Biology subjects

O'Callaghan, C.

Publications and source records attributed to O'Callaghan, C..

8 recordsLinked to original sources

bioRxiv2018

Whole genome sequencing enables definitive diagnosis of Cystic Fibrosis and Primary Ciliary Dyskinesia

Understanding the genomic basis of inherited respiratory disorders can assist in the clinical management of individuals with these rare disorders. We apply whole genome sequencing for the discovery of disease-causing variants in the non-coding regions of known disease genes for two individuals with inherited respiratory disorders. We describe analysis strategies to pinpoint candidate non-coding variants within the non-coding genome and demonstrate aberrant RNA splicing as a result of deep intronic variants in DNAH11 and CFTR. These findings confirm clinical diagnoses of primary ciliary dyskinesia and cystic fibrosis, respectively.

genomics↗

bioRxiv2018

Meta-analytic evidence for the plurality of mechanisms in transdiagnostic structural MRI studies of hallucination status

BACKGROUNDHallucinations are transmodal and transdiagnostic phenomena, occurring across sensory modalities and presenting in psychiatric, neurodegenerative, neurological, and non-clinical populations. Despite their cross-category occurrence, little empirical work has directly compared between-group neural correlates of hallucinations.\n\nMETHODSWe performed whole-brain voxelwise meta-analyses of hallucination status across diagnoses using AES-SDM, and conducted a comprehensive systematic review in PubMed and Web of Science until May 2018 on other structural correlates of hallucinations, including cortical thickness and gyrification.\n\nFINDINGS3214 abstracts were identified. Patients with psychiatric disorders and hallucinations (eight studies) exhibited reduced gray matter (GM) in the left insula, right inferior frontal gyrus, left anterior cingulate/paracingulate gyrus, left middle temporal gyrus, and increased in the bilateral fusiform gyrus, while patients with neurodegenerative disorders with hallucinations (eight studies) showed GM decreases in the left lingual gyrus, right supramarginal gyrus/parietal operculum, left parahippocampal gyrus, left fusiform gyrus, right thalamus, and right lateral occipital gyrus. Group differences between meta-analyses were formally confirmed and a jackknife sensitivity analysis established the reproducibility of results across nearly all study combinations. For other measures (28 studies), the most consistent findings associated with hallucination status were reduced cortical thickness in temporal gyri in schizophrenia and altered hippocampal volume in Parkinsons disease and dementia.\n\nINTERPRETATIONDistinct patterns of neuroanatomical alteration characterize hallucination status in patients with psychiatric and neurodegenerative diseases, suggesting a plurality of anatomical signatures. This approach has implications for treatment, theoretical frameworks, and generates refutable predictions for hallucinations in other diseases and their occurrence within the general population.\n\nFUNDINGNone.\n\nResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSThere is increasing recognition that hallucinations occur beyond the archetype of schizophrenia, presenting in other psychiatric disorders, neurological and neurodegenerative conditions, and among the general population. Not only are hallucinations a transdiagnostic phenomenon, but also the experience of hallucinating is phenomenologically diverse, varying in modality, content, frequency, and affect. It has been suggested that no one type of hallucination is pathognomic to any one disorder, but rather that hallucinations may exist on a continuum. However, limited research has been done to directly compare the underlying neuroanatomy of hallucinations between different disorders. With this aim, we conducted a meta-analysis and systematic review of structural MRI studies comparing individuals who experience hallucinations with those who do not, to investigate the brain morphology related to the transdiagnostic presentation of hallucinations. We searched PubMed and Web of Science with no start date limit, up to May 2018 using the keyword combination (hallucinat*) AND (MRI OR magnetic resonance imaging OR morphology OR voxel?based OR morphometr* OR neural correlate OR structur*). We included only studies with a within-group no-hallucination control to tease out structural changes specific to hallucinations from effects of the broader pathology. Neuroimaging meta-analyses were conducted on studies performing whole-brain voxelwise gray matter differences, while studies assessing other structural correlates were qualitatively synthesized.\n\nAdded value of this studyThis is the first meta-analysis to illustrate the brain structural correlates of hallucination occurrence derived from T1-weighted MRI, and to do so in a comparative manner across clinical groups. We identified two distinct gray matter substrates for hallucination presence in psychiatric compared to neurodegenerative diseases, which we hypothesise constitute at least two distinct mechanisms. In addition, we qualitatively assessed other structural neuroimaging studies over a variety of morphometric indices. We therefore provide a complete characterization of current knowledge of the brain morphology associated with hallucinations across clinical status and modality.\n\nImplications of all the available evidenceOur findings show at least two structural substrates that link to the hallucinatory experience. This informs theoretical work on hallucinations which have to date been limited in generating unifying direction-specific predictions of brain structure and function. Understanding the plurality of anatomical signatures of hallucinations may also inform treatment strategies. We predict that other disorders in which patients experience hallucinations can be categorised by our approach based on the broader phenotype; for example, hallucinations in personality disorder may be of the psychiatric type, and similarly for early onset hallucinations in the general population, whilst later onset will be neurodegenerative. Moreover, by differentiating the mechanisms of hallucinations we recommend the contextualising of research by the appropriate phenotype.

neuroscience↗

bioRxiv2018

Changes in structural network topology correlate with severity of hallucinatory behaviour in Parkinson’s disease

An inefficient integration between bottom-up visual input and higher-order visual processing regions is implicated in the manifestation of visual hallucinations (VH) in Parkinsons disease (PD). Using graph theory, the current study aimed to investigate white matter contributions to this perceptual imbalance hypothesis. Twenty-nine PD patients reported their hallucinatory behaviour on a questionnaire and performed a behavioural test that has been shown to elicit misperceptions. A composite score derived from these measures was used as a proxy for hallucinations severity and was correlated to connectivity strength of the network using the Network Based Statistic approach. The results showed that the severity of VH was associated with reduced connectivity within a large sub-network. This network included the majority of the diverse club and showed overall greater between- and within-module scores, compared to nodes not associated with hallucination severity. Furthermore, a reduction in between-module connectivity in the lateral occipital cortex, insula and pars orbitalis, as well as decreased within-module connectivity in the prefrontal, somatosensory and primary visual cortices were associated with VH severity. In contrast, the severity of VH was associated with an increase in between- and within-module connectivity in the orbitofrontal and temporal cortex, as well as regions comprising the dorsal attentional and DMN. These results suggest that the severity of VHs is associated with marked alterations in structural network topology, highlighted by a reduction in connectivity strength across a large sub-network, as well as changes in participation across top-down visual processing centres, visual and attentional networks. Therefore, impaired integration across the perceptual hierarchy may result in the inefficient transfer of information that gives rise to VHs in PD.

neuroscience↗

bioRxiv2018

Dopamine Depletion Alters Macroscopic Network Dynamics in Parkinsons Disease

AbstractParkinsons disease is primarily characterised by diminished dopaminergic function, however the impact of these impairments on large-scale brain dynamics remains unclear. It has been difficult to disentangle the direct effects of Parkinsons disease from compensatory changes that reconfigure the functional signature of the whole brain network. To examine the causal role of dopamine depletion in network-level topology, we investigated time-varying network structure in 37 individuals with idiopathic Parkinsons disease, both On and Off dopamine replacement therapy, along with 50 age-matched, healthy control subjects using resting-state functional MRI. By tracking dynamic network-level topology, we found that the Parkinsons disease Off state was associated with greater network-level integration than in the On state. The extent of integration in the Off state inversely correlated with motor symptom severity, suggesting that a shift toward a more integrated network topology may be a compensatory mechanism associated with preserved motor function in the dopamine depleted Off state. Furthermore, we were able to demonstrate that measures of both cognitive and brain reserve (i.e., premorbid intelligence and whole brain grey matter volume) had a positive relationship with the relative increase in network integration observed in the dopaminergic Off state. This suggests that each of these factors plays an important role in promoting network integration in the dopaminergic Off state. Our findings provide a mechanistic basis for understanding the PD Off state and provide a further conceptual link with network-level reconfiguration. Together, our results highlight the mechanisms responsible for pathological and compensatory change in Parkinsons disease.

neuroscience↗

bioRxiv2018

Default mode and primary visual network coupling is associated with increased mind-wandering frequency in Parkinson’s disease with visual hallucinations

A mismatch between top-down expectations and incoming sensory information is thought to be associated with hallucinations across a range of neuropsychiatric disorders. In Parkinsons disease with visual hallucinations, abnormal activity within the default network, and its pattern of connectivity with early visual regions, has been identified as a potential pathological source of the internally generated expectations that override incoming sensory input. In the context of attention deficits and visual dysfunction, mental imagery and perceptual expectancies generated across the default network are suggested to exert excessive influence over earlier visual regions, leading to aberrant perceptual experiences. Whilst converging neuroimaging evidence has identified unconstrained default network activity in Parkinsons disease with hallucinations, to date there has been a lack of behavioural evidence to confirm the consequences of an over-engaged default mode network - therefore the contributions it might make to hallucination phenomenology remain speculative. To address this, we administered a validated thought-sampling task to 38 Parkinsons disease patients (18 with hallucinations; 20 without) and 40 controls, to test the hypothesis that individuals with hallucinations experience an increased frequency of mind-wandering - a form of spontaneous cognition strongly associated with mental imagery and default network activity. The neural correlates of mind-wandering frequency were examined in relation to resting-state functional connectivity. Our results showed that patients with hallucinations exhibited significantly higher mind-wandering frequencies compared to non-hallucinators, who in turn had reduced levels of mind-wandering relative to controls. Inter-network connectivity and seed-to-voxel analyses confirmed that increased mind-wandering in the hallucinating vs. non-hallucinating group was associated with greater coupling between the primary visual cortex and dorsal default network. Taken together, both elevated mind-wandering and increased default-visual network coupling emerged as a distinguishing feature of the hallucinatory phenotype. We propose that the finding of increased mind-wandering reflects unconstrained spontaneous thought and mental imagery, which in turn furnish the content of visual hallucinations. Our findings suggest that primary visual cortex to dorsal default network coupling may provide a neural substrate by which regions of the default network exert disproportionate influence over ongoing visual perception. These findings refine current models of visual hallucinations by identifying a specific cognitive phenomenon and neural substrate consistent with the top-down influences over perception that have been implicated in visual hallucinations.

neuroscience↗

bioRxiv2018

Biallelic Mutations in LRRC56 encoding a protein associated with intraflagellar transport, cause mucociliary clearance and laterality defects

Defective motile cilia are responsible for a group of heterogeneous genetic conditions characterised by dysfunction of the apparatus responsible for generating fluid flows. Primary ciliary dyskinesia (PCD) is the prototype for such disorders and presents with impaired pulmonary mucus clearance, susceptibility to chronic recurrent respiratory infections, male infertility and laterality defects in about 50 % of patients. Here we report biallelic variants in LRRC56 (also known as ODA8), identified in two unrelated consanguineous families. The phenotype comprises laterality defects and chronic pulmonary infections. High speed video microscopy of cultured patient epithelial cells showed severely dyskinetic cilia, but no obvious ultra-structural abnormalities on routine transmission electron microscopy (TEM). Further investigation revealed that LRRC56 interacts with the intraflagellar transport (IFT) protein IFT88. The link to IFT was interrogated in Trypanosoma brucei. In this protist, LRRC56 is recruited to the cilium during axoneme construction, where it co-localises with IFT trains and facilitates the addition of dynein arms to the distal end of the flagellum. In T. brucei carrying LRRC56 null mutations, or a mutation (p.Leu259Pro) corresponding to the p.Leu140Pro variant seen in one of the affected families, we observed abnormal ciliary beat patterns and an absence of outer dynein arms restricted to the distal portion of the axoneme. Together, our findings confirm that deleterious variants in LRRC56 result in a human disease, and suggest this protein has a likely role in dynein transport during cilia assembly that is evolutionarily important for cilia motility.

genetics↗

bioRxiv2017

Hippocampal atrophy and intrinsic brain network alterations relate to impaired capacity for mind wandering in neurodegeneration

Mind wandering represents the human capacity for internally focussed thought, and relies upon the brains default network and its interactions with attentional networks. Studies have characterised mind wandering in healthy people, yet there is limited understanding of how this capacity is affected in clinical populations. This study used a validated thought-sampling task to probe mind wandering capacity in two neurodegenerative disorders: behavioural variant frontotemporal dementia (bvFTD; n=35) and Alzheimers disease (AD; n=24), compared to older controls (n=37). These patient groups were selected due to canonical structural and functional changes across sites of the default and frontoparietal networks, and well-defined impairments in cognitive processes that support mind wandering. Relative to controls, bvFTD patients displayed significantly reduced mind wandering capacity, offset by a significant increase in stimulus-bound thought. In contrast, AD patients demonstrated comparable levels of mind wandering to controls, in the context of a relatively subtle shift towards stimulus-/task-related forms of thought. In the patient groups, mind wandering was associated with grey matter integrity in the hippocampus/parahippocampus, striatum, insula and orbitofrontal cortex. Resting state functional connectivity revealed associations between mind wandering capacity and connectivity within and between regions of the frontoparietal and default networks, with distinct patterns evident in patients vs. controls. These findings support a relationship between altered mind wandering capacity in neurodegenerative disorders, and structural and functional integrity of the default and frontoparietal networks. This study highlights a dimension of cognitive dysfunction not well documented in neurodegenerative disorders, and validates current models of mind wandering in a clinical population.\n\nSignificance statementHumans spend much of their waking life engaged in mind wandering. Underlying brain systems supporting this complex ability have been established in healthy individuals, yet it remains unclear how mind wandering is altered in neuropsychiatric populations. We reveal changes in the thought profiles elicited during periods of low cognitive demand in dementia, resulting in reduced mind wandering and an increased propensity towards stimulus-bound thought. These altered thought profiles were associated with structural and functional brain changes in the hippocampus, default and frontoparietal networks; key regions implicated in internal mentation in healthy individuals. Our findings provide a unique clinical validation of current theoretical models of mind wandering, and reveal a dimension of cognitive dysfunction that has received scant attention in dementia.

neuroscience↗

bioRxiv2017

Accumulation of sensory evidence is impaired in Parkinson’s disease with visual hallucinations

Models of hallucinations across disorders emphasise an imbalance between sensory input and top-down influences over perception. However, the psychological and mechanistic correlates of this imbalance remain underspecified. Visual hallucinations in Parkinsons disease (PD) are associated with impairments in lower level visual processes and attention, accompanied by over activity and connectivity in higher-order association brain networks. PD therefore provides an attractive framework to explore the relative contributions of bottom-up versus top-down disturbances in hallucinations. Here, we characterised sensory processing in PD patients with and without visual hallucinations, and in healthy controls, by fitting a hierarchical drift diffusion model (hDDM) to an attentional task. The hDDM uses Bayesian estimates to decompose reaction time and response output into parameters reflecting drift rates of evidence accumulation, decision thresholds and non-decision time. We observed slower drift rates in PD patients with hallucinations, which were insensitive to changes in task demand. In contrast, wider decision boundaries and shorter non-decision times relative to controls were found in PD regardless of hallucinator status. Inefficient and less flexible sensory evidence accumulation emerge as unique features of PD hallucinators. We integrate these results with current models of hallucinations, suggesting that slow and inefficient sensory input in PD is less informative, and may therefore be down-weighted leading to an over reliance on top-down influences. Our findings provide a novel computational framework to better specify the impairments in dynamic sensory processing that are a risk factor for visual hallucinations.

neuroscience↗