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subjects to generate a group-wise image rather than individual subject maps. Statistical analyses are
performed to assess BOLD signal differences between the experimental condition (i.e., task).

One of the limitations of fMRI, is the large number of subjects required to account for inter-subject
variability in order to achieve an acceptable signal-to-noise ratio. Therefore, adaptations need to be made
when studying rare disorders since the sample sizes are typically small. There has yet to be a consensus on
using fMRI to probe neurocognitive phenotypes at the single subject level but it is useful in monitoring
brain function at the group level.

RESTING STATE FMRI
A recent development in neuroimaging research is the study of brain function in “resting” conditions,
i.e., when the subject is at rest and not performing a task. There are several networks that operate at rest.
The most widely studied resting state network (RSN) is the default mode network (DMN). DMN includes
the precuneus/posterior cingulate cortex (PCC), mesiofrontal/anterior cingulate cortex (ACC), and
[82]
temporoparietal areas .
[83]
The term “default mode” was first used by Raichle in 2007 to describe resting brain function. It has been
associated with introspective thought [84,85] . Disruption of default mode has been linked to several disorders
including Alzheimer disease and autism . It is being explored in some IEMs.
[86]
PKU: fMRI in PKU has been robustly developed. Christ et al. have achieved the most in this regard
[87]
and found the prefrontal cortex of PKU subjects had atypical neural activity during working memory
performance even in those who were treated in childhood.

Resting state studies in PKU have demonstrated alterations in default mode, salience, and visual network.
Patients showed alterations in networks involving the medial prefrontal cortex, parietal lobule and (pre)
[88]
cuneus, which have been shown to underlie spatial orientation and attention .
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]

TASK BASED FMRI
PKU
[34]
Patients with PKU show deficits in inhibitory control despite early dietary treatment. Sundermann et al.
used a Go-No Go task in young adult patients with PKU vs. control subjects and demonstrated more errors
of commission and slightly increased activation associated with inhibitory control. This did not reach
statistical significance.

UCD
Patients with OTCD also experience impairment in frontal lobe function, especially in executive
functioning, working memory, and motor planning. fMRI studies have been performed to evaluate
functional connectivity of two resting-state networks, the default mode and set-maintenance--between
OTCD patients and healthy controls, demonstrating reduced internodal functional connectivity in the
DMN and set-maintenance network as a likely consequence of hyperammonemia [90,91] .

FUNCTIONAL NEAR INFRARED SPECTROSCOPY
Most recently, several research groups have used fNIRS as a surrogate to fMRI imaging as it is portable,
not subjected to the confines of the scanner and is not degraded by movement. Since subjects are awake in