Hans C. Lou

Impaired autoregulation of cerebral blood flow in the distressed newborn infant

Cerebral blood flow was measured, using the 133Xe clearance technique, a few hours after birth in 19 infants with varying degrees of respiratory distress syndrome. Ten of these infants had had asphyxia at birth. The least affected infants with normotension (systolic blood pressure 60 to 65 mm Hg) had CBF values of about 40 ml/100 gm/minute. Hypotensive infants with asphyxia at birth or RDS or both had values for CBF of about 20 ml/100 gm/minute, or less. CBF was strongly correlated with the arterial blood pressure, showing a linear relationship that was identical in infants with asphyxia at birth and infants with RDS only. CBF varied considerably with spontaneous variations in blood pressure, suggesting that autoregulation was lacking. This finding may explain why distressed premature infants are prone to develop massive capillary bleeding in the germinal layer with penetration to the ventricles.

Reflective self-awareness and conscious states: PET evidence for a common midline parietofrontal core.

A recent meta-analysis has shown precuneus, angular gyri, anterior cingulate gyri, and adjacent structures to be highly metabolically active in support of resting consciousness. We hypothesize that these regions constitute a functional network of reflective self-awareness thought to be a core function of consciousness. Seven normal volunteers were asked to think intensely on how they would describe the personality traits and physical appearance of themselves and a neutral reference person known to all the subjects (the Danish Queen). During each of the four conditions cerebral blood flow distribution was measured by the intravenous H(2)(15)O PET scanning technique. During scanning, no sensory or motor activity was intended. After each scan, the subjects reported the contents of their thoughts during the scan to ascertain that the instructions had been followed. The results confirmed our hypothesis: Statistical parametric mapping showed differential activity in precuneus and angular gyri during reflection on own personality traits and in anterior cingulate gyri during reflection on own physical traits. Connectivity analysis of synchrony showed these regions to be functionally connected during reflective self-awareness. The commonality between the neural networks of the resting conscious state and self-awareness reflects the phenomenological concept of a fundamental contribution of reflective self-awareness to the contents and coherence of the conscious state.

PRENATAL STRESSORS OF HUMAN LIFE AFFECT FETAL BRAIN DEVELOPMENT

In a population‐based study, 3021 women in a central Copenhagen district received a questionnaire on environmental and psychological factors during mid‐gestation. Of these, 70 women were selected consecutively on the basis of moderate to severe stressful life‐events (DSM‐111‐R categories 3 to 5), in combination with an inadequate social network. They were compared with 50 non‐stressed women with an intact social network. Stress and smoking significantly affected birthweight and head circumference. When birthweight was corrected, stress remained a significant determinant of small head circumference, indicating a specific effect on brain development. Stress also led to a sub‐optimal Prechtl neonatal neurological score. These findings suggest the existence of a fetal stress syndrome with adverse effects on fetal development, including deficient brain development.

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.

Increased dopamine tone during meditation-induced change of consciousness

This is the first in vivo demonstration of an association between endogenous neurotransmitter release and conscious experience. Using 11C-raclopride PET we demonstrated increased endogenous dopamine release in the ventral striatum during Yoga Nidra meditation. Yoga Nidra is characterized by a depressed level of desire for action, associated with decreased blood flow in prefrontal, cerebellar and subcortical regions, structures thought to be organized in open loops subserving executive control. In the striatum, dopamine modulates excitatory glutamatergic synapses of the projections from the frontal cortex to striatal neurons, which in turn project back to the frontal cortex via the pallidum and ventral thalamus. The present study was designed to investigate whether endogenous dopamine release increases during loss of executive control in meditation. Participants underwent two 11C-raclopride PET scans: one while attending to speech with eyes closed, and one during active meditation. The tracer competes with endogenous dopamine for access to dopamine D2 receptors predominantly found in the basal ganglia. During meditation, 11C-raclopride binding in ventral striatum decreased by 7.9%. This corresponds to a 65% increase in endogenous dopamine release. The reduced raclopride binding correlated significantly with a concomitant increase in EEG theta activity, a characteristic feature of meditation. All participants reported a decreased desire for action during meditation, along with heightened sensory imagery. The level of gratification and the depth of relaxation did not differ between the attention and meditation conditions. Here we show increased striatal dopamine release during meditation associated with the experience of reduced readiness for action. It is suggested that being in the conscious state of meditation causes a suppression of cortico-striatal glutamatergic transmission. To our knowledge this is the first time in vivo evidence has been provided for regulation of conscious states at a synaptic level.

Serious life events and congenital malformations: a national study with complete follow-up

BACKGROUND Emotional stress during organogenesis could, in theory, cause congenital malformations. We undertook a follow-up study to test the hypothesis that psychosocial stress increases the prevalence of malformations, particularly of the cranial neural crest. METHODS We defined severe life events as death or first hospital admission for cancer or acute myocardial infarction in partners or children. From 1980 to 1992 all women exposed to severe life events during pregnancy and up to 16 months previously were identified by means of five national registers. We included 3560 exposed pregnancies and 20,299 pregnancies without such exposures randomly selected as a control cohort. FINDINGS The frequency of cranial-neural-crest malformations was higher in pregnancies with exposure to severe life events than in those without such exposure (42 [1.18%] vs 131 [0.65%]; adjusted odds ratio 1.54 [95% CI 1.05-2.27]). For other malformations, the frequencies were 3.04% and 3.26% (1.14 [0.94-1.42]). Women exposed in two consecutive pregnancies had a higher risk of cranial-neural-crest malformations (2.99 [1.06-8.43]). Death of an older child during the first trimester was associated with an adjusted odds ratio of cranial-neural-crest malformations of 4.75 (1.63-13.8). Unexpected death of a child during the first trimester was associated with adjusted odds ratios of 8.36 (2.41-29.0) for cranial-neural-crest malformations and 3.64 (1.29-10.3) for other malformations. INTERPRETATION These findings support the hypothesis that severe emotional stress during pregnancy, especially that related to death of a child, may cause congenital malformations, particularly those of the cranial neural crest.

Heterogeneity of cerebral vasoreactivity in preterm infants supported by mechanical ventilation

The reaction of cerebral blood flow to acute changes in arterial carbon dioxide pressure (PaCO2) and mean arterial blood pressure was determined in 57 preterm infants supported by mechanical ventilation (mean gestational age 30.1 weeks) during the first 48 hours of life. All infants had normal brain sonograms at the time of the investigation. In each infant, global cerebral blood flow was determined by xenon-133 clearance two to five times within a few hours at different levels of PaCO2. Changes in PaCO2 followed adjustments of the ventilator settings. Arterial oxygen pressure was intended to be kept constant, and mean arterial blood pressure fluctuated spontaneously between measurements. The data were analyzed by stepwise multiple regression, with changes in global cerebral blood flow, PaCO2, mean arterial blood pressure, and postnatal age or intracranial hemorrhage used as variables. In infants with persistently normal brain sonograms, the global cerebral blood flow-carbon dioxide reactivity was markedly lower during the first day of life (mean 11.2% to 11.8%/kPa PaCO2) compared with the second day of life (mean 32.6/kPa PaCO2), and pressure-flow autoregulation was preserved. Similarly, global cerebral blood flow-carbon dioxide reactivity and pressure-flow autoregulation were present in infants in whom mild intracranial hemorrhage developed after the study. In contrast, global cerebral blood flow reactivity to changes in PaCO2 and mean arterial blood pressure was absent in infants in whom ultrasonographic signs of severe intracranial hemorrhage subsequently developed. These infants also had about 20% lower global cerebral blood flow before hemorrhage, in comparison with infants whose sonograms were normal, a finding that suggests functional disturbances of cerebral blood flow regulation. Several perinatal factors were tested, but only birth after abruptio placentae was related to subsequent periventricular hemorrhage (p = 0.037).

Focal cerebral dysfunction in developmental learning disabilities

In 24 children with developmental learning disabilities and 15 age-matched controls regional cerebral activity was studied with xenon-133 single photon emission tomography. In the 9 children with pure attention deficit and hyperactivity disorder (ADHD), the distribution of regional cerebral activity was abnormal--low in striatal and posterior periventricular regions and high in occipital regions. Low activity in striatal and posterior periventricular areas was also seen in the 8 children with ADHD in combination with phonologic-syntactic dysphasia. 7 children with dysphasia, but without hyperactive behaviour, had low cerebral activity in left temporofrontal regions.

Molecular basis of phenotypic heterogeneity in phenylketonuria.

BACKGROUND Phenylketonuria is a metabolic disorder that results from a deficiency of the hepatic enzyme phenylalanine hydroxylase. Its clinical phenotype varies widely, and to date more than 10 mutations in the phenylalanine hydroxylase gene have been identified in persons with the disorder. We attempted to relate the clinical phenotype of patients to their genotype. METHODS We studied 258 patients with phenylketonuria from Denmark and Germany for the presence of eight mutations previously found in patients from these countries. The in vitro activity of the enzymes associated with these mutations was determined by expression analysis in heterologous mammalian cells. The level of activity was then used to predict the in vivo level of phenylalanine hydroxylase activity in patients with various combinations of mutant phenylalanine hydroxylase alleles. RESULTS The eight mutations involved 64 percent of all mutant phenylalanine hydroxylase alleles in the patients. Expression analysis showed that these mutant enzymes produced from 0 to 50 percent of normal enzyme activity. The predicted level of phenylalanine hydroxylase activity correlated strongly with the pretreatment serum level of phenylalanine (r = 0.91, P less than 0.001 in the Danish patients and r = 0.74, P less than 0.001 in the German patients), phenylalanine tolerance in the Danish patients (r = 0.84, P less than 0.001), and the serum phenylalanine level measured after standardized oral protein loading in the German patients (r = 0.84, P less than 0.001). CONCLUSIONS Our results strongly support the hypothesis that there is a molecular basis for phenotypic heterogeneity in phenylketonuria. The establishment of genotype will therefore aid in the prediction of biochemical and clinical phenotypes in patients with this disease.

Vasoparalysis associated with brain damage in asphyxiated term infants

The relationship of cerebral blood flow to acute changes in arterial carbon dioxide and mean arterial blood pressure (MABP) was determined during the first day of life in 19 severely asphyxiated term infants supported by mechanical ventilation. For comparison, 12 infants without perinatal asphyxia were also investigated. Global cerebral blood flow (CBF infinity) was determined by xenon 133 clearance two or three times within approximately 2 hours. During the cerebral blood flow measurement, the amplitude-integrated electroencephalogram and visual-evoked potential were recorded. Changes in arterial carbon dioxide pressure followed adjustments of the ventilator settings, whereas MABP fluctuated spontaneously. Arterial oxygen pressure and blood glucose concentration were in the normal range. Five of the asphyxiated infants had isoelectric electroencephalograms and died subsequently with severe brain damage. They had a high CBF infinity (mean 30.6 ml/100 gm/min) and abolished carbon dioxide and MABP reactivity. Lower CBF infinity (mean 14.7 ml/100 gm/min) and abolished MABP reactivity were found in another five asphyxiated infants with burst-suppression electroencephalograms in whom computed tomographic or clinical signs of brain lesions developed. The carbon dioxide reactivity was preserved in these infants. In the remaining nine asphyxiated infants without signs of central nervous system abnormality, carbon dioxide and MABP reactivity were preserved, as was also the case in the control group. We conclude that abolished autoregulation is associated with cerebral damage in asphyxiated infants and that the combination of isoelectric electroencephalograms and cerebral hyperperfusion is an early indicator of very severe brain damage.