Towards a cognitive neuroscience of self-awareness.

Self-awareness is a pivotal component of conscious experience. It is correlated with a paralimbic network of medial prefrontal/anterior cingulate and medial parietal/posterior cingulate cortical "hubs" and associated regions. Electromagnetic and transmitter manipulation have demonstrated that the network is not an epiphenomenon but instrumental in generation of self-awareness. Thus, transcranial magnetic stimulation (TMS) targeting the hubs impedes different aspects of self-awareness with a latency of 160ms. The network is linked by ∼40Hz oscillations and regulated by dopamine. The oscillations are generated by rhythmic GABA-ergic inhibitory activity in interneurons with an extraordinarily high metabolic rate. The hubs are richly endowed with interneurons and therefore highly vulnerable to disturbed energy supply. Consequently, deficient paralimbic activity and self-awareness are characteristic features of many disorders with impaired oxygen homeostasis. Such disorders may therefore be treated unconventionally by targeting interneuron function.

Visual cortex reactivity in sedated children examined with perfusion MRI (FAIR).

Sleeping and sedated children can respond to visual stimulation with a decrease in blood oxygenation level dependent (BOLD) functional MRI signal response. The contribution of metabolic and hemodynamic parameters to this inverse signal response is incompletely understood. It has been hypothesized that it is caused by a relatively greater increase of oxygen consumption compared to rCBF (regional cerebral blood flow) increase. We studied the rCBF changes during visual stimulation in four sedated children, aged 4-71 months, and four alert adults, with an arterial water spin labeling technique (FAIR) and BOLD fMRI in a 1.5T MR scanner. In the children, FAIR signal decreased by a mean of 0.96% (range 0.77-1.05) of the baseline periods of the non-selective images, while BOLD signal decreased by 2.03% (range 1.99-2.93). In the adults, FAIR and BOLD signal increased by 0.88% (range 0.8-0.99) and 2.63% (range 1.99-2.93), respectively. Thus, in the children, an rCBF increase could not be detected by perfusion MRI, but indications of a FAIR signal decrease were found. An rCBF decrease in the primary visual cortex during stimulation has not been reported previously, but it is a possible explanation for the negative BOLD response. Future studies will have to address if this response pattern is a consequence of age or sleep/sedation.

Precuneus-prefrontal activity during awareness of visual verbal stimuli.

Awareness is a personal experience, which is only accessible to the rest of world through interpretation. We set out to identify a neural correlate of visual awareness, using brief subliminal and supraliminal verbal stimuli while measuring cerebral blood flow distribution with H(2)(15)O PET. Awareness of visual verbal stimuli differentially activated medial parietal association cortex (precuneus), which is a polymodal sensory cortex, and dorsolateral prefrontal cortex, which is thought to be primarily executive. Our results suggest participation of these higher order perceptual and executive cortical structures in visual verbal awareness.

[Serious life events and congenital malformations. A national study with a complete follow-up]. / Alvorlige livsbegivenheder og medfødte misdannelser. Et national studie med komplet followup.

INTRODUCTION: Emotional stress during organogenesis could, in theory, cause congenital malformations by increasing the level of cortisone, but documentation is lacking. We undertook a follow-up study to test the hypothesis that psychosocial stress increases the prevalence of malformations, in particular malformations of the cranial neural crest. MATERIAL AND METHODS: We defined serious life events as the death or first hospital admission for cancer or acute myocardial infarction of partners or children. All women exposed to severe life events during and up to 16 months before pregnancy in the period 1980 to 1992 were identified by means of five national registers. We studied 3560 exposed pregnancies and randomly selected 20,299 "not-exposed" pregnancies as the control cohort. RESULTS: Women exposed to severe life events gave birth to offspring with an increased prevalence of cranial neural crest malformations, at an adjusted odds ratio of 1.54; 95% CI (1.05-2.27). For other malformations the adjusted odds ratio was 1.14-95% CI (0.94-1.42). Women exposed in two consecutive pregnancies had a higher odds ratio for cranial neural crest malformations, with an adjusted odds ratio of 2.99; 95% CI (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 in the offspring of 4.75; 95% CI (1.63-13.78). Unexpected death of a child during the first trimester was associated with an adjusted odds ratio of 8.36 in the offspring, 95% CI (2.41-28.99) for cranial neural crest malformations and 3.64, 95% CI (1.29-10.32) for other kinds of malformations. DISCUSSION AND CONCLUSION: These findings support the hypothesis that severe emotional stress during pregnancy, especially stress related to the death of a child, may cause congenital malformations, particularly those of the cranial neural crest.

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.

Current status of the Maze procedure for the treatment of atrial fibrillation.

Since the first patient underwent the Maze procedure on September 25, 1987, 346 patients have undergone this operation for the treatment of atrial fibrillation. The procedure was designed as an open-heart operation performed through a median sternotomy. It underwent 2 major modifications relatively early in the series, evolving into the so-called Maze-III procedure, which has been used exclusively since April 16, 1992. Since that time, the Maze-III procedure has been adapted to allow it to be done by minimally invasive techniques. In addition, we recently performed the entire procedure in 2 patients without the use of cardiopulmonary bypass. The operative mortality rate has remained at 2% to 3%. This includes patients undergoing concomitant high-risk cardiac surgical procedures and all re-do cases. The overall success rate in curing atrial fibrillation has been 99%. The procedure itself has been shown to cause no permanent damage to the sinus node. The left atrium has been documented to function long-term postoperatively in 93% of patients and the right atrium functions in 99% of patients. The Maze-III procedure remains the surgical procedure of choice for the treatment of medically refractory atrial fibrillation.

The Maze-III procedure combined with valve surgery.

Previous studies have suggested that the Maze procedure is not as effective in controlling atrial fibrillation when the arrhythmia is associated with significant valvular heart disease. In this study, we evaluate our own results in 83 patients who underwent 96 valve procedures in combination with the Maze-III procedure. Our results indicate that the Maze-III procedure is just as safe and effective in controlling atrial fibrillation associated with valvular heart disease as it is in controlling atrial fibrillation not associated with valvular heart disease.

Observations on the perioperative management of patients undergoing the Maze procedure.

In addition to the usual measures that constitute optimal perioperative care after cardiac surgery, the Maze procedure demands several other measures because of certain complications that are unique to this particular operation. These complications include preoperative conditions such as amiodarone therapy, thromboembolism, diastolic dysfunction of the left ventricle, and associated valvular heart disease, as well as intraoperative differences that include multiple atriotomies and excision of both atrial appendages. The most common postoperative complications are atrial arrhythmias, excessive fluid retention, and pulmonary complications. In this article, we outline our own approach to the perioperative care of patients undergoing the Maze procedure.

Functional magnetic resonance imaging of the normal and abnormal visual system in early life.

Functional magnetic resonance imaging (fMRI) in young children may provide information about the development of the visual cortex, and may have predictive value for later visual performance. The purpose of this study was to evaluate the usefulness of fMRI for examining cerebral processing of vision in very young infants and in infants with brain damage. We examined 15 preterm infants, 12 children suspected of having a cerebral visual impairment and 10 children with a normal visual system, all of whom were either spontaneously asleep or sedated with chloral hydrate. Cortical response to stroboscopic light stimulation could be demonstrated in all technically acceptable data sets from children with a post-menstrual age (PMA) of > 41 weeks, but not in younger infants. Children < 60 weeks PMA showed either a blood oxygenation level-dependent (BOLD) signal increase or decrease, while all older children showed a signal decrease. The activated cortical volumes showed a linear relation to age for healthy children younger than 90 weeks PMA, but were small in children with visual impairment. In two children with unilateral damage to the optic radiations, activation was strongly asymmetrical with greatest activation on the healthy side. In future prospective studies, results from the period from birth to six months of age should be interpreted with caution, as inter-individual variation of cortical development may be confused with functional deficit.

Brain lesions in preterms: origin, consequences and compensation.

Twenty-nine high-risk preterm born children, from a cohort with cerebral blood flow (CBF) measurements in the first 2 d of life, were examined prospectively at the age of 5.5-7 y neurologically, neuropsychologically and by magnetic resonance imaging (MRI). They were compared to 57 control children in terms of neurology and neuropsychology. Abnormal MRI was found in 19 children. Low oxygen delivery to the brain was found in 63% of them, in contrast to 12.5% in those with normal MRI, indicating neonatal hypoxia-ischemia as an important factor. The MRI abnormalities were mainly periventricular lesions (n = 19), especially periventricular leucomalacia (PVL, n = 17). Three of the very preterm children had severe cerebellar atrophy in addition to relatively mild periventricular abnormalities. MRI showed specific morphological correlates for the major disabilities, e.g. spastic CP (involvement of motor tracts), mental retardation (bilateral extensive white matter reduction or cerebellar atrophy) and severe visual impairment (severe optic radiation involvement). A morphological correlate for minor disabilities, i.e. functional variations in motor performance or intelligence, was not found, with the exception that symptoms of attention deficit hyperactivity disorder were related to mild MRI abnormalities. This could mean that with respect to cognitive functions, mild or unilateral periventricular MRI lesions could be compensated. However, as among preterms without mental retardation (n = 19), IQ was generally and significantly lower than in the control group; other, more chronic pathogenetic factors, not detectable by MRI alone, may play a role.

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-H20 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 (H2)15O 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.

Visual activation in infants and young children studied by functional magnetic resonance imaging.

The purpose of this study was to determine whether visual stimulation in sleeping infants and young children can be examined by functional magnetic resonance imaging. We studied 17 children, aged 3 d to 48 mo, and three healthy adults. Visual stimulation was performed with 8-Hz flickering light through the sleeping childs' closed eyelids. Functional magnetic resonance imaging was performed with a gradient echoplanar sequence in a l.5-T magnetic resonance scanner. Six subjects were excluded because of movement artifacts; the youngest infant showed no response. In 10 children, we could demonstrate areas of signal decrease during visual stimulation in the occipital cortex (mean decrease 2.21%), contrary to the signal increase observed in the adult controls (mean increase 2.82%). This decrease may be due to a higher proportional increase in oxygen extraction compared with increase in cerebral blood flow during activation. The different response patterns in young children and adults can reflect developmental or behavioral differences. Localization of the activation seemed to be age-dependent. In the older children and the adults, it encompassed the whole length of the calcarine sulcus, whereas it was restricted to the anterior and medial part of the calcarine sulcus in the younger infants. This may reflect a different functional organization of the young child's visual cortex or the on-going retinal development.

Aberrant phenylalanine metabolism in phenylketonuria heterozygotes.

The wide variation in phenylalanine hydroxylating capacity observed among patients with phenylketonuria (PKU) is primarily due to allelic heterogeneity at the phenylalanine hydroxylase (PAH) locus. In this study, we examined phenylalanine metabolism after an oral phenylalanine load in 148 carriers of known PAH gene mutations. As a group, heterozygotes formed less tyrosine than normozygotes (p < 0.001), and there was a tendency that carriers of a severe PAH mutation formed less tyrosine than carriers of a mild mutation. Nevertheless, the interindividual variation was extensive, and we identified a group of individuals who formed no or very little tyrosine after the phenylalanine load. This tyrosine response was accompanied by a decreased ability to eliminate the phenylalanine test dose but did not correlate with the intrinsic severity of the mutant PAH allele. Examination of the entire coding region of the PAH gene revealed no additional sequence alterations in these subjects. Our data suggest that a subset of PKU heterozygotes have reduced phenylalanine hydroxylating capacity approaching or equalling the levels observed in genetic compounds with non-PKU mild hyperphenylalaninaemia (MHP). Awareness of this phenotypic overlap between PKU carriers and genetic compounds with two mutant alleles may be useful for clinicians and paediatricians involved in diagnosis and genetic counselling.

[Intrauterine growth retardation and premature delivery. The effect of smoking and psychosocial factors]. / Intrauterin vaeksthaemning og praematur fødsel. Effekten af rygning og psykosociale faktorer.

The purpose of the study is to investigate the influence of psychosocial stress, maternal schooling, social support, psychological well-being, alcohol and smoking on intrauterine growth retardation and premature delivery. At a Copenhagen university hospital 2432 consecutive Danish-speaking women in 20th week of pregnancy completed a questionnaire including the General Health Questionnaire and Severity of Psychosocial Stressor Scale and questions about social network, education, smoking and drinking habits. In 212 cases (8.7%) the women delivered before day 259 of gestation. In a multiple logistic regression model, pre-term delivery proved to be associated with psychosocial stress and poor school education. In 152 cases (6.3%) infants had a birth weight below the defined 10th percentile. In a multiple logistic regression model, IUGR was associated with smoking. In preventive programmes, such as anti-smoking campaigns, it should be kept in mind that women who smoke are also the least educated and have the poorest support from a social network.

Metabolic changes in the striatum after germinal matrix hemorrhage in the preterm infant.

To investigate the metabolic consequences of germinal matrix hemorrhage (GMH) we used volume-selective 1H magnetic resonance spectroscopy in the striatal region in 12 preterm infants with predominantly small GMH. Both sides of the brain were investigated twice. Metabolite indices were calculated as the metabolite signal, recorded with TR = 1.6 s and TE = 272 ms, divided by the fully relaxed water signal corrected for transverse relaxation time constant (T2) decay. At the first investigation, when the infants were 32.5 +/- 2.0 (mean +/- SD) wk postmenstrual age, the hemorrhage was unilateral or markedly asymmetrical in size in 10 of 12 infants. The lactate index was higher (p < 0.01) and the phosphocreatine + creatine (Cr) (p < 0.05) and N-acetyl-L-aspartate (NAA) (p < 0.05) indices lower in the side with the larger hemorrhage. At the second investigation, 54.1 +/- 2.7 wk postmenstrual age, no sign of a previous GMH could be seen on magnetic resonance imaging in three of 10 infants. Lactate could be detected in two of 10 infants only, and the Cr and NAA indices did not differ between sides. However, the choline index was significantly higher in the side with the larger hemorrhage (p < 0.01). We conclude that GMH is initially followed by lactate accumulation and possibly a delay in maturation as indicated by the transiently low Cr and NAA indices. Moreover, an increased choline index at the corrected age of 3 mo indicates a more persistent metabolic change after small GMH.