Biology subjects

Michie, P.

Publications and source records attributed to Michie, P..

3 recordsLinked to original sources

bioRxiv2025

Neuroanatomical Correlates of Negative Symptoms in Schizophrenia

BackgroundSchizophrenia is characterized by widespread structural brain abnormalities, but associations between structural abnormalities and negative symptom severity are not well understood. Negative symptoms have been conceptualized in a hierarchical structure of two second-order dimensions--motivation and pleasure (MAP) and expression (EXP)--and five first-order domains: anhedonia, avolition, and asociality (MAP), and blunted affect and alogia (EXP). A better understanding of the neural circuitry underlying negative symptom dimensions and domains is important given their reported association with poor functional outcome and lack of available treatments. Study DesignThe meta-analysis included 1,591 individuals with schizophrenia across 16 samples with structural imaging and Scale for Assessment of Negative Symptoms data. The study generated correlations of cortical thickness and subcortical volumes with the negative symptom dimensions and domains. Study resultsNegative symptoms showed mainly negative associations with cortical thickness and subcortical volumes. The effect sizes were small but there was a pattern of associations in predominantly frontal lobe cortical thickness and limbic subcortical volumes. The regional correlation patterns of cortical thickness and subcortical volumes with symptom domains support the conceptualized hierarchical structure of negative symptoms: correlations of MAP domains were stronger with the MAP than EXP dimension, and vice versa. Exploratory analyses with receptor densities further supported the hierarchy. ConclusionOur findings reveal small but consistent associations between negative symptom dimensions and predominantly prefrontal region cortical thickness, and limbic region volumes. These findings advance our understanding of the network of anatomical regions that may contribute to the severity of negative symptoms in schizophrenia.

neuroscience↗

bioRxiv2023

Connectome architecture shapes large-scale cortical reorganization in schizophrenia: a worldwide ENIGMA study

While schizophrenia is considered a prototypical network disorder characterized by widespread brain-morphological alterations, it still remains unclear whether distributed structural alterations robustly reflect underlying network layout. Here, we tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2,439 adults with schizophrenia and 2,867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n=207), we evaluated structural alterations of schizophrenia against two network susceptibility models: i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; ii) epicenter mapping, which identify regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Schizophrenia-related structural alterations co-localized with interconnected functional and structural hubs and harbored temporo-paralimbic and frontal epicenters. Findings were robust across sites and related to individual symptom profiles. We observed localized unique epicenters for first-episode psychosis and early stages, and transmodal epicenters that were shared across first-episode to chronic stages. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, yielding insights in pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work contributes to recognizing potentially common pathways to better understand macroscale structural alterations, and inter-individual variability in schizophrenia.

neuroscience↗

bioRxiv2019

The effect of NMDA-R antagonist, MK-801, on Neuronal Mismatch along the Auditory Thalamocortical System

Efficient sensory processing requires that the brain is able to maximize its response to unexpected stimuli, while suppressing responsivity to expected events. Mismatch negativity (MMN) is an auditory event-related potential that occurs when a regular pattern is interrupted by an event that violates the expected properties of the pattern. MMN has been found to be reduced in individuals with schizophrenia in over 100 separate studies, an effect believed to be underpinned by glutamate N-methyl-D-aspartate receptor (NMDA-R) dysfunction, as it is observed that NMDA-R antagonists also reduce MMN in healthy volunteers. The aim of the current study is to examine this effect in rodents. Using single unit recording in specific auditory areas using methods not readily utilized in humans, we have previously demonstrated that neuronal indices of rodent mismatch responses recorded from thalamic and cortical areas of the brain can be decomposed into a relatively simple repetition suppression and a more sophisticated prediction error process. In the current study, we aimed to test how the NMDA-R antagonist, MK-801, affected both of these processes along the rat auditory thalamocortical pathway. We found that MK-801 had the opposite effect than expected, and enhanced thalamic repetition suppression and cortical prediction error. These single unit data correlate with the recordings of local field responses. Together with previous data, this study suggests that our understanding of the contribution of NMDA-R system to MMN generation is far from complete, and also has potential implications for future research in schizophrenia.\n\nSignificance StatementIn this study, we demonstrate that an NMDA-R antagonist, MK-801, differentially affects single neuron responses to auditory stimuli along the thalamocortical axis by increasing the response magnitude of unexpected events in the auditory cortex and intensifying the adaptation of responses to expected events in the thalamus. Thus, we provide evidence that NMDA-R antagonists alter the balance between prediction-error and repetition suppression processes that underlie the generation of mismatch responses in the brain, and these effects are differentially expressed at different levels of auditory processing. As effects of MK-801 were in the opposite direction to our expectations, it demonstrates that our understanding of role of NMDA-R in synaptic plasticity and the neural processes underpinning MMN generation are far from complete.

neuroscience↗