The value of instability: an investigation of intrasubject variability in brain activity among obese adolescent girls.

BACKGROUND: The present study investigated the value of intrasubject variability (ISV) as a metric for revealing differences in cognition and brain activation associated with an obese versus lean body mass. METHODS: Ninety-six adolescents with a lean body mass (body mass index (BMI) percentile=5-85), and 92 adolescents with an obese body mass (BMI percentile ⩾95), performed two tasks (Stroop and Go/No-Go) challenging response inhibition skills. The s.d. values and averages of their reaction time and P300 electroencephalographic responses to task stimuli were computed across trials. RESULTS: During the Go/No-Go task, the reaction times of subjects with an obese body mass were more variable than those of their lean body mass peers. Accompanying the greater ISV in reaction times was a group difference in P300 amplitude ISV in the opposite direction across both tasks. The effect sizes associated with these group differences in ISV were marginally greater than the effect sizes for the comparisons of the group means. CONCLUSIONS: ISV may be superior to the mean as a tool for differentiating groups without significant cognitive impairment. The co-occurrence of reduced ISV in P300 amplitude and elevated ISV in reaction time may indicate a constraint among obese adolescent girls in the range of information processing strategies and neural networks that can compete to optimize response output. It remains to be determined whether this decrement in neural plasticity has implications for their problem solving skills as well as their response to weight management interventions.

Effects of sulfonylurea derivatives on ischemia-induced loss of function in the isolated rat heart.

This study determined whether sulfonylurea derivatives affect cardiac function prior to and after a mild ischemic incident (stunning). This was investigated using an isolated, erythrocyte-perfused, working rat heart model. In total, 11 groups were studied: five increasing (clinically relevant) concentrations of the classical glibenclamide (range 0.005-4 micromol l(-1)), five increasing concentrations of the newly developed glimepiride (range 0.005-0.8 micromol l(-1)), and one control group. Pre-ischemically, glibenclamide and glimepiride reduced coronary blood flow concentration dependently to 55.2+/-4.5% and 58.5+/-5.5%, respectively (P<0.001). Twenty minutes after a 12-min ischemic incident, these reductions of flow were even more pronounced (to 38.3+/-6.7% and 45.8+/-5.8%, P<0.001). This shows that both sulfonylureas reduce coronary blood flow at concentrations slightly higher than therapeutic ones. In the control group, the ischemic incident significantly lowered cardiac function by 22.2+/-2.9%. In the therapeutic range, glimepiride, but not glibenclamide, significantly reduced this ischemia-induced cardiac functional loss to 4.9+/-1.2% (P<0.01). Therefore, we suggest that both sulfonylureas and in particular glimepiride can be used safely in patients with type 2 diabetes mellitus, as long as the coronary vascular system is not compromised. Because of the obvious vasocontrictor response to sulfonylurea derivatives, these drugs must be used with caution in patients with a reduced coronary reserve.

Prenatal fumonisin (FB1) treatment in rats results in minimal maternal or offspring toxicity.

To investigate the neurobehavioral and developmental effects of the mycotoxin, FB1, Sprague-Dawley rats were treated with FB1 on gestational days 13-20. In Experiment 1, FB1 was obtained from culture material and pregnant rats were gavaged with 0, 0.8 or 1.6 mg/kg. In Experiment 2, pregnant rats were gavaged with purified FB1 at doses of 0, 1.6 or 9.6 mg/kg. Offspring were evaluated on a battery of behavioral tests as well as measures of whole and regional brain weight. There were no effects on maternal weight gain, reproductive outcomes, or offspring body weight through adulthood in either experiment. Complex maze performance, open field and running wheel activity were not altered by prenatal FB1 treatment. In Experiment 2, acoustic startle response was depressed at two ages during the first or second block of 9 trials in males treated with purified FB1. Females exhibited no such alterations. Play behavior at PND 33, but not PND 26, was increased in males prenatally treated with 9.6 mg/kg relative to those treated with 1.6 mg/kg. There were no substantive treatment effects on regional brain weight. These results suggest that doses of < or = 9.6 mg purified FB1/kg and/or < or = 1.6 mg FB1/kg obtained from culture material cause minimal maternal toxicity and produce few development functional alterations. In addition, potential FB1-related functional alterations were evident only in males providing further support for a mild sex-specific effect for fumonisin.

Impact of threat relevance on P3 event-related potentials in combat-related post-traumatic stress disorder.

The purpose of this study was to examine electrophysiological response to trauma-relevant stimuli in combat-related post-traumatic stress disorder (PTSD). Study design incorporated comparison of 10 Vietnam War veterans with PTSD diagnosis to 10 Vietnam War veterans with no mental disorder diagnosis on P3 components in a series of two oddball tasks (trauma-relevant threat, trauma-irrelevant threat) counterbalanced for order. Each task included high probability emotionally neutral distractor words and low probability neutral target words, but differed in the content of low probability threat words. Whereas threat words in the trauma-relevant oddball task pertained directly to combat trauma, threat words in the trauma-irrelevant oddball task were socially threatening words. Results revealed that, in comparison to healthy combat veterans, those diagnosed with PTSD demonstrated: (a) attenuated P3 response to neutral target items at selected electrode sites across both oddball tasks; and (b) increased responsivity to trauma-relevant combat stimuli but not to trauma-irrelevant social-threat stimuli at frontal electrode sites (F3, F4). Results are consistent with resource allocation models of PTSD, which suggest that PTSD is characterized by attentional bias to threat stimuli at the expense of attention to emotionally neutral information.

A double-blind placebo-controlled crossover study of phenytoin in individuals with impulsive aggression.

The present study examines the behavioral and psychophysiological effects of phenytoin (PHT) in individuals who display impulsive-aggressive outbursts. In a double-blind placebo-controlled crossover design, individuals meeting previously established criteria for impulsive aggression were administered PHT and placebo during separate 6-week conditions. The efficacy measures used were the Overt Aggression Scale (OAS) and the Profile of Mood States (POMS). Psychophysiological measures (evoked potentials) were taken at baseline and at the end of each 6-week condition. Photic stimulation was used to evoke the mid-latency P1-N1-P2 waveform complex. Analysis indicated a significant decrease in the frequency of impulsive-aggressive outbursts during PHT administration compared to baseline and placebo. Analysis of the psychophysiological data showed significantly increased P1 amplitude and significantly longer N1 latency during PHT administration. In addition, a reduction in N1 amplitude during PHT administration was also suggested. These findings indicate reparation of physiological abnormalities previously observed in impulsive-aggressive individuals and imply more efficient sensory processing and effective orienting of attention. Taken together, these results provide insight as to the physiological mechanisms by which PHT serves to ameliorate impulsive-aggressive behavior.

Mid-latency evoked potentials in self-reported impulsive aggression.

The present study was conducted to examine psychophysiological differences in arousability among individuals who display impulsive aggressive outbursts. Amplitude and latency for the mid-latency evoked potentials (P1, N1 and P2) were obtained at scalp electrode sites. The evoking stimuli were three intensities (low, medium, high) of photic stimulation. Compared to non-aggressive controls, impulsive aggressive subjects showed significantly reduced P1 amplitude, which is indicative of an inefficient sensory gating mechanism. In addition, these subjects exhibited significantly larger N1 amplitude implying an enhanced orienting of attention to stimuli. Impulsive aggressive subjects also exhibited shorter P1, N1 and P2 peak latency. These results suggest that impulsive aggressive individuals may display quicker orienting and processing of stimuli in an attempt to compensate for low resting arousal levels. Finally, impulsive aggressive subjects augmented the P1-N1 component more frequently than controls, which is consistent with previous studies examining impulsivity and sensation seeking. Together, these findings extend previous work concerning the underlying physiology of impulsive aggression. It has been suggested that impulsive aggressive individuals may attempt to compensate for low resting arousal levels by engaging in stimulus seeking behaviors. Accordingly, the present findings imply similar physiological compensatory responses as demonstrated by heightened orienting of attention, processing and arousability. In addition, a compromised sensory gating system in impulsive aggressors may exacerbate such circumstances, and lead to later cognitive processing deficits.

Coronary flow response after myocardial ischemia may predict level of functional recovery.

Is there a quantity, potentially measurable in the operating theater, which predicts rapid recovery of heart power output after surgical intervention with ischemia? We have enhanced our blood-perfused, ejecting, isolated rat heart model for use inside the magnet of an NMR spectrometer, in order to conduct fundamental research into cardioprotective techniques. To provide a baseline, we investigated the effect of normothermic ischemic insults of varying duration. Hemodynamic and metabolic data were collected, and analyzed to seek measures predictive of rapid recovery of aortic power output, which was selected as the most important measure of function. The presence of erythrocytes in the perfusate ensures that oxygen supply is sufficient to support a physiological workload, and that there is reserve coronary flow. On reperfusion, reactive hyperemia occurs: coronary flow increases to a peak, then declines to a steady value. This response was mathematically modeled, and the data for each of fifteen experiments were fitted to the model. Correlating power output recovery against time to reach peak coronary flow yielded the following equation: R = -0.45 log10tp + 1.74 where R is the ratio of power output ten minutes after reperfusion to that before the ischemic insult, and tp is the time taken to reach peak coronary flow, in seconds. The correlation is very significant (p = 0.005). In the clinic, coronary flow response on reperfusion could be used to predict the patient's need for post-operative support.

Hemodynamic changes caused by glibenclamide in isolated, working, erythrocyte perfused rat heart.

Glibenclamide-induced cardiac hemodynamic changes before and after ischemia have been frequently studied. In general a Langendorff buffer perfused heart model was used to examine these effects. However these models used protein-free buffer perfusates. To improve clinical relevance and thereby enhance extrapolation to the in vivo condition we studied the effects of glibenclamide on cardiac hemodynamics using a working, erythrocyte perfused, rat heart model, where the perfusate was enriched with albumin. The results show a dose-dependent decline in CBF in normoxia and at the end of reperfusion (after an ischemic period) with glibenclamide treatment compared to control. Cardiac functional recovery improved with 1 and 4 mumol.L-1 glibenclamide concentrations. From this study it seems that there is a marked decrease in CBF but this did not result in impaired myocardial function after a period of ischemia, so it appears that there are no startling side effects of glibenclamide in the ischemic rat heart.

Post-ischemic 31P NMR determination of myocardial intracellular pH in vivo using ATP peak.

31P NMR allows non-invasive measurement of intracellular pH, which drops during tissue hypoxia or ischemia. Determination is usually based on the chemical shift between the inorganic phosphate (P(i)) and phosphocreatine (PCr) peaks. During reperfusion, P(i) is taken up to form PCr and ATP, and in our model at least (an isolated, working rat heart perfused with an erythrocyte suspension), the level of P(i) reduces well below the pre-ischemic level, making pH determination difficult. The chemical shifts of the three ATP peaks also depend on pH, and the level of ATP remains high during reperfusion, so these might be used to determine pH. The results of one experiment are presented in detail, showing the time course of high energy phosphate levels before, during and after a 32 min ischemic insult, and close agreement between the pH determinations from the Pi and gamma-ATP peaks can be seen. The formula used to calculate pH from the ATP peak was: pH (ATP) = 0.59 delta 2-5.0 delta + 15.9 where delta is the shift in ppm between PCr and gamma-ATP. All pH readings by both methods from a series of seven experiments were compared and a 1:1 agreement demonstrated (correlation coefficient 0.63, p < 0.0001). Although the ATP shifts also depend on magnesium complexation which we have ignored, this appears to be justifiable within the errors of the method; the good agreement between the results of the two methods, and the ability to determine pH during reperfusion suggest that calculation of intracellular pH from the chemical shift of gamma-ATP is a useful technique.

Metformin improves cardiac functional recovery after ischemia in rats.

The biguanide, metformin, is widely used for the treatment of type 2 diabetes mellitus. In the recently published United Kingdom Prospective Diabetes Study (UKPDS), it was shown that the use of metformin was associated with a reduction of macrovascular complications compared to other blood glucose-lowering strategies. The present study was aimed at determining whether metformin has direct beneficial effects on the heart. We tested the effects of metformin on cardiac functional recovery after a mild ischemic incident (stunning) in our isolated, erythrocyte perfused, rat working-heart model. Three groups were tested: vehicle, 50 and 500 micromol/l metformin (total n = 6). In diabetic rats, a concentration of 50 microM has been shown to reduce the blood glucose concentration. Slight metformin-induced increases in coronary blood flow during normoxia (pre-ischemically) and during reperfusion (post-ischemically) were observed and compared to vehicle (p < 0.05). Both metformin concentrations significantly reduced cardiac functional loss induced by the 12-min global ischemic incident compared with vehicle (3.4 +/- 1.0 % and 3.5 +/- 0.6 % loss during metformin versus 10.7 +/- 0.8 % during vehicle, p < 0.001). This study clearly shows that metformin acutely improves cardiac function after a mild ischemic incident (stunning) in rats.

ATP content measured by 31P NMR correlates with post-ischaemic recovery of external work output in an isolated rat heart perfused with erythrocyte suspension.

The limited capacity of the heart to survive ischaemia presents a recognized problem during open-heart surgery. In order to provide a baseline for the study of cardioprotection we subjected a series of isolated rat hearts to periods of ischaemia of increasing duration, and sought correlations between phosphate metabolite levels as measured by 11P NMR and post-ischaemic recovery of external work output. A strong linear correlation was found between the fraction of ATP measured after reperfusion expressed as a ratio. RATP to the pre-ischaemic level, and the fractional recovery of external work output, RW: Rw = 1.06 (SE 0.27) RATP + 0.01 (SE 0.21) (Spearman rank correlation coefficient 0.72, two-tailed P value 0.006).

Classification accuracy of the portland digit recognition test in traumatic brain injury.

This study examined the classification accuracy of the Portland Digit Recognition Test (PDRT) in traumatic brain injury (TBI). It differs from past studies in assigning patients to malingering and control groups on the basis of compensation-seeking status and the presence of external markers for malingering. Sensitivity and Specificity were.77 and 1.00, respectively. Past research comparing compensation-seekers to noncompensation-seekers reported Sensitivities of.33 or lower (Specificity is always high). This study demonstrates that past research has seriously underestimated the Sensitivity of the PDRT and raises questions about the true Sensitivity of other malingering techniques as well.