Metachromatic Leukodystrophy: A Model for the Study of Psychosis

Black, Deborah N.; Taber, Katherine H.; Hurley, Robin A.

doi:10.1176/jnp.15.3.289

Cited by 43 publications

(25 citation statements)

References 37 publications

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“…Adult MLD is the less severe form of the disease. In the adult form, psychoses (55), cognitive and behavioral impairment (53,56), ataxia, polyneuropathy, and epileptic seizures (57) are found. Patients experience depressive disorder and sudden mood swings (58).…”

Section: Mld Classificationmentioning

confidence: 99%

Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

et al. 2020

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Section: Mld Classificationmentioning

confidence: 99%

Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

et al. 2020

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“…These examples highlight the possibility that idiopathic disorders with cognitive dimensions may be understood by considering myelin disturbances that result in network dysfunction. The connectopathy so produced may include both psychiatric and neurological dysfunction, as illustrated by the dysmyelinative disease metachromatic leukodystrophy (MLD), in which a typical progression from early psychosis to later dementia has been identified, presumably as a result of advancing white matter disease (Black et al 2003).…”

Section: The Role Of White Matter In Distributed Neural Networkmentioning

confidence: 99%

White matter and cognition: making the connection

Filley

Fields

2016

Journal of Neurophysiology

302

227

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Whereas the cerebral cortex has long been regarded by neuroscientists as the major locus of cognitive function, the white matter of the brain is increasingly recognized as equally critical for cognition. White matter comprises half of the brain, has expanded more than gray matter in evolution, and forms an indispensable component of distributed neural networks that subserve neurobehavioral operations. White matter tracts mediate the essential connectivity by which human behavior is organized, working in concert with gray matter to enable the extraordinary repertoire of human cognitive capacities. In this review, we present evidence from behavioral neurology that white matter lesions regularly disturb cognition, consider the role of white matter in the physiology of distributed neural networks, develop the hypothesis that white matter dysfunction is relevant to neurodegenerative disorders, including Alzheimer's disease and the newly described entity chronic traumatic encephalopathy, and discuss emerging concepts regarding the prevention and treatment of cognitive dysfunction associated with white matter disorders. Investigation of the role of white matter in cognition has yielded many valuable insights and promises to expand understanding of normal brain structure and function, improve the treatment of many neurobehavioral disorders, and disclose new opportunities for research on many challenging problems facing medicine and society.

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“…First, damage to these frontal fasciculi has been associated with the development of first-rank psychotic symptoms, such as, eg, in patients with multiple sclerosis 37 and, more commonly, in patients with the demyelinating disorder metachromatic leukodystrophy, particularly when the disorder first presents in early adulthood. 38,39 Second, these frontal fasciculi are among the last fasciculi to structurally mature in the developing human brain, with myelination thought to continue through adolescence and into early adulthood, [40][41][42][43] which is a period that corresponds to the most common age-of-onset for schizophrenia. When combined with the fact that schizophrenia patients exhibit a range of myelin-specific abnormalities-including reduced numbers of oligodendrocytes, 19 irregular myelin microstructure, 20 and subnormal expression of myelin-related genes 44 -there is reason to believe that schizophrenia may be underpinned by irregularities in the normative processes of periadolescent myelination, 13 particularly in the latedeveloping frontal fasciculi.…”

mentioning

confidence: 99%

Schizophrenia, Myelination, and Delayed Corollary Discharges: A Hypothesis

Whitford

Ford

Mathalon

et al. 2010

Schizophrenia Bulletin

123

102

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Any etiological theory of schizophrenia must account for at least 3 distinctive features of the disorder, namely its excessive dopamine neurotransmission, its frequent periadolescent onset, and its bizarre, pathognomonic symptoms. In this article, we theorize that each of these features could arise from a single underlying cause--namely abnormal myelination of late-developing frontal white matter fasciculi. Specifically, we suggest that abnormalities in frontal myelination result in conduction delays in the efference copies initiated by willed actions. These conduction delays cause the resulting corollary discharges to be generated too late to suppress the sensory consequences of the willed actions. The resulting ambiguity as to the origins of these actions represents a phenomenologically and neurophysiologically significant prediction error. On a phenomenological level, the perception of salience in a self-generated action leads to confusion as to its origins and, consequently, passivity experiences and auditory hallucinations. On a neurophysiological level, this prediction error leads to the increased activity of dopaminergic neurons in the midbrain. This dopaminergic activity causes previously insignificant events to be perceived as salient, which exacerbates the budding hallucinations and passivity experiences and triggers additional first-rank symptoms such as delusions of reference. The article concludes with a discussion of the implications of the theory and some testable predictions which may form a worthwhile basis for future research.

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Metachromatic Leukodystrophy: A Model for the Study of Psychosis

Cited by 43 publications

References 37 publications

Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

White matter and cognition: making the connection

Schizophrenia, Myelination, and Delayed Corollary Discharges: A Hypothesis

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