Copy Number Variations in DISC1 and DISC1-Interacting Partners in Major Mental Illness

Acknowledgements We would like to thank all of the patients, relatives and control individuals who participated in the study. We are indebted to the late Prof. Walter Muir, Chair of Developmental Psychiatry and Honorary Consultant in Learning Disability Psychiatry, University of Edinburgh, who initiated these studies and whose work was dedicated to the welfare of the patients who generously participated. We are also grateful to Mrs. Pat Malloy for her assistance with DNA collection and MAQ assays screening of the Scottish samples. The Scottish sample collection was supported by a grant from the Chief Scientist Office (CSO), part of the Scottish Government Health and Social Care Directorates. This research was funded by grants from the CSO to B.S.P. (grant CZB/4/610), The Academy of Medical Sciences/Wellcome Trust to M.J. (grant R41455) and The RS Macdonald Charitable Trust (grant D21419 together with J.H.), the Swedish Research Council (grants 2003-5158 and 2006-4472), the Medical Faculty, Umeå University, and the County Councils of Västerbotten and Norrbotten, Sweden, as well as by grants from the Fund for Scientific Research Flanders (FWO-F), the Industrial Research Fund (IWT) and the Special Research Fund of the University of Antwerp, Belgium. M.J. is funded by a Wellcome Trust Clinical Research Fellowship for MB PhD graduates (R42811). We acknowledge the contribution of the personnel of the VIB Genetic Service Facility (http://www.vibgeneticservicefacility.be/) for the genetic analysis of the Swedish samples. Research nurses Gunnel Johansson, Lotta Kronberg, Tage Johansson and Lisbeth Bertilsson are thankfully acknowledged for their help and expertise. The Betula Study was funded by the Swedish Research Council (grants 345-2003-3883 and 315-2004-6977). We also acknowledge the contribution by the staff in the Betula project

The neurological basis of conscious color perception in a blind patient

We have studied patient PB, who, after an electric shock that led to vascular insufficiency, became virtually blind, although he retained a capacity to see colors consciously. For our psychophysical studies, we used a simplified version of the Land experiments [Land, E. (1974) Proc. R. Inst. G. B. 47, 23–58] to learn whether color constancy mechanisms are intact in him, which amounts to learning whether he can assign a constant color to a surface in spite of changes in the precise wavelength composition of the light reflected from that surface. We supplemented our psychophysical studies with imaging ones, using functional magnetic resonance, to learn something about the location of areas that are active in his brain when he perceives colors. The psychophysical results suggested that color constancy mechanisms are severely defective in PB and that his color vision is wavelength-based. The imaging results showed that, when he viewed and recognized colors, significant increases in activity were restricted mainly to V1-V2. We conclude that a partly defective color system operating on its own in a severely damaged brain is able to mediate a conscious experience of color in the virtually total absence of other visual abilities.

Thalamocortical dysrhythmia: A neurological and neuropsychiatric syndrome characterized by magnetoencephalography

Spontaneous magnetoencephalographic activity was recorded in awake, healthy human controls and in patients suffering from neurogenic pain, tinnitus, Parkinson's disease, or depression. Compared with controls, patients showed increased low-frequency θ rhythmicity, in conjunction with a widespread and marked increase of coherence among high- and low-frequency oscillations. These data indicate the presence of a thalamocortical dysrhythmia, which we propose is responsible for all the above mentioned conditions. This coherent θ activity, the result of a resonant interaction between thalamus and cortex, is due to the generation of low-threshold calcium spike bursts by thalamic cells. The presence of these bursts is directly related to thalamic cell hyperpolarization, brought about by either excess inhibition or disfacilitation. The emergence of positive clinical symptoms is viewed as resulting from ectopic γ-band activation, which we refer to as the “edge effect.” This effect is observable as increased coherence between low- and high-frequency oscillations, probably resulting from inhibitory asymmetry between high- and low-frequency thalamocortical modules at the cortical level.

Demographic and epidemiological determinants of healthcare costs in Netherlands: cost of illness study

Objectives: To determine the demands on healthcare resources caused by different types of illnesses and variation with age and sex.

An unliganded thyroid hormone receptor causes severe neurological dysfunction

Congenital hypothyroidism and the thyroid hormone (T3) resistance syndrome are associated with severe central nervous system (CNS) dysfunction. Because thyroid hormones are thought to act principally by binding to their nuclear receptors (TRs), it is unexplained why TR knock-out animals are reported to have normal CNS structure and function. To investigate this discrepancy further, a T3 binding mutation was introduced into the mouse TR-β locus by homologous recombination. Because of this T3 binding defect, the mutant TR constitutively interacts with corepressor proteins and mimics the hypothyroid state, regardless of the circulating thyroid hormone concentrations. Severe abnormalities in cerebellar development and function and abnormal hippocampal gene expression and learning were found. These findings demonstrate the specific and deleterious action of unliganded TR in the brain and suggest the importance of corepressors bound to TR in the pathogenesis of hypothyroidism.

Ion channel genes and human neurological disease: Recent progress, prospects, and challenges

What do epilepsy, migraine headache, deafness, episodic ataxia, periodic paralysis, malignant hyperthermia, and generalized myotonia have in common? These human neurological disorders can be caused by mutations in genes for ion channels. Many of the channel diseases are “paroxysmal disorders” whose principal symptoms occur intermittently in individuals who otherwise may be healthy and active. Some of the ion channels that cause human neurological disease are old acquaintances previously cloned and extensively studied by channel specialists. In other cases, however, disease-gene hunts have led the way to the identification of new channel genes. Progress in the study of ion channels has made it possible to analyze the effects of human neurological disease-causing channel mutations at the level of the single channel, the subcellular domain, the neuronal network, and the behaving organism.