Atypical multisensory integration in Niemann-Pick type C disease – towards potential biomarkers

Abstract

BackgroundNiemann-Pick type C (NPC) is an autosomal recessive disease in which cholesterol and glycosphingolipids accumulate in lysosomes due to aberrant cell-transport mechanisms. It is characterized by progressive and ultimately terminal neurological disease, but both pre-clinical studies and direct human trials are underway to test the safety and efficacy of cholesterol clearing compounds, with good success already observed in animal models. Key to assessing the effectiveness of interventions in patients, however, is the development of objective neurobiological outcome measures. Multisensory integration mechanisms present as an excellent candidate since they necessarily rely on the fidelity of long-range neural connections between the respective sensory cortices (e.g. the auditory and visual systems).MethodsA simple way to test integrity of the multisensory system is to ask whether individuals respond faster to the occurrence of a bisensory event than they do to the occurrence of either of the unisensory constituents alone. Here, we presented simple auditory, visual, and audio-visual stimuli in random sequence. Participants responded as fast as possible with a button push. One 11-year-old and two 14-year-old boys with NPC participated in the experiment and their results were compared to those of 35 age-matched neurotypical boys.ResultsReaction times (RTs) to the stimuli when presented simultaneously were significantly faster than when they were presented alone in the neurotypical children, a facilitation that could not be accounted for by probability summation, as evidenced by violation of the so-called ‘race’ model. In stark contrast, the NPC boys showed no such speeding, despite the fact that their unisensory RTs fell within the distribution of RTs observed in the neurotypicals.ConclusionsThese results uncover a previously undescribed deficit in multisensory integrative abilities in NPC, with implications for ongoing treatment of the clinical symptoms of these children. They also suggest that multisensory processes may represent a good candidate biomarker against which to test the efficacy of therapeutic interventions.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0149-x) contains supplementary material, which is available to authorized users.

Keeping in touch with the visual system: spatial alignment and multisensory integration of visual-somatosensory inputs

“…These speeded responses to all four VS conditions, indicative of the so-called RSE, also violated the race model. That is, these violations confirmed that the RSE could not be accounted for by simple probability summation, consistent with previous work using other sensory pairings ( Molholm et al, 2002 ; Murray et al, 2005 ; Brandwein et al, 2011 , 2013 ; Girard et al, 2011 ; Mahoney et al, 2011 ; Megevand et al, 2013 ; Andrade et al, 2014 ). Thus, the current behavioral results suggest that visual and somatosensory neural responses interacted to produce significant RT facilitation, regardless of spatial alignment.…”

Visual evoked potentials of Niemann-Pick type C1 mice reveal an impairment of the visual pathway that is rescued by 2-hydroxypropyl-ß-cyclodextrin

“…The rationale for undertaking this study was grounded on accumulating evidence that there is severe neuronal and glial damage in thalamocortical areas of Npc1 −/− mice [ 15 , 47 ], as well as defective myelin formation and maintenance associated with Npc1 functional deficiency [ 46 , 48 ]. These abnormalities are likely associated with an impairment of various sensory pathways, as already indicated by the deficit of auditory [ 11 , 49 ] and olfactory [ 50 ] systems in Npc1 −/− mice and of multisensory processing in NPC patients [ 51 ]. As for the visual system of Npc1 −/− mice, retinal cellular and functional defects were recently described [ 19 , 20 ], but the functional integrity of their visual pathway has not been investigated yet.…”

Ripe for solution: Delayed development of multisensory processing in autism and its remediation

“…Given the multiple processes that MSI must be built upon, which require long-range network integrity and functionality, it is a reasonable proposition that MSI may be particularly vulnerable to insult. Indeed, MSI has been shown to be impaired in a number of complex neurodevelopmental and neuropsychiatric disorders, such as dyslexia (Francisco, Jesse, Groen, & McQueen, 2017; Hahn, Foxe, & Molholm, 2014), schizophrenia (Ross, Saint-Amour, Leavitt, Molholm, et al, 2007) and rare lysosomal storage disorders (Andrade et al, 2014), to mention just a few. As we will elaborate below, however, it is ASD in particular that has been most extensively investigated and associated with dysfunction in MSI processing.…”