Serotonin1A-receptor agonism attenuates the cocaine-induced increase in serotonin levels in the hippocampus and nucleus accumbens but potentiates hyperlocomotion: an in vivo microdialysis study.

The hippocampus and the nucleus accumbens (Nac) are important structures for the modulation of spontaneous locomotor activity. Both structures receive a serotonergic (5-HT) innervation. We have previously reported that the 5-HT(1A)-receptor antagonist WAY 100635 blocked cocaine-induced hyperactivity, while potentiating cocaine-induced 5-HT increases in the hippocampus and the Nac. In order to further investigate the relationship between extracellular 5-HT concentration and cocaine-induced behaviour, we used in vivo microdialysis to measure the effects of the 5-HT(1A)-receptor agonist 8-OH-DPAT on cocaine-induced changes in the extracellular 5-HT concentration in the hippocampus and the Nac and on behavioural activity. Following a pilot pretest in which we determined the lowest effective dose of 8-OH-DPAT for potentiating cocaine-induced hyperlocomotion, four groups of rats were given one of the following drug treatments: 8-OH-DPAT (0.2 mg/kg) and cocaine (10 mg/kg), saline and cocaine (10 mg/kg), 8-OH-DPAT (0.2 mg/kg) and saline, or saline and saline. The injections were administered i.p. and spaced 30 min apart. We found that the 5-HT(1A)-receptor agonist 8-OH-DPAT attenuated the cocaine-induced increases in 5-HT in the hippocampus and the Nac, but potentiated cocaine-induced hyperlocomotion. 5-HT metabolite measurements revealed a complex role for the 5-HT(1A)-receptor in the broad spectrum of cocaine's neurochemical effects. Altogether, these observations support an important role of the 5-HT(1A)-receptor in the hippocampus and Nac in the modulation of cocaine stimulant effects.

Subcortical correlates of craving in recently abstinent alcoholic patients.

OBJECTIVE: This study investigated functional cerebral correlates of craving in alcoholic patients and examined the state/trait characteristics of the regional cerebral network implicated in craving. METHOD: Functional magnetic resonance imaging (fMRI) was used to map cerebral response elicited by ethanol odor in 10 male patients with alcohol dependence who had undergone detoxification and 10 matched nonpatients. After 3 weeks, during which the patients underwent standardized behavioral therapy with psychopharmacological intervention, all subjects were studied a second time with fMRI to evaluate the effects of therapy on the functional cerebral correlates of craving. RESULTS: In the alcoholic patients, cue-induced craving before treatment elicited activation primarily in the subcortical-limbic region of the right amygdala/hippocampal area and in the cerebellum. After treatment, activation was found in the superior temporal sulcus, while subcortical or cerebellar participation was no longer present. Comparison subjects showed no comparable amygdala or cerebellar activation during ethanol stimulation and demonstrated no change in activation pattern between measurements. CONCLUSIONS: This investigation points to state-dependent neurobiological correlates of cue-induced craving in alcoholic patients and suggests that these correlates can be influenced by therapeutic interventions. The presence of emotional aspects of craving is suggested by amygdala activation.

Transcranial magnetic stimulation: no effect on mood with single pulse during learned helplessness.

1. Transcranial Magnetic Stimulation (TMS) is suggested to be an effective tool in the treatment of depression. However, the methodology most suitable for clinical application remains unclear. 2. The effect of TMS was tested in a double-blind and placebo-controlled setting on 18 healthy subjects. At the same time an established learned helplessness paradigm was applied to induce dysphoria, which consisted of unsolvable anagrams. 3. Sixty 0.5 Hz stimuli were administered at an intensity of 130% of the subject's motor threshold after the subjects were exposed to the learned helplessness situation. Using a vertically positioned coil, the stimuli were applied to the right or to the left frontal cortex, or on the occipital cortex as a placebo condition. 4. Although dysphoria was successfully induced by unsolvable anagrams, TMS on either of the two frontal locations did not influence mood. This lack of effect may be due to the stimulation characteristics employed here (low TMS intensity, and low frequency). On the other hand, the findings may reflect the neurobiological difference between experimentally induced sad mood and clinical depression.

A new approach to measure single-event related brain activity using real-time fMRI: feasibility of sensory, motor, and higher cognitive tasks.

Real-time fMRI is a rapidly emerging methodology that enables monitoring changes in brain activity during an ongoing experiment. In this article we demonstrate the feasibility of performing single-event sensory, motor, and higher cognitive tasks in real-time on a clinical whole-body scanner. This approach requires sensitivity optimized fMRI methods: Using statistical parametric mapping we quantified the spatial extent of BOLD contrast signal changes as a function of voxel size and demonstrate that sacrificing spatial resolution and readout bandwidth improves the detection of signal changes in real time. Further increases in BOLD contrast sensitivity were obtained by using real-time multi-echo EPI. Real-time image analysis was performed using our previously described Functional Imaging in REal time (FIRE) software package, which features real-time motion compensation, sliding window correlation analysis, and automatic reference vector optimization. This new fMRI methodology was validated using single-block design paradigms of standard visual, motor, and auditory tasks. Further, we demonstrate the sensitivity of this method for online detection of higher cognitive functions during a language task using single-block design paradigms. Finally, we used single-event fMRI to characterize the variability of the hemodynamic impulse response in primary and supplementary motor cortex in consecutive trials using single movements. Real-time fMRI can improve reliability of clinical and research studies and offers new opportunities for studying higher cognitive functions.

Gender differences in regional cerebral activity during sadness.

Functional magnetic resonance imaging and echo-planar-imaging were used to investigate affect related gender differences in regional cerebral activity. The experiment was conducted using a standardized mood induction procedure. Blood-oxygen-level-dependent effect was measured in 13 male and 13 female healthy subjects, during both moods of happiness and sadness, respectively. Parallel to earlier neuroimaging findings, our results show brain activity in the amygdala of males during negative affect. Females failed to demonstrate a similar activation pattern despite matched subjective ratings of negative affect to males. Results point to differential regional cerebral correlates of emotional experience in males and females, which is suggestive of a more focal and subcortical processing of sadness in men.

Emotional processing in schizophrenia across cultures: standardized measures of discrimination and experience.

Schizophrenia appears quite similar across a range of cultures. However, variability has been noted, and understanding the variant and invariant features of the disorder is necessary for elucidating its biological and environmental basis. Evidence of prominent emotion processing deficits in schizophrenia, including perceptual and experiential aspects, led us to extend the paradigm of standardized measures cross-culturally. We assessed performance of American, German, and Indian patients with schizophrenia and healthy controls on standardized emotion discrimination and experience (mood induction) procedures using happy, sad, and neutral facial expressions of Caucasian actors. Participants were 80 Americans (40 patients; 40 controls), 48 Germans (24 patients; 24 controls), and 58 Indians (29 patients; 29 controls). Face discrimination performance was impaired across patient groups, but was most impaired in those of Indian origin. Lower performance was also found in Indian controls, relative to their American and German counterparts. Mood induction produced weaker effects in all patient groups relative to their respective controls. The results supported the feasibility of cross-cultural comparisons and also emphasized the importance of poser ethnic background for facial affect identification, while poser ethnicity was less consequential for mood induction effects. Emotion processing deficits in schizophrenia may add to the clinical burden, and merit further examination.

Intraosseous orbitosphenoidal cavernous angioma. Case report.

Primary orbital intraosseous angiomas are rare. The authors report the case of a 55-year-old man who harbored a multifocal cavernous angioma in an unusual sphenoorbital location. The lesion was responsible for unilateral exophthalmos and blindness. Characteristic imaging findings, which included a honeycomb pattern on plain x-ray films and computerized tomography scans, a heterogeneous high signal intensity on T2-weighted magnetic resonance images, and slowly flowing venous lakes on power Doppler ultrasonograms and angiograms, are presented and discussed.

Acute pulmonary edema after lung transplantation: the pulmonary reimplantation response.

BACKGROUND: Although the development of noncardiogenic pulmonary edema or pulmonary reimplantation response (PRR) after lung transplantation has been well described, the incidence has not been established and the relationship of PRR to clinical risk factors has not been analyzed. STUDY OBJECTIVES: (1) To describe the incidence of PRR in lung transplant recipients, (2) to identify the predictors of PRR, (3) to examine the correlation of suspected predictors with the severity of PRR, and (4) to evaluate the impact of PRR on morbidity and mortality of lung transplant recipients. DESIGN: Retrospective review of clinical records and radiographic studies. SETTING: Tertiary care referral center. PATIENTS: Ninety-nine consecutive patients with end-stage lung disease undergoing lung transplantation between February 1990 and October 1995. METHODS: Review of clinical records and postoperative chest radiographs of all lung transplant recipients to identify patients who experienced PRR. Chest radiographs of patients with PRR were graded for severity on a scale of 0 (none) to 5 (very severe). Demographic, pre- and perioperative factors were also evaluated along with short- and long-term survival of patients with PRR. RESULTS: Fifty-six of 99 lung transplant recipients (57%) experienced PRR. The median ischemia time of patients with and without PRR was 168 and 180 min, respectively (p = 0.62). The incidence of PRR was 51% in patients without preoperative pulmonary hypertension, 78% in mild to moderate pulmonary hypertension, and 58% in patients with severe pulmonary hypertension (p = 0.10). Incidence and severity of PRR was similar in patients receiving right, left, or double-lung transplantation. Similarly, age and sex of the recipients and underlying lung disease did not affect the incidence or severity of PRR. The incidence and severity of PRR was higher in patients undergoing cardiopulmonary bypass during lung transplantation. Patients with PRR had prolonged duration of mechanical ventilation and ICU stay. Overall, PRR did not affect the survival of the patients. However, survival of female lung transplant recipients was significantly better than male recipients (median survival, 60 vs 21 months; p = 0.02). CONCLUSIONS: Acute pulmonary edema or PRR occurs frequently (57%) after lung transplantation. In this series, PRR was not associated with a prolonged ischemia time, preoperative pulmonary hypertension, the type of lung transplant, underlying lung disease, or age or sex of recipients. However, use of cardiopulmonary bypass during surgery was associated with increased incidence and severity of PRR. Also, the development of PRR resulted in prolonged mechanical ventilation and a longer ICU stay, but did not affect survival. Female lung transplant recipients survived significantly longer than male recipients. The reason for this difference in survival is unclear.

Correspondence of emotional self-rating with facial expression.

Emotional processing abilities are difficult to measure psychometrically. Ultimately their quantification has to rely on 'subjective' judgment thereby leaving open the problem of response biases. Assessments of autonomic arousal similarly provide a mere unspecified measurement of a specific emotion. A standardized mood induction procedure capable of obtaining reliable happy and sad mood changes in healthy subjects was used to demonstrate the effectiveness of this procedure. We performed a two-part experiment using a rater-based analysis of facial expressions. This entailed analyzing the emotion portrayed in the faces. The faces of 24 healthy subjects were videotaped during the mood induction procedure of happiness and sadness, respectively. A group of 20 raters naive to the experimental task and conditions rated the facial expressions on six basic emotions. Results showed that ratings corresponded with the facial expressions, which were reflecting the mood of the task condition. Subjects' facial expressions together with self-ratings demonstrate the successful applicability of this standardized mood induction procedure for eliciting happy and sad mood.

Subcortical correlates of differential classical conditioning of aversive emotional reactions in social phobia.

BACKGROUND: Conditioning processes have been proposed to play a role in the development of anxiety disorders. As yet, the neurobiologic correlates of emotional learning have not been fully understood in these patients. Accordingly, brain activity was studied in subcortical and cortical regions involved in the processing of negative affect during differential aversive classical conditioning. METHODS: Twelve patients with social phobia and 12 healthy control subjects were presented with paired conditioned (CS; neutral facial expressions) and unconditioned stimuli (US; negative odor vs unmanipulated air). Functional magnetic resonance imaging (fMRI) was utilized to examine regional cerebral activity during habituation, acquisition,a nd extinction trials. Activity was measured with echo-planar-imaging (EPI), and signal intensity in individually defined anatomic regions were analyzed. RESULTS: Subjective ratings of emotional valence to the CS indicated that behavioral conditioning occurred in both groups. The presentation of CS associated with negative odor led to signal decreases in the amygdala and hippocampus of normal subjects, whereas an opposite increased activation in both regions was observed in patients. Regional differences were not found during habituation and extinction. CONCLUSIONS: Results suggest that conditioned aversive stimuli are processed in subcortical regions, with phobic patients differing from control subjects.

Differential amygdala activation in schizophrenia during sadness.

Several studies have reported impaired emotion processing in schizophrenic patients. However, the corresponding functional cerebral correlates of such impairment have not been fully understood, leaving the neurobiological basis of their affective symptoms unknown. Functional magnetic resonance imaging (fMRI) was utilized to examine brain activity in subcortical and cortical regions of 13 medicated male schizophrenic patients and 13 matched healthy controls during happy and sad mood induction. Results show brain activity in the amygdala of normal controls during negative affect, which is in line with previous neuroimaging findings. Unlike controls, schizophrenic patients have not demonstrated amygdala activation during sadness despite matched ratings to normal controls indicating a similar negative affect. Recognizing that structural abnormalities exist in the amygdala of schizophrenic patients, our results provide new evidence of functional abnormalities in the limbic system.

Hemodynamic and neurohormonal effects of flosequinan in patients with heart failure.

In a double-blind, placebo-controlled study, the central and peripheral hemodynamic effects of 100 mg oral flosequinan and the impact of this drug on neurohormonal activation were noninvasively evaluated in 18 patients with congestive heart failure, after the first administration and after 10 days of treatment. No significant hemodynamic and neurohormonal changes were observed after acute administration. After 10 days, flosequinan produced central and peripheral hemodynamic improvement characterized by an increase in left ventricular circumferential fiber shortening velocity (+12%), a decrease in total systemic resistance (-36%), and an increase in leg blood flow (+37%). No significant changes were observed in heart rate and arterial pressure in patients receiving flosequinan, though a slight increase in heart rate (+17%) was recorded. Despite these favorable hemodynamic effects, flosequinan significantly increased plasma norepinephrine (+38%) and plasma renin activity (+13%) after 10 days of treatment. Thus, the beneficial central and peripheral hemodynamic effects of flosequinan are accompanied by activation of the sympathetic and reninangiotensin systems. This might be related to the unfavorable effects of the drug on survival in patients with heart failure.

Muscular blood flow response to submaximal leg exercise in normal subjects and in patients with heart failure.

Blood flow to working skeletal muscle is usually reduced during exercise in patients with congestive heart failure. An intrinsic impairment of skeletal muscle vasodilatory capacity has been suspected as a mechanism of this muscle underperfusion during maximal exercise, but its role during submaximal exercise remains unclear. Therefore, we studied by transcutaneous Doppler ultrasonography the arterial blood flow in the common femoral artery at rest and during a submaximal bicycle exercise in 12 normal subjects and in 30 patients with heart failure. Leg blood flow was lower in patients than in control subjects at rest [0.29 +/- 0.14 (SD) vs. 0.45 +/- 0.14 l/min, P < 0.01], at absolute powers and at the same relative power (2.17 +/- 1.06 vs. 4.39 +/- 1.4 l/min, P < 0.001). Because mean arterial pressure was maintained, leg vascular resistance was higher in patients than in control subjects at rest (407 +/- 187 vs. 247 +/- 71 mmHg.l-1.min, P < 0.01) and at the same relative power (73 +/- 49 vs. 31 +/- 13 mmHg.l-1.min, P < 0.01) but not at absolute powers. Although the magnitude of increase in leg blood flow corrected for power was similar in both groups (31 +/- 10 vs. 34 +/- 10 ml.min-1.W-1), the magnitude of decrease of leg vascular resistance corrected for power was higher in patients than in control subjects (5.9 +/- 3.3 vs. 1.9 +/- 0.94 mmHg.l-1.min.W-1, P < 0.001). These results suggest that the ability of skeletal muscle vascular resistance to decrease is not impaired and that intrinsic vascular abnormalities do not limit vasodilator response to submaximal exercise in patients with heart failure.

[Right retroauricular hematoma of late manifestation. Contribution of cardiac imaging]. / Hématome rétro-auriculaire droit de révélation tardive. Apport de l'imagerie cardiaque.

Right intrapericardial retroatrial haematomas are usually discovered in an acute context of tamponade, following cardiac surgery. The original feature of this case was the asymptomatic nature of a right retroatrial haematoma, after surgical closure of an ostium secundum atrial septal defect, with a free interval of more than 20 years between the surgical procedure and the first relatively minor symptoms, consisting of supraventricular arrhythmias. It can be difficult to determine the intra- or extra-atrial topography of a right-sided mass by transthoracic echocardiography. On the other hand, transoesophageal echocardiography and ultrafast CT can provide a precise topographic diagnosis and appear to be complementary to assess the nature of pericardial masses.

Eicosanoid biosynthesis in patients with stable angina: beneficial effects of very low dose aspirin.

OBJECTIVE: We assessed the production of eicosanoids and the effects of very low dose aspirin in patients with stable angina under basal conditions and during rapid atrial pacing. BACKGROUND: Platelet activation occurs in acute ischemic syndromes but is still controversial in stable angina. Very low dose aspirin is known to be platelet selective and can be used to test the hypothesis of the platelet origin of increased thromboxane production in stable angina. METHODS: Urinary excretion of eicosanoids was measured in 42 patients, including 24 patients with and 18 patients without coronary artery disease. The effects of 50 mg/day of aspirin were measured at rest and during pacing-induced ischemia in 10 patients with stable angina and were compared with a similar group of patients not treated by aspirin. RESULTS: Excretion of 11-dehydro-thromboxane B2 was 2.6 times higher in patients with stable angina than in healthy subjects (mean [+/- SEM] 74.8 +/- 13.0 [24 patients] vs. 29.0 +/- 5.4 [18 patients] ng/mmol of creatinine, p < 0.01). Urinary prostacyclin metabolite levels did not differ between the two groups. Treatment for 8 days with 50 mg/day of aspirin inhibited platelet cyclooxygenase, as reflected by the 97% reduction of in vitro serum thromboxane production. This aspirin regimen normalized the level of urinary thromboxane metabolites in patients with angina (17.3 +/- 3.4 ng/mmol of creatinine [10 patients], p < 0.001 from baseline level before treatment) and did not change prostacyclin metabolite levels. Atrial pacing in patients with angina not treated with aspirin caused lactate and thromboxane release into the coronary sinus. In patients with very low dose aspirin therapy, pacing did not cause thromboxane release despite inducing myocardial ischemia. However, fractional lactate extraction decreased less sharply in patients with than without aspirin therapy. CONCLUSIONS: Thromboxane production is greatly increased in patients with stable angina. Very low dose aspirin administered to these patients reduces thromboxane synthesis to normal levels, preserves prostacyclin biosynthesis and prevents acute thromboxane release into the coronary circulation during pacing-induced ischemia. Our data suggest that platelets (not monocytes/macrophages) are activated in stable angina to produce thromboxane.

Aneurysm of the interventricular membranous septum with thrombo-embolism--an indication for surgical repair?

A 40-year-old woman with a significant neurological history presented with right hemiparesia, paraesthesia of the right upper member and of the hemiface. Computer tomography scanning revealed hypodensity along the right lateral ventricle which corresponded to the left hemiplegia which had developed when she was 20 years old. Arteriography of the four cervical axes was normal. Echocardiography visualized an aneurysm of the membraneous septum free of thrombosis without ventricular septal defect. The embolism was thought to be of cardiac origin and a decision was taken to correct it by surgery. Ten years after surgical repair no other neurological event has occurred.

[Changes in plasma endothelin during coronary spasm]. / Variations de l'endothéline plasmatique au cours du spasme coronaire.

The role of endothelin, a powerful vasoconstrictor, was studied in coronary spasm. A methylergonovine stress test was performed in patients with normal coronary angiography. Patients who developed spasm (Group I, n = 6) were compared with those who did not (Group II, n = 6). Plasma endothelin was measured at 8, 11 a.m., 2 p.m., 4, 7, 9, 11 p.m. and 1 a.m. The stress test was carried out at 17 hours and an additional endothelin measurement was performed during spasm in positive cases. The clinical characteristics of the two groups were comparable especially with regards to cardiovascular risk factors. Except for the value recorded during coronary spasm, the plasma endothelin levels were significantly higher in the group with coronary spasm. A time-dependent variation was observed in both groups with higher endothelin levels in the morning. In group I the plasma endothelin levels were higher under basal conditions and during spasm in patients with spastic angina.

[Course of unstable angina and therapeutic implications. Apropos of 74 cases]. / Evolution de l'angor instable et implications thérapeutiques. A propos de 74 cas.

The role of thrombosis in the pathogenesis of unstable angina has been demonstrated experimentally. This retrospective study was designed to identify the potential usefulness of fibrinolytic treatment in this situation. The following parameters were evaluated in 74 patients (62 men, 12 women; mean age: 60 +/- 10.2) with primary unstable angina: the course of unstable angina (Braunwald classification), risk factors, electrocardiographic changes, echocardiographic segmental kinetics, coronary arteriography findings, treatment used and outcome with a minimum follow-up of 3 months (mean: 6.3 months). Thirty nine per cent of class I patients and 18% of classes II and III were stabilised by medical treatment only. This accounted for 18 patients in our series (24%). The other patients (76%) required one or more reperfusion techniques (thrombolysis: 5 patients; angioplasty: 42; bypass: 19). Serious complications were seen in 3 patients: myocardial infarction: 2 postoperative (including one fatal) and 1 occurring 24 hours after angioplasty followed by cardiogenic shock and death. Five patients required thrombolytic treatment leading to clinical stabilisation enabling an additional procedure (angioplasty or bypass). No complications of thrombolytic treatment were seen. Thus thrombolytic treatment appears to be useful for the stabilisation of unstable angina and enables subsequent radical treatment under better conditions.

[Antioxidative treatment in myocardial reperfusion ischemia]. / Le traitement antioxydant dans l'ischémie reperfusion myocardique.

Perfusion-induced myocardial ischaemia is observed in several situations: chronic coronary insufficiency, unstable angina, myocardial infarction, and during coronary angioplasty or bypass surgery. Oxygen-derived free radicals are liberated in large quantities during myocardial reperfusion ischaemia. Though very toxic in experimental studies, the responsibility of these free radicals in myocardial injury remains to be demonstrated clinically. Oxidant stress, characterised by an imbalance between the free radical attack and insufficient cellular defense seems partially responsible for reperfusion arrhythmias and post-ischemic stunning. On the other hand, its role is less evident in prolonged myocardial ischaemia causing irreversible myocardial lesions such as infarction. Antioxidant therapy is under evaluation in clinical trials. There are several options: some prevent the formation of free radicals by inhibiting the biochemical reactions which may produce them or by limiting the intervention of the neutrophils--the "fulcrum" of free radicals formations. Other antioxidant therapies inactivate free radicals as they are formed by promoting their degradation or their neutralisation. Experimental data is profuse and discordant. The models are very different. The first clinical trials are under way using either specific antioxidant molecules or molecules having other beneficial effects: in the latter case, the benefit of the antioxidant action is more difficult to demonstrate. Antioxidant therapy could play a role in surgical myocardial protection, especially of transplant organs, in very early forms of ischaemia. It could also prevent the pejorative hemodynamic consequences of myocardial stunning of the border zones of infarction, so enabling patients to survive a difficult period. The results of on-going studies should clarify the role of antioxidant therapy in reperfusion-induced myocardial ischaemia.