Biology subjects

O'Brien, J. T.

Publications and source records attributed to O'Brien, J. T..

9 recordsLinked to original sources

bioRxiv2025

Brain Network Analysis in Alzheimer's Disease and Mild Cognitive Impairment using High-Density Diffuse Optical Tomography

Dementia is associated with altered resting state connectivity, measures of which could aid in its early detection and monitoring. High-density diffuse optical tomography (HD-DOT) is well-suited to detect these alterations at scale due to its numerous practical advantages, but it has not yet been applied to dementia. In this study, we investigated resting state functional connectivity across the prefrontal cortex in individuals with Mild Cognitive Impairment (MCI, n = 22), Alzheimers Disease (AD, n = 21), and in healthy controls (n = 22). A graph theoretical approach was taken to characterise both global and local patterns of connectivity over a five-minute resting period. We found that individuals with AD and MCI exhibited denser and stronger networks, with shorter path lengths, as well as a loss of consistent key network hubs with worsening cognitive impairment. These results indicate that networks in dementia are more globally connected, albeit in a disorganised manner, perhaps reflecting the recruitment of additional connections for short-term stability which may be ultimately damaging in the long-term. Following the demonstration of HD-DOTs capacity to detect differences between healthy ageing and dementia, this work opens up new possibilities for the use of optical imaging in the study of this clinical population and HD-DOTs potential for scalable clinical use.

neuroscience↗

bioRxiv2024

Vagus nerve stimulation (VNS) modulates synaptic plasticity in the rat infralimbic cortex via Trk-B receptor activation to reduce drug-seeking

Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces relapse. Vagus nerve stimulation (VNS) has previously been shown to enhance extinction learning and reduce drug-seeking. Here we determined the effects of VNS-mediated release of brain-derived neurotrophic factor (BDNF) on extinction and cue-induced reinstatement in rats trained to self-administer cocaine. Pairing 10 days of extinction training with VNS facilitated extinction and reduced drug-seeking behavior during reinstatement. Rats that received a single extinction session with VNS showed elevated BDNF levels in the medial PFC as determined via an enzyme-linked immunosorbent assay (ELISA). Systemic blockade of Tropomyosin receptor kinase B (TrkB) receptors during extinction, via the TrkB antagonist ANA-12, decreased the effects of VNS on extinction and reinstatement. Whole-cell recordings in brain slices showed that cocaine self-administration induced alterations in the ratio of AMPA and NMDA receptor-mediated currents in layer 5 pyramidal neurons of the infralimbic cortex (IL). Pairing extinction with VNS reversed cocaine-induced changes in glutamatergic transmission by enhancing AMPAR currents, and this effect was blocked by ANA-12. Our study suggests that VNS consolidates extinction of drug-seeking behavior by reversing drug-induced changes in synaptic AMPA receptors in the IL, and this effect is abolished by blocking TrkB receptors during extinction, highlighting a potential mechanism for the therapeutic effects of VNS in addiction. Significance StatementExtinction training can reverse maladaptive neuroplasticity induced by drugs of abuse, but adjunct treatments are sought that can facilitate the process and consolidate the newly formed memories. Pairing extinction training with vagus nerve stimulation (VNS) facilitates extinction and reduces drug-seeking behavior during reinstatement. Here, we show that rats receiving a single extinction session with VNS exhibit elevated brain-derived neurotrophic factor (BDNF) levels in the medial prefrontal cortex (mPFC). We also demonstrate that VNS consolidates the extinction of drug-seeking behavior by reversing cocaine-induced changes in synaptic AMPA receptors in the infralimbic cortex (IL) of the mPFC. This effect is blocked by the TrkB antagonist ANA-12, emphasizing the role of BDNF and TrkB receptors in the therapeutic effects of VNS in addiction.

neuroscience↗

bioRxiv2023

The mitochondrial matrix protein cyclophilin D contributes to deficits in parvalbumin interneurons in schizophrenia

BACKGROUNDCognitive deficits in schizophrenia are linked to dysfunctions of the dorsolateral prefrontal cortex (DLPFC), including alterations in parvalbumin (PV)-expressing interneurons (PVIs). Redox dysregulation and oxidative stress may represent convergence points in the pathology of schizophrenia, causing dysfunction of GABAergic interneurons and loss of PV. Here, we show that the mitochondrial matrix protein cyclophilin-D (CypD), a critical initiator of the mitochondrial permeability transition pore (mPTP) and modulator of the intracellular redox state, is altered in PVIs in schizophrenia. METHODSWestern blotting was used to measure CypD protein levels in postmortem DLPFC specimens of schizophrenic (n=27) and matched comparison subjects with no known history of psychiatric or neurological disorders (n=26). In a subset of this cohort, multilabel immunofluorescent confocal microscopy with unbiased stereological sampling methods were used to quantify 1) numbers of PVI across the cortical mantle (20 control, 15 schizophrenia) and 2) PV and CypD protein levels from PVIs in the cortical layers 2-4 (23 control, 19 schizophrenia). RESULTSIn schizophrenic subjects, the overall number of PVIs in the DLPFC was not significantly altered, but in individual PVIs of layers 2-4 PV protein levels decreased along a superficial-to-deep gradient when compared to unaffected comparison subjects. These laminar-specific PVI alterations were reciprocally linked to significant CypD elevations both in PVIs and within total DLPFC gray matter. CONCLUSIONSOur findings support previously reported PVI anomalies in schizophrenia and suggest that CypD-mediated mPTP formation could be a potential contributor to PVI dysfunction in schizophrenia.

neuroscience↗

bioRxiv2020

A synergistic core for human brain evolution and cognition

A fundamental question in neuroscience is how brain organisation gives rise to humans unique cognitive abilities. Although complex cognition is widely assumed to rely on frontal and parietal brain regions, the underlying mechanisms remain elusive: current approaches are unable to disentangle different forms of information processing in the brain. Here, we introduce a powerful framework to identify synergistic and redundant contributions to neural information processing and cognition. Leveraging multimodal data including functional MRI, PET, cytoarchitectonics and genetics, we reveal that synergistic interactions are the fundamental drivers of complex human cognition. Whereas redundant information dominates sensorimotor areas, synergistic activity is closely associated with the brains prefrontal-parietal and default networks; furthermore, meta-analytic results demonstrate a close relationship between high-level cognitive tasks and synergistic information. From an evolutionary perspective, the human brain exhibits higher prevalence of synergistic information than non-human primates. At the macroscale, we demonstrate that high-synergy regions underwent the highest degree of evolutionary cortical expansion. At the microscale, human-accelerated genes promote synergistic interactions by enhancing synaptic transmission. These convergent results provide critical insights that synergistic neural interactions underlie the evolution and functioning of humans sophisticated cognitive abilities, and demonstrate the power of our widely applicable information decomposition framework.

neuroscience↗

bioRxiv2019

Correlation Of Microglial Activation With White Matter Changes In Dementia With Lewy Bodies

Dementia with Lewy bodies (DLB) is the second-leading degenerative dementia after Alzheimers disase. Neuropathologically, it is characterized by alpha-synuclein protein deposition with variable degree of concurrent Alzheimer pathology. Neuroinflammation is increasingly recognized as a significant contributor of degeneration.\n\nObjectiveto examine the relationship between microglial activation as measured with [11C]-PK11195 brain PET and MR diffusion tensor imaging (DTI) in DLB.\n\nMethodsnineteen clinically probable DLB and 20 similarly aged controls underwent structural MRI with T1-weighted and 3T DTI sequences. Eighteen DLB subjects also underwent [11C]-PK11195 PET imaging. Tract-Based Spatial Statistics (TBSS) were performed to compare DTI parameters in DLB relative to controls and identify associations of [11C]-PK11195 binding with white matter integrity.\n\nResultsTBSS showed widespread changes in all DTI parameters in the DLB group compared to controls (Threshold Free Cluster Enhancement (TFCE) p < 0.05). [11C]-PK11195 binding in parietal cortices also correlated with widespread lower mean and radial diffusivity (TFCE p < 0.05).\n\nConclusionOur study demonstrates that higher PK11195 binding is associated with a relative preservation of white matter, positioning neuroinflammation as a potential early marker in the DLB pathogenic cascade.

neuroscience↗

bioRxiv2019

Neuroinflammation and functional connectivity in Alzheimer's disease: interactive influences on cognitive performance

Neuroinflammation is a key part of the etio-pathogenesis of Alzheimers disease. We test the relationship between neuroinflammation and the disruption of functional connectivity in large-scale networks, and their joint influence on cognitive impairment. We combined [11C]PK11195 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in 28 humans (13 females/15 males) with clinical diagnosis of probable Alzheimers disease or mild cognitive impairment with positive PET biomarker for amyloid, and 14 age-, sex-, and education-matched healthy humans (8 females/6 males). Source-based inflammetry was used to extract principal components of [11C]PK11195 PET signal variance across all participants. rs-fMRI data were pre-processed via independent component analyses to classify neuronal and non-neuronal signals. Multiple linear regression models identified sources of signal co-variance between neuroinflammation and brain connectivity profiles, in relation to group and cognitive status. Patients showed significantly higher [11C]PK11195 binding relative to controls, in a distributed spatial pattern including the hippocampus, medial, and inferior temporal cortex. Patients with enhanced loading on this [11C]PK11195 binding distribution displayed diffuse abnormal functional connectivity. The expression of a stronger association between such abnormal connectivity and higher levels of neuroinflammation correlated with worse cognitive deficits. Our study suggests that neuroinflammation relates to the pathophysiological changes in network function that underlie cognitive deficits in Alzheimers disease. Neuroinflammation, and its association with functionally-relevant reorganisation of brain networks, is proposed as a target for emerging immuno-therapeutic strategies aimed at preventing or slowing the emergence of dementia. Significance StatementNeuroinflammation is an important aspect of Alzheimers disease (AD), but it was not known whether the influence of neuroinflammation on brain network function in humans was important for cognitive deficit. Our study provides clear evidence that in vivo neuroinflammation in AD impairs large-scale network connectivity; and that the link between inflammation and functional network connectivity is relevant to cognitive impairment. We suggest that future studies should address how neuroinflammation relates to network function as AD progresses; and whether the neuroinflammation in AD is reversible, as the basis of immunotherapeutic strategies to slow the progression of AD.

neuroscience↗

bioRxiv2018

The functional brain favours segregated modular connectivity at old age unless targeted by neurodegeneration

Brains modular connectivity gives this organ resilience and adaptability. The ageing process alters the human brain, leading to modifications to its organised modularity and these changes are further accentuated by neurodegeneration, leading to disorganisation. To understand this further, we analysed modular variability--heterogeneity of modules--and modular dissociation--detachment from segregated connectivity--in two ageing cohorts and a mixed cohort of neurodegenerative diseases. Our results revealed that the brain follows a universal pattern of modular variability that matches highly active and metacognitive brain regions: the association cortices. We also proved that in ageing the brain moves towards a modular segregated structure despite presenting with increased modular heterogeneity--modules in older adults are not only segregated but their shape and size are more variable than in young adults. In the presence of neurodegeneration, the brain maintains its segregated connectivity globally but not locally; the modular brain shows patterns of differentiated pathology.

neuroscience↗

bioRxiv2018

Dynamic functional connectivity changes in dementia with Lewy bodies and Alzheimer’s disease

We studied the dynamic functional connectivity profile of dementia with Lewy bodies (DLB) and Alzheimers disease (AD) and the relationship between dynamic connectivity and the temporally transient symptoms of cognitive fluctuations and visual hallucinations in DLB.\n\nResting state fMRI data from 31 DLB, 29 AD, and 31 healthy control participants were analysed using dual regression to determine between-network functional connectivity. We used a sliding window approach followed by k-means clustering and dynamic network analyses to study dynamic functional connectivity changes associated with AD and DLB. Network measures that showed significant group differences were tested for correlations with clinical symptom severity.\n\nAD and DLB patients spent more time than controls in sparse connectivity configurations with absence of strong positive and negative connections and a relative isolation of motor networks from other networks. Additionally, DLB patients spent less time in a more strongly connected state and the variability of global brain network efficiency was reduced in DLB compared to controls. However, there were no significant correlations between dynamic connectivity measures and clinical scores.\n\nThe loss of global efficiency variability in DLB might indicate the presence of an abnormally rigid brain network and the lack of economical dynamics, factors which could contribute to an inability to respond appropriately to situational demands. However, the absence of significant clinical correlations indicates that the severity of transient cognitive symptoms such as cognitive fluctuations and visual hallucinations might not be directly related to these dynamic connectivity changes observed during a short resting state scan.

neuroscience↗

bioRxiv2017

Evidence of compensation in the brain networks of Lewy body dementia and Alzheimer’s disease patients

Dementia with Lewy bodies (DLB) and Alzheimers disease (AD) require differential management despite presenting with symptomatic overlap. A human electrophysiological difference is a decrease of dominant frequency (DF) -the highest power frequency between 4-15Hz- in DLB; a characteristic of Parkinsonian diseases. We analysed electroencephalographic (EEG) recordings from old adults: healthy controls (HCs), AD, DLB and Parkinsons disease dementia (PDD) patients. Brain networks were assessed with the minimum spanning tree (MST) within six EEG bands: delta, theta, high-theta, alpha, beta and DF. Patients showed lower alpha band connectivity and lower DF than HCs. Lewy body dementias showed a randomised MST compared with HCs and AD in high-theta and alpha but not within the DF. The MST randomisation in DLB and PDD reflects decreased brain efficiency as well as impaired neural synchronisation. However, the lack of network topology differences at the DF indicates a compensatory response of the brain to the neuropathology.

neuroscience↗