Optical Imaging as a Diagnostic Tool for Monitoring Brain Function in X-linked Rare Disorders

Fragile X syndrome (FXS, OMIM #300624) and Creatine Transporter Deficiency (CTD, #300352) are the two most common causes of X-linked intellectual disability. FXS and CTD affect hemizygous males and with highly variable severity heterozygous females. Both these neurodevelopmental disorders (NDDs) have a dramatic impact on the family quality of life and the health-care system. These disorders share common clinical traits, including intellectual disability, autistic-like features, behavioural and mood alterations and seizures. Brain anatomy appears largely normal, suggesting that functional deficits result from subtle changes in synaptic connectivity. Moreover, common physiological mechanisms related to brain energetics might concur to the pathophysiology of FXS and CTD. Indeed, FMR1 and SLC6A8 are directly involved in the regulation of metabolism and the loss-of-function of both genes leads to a disruption of the mitochondrial network.

There is no cure for these disorders and the efficacy study of potential treatments is hindered by the scarcity of unbiased, quantitative, non-invasive biomarkers for monitoring brain function.

This is a critical problem, since the often-used phenotypic observation of behavioural endpoints to score NDDs such as FXS and CTD is highly prone to subjective bias. For successful clinical trials, the availability of objective readouts is crucial to evaluate the therapeutic response to new drugs. There are multiple techniques to visualize neural circuit activity in the living brain. Interestingly, FXS and CTD are the only two NDDs that at preclinical level show an abnormally large hemodynamic response to sensory stimulation in functional imaging studies of intrinsic optical signals.

The objective of this project is to exploit optical imaging techniques to devise a measurable and non-invasive biomarker of brain function in FXS and CTD. Since a disruption of brain energy metabolism is a major disease mechanism linking these disorders, we hypothesized that the assessment of the cerebral blood flow and oxygen consumption represents a sensitive readout for quantifying functional alterations of neural circuits.

Functional near-infrared spectroscopy (fNIRS), allows quantifying changes of hemoglobin species and local blood flow in the cerebral cortex of humans, providing an indirect measure of neuronal activity. In the clinical framework, this blood-oxygen-level-dependent signal is similar to that detected with functional MRI (fMRI). However, fNIRS has the advantage of being completely non-invasive, low-cost, portable, noiseless, endowed with high experimental flexibility and easy to implement in both laboratory and clinical settings. Moreover, fNIRS is more tolerant to motion artifacts than fMRI, and robust methods for motion detection/correction allow to image very young children without sedation. These methodological strengths make fNIRS as an outstanding choice for investigating neural circuits in clinically relevant populations at the very-low cost. Although introduced into the clinical care almost 40 years ago, fNIRS gained much popularity in the study of brain development and NDDs only recently. To date, however, fNIRS has been used primarily to investigate the typical maturation of speech perception and language, sensory and motor functions, social communication and interaction, object and action processing in toddlers and children.

In this proposal, the investigators hypothesize that by combining the above-mentioned strengths of fNIRS to the clinical study of several cognitive and motor parameters, the investigators can define unique "fNIRS signatures" for FXS and CTD as brain biomarkers for the diagnosis and the assessment of treatment outcomes. Since the measurement of visual responses has been introduced as a quantitative method to assess brain function in NDDs, the investigators will test the value of visually-evoked fNIRS signals in classifying patients and predicting symptom severity in the FXS and CTD clinical population. Preliminary data in the mouse models of CTD and FXS strongly suggest that visual hemodynamic responses (vHDR) are markedly altered in the occipital cortex of mutant animals. Morever, the investigators will use a standardized procedure with high entertaining value to measure vHDR in the occipital cortex of children.