A surprisingly diverse range of psychiatric and nervous system disorders are accompanied by changes in white matter structure or abnormalities in myelin genes (see Box 1
). Polymorphisms for several myelin genes have emerged as unexpected risk factors for schizophrenia [3
], depression [4
] and obsessive-compulsive disorder [5
]. Post mortem
examination of brain tissue from patients suffering schizophrenia [4
], major depression [7
] and bipolar disorder [4
] reveals reduced abundance of several mRNA transcripts of myelin genes or genes regulating differentiation and survival of myelin-forming cells (oligodendrocytes).
Box 1. White matter in neurological disease and mental illness
Many neurological disorders result from damage or disease affecting the myelin sheath on nerve fibers, but recently, white matter defects have also been associated with a wide range of psychiatric and neurological disorders.
Conduction failure resulting from myelin damage can cause paralysis, sensory-motor dysfunction, cognitive impairment, mental retardation and death. Myelin can be damaged by autoimmune disease, as in Guillain-Barré syndrome in the peripheral nervous system and multiple sclerosis in the central nervous system. Inherited disorders affecting structural genes in myelin are the cause of such diseases as Charcot-Marie-Tooth disease, Dejerine-Sottas syndrome and Pelizaeus-Marzbacher disease. Myelin is damaged by many metabolic disorders, including Canavan, Menke’s, Krabbe’s and Refsum’s disease, and by infection, trauma, toxins (including alcohol), hormonal imbalance and asphyxia. Oligodendrocytes are especially vulnerable to perinatal asphyxia, resulting in cerebral palsy. Some disorders affecting astrocytes, which provide factors promoting oligodendrocyte development and myelination [87
], can impair myelin. For example, Alexander disease is caused by a genetic defect in astrocytes and this results in severe hypomyelination, mental retardation and death at a young age.
A wide range of psychiatric disorders, including schizophrenia, chronic depression, bipolar disorder, obsessive-compulsive disorder and posttraumatic stress disorder, have recently been associated with white matter defects, as have neurodevelopmental cognitive and emotional disorders including autism, dyslexia and attention-deficit hyperactivity disorder (see table in supplementary material
). The evidence for white matter involvement consists of gene expression studies, at least five different types of brain imaging methods and histological analysis of post mortem
In an analysis of 6000 genes in prefrontal cortex of schizophrenic brains, 89 genes were abnormally regulated; remarkably, of these 35 were genes involved in myelination [3
]. From multiple studies, this includes genes encoding myelin MAG, MAL, MBP, PLP, MOG and CNP PMP22; growth factors and receptors ErbB3, NRG1 and BDNF; transcription factors SOX10, Olig 1 and Olig 2; and other genes associated with oligodendroctye development and myelination, including transferrin, QKI and CLDN11. Polymorphisms of several other genes coding proteins in myelin or regulating oligodendrocyte development are indicators of susceptibility to schizophrenia, including MAG, CNP, MOG, NRG1, ERRB4, Olig 2 and Nogo.
Post mortem studies show abnormalities in white matter tracts of schizophrenic brains, including corpus callosum, anterior commissure and fornix. Decreased number of oligodendrocytes is reported in cortex and thalamic nucleus, and myelin abnormalities or apoptotic oligodendrocytes are seen in prefrontal regions.
Several brain imaging methods show volumetric and microstructural white matter differences in patients with schizophrenia, as well as differences in functional connectivity, and biochemical changes in white matter (MRI spectroscopy). Decreased fractional anisotropy or magnetization transfer have been reported in prefrontal white matter, ventromedial prefrontal white matter, frontal white matter, inferior frontal white matter, anterior cingulate, temporal regions, uncinate fasciculus, corpus callosum and internal capsule.
Several other disorders with pronounced cognitive impairments involve alterations in white matter tracts or myelin genes. This includes major depressive and bipolar disorder, Alzheimer’s disease and autism, supporting the concept that myelin abnormalities affect information processing and cognition. Autism, a neurodevelopmental disorder of heterogeneous origins and symptoms, is interesting in this regard, as EEG measurements show increased coherence in the autistic brain. The brain of autistic children is enlarged, and the majority of this enlargement is due to increased white matter volume, particularly in cortico-cortical connections. Hyperconnectivity between particular cortical regions in autism might relate to savant abilities for specific types of knowledge, and early environmental factors are thought to be involved in autism. Similarly, dyslexia is a developmental disorder associated with abnormal temporal processing and EEG coherence in parieto-occipital EEG recording, and microstructural differences in white matter have been reported. (For references to the studies above, see supplementary table
Noninvasive brain imaging is revealing structural differences in appropriate white matter tracts in association with a wide range of neurological and psychiatric illnesses, including dyslexia, ADHD, depression, bipolar disorder, language disorders, stuttering, autism, obsessive-compulsive disorder, posttraumatic stress disorder, cognitive decline in aging, Alzheimer’s disease, Tourette’s disorder, schizophrenia and such idiosyncratic disorders as tone deafness and pathological lying. (See bibliography of white matter abnormalities in psychiatric and neurological disorders in supplementary material
An important issue is whether these changes in myelin gene expression or white matter structure are a direct cause of the psychiatric disorder or alternatively, a secondary consequence of abnormal brain function on white matter. Medications or drug abuse can also affect white matter genes or white matter structure in some psychiatric patients. However, the genetic risk factors involving myelin genes, and changes in levels of mRNA transcripts of myelin genes in the absence of changes in neuronal genes in several psychiatric disorders, suggest that white matter is a contributing cause of many disorders affecting mood or cognition. Moreover, as will be described below, experimental manipulation of genes selectively in oligodendrocytes that regulate glial development and myelination can cause behavioral changes mimicking schizophrenia.
Although synaptic dysfunction is the cellular basis for most mental illnesses, disruptions in functional connectivity between distant brain regions can impair information processing in association with a range of neurological processes. Defects in myelin insulation can lead to impaired cognitive function in 40% of multiple sclerosis patients, for example [8
]. Cognitive decline in aging also parallels subtle changes in the integrity of white matter [9
]. This suggests that impaired cognitive ability, disorganized thinking, mood disorders or hallucinations, accompanying psychiatric illness, might result from slowed or desynchronized impulse conduction between distant cortical regions.
Correlative evidence suggests involvement of myelin in cognition, learning, development of skills and memory. Myelin genes change during REM sleep, for example [10
], suggesting myelin remodeling outside the context of disease and in parallel with states of activity in the brain. Changes in gene expression are especially intriguing in the context of sleep-dependent memory consolidation. Myelination of appropriate brain regions coincides with the development of specific cognitive functions [11
], such as reading [14
], development of vocabulary [15
] and proficiency in executive decision making [16
]. Incomplete myelination of the forebrain until the early twenties has been suggested as a neurological basis for weaker decision-making skills in adolescence [17
Individual differences in normal
cognitive development [16
], IQ [20
], normal variation in reading skill [22
], working memory [22
] and musical proficiency [26
] are correlated with differences in white matter structure in specific brain regions mediating these tasks.
Learning complex skills, such as playing the piano, are accompanied by increased organization of white matter structure in appropriate brain tracts involved in musical performance [26
]. Importantly, the level of white matter structure increased proportionately to the number of hours each subject had practiced the instrument, indicating white matter changes in acquiring the skill rather than performance being predetermined by a limitation on white matter development. Myelin plasticity might provide another cellular mechanism of learning complementing the well-studied mechanisms of synaptic plasticity.