Biology subjects

MacKinley, M.

Publications and source records attributed to MacKinley, M..

6 recordsLinked to original sources

bioRxiv2024

Stable White Matter Structure in the First Three Years after Psychosis Onset

BackgroundWhite matter alterations observed using diffusion weighted imaging have become a hallmark of chronic schizophrenia, but it is unclear when these changes arise over the course of the disease. Nearly all studies thus far have been cross-sectional, so despite their large sample sizes, they cannot determine if changes accumulate as a degenerative process, or if patients with pre-existing white matter damage are predisposed to more chronic forms of schizophrenia. MethodsWe examined 160 scans comprising two years of annual follow-up data from n=42 controls and n=28 schizophrenia patients recruited in the first two years since their diagnosis, totalling two to three scans per subject. We additionally examined six-month follow-up data obtained from an ultra-high field (7 Tesla) scanner (n=68 scans; n=19 first-episode schizophrenia patients; n=15 controls) as a validation dataset. A longitudinal model was used to compare the trajectory of diffusion tenor parameters between patients and controls. Positive and negative symptom scores were correlated with diffusion parameters using ROI- and clustering-based approaches. ResultsWe failed to observe any longitudinal differences in any diffusion tensor imaging parameters between patients and controls in either dataset. We did, however, observe consistent associations between white matter alterations and negative symptoms in both datasets. ConclusionsWhite matter does not appear susceptible to schizophrenia-linked degeneration in the early stages of disease, but pre-existing pathology may be linked to disease severity.

neuroscience↗

bioRxiv2024

GPT-3 reveals selective insensitivity to global vs. local linguistic context in speech produced by treatment-naive patients with positive thought disorder

BackgroundEarly psychopathologists proposed that certain features of positive thought disorder, the disorganized language output produced by some people with schizophrenia, suggest an insensitivity to global, relative to local, discourse context. This idea has received support from carefully controlled psycholinguistic studies in language comprehension. In language production, researchers have so far remained reliant on subjective qualitative rating scales to assess and understand speech disorganization. Now, however, recent advances in large language models mean that it is possible to quantify sensitivity to global and local context objectively by probing lexical probability (the predictability of a word given its preceding context) during natural language production. MethodsFor each word in speech produced by 60 first-episode psychosis patients and 35 healthy, demographically-matched controls, we extracted lexical probabilities from GPT-3 based on contexts that ranged from very local-- a single preceding word: P(Wn | Wn-1)--to global-- up to 50 preceding words: P(Wn|Wn-50, Wn-49, ..., Wn-1). ResultsWe show, for the first time, that disorganized speech is characterized by disproportionate insensitivity to global, versus local, linguistic context. Critically, this global-versus-local insensitivity selectively predicted clinical ratings of positive thought disorder, above and beyond overall symptom severity. There was no evidence of a relationship with negative thought disorder (impoverishment). ConclusionsWe provide an automated, interpretable measure that can potentially be used to quantify speech disorganization in schizophrenia. Our findings directly link the clinical phenomenology of thought disorder to neurocognitive constructs that are grounded in psycholinguistic theory and neurobiology.

neuroscience↗

bioRxiv2023

Cortical Network Disruption is Minimal in Early Stages of Psychosis

1Background and HypothesisChronic schizophrenia is associated with white matter disruption and topological reorganization of cortical connectivity but the trajectory of these changes over the disease course are poorly understood. Current white matter studies in first-episode psychosis (FEP) patients using diffusion magnetic resonance imaging (dMRI) suggest such disruption may be detectable at the onset of psychosis, but specific results vary widely and few reports have contextualized their findings with direct comparison to chronic patients. Here, we test the hypothesis that structural changes are not a significant feature of early psychosis. Study DesignDiffusion and T1-weighted 7T MR scans were obtained from N=113 (61 FEP patients, 37 controls, 15 chronic patients) recruited from an established cohort in London, Ontario. Voxel- and network-based analyses were used to detect changes in diffusion microstructural parameters. Graph theory metrics were used to probe changes in the cortical network hierarchy and to assess the vulnerability of hub regions to disruption. Experiments were replicated with N=167 (111 patients, 56 controls) from the Human Connectome Project - Early Psychosis (HCP-EP) dataset. Study ResultsWidespread microstructural changes were found in chronic patients, but changes in FEP patients were minimal. Unlike chronic patients, no appreciable topological changes in the cortical network were observed in FEP patients. These results were replicated in the early psychosis patients of the HCP-EP datasets, which were indistinguishable from controls on nearly all metrics. ConclusionsThe white matter structural changes observed in chronic schizophrenia are not a prominent feature in the early stages of this illness.

neuroscience↗

bioRxiv2021

Myelin imaging of the basal forebrain in first-episode psychosis

Cholinergic dysfunction has been implicated in the pathophysiology of psychiatric disorders such as schizophrenia, depression, and bipolar disorder. The basal forebrain (BF) cholinergic nuclei, defined as cholinergic cell groups Ch1-3 and Ch4 (Nucleus Basalis of Meynert; NBM), provide extensive cholinergic projections to the rest of the brain. Here, we examined microstructural neuroimaging measures of the cholinergic nuclei in patients with untreated psychosis ([~] 31 weeks of psychosis, <2 defined daily dose of antipsychotics) and used Magnetic Resonance Spectroscopy (1H-MRS) and transcriptomic data to support our findings. We used a cytoarchitectonic atlas of the BF to map the nuclei and obtained measures of myelin (quantitative T1, or qT1 as myelin surrogate) and microstructure (axial diffusion; AxD). In a clinical sample (n=85; 29 healthy controls, 56 first-episode psychosis), we found significant correlations between qT1 and 1H-MRS-based dorsal anterior cingulate choline in healthy controls, while this relationship was disrupted in FEP. Case-control differences in qT1 and AxD were observed in the Ch1-3, with increased qT1 (reflecting reduced myelin content) and AxD (reflecting reduced axonal integrity). We found clinical correlates between left NBM qT1 with manic symptom severity, and AxD with negative symptom burden in FEP. Intracortical and subcortical myelin maps were derived and correlated with BF myelin. BF-cortical and BF-subcortical myelin correlations demonstrate known projection patterns from the BF. Using data from the Allen Human Brain Atlas, cholinergic nuclei showed significant enrichment for schizophrenia and depression-related genes. Cell-type specific enrichment indicated enrichment for cholinergic neuron markers as expected. Further relating the neuroimaging correlations to transcriptomics demonstrated links with cholinergic receptor genes and cell type markers of oligodendrocytes and cholinergic neurons, providing biological validity to the measures. These results provide genetic, neuroimaging, and clinical evidence for cholinergic dysfunction in schizophrenia and other psychiatric disorders such as depression.

neuroscience↗

bioRxiv2019

Ultra-high field imaging of hippocampal neuroanatomy in first episode psychosis demonstrates receptor-specific morphometric patterning

ObjectiveThe hippocampus is considered a putative marker in schizophrenia with early volume deficits of select subfields. Certain subregions are thought to be more vulnerable due to a glutamate-driven mechanism of excitotoxicity, hypermetabolism, and then degeneration. Here, we explored whether hippocampal anomalies in first-episode psychosis (FEP) correlate with glutamate receptor density via a serotonin receptor proxy by leveraging structural neuroimaging, spectroscopy (MRS), and gene expression.\n\nMethodsHigh field 7T brain MR images were collected from 27 control, 41 FEP participants, along with 1H-MRS measures of glutamate. Automated methods were used to delineate the hippocampus and atlases of the serotonin receptor system were used to map receptor density across the hippocampus and subfields. We used gene expression data from the Allen Human Brain Atlas to test for correlations between serotonin and glutamate receptor genes.\n\nResultsWe found reduced hippocampal volumes in FEP, replicating previous findings. Amongst the subfields, CA4-dentate gyrus showed greatest reductions. Gene expression analysis indicated 5-HTR1A and 5-HTR4 receptor subtypes as predictors of AMPA and NMDA receptor expression, respectively. Volumetric differences in the subfields correlated most strongly with 5-HT1A (R=0.64, p=4.09E-03) and 5-HT4 (R=0.54, p=0.02) densities as expected, and replicated using previously published data from two FEP studies. Measures of individual structure-receptor alignment were derived through normative modeling of hippocampal shape and correlations to receptor distributions, termed Receptor-Specific Morphometric Signatures (RSMS). Right-sided 5-HT4 RSMS was correlated with glutamate (R=0.357, p=0.048).\n\nConclusionsWe demonstrate glutamate-driven hippocampal remodeling in FEP through a receptor-density gated mechanism, thus providing a mechanistic explanation of how redox dysregulation affects brain structure and symptomatic heterogeneity in schizophrenia.

neuroscience↗

bioRxiv2019

Early Treatment Response in First Episode Psychosis: A 7-Tesla Magnetic Resonance Spectroscopic Study of Glutathione and Glutamate

Early response to antipsychotic medications is one of the most important determinants of later symptomatic and functional outcomes in psychosis. Glutathione and glutamate have emerged as promising therapeutic targets for patients demonstrating inadequate response to dopamine-blocking antipsychotics. Nevertheless, the role of these neurochemicals in the mechanism of early antipsychotic response remains poorly understood. Using a longitudinal design and ultra-high field 7-Tesla magnetic resonance spectroscopy (MRS) protocol in 53 subjects, we report the association between dorsal anterior cingulate cortex glutamate and glutathione, with time to treatment response in drug-naive (34.6% of the sample) or minimally medicated first episode patients with non-affective psychosis. Time to response was defined as the number of weeks required to reach a 50% reduction in the PANSS-8 scores. Higher glutathione was associated with shorter time to response (F=4.86, P= .017), while higher glutamate was associated with more severe functional impairment (F=5.33, P= .008). There were no significant differences between patients and controls on measures of glutamate or glutathione. For the first time, we have demonstrated an association between higher glutathione and favourable prognosis in FEP. We propose that interventions that increase brain glutathione levels may improve outcomes of early intervention in psychosis.

neuroscience↗