Practitioner Review: Neurobiological consequences of childhood maltreatment - clinical and therapeutic implications for practitioners.

BACKGROUND: Childhood maltreatment is one of the most important preventable risk factors for a wide variety of psychiatric disorders. Further, when psychiatric disorders emerge in maltreated individuals they typically do so at younger ages, with greater severity, more psychiatric comorbid conditions, and poorer response to established treatments, resulting in a more pernicious course with an increased risk for suicide. Practitioners treating children, adolescents, and young adults with psychiatric disorders will likely encounter the highest prevalence of clients with early-onset maltreatment-associated psychiatric disorders. These may be some of their most challenging cases. METHOD: In this report, we explore key validated alterations in brain structure, function, and connectivity associated with exposure to childhood maltreatment as potential mechanisms behind their patients' clinical presentations. RESULTS: We then summarize key behavioral presentations likely associated with neurobiological alterations and propose a toolkit of established trauma and skills-based strategies that may help diminish symptoms and foster recovery. We also discuss how some of these alterations may serve as latent vulnerability factors for the possible development of future psychopathology. CONCLUSIONS: Research on the neurobiological consequences of childhood adversity provides a vastly enriched biopsychosocial understanding of the developmental origins of health and pathology that will hopefully lead to fundamental advances in clinical psychology and psychiatry.

Immunotherapy in Biliary Tract Cancers: Current Standard-of-Care and Emerging Strategies.

Biliary tract cancers (BTCs), comprising intrahepatic, perihilar, and distal cholangiocarcinoma as well as gallbladder adenocarcinoma, continue to be challenging to manage. Conventional chemotherapy regimens for advanced disease are limited in both options and benefits, and more effective perioperative regimens are also needed. Over the last decade, immunotherapy has had a profound impact on the management of many solid tumor types, particularly in using immune checkpoint inhibition to enable a tumor-directed T cell response. Immunotherapy administered on its own has had limited utility in BTCs, in part due to a hostile immune microenvironment and the relative infrequency of biomarker-based tumor-agnostic indications for immunotherapy. However, immunotherapy in conjunction with chemotherapy, molecularly targeted therapies, and/or anti-angiogenic therapies has gained traction, supported by evidence that these agents can impart favorable immunomodulatory effects on the tumor microenvironment. The TOPAZ-1 trial led to the first BTC-specific immunotherapy approval, establishing the combination of durvalumab with gemcitabine and cisplatin as the preferred first-line treatment for advanced or metastatic disease. Recently, the KEYNOTE-966 trial showed positive results for the combination of pembrolizumab with gemcitabine and cisplatin in the same setting, adding further evidence for the addition of immune checkpoint inhibition to the standard chemotherapy backbone. Meanwhile, advances in the molecular profiling of BTCs has contributed to the recent proliferation of molecularly targeted therapeutics for the subset of BTCs harboring alterations in IDH1, FGFR2, MAP kinase signaling, HER2, and beyond, and there has been great interest in investigating combinations of these agents with immunotherapy. Emerging immunotherapy strategies beyond immune checkpoint inhibition are also being studied in BTCs, and these include immunostimulatory receptor agonists, Wnt signaling modulators, adoptive cell therapy, and cancer vaccines. A large number of trials are underway to explore promising new combinations and immune-targeted strategies, offering opportunities to expand the role of immunotherapy in BTC management in the near future.

A randomized, phase II trial of oral azacitidine (CC-486) in patients with resected pancreatic adenocarcinoma at high risk for recurrence.

BACKGROUND: Of the only 20% of patients with resectable pancreatic ductal adenocarcinoma (rPDA), cancer recurs in 80% of cases. Epigenetic dysregulation is an early hallmark of cancer cells acquiring metastatic potential, and epigenetic modulators may reactivate tumor suppressor genes, delay recurrence, and sensitize PDA to future chemotherapy. METHODS: This was a randomized phase II study (NCT01845805) of CC-486 (oral DNA methyltransferase inhibitor azacitidine) vs. observation (OBS) in rPDA patients harboring high-risk features (stage pN1-2, R1 margins, or elevated CA 19-9 level) with no evidence of disease following standard adjuvant therapy. Patients were randomized to oral CC-486 treatment (300 mg daily on days 1-21 on a 28-day cycle) or OBS for up to 12 cycles or until disease relapse/unacceptable toxicities. Following recurrence, records of next-line therapies, imaging, and survival were obtained. The primary endpoint was progression-free survival (PFS)-time from randomization to recurrence (imaging/biopsy confirmed or death). Secondary endpoints included OS and PFS and ORR and metastatic PFS with subsequent next-line systemic therapy in metastatic setting. RESULTS: Forty-nine patients (24 in CC-486 arm, 25 in OBS arm) were randomized: median age 66 (range 36-81), 53% male, 73% node positive, 49% elevated CA 19-9, 20% R1 resection, 63% and 100% received perioperative concurrent chemoradiation and chemotherapy, respectively. Median time from surgery to randomization was 9.6 mo (range 2.9-36.8). For the CC-486 arm, median treatment duration was 5.6 mo (range 1.3 to 12.8) with 14 treatment-related grade 3 or 4 AEs among 5 patients (22%) resulting in dose-reduction. Four patients (17%) discontinued therapy due to AEs. With median follow-up of 20.3mo (IQR 12.8, 41.4), 38 (79%) of evaluable patients recurred (34 imaging-confirmed, 4 clinically). Median PFS in imagining-confirmed cases was 9.2 and 8.9mo (HR 0.94, 95% CI 0.46-1.87, p = 0.85) for CC-486 and OBS patients, respectively. Median OS (2-yr OS%) was 33.8 (50%) and 26.4 mo (61%) in CC-486 and OBS patients, respectively. (HR 0.98, 95% CI 0.46-2.05, p = 0.96). ORR with subsequent chemotherapy in the metastatic setting was minimal in both arms. CONCLUSIONS: Treatment with CC-486 following adjuvant therapy did not prolong time-to-relapse in patients with high-risk rPDA or improve disease response on 1st-line metastatic therapy.

The effects of bovine colostrum supplementation on in vivo immunity following prolonged exercise: a randomised controlled trial.

BACKGROUND: Bovine colostrum (COL) has been advocated as a nutritional countermeasure to exercise-induced immune dysfunction, but there is a lack of research with clinically relevant in vivo measures. AIM: To investigate the effects of COL supplementation on in vivo immunity following prolonged exercise using experimental contact hypersensitivity (CHS) with the novel antigen diphenylcyclopropenone (DPCP). METHODS: In a double-blind design, 31 men were randomly assigned to COL (20 g/day) or placebo (PLA) for 58 days. Participants ran for 2 h at 60% maximal aerobic capacity on day 28 and received a primary DPCP exposure (sensitisation) 20 min after. On day 56, participants received a low-dose-series DPCP challenge to elicit recall of in vivo immune-specific memory (quantified by skinfold thickness 24 and 48 h later). Analysis of the dose-response curves allowed determination of the minimum dose required to elicit a positive response (i.e., sensitivity). RESULTS: There was no difference in summed skinfold thickness responses between COL and PLA at 24 h (p = 0.124) and 48 h (p = 0.405). However, sensitivity of in vivo immune responsiveness was greater with COL at 24 h (p < 0.001) and 48 h (p = 0.023) with doses ~ twofold greater required to elicit a positive response in PLA. CONCLUSIONS: COL blunts the prolonged exercise-induced decrease in clinically relevant in vivo immune responsiveness to a novel antigen, which may be a mechanism for reduced illness reports observed in the previous studies. These findings also suggest that CHS sensitivity is highly relevant to host defence.

Intelligence and eeg measures of information flow: efficiency and homeostatic neuroplasticity.

The purpose of this study was to explore the relationship between the magnitude of EEG information flow and intelligence. The electroencephalogram (EEG) was recorded from 19 scalp locations from 371 subjects ranging in age from 5 years to 17.6 years. The Wechler Intelligence Scale for Children (WISC-R) was administered for individuals between 5 years of age and 16 years and the Weschler Adult Intelligence Scale revised (WAIS-R) was administered to subjects older than 16 years to estimate I.Q. The phase slope index estimated the magnitude of information flow between all electrode combinations for difference frequency bands. Discriminant analyses were performed between high I.Q. (>120) and low I.Q. groups (<90). The magnitude of information flow was inversely related to I.Q. especially in the alpha and beta frequency bands. Long distance inter-electrode distances exhibited greater information flow than short inter-electrode distances. Frontal-parietal correlations were the most significant. It is concluded that higher I.Q. is related to increased efficiency of local information processing and reduced long distance compensatory dynamics that supports a small-world model of intelligence.

CD30+ Cutaneous T Cell Lymphoma: Response to Rotational Total Skin Electron Irradiation.

INTRODUCTION: Rotational total skin electron irradiation (RTSEI) is an effective therapy for cutaneous T cell lymphoma (CTCL). CD30 expression has been identified as a prognostic factor in CTCL. Therefore, we investigated CD30 status, treatment response, and survival in our cohort of patients with CTCL treated with RTSEI. METHODS: Patients with CTCL treated with RTSEI (≥30 Gy) between 2000 and 2013 at our institution were identified, and clinical and pathologic data were retrospectively reviewed. Primary outcomes were complete clinical response (CCR; >90% reduction of skin disease burden), relapse-free survival (RFS), and overall survival (OS). RESULTS: Sixty-eight patients with CTCL treated with RTSEI were identified. Median age at diagnosis was 51 years with median follow-up of 61 months. Median OS was 76 months and median RFS was 11 months. Thirteen patients (19%) had CD30+ lymphocytes on initial pathology. In the CD30+ cohort, there were no T2, eight T3, and five T4 cases. In comparison, in the CD30- cohort, there were 18 T2, 29 T3, and 8 T4 cases (P = 0.01). Six weeks post-RTSEI, CCR was 85% in CD30+ and 81% in CD30- cases (P = 1). Six months post-RTSEI, CCR was 23% in CD30+ and 50% in CD30- cases (P = 0.083). CONCLUSION: RTSEI resulted in excellent CCR at 6 weeks in our cohort of patients with CTCL, with a median RFS of 11 months. We found CD30+ patients presented with significantly higher T stage at time of RTSEI and trended towards decreased CCR at 6 months post-RTSEI compared with the CD30- group.

Influence of 4 weeks of bovine colostrum supplementation on neutrophil and mucosal immune responses to prolonged cycling.

Bovine colostrum (COL) has been advocated as a nutritional countermeasure to exercise-induced immune dysfunction. The aims of this study were to identify the effects of 4 weeks of COL supplementation on neutrophil responses and mucosal immunity following prolonged exercise. In a randomized double-blind, parallel group design, participants [age 28 ± 8 years; body mass 79 ± 7 kg; height 182 ± 6 cm; maximal oxygen uptake (V̇O2max) 55 ± 9 mL/kg/min] were assigned to 20 g per day of COL (n = 10) or an isoenergetic/isomacronutrient placebo (PLA; n = 10) for 4 weeks. Venous blood and unstimulated saliva samples were obtained before and after 2.5 h of cycling at 15% Δ (∼55-60% V̇O2max). A significantly greater formyl-methionyl-leucyl phenylalanine-stimulated oxidative burst was observed in the COL group compared with PLA group (P < 0.05) and a trend toward a time × group interaction (P = 0.06). However, there was no effect of COL on leukocyte trafficking, phorbol-12-myristate-13-acetate-stimulated oxidative burst, bacterial-stimulated neutrophil degranulation, salivary secretory IgA, lactoferrin or lysozyme (P > 0.05). These findings provide further evidence of the beneficial effects of COL on receptor-mediated stimulation of neutrophil oxidative burst in a model of exercise-induced immune dysfunction.

Total skin electron therapy for cutaneous T-cell lymphoma using a modern dual-field rotational technique.

PURPOSE: To report our experience with rotational total skin electron irradiation (RTSEI) in cutaneous T-cell lymphoma (CTCL), and to examine response by disease stage and race. METHODS AND MATERIALS: We reviewed our outcomes for 68 CTCL patients who received RTSEI (≥ 30 Gy) from 2000 to 2013. Primary outcomes were complete clinical response (CCR), recurrence-free survival (RFS), and overall survival (OS). Using log-rank tests and Cox proportional hazards, OS and RFS were compared across tumor stages at time of RTSEI with further racial subgroup analysis. RESULTS: Median age at diagnosis and at time of radiation was 52 and 56 years, respectively. Median follow-up was 5.1 years, 49% were African American, and 49% were female. At time of treatment, 18, 37, and 13 patients were T stage 2, 3, and 4, respectively. At 6 weeks after RTSEI, overall CCR was 82% (88%, 83%, and 69% for T2, T3, and T4, respectively). Median RFS was 11 months for all patients and 14, 10, and 12 months for stage T2, T3, and T4, respectively. Tumor stage was not associated with RFS or CCR. Maintenance therapy after RTSEI was associated with improved RFS in both crude and multivariable analysis, controlling for T stage. Median OS was 76 months (91 and 59 months for T3 and T4, respectively). With the exception of improved OS in African Americans compared with whites at stage T2, race was not associated with CCR, RFS, or OS. CONCLUSIONS: These results represent the largest RTSEI clinical outcomes study in the modern era using a dual-field rotational technique. Our observed response rates match or improve upon the standard set by previous outcome studies using conventional TSEI techniques, despite a large percentage of advanced CTCL lesions in our cohort. We found that clinical response after RTSEI did not seem to be affected by T stage or race.

Bone marrow-derived angiogenic cells restore lung alveolar and vascular structure after neonatal hyperoxia in infant mice.

Neonatal hyperoxia impairs vascular and alveolar growth in mice and decreases endothelial progenitor cells. To determine the role of bone marrow-derived cells in restoration of neonatal lung structure after injury, we studied a novel bone marrow myeloid progenitor cell population from Tie2-green fluorescent protein (GFP) transgenic mice (bone marrow-derived angiogenic cells; BMDAC). We hypothesized that treatment with BMDAC would restore normal lung structure in infant mice during recovery from neonatal hyperoxia. Neonatal mice (1-day-old) were exposed to 80% oxygen for 10 days. BMDACs (1 x 10(5)), embryonic endothelial progenitor cells, mouse embryonic fibroblasts (control), or saline were then injected into the pulmonary circulation. At 21 days of age, saline-treated mice had enlarged alveoli, reduced septation, and a reduction in vascular density. In contrast, mice treated with BMDAC had complete restoration of lung structure that was indistinguishable from room air controls. BMDAC comprised 12% of distal lung cells localized to pulmonary vessels or alveolar type II (AT2) cells and persist (8.8%) for 8 wk postinjection. Coculture of AT2 cells or lung endothelial cells (luEC) with BMDAC augmented AT2 and luEC cell growth in vitro. We conclude that treatment with BMDAC after neonatal hyperoxia restores lung structure in this model of bronchopulmonary dysplasia.

Intelligence and EEG phase reset: a two compartmental model of phase shift and lock.

OBJECTIVES: The purpose of this study was to explore the relationship between EEG phase reset and performance on the Wechsler Intelligence test. METHODS: The electroencephalogram (EEG) was recorded from 19 scalp locations from 378 subjects ranging in age from 5 years to 17.6 years. The Wechsler Intelligence test (WISC-R) was administered to the same subjects on the same day but not while the EEG was recorded. Complex demodulation was used to compute instantaneous EEG phase differences between pairs of electrodes and the 1st and 2nd derivatives were used to measure phase reset by phase shift duration and phase lock duration. The dependent variable was full scale I.Q. and the independent variables were phase shift duration (SD) and phase lock duration (LD) with age as a covariate. RESULTS: Phase shift duration (40-90 ms) was positively related to intelligence (P<.00001) and the phase lock duration (100-800 ms) was negatively related to intelligence (P<.00001). Phase reset in short interelectrode distances (6 cm) was more highly correlated to I.Q. (P<.0001) than in long distances (>12 cm). CONCLUSIONS: The duration of unstable phase dynamics and phase locking represent a bounded optimization process, for example, too long a duration of phase locking then less flexibility and too short of a phase shift then reduced neural resources. A two compartmental model of local field coupling and neuron synchrony to a preferred phase was developed to explain the findings.

Spatial-temporal current source correlations and cortical connectivity.

The purpose of this study was to explore spatial-temporal correlations between 3-dimensional current density estimates using Low Resolution Electromagnetic Tomography (LORETA). The electroencephalogram (EEG) was recorded from 19 scalp locations from 97 subjects. LORETA current density was computed for 2,394 gray matter pixels. The gray matter pixels were grouped into 33 left hemisphere and 33 right hemisphere regions of interest (ROIs) based on groupings of Brodmann areas. The average source current density in a given region of interest (ROI) was computed for each 2 second epoch of EEG and then a Pearson product correlation coefficient was computed over the time series of successive 2 second epochs of current density between all pairwise combinations of ROIs during the resting eyes-closed EEG session. Rhythmic changes in source correlation as a function of distance were present in all regions of interest. Also, maximum correlations at certain frequencies were present independent of distance. The occipital regions exhibited the highest short distance correlations and the frontal regions exhibited the highest long distance correlations. In general, the right hemisphere exhibited higher intra-hemispheric source correlations than the left hemisphere especially in the temporal, parietal and occipital cortex. The strongest left vs. right hemisphere differences were in the alpha frequency band (8-12 Hz) and in the gamma frequency band (37-40 Hz). The pattern of spatial frequencies in different cortical lobules is consistent with differences in neural packing density and the operation of 'U' shaped fiber systems. The general conclusions were: 1--the higher the packing density then the greater the intra-cortical connection contribution to LORETA source correlations, 2--spatial frequencies are primarily due to intra-cortical 'U' shaped fiber connections and long distance fiber connections, 3--posterior and temporal cortical intra-hemispheric coupling is generally stronger in the right hemisphere than in the left hemisphere.

Intelligence and EEG current density using low-resolution electromagnetic tomography (LORETA).

The purpose of this study was to compare EEG current source densities in high IQ subjects vs. low IQ subjects. Resting eyes closed EEG was recorded from 19 scalp locations with a linked ears reference from 442 subjects ages 5 to 52 years. The Wechsler Intelligence Test was administered and subjects were divided into low IQ (< or =90), middle IQ (>90 to <120) and high IQ (> or =120) groups. Low-resolution electromagnetic tomographic current densities (LORETA) from 2,394 cortical gray matter voxels were computed from 1-30 Hz based on each subject's EEG. Differences in current densities using t tests, multivariate analyses of covariance, and regression analyses were used to evaluate the relationships between IQ and current density in Brodmann area groupings of cortical gray matter voxels. Frontal, temporal, parietal, and occipital regions of interest (ROIs) consistently exhibited a direct relationship between LORETA current density and IQ. Maximal t test differences were present at 4 Hz, 9 Hz, 13 Hz, 18 Hz, and 30 Hz with different anatomical regions showing different maxima. Linear regression fits from low to high IQ groups were statistically significant (P < 0.0001). Intelligence is directly related to a general level of arousal and to the synchrony of neural populations driven by thalamo-cortical resonances. A traveling frame model of sequential microstates is hypothesized to explain the results.

Comparison of the Lactate Pro and Analox GM7 blood lactate analysers.

The purpose of this study was firstly, to determine the level of agreement between the Lactate Pro and Analox GM7 for the measurement of blood lactate, and secondly, to examine whether these analysers may be used interchangeably to identify lactate parameters routinely used in the physiological assessment of athletes. Twenty well-trained male cyclists performed an incremental cycle ergometry test; duplicate blood samples were taken simultaneously throughout the test for lactate determination using the two analysers. Power output and heart rate at LT, LT1, 2 mmol.L-1, and 4 mmol.L-1 were calculated from the lactate values obtained from the two analysers. There was a strong linear relationship between the two analysers (Lactate Pro=1.4541xAnalox GM7-0.1287; R2=0.969, p<0.001; SEE=0.704) though the Lactate Pro overestimated blood lactate when compared to the Analox GM7; 95% ratio limits of agreement (Lactate Pro/Analox GM7) were 1.40x//1.35. Differences were found between analysers for power output and heart rate at LT1 (p<0.01), 2 mmol.L-1 (p<0.001), and 4 mmol.L-1 (p<0.001); no differences were found between analysers for power output or heart rate at LT. In conclusion, the average difference in blood lactate concentration measured by the Lactate Pro and the Analox GM7 was 40%, with 95% of measures differing by between 4% and 89%. This poor level of agreement and the significant differences between the two analysers in power output and heart rate associated with a number of lactate parameters indicate that these analysers should not be used interchangeably.

Evaluation and validity of a LORETA normative EEG database.

To evaluate the reliability and validity of a Z-score normative EEG database for Low Resolution Electromagnetic Tomography (LORETA), EEG digital samples (2 second intervals sampled 128 Hz, 1 to 2 minutes eyes closed) were acquired from 106 normal subjects, and the cross-spectrum was computed and multiplied by the Key Institute's LORETA 2,394 gray matter pixel T Matrix. After a log10 transform or a Box-Cox transform the mean and standard deviation of the *.lor files were computed for each of the 2394 gray matter pixels, from 1 to 30 Hz, for each of the subjects. Tests of Gaussianity were computed in order to best approximate a normal distribution for each frequency and gray matter pixel. The relative sensitivity of a Z-score database was computed by measuring the approximation to a Gaussian distribution. The validity of the LORETA normative database was evaluated by the degree to which confirmed brain pathologies were localized using the LORETA normative database. Log10 and Box-Cox transforms approximated Gaussian distribution in the range of 95.64% to 99.75% accuracy. The percentage of normative Z-score values at 2 standard deviations ranged from 1.21% to 3.54%, and the percentage of Z-scores at 3 standard deviations ranged from 0% to 0.83%. Left temporal lobe epilepsy, right sensory motor hematoma and a right hemisphere stroke exhibited maximum Z-score deviations in the same locations as the pathologies. We conclude: (1) Adequate approximation to a Gaussian distribution can be achieved using LORETA by using a log10 transform or a Box-Cox transform and parametric statistics, (2) a Z-Score normative database is valid with adequate sensitivity when using LORETA, and (3) the Z-score LORETA normative database also consistently localized known pathologies to the expected Brodmann areas as an hypothesis test based on the surface EEG before computing LORETA.

EEG and intelligence: relations between EEG coherence, EEG phase delay and power.

OBJECTIVE: There are two inter-related categories of EEG measurement: 1, EEG currents or power and; 2, EEG network properties such as coherence and phase delays. The purpose of this study was to compare the ability of these two different categories of EEG measurement to predict performance on the Weschler Intelligence test (WISC-R). METHODS: Resting eyes closed EEG was recorded from 19 scalp locations with a linked ears reference from 442 subjects aged 5-52 years. The Weschler Intelligence test was administered to the same subjects but not while the EEG was recorded. Subjects were divided into high IQ (> or = 120) and low IQ (< or = 90) groups. EEG variables at P<.05 were entered into a factor analysis and then the single highest loading variable on each factor was entered into a discriminant analysis where groups were high IQ vs. low.Q. RESULTS: Discriminant analysis of high vs. low IQ was 92.81-97.14% accurate. Discriminant scores of intermediate IQ subjects (i.e. 90 < IQ < 120) were intermediate between the high and low IQ groups. Linear regression predictions of IQ significantly correlated with the discriminant scores (r = 0.818-0.825, P < 10(-6)). The ranking of effect size was EEG phase > EEG coherence > EEG amplitude asymmetry > absolute power > relative power and power ratios. The strongest correlations to IQ were short EEG phase delays in the frontal lobes and long phase delays in the posterior cortical regions, reduced coherence and increased absolute power. CONCLUSIONS: The findings are consistent with increased neural efficiency and increased brain complexity as positively related to intelligence, and with frontal lobe synchronization of neural resources as a significant contributing factor to EEG and intelligence correlations. SIGNIFICANCE: Quantitative EEG predictions of intelligence provide medium to strong effect size estimates of cognitive functioning while simultaneously revealing a deeper understanding of the neurophysiological substrates of intelligence.

Parametric vs. non-parametric statistics of low resolution electromagnetic tomography (LORETA).

This study compared the relative statistical sensitivity of non-parametric and parametric statistics of 3-dimensional current sources as estimated by the EEG inverse solution Low Resolution Electromagnetic Tomography (LORETA). One would expect approximately 5% false positives (classification of a normal as abnormal) at the P < .025 level of probability (two tailed test) and approximately 1% false positives at the P < .005 level. EEG digital samples (2 second intervals sampled 128 Hz, 1 to 2 minutes eyes closed) from 43 normal adult subjects were imported into the Key Institute's LORETA program. We then used the Key Institute's cross-spectrum and the Key Institute's LORETA output files (*.lor) as the 2,394 gray matter pixel representation of 3-dimensional currents at different frequencies. The mean and standard deviation *.lor files were computed for each of the 2,394 gray matter pixels for each of the 43 subjects. Tests of Gaussianity and different transforms were computed in order to best approximate a normal distribution for each frequency and gray matter pixel. The relative sensitivity of parametric vs. non-parametric statistics were compared using a "leave-one-out" cross validation method in which individual normal subjects were withdrawn and then statistically classified as being either normal or abnormal based on the remaining subjects. Log10 transforms approximated Gaussian distribution in the range of 95% to 99% accuracy. Parametric Z score tests at P < .05 cross-validation demonstrated an average misclassification rate of approximately 4.25%, and range over the 2,394 gray matter pixels was 27.66% to 0.11%. At P < .01 parametric Z score cross-validation false positives were 0.26% and ranged from 6.65% to 0% false positives. The non-parametric Key Institute's t-max statistic at P < .05 had an average misclassification error rate of 7.64% and ranged from 43.37% to 0.04% false positives. The nonparametric t-max at P < .01 had an average misclassification rate of 6.67% and ranged from 41.34% to 0% false positives of the 2,394 gray matter pixels for any cross-validated normal subject. In conclusion, adequate approximation to Gaussian distribution and high cross-validation can be achieved by the Key Institute's LORETA programs by using a log10 transform and parametric statistics, and parametric normative comparisons had lower false positive rates than the non-parametric tests.

Development and validation of a sport-specific exercise protocol for elite youth soccer players.

AIM: The aims of the current study were, firstly, to quantify the motion characteristics of professional youth soccer players and, secondly, to develop and validate a soccer-specific exercise protocol (SSEP). METHODS: The motion characteristics of 12 first team members and 12 scholars (under 19s), signed to an English Premiership club were determined via motion analysis. Motion profiles from the analysis were then used to develop a SSEP for a non-motorised treadmill. Validity of the protocol was checked with 6, healthy, male soccer players who completed the SSEP and, on a separate occasion, a soccer match. Heart rates were recorded during both trials, in addition, capillary blood and expired air samples were taken, and RPE recorded, during the SSEP. RESULTS: Youth team players covered 10274+/-609 m, compared to 9741+/-882 m by the first team players (t=1.72, p>0.05; 95% CI for the difference = -1174 m to 109 m). The trend for greater mean distance covered by youth players could be attributed to the distances covered while jogging and running. Mean heart rate response was 166+/-9 beatsxmin(-1) during match play and 166+/-12 beatsxmin(-1) during the SSEP (t=0.164, p>0.05). Mean .VO(2) during the SSEP was 70+/-3% of .VO(2max). Blood lactate concentration fell from a mean value of 5.37+/-1.15 mmol x L(-1) during the first half to 4.74+/-1.25 mmol x L(-1) during the 2(nd) half (t=2.52, p<0.05). CONCLUSION: The findings of this study suggest that the protocol developed induced a similar physiological load to soccer match play and provides the opportunity to study the physiological demands of soccer.

Gender differences in the pre-competition temporal patterning of anxiety and hormonal responses.

AIM: This study examined gender differences in the pre-competition temporal patterning of anxiety and hormonal responses. METHODS: Six male and 6 female field hockey players completed the modified Competitive State Anxiety Inventory-2, including both intensity and direction subscales, and provided saliva and urine samples 24, 2, and 1 hour prior to competition. These samples were analyzed for cortisol, and noradrenaline and adrenaline, respectively. RESULTS: Two x 3 repeated measures ANOVAs revealed significant gender x time interactions for cognitive and somatic anxiety intensity and adrenaline and noradrenaline, but not cortisol. While males' anxiety and hormonal responses demonstrated no significant changes, significant increases in females' anxiety, and significant decreases in their adrenaline and noradrenaline were observed over time. Moreover, while males' anxiety and hormonal responses mirrored each other, this was not the case for the females with increases in females' cognitive and somatic anxiety intensity levels accompanied by decreases in adrenaline and noradrenaline. CONCLUSIONS: Although this study has extended this line of research by adopting a psycho-physiological approach and measuring anxiety intensity and direction in male and female athletes, replication is required with larger samples from a greater diversity of sports.