Summary Findings: Cognitive Function in Cystinosis

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With critical support from CRN, Drs. Foxe, Molholm, and Francisco from the Cognitive Neurophysiology Laboratory (CNL) in New York are characterizing perceptual and cognitive function in cystinosis using cutting-edge non-invasive electrical brain imaging (scalp recorded electroencephalograms, EEG) and behavioral measures. In the past three years, they have tested a total of 42 children, adolescents, and adults with cystinosis from all over the country, plus an age matched comparison group of 50 individuals without cystinosis.  This work has revealed novel information on how brain function is affected by cystinosis in children and adults.  This work has been presented at the Cystinosis Family meetings in Utah and Philadelphia and several local and international scientific meetings, as well as published (or is being prepared for publication) in scientific journals. Here we present a summary of their findings to date.

Executive functions encompass brain processes that govern goal-directed behavior and serve to optimize performance on complex cognitive tasks, allowing one to behave flexibly and to adapt to novel, changing circumstances. Executive Functions are often affected in cystinosis.  Executive function abilities—such as working memory, cognitive flexibility, and response inhibition—are critical for academic, professional, and social achievements. Response inhibition, the process by which one suppresses a well-learned response that might be irrelevant or inappropriate in a given context, is clearly essential for adjusting behavior dynamically with changing environmental contexts.

The CNL team has found that when it comes to response inhibition, there is a lot that works really well in cystinosis, in children and adults alike. Individuals with cystinosis can withhold their responses just as well as healthy controls. However, they make a few more errors, and brain activity shows that withholding a response takes more effort. Cognitive tests of executive function show that these individuals with cystinosis can perform the tasks just fine, but that it takes them a little bit longer.  So, giving a little more time to execute tasks and process information may go a long way in academic success for children with cystinosis.

The ease with which we make sense of what we see and hear belies the complexity of auditory and visual processing in the brain.  However, even basic recognition that the object you see in front of you is a cup of coffee involves a complex hierarchy of cortical brain processing that begins with extraction of the very simple features that comprise the object, and includes detecting where the event is, storing it in memory, comparing it with other events, and identifying it.  Along the way you will likely even assign some value to it (caffeine = high value!). Brain processing can break down at any of these stages, and have cascading effects on later stages of information processing such as described under Executive Functions.  The CNL therefore has also looked into auditory and visual processing in cystinosis.

For auditory processing, the CNL research team found that while basic auditory processing is fully functional, children and adolescents with cystinosis seem to have some difficulties with auditory sensory memory. Sensory memory is the shortest type of memory and it helps keeping track of sequences of information. Because basic and complex aspects of brain processing are related and co-dependent (for example, a problem in a more basic process can hinder the processing at a more complex level), difficulties at this very basic level of memory could impact, for example, working memory—crucial to fulfill day-to-day tasks and to academic success. Remarkably, though, in adults with cystinosis both auditory processing and auditory sensory memory appear fully intact. This means that though some difficulties are present in younger individuals with cystinosis, they appear to be resolved in adulthood. Since this could have a negative impact in both school and home contexts, this should be considered when developing education plans.

Focusing in on visual processing, brain data from the CNL show that the visual response is substantially larger in individuals with cystinosis, and this is the case for both children and adults. This presents a powerful biomarker that can be used to see if treatments help to normalize brain function. This increased visual brain response may reflect reduced neural inhibition in visual cortex, which would lead to an imbalance of sensory processing in the brain.  This in turn might be related to the impaired visuo-spatial ability that has been observed behaviorally in cystinosis. The team at CNL are conducting analyses of additional data to understand the basis of this difference, which may provide clues for treatments to counteract the impact of cystinosis on brain function.

In conclusion, we are pleased to report to you that the CNL teams’ investigations into brain function are providing critical information on the strengths and weaknesses that are present, on average, in individuals with cystinosis.  This information in turn hints at the types of additional cognitive support that will be of most use to affected individuals in our community.