Biology subjects

Dick, F.

Publications and source records attributed to Dick, F..

33 records · Page 2Linked to original sources

bioRxiv2021

Slow phase-locked endogenous modulations support selective attention to sound

To make sense of complex soundscapes, listeners must select and attend to task-relevant streams while ignoring uninformative sounds. One possible neural mechanism underlying this process is alignment of endogenous oscillations with the temporal structure of the target sound stream. Such a mechanism has been suggested to mediate attentional modulation of neural phase-locking to the rhythms of attended sounds. However, such modulations are compatible with an alternate framework, where attention acts as a filter that enhances exogenously-driven neural auditory responses. Here we attempted to adjudicate between theoretical accounts by playing two tone steams varying across condition in tone duration and presentation rate; participants attended to one stream or listened passively. Attentional modulation of the evoked waveform was roughly sinusoidal and scaled with rate, while the passive response did not. This suggests that auditory attentional selection is carried out via phase-locking of slow endogenous neural rhythms.

neuroscience↗

bioRxiv2020

A Bayesian optimisation approach for rapidly mapping residual network function in stroke

Post-stroke cognitive and linguistic impairments are debilitating conditions, with current therapies only showing small improvements. Domain-general brain networks seem to play a critical role in stroke recovery and characterising their residual function with functional neuroimaging (fMRI) has the potential to yield biomarkers capable of guiding patient-specific rehabilitation. However, this is currently challenging in patients as such detailed characterisation requires too many different cognitive tasks. Here, we use neuroadaptive Bayesian optimisation to overcome this problem, an approach combining real-time fMRI with machine-learning. By intelligently searching across many tasks, this approach rapidly maps out patient-specific profiles of residual domain-general network function. Whereas controls have highly similar profiles, patients show idiosyncratic profiles of network abnormalities that are associated with behavioural performance. This approach can be extended to diverse brain networks and combined with brain stimulation or other therapeutics, thereby opening new avenues for precision medicine targeting diverse neurological and psychiatric conditions.

neuroscience↗

bioRxiv2020

GO-CRISPR: a highly controlled workflow to discover gene essentiality in loss-of-function screens

Genome-wide CRISPR screens are an effective discovery tool for genes that underlie diverse cellular mechanisms that can be scored through cell fitness. Loss-of-function screens are particularly challenging compared to gain-of-function because of the limited dynamic range of decreased sgRNA sequence detection. Here we describe Guide-Only control CRISPR (GO-CRISPR), an improved loss-of-function screening workflow, and its companion software package, Toolset for the Ranked Analysis of GO-CRISPR Screens (TRACS). We demonstrate a typical GO-CRISPR workflow in a non-proliferative 3D spheroid model of dormant high grade serous ovarian cancer and demonstrate superior performance to standard screening methods. The unique integration of the pooled sgRNA library quality and guide-only controls allows TRACS to identify novel molecular pathways that were previously unidentified in tumor dormancy. Together, GO-CRISPR and TRACS can robustly improve the discovery of essential genes in challenging biological scenarios.

systems biology↗

bioRxiv2019

Reduced functional connectivity between left frontal and right auditory cortices during speech perception in congenital amusia.

Individuals with congenital amusia have a lifelong history of unreliable pitch processing. Accordingly, they downweight pitch cues during speech perception (even large, obvious ones) and instead rely on other dimensions such as duration. We investigated the neural basis for this strategy. During fMRI, individuals with amusia and controls (N=30) matched auditory and visual sentences using pitch and duration cues. A data-driven analysis procedure detected prominent reductions in functional connectivity in the amusia group, between left prefrontal language-related regions (inferior and middle frontal gyrus/DLPFC) and right hemisphere pitch-related regions (auditory and anterior insular cortex). Functional connectivity levels were correlated with prosodic cue weights measured outside the scanner. Furthermore, group differences in functional connectivity between these regions was not present during a control task (passive listening to tones). Our results suggest that individuals compensate for differences in the reliability of perceptual dimensions by regulating functional connectivity between task-relevant frontal and perceptual regions.

neuroscience↗

bioRxiv2019

Common gene expression signatures in Parkinson’s disease are driven by changes in cell composition

BackgroundThe etiology of Parkinsons disease (PD) is largely unknown. Genome-wide transcriptomic studies in bulk brain tissue have identified several molecular signatures associated with the disease. While these studies have the potential to shed light into the pathogenesis of PD, they are also limited by two major confounders: RNA post mortem degradation and heterogeneous cell type composition of bulk tissue samples. We performed RNA sequencing following ribosomal RNA depletion in the prefrontal cortex of 49 individuals from two independent case-control cohorts. Using cell-type specific markers, we estimated the cell-type composition for each sample and included this in our analysis models to compensate for the variation in cell-type proportions.\n\nResultsRibosomal RNA depletion results in substantially more even transcript coverage, compared to poly(A) capture, in post mortem tissue. Moreover, we show that cell-type composition is a major confounder of differential gene expression analysis in the PD brain. Correcting for cell-type proportions attenuates numerous transcriptomic signatures that have been previously associated with PD, including vesicle trafficking, synaptic transmission, immune and mitochondrial function. Conversely, pathways related to endoplasmic reticulum, lipid oxidation and unfolded protein response are strengthened and surface as the top differential gene expression signatures in the PD prefrontal cortex.\n\nConclusionsDifferential gene expression signatures in PD bulk brain tissue are significantly confounded by underlying differences in cell-type composition. Modeling cell-type heterogeneity is crucial in order to unveil transcriptomic signatures that represent regulatory changes in the PD brain and are, therefore, more likely to be associated with underlying disease mechanisms.

neuroscience↗

bioRxiv2019

The Multidimensional Battery of Prosody Perception (MBOPP)

Prosody can be defined as the rhythm and intonation patterns spanning words, phrases and sentences. Accurate perception of prosody is an important component of many aspects of language processing, such as parsing grammatical structures, recognizing words, and determining where emphasis may be placed. Prosody perception is important for language acquisition and can be impaired in language-related developmental disorders. However, existing assessments of prosodic perception suffer from some shortcomings. These include being unsuitable for use with typically developing adults due to ceiling effects, or failing to allow the investigator to distinguish the unique contributions of individual acoustic features such as pitch and temporal cues. Here we present the Multi-Dimensional Battery of Prosody Perception (MBOPP), a novel tool for the assessment of prosody perception. It consists of two subtests - Linguistic Focus, which measures the ability to hear emphasis or sentential stress, and Phrase Boundaries, which measures the ability to hear where in a compound sentence one phrase ends, and another begins. Perception of individual acoustic dimensions (Pitch and Time) can be examined separately, and test difficulty can be precisely calibrated by the the experimenter because stimuli were created using a continuous voice morph space. We present validation analyses from a sample of 57 individuals and discuss how the battery might be deployed to examine perception of prosody in various populations.

neuroscience↗

bioRxiv2019

Attentional modulation of neural phase is enhanced by short-term training and linked to musical experience

How does the brain follow a sound that is mixed with others in a noisy environment? A possible strategy is to allocate attention to task-relevant time intervals while suppressing irrelevant intervals - a strategy that could be implemented by aligning neural modulations with critical moments in time. Here we tested whether selective attention to non-verbal sound streams is linked to shifts in the timing of attentional modulations of EEG activity, and investigated whether this neural mechanism can be enhanced by short-term training and musical experience. Participants performed a memory task on a target auditory stream presented at 4 Hz while ignoring a distractor auditory stream also presented at 4 Hz, but with a 180-degree shift in phase. The two attention conditions were linked to a roughly 180-degree shift in phase in the EEG signal at 4 Hz. Moreover, there was a strong relationship between performance on the 1-back task and the timing of the EEG modulation with respect to the attended band. EEG modulation timing was also enhanced after several days of training on the selective attention task and enhanced in experienced musicians. These results support the hypothesis that modulation of neural timing facilitates attention to particular moments in time and indicate that phase timing is a robust and reliable marker of individual differences in auditory attention. Moreover, these results suggest that nonverbal selective attention can be enhanced in the short term by only a few hours of practice and in the long term by years of musical training.

neuroscience↗

bioRxiv2018

Rapid ocular responses are a robust marker for bottom-up driven auditory salience

Despite the prevalent use of alerting sounds in alarms and human-machine interface systems, we have only a rudimentary understanding of what determines auditory salience - the automatic attraction of attention by sound - and the brain mechanisms which underlie this process. A major roadblock to understanding has been the lack of a robust, objective means of quantifying sound-driven attentional capture. Here we demonstrate that microsaccade inhibition - an oculomotor response arising within 300ms of sound onset - is a robust marker for the salience of brief sounds. Specifically, we show that a crowd sourced (N=911) subjective salience ranking correlated robustly with the superior colliculus (SC) mediated ocular freezing response measured in naive, passively listening participants (replicated in two groups of N=15 each). More salient sounds evoked earlier microsaccadic inhibition, consistent with a faster orienting response. These results establish that microsaccade-indexed activity within the SC is a practical objective measure for auditory salience.\n\nSignificance statementMicrosaccades are small, rapid, fixational eye movements, measurable with sensitive eye-tracking equipment. We reveal a novel, robust link between microsaccade dynamics and the subjective salience of brief sounds (salience ranking obtained from a large number of participants in an online experiment): Within 300 ms of sound onset, the eyes of naive, passively listening participants demonstrate different microsaccade patterns as a function of the sounds perceptual salience. These results position the Superior Colliculus (the generator of microsaccades) as an important brain area to investigate in the context of a putative multi-modal salience-hub and establish a robust objective means for quantifying auditory salience, critical in the development of sound-based human machine interfaces.

neuroscience↗

bioRxiv2018

Phasic norepinephrine is a neural interrupt signal for unexpected events in rapidly unfolding sensory sequences - evidence from pupillometry

The ability to track the statistics of our surroundings is a key computational challenge. A prominent theory (Dayan & Yu, 2006) proposes that the brain monitors for unexpected uncertainty - events which deviate substantially from model predictions, indicating model failure. Norepinephrine (NE) is thought to play a key role in this process by serving as an interrupt signal, initiating model-resetting. However, evidence is from paradigms where participants actively monitored stimulus statistics. To determine whether NE routinely reports the statistical structure of our surroundings, even when not behaviourally relevant, we used rapid tone-pip sequences that contained perceptually salient pattern-changes associated with abrupt structural violations vs. emergence of regular structure. Phasic pupil dilations (PDR) were monitored to assess NE. We reveal a remarkable specificity: When not behaviourally relevant, only abrupt structural violations evoked a PDR. The results demonstrate that NE tracks unexpected uncertainty on rapid time scales relevant to sensory signals.

neuroscience↗

bioRxiv2018

Context dependent roles for RB-E2F transcriptional regulation in tumor suppression

RB-E2F transcriptional control plays a key role in regulating the timing of cell cycle progression from G1 to S-phase in response to growth factor stimulation. Despite this role, it is genetically dispensable for cell cycle exit in primary fibroblasts in response to growth arrest signals. Mice engineered to be defective for RB-E2F transcriptional control at cell cycle genes were also found to live a full lifespan with no susceptibility to cancer. Based on this background we sought to probe the vulnerabilities of RB-E2F transcriptional control defects found in Rb1R461E,K542E mutant mice (Rb1G) through genetic crosses with other mouse strains. We generated Rb1G/G mice in combination with Trp53 and Cdkn1a deficiencies, as well as in combination with KrasG12D. The Rb1G mutation enhanced Trp53 cancer susceptibility, but had no effect in combination with Cdkn1a deficiency or KrasG12D. Collectively, this study indicates that compromised RB-E2F transcriptional control is not uniformly cancer enabling, but rather has potent oncogenic effects when combined with specific vulnerabilities.

cancer biology↗

bioRxiv2018

Redundancy makes music and speech robust to individual differences in perception

In speech, linguistic information is conveyed redundantly by many simultaneously present acoustic dimensions, such as fundamental frequency, duration and amplitude. Listeners show stable tendencies to prioritize these acoustic dimensions differently, relative to one another, which suggests individualized speech perception strategies. However, it is unclear what drives these strategies, and more importantly, what impact they have on diverse aspects of communication. Here we show that such individualized perceptual strategies can be related to individual differences in perceptual ability. In a cue weighting experiment, we first demonstrate that individuals with a severe pitch perception deficit (congenital amusics) categorize linguistic stimuli similarly to controls when their deficit is unrelated to the main distinguishing cue for that category (in this case, durational or temporal cues). In contrast, in a prosodic task where pitch-related cues are typically more informative, amusics place less importance on this pitch-related information when categorizing speech. Instead, they relied more on duration information. Crucially, these differences in perceptual weights were observed even when pitch-related differences were large enough to be perceptually distinct to amusic listeners. In a second set of experiments involving musical and prosodic phrase interpretation, we found that this reliance on duration information allowed amusics to overcome their perceptual deficits and perceive both speech and music successfully. These results suggest that successful speech - and potentially music - comprehension is achieved through multiple perceptual strategies whose underlying weights may in part reflect individuals perceptual abilities.

neuroscience↗

bioRxiv2017

Laminar-specific cortical dynamics in human visual and sensorimotor cortices

Lower frequency, feedback, activity in the alpha and beta range is thought to predominantly originate from infragranular cortical layers, whereas feedforward signals in the gamma range stem largely from supragranular layers. Distinct anatomical and spectral channels may therefore play specialized roles in communication within hierarchical cortical networks; however, empirical evidence for this organization in humans is limited. We leverage high precision MEG to test this proposal, directly and non-invasively, in human participants during visually guided actions. Visual alpha activity mapped onto deep cortical laminae, whereas visual gamma activity predominantly arose from superficial laminae. This laminar-specificity was echoed in sensorimotor beta and gamma activity. Visual gamma activity scaled with task demands in a way compatible with feedforward signaling. For sensorimotor activity, we observed a more complex relationship with feedback and feedforward processes. Distinct frequency channels thus operate in a laminar-specific manner, but with dissociable functional roles across sensory and motor cortices.

neuroscience↗

bioRxiv2017

Non-invasive laminar inference with MEG: Comparison of methods and source inversion algorithms

Magnetoencephalography (MEG) is a direct measure of neuronal current flow; its anatomical resolution is therefore not constrained by physiology but rather by data quality and the models used to explain these data. Recent simulation work has shown that it is possible to distinguish between signals arising in the deep and superficial cortical laminae given accurate knowledge of these surfaces with respect to the MEG sensors. This previous work has focused around a single inversion scheme (multiple sparse priors) and a single global parametric fit metric (free energy). In this paper we use several different source inversion algorithms and both local and global, as well as parametric and non-parametric fit metrics in order to demonstrate the robustness of the discrimination between layers. We find that only algorithms with some sparsity constraint can successfully be used to make laminar discrimination. Importantly, local t-statistics, global cross-validation and free energy all provide robust and mutually corroborating metrics of fit. We show that discrimination accuracy is affected by patch size estimates, cortical surface features, and lead field strength, which suggests several possible future improvements to this technique. This study demonstrates the possibility of determining the laminar origin of MEG sensor activity, and thus directly testing theories of human cognition that involve laminar- and frequency- specific mechanisms. This possibility can now be achieved using recent developments in high precision MEG, most notably the use of subject-specific head-casts, which allow for significant increases in data quality and therefore anatomically precise MEG recordings.

neuroscience↗

bioRxiv2017

Extensive Tonotopic Mapping Across Auditory Cortex Is Recapitulated By Spectrally-Directed Attention, And Systematically Related To Cortical Myeloarchitecture

Auditory selective attention is vital in natural soundscapes. But, it is unclear how attentional focus on the primary dimension of auditory representation - acoustic frequency - might modulate basic auditory functional topography during active listening. In contrast to visual selective attention, which is supported by motor-mediated optimization of input across saccades and pupil dilation, the primate auditory system has fewer means of differentially sampling the world. This makes spectrally-directed endogenous attention a particularly crucial aspect of auditory attention. Using a novel functional paradigm combined with quantitative MRI, we establish that human frequency-band-selective attention drives activation in both myeloarchitectonically-estimated auditory core, and across the majority of tonotopically-mapped non-primary auditory cortex. The attentionally-driven best-frequency maps show strong concordance with sensory-driven maps in the same subjects across much of the temporal plane, with poor concordance in non-auditory areas. There is significantly greater activation across most of auditory cortex when best frequency is attended, versus ignored. Moreover, the single frequency bands that evoke the least activation and the frequency bands that elicit the least activation when attention is directed to them also correspond closely. Finally, the results demonstrate that there is spatial correspondence between the degree of myelination and the strength of the tonotopic signal across a number of regions in auditory cortex. Strong frequency preferences across tonotopically-mapped auditory cortex spatially correlate with R1-estimated myeloarchitecture, indicating shared functional and anatomical organization that may underlie intrinsic auditory regionalization.\n\nSignificancePerception is an active process especially sensitive to attentional state. Listeners direct auditory attention to track a violins melody within an ensemble performance, or to follow a voice in a crowded cafe. Although diverse pathologies reduce quality of life by impacting such spectrally-directed auditory attention, its neurobiological bases are unclear. We demonstrate that human primary and non-primary auditory cortical activation is modulated by spectrally-directed attention in a manner that recapitulates its tonotopic sensory organization. Further, the graded activation profiles evoked by single frequency bands are correlated with attentionally-driven activation when these bands are presented in complex soundscapes. Finally, we observe a strong concordance in the degree of cortical myelination and the strength of tonotopic activation across several auditory cortical regions.

neuroscience↗

bioRxiv2017

Quantitative MRI Provides Markers Of Intra-, Inter-Regional, And Age-Related Differences In Young Adult Cortical Microstructure

Measuring the structural composition of the cortex is critical to understanding typical development, yet few investigations in humans have charted markers in vivo that are sensitive to tissue microstructural attributes. Here, we used a well-validated quantitative MR protocol to measure four parameters (R1, MT, R2*, PD*) that differ in their sensitivity to facets of the tissue microstructural environment (R1, MT: myelin, macromolecular content; R2*: paramagnetic ions, i.e., iron; PD*: free water content). Mapping these parameters across cortical regions in a young adult cohort (18-30 years, N=93) revealed expected patterns of increased macromolecular content as well as reduced tissue water content in primary and primary adjacent cortical regions. Mapping across cortical depth within regions showed decreased expression of myelin and related processes - but increased tissue water content - when progressing from the grey/white to the grey/pial boundary, in all regions. Charting developmental change in cortical microstructure, we found that parameters with the greatest sensitivity to tissue myelin (R1 & MT) showed linear increases with age across frontal and parietal cortex (change 0.5-1.0% per year). Overlap of robust age effects for both parameters emerged in left inferior frontal, right parietal and bilateral pre-central regions. Our findings afford an improved understanding of ontogeny in early adulthood and offer normative quantitative MR data for inter- and intra-cortical composition, which may be used as benchmarks in further studies.\n\nHighlights O_LIWe mapped multi-parameter maps (MPMs) across and within cortical regions\nC_LIO_LIWe charted age effects on myelin and related processes at mid-cortical depth\nC_LIO_LIInter- and intra-regional differences in MPMs emerged at primary and association cortex\nC_LIO_LIIron-sensitive R2* map foci tended to overlap MPMs sensitive to myelin (R1, MT)\nC_LIO_LIR1 and MT increased with age (0.5-1.0% per year) in frontal and parietal cortex\nC_LI

neuroscience↗