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are able to reformat a high resolution T1 weighted image and perform volume analysis using voxel-
based morphometry (VBM) to measure differences in gray and white matter volumes. To understand
the cognitive outcomes of IEMs, one can use fMRI to study the neural networks that underlie cognitive
[12]
pathways . Another modality that can also give information about neural networks is fNRIs which is a
less invasive and portable imaging modality (described below).

MAGNETIC RESONANCE IMAGING, HOW IT WORKS
MRI works by exploiting differences in water proton spins between tissue types (gray matter, white
matter, and cerebral spinal fluid) after the tissue is exposed to a radiofrequency pulse in a strong magnetic
field. The subject’s head is enclosed in a head coil, and there is a body coil at the bed of the scanner. The
coil serves as an antenna, converting electromagnetic waves into an electrical current, which is used to
reconstruct the three dimensional images.

Despite its utility as both a research and clinical tool, routine MRI detection is limited to macroscopic
alterations in brain structure. It lacks the spatial resolution to provide information regarding
microstructural neuropathology, and does not capture dynamic processes in space and time related to brain
function and metabolism. Additionally, many macrostructural neuropathological phenotypes lag behind
the presentation of associated clinical manifestations until there is critical amount of macroscopic damage
that can be seen on an image.

The advantages of MRI over CT include the lack of ionizing radiation, the ability to image in three
orthogonal planes and the ability to better visualize the brainstem and cerebellum which are difficult
to see in CT due to beam hardening artefacts. MRI is superior to CT in the evaluation of white matter
pathologies. This is at the expense of longer imaging sequence times, need for sedation in children and
sometimes lack of accessibility in an emergency situation.

DIFFUSION TENSOR IMAGING
How DTI works
[13]
DTI is an imaging technique in which contrast is based on differences in the diffusion of water molecules .
As a result, maps of white matter fibers can be generated. Since water diffusion in cells corresponds to cell
geometry in axons, diffusion MRI can also be used to make inferences about white matter architecture.
One standard measure is anisotropy which refers to the property of being directionally dependent. Three
measures of diffusion in tissue can be quantitated using DTI: magnitude (ADC), orientation of diffusion,
and degree of anisotropy (orientation of diffusion and deviation from uniform diffusion in all directions).
The more unrestricted the water molecules are in their movement, the higher the ADC and the lower
the anisotropy. DTI has in some cases shown to have predictive ability for example, in recovery from a
[14]
traumatic brain injury .

Understanding white matter integrity is important because underlying changes in neural networks are often
aberrant white matter tracks. There are many well defined neural networks that play a role in cognitive
[15]
functions such as working memory, attention and cognitive flexibility . There is a rich literature that
has focused on alterations in executive function, for example on large cohorts of children and adults with
attention deficit disorders, Alzheimer disease, autism and post traumatic brain injury to name a few. Only
recently has this been a topic of interest in inborn errors of metabolism.

GALACTOSEMIA
Doyle et al. used a cognitive function battery demonstrating low scores for verbal and performance IQ,
[16]
as well as low scores for memory and executive function. Subsequently, using diffusion tensor imaging,