Event-related potential (ERP) evidence for visual processing differences in children and adults with cystinosis (CTNS gene mutations).

BACKGROUND: Cystinosis, a rare lysosomal storage disease caused by mutations in the CTNS gene, is characterized by cystine crystallization and accumulation within multiple tissues, including kidney and brain. Its impact on neural function appears mild relative to its effects on other organs during early disease, but since therapeutic advances have led to substantially increased life expectancy, neurological implications are of increasing interest, necessitating deeper understanding of the impact of cystinosis on neurocognitive function. Behavioral difficulties have been reported in cystinosis in the visual domain. Very little is known, however, about how the brains of people living with cystinosis process visual information. This is especially interesting given that cystine accumulation in the cornea and posterior ocular structures is a hallmark of cystinosis. METHODS: Here, high-density scalp electrophysiology was recorded to visual stimuli (during a Go/No-Go task) to investigate visual processing in individuals with cystinosis, compared to age-matched controls. Analyses focused on early stages of cortical visual processing. RESULTS: The groups differed in their initial cortical response, with individuals with cystinosis exhibiting a significantly larger visual evoked potential (VEP) in the 130-150 ms time window. The groups also differed in the associations between neural responses and verbal abilities: While controls with higher IQ scores presented larger neural responses, that relationship was not observed in cystinosis. CONCLUSIONS: The enlarged VEP in cystinosis could be the result of cortical hyperexcitability and/or differences in attentional engagement and explain, at least partially, the visual and visual-spatial difficulties described in this population.

No evidence for differential saccadic adaptation in children and adults with an autism spectrum diagnosis.

Background: Altered patterns of eye-movements during scene exploration, and atypical gaze preferences in social settings, have long been noted as features of the Autism phenotype. While these are typically attributed to differences in social engagement and interests (e.g., preferences for inanimate objects over face stimuli), there are also reports of differential saccade measures to non-social stimuli, raising the possibility that fundamental differences in visuo-sensorimotor processing may be at play. Here, we tested the plasticity of the eye-movement system using a classic saccade-adaptation paradigm to assess whether individuals with ASD make typical adjustments to their eye-movements in response to experimentally introduced errors. Saccade adaptation can be measured in infants as young as 10 months, raising the possibility that such measures could be useful as early neuro-markers of ASD risk. Methods: Saccade amplitudes were measured while children and adults with ASD (N = 41) and age-matched typically developing (TD) individuals (N = 68) made rapid eye-movements to peripherally presented targets. During adaptation trials, the target was relocated from 20-degrees to 15-degrees from fixation once a saccade to the original target location was initiated, a manipulation that leads to systematic reduction in saccade amplitudes in typical observers. Results: Neither children nor adults with ASD showed any differences relative to TD peers in their abilities to appropriately adapt saccades in the face of persistently introduced errors. Conclusion: Of the three studies to date of saccade adaptation in ASD, none have shown deficits in saccade adaptation that are sufficient to generalize to the whole or a subgroup of the ASD population. Unlike prior studies, we found no evidence for a slower adaptation rate during the early adaptation phase, and no of evidence greater variance of saccade amplitudes in ASD. In post hoc analysis, there was evidence for larger primary saccades to non-adapted targets, a finding requiring replication in future work.

Event-related potential (ERP) evidence of early visual processing differences in cystinosis.

Cystinosis, a rare lysosomal storage disease, is characterized by cystine crystallization and accumulation within tissues and organs, including the kidneys and brain. Its impact on neural function appears mild relative to its effects on other organs, but therapeutic advances have led to substantially increased life expectancy, necessitating deeper understanding of its impact on neurocognitive function. Behavioral difficulties have been reported in cystinosis in the visual and visual-processing domain. Very little is known, however, about how the brains of people living with cystinosis process visual information, although cysteamine accumulation in the retina is a prominent feature of cystinosis. Here, electrophysiology was recorded during a Go/No-Go task to investigate early visual processing in cystinosis, compared to an age-matched control group. Analyses focused on early stages of cortical visual processing. The groups differed in their initial cortical response, with individuals with cystinosis exhibiting a significantly larger visual evoked potential (VEP) in the 130 to 150 ms time window. The timing and topography of this response suggested an enhanced P1 in cystinosis that could be the result of cortical hyperexcitability and/or differences in attentional engagement and explain, at least partially, the visual and visual-spatial difficulties described in this population. The groups also differed in the associations between neural responses and verbal abilities: While controls with higher IQ scores presented larger neural responses, that relationship was not observed in cystinosis.

Response inhibition and error-monitoring in cystinosis (CTNS gene mutations): Behavioral and electrophysiological evidence of a diverse set of difficulties.

Cystinosis, a rare lysosomal storage disease, is characterized by cystine crystallization and accumulation within tissues and organs, including the kidneys and brain. Its impact on neural function appears mild relative to its effects on other organs, but therapeutic advances have led to substantially increased life expectancy, necessitating deeper understanding of its impact on neurocognitive function. Behaviorally, some deficits in executive function have been noted in this population, but the underlying neural processes are not understood. Using standardized cognitive assessments and a Go/No-Go response inhibition task in conjunction with high-density electrophysiological recordings (EEG), we sought to investigate the behavioral and neural dynamics of inhibition of a prepotent response and of error monitoring (critical components of executive function) in individuals with cystinosis, when compared to age-matched controls. Thirty-seven individuals diagnosed with cystinosis (7-36 years old, 24 women) and 45 age-matched controls (27 women) participated in this study. Analyses focused on N2 and P3 No-Go responses and error-related positivity (Pe). Atypical inhibitory processing was shown behaviorally. Electrophysiological differences were additionally found between the groups, with individuals with cystinosis showing larger No-Go P3s. Error-monitoring was likewise different between the groups, with those with cystinosis showing reduced Pe amplitudes.

Neural signature of mobility-related everyday function in older adults at-risk of cognitive impairment.

Assessment of everyday activities is central to the diagnosis of dementia. Yet, little is known about brain processes associated with everyday functional limitations, particularly during early stages of cognitive decline. Twenty-six older adults (mean = 74.9 y) were stratified by risk using the Montreal Cognitive Assessment battery (MoCA, range: 0- 30) to classify individuals as higher (22-26) and lower risk (27+) of cognitive impairment. We investigated everyday function using a gait task designed to destabilize posture and applied Mobile Brain/Body Imaging. We predicted that participants would increase step width to gain stability, yet the underlying neural signatures would be different for lower versus higher risk individuals. Step width and fronto-parietal activation increased during visually perturbed input. Frontomedial theta increased in higher risk individuals during perturbed and unperturbed inputs. Left sensorimotor beta decreased in lower risk individuals during visually perturbed input. Modulations in theta and beta power were associated with MoCA scores. Our findings suggest that older adults at-risk of cognitive impairment can be characterized by a unique neural signature of everyday function.

Early visual processing and adaptation as markers of disease, not vulnerability: EEG evidence from 22q11.2 deletion syndrome, a population at high risk for schizophrenia.

We investigated visual processing and adaptation in 22q11.2 deletion syndrome (22q11.2DS), a condition characterized by an increased risk for schizophrenia. Visual processing differences have been described in schizophrenia but remain understudied early in the disease course. Electrophysiology was recorded during a visual adaptation task with different interstimulus intervals to investigate visual processing and adaptation in 22q11.2DS (with (22q+) and without (22q-) psychotic symptoms), compared to control and idiopathic schizophrenia groups. Analyses focused on early windows of visual processing. While increased amplitudes were observed in 22q11.2DS in an earlier time window (90-140 ms), decreased responses were seen later (165-205 ms) in schizophrenia and 22q+. 22q11.2DS, and particularly 22q-, presented increased adaptation effects. We argue that while amplitude and adaptation in the earlier time window may reflect specific neurogenetic aspects associated with a deletion in chromosome 22, amplitude in the later window may be a marker of the presence of psychosis and/or of its chronicity/severity.

Atypical response inhibition and error processing in 22q11.2 Deletion Syndrome and schizophrenia: Towards neuromarkers of disease progression and risk.

22q11.2 deletion syndrome (also known as DiGeorge syndrome or velo-cardio-facial syndrome) is characterized by increased vulnerability to neuropsychiatric symptoms, with approximately 30% of individuals with the deletion going on to develop schizophrenia. Clinically, deficits in executive function have been noted in this population, but the underlying neural processes are not well understood. Using a Go/No-Go response inhibition task in conjunction with high-density electrophysiological recordings (EEG), we sought to investigate the behavioral and neural dynamics of inhibition of a prepotent response (a critical component of executive function) in individuals with 22q11.2DS with and without psychotic symptoms, when compared to individuals with idiopathic schizophrenia and age-matched neurotypical controls. Twenty-eight participants diagnosed with 22q11.2DS (14-35 years old; 14 with at least one psychotic symptom), 15 individuals diagnosed with schizophrenia (18-63 years old) and two neurotypical control groups (one age-matched to the 22q11.2DS sample, the other age-matched to the schizophrenia sample) participated in this study. Analyses focused on the N2 and P3 no-go responses and error-related negativity (Ne) and positivity (Pe). Atypical inhibitory processing was shown behaviorally and by significantly reduced P3, Ne, and Pe responses in 22q11.2DS and schizophrenia. Interestingly, whereas P3 was only reduced in the presence of psychotic symptoms, Ne and Pe were equally reduced in schizophrenia and 22q11.2DS, regardless of the presence of symptoms. We argue that while P3 may be a marker of disease severity, Ne and Pe might be candidate markers of risk.

Assessing auditory processing endophenotypes associated with Schizophrenia in individuals with 22q11.2 deletion syndrome.

22q11.2 Deletion Syndrome (22q11.2DS) is the strongest known molecular risk factor for schizophrenia. Brain responses to auditory stimuli have been studied extensively in schizophrenia and described as potential biomarkers of vulnerability to psychosis. We sought to understand whether these responses might aid in differentiating individuals with 22q11.2DS as a function of psychotic symptoms, and ultimately serve as signals of risk for schizophrenia. A duration oddball paradigm and high-density electrophysiology were used to test auditory processing in 26 individuals with 22q11.2DS (13-35 years old, 17 females) with varying degrees of psychotic symptomatology and in 26 age- and sex-matched neurotypical controls (NT). Presentation rate varied across three levels, to examine the effect of increasing demands on memory and the integrity of sensory adaptation. We tested whether N1 and mismatch negativity (MMN), typically reduced in schizophrenia, related to clinical/cognitive measures, and how they were affected by presentation rate. N1 adaptation effects interacted with psychotic symptomatology: Compared to an NT group, individuals with 22q11.2DS but no psychotic symptomatology presented larger adaptation effects, whereas those with psychotic symptomatology presented smaller effects. In contrast, individuals with 22q11.2DS showed increased effects of presentation rate on MMN amplitude, regardless of the presence of symptoms. While IQ and working memory were lower in the 22q11.2DS group, these measures did not correlate with the electrophysiological data. These findings suggest the presence of two distinct mechanisms: One intrinsic to 22q11.2DS resulting in increased N1 and MMN responses; another related to psychosis leading to a decreased N1 response.

Impaired auditory sensory memory in Cystinosis despite typical sensory processing: A high-density electrical mapping study of the mismatch negativity (MMN).

Cystinosis, a genetic rare disease characterized by cystine accumulation and crystallization, results in significant damage in a multitude of tissues and organs, such as the kidney, thyroid, eye, and brain. While Cystinosis' impact on brain function is relatively mild compared to its effects on other organs, the increased lifespan of this population and thus potential for productive societal contributions have led to increased interest on the effects on brain function. Nevertheless, and despite some evidence of structural brain differences, the neural impact of the mutation is still not well characterized. Here, using a passive duration oddball paradigm (with different stimulus onset asynchronies (SOAs), representing different levels of demand on memory) and high-density electrophysiology, we tested basic auditory processing in a group of 22 children and adolescents diagnosed with Cystinosis (age range: 6-17 years old) and in neurotypical age-matched controls (N = 24). We examined whether the N1 and mismatch negativity (MMN) significantly differed between the groups and if those neural measures correlated with verbal and non-verbal IQ. Individuals diagnosed with Cystinosis presented similar N1 responses to their age-matched peers, indicating typical basic auditory processing in this population. However, whereas both groups showed similar MMN responses for the shortest (450 ms) SOA, suggesting intact change detection and sensory memory, individuals diagnosed with Cystinosis presented clearly reduced responses for the longer (900 ms and 1800 ms) SOAs. This could indicate reduced duration auditory sensory memory traces, and thus sensory memory impairment, in children and adolescents diagnosed with Cystinosis. Future work addressing other aspects of sensory and working memory is needed to understand the underlying bases of the differences described here, and their implication for higher order processing.