Effect of side and rate of stimulation on cerebral blood flow changes in motor areas during finger movements in humans.

We measured, using single photon emission computed tomography, the regional CBF (rCBF) changes in the motor areas of 24 right-handed normal volunteers during the performance of a motor task consisting of sequential finger-to-thumb opposition. Twelve of them performed the task with their right and their left hands consecutively with a fast frequency and large amplitude. The other 12 subjects performed the task with their right hand only at a slow frequency and small amplitude. The contralateral primary sensorimotor areas (S1/M1), supplementary motor area (SMA), and ipsilateral cerebellum were significantly activated during right and left finger movements performed at fast frequency and large amplitude. No significant difference was found between the rCBF changes induced by the right dominant and left nondominant hands. When the task was performed with a slow rate and small amplitude, the SMA was significantly activated while no significant changes were observed in the contralateral S1/M1 or in the ipsilateral cerebellum. These results demonstrate (a) that hand dominance evokes no differences in the activation of the main motor areas and (b) that the frequency and amplitude of the movement have a major effect on the quantitative and qualitative aspect of activation of motor areas in humans.

Supplementary and primary sensory motor area activity in Parkinson's disease. Regional cerebral blood flow changes during finger movements and effects of apomorphine.

We have measured with single-photon emission tomography the regional cerebral blood flow changes that occurred in the supplementary motor areas and in the primary sensory motor areas during sequential finger-to-thumb opposition movements of the right hand in seven akinetic patients with Parkinson's disease and in nine normal volunteers. Parkinsonian patients were studied before ("off" condition) and after a subcutaneous injection of apomorphine hydrochloride which was able to switch them "on" (on condition). In normal volunteers and parkinsonian patients in the on condition, regional cerebral blood flow significantly increased in the supplementary motor areas and in the contralateral primary sensory motor cortex but not in the ipsilateral primary sensory motor cortex. On the contrary, no significant regional cerebral blood flow change was observed in these areas in parkinsonian patients in the off condition. These results support the hypothesis that a functional cortical motor area deafferentation is involved in the pathophysiological makeup of akinesia and that this abnormality is reversed by dopaminergic drugs.

Levorotatory form of 5-hydroxytryptophan in Friedreich's ataxia. Results of a double-blind drug-placebo cooperative study.

OBJECTIVE: To study the effect of the levorotatory form of 5-hydroxytryptophan on the cerebellar symptoms of Friedreich's ataxia. DESIGN: Cooperative double-blind study of the levorotatory form of 5-hydroxytryptophan vs placebo. SETTING: Twelve centers in research hospitals. PATIENTS: Twenty-six patients were included; 19 completed the study (mean +/- SD age of patients, 25.9 +/- 8.1 years). Of these 19 patients, eight were treated with placebo and 11 were treated with the drug. MAIN OUTCOME MEASURES: A semiquantitative scale for kinetic and static ("postural") cerebellar functions and quantitative measurements of time in standard tests that evaluated stance, speech, writing, and drawing. RESULTS: In the active treatment group, a significant decrease of the kinetic score was observed (P = .03), indicating an improvement in coordination. CONCLUSIONS: These results demonstrated that the levorotatory form of 5-hydroxytryptophan is able to modify significantly the cerebellar symptoms in patients with Friedreich's ataxia. However, the effect is only partial and not clinically major.

Parkinson's disease and hypertension: chronic bromocriptine treatment.

We studied the effects of bromocriptine therapy (mean dosage, 56.0 mg daily) for 12 months in five patients with both Parkinson's disease and hypertension. Therapy improved neurologic manifestations and reduced both supine and standing systolic blood pressures and standing diastolic blood pressure with no consistent change in heart rate. Transient episodes of orthostatic hypotension appeared in two cases. Domperidone (60 mg daily for 1 month) did not abolish the antihypertensive effect of bromocriptine, suggesting that central dopaminergic or alpha-adrenolytic mechanisms are involved in this effect. Bromocriptine may be useful in the treatment of hypertension in patients with Parkinson's disease.

Two weeks of treatment with deprenyl (selegiline) does not prolong L-dopa effect in parkinsonian patients: a double-blind cross-over placebo-controlled trial.

We investigated the influence of 2 weeks of treatment with deprenyl on the acute effect of a single dose of 200 mg of L-dopa in a double-blind cross-over placebo-controlled trial in 16 parkinsonian patients with wearing-off phenomena. Deprenyl induced no significant benefit in the duration or the maximal improvement of L-dopa's effect. Moreover, deprenyl treatment did not improve the patient's motor status.

Blood pressure and plasma catecholamines in never-treated parkinsonian patients: effect of a selective D1 agonist (CY 208-243).

We found blood pressure (BP), heart rate (HR), plasma norepinephrine (NE), and epinephrine (E) levels in the lying and the standing positions to be similar in never-treated parkinsonian patients (stages 1 and 2) and age-matched controls. CY 208-243, a new centrally active D1 agonist, significantly decreased BP, HR, and NE (but not E) values in the lying position; it elicited orthostatic hypotension and blunted the rise in NE elicited by standing up. These results indicate that the early stages of Parkinson's disease are not accompanied by major changes in autonomic cardiovascular function and suggest the involvement of central D1-receptors in the control of sympathetic tone.

Cerebral blood flow correlates of word monitoring in sentences: influence of semantic incoherence. A spect study in normals.

The aim of this study was to assess the cerebral blood flow (CBF) changes induced by the semantic incoherence of sentences whose words were to be monitored by the subjects. According to Marslen-Wilson and Tyler, word processing would be parallel (global) in semantically coherent sentences, and serial (local) in semantically incoherent ones. We hypothesized that, in comparison with the parallel mode, the serial mode of word processing would result in a preponderant activation of the frontal lobes and/or of the left hemisphere, hence in a flow increase in these regions. In addition, one could assume that the increase in task complexity resulting from the breaking of semantic coherence would reinforce the functional links between hemispheres. Furthermore, as interactions between the processing of semantically coherent vs incoherent of verbal materials and the processing of imageable vs non-imageable stimuli was recently suspected, we designed a study combining coherent vs incoherent sentences and imageable vs non-imageable words. The results we obtained in 12 normal volunteers by measuring regional cerebral blood flow by SPECT and IV injection of Xenon 133 during the four experimental conditions, did not allow us to firmly establish our hypotheses. Indeed, we failed to demonstrate any significant CBF changes across conditions and there was no interaction between coherent vs incoherent and imageable vs non-imageable conditions. However, the analysis of the inter-regional correlations pointed to an increase in the functional links between the hemispheres in the incoherent conditions, whatever the imageability.

Normal CSF levels of met-enkephalin-like material in a case of naloxone-reversible congenital insensitivity to pain.

In a case of naloxone-reversible congenital insensitivity to pain, met-enkephalin-like immunoreactivity in the CSF was in the normal range and not affected by the administration of naloxone. Chromatographic analysis of the met-enkephalin-like material revealed that it corresponded to at least two classes of molecules. A clear difference in the relative proportions of these two classes was detected in the CSF of the patient insensitive to pain when compared to controls. The possible functional significance of this alteration is discussed in relation to the well known antinociceptive action of enkephalins.

Platelet arachidonic acid metabolism in severe cerebrovascular disease.

The ability of platelets to synthetise thromboxane B2 and hydroxylated fatty acids from arachidonic acid was studied simultaneously with arachidonic acid-induced aggregation in 42 patients suffering from severe cerebral atherosclerosis and also in 34 healthy controls. Additionally, phospholipase-A2-induced aggregation was performed as a probe for arachidonic acid located at the platelet surface. All the assays were performed with washed platelets, eliminating a possible influence of plasma. Platelets from patients were found responsive to significantly lower concentrations of arachidonic acid whereas thromboxane and hydroxylated fatty acid biosynthesis did not differ from controls. In the experimental conditions used, 75% of the control platelets underwent aggregation with phospholipase A2 plus sphingomyelinase C, in comparison to only 50% for the patients, indicating the necessity for further analysis of the platelet membrane lipids in atherosclerosis.

Investigation of extracranial cerebral arteries by intravenous angiography: report of 1,000 cases.

Intravenous angiography is a a safe, rapid, simple examination, which, with sonography, is complementary in selecting patients for conventional angiography. This examination is not designed to replace conventional angiography, but, rather, to study high-risk stroke patients, patients with asymptomatic cervical bruit, or postoperative patients. Improvements in contrast media, film subtraction, the use of oral anesthesia with viscous lidocaine, and the technique of cooling the contrast medium have made the procedure more successful. A review of 1,000 examinations was undertaken to determine the accuracy of the technique and to emphasize technical points. Excellent results, comparable to conventional angiography, were obtained in 50.3% patients and good results in 32%. Poor or uninterpretable results were obtained in 17.7%. These were secondary to either patient movement or the presence of venous reflux or statis of contrast medium.

Internal capsule: normal anatomy and ischemic changes demonstrated by computed tomography.

The purpose of this study was two-fold: (1) to attempt to localize the different parts of the internal capsule on computed tomography (CT) axial sections and (2) to correlate clinical data and CT appearance of 25 cases of ischemic capsular lesions. Twenty-three of the ischemic lesions produced a pure motor hemiplegia. The internal capsule was studied on routine CT axial sections parallel to the canthomeatal line with 8 mm collimation before and after intravenous contrast medium injection. Absorption values of the white matter at the level of the anterior limb of the internal capsule were found to be a little higher (mean, 32 Hounsfield units [H]) when compared with the posterior limb (mean, 28 H). Lesions were classified according to the topography of the internal capsule: anterior limb (three), genu (one), posterior limb (seven), and putaminocapsulocaudate (14). CT appears to be the most sensitive and reliable method to investigate small deep cerebral infarcts since isotope scans were positive in only two of 13 cases, while angiography was positive in eight of 17 cases.

Delayed hypersensitivity to human encephalitogenic protein as assayed by agarose leucocyte migration in multiple sclerosis patients.

Using a leucocyte migration test (Clausen's direct agarose gel migration method) hypersensitivity to human encephalitogenic protein has been examined in 50 multiple sclerosis patients (group 1), 50 healthy persons (group 2) and 25 patients with other neurological diseases (group 3). In group 1, 30 MS patients (60%) show an abnormal migration index, manifested either as inhibition or stimulation of migration; 29 controls in group 2 (58%), 11 O.N.D. patients in group 3 (44%) show an abnormal migration index. These results mean that lymphocyte hypersensitivity to myelin basic protein appears neither to be constant nor specific to multiple sclerosis. Three migration index curve types at different antigen concentration are obtained: monophasic curves within the normal index zones; monophasic curves staying in the inhibition or stimulation zone and biphasic curves with dose-effect relationship. Whatever the antigen used, this dose-effect relationship implies that the test must be carried out at different concentrations. The meaning of spontaneous sensitisation in healthy controls is discussed.

Immunoglobulin allotypes and susceptibility to multiple sclerosis. An epidemiological and genetic study in the Hautes-Pyrénées county of France.

Serum samples collected from 69 patients with multiple sclerosis (MS) living in the Hautes-Pyrénées county were tested for immunoglobulin Gm gamma 1, gamma 2, and gamma 3, heavy chain allotypes (Gm system), and immunoglobulin light chain Kappa (Km system). A control group was made up of normal individuals living in the same county. We found a significant excess of individuals with Gm3; +/- 23;5/Gm3; +/- 23;5 amongst the MS patients as compared with controls (relative risk = 2.4). A slight increase of the Km (1) frequency was found in MS patients compared with controls, 21.7% vs 11.8%, but this difference was not significant.

Lateral asymmetries in primary degenerative dementia of the Alzheimer type. A correlative study of cognitive, haemodynamic and EEG data, in relation with severity, age of onset and sex.

Cognitive, haemodynamic and EEG lateral asymmetries have been quantified in 20 patients with Primary Degenerative Dementia (PDD) and in 20 age-matched normal volunteers. Normalized asymmetry scores were calculated from the data obtained with a test battery, with SPECT and with quantitative EEG. Significant correlations were found between cognitive, haemodynamic and EEG scores in patients but not in controls. The functional asymmetries correlated to the Mini Mental State (MMS) score, the lowest MMS values being observed in patients with right hemisphere predominant impairment. Besides, in these patients, a significant correlation was observed between age at onset and MMS score so that, in this subgroup only, the earlier the onset the more severe the disease. Finally, the prevalence of pronounced functional asymmetry seemed to be higher in our male patients. Our study shows that lateral asymmetries are frequent in patients with PDD and that preferential lateralization of the abnormalities should be given further attention, especially with regards to age, sex and overall severity.

Sublingual apomorphine: a new pharmacological approach in Parkinson's disease?

Apomorphine, a potent dopamine agonist with mixed D1 and D2 properties, has long been recognized to have antiparkinsonian effect. Its oral administration is limited by both its hepatic first pass metabolism and adverse side effects (nausea, vomiting, azotemia). It is now widely used by subcutaneous route for the treatment of severe "off" periods seen with levodopa treatment. However, the use of penjects can be difficult in some patients with severe tremor or akineto-rigid symptoms during "off" periods. Our group has recently investigated the effect of sublingual administration of apomorphine in patients suffering from Parkinson's disease. Sublingual apomorphine was shown to reduce extrapyramidal symptoms. The main characteristics of the pharmacodynamic effects of sublingual apomorphine in parkinsonians and the relationship between pharmacodynamic and pharmacokinetic effects are discussed. Sublingual apomorphine has the advantage of being easier to administer than subcutaneous injection. For the moment, the long-term use of sublingual apomorphine is limited by two major problems: first, time for dissolution and switch "on" (which is longer than after subcutaneous route) and secondly, the occurrence of local side effects (stomatitis). Further clinical studies using either more efficient (tablets with faster dissolution) and better tolerated sublingual formulations or other dopamine agonists should be carried on before recommending this approach in the treatment of Parkinson's disease.

Lack of yohimbine effect on ambulatory blood pressure recording: a double-blind cross-over trial in parkinsonians with orthostatic hypotension.

Yohimbine is an alpha 2-adrenergic antagonist which has been proposed for the treatment of orthostatic hypotension (OH). We investigated in a double-blind placebo-controlled crossover trial the effects of yohimbine (2 mg tid) on blood pressure (BP) and heart rate (HR) using ambulatory monitoring of blood pressure (AMBP) in 17 patients (69 +/- 5 years) with Parkinson's disease (PD) suffering from non drug-induced OH. At the end of each sequence of 4 weeks, mean systolic (SBP) and diastolic (DBP) BP and HR (+/- SD), BP variability (coefficient of variation of the mean) and nychtemeral rhythm were calculated for day-time (09:00-19:00 h) and night-time (23:00-06:00 h). OH related to PD was characterized by: i) loss of the nychtemeral rhythm of BP (night/day ratio: 1.18 +/- 0.14) but not of HR (night/day ratio: 0.87 +/- 0.04), ii) high variability of BP during day-time and iii) post-prandial hypotension (12 out of 17 patients). There was no significant difference in AMBP parameters between baseline, yohimbine and placebo periods. This study shows that AMBP is a simple and reproducible method to assess the effects of drugs used in the management of OH on BP parameters (mean values and variability) and that yohimbine is not effective to correct OH of PD. Future studies must investigate other more selective alpha 2-adrenergic antagonists.

Mesulergine (CU 32-085) in the treatment of Parkinson's disease.

The long-term effects of mesulergine, a new drug with dopamine agonistic properties, were studied in 28 patients with Parkinson's disease. In 18 patients with late side effects of levodopa, the addition of mesulergine (10.9 mg/day) induced significant decreases in the global (-48%), rigidity (-62%), and akinesia (-37%) scores. The drug was found to be very effective on tremor (-71%). Mesulergine was useful in cases of inefficacy of levodopa alone or persistent intolerable side effects. The decrease in levodopa dose and the addition of mesulergine permitted a significant reduction in dyskinesia. Used as sole therapeutic agent (10.9 mg/day), mesulergine was found to be active on tremor and rigidity scores but not on akinesia or global scores. Mesulergine induced few side effects. These results show the antiparkinsonian properties of mesulergine that seem to be of significant therapeutic value in patients with tremor or in combination with levodopa.

Beta-adrenergic sensitivity in Parkinson's disease: effect of levodopa treatment.

The beta-adrenergic sensitivity in never-treated and levodopa-treated patients with Parkinson's disease (PD) was studied through the evaluation of lymphocyte beta-adrenoceptor number ([125I]cyanopindolol binding sites) and chronotropic and metabolic (plasma nonesterified fatty acids--NEFA) responses to isoproterenol. No change was found in Bmax values or affinity constant Kd between never-treated patients, levodopa-treated patients with PD, and controls. At rest, no difference was observed in heart rate, plasma catecholamine, or NEFA levels between the three groups. Isoproterenol sensitivity (chronotropic response and plasma NEFA increase) was similar in never-treated and treated PD. The results suggest that peripheral beta-adrenergic sensitivity is unaffected either by the pathophysiological process of PD or by levodopa treatment.

Effects of levodopa and bromocriptine on blood pressure and plasma catecholamines in parkinsonians.

Blood pressure (BP), heart rate (HR), plasma noradrenaline (NA), and adrenaline (A) levels in the lying and standing position were compared in patients with Parkinson's disease (PD) and control subjects. Three groups of PD patients (stage 2 and 3) were investigated: six patients deprived of antiparkinsonian drugs from 48 h, seven levodopa + benserazide-treated patients, and seven bromocriptine-treated patients. BP, HR, NA, and A were similar at rest and in the standing position in controls and in PD patients deprived of antiparkinsonian drugs from 48 h. Chronic treatment with levodopa (+ benserazide) failed to modify BP, HR, NA, and A. Bromocriptine decreased BP, HR, and NA (but not A) at rest. In PD patients treated with levodopa (+ benserazide) or bromocriptine alone, the rise in NA (but not A) elicited by standing up was reduced. These results indicate that (a) stages 2 to 3 of Parkinson's disease are not accompanied by major changes in autonomic cardiovascular function and (b) dopaminergic drugs blunted the sympathetic response to standing up.

Measurement of plasma levels of clomipramine in the treatment of chronic pain.

The analgesic effect of clomipramine and the possible relationships between the antalgic action and the plasma levels of this tricyclic drug have been studied in 30 patients with chronic pain induced by nervous lesions determining a deafferentation. Twenty of 30 patients treated with clomipramine reported a significant improvement (up to 50%) observed as soon as the 4th day, with few side effects. The pharmacokinetic analysis shows the existence (r = 0.358; p less than 0.001) of a relationship between analgesia and plasma levels of clomipramine for each individual patient. This study also indicates a "therapeutic window" of plasma levels between 20 and 85 ng/ml. These results permit discussion of measurement of plasma levels of clomipramine in the treatment of chronic pain.