Alfred Peter Born

Regional differences in the CBF and BOLD responses to hypercapnia: a combined PET and fMRI study.

Previous fMRI studies of the cerebrovascular response to hypercapnia have shown signal change in cerebral gray matter, but not in white matter. Therefore, the objective of the present study was to compare (15)O PET and T *(2)-weighted MRI during a hypercapnic challenge. The measurements were performed under similar conditions of hypercapnia, which were induced by inhalation of 5 or 7% CO(2). The baseline rCBF values were 65.1 ml hg(-1) min(-1) for temporal gray matter and 28.7 ml hg(-1) min(-1) for white matter. By linear regression, the increases in rCBF during hypercapnia were 23.0 and 7. 2 ml hg(-1) min(-1) kPa(-1) for gray and white matter. The signal changes were 6.9 and 1.9% for the FLASH sequence and were 3.8 and 1. 7% for the EPI sequence at comparable echo times. The regional differences in percentage signal change were significantly reduced when normalized by regional flow values. A deconvolution analysis is introduced to model the relation between fMRI signal and end-expiratory CO(2) level. Temporal parameters, such as mean transit time, were derived from this analysis and suggested a slower response in white matter than in gray matter regions. It was concluded that the differences in the magnitude of the fMRI response can largely be attributed to differences in flow and that there is a considerable difference in the time course of the response between gray and white matter.

Cortical Deactivation Induced by Visual Stimulation in Human Slow-Wave Sleep

It has previously been demonstrated that sleeping and sedated young children respond with a paradoxical decrease in the blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal in the rostro-medial occipital visual cortex during visual stimulation. It is unresolved whether this negative BOLD response pattern is of developmental neurobiological origin particular to a given age or to a general effect of sleep or sedative drugs. To further elucidate this issue, we used fMRI and positron emission tomography (PET) to study the brain activation pattern during visual stimulation in spontaneously sleeping adult volunteers. In five sleeping volunteers fMRI studies confirmed a robust signal decrease during stimulation in the rostro-medial occipital cortex. A similar relative decrease at the same location was found during visual stimulation and polysomnographically verified slow-wave sleep in a separate group of six subjects using H(2)(15)O PET measures of the regional cerebral blood flow (rCBF). This decrease was more rostro-dorsal compared to the relative rCBF increase along the calcarine sulcus found during visual stimulation in the awake state. This study reconfirms the previously described paradoxical stimulation-correlated negative BOLD signal change in the rostro-medial occipital cortex, expanding this response mode to an age spectrum ranging from the newborn to the adult. Further, the use of complementary brain mapping techniques suggests that this decrease was secondary to a relative rCBF decrease. Possible mechanisms for the paradoxical response pattern during sleep include an active inhibition of the visual cortex or a disruption of an energy-consuming process.

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.

Changes in BOLD and ADC weighted imaging in acute hypoxia during sea-level and altitude adapted states

Acute normobaric hypoxia as well as longstanding hypobaric hypoxia induce pronounced physiological changes and may eventually lead to impairment of cerebral function. The aim of the present study is to investigate the effect of hypoxia on the cerebral activation response as well as to explore possible structural changes as measured by diffusion weighted imaging. Eleven healthy sea-level residents were studied after 5 weeks of adaptation to high altitude conditions at Chacaltaya, Bolivia (5260 m). The subjects were studied immediately after return to sea-level in hypoxic and normoxic conditions, and the examinations repeated 6 months later after re-adaptation to sea-level conditions. The BOLD response, measured at 1.5 T, was severely reduced during acute hypoxia both in the altitude and sea-level adapted states (50% reduction during an average S(a)O(2) of 75%). On average, the BOLD response magnitude was 23% lower in altitude than sea-level adaptation in the normoxic condition, but in the hypoxic condition, no significant differences were found. A small but statistically significant decrease in the apparent diffusion coefficient (ADC) was seen in some brain regions during acute hypoxia, whereas ADC was slightly elevated in high altitude as compared to sea-level adaptation. It is concluded that hypoxia significantly diminishes the BOLD response, and the mechanisms underlying this finding are discussed. Furthermore, altitude adaptation may influence both the magnitude of the activation-related response, as well as micro-structural features.

Exogenous glucocorticoids and adverse cerebral effects in children.

Glucocorticoids are commonly used in treatment of paediatric diseases, but evidence of associated adverse cerebral effects is accumulating. The various pharmacokinetic profiles of the exogenous glucocorticoids and the changes in pharmacodynamics during childhood, result in different exposure of nervous tissue to exogenous glucocorticoids. Glucocorticoids activate two types of intracellular receptors, the mineralocorticoid receptor and the glucocorticoid receptor. The two receptors differ in cerebral distribution, affinity and effects. Exogenous glucocorticoids favor activation of the glucocorticoid receptor, which is associated with unfavorable cellular outcomes. Prenatal treatment with glucocorticoids can compromise brain growth and is associated with periventricular leukomalacia, attentions deficits and poorer cognitive performance. In the neonatal period exposure to glucocorticoids reduces neurogenesis and cerebral volume, impairs memory and increases the incidence of cerebral palsy. Cerebral effects of glucocorticoids in later childhood have been less thoroughly studied, but apparent brain atrophy, reduced size of limbic structures and neuropsychiatric symptoms have been reported. Glucocortioids affect several cellular structures and functions, which may explain the observed adverse effects. Glucocorticoids can impair neuronal glucose uptake, decrease excitability, cause atrophy of dendrites, compromise development of myelin-producing oligodendrocytes and disturb important cellular structures involved in axonal transport, long-term potentiation and neuronal plasticity. Significant maturation of the brain continues throughout childhood and we hypothesize that exposure to exogenous glucocorticoids during preschool and school age causes adverse cerebral effects. It is our opinion that studies of associations between exposure to glucocorticoids during childhood and impaired neurodevelopment are highly relevant.

Mutations in COA3 cause isolated complex IV deficiency associated with neuropathy, exercise intolerance, obesity, and short stature

Background We investigated a subject with an isolated cytochrome c oxidase (COX) deficiency presenting with an unusual phenotype characterised by neuropathy, exercise intolerance, obesity, and short stature. Methods and results Blue-native polyacrylamide gel electrophoresis (BN-PAGE) analysis showed an almost complete lack of COX assembly in subject fibroblasts, consistent with the very low enzymatic activity, and pulse-labelling mitochondrial translation experiments showed a specific decrease in synthesis of the COX1 subunit, the core catalytic subunit that nucleates assembly of the holoenzyme. Whole exome sequencing identified compound heterozygous mutations (c.199dupC, c.215A>G) in COA3, a small inner membrane COX assembly factor, resulting in a pronounced decrease in the steady-state levels of COA3 protein. Retroviral expression of a wild-type COA3 cDNA completely rescued the COX assembly and mitochondrial translation defects, confirming the pathogenicity of the mutations, and resulted in increased steady-state levels of COX1 in control cells, demonstrating a role for COA3 in the stabilisation of this subunit. COA3 exists in an early COX assembly complex that contains COX1 and other COX assembly factors including COX14 (C12orf62), another single pass transmembrane protein that also plays a role in coupling COX1 synthesis with holoenzyme assembly. Immunoblot analysis showed that COX14 was undetectable in COA3 subject fibroblasts, and that COA3 was undetectable in fibroblasts from a COX14 subject, demonstrating the interdependence of these two COX assembly factors. Conclusions The mild clinical course in this patient contrasts with nearly all other cases of severe COX assembly defects that are usually fatal early in life, and underscores the marked tissue-specific involvement in mitochondrial diseases.

Basilar Artery Thrombosis in a Child Treated With Intravenous Tissue Plasminogen Activator and Endovascular Mechanical Thrombectomy.

Basilar artery occlusion in children is rare. It has a high mortality and morbidity if recanalization is not achieved before extensive brainstem infarction has occurred. An 11-year-old boy presented with a clinical and radiological “top-of-the-basilar” syndrome. Intravenous tissue plasminogen activator was administered, and the patient was immediately referred to the regional stroke center. Subsequent mechanical thrombectomy using a Solitaire stent (Solitaire FR stent; ev3, Irvine, CA, USA) resulted in clot removal and recanalization of the basilar artery 4 hours after stroke onset. The patient made a full clinical recovery. To the authors’ knowledge this is the first report on basilar artery occlusion in a child treated with “bridging” therapy, the combination of intravenous thrombolysis and endovascular thrombectomy. If the diagnosis can be made within the time window for intravenous thrombolysis (4.5 hours), the present case suggests that bridging therapy in pediatric basilar artery occlusion can be safe and effective.

New Hyperekplexia Mutations Provide Insight into Glycine Receptor Assembly, Trafficking, and Activation Mechanisms

Background: Hyperekplexia mutations have provided much information about glycine receptor structure and function. Results: We identified and characterized nine new mutations. Dominant mutations resulted in spontaneous activation, whereas recessive mutations precluded surface expression. Conclusion: These data provide insight into glycine receptor activation mechanisms and surface expression determinants. Significance: The results enhance our understanding of hyperekplexia pathology and glycine receptor structure-function. Hyperekplexia is a syndrome of readily provoked startle responses, alongside episodic and generalized hypertonia, that presents within the first month of life. Inhibitory glycine receptors are pentameric ligand-gated ion channels with a definitive and clinically well stratified linkage to hyperekplexia. Most hyperekplexia cases are caused by mutations in the α1 subunit of the human glycine receptor (hGlyR) gene (GLRA1). Here we analyzed 68 new unrelated hyperekplexia probands for GLRA1 mutations and identified 19 mutations, of which 9 were novel. Electrophysiological analysis demonstrated that the dominant mutations p.Q226E, p.V280M, and p.R414H induced spontaneous channel activity, indicating that this is a recurring mechanism in hGlyR pathophysiology. p.Q226E, at the top of TM1, most likely induced tonic activation via an enhanced electrostatic attraction to p.R271 at the top of TM2, suggesting a structural mechanism for channel activation. Receptors incorporating p.P230S (which is heterozygous with p.R65W) desensitized much faster than wild type receptors and represent a new TM1 site capable of modulating desensitization. The recessive mutations p.R72C, p.R218W, p.L291P, p.D388A, and p.E375X precluded cell surface expression unless co-expressed with α1 wild type subunits. The recessive p.E375X mutation resulted in subunit truncation upstream of the TM4 domain. Surprisingly, on the basis of three independent assays, we were able to infer that p.E375X truncated subunits are incorporated into functional hGlyRs together with unmutated α1 or α1 plus β subunits. These aberrant receptors exhibit significantly reduced glycine sensitivity. To our knowledge, this is the first suggestion that subunits lacking TM4 domains might be incorporated into functional pentameric ligand-gated ion channel receptors.

Children and adolescents previously treated with glucocorticoids display lower verbal intellectual abilities

Perinatal exposure to glucocorticoids has been associated with adverse cerebral effects, but little is known about their effect on cognitive development and exposure later in childhood. This study examined intellectual abilities, memory and behavioural problems in children previously treated with glucocorticoids.

A novel RNASEH2B splice site mutation responsible for Aicardi–Goutieres syndrome in the Faroe Islands

Aim:  The aim of the study was to identify the genetic background for Aicardi–Goutieres syndrome (AGS) in the Faroe Islands.