Modafinil Decreased Thalamic Activation in Auditory Emotional Processing: A Randomized Controlled Functional Magnetic Resonance Imaging Study.

BACKGROUND: Modafinil improves wakefulness and attention, is approved in Japan for treatment of narcolepsy, and was reported to be effective for attention-deficit/hyperactivity disorder. However, it was reported to induce emotional instability, including mania, depression, and suicidal ideation. Such side effects may be related to changes in cognitive behavior caused by the effects of modafinil on emotional recognition. However, the effects of modafinil on the neural basis of emotional processing have not been fully verified. We used functional magnetic resonance imaging to investigate the effects of modafinil on the neural basis of auditory emotional processing. METHODS: This study adopted a placebo-controlled within-subject crossover design. Data from 14 participants were analyzed. The effects of modafinil on cerebral activation and task performance during an emotional judgement task were analyzed. RESULTS: Task accuracy decreased significantly and response time of emotional judgement was significantly delayed by modafinil, as compared with placebo. Right thalamic activation in auditory emotional processing was significantly less in the modafinil condition than in the placebo condition. In addition, reduction of right thalamic activation by modafinil was positively correlated with accuracy of emotional judgement. CONCLUSIONS: Our findings suggest that modafinil acts on the right thalamus and changes behavior and brain function associated with auditory emotional processing. These results indicate that modafinil might change emotional recognition by reducing emotional activation related to social communication.

Bupropion increases cerebral activation in auditory affective processing: A randomized controlled fMRI study.

INTRODUCTION: Bupropion is an antidepressant with less possibility to give rise to emotional blunting as side effect, and it also acts on improving negative self-recognition in a depressive state. Previous neuroimaging studies indicated a change in brain function by facial expression as an effect of antidepressants. As well as facial expression, vocal affective processing is essential for accurately recognizing another's feelings, but to our knowledge, no study has investigated whether bupropion affects the cerebral function of recognition of auditory affective processing. In this study, we aimed to investigate the acute effect of bupropion on cerebral response to vocal affective processing. METHODS: Sixteen healthy volunteers (male = 8) participated in this study. With a randomized placebo-controlled within-subject trial, two series of fMRI scans, using either placebo or bupropion (150 mg), were examined. An auditory emotional valence judgement task was performed during fMRI scanning. The acute effects of bupropion on cerebral activation in the emotional circuit and behavioral performance during emotional processing were analyzed. RESULTS: Compared with placebo, bupropion caused a significantly greater activation of emotional voices in the left insula and right superior temporal gyrus, whereas the amygdala was not activated. By bupropion, a significantly greater activation of the positive emotional circuit was observed at the superior temporal gyrus and middle frontal gyrus. As for behavioral performance, no significant difference was observed between placebo and bupropion. CONCLUSIONS: Our findings suggest that bupropion enhances the cerebral response to affective processing, especially positive emotional vocalizations, indicating a possible mechanism underlying the therapeutic effects for patients with depression.

Heart rate response to orthostatic challenge in patients with dementia with Lewy bodies and Alzheimer's disease.

BACKGROUND: To elucidate the differences in autonomic dysfunction between dementia with Lewy bodies (DLB) and Alzheimer's disease using a simple and convenient method, we investigated the heart rate response to orthostatic challenge. METHODS: Ninety-seven people participated in this cross-sectional study, and data from 26 DLB patients, 29 Alzheimer's disease patients, and 25 healthy elderly individuals were analysed. Participants underwent postural changes, including 5 min in a supine position, 1 min in a sitting position, and 3 min in an orthostatic position. Their heart rates were continuously recorded. Two heart rate variables were analysed as main outcomes: (i) the difference between heart rate in the sitting position and the peak heart rate within 15 s of orthostasis, defined as the 'early heart rate increase'; and (ii) the difference between the peak heart rate and the negative peak heart rate after this, defined as 'early heart rate recovery.' An early heart rate increase has been considered to reflect parasympathetic and sympathetic functions. Early heart rate recovery is considered to reflect parasympathetic function. We also investigated the frequency domains of resting heart rate variability. RESULTS: A significant difference was observed across the three groups in early heart rate increase, and that of the DLB group was lower than that of the healthy control group. Early heart rate recovery also differed significantly across the three groups, and that of the DLB group was less than that of the healthy control group. In addition, the power of the low-frequency component, which represents both sympathetic and parasympathetic activity, was significantly decreased in the DLB group compared to the Alzheimer's disease group. CONCLUSIONS: Impaired heart rate response to standing was detected in patients with DLB. Electrocardiogram is a convenient, non-invasive method that might be useful as a subsidiary marker for DLB diagnosis and differentiation from Alzheimer's disease.

Changes in cardiac autonomic nervous system activity during a course of electroconvulsive therapy.

AIM: Although electroencephalogram (EEG) seizure duration and seizure threshold change during a course of electroconvulsive therapy, the mechanisms by which these factors influence heart rate during subsequent electroconvulsive therapy sessions are currently unclear. In the current study, we investigated changes in heart rate during electroconvulsive therapy. METHODS: We recorded electroencephalography and electrocardiography during electroconvulsive therapy in 12 patients with major depressive disorder. Baseline heart rate was defined as the mean heart rate in the 30 seconds prior to stimulus onset. The TimeMax peak refers to the maximum heart rate after stimulus onset. Time1/2 points represent the time points at which the heart rate had decreased to a value midway between the baseline heart rate and the TimeMax peak. We examined the relationships between EEG seizure duration, TimeMax , and Time1/2 throughout the course of electroconvulsive therapy. RESULTS: Time1/2 decreased as the number of electroconvulsive sessions increased. Time1/2 was positively correlated with EEG seizure duration. CONCLUSION: The duration in which electroconvulsive therapy-induced sympathetic nervous system activation returned halfway to baseline levels gradually shortened during the course of electroconvulsive therapy.

Is prolongation of corrected QT interval associated with seizures induced by electroconvulsive therapy reduced by atropine sulfate?

BACKGROUND: Electrocardiogram abnormalities have been reported during electroconvulsive therapy (ECT). A corrected QT interval (QTc) prolongation indicates delayed ventricular repolarization, which can trigger ventricular arrhythmias such as torsade de pointes (TdP). We examined the QTc changes during generalized tonic-clonic seizures induced by ECT, and the effects of atropine sulfate on these QTc changes. METHODS: We analyzed heart rate, QT interval, and QTc in 32 patients with depression who underwent ECT (25 women, 67.4 ± 8.7 years of age). The QTc from -30 to 0 seconds prestimulation was used as baseline, which was compared with QTc at 20-30 seconds and 140-150 seconds poststimulus onset. RESULTS: QTc was significantly prolonged at 20-30 seconds poststimulus, then significantly decreased at 140-150 seconds poststimulus, compared with baseline. QTc prolongation induced by ECT was significantly decreased by atropine sulfate. CONCLUSIONS: These data suggest that the risk of TdP may be enhanced by ECT. Further, the risk of cardiac ventricular arrhythmias, including TdP, may be reduced by administration of atropine sulfate.

A Triphasic Change of Cardiac Autonomic Nervous System During Electroconvulsive Therapy.

OBJECTIVES: Dynamic autonomic activity changes have been repeatedly reported during electroconvulsive therapy (ECT). However, the specific timing of these changes remains unclear. To clarify whether sympathetic or parasympathetic nervous activity contributes separately to the second stage and the third stage during and after induced seizures by ECT, we examined heart rate (HR) and spectral analysis of variability (HRV) during ECT. METHODS: Seventeen patients with depression participated in the study and underwent ECT. The R-R intervals (RRI) were recorded and analyzed sequentially for the HRV indices high-frequency (HF) (an index of parasympathetic activity) and low-frequency (LF)/high-frequency (an index of sympathetic activity) for 4 minutes before and after stimulus onset by the maximum entropy method. Averaged HRs were compared between 3 heart beats prestimulus and poststimulus onset. The HRV power in the range of 30 to 80 and 80 to 130 seconds after a seizure was compared between the HF and LF/HF components. RESULTS: There was a significant reduction of the averaged HR over 3 HRs just after stimulus onset, suggesting parasympathetic dominance in the first phase. The LF/HF power significantly increased in the 30 to 80 s range after stimulus onset, whereas the HF power significantly increased in the 80 to 130 s range after stimulus onset, reflecting sympathetic activation in the second phase and parasympathetic activation in the third phase, respectively. CONCLUSIONS: The evaluation of HR and HRV revealed a triphasic change from parasympathetic to sympathetic to parasympathetic cardiac autonomic activity after ECT stimulus onset in depression patients.

Symptoms of atrial fibrillation in patients with and without subsequent permanent atrial fibrillation based on a retrospective questionnaire survey.

The aim of the present study was to determine whether symptoms of atrial fibrillation (AF) differ between patients with and without subsequent permanent AF. Sixty-four patients (68 +/- 10 years old, 45 males) were recruited. AF follow-up was started at the age of 61 +/- 10 years and accomplished in a median period of 4.9 years (396 person-years). Permanent AF, defined as lasting > 180 days, developed in 17 patients (14 males) (43 per 1000 person-years). The AF follow-up period was longer in the permanent AF group than in the non-permanent AF group (median, 9.8 versus 4.2 years, P < 0.001). For baseline characteristics, hypertension was less frequent in the permanent AF group than in the nonpermanent AF group (18% versus 45%, P < 0.05). A retrospective questionnaire survey regarding initial AF symptoms was conducted. The severity of AF symptoms by a 4-grade scale was significantly milder in the permanent AF group than in the nonpermanent AF group (P < 0.05). Cox proportional hazards model analysis revealed that the severity of initial AF symptoms was related to the subsequent development of permanent AF (hazard ratio 0.46 per grade, 95% confidence interval 0.23 - 0.93, P < 0.05), but age, gender, hypertension, diabetes mellitus, organic heart disease, and left atrial dimension were not. The permanent AF-free rate was significantly lower in 33 patients with mild symptoms than in 31 patients with severe symptoms (log-rank test, P < 0.05). These results point to an inconspicuous feature in the development of permanent AF.

Ultrasonic anisotropy measured in 2-dimensional echocardiograms in vitro and verified by histology.

This study aims to validate ultrasonic anisotropy in 2-dimensional echocardiograms by one-to-one histological correlation. Thirteen echograms were obtained in vitro from 9 specimens of 2 left ventricles of healthy adult beagle dogs and were correlated with corresponding histology in regard to ultrasound orientation relative to the local fiber direction. Median value of pixel echogenicity (255-rank) was lower in areas with parallel (n = 9, 18 ± 13) than in those with oblique (n = 7, 41 ± 14, P < 0.05) and perpendicular (n = 13, 57 ± 21, P < 0.01) ultrasound orientations. Echogenicity in the proximal part within 0.5 cm from an edge was relatively high (n = 9, 33 ± 15; n = 5, 66 ± 27; n = 8, 65 ± 32, respectively) and was different between parallel and perpendicular orientations (P < 0.05). The ratio of the distal adjacent 0.5-cm part to the proximal part echogenicity was lower for either parallel or oblique orientation (0.35 ± 0.25, 0.51 ± 0.16) than for perpendicular orientation (0.95 ± 0.16, P < 0.01, respectively). Acoustic dropouts appeared beyond myocardial areas with parallel or oblique ultrasound orientation. These results disclosed precise acoustic anisotropy in the 2-dimensional echocardiograms.

Oxygen uptake kinetics during and after exercise are useful markers of coronary artery disease in patients with exercise electrocardiography suggesting myocardial ischemia.

BACKGROUND: The aim of the current study was to determine if the slowed exercise oxygen uptake (VO(2)) kinetics, which is developed by myocardial ischemia, would be accompanied by delayed recovery VO(2) kinetics in patients with coronary artery disease (CAD). METHODS AND RESULTS: Thirty-seven patients with significant ST depression during treadmill exercise underwent cardiopulmonary exercise testing with cycle ergometer. Measurements performed are the ratios of change in increase in oxygen (O(2)) uptake relative to increase in work rate (DeltaVO(2)/DeltaWR) across anaerobic threshold (AT) and 1 mm ST depression point (ST-dep), the time constants of VO(2) during recovery (T(1/2) VO(2)), stress radio-isotope scintigraphy and coronary angiography. Patients were divided into CAD positive (CAD+) and CAD negative (CAD-) groups, based on coronary angiography. In CAD+, DeltaVO(2)/DeltaWR decreased above AT and ST-dep, in contrast to CAD- patients. The T(1/2) VO(2) in CAD+ (103.1 +/-13.0 s) was greater than that of CAD- (76.5 +/-8.7 s) and showed negative correlations to the ratios of DeltaVO(2)/DeltaWR across AT and ST-dep. These parameters improved in the patients who underwent coronary bypass surgery. CONCLUSIONS: Exercise and recovery VO(2) kinetics were slowed when myocardial ischemia was provoked by exercise. Measurement of exercise and recovery VO(2) kinetics improve the accuracy of the exercise electrocardiogram diagnosis of CAD.

Molecular heterogeneity of urinary albumin in glomerulonephritis: comparison of cardiovascular disease with albuminuria.

BACKGROUND: Despite the unstable structure of urinary albumin in kidney diseases, urinary albumin fragments have been identified by denaturing methods such as two-dimensional electrophoresis. This study examined the relationship between the structural heterogeneity of urinary albumin and protease effects. METHODS: Urine samples from patients with glomerulonephritis (GN), cardiovascular diseases (CVD), and healthy subjects were analyzed by non-reducing sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE), Western blot, diagonal 2-dimensional non-reducing/reducing (d2D) SDS PAGE, and albumin zymography. RESULTS: The major band was monomer albumin in CVD and healthy subjects; however, 13 urinary albumin bands ranging from 55 to 172 kDa were identified by non-reducing SDS PAGE in GN. The results from d2D SDS PAGE showed urinary albumin polymerization between disulfide bridges, interactions with other proteins, and reduction induced degradation in GN patients. The results from albumin zymography showed that low-molecular mass forms of albumin did not necessarily correspond to high protease activity. Furthermore, concentrated healthy urine showed similar protease digestion as in GN without low-molecular mass of albumin. CONCLUSIONS: The molecular alterations observed cannot be explained only by urinary proteases. The specific alteration of urinary albumin molecules in GN can be attributed to different mechanisms to CVD.

Reentrant circuits in the canine atrioventricular node during atrial and ventricular echoes: electrophysiological and histological correlation.

BACKGROUND: The anatomic-electrophysiological correlation of AV nodal reentry is unclear. To localize reentrant circuits during atrial and ventricular echoes and to characterize sites of slow conduction and block, we correlated histology with electrophysiology of the AV node. METHODS AND RESULTS: In 10 isolated dog hearts, extracellular electrical activity was recorded in Koch's triangle at 208 or 247 sites (interelectrode distance, 0.5 and 0.3 mm) after removal of 0.7 to 1.5 mm of overlying atrial tissue. Resection did not affect refractory periods. Five hearts were subjected to histology. Complete atrial echoes were induced in 1 heart, incomplete atrial echoes in 5 hearts. Unidirectional conduction block occurred at the atrial-transitional cell junction in the superior area. Zones of slow conduction arose at the atrial-transitional or the transitional-compact node junction in the inferior area. Complete reentrant circuits of ventricular echoes were obtained in 5 hearts. Unidirectional conduction block occurred at the compact node-transitional cell junction in the superior area. Localized zones of slow conduction arose at the junctions between the different types of tissue in the inferior area. CONCLUSIONS: In the dog heart, tissue architecture and functional dissociation between the inferior and the superior region of the AV node enable dual physiology and reentry. Slow conduction and functional conduction block occur at the junctions between the different types of tissue in the AV nodal area. Atrial echoes were enabled by conduction block at the atrial-transitional cell junction, whereas during ventricular echoes conduction block occurred at the compact node-transitional cell junction.

Correlation between electroencephalography and heart rate variability during sleep.

It is known that autonomic nervous activities change in correspondence with sleep stages. However, the characteristics of continuous fluctuations in nocturnal autonomic nerve tone have not been clarified in detail. The study aimed to determine the possible correlation between the electroencephalogram (EEG) and autonomic nervous activities, and to clarify in detail the nocturnal fluctuations in autonomic nerve activities. Overnight EEGs and electrocardiograms of seven healthy males were obtained. These EEGs were analyzed by fast Fourier transformation algorithm to extract delta, sigma and beta power. Heart rate and heart rate variability (HRV) were calculated in consecutive 5-min epochs. The HRV indices of low frequency (LF), high frequency (HF) and LF/HF ratio were calculated from the spectral analysis of R-R intervals. The sleep stages were manually scored according to Rechtschaffen and Kales' criteria. Low frequency and LF/HF were significantly lower during non-rapid eye movement (NREM) than REM, and were lower in stages 3 and 4 than in stages 1 and 2. Furthermore, delta EEG showed inverse correlations with LF (r = - 0.44, P < 0.001) and LF/HF (r = - 0.41, P < 0.001). In contrast, HF differed neither between REM and NREM nor among NREM sleep stages. Detailed analysis revealed that correlation was evident from the first to third NREM, but not in the fourth and fifth NREM. Delta EEG power showed negative correlations with LF and LF/HF, suggesting that sympathetic nervous activities continuously fluctuate in accordance with sleep deepening and lightening.

Electrical conduction in canine pulmonary veins: electrophysiological and anatomic correlation.

BACKGROUND: Paroxysmal atrial fibrillation in patients is often initiated by foci in the pulmonary veins. The mechanism of these initiating arrhythmias is unknown. The aim of this study was to determine electrophysiological characteristics of canine pulmonary veins that may predispose to initiating arrhythmias. METHODS AND RESULTS: Extracellular recordings were obtained from the luminal side of 9 pulmonary veins in 6 Langendorff-perfused dog hearts after the veins were incised from the severed end to the ostium. Pulmonary veins were paced at the distal end, the ostium, and an intermediate site. During basic and premature stimulation, extracellular electrical activity was recorded with a grid electrode that harbored 247 electrode terminals. In 4 hearts, intracellular electrograms were recorded with microelectrodes. Myocyte arrangement immediately beneath the venous walls was determined by histological analysis in 3 hearts. Extracellular mapping revealed slow and complex conduction in all pulmonary veins. Activation delay after premature stimulation could be as long as 96 ms over a distance of 3 mm. Action potential duration was shorter at the distal end of the veins than at the orifice. No evidence for automaticity or triggered activity was found. Histological investigation revealed complex arrangements of myocardial fibers that often showed abrupt changes in fiber direction and short fibers arranged in mixed direction. CONCLUSIONS: Zones of activation delay were observed in canine pulmonary veins and correlated with abrupt changes in fascicle orientation. This architecture of muscular sleeves in the pulmonary veins may facilitate reentry and arrhythmias associated with ectopic activity.