Lars Friberg

Migraine pain associated with middle cerebral artery dilatation: reversal by sumatriptan

The combination of measurements of regional cerebral blood flow (rCBF) and blood velocity in the middle cerebral arteries (MCA) by transcranial doppler sonography was used to investigate cerebrovascular involvement in migraine. Ten migraine patients with unilateral headache were studied during an attack and when they had been free of attacks for 5 days (non-attack). On both occasions they were given as intravenous infusion of sumatriptan (2 mg), a 5-HT1-like receptor agonist, which relieved the symptoms within 30 min without affecting rCBF. The MCA velocity was normal on both sides on the non-attack day and on the unaffected side during the attack. However, during the attack the MCA velocity on the headache side was significantly lower than that on the non-headache side (45 vs 61 cm/s:mean difference 16.3 [95% confidence interval 10.3-22.3]; p = 0.02). The MCA velocity on the headache side returned to normal after treatment with sumatriptan and recovery. Since rCBF in the MCA supply territory was unaffected, the lower velocity can be explained only by dilatation of the MCA. The mean MCA diameter increase was estimated to be 20%. Thus, headache was associated with intracranial large arterial dilatation on the headache side. Sumatriptan predominantly had effects on the distended artery, which suggests that the 5-HT receptor system has a role in the pathogenesis of migraine.

A 15O‐H2O PET study of meditation and the resting state of normal consciousness

The aim of the present study was to examine whether the neural structures subserving meditation can be reproducibly measured, and, if so, whether they are different from those supporting the resting state of normal consciousness. Cerebral blood flow distribution was investigated with the 15O‐H2O PET technique in nine young adults, who were highly experienced yoga teachers, during the relaxation meditation (Yoga Nidra), and during the resting state of normal consciousness. In addition, global CBF was measured in two of the subjects. Spectral EEG analysis was performed throughout the investigations. In meditation, differential activity was seen, with the noticeable exception of V1, in the posterior sensory and associative cortices known to participate in imagery tasks. In the resting state of normal consciousness (compared with meditation as a baseline), differential activity was found in dorso‐lateral and orbital frontal cortex, anterior cingulate gyri, left temporal gyri, left inferior parietal lobule, striatal and thalamic regions, pons and cerebellar vermis and hemispheres, structures thought to support an executive attentional network. The mean global flow remained unchanged for both subjects throughout the investigation (39 ± 5 and 38 ± 4 ml/100 g/min, uncorrected for partial volume effects). It is concluded that the H215O PET method may measure CBF distribution in the meditative state as well as during the resting state of normal consciousness, and that characteristic patterns of neural activity support each state. These findings enhance our understanding of the neural basis of different aspects of consciousness. Hum. Brain Mapping 7:98–105, 1999.

Human regional cerebral blood flow during rapid-eye-movement sleep.

Owing to the coupling between CBF and neuronal activity, regional CBF is a reflection of neural activity in different brain regions. In this study we measured regional CBF during polysomnographically well-defined rapid-eye-movement (REM) sleep by the use of single photon emission computerized tomography and the new tracer 99mTc-dl-hexamethylpropyleneamine. Eleven healthy volunteers aged between 22 and 27 years were studied. CBF was measured on separate nights during REM sleep and during EEG-verified wakefulness. On awakening from REM sleep, all subjects reported visual dreams. During REM sleep CBF increased by 4% (p < 0.01) in the associative visual area, while it decreased by 9% (p < 0.01) in the inferior frontal cortex. The CBF increase in the associative visual area suggests that activation of cerebral structures processing complex visual material is correlated to visual dream experiences. On the other hand, the reduced involvement of the inferior frontal cortex observed during REM sleep might explain the poor temporal organization and bizarreness often experienced in dreams.

Potential Language and Attentional Networks Revealed through Factor Analysis of rCBF Data Measured with SPECT

We used changes in regional cerebral blood flow (rCBF) to disclose regions involved in central auditory and language processing in the normal brain. rCBF was quantified with a fast-rotating, single-photon emission computerized tomograph (SPECT) and inhalation of 133Xe. rCBF data were obtained simultaneously from parallel, transverse slices of the brain. The lower slice was positioned to include both Brocas and Wernickes areas. The upper slice included regions generally regarded by neurobehaviorists as less related to primary auditory or linguistic functions. We presented three types of auditory stimuli to ten healthy, young volunteers: (a) diotically presented Danish speech, (b) dichotic word stimulation, and (c) white noise. Wilcoxons signed ranks sum test revealed increased rCBF in language-related areas of cortex, viz., Wernickes area and its right-sided homologous area as well as in Brocas area (left hemisphere), when subjects listened to narrative speech, compared to white noise (baseline). No significant rCBF differences were detected with this test during dichotic stimulation vs. white noise. A more sophisticated statistical method (factor analysis) disclosed patterns of functionally intercorrelated regions. The factor analysis reduced the highly intercorrelated rCBF measures from 28 regions of interest to a set of three independent factors. These factors accounted for 77% of the total variation in rCBF values. These three factors appeared to represent statistical analogues of independent brain networks involved in (I) auditory/linguistic, (II) attentional, and (III) visual imaging activity.

Cerebral oxygen extraction, oxygen consumption, and regional cerebral blood flow during the aura phase of migraine.

Background and Purpose The aura phase of migraine is associated with focal blood flow changes, but it has been largely unknown whether these changes are correlated to changes in the cerebral metabolism. Methods Eight patients required carotid angiography for evaluation of transient neurological attacks. Cerebral blood flow (CBF) results, angiography, and clinical observations subsequently suggested the diagnosis: migraine with aura and occasional aura attacks without headache. In the same setting the cerebral angiography was followed by four to six repeated recordings of regional CBF using the intra-arterial 133Xe injection method. Blood samples were drawn from the carotid artery and the internal jugular vein to measure oxygen extraction fraction and cerebral metabolic rate for oxygen. Results The intracarotid regional CBF technique provoked aura symptoms and typical, migraine-related, posterior focal hypoperfusion in four patients, followed by typical unilateral headache in three patients. The remaining four patients had no symptoms or regional CBF changes during the examination. There was a significant increase (mean, 13%) of global oxygen extraction fraction in the four patients during aura symptoms, whereas no significant changes of oxygen extraction fraction were found in the nonsymptomatic group. The increase in global oxygen extraction fraction in the symptomatic group coincided with a drop of hemispheric CBF (mean, 12%). Cerebral metabolic oxygen rate remained essentially unchanged, as did Paco2. Conclusions The data presented suggest that the focal flow reduction during the migraine-aura phase is not a secondary phenomenon of reduced cerebral metabolism. However, arte riolar vasoconstriction might offer a possible explanation for the regional CBF changes observed during the migraine aura.

Missense dopamine transporter mutations associate with adult parkinsonism and ADHD

Parkinsonism and attention deficit hyperactivity disorder (ADHD) are widespread brain disorders that involve disturbances of dopaminergic signaling. The sodium-coupled dopamine transporter (DAT) controls dopamine homeostasis, but its contribution to disease remains poorly understood. Here, we analyzed a cohort of patients with atypical movement disorder and identified 2 DAT coding variants, DAT-Ile312Phe and a presumed de novo mutant DAT-Asp421Asn, in an adult male with early-onset parkinsonism and ADHD. According to DAT single-photon emission computed tomography (DAT-SPECT) scans and a fluoro-deoxy-glucose-PET/MRI (FDG-PET/MRI) scan, the patient suffered from progressive dopaminergic neurodegeneration. In heterologous cells, both DAT variants exhibited markedly reduced dopamine uptake capacity but preserved membrane targeting, consistent with impaired catalytic activity. Computational simulations and uptake experiments suggested that the disrupted function of the DAT-Asp421Asn mutant is the result of compromised sodium binding, in agreement with Asp421 coordinating sodium at the second sodium site. For DAT-Asp421Asn, substrate efflux experiments revealed a constitutive, anomalous efflux of dopamine, and electrophysiological analyses identified a large cation leak that might further perturb dopaminergic neurotransmission. Our results link specific DAT missense mutations to neurodegenerative early-onset parkinsonism. Moreover, the neuropsychiatric comorbidity provides additional support for the idea that DAT missense mutations are an ADHD risk factor and suggests that complex DAT genotype and phenotype correlations contribute to different dopaminergic pathologies.

Absence of Vasoactive Peptide Release from Brain to Cerebral Circulation During Onset of Migraine With Aura

In eight patients carotid angiography was required for evaluation of transient neurological attacks. Cerebral blood flow results, angiography and clinical observations subsequently suggested the diagnosis of migraine. We measured plasma concentrations of substance P(SP), neuropeptide Y (NPY), calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) in repeated blood samples obtained from the carotid artery and the internal jugular vein in conjunction with cerebral angiography followed by 4 to 6 repeated recordings of regional cerebral blood flow (rCBF) with the intracarotid Xenon-133 injection technique. This technique is known to induce attacks of migraine with aura in many sufferers. Four patients developed aura symptoms. In three this was succeeded by throbbing headache, Typical, migraine-related, focal hypoperfusion occurred in conjunction with the aura symptoms. The remaining four patients had no symptoms or rCBF changes. There were no systematic or statistically significant changes over time in arterial-venous plasma concentrations or in the release rates of any of the peptides. All migraineurs had an overall elevated mean CGRP value compared to control values from the literature. The overall plasma levels of the potent vasoconstrictor NPY were higher (p < 0.10) in the group that developed symptoms and rCBF changes (136 pmol/l) than in the non-symptomatic group (97 pmol/l). The difference in NPY levels could perhaps be associated with the focal rCBF decrease seen in the attack group.

Clinical impact of diagnostic SPET investigations with a dopamine re-uptake ligand

Abstract. The diagnosis of Parkinsons disease is based on clinical features with pathological verification. However, autopsy has been found to confirm a specialist diagnosis in only about 75% of cases. Especially early in the course of the disease, the clinical diagnosis can be difficult. Imaging of presynaptic dopamine transporters (DAT receptors) has provided a possible diagnostic probe in the evaluation of Parkinsons disease. The cocaine analogue [123I]-2-β-carboxymethoxy-3-β(4-iodophenyl)tropane ([123I]-β-CIT) is one of several radioligands that have been developed for single-photon emission tomography (SPET). The purpose of this study was to evaluate the impact of [123I]-β-CIT SPET on the diagnosis and clinical management of patients with a primary, tentative diagnosis of parkinsonism. We undertook a retrospective evaluation of the clinical records of 90 consecutive patients referred to [123I]-β-CIT SPET from the neurological department, Bispebjerg Hospital. In 58 subjects the scans revealed altered tracer uptake consistent with Parkinsons disease, progressive supranuclear palsy and multiple system atrophy. A significant change in the management or treatment because of the scan was found in 25 patients (28%). The sensitivity of the examination was 97% and the specificity 83%. In conclusion, a significant clinical impact of DAT receptor SPET imaging was found. DAT receptor imaging is a useful diagnostic probe in patients with a possible diagnosis of parkinsonism.

The Effect of the GABA-A Agonist THIP on Regional Cortical Blood Flow in Humans. A New Test of Hemispheric Dominance

We studied the effect of a γ-aminobutyric acid (GABA)–A receptor–induced postsynaptic inhibition on regional CBF (rCBF) in awake humans. For this purpose we used a new specific GABA–A agonist, 4,5,6,7-tetrahydroisoxazolo(5,4)-pyridin-3-ol (THIP). As part of a new diagnostic procedure for the determination of which hemisphere subserved language, THIP was infused into the internal carotid artery 20 s before measurement of the rCBF. Administered by this route the THIP is distributed to the neocortex and neostriatum. THIP induced a dosage-dependent decrease of the rCBF. The rCBF decrease was not due to any direct effect on the cerebral vessels. The efficiency of the THIP-induced postsynaptic inhibition was tested by having the subjects voluntarily activate the inhibited cortex. During submaximal inhibition the subjects were able voluntarily to counteract decreases of rCBF in superior frontal cortex and motor cortex. Larger doses of THIP abolished this response and depressed the rCBF to baseline levels (20 ml/100 g/min). This was associated with 10-min total depression of function of the anterior two-thirds of the injected hemisphere. An analysis of the changes of rCBF in activated and nonactivated cortex—with and without THIP-induced inhibition—showed that it would be very unlikely that average increases in synaptic inhibition would increase rCBF in neocortical areas. Intracarotid injection of the water-soluble, nonirritative THIP is a very useful alternative to sodium amytal injection for determination of hemispheric dominance.

Interictal "patchy" regional cerebral blood flow patterns in migraine patients. A single photon emission computerized tomographic study.

In 92 migraine patients and 44 healthy control subjects we recorded regional cerebral blood flow (rCBF) with single photon emission computerized tomography and 133Xe inhalation or with i.v. 99mTc‐HMPAO. Migraine patients were studied interictally. A quantitated analysis of right‐left asymmetry indices in a fixed set of regions of interest was compared with the normal asymmetry indices in the healthy controls. An asymmetry index deviating more than ± 2.5 S.D.s in normals was defined as pathological asymmetry. By quantitated analysis 47% of images from patients with aura attacks and 48% of images from patients without aura attacks were established to contain higher rate of asymmetries, the difference being statistically significant (p < 0.05, Wilcoxon). A blinded visual analysis and scoring by a four level scale were done by four experienced observers. rCBF images from 18% of patients having attacks with aura and from 19% of patients without aura attacks was scored as containing abnormal right‐left asymmetries by the visual analysis. Images from healthy controls were all scored to be normal. In 37% of the images (all from patients) there was lack of consensus among observers (κ = 0.28). There was no correlation between visual or quantitated abnormalities and age, duration of migraine, frequency of attacks or prophylactic medication. No correlation could be established between asymmetries and the usual side of headache or aura symptoms. Two conclusions emerged: (1) visual evaluation of interictal migraine rCBF images is insufficient to pick up abnormalities; (2) almost 50% of the migraine sufferers had abnormal rCBF/asymmetries. However, these are discrete compared with those typically seen during the aura phase of a migraine attack. One explanation to the patchy rCBF patterns might be that they reflect interictal cerebrovascular dysregulation which might to be a common feature in both types of migraine.