Exploration of the Brain in Rest: Resting-State Functional MRI Abnormalities in Patients with Classic Galactosemia

Abstract

Patients with classic galactosemia, a genetic metabolic disorder, encounter cognitive impairments, including motor (speech), language, and memory deficits. We used functional magnetic resonance imaging to evaluate spontaneous functional connectivity during rest to investigate potential abnormalities in neural networks. We characterized networks using seed-based correlation analysis in 13 adolescent patients and 13 matched controls. Results point towards alterations in several networks, including well-known resting-state networks (e.g. default mode, salience, visual network). Particularly, patients showed alterations in networks encompassing medial prefrontal cortex, parietal lobule and (pre)cuneus, involved in spatial orientation and attention. Furthermore, altered connectivity of networks including the insula and superior frontal gyrus -important for sensory-motor integration and motor (speech) planning- was demonstrated. Lastly, abnormalities were found in networks involving occipital regions, linked to visuospatial capacities and working memory. Importantly, across several seeds, altered functional connectivity to the superior frontal cortex, anterior insula, parietal lobule and the (pre)cuneus was observed in patients, suggesting special importance of these brain regions. Moreover, these alterations correlated with neurocognitive test results, supporting a relation with the clinical phenotype. Our findings contribute to improved characterization of brain impairments in classic galactosemia and provide directions for further investigations.

Identification of neuronal structures and pathways corresponding to clinical functioning in galactosemia

“…Galactosemia subjects had significantly lower volumes in the left cerebellar white matter and bilateral putamen. Motor and movement difficulties (ataxia) in the galactosemia subjects might be explained by lower volume of the left cerebellar white matter 48,51‐53 and the putamen, consistent with previous studies 25,32 . Disruption of this network by aberrant connections with consequent lower gray matter volumes, might explain the involuntary movements, tremors, and dysarthria experienced by galactosemia subjects 54 …”

“…Motor and movement difficulties (ataxia) in the galactosemia subjects might be explained by lower volume of the left cerebellar white matter 48,[51][52][53] and the putamen, consistent with previous studies. 25,32 Disruption of this network by aberrant connections with consequent lower gray matter volumes, might explain the involuntary movements, tremors, and dysarthria experienced by galactosemia subjects. 54 Two of the subjects had hypertonia which may correlate with abnormalities in the CST.…”

“…31 A resting-state functional magnetic resonance imaging (fMRI) study showed alterations in the brain networks involved in spatial orientation, attention, sensory-motor integration, speech planning, visuospatial capacities, and working memory in patients with galactosemia. 32 A task-based fMRI study found that patients with galactosemia had more extensive brain activity during language production compared to typically developing controls. 33 An event related potential study of language production showed atypical activity in galactosemia compared to typical controls, possibly reflecting difficulties in lexical access and syntactic planning of an utterance.…”

The Human Body as a Super Network: Digital Methods to Analyze the Propagation of Aging

“…For instance, classical galactosemia is a rare genetic metabolic disorder that impairs the ability to metabolize the sugar galactose. It results in chronic deterioration with a significant influence on the quality of life and general cognitive performance, including alterations to rest-state behavior (van Erven et al, 2017). In another recent example, fMRI or echocardiogram measurements pointed to a possible connection between the modulations of intrinsic resting-state and chronic migraines of female patients (Androulakis et al, 2017).…”

Novel imaging technologies for genetic diagnoses in the inborn errors of metabolism

“…rsFMRI in galactosemia has shown alterations in activation of several important pathways including default mode, salience and visual networks. Patients showed alterations in networks underlying spatial orientation and attention, working memory, sensory-motor integration and motor speech planning [89] .…”