Biology subjects

Molholm, S.

Publications and source records attributed to Molholm, S..

33 records · Page 2Linked to original sources

bioRxiv2022

All-or-None Evaluation of Prediction Certainty in Autism

The brain generates predictions to prepare for upcoming events. As life is not always 100% predictable, it also estimates a level of certainty for these predictions. Given that autistic individuals resist even small changes in everyday life, we hypothesized impaired tuning of prediction certainty in autism. To study this, EEG was recorded from adolescents and young adults with autism while they performed a probabilistic prediction task in which cue validity was parametrically manipulated. A fully predictable condition (100% cue validity) was contrasted with less predictable conditions (84, 67 and 33% cue validity). Well characterized brain potentials were examined to assess the influence of cue validity on target anticipation (contingent negative variation; CNV), the evaluation of target statistics (P3), and prediction model updating (slow wave; SW). As expected, cue validity systematically influenced the amplitudes of the CNV, P3 and SW in controls. In contrast, cue-validity effects on CNV and SW were substantially reduced in autism. This suggests that although target statistics are accurately registered in autism, as indicated by intact modulation of the P3, they are not effectively applied to generate expectations for upcoming input or model updating. Contrasting the fully predictable with the less predictable conditions, our data suggest that autistic individuals adopted an all-or-none evaluation of certainty of their environment, rather than adjusting certainty of predictions to different levels of environmental statistics. Social responsiveness scores were associated with flexibility in representing prediction certainty, suggesting that impaired representation and updating of prediction certainty may contribute to social difficulties in autism. SIGNIFICANCE STATEMENTThe ability to make predictions is integral to everyday life. Yet, as life is not always 100% predictable and it is also essential to adjust the certainty of these predictions based on the current context. This study reveals that individuals with autism are less efficient in adjusting the certainty of their predictions to the level of predictability of events. Instead, they may adopt an all-or-none evaluation of certainty. Our findings reveal novel insights into the processes underlying impaired predictive processing in autism, which may open the door to developing targeted behavioral interventions and/or non-invasive brain stimulation therapies that help autistic individuals make more accurate predictions to ease social- and rigidity-based symptoms.

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bioRxiv2022

The strength of feedback processing is associated with resistance to visual backward masking during illusory contour processing in adult humans.

Re-entrant feedback processing is a key mechanism of visual object-recognition, especially under compromised viewing conditions where only sparse information is available and object features must be interpolated. Illusory contour stimuli are commonly used in conjunction with visual evoked potentials (VEP) to study these filling-in processes, with characteristic modulation of the VEP in the ~100-150ms timeframe associated with this re-entrant processing. Substantial inter-individual variability in timing and amplitude of feedback-related VEP modulation is observed, raising the question whether this variability might underlie inter-individual differences in the ability to form strong perceptual gestalts. Backward masking paradigms have been used to study inter-individual variance in the ability to form robust object perceptions before processing of the mask interferes with object-recognition. Some individuals recognize objects when the time between target object and mask is extremely short, whereas others struggle to do so even at longer target-to-mask intervals. We asked whether timing and amplitude of feedback-related VEP modulations were associated with individual differences in resistance to backward masking. Participants (N=40) showed substantial performance variability in detecting illusory contours at intermediate target-to-mask intervals (67ms and 117ms), allowing us to use kmeans clustering to divide the population into four performance groups (poor, low-average, high-average, superior). There was a clear relationship between the amplitude (but not the timing) of feedback-related VEP modulation and illusory contour detection during backward masking. We conclude that individual differences in the strength of feedback processing in neurotypical humans lead to differences in the ability to quickly establish perceptual awareness of incomplete visual objects.

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bioRxiv2022

Neural correlates of multisensory enhancement in audiovisual narrative speech perception: a fMRI investigation

This fMRI study investigated the effect of seeing articulatory movements of a speaker while listening to a naturalistic narrative stimulus. It had the goal to identify regions of the language network showing multisensory enhancement under synchronous audiovisual conditions. We expected this enhancement to emerge in regions known to underlie the integration of auditory and visual information such as the posterior superior temporal gyrus as well as parts of the broader language network, including the semantic system. To this end we presented 53 participants with a continuous narration of a story in auditory alone, visual alone, and both synchronous and asynchronous audiovisual speech conditions while recording brain activity using BOLD fMRI. We found multisensory enhancement in an extensive network of regions underlying multisensory integration and parts of the semantic network as well as extralinguistic regions not usually associated with multisensory integration, namely the primary visual cortex and the bilateral amygdala. Analysis also revealed involvement of thalamic brain regions along the visual and auditory pathways more commonly associated with early sensory processing. We conclude that under natural listening conditions, multisensory enhancement not only involves sites of multisensory integration but many regions of the wider semantic network and includes regions associated with extralinguistic sensory, perceptual and cognitive processing.

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bioRxiv2022

Neurophysiological Measures Of Auditory Sensory Processing Are Associated With Adaptive Behavior In Children With Autism Spectrum Disorder

BackgroundAtypical auditory cortical processing is consistently found in scalp electrophysiological and magnetoencephalographic studies of Autism Spectrum Disorder (ASD), and may provide a marker of neuropathological brain development. However, the relationship between atypical cortical processing of auditory information and adaptive behavior in ASD is not yet well understood. MethodsWe sought to test the hypothesis that early auditory processing in ASD is related to everyday adaptive behavior through the examination of auditory event-related potentials (AEPs) in response to simple tones and Vineland Adaptive Behavior Scales in a large cohort of children with ASD (N=89), aged 6-17, and in age- and IQ-matched neurotypically (NT) developing controls (N=120). ResultsStatistical analyses revealed significant group differences in early AEPs over temporal scalp regions. Whereas the expected rightward lateralization of the AEP to tonal stimuli occurred in both groups, lateralization of the AEP was only significantly associated with adaptive functioning, in the domains of communication and daily living, in the ASD group. ConclusionsThese results lend support to the hypothesis that atypical processing of sensory information is related to everyday adaptive behavior in autism.

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bioRxiv2021

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

Assessment of everyday activities are central to the diagnosis of pre-dementia and dementia. Yet, little is known about the brain substrates and processes that contribute to everyday functional impairment, particularly during early stages of cognitive decline. We investigated everyday function using a complex gait task in normal older adults stratified by risk of cognitive impairment. We applied a novel EEG approach, which combines electroencephalographic with 3D-body tracking technology to measure brain-gait dynamics with millisecond precision while participants are in motion. Twenty-six participants (mean age = 74.9 years) with cognitive and everyday functional profiles within the normal range for their age and sex were ranked for risk of cognitive impairment. We used the Montreal Cognitive Assessment battery, a global index of cognition with a range from 0 to 30, to classify individuals as being at higher (22-26) and lower risk (27+). Individuals walking on a treadmill were exposed to visual perturbation designed to destabilize gait. Assuming that brain changes precede behavioral decline, we predicted that older adults increase step width to gain stability, yet the underlying neural signatures would be different for lower versus higher risk individuals. When pooling across risk groups, we found that step width increased and fronto-parietal activation shifted from transient, during swing phases, to sustained across the gait cycle during visually perturbed input. As predicted, step width increased in both groups but underlying neural signatures were different. Fronto-medial theta (3-7Hz) power of gait-related brain oscillations were increased in higher risk individuals during both perturbed and unperturbed inputs. On the other hand, left central gyri beta (13-28Hz) power was decreased in lower risk individuals, specifically during visually perturbed input. Finally, relating MoCA scores to spectral power pooled across fronto-parietal regions, we found associations between increased theta power and worse MoCA scores and between decreased beta power and better MoCA scores.Able-bodied older adults at-risk of cognitive impairment are characterized by unique neural signatures of mobility. Stronger reliance on frontomedial theta activation in at-risk individuals may reflect higher-order compensatory responses for deterioration of basic sensorimotor processes. Region and spectral-specific signatures of mobility may provide brain targets for early intervention against everyday functional decline.

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bioRxiv2021

Learning a new class of multisensory associations: High-density electrophysiological mapping of the temporal course of audio-visual object processing.

Multisensory objects that are frequently encountered in the natural environment lead to strong associations across a distributed sensory cortical network, with the end result experience of a unitary percept. Remarkably little is known, however, about the cortical processes sub-serving multisensory object formation and recognition. To advance our understanding in this important domain, the present study investigated the brain processes involved in learning and identification of novel visual-auditory objects. Specifically, we introduce and test a rudimentary three-stage model of multisensory object-formation and processing. Thirty adults were remotely trained for a week to recognize a novel class of multisensory objects (3D shapes paired to complex sounds), and high-density event related potentials (ERPs) were recorded to the corresponding unisensory (shapes or sounds only) and multisensory (shapes and sounds) stimuli, before and after intensive training. We identified three major stages of multisensory processing: 1) an early, multisensory, automatic effect (<100 ms) in occipital areas, related to the detection of simultaneous audiovisual signals and not related to multisensory learning 2) an intermediate object-processing stage (100-200 ms) in occipital and parietal areas, sensitive to the learned multisensory associations and 3) a late multisensory processing stage (>250 ms) that appears to be involved in both object recognition and possibly memory consolidation. Results from this study provide support for multiple stages of multisensory object learning and recognition that are subserved by an extended network of cortical areas.

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bioRxiv2020

Oscillatory entrainment mechanisms and anticipatory predictive processes in Autism Spectrum Disorder (ASD)

Anticipating near-future events is fundamental to adaptive behavior, whereby neural processing of predictable stimuli is significantly facilitated relative to non-predictable inputs. Neural oscillations appear to be a key anticipatory mechanism by which processing of upcoming stimuli is modified, and they often entrain to rhythmic environmental sequences. Clinical and anecdotal observations have led to the hypothesis that people with Autism Spectrum Disorder (ASD) may have deficits in generating predictions in daily life, and as such, a candidate neural mechanism may be failure to adequately entrain neural activity to repetitive environmental patterns. Here, we tested this hypothesis by interrogating rhythmic entrainment both behaviorally and electrophysiologically. We recorded high-density electroencephalography in children with ASD (n=31) and Typically Developing (TD) age- and IQ-matched controls (n=20), while they reacted to an auditory target as quickly as possible. This auditory event was either preceded by predictive rhythmic visual cues, or not. Results showed that while both groups presented highly comparable evoked responses to the visual stimuli, children with ASD showed reduced neural entrainment to the rhythmic visual cues, and altered anticipation of the occurrence of these stimuli. Further, in both groups, neuro-oscillatory phase coherence correlated with behavior. These results describe neural processes that may underlie impaired event anticipation in children with ASD, and support the notion that their perception of events is driven more by instantaneous sensory inputs and less by their temporal predictability.

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bioRxiv2020

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.

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bioRxiv2019

Mobile Brain/Body Imaging of cognitive-motor impairment in multiple sclerosis: deriving EEG-based neuro-markers during a dual-task walking study

Individuals with a diagnosis of multiple sclerosis (MS) often present with deficits in the cognitive as well as the motor domain. The ability to perform tasks that rely on both domains may therefore be particularly impaired. Yet, behavioral studies designed to measure costs associated with performing two tasks at the same time such as dual-task walking have yielded mixed results. Patients may mobilize additional brain resources to sustain good levels of performance. To test this hypothesis, we acquired event-related potentials (ERP) in thirteen individuals with MS and fifteen healthy control (HC) participants performing a Go/NoGo response inhibition task while sitting (i.e., single task) or walking on a treadmill (i.e., dual-task). In previous work, we showed that the nogo-N2 elicited by the cognitive task was reduced when healthy adults are also asked to walk, and that nogo-N2 reduction was accompanied by sustained dual-task performance. We predicted that some MS patients, similar to their healthy peers, may mobilize N2-indexed brain resources and thereby reduce costs. Somewhat to our surprise, the HC group performed the Go/NoGo task more accurately while walking, thus showing a dual-task benefit, whereas, in line with expectation, the MS group showed a trend towards dual-task costs. The expected nogo-N2 reduction during dual-task walking was found in the HC group, but was not present at the group level in the MS group, suggesting that this group did not modulate the nogo-N2 process in response to higher task load. Regression analysis for the pooled sample revealed a robust link between nogo-N2 reduction and better dual-task performance. We conclude that impaired nogo-N2 adaptation reflects a neurophysiological marker of cognitive-motor dysfunction in MS.

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bioRxiv2019

Electrophysiological evidence for impaired auditory sensory memory in Cystinosis despite typical sensory processing: An MMN investigation

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.\n\nHere, 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 (450ms) SOA, suggesting intact change detection and sensory memory, individuals diagnosed with Cystinosis presented clearly reduced responses for the longer (900ms and 1800ms) 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.

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bioRxiv2019

Assessing auditory processing endophenotypes associated with Schizophrenia in individuals with 22q11.2 Deletion Syndrome

Background22q11.2 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.\n\nMethodsA 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.\n\nResultsN1 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.\n\nConclusionsThese 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.

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bioRxiv2019

Auditory processing atypicalities for pure tones and complex speech sounds in Rett Syndrome: towards neuromarkers of disease progression.

Due to severe motor impairments and the lack of expressive language abilities seen in most patients with Rett Syndrome (RTT), it has proven extremely difficult to obtain accurate measures of auditory processing capabilities in this population. Here, we examined early auditory cortical processing of pure tones and more complex phonemes females with confirmed mutation of the MECP2 gene. We recorded high-density auditory evoked potentials (AEP), which allow for objective evaluation of the timing and severity of processing deficits along the auditory processing hierarchy. We compared AEPs of 12 females with RTT to those of 21 typically developing (TD) peers aged 4-21 years, interrogating the first four major components of the AEP (P1: 60-90ms; N1: 100-130ms; P2: 135-165ms; N2: 245-275ms). Atypicalities were evident in RTT at the initial stage of processing. Whereas the initial P1 showed increased amplitude to phonemic inputs relative to tones in TD participants, this modulation by stimulus complexity was absent in RTT. Interestingly, the subsequent N1 did not differ between groups, whereas the following P2 was hugely diminished in RTT, regardless of stimulus complexity. The N2 was similarly smaller in RTT, and did not differ as a function of stimulus type. The P2 effect was remarkably robust in differentiating between groups with near perfect separation between the two groups despite the wide age range of our samples. Given this robustness, along with the observation that P2 amplitude was significantly associated with RTT symptom severity, the P2 has the potential to serve as a biomarker of treatment efficacy.\n\nSignificance statementOur study points to dramatic reduction of the P2 component of the auditory evoked potential (AEP) as a potentially reliable biomarker of Rett Syndrome severity, with prospective applicability as an objective readout (neuromarker) of change in functional brain activity following therapeutic interventions administered in the context of clinical trials. Compellingly, the reduction of P2 amplitude in patients with RTT mimics findings in animal models of RTT, providing a translational bridge between pre-clinical and human research.

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bioRxiv2019

Dissociable neural circuits underlie the resolution of three discrete sources of competition during task-switching.

Humans perform sub-optimally when juggling more than one task, but are nonetheless required to multitask during many daily activities. Rapidly and effectively switching attentional focus between tasks is fundamental to navigating complex environments. Task-switching paradigms in conjunction with neuroimaging have identified brain networks underpinning flexible reallocation of cognitive resources and a core network of neural regions is repeatedly implicated (i.e., posterior parietal, inferior frontal, anterior cingulate, and middle frontal cortex). Performance costs such as reduced accuracy and slowed responses accompany the first execution of a task following a task-switch. These costs stem from three main sources of competition: 1) the need to reconfigure task-rules, 2) the immediate history of motor responding, and 3) whether inputs to be acted upon provide congruent or incongruent information regarding the appropriate motor response, relative to the recently \"switched-away-from\" task. Here, we asked whether both common (domain-general) and non-overlapping (dissociable) neural circuits were involved in resolving these three distinct sources of competition under high-demand task-switching conditions. Dissociable neural circuits were active in resolving each of the three sources of competition. No domain-general regions were implicated in all three. Rather, two regions were common across rule-switching and stimulus incongruence, and five regions to incongruence and response-switching. Each source of conflict elicited activation from many regions including the posterior cingulate, thalamus, and cerebellum, regions not commonly implicated in the task-switching literature. These results suggest that dissociable neural networks are principally responsible for resolving different sources of competition, but with partial interaction of some overlapping domain-general circuitry.

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bioRxiv2019

Auditory sensory memory span for duration is severely curtailed in females with Rett Syndrome.

Rett syndrome (RTT), a rare neurodevelopmental disorder caused by mutations in the MECP2 gene, is typified by profound cognitive impairment and severe language impairment, rendering it very difficult to accurately measure auditory processing capabilities behaviorally in this population. Here we leverage the mismatch negativity (MMN) component of the event-related potential to measure the ability of RTT patients to decode and store occasional duration deviations in a stream of auditory stimuli. Sensory memory for duration, crucial for speech comprehension, has not been studied in RTT.\n\nHigh-density EEG was successfully recorded in 18 females with RTT and 27 age-matched typically developing (TD) controls (aged 6-22 years). Data from 7 RTT and 3 TD participants were excluded for excessive noise. Stimuli were 1kHz tones with a standard duration of 100ms and deviant duration of 180ms. To assess the sustainability of sensory memory, stimulus presentation rate was varied with stimulus onset asynchronies (SOAs) of 450, 900 and 1800ms. MMNs with maximum negativity over fronto-central scalp and a latency of 220-230ms were clearly evident for each presentation rate in the TD group, but only for the shortest SOA in the RTT group. Repeated-measures ANOVA revealed a significant group by SOA interaction. MMN amplitude correlated with age in the TD group only. MMN amplitude was not correlated with the Rett Syndrome Severity Scale. This study indicates that while RTT patients can decode deviations in auditory duration, the span of this sensory memory system is severely foreshortened, with likely implications for speech decoding abilities.

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bioRxiv2019

Developmental Recovery of Impaired Multisensory Processing in Autism and the Cost of Switching Sensory Modality

Children with autism spectrum disorder (ASD) are often impaired in their ability to cope with and process multisensory information, which may contribute to some of the social and communicative deficits that are prevalent in this population. Amelioration of such deficits in adolescence has been observed for ecologically-relevant stimuli such as speech. However, it is not yet known if this recovery generalizes to the processing of nonsocial stimuli such as more basic beeps and flashes, typically used in cognitive neuroscience research. We hypothesize that engagement of different neural processes and lack of environmental exposure to such artificial stimuli leads to protracted developmental trajectories in both neurotypical (NT) individuals and individuals with ASD, thus delaying the age at which we observe this "catch up". Here, we test this hypothesis using a bisensory detection task by measuring human response times to randomly presented auditory, visual and audiovisual stimuli. By measuring the behavioral gain afforded by an audiovisual signal, we show that the multisensory deficit previously reported in children with ASD recovers in adulthood by the mid-twenties. In addition, we examine the effects of switching between sensory modalities and show that teenagers with ASD incur less of a behavioral cost than their NT peers. Computational modelling reveals that multisensory information interacts according to different rules in children and adults, and that sensory evidence is weighted differently too. In ASD, weighting of sensory information and allocation of attention during multisensory processing differs to that of NT individuals. Based on our findings, we propose a theoretical framework of multisensory development in NT and ASD individuals.

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