Effect of dorsolateral prefrontal cortex structural measures on neuroplasticity and response to paired-associative stimulation in Alzheimer's dementia.

Long-term potentiation (LTP)-like activity can be induced by stimulation protocols such as paired associative stimulation (PAS). We aimed to determine whether PAS-induced LTP-like activity (PAS-LTP) of the dorsolateral prefrontal cortex (DLPFC) is associated with cortical thickness and other structural measures impaired in Alzheimer's dementia (AD). We also explored longitudinal relationships between these brain structures and PAS-LTP response after a repetitive PAS (rPAS) intervention. Mediation and regression analyses were conducted using data from randomized controlled trials with AD and healthy control participants. PAS-electroencephalography assessed DLPFC PAS-LTP. DLPFC thickness and surface area were acquired from T1-weighted magnetic resonance imaging. Fractional anisotropy and mean diffusivity (MD) of the superior longitudinal fasciculus (SLF)-a tract important to induce PAS-LTP-were measured with diffusion-weighted imaging. AD participants exhibited reduced DLPFC thickness and increased SLF MD. There was also some evidence that reduction in DLPFC thickness mediates DLPFC PAS-LTP impairment. Longitudinal analyses showed preliminary evidence that SLF MD, and to a lesser extent DLPFC thickness, is associated with DLPFC PAS-LTP response to active rPAS. This study expands our understanding of the relationships between brain structural changes and neuroplasticity. It provides promising evidence for a structural predictor to improving neuroplasticity in AD with neurostimulation. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Prehospital identification of stroke--room for improvement.

INTRODUCTION: Rapid recognition of stroke is important because it allows early brain imaging and management such as thrombolytic therapy. We evaluated the identification of the diagnosis acute cerebrovascular incident in a physician-based prehospital emergency medical system. METHODS: From the Copenhagen Mobile Emergency Care Unit (MECU) register we identified patients classified as having an acute cerebrovascular incident through a 2-year period. We subsequently searched the hospital registration system and compared the consistency between the primary hospital discharge diagnosis and the MECU diagnosis made on referral. Our primary aim was to calculate the proportion of admitted patients with a hospital discharge diagnosis from the category 'acute cerebrovascular incident.' RESULTS: In total, 583 patients were included in our study. In 25 patients, no hospital discharge diagnosis could be found. Of the remaining 558 patients, a hospital discharge diagnosis of cerebrovascular incident was made for 168 (30.1%) patients. Other cerebral disease was found in 171 (30.7%), systemic disease in 52 (9.3%), and other diagnoses in 167 (29.9%). DISCUSSION: We found a low accuracy of the clinical diagnosis acute cerebrovascular incident in the prehospital setting with room and need for improvement in order to allow appropriate and expeditious referral for thrombolytic therapy.

Precision and accuracy of CT-based measurements of masticatory muscles in patients with hemifacial microsomia.

OBJECTIVE: The objective of this study was to quantitatively assess masticatory muscle volumes in patients with hemifacial microsomia. Until recently, this congenital malformation was only studied in terms of restoring bony and skin morphologies. Study of the masticatory muscles, however, adds a new dimension. MATERIALS AND METHODS: Contiguous 1.5 mm CT scans were made using a Philips Tomoscan 350 in six patients with hemifacial microsomia and in one patient without asymmetry. These CT scans were processed by a Cemax 1500X 3D workstation. The volume of the masseter, temporal, and medial and lateral pterygoid muscles was measured from CT scans using three-dimensional (3D) segmentation followed by 3D imaging. The precision and accuracy of measurements of masticatory muscle volumes were investigated. The precision of 3D imaging was assessed by carrying out repeated measurements by two observers. The accuracy of the volume determination technique was assessed by scanning a piece of porcine muscle tissue with a known volume. RESULTS: Intraobserver repeatability was near perfect, with the lowest alpha being 0.96 (for the medial pterygoid muscle). All interobserver correlations were high (>0.99). The accuracy of the method of measurement demonstrated differences ranging from 2.3% to 4.4%. CONCLUSION: Craniofacial soft tissue measurements obtained from CT scans in patients with hemifacial microsomia were accurate and reproducible but time consuming.

Relationship in hypoplasia between the masticatory muscles and the craniofacial skeleton in hemifacial microsomia, as determined by 3-D CT imaging.

The purpose of this study, based on three-dimensional (3-D) computed tomographic (CT) reconstructions, was to evaluate the relation between underdevelopment of masticatory muscles and hypoplasia of the craniofacial skeleton in hemifacial microsomia (HFM). In 25 patients with HFM and 19 control patients the volumes of the masseter, the temporal, and the medial-pterygoid and lateral-pterygoid muscles were measured on the basis of CT scans, using three-dimensional segmentation and voxel addition. The size and shape of the craniofacial structures were classified, using three-dimensional imaging based on CT scans. Contiguous 1.5-mm computed tomography scans were made with a Philips Tomoscan 350 and processed by a Cemax 1500X 3-D workstation. Using the Pearson product moment correlation coefficient, the Pruzansky/Kaban classification system, the new Craniofacial Deformity Scoring System, Cranial Deformity Scoring System, and Mandibular Deformity Scoring System (MDS) demonstrated correlation coefficients with the "masseter muscle percentage" varying from 0.71 to 0.81 (P < 0.05), with the medial pterygoid muscle percentage correlation coefficient varying from 0.43 to 0.56 (P < 0.05), with the lateral pterygoid muscle percentage correlation coefficient varying from 0.55 to 0.61 (P < 0.05), and with the temporal muscle percentage correlation coefficient varying from 0.67 to 0.84 (P < 0.05). The normal right/left difference in volume of the masticatory muscles of the control patients, calculated as a percentage of the total, demonstrated small differences of 3.4% to 4.8%. Bony malformations are associated with underdevelopment of the masseter and the temporal muscles, and demonstrate a tendency toward a clear relationship. The degree of muscular underdevelopment of the different muscles of mastication in one patient could vary widely. The normal right/left difference of the masticatory muscles of the control patients is minimal. The volume of the masticatory muscles of the non-affected side does not demonstrate a compensatory effect in patients with HFM.

CT-based size and shape determination of the craniofacial skeleton: a new scoring system to assess bony deformities in hemifacial microsomia.

The purpose of this study was to design a better craniofacial classification system for bony deformities in patients with hemifacial microsomia than the existing ones. It was meant to incorporate the deformity of the craniofacial skeleton other than that of the mandible. The "Mandibular Deformity Scoring" System (MDS), the "Cranial Deformity Scoring" System (CDS), the the "Craniofacial Deformity Scoring" System (CFDS) are three newly developed classification systems, which are based on three-dimensional computed tomography (3-D CT) reconstructions. The size and shape of the craniofacial structures of 34 children, 25 with hemifacial microsomia and 9 with minimal dysplasia or trauma, were determined from CT scans, using 3-D image segmentation and rendering. Contiguous 1.5-mm CT scans were made using a Philips Tomoscan 350 and were processed using a Cemax 1500X 3-D workstation. The precision of the 3-D imaging was assessed by repeated determinations carried out by two observers (intra- and interreliability). Accuracy of the bone determination technique was assessed by comparing the interpretations of the craniofacial skeleton by 3-D CT reconstructions of laser-stereolithographic 3-D models. Correlations of the Pruzansky/Kaban classification system and the newly developed classification systems were demonstrated by the use of the Pearson product moment correlation coefficients. The new CFDS (= CDS + MDS) provides an adequate basis for assessment of bony structures using three-dimensional imaging and demonstrates a high correlation with the known Pruzansky/Kaban classification system. This new scoring system can handle the wide variety of individual variation of the deformity seen in patients with hemifacial microsomia better than the existing scoring systems.

[Hemifacial microsomia. A review]. / Hemifaciale microsomie. Een overzicht.

Hemifacial microsomia is a congenital asymmetrical malformation of the skull and the face. As a congenital malformation of the face hemifacial microsomia is second in prevalence after cleft lip and palate disorders. Combinations and degrees of underdevelopment of craniofacial structures vary greatly. Therapy varies and depends on the different anomalies, but mostly contains orthodontic and surgical treatment to improve symmetry. It is generally accepted that children with asymmetrical facial malformations are best treated in multidisciplinary craniofacial centres.

Management of developmental asymmetrical facial growth.

Several aspects of the management of developmental asymmetrical facial growth are addressed. The abnormality is further defined. Methods of examination and assessment of records are discussed. A complicating factor has been the adoption of too many classification systems. With three-dimensional imaging techniques (computed tomography scan and stereophotography) great advancement has been made in efforts at describing the range of variation. Hemifacial microsomia patients are best treated in multidisciplinary centers by competent specialists with the necessary expertise and skills. The procedure followed in the craniofacial center in Rotterdam is described and discussed in relation to current treatment strategies. The success of the treatment of the asymmetrical facial growth depends on the original abnormality, on secondary abnormal development, and on orthodontic and surgical intervention. International cooperation is necessary to compile sufficient statistical data for a scientific evaluation of treatment results and to improve the effectiveness and the efficiency of treatment.

Effects of high- and low-carbohydrate meals on maximum exercise performance in chronic airflow obstruction.

The purpose of this study was to compare the effects of isocaloric liquid meals with high fat (55 percent) and low carbohydrate (28 percent) content (Pulmocare) to meals with low fat (30 percent) and high carbohydrate (53 percent) content (Ensureplus) on exercise performance in subjects with chronic airflow obstruction (CAO). Twelve stable subjects with CAO (FEV1 = 1.30 +/- 0.47 L) underwent incremental symptom-limited exercise tests 90 minutes following the ingestion of 920 calories of EnsurePlus HN (E), 920 calories of Pulmocare (P), or a noncaloric placebo (C). Tests were performed on three days, in a double-blind randomized fashion. Expired gases were collected continuously and analyzed every 30 seconds. The mean maximal work load after E (81 +/- 24 W) was significantly less than that after P (88 +/- 21 W) or C (88 +/- 24 W). The mean ventilation at exhaustion was similar after E (48 +/- 13 L/min), P (51 +/- 11 L/min), and C (49 +/- 10 L/min). In comparison to C, six of the 12 individuals had a decreased work load following E, while only one had a decreased maximal tolerated work load following P. The results of this study suggest that meals with a higher fat and lower carbohydrate content may be less likely to impair work performance of patients with CAO in the absorptive phase than meals with a lower fat and higher carbohydrate content. These findings may have clinical significance to patients with CAO who complain of postprandial exertional dyspnea.

Lack of effect of dextromethorphan on breathlessness and exercise performance in patients with chronic obstructive pulmonary disease (COPD).

We have previously shown that the exercise performance of patients with severe chronic obstructive pulmonary disease (COPD) can be increased with the administration of oral morphine (0.8 mg.kg-1). The purpose of this study was to determine whether the administration of dextromethorphan (DXT), an antitussive structurally similar to codeine, would result in increased exercise performance and decreased dyspnoea in patients with COPD, without the side-effects of opiates. Six eucapnic patients (mean age = 66 +/- 3.8 yrs) with COPD (mean forced expiratory volume in one second (FEV1) = 1.01 +/- 0.07 l) underwent two incremental cycle ergometer tests to exhaustion (Emax) and assessment of their hypercapnic and hypoxic ventilatory responses and mouth occlusion pressure responses following first the oral administration of placebo (P) and then dextromethorphan (60 mg) in a single-blind fashion. There was no statistically significant difference in the maximal exercise performance, perceived dyspnoea (modified Borg scale), breathing pattern or expired gases after the two different treatments. In addition, the ventilatory response to CO2 production during exercise (delta VE/VCO2) and the ventilatory and mouth occlusion pressure responses to hypoxia and hypercapnia did not differ significantly after DXT as compared with after P. Indeed the exercise performance was poorer and the ventilatory responses were brisker after DXT. We conclude from this study that the administration of this opiate analogue does not improve the exercise capacity or decrease the ventilatory response of patients with COPD.

Effect of naloxone on maximal exercise performance and control of ventilation in COPD.

Elevated endorphin levels in patients with COPD may act to diminish the sensation of dyspnea. Exogenous opioids decrease exertional dyspnea and increase exercise capacity in COPD patients. The purpose of this study was to determine the effects of endogenous opioids on the exercise capacity and control of breathing in patients with COPD. We hypothesized that naloxone, an opioid antagonist, would block the endogenous endorphins and decrease the exercise capacity of our patients. Six patients (mean age, 58.8 +/- 3.2 years) with COPD (mean FEV1, 1.28 +/- 0.46 L) underwent identical incremental cycle ergometer tests to exhaustion (Emax) and assessment of their hypercapnic and hypoxic ventilatory responses and mouth occlusion pressure responses following the IV administration of naloxone (0.4 mg/kg) (N) or placebo (P) in a randomized, double-blind fashion. Perceived dyspnea (modified Borg scale), breathing patterns, and expired gas levels were compared at rest and at maximal workload (WL). There was no significant difference after N compared with after P in the WL or the duration of work. At Emax there were no significant differences after N compared with after P in ventilation, the level of dyspnea, P0.1, VO2, or VCO2. The ventilatory response to CO2 production during exercise (delta VE/delta VCO2) and the ventilatory and mouth occlusion pressure responses to hypoxia and hypercapnia did not differ significantly after N compared with after P. This study does not support the hypothesis that endogenous opioids play a significant role in dampening dyspnea and facilitating exercise in patients with COPD.

Relationship between improvement in exercise performance with supplemental oxygen and hypoxic ventilatory drive in patients with chronic airflow obstruction.

The purpose of this study was to determine if there is a relationship between improvement in exercise capacity with supplemental oxygen and the magnitude of hypoxic ventilatory drive in patients with CAO. We hypothesized that those patients with the highest hypoxic drives would be the most likely to have increased exercise tolerance with supplemental oxygen. Seventeen patients with CAO (mean FEV1 = 0.99 +/- 0.45 L) underwent identical maximal cycle ergometry exercise tests on two occasions 45 minutes apart while breathing either air or 30 percent oxygen in a randomized single-blind fashion. With supplemental oxygen, the ventilation decreased and the PaCO2 increased significantly at rest. The patients had a significantly greater exercise tolerance on supplemental oxygen (76.7 vs 69.1 watts, p less than 0.005) but no increase in the maximal ventilation. When the nine patients who improved were compared to the eight patients who did not improve, the two groups were basically identical. Specifically, there were no significant differences in the mean ventilatory or mouth occlusion responses to hypoxia or in the blood gases. The patients who did improve tended to have a greater reduction in their ventilatory response to exercise while exercising on oxygen as compared to when they were exercising on room air. From this study, it was concluded that measurements of hypoxic ventilatory drive are not helpful in predicting which patients with CAO are likely to have improved exercise capability while breathing supplemental oxygen.

Effects of oral morphine on breathlessness and exercise tolerance in patients with chronic obstructive pulmonary disease.

Previous studies have shown that opiates increase the maximal external work performed at exhaustion in patients with chronic obstructive pulmonary disease (COPD). The mechanism responsible for this improvement in exercise tolerance is unknown. The purpose of this study was to determine the effects of an oral morphine solution (0.8 mg/kg) on the exercise tolerance, perception of dyspnea, and arterial blood gases of patients with COPD. Thirteen eucapnic patients with stable COPD (FEV1 = 0.99 +/- 0.48) underwent duplicate incremental cycle ergometer tests to exhaustion (Emax) after the ingestion of placebo and after the ingestion of morphine. After the ingestion of morphine, the maximal workload increased by 18% (p less than 0.001) and the VO2 increased by 19.3% (p less than 0.001). Ten of the 13 patients had a higher ventilation at Emax after morphine ingestion. Despite the higher ventilation at Emax after morphine, the mean Borg score was not significantly higher. At Emax after morphine ingestion, the PaO2 (65.8 +/- 11.6 mm Hg) was significantly lower and the PaCO2 (43.5 +/- 8.3 mm Hg) was significantly higher than at Emax after placebo (71.9 +/- 15.5 and 38.3 +/- 8.5, respectively). When data at the highest equivalent workload were analyzed, the ventilation and the Borg scores were significantly lower, whereas the VO2 and VCO2 were comparable. From this study, we conclude that the administration of opiates can substantially increase the exercise capacity of patients with COPD. The improved exercise tolerance appears to be related to both a higher PaCO2 resulting in lowered ventilation requirements for a given workload and also to a reduced perception of breathlessness for a given level of ventilation.

Indomethacin and perception of dyspnea in chronic airflow obstruction.

A recent study showed that indomethacin reduces the perception of dyspnea during submaximal exercise in normal subjects (1). The purpose of this study was to determine whether indomethacin alters the perception of dyspnea in patients with chronic airflow obstruction during exercise. In a randomized double-blind crossover fashion, 11 subjects (FEV1 = 0.97 +/- 0.58 L) performed an incremental (15 W/min) cycle ergometer exercise test to exhaustion on 2 study days. Testing was performed 3 to 4 h after placebo or 50 mg of indomethacin. Perception of dyspnea was measured using the modified Borg scale. Minute ventilation, workload, and Borg scale measurements at exhaustion and during moderate exercise were determined. The data demonstrated no statistically significant differences between values obtained for minute ventilation, workload, or Borg scale measurements on placebo and indomethacin study days. Contrary to the previous findings in normal subjects, indomethacin failed to significantly alter perceived dyspnea during exercise in patients with chronic airflow limitation. This suggests that prostanoids do not play a major role in the perception of dyspnea in these patients during exercise.

Cardiopulmonary responses to exercise in chronic airflow obstruction. Effects of inhaled atropine sulfate.

The purpose of this study was to evaluate the effects of inhaled atropine sulfate on the exercise capacity and cardiopulmonary responses to exercise in patients with chronic airflow obstruction (CAO). Eighteen patients underwent duplicate incremental (15 watts/min) maximal cycle ergometer exercise tests 60 minutes after either inhaled atropine (0.075 mg/kg) or placebo, in double blind randomized fashion on consecutive days. Bronchodilator medications were withheld before each study. Spirograms were obtained before and 60 minutes after each aerosol treatment. Atropine increased the FEV1 by 25 percent, from 1.37 +/- 0.49 to 1.71 +/- 0.52 L (p less than 0.001), as compared to placebo. Although the ventilation at exhaustion (VEmax) increased significantly (from 52.3 +/- 11.5 to 55.9 +/- 10.0 L/min, P less than 0.05) after atropine, the increase in the mean maximum work load (95 +/- 28 vs 101 +/- 19 watts) did not achieve significance. The drug resulted in a significant decrease in oxygen consumption at all equivalent workloads greater than "0" watts (unloaded cycling), presumably because the improvement in airway mechanics decreased the oxygen cost of ventilation. Atropine-induced increases in FEV1 did not result in a significant group mean increase in maximum exercise capacity, but the drug did result in a lower oxygen cost of performing work in patients with CAO.

Effects of a large carbohydrate load on walking performance in chronic air-flow obstruction.

The purpose of this study was to determine whether a single large liquid carbohydrate (CHO) load (920 calories) affects walking performance in patients with chronic air-flow obstruction (CAO). Walking performance was measured using the 12-min walking test. Fifteen patients with stable CAO (FEV1, 1.30 +/- 0.41 L; FVC, 3.26 +/- 0.46 L) underwent 12-min walking tests 40 min after ingestion of either CHO or placebo on consecutive days in randomized double-blind fashion. Three practice walks were performed on a preliminary day in order to eliminate learning effects. Resting measurements of ventilation (VE) and carbon dioxide output (VCO2) were obtained prior to each walking test. Carbohydrate significantly increased both VCO2 (from 0.288 +/- 0.060 to 0.372 +/- 0.057 L/min, p less than 0.001) and VE (from 15.2 +/- 3.5 to 18.5 +/- 3.1 L/min, p less than 0.001) at rest. The total 12-minute walking distance decreased from 894 +/- 199 to 847 +/- 191 m following CHO (p less than 0.005). This distance decreased in 14 of the 15 study patients. The decrease in walking distance ranged from 1.5 to 168 m (0.2 to 15.2%). From this study we conclude that a large liquid carbohydrate load adversely affects walking performance in patients with CAO. This potential impairment of functional capacity should be considered when caloric intake is increased in attempts to improve nutritional status in this patient population.

Reproducibility of VO2max in patients with chronic air-flow obstruction.

The purpose of this study was to determine the variability in maximal oxygen consumption (VO2 max) determined from repeated exercise tests in patients with chronic air-flow obstruction (CAO). Three incremental maximal cycle ergometer tests were performed in each of 11 CAO patients who were familiar with such testing. Two tests (Test 1, Test 2) were carried out on the same day, separated by a 60-min rest period, and 1 (Test 3) was performed on a consecutive day. Group mean values for VO2 max were: 1.313 +/- 0.259, 1.311 +/- 0.281, 1.306 +/- 0.288 L/min, for Tests 1 to 3, respectively. These nearly identical values did not differ significantly. There was no systematic "fatigue" or "learning" effect from test to test. Other mean measurements obtained at maximal exercise were likewise not significantly different among the 3 tests. For tests performed on the same day, the mean of the absolute values of the individual patient VO2 max differences (delta VO2 max) was 53 +/- 30 ml. The delta VO2 max was less than 6% in 10 of the 11 patients and less than 10% in the remaining patient. For tests performed on consecutive days, delta VO2 max was 93 +/- 81 ml; delta VO2 max was less than 6% in 6 patients and less than 10% in 9 patients. From this study we concluded that repeated maximal exercise testing is highly reproducible for groups of CAO patients, although some individual patient variability is seen. Individual patient differences in delta VO2 max are less when the 2 tests are performed on the same day than when duplicate testing is performed on consecutive days.

Effects of digoxin on exercise capacity and right ventricular function during exercise in chronic airflow obstruction.

We evaluated 12 patients with stable chronic airflow obstruction (CAO) and no clinical evidence of left ventricular disease to determine the effects of oral digoxin on exercise capacity (VO2 max) and on right ventricular pump function during exercise. In this randomized, double blind, placebo controlled, cross-over study, patients performed exercise tests and underwent measurement of ejection fractions after two weeks of therapy with oral digoxin (0.25 mg/day) and after two weeks of placebo. Incremental upright exercise testing to a symptom-limited maximum was performed on a cycle ergometer. Right and left ventricular ejection fractions (RVEF, LVEF) were obtained in the supine position at rest and at approximately 75 percent of the maximum workload by gated equilibrium radionuclide angiography. All patients had abnormal right ventricular function, manifested either by a low resting RVEF (less than 45 percent) or a subnormal response to exercise (less than 5 percent increase). The small increases in RVEF with digoxin (mean +/- SE) at rest (44 +/- 5 vs 41 +/- 4 percent) and during exercise (46 +/- 4 vs 44 +/- 3 percent) did not achieve statistical significance. With digoxin, small increases in exercise duration (10.0 +/- 1.5 vs 9.0 +/- 1.4 min), maximum workload achieved (48 +/- 6 vs 42 +/- 5 W), VO2 max (0.85 +/- 0.06 vs 0.81 +/- 0.06 L/min), and oxygen-pulse (O2-P) (6.6 +/- 0.5 vs 6.3 +/- 0.4 ml/beat) occurred. Only the increase in O2-P was significant (p less than 0.05). From this study we conclude that digoxin does not significantly improve exercise capacity in severe chronic airflow obstruction with impaired right ventricular function, nor does it improve RVEF either at rest or during supine submaximal exercise.