p2PSA/f-PSA × âˆšt-PSA). Uni- and multivariable logistic regression models and an artificial neural network (ANN) were complemented by decision curve analysis (DCA). RESULTS: In univariate analysis %p2PSA and PHI were the best predictors of prostate cancer detection in all patients (area under the curve [AUC] 0.72 and 0.73, respectively), at initial (AUC 0.67 and 0.69) and repeat biopsy (AUC 0.74 and 0.74). t-PSA and %f-PSA performed less accurately for all patients (AUC 0.54 and 0.62). For detection of significant prostate cancer (based on Prostate Cancer Research International Active Surveillance [PRIAS] criteria) the %p2PSA and PHI equally demonstrated best performance (AUC 0.70 and 0.73) compared with t-PSA and %f-PSA (AUC 0.54 and 0.59). In multivariate analysis PHI we added to a base model of age, prostate volume, digital rectal examination, t-PSA and %f-PSA. PHI was strongest in predicting prostate cancer in all patients, at initial and repeat biopsy and for significant prostate cancer (AUC 0.73, 0.68, 0.78 and 0.72, respectively). In DCA for all patients the ANN showed the broadest threshold probability and best net benefit. PHI as single parameter and the base model + PHI were equivalent with threshold probability and net benefit nearing those of the ANN. For significant cancers the ANN was the strongest parameter in DCA. CONCLUSION: The present multicentre study showed that %p2PSA and PHI have a superior diagnostic performance for detecting prostate cancer in the PSA range of 1.6-8.0 ng/mL compared with t-PSA and %f-PSA at initial and repeat biopsy and for predicting significant prostate cancer in men aged ≤65 years. They are equally superior for counselling patients before biopsy.

Spatio-temporal models to estimate daily concentrations of fine particulate matter in Montreal: Kriging with external drift and inverse distance-weighted approaches.

Air pollution is a major environmental and health problem, especially in urban agglomerations. Estimating personal exposure to fine particulate matter (PM2.5) remains a great challenge because it requires numerous point measurements to explain the daily spatial variation in pollutant levels. Furthermore, meteorological variables have considerable effects on the dispersion and distribution of pollutants, which also depends on spatio-temporal emission patterns. In this study we developed a hybrid interpolation technique that combined the inverse distance-weighted (IDW) method with Kriging with external drift (KED), and applied it to daily PM2.5 levels observed at 10 monitoring stations. This provided us with downscaled high-resolution maps of PM2.5 for the Island of Montreal. For the KED interpolation, we used spatio-temporal daily meteorological estimates and spatial covariates as land use and vegetation density. Different KED and IDW daily estimation models for the year 2010 were developed for each of the six synoptic weather classes. These clusters were developed using principal component analysis and unsupervised hierarchical classification. The results of the interpolation models were assessed with a leave-one-station-out cross-validation. The performance of the hybrid model was better than that of the KED or the IDW alone for all six synoptic weather classes (the daily estimate for R(2) was 0.66-0.93 and for root mean square error (RMSE) 2.54-1.89 µg/m(3)).

Chromosomal rearrangements involving the NTRK1 gene in colorectal carcinoma.

Chromosomal rearrangements of the NTRK1 gene, which encodes the high affinity nerve growth factor receptor (tropomyosin related kinase, TRKA), have been observed in several epithelial cancers, such as colon cancer, papillary thyroid carcinoma or non small cell lung cancer. The various NTRK1 fusions described so far lead to constitutive activation of TRKA kinase activity and are oncogenic. We further investigated here the existence and the frequency of NTRK1 gene rearrangements in colorectal cancer. Using immunohistochemistry and quantitative reverse transcriptase PCR, we analyzed a series of human colorectal cancers. We identified two TRKA positive cases over 408, with NTRK1 chromosomal rearrangements. One of these rearrangements is a TPM3-NTRK1 fusion already observed in colon cancer, while the second one is a TPR-NTRK1 fusion never described in this type of cancer. These findings further confirm that translocations in the NTRK1 gene are recurring events in colorectal cancer, although occurring at a low frequency (around 0.5%).

From prostate-specific antigen (PSA) to precursor PSA (proPSA) isoforms: a review of the emerging role of proPSAs in the detection and management of early prostate cancer.

Despite the popularity of PSA blood testing for prostate cancer, there are a number of important limitations of this popular serum marker including the limited ability to accurately distinguish patients with and without prostate cancer and those who harbour an aggressive form of the disease. This is especially true when the total PSA is <10 ng/mL. Thus, significant efforts have been placed to find new serum markers that can help overcome these limitations. In this review article, we discuss the emerging role of the various precursor forms of PSA (proPSAs), with a special emphasis on [-2]proPSA in the detecion and management of early prostate cancer. The clinical utility of Prostate Health Index (phi) is also discussed. Despite the overall success of prostate-specific antigen (PSA) blood test, its use as a serum marker for prostate cancer has been limited due to the lack of specificity, especially in men presenting with a total PSA (tPSA) level of <10 ng/mL. PSA testing has also resulted in an increase in the number of patients being diagnosed with low-grade, potentially clinically insignificant prostate cancer. There is therefore an urgent need for new markers that can accurately detect as well as differentiate patients with aggressive vs unaggressive prostate cancer. In this review, we discuss the emerging role of precursor forms of PSA (proPSAs) and the Prostate Health Index (phi) measurement in the detection and management of early stage prostate cancer. A literature search was conducted using PubMed® to identify key studies. Studies to date suggest that [-2]proPSA, a truncated form of proPSA is the most cancer-specific form of all, being preferentially expressed in cancerous prostatic epithelium and being significantly elevated in serum of men with prostate cancer. There is evidence to suggest that %[-2]proPSA measurement ([-2]proPSA/free PSA [fPSA] × 100) improves the specificity of both tPSA and fPSA in detecting prostate cancer. phi incorporating [-2]proPSA, fPSA and tPSA measurements has also yielded promising results and appears superior to tPSA and fPSA in predicting those patients with prostate cancer. Increased phi levels also seem to preferentially detect patients harbouring more aggressive disease. Further studies in the form of large, multicentre, prospective trials with detailed health economic analyses are required to evaluate the true clinical applicability of these novel markers.

High visibility pump reconstruction via ultra broadband sum frequency mixing of intense phase-conjugated twin beams.

In this paper we show how after the generation of parametric down-conversion radiation (PDC) in the very high gain pulsed regime, we are able to reconstruct the pump via up-conversion of the twin beams originated from that PDC process. The peculiarity of the experiment is the ultra-broad spectral and angular bandwidth sent into the process of sum frequency mixing thanks to an achromatic imaging technique from the exit face of the PDC crystal using off-axis parabolic mirrors. The recorded spectra presented illustrate the high visibility recombination of the intense phase-conjugated signal and idler beams and pave the way for the investigation of both the spatial and temporal properties of the near field biphoton amplitude.

Measurement of sub-shot-noise correlations of spatial fluctuations in the photon-counting regime.

We have measured sub-shot-noise quantum correlations of spatial fluctuations in the far-field image of the parametric fluorescence created in a type I beta-barium-borate nonlinear crystal. Imaging is performed at very low light level (0.15 photons per pixel) with an electron multiplying charge coupled device camera. Experimental results overcome the standard quantum limit shot-noise level without subtraction of the variance of the detection noise.

Effective signal-to-noise ratio improvement by parametric image amplification.

We show experimentally that parametric optical preamplification greatly improves the signal-to-noise ratio of an image if the detector has a poor quantum efficiency and/or a great level of readout noise. Results are fully consistent with the theory of quantum-noise-limited amplification.

Donitriptan decreases jugular venous oxygen saturation in rats in the absence of cranial vasoconstriction: an overlooked mechanism of antimigraine action?

The aim of the present study was to determine whether donitriptan and sumatriptan decreased jugular venous oxygen saturation and increased carbon dioxide partial pressure in venous blood. However, previous studies conducted with these compounds cannot discriminate whether the decrease of venous oxygen saturation is dependent of cranial vasoconstrictor. In the present study, vehicle (n = 10), donitriptan (2.5, 10, and 40 microg/kg; n = 8) or sumatriptan (630 microg/kg; n = 8) were infused into the carotid artery in the anesthetized rat. Regional blood flows were evaluated in the presence of donitriptan (10 microg/kg; n = 6) or vehicle (n = 6). Jugular venous oxygen saturation was significantly decreased by donitriptan (from 10 microg/kg) with maximal changes of -32.9 +/- 8.0%. Jugular carbon dioxide partial pressure was increased by donitriptan, reaching maximal changes of 17.7 +/- 4.6% (P < 0.05 versus vehicle). Similarly, sumatriptan significantly decreased venous oxygen saturation and increased jugular carbon dioxide partial pressure. These changes induced by donitriptan are abolished by the 5-hydroxytryptamine (5-HT)(1B/1D) receptor antagonist GR 127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2-[-methyl-4(5-methyl-1,2,4)-oxadiazol-3-yl]-(1,1 biphenyl)-4-carboxamide dihydrochloride). In addition, donitriptan was devoid of significant effects on systemic arterial pressure, heart rate, or regional blood flows, including systemic arterial-jugular venous anastomotic, systemic, or cranial. The results demonstrate that donitriptan increases cerebral oxygen consumption by 5-HT(1B/1D) receptor activation in the absence of cranial vasoconstriction.