Michael Mackinley

London Health Sciences Centre

Background: Several disturbances in speech are present in psychosis; however, the relationship between these disturbances during the first-episode of psychosis (FEP) and later vocational functioning is unclear. Demonstrating this relationship is critical if we expect speech and communication deficits to emerge as targets for early intervention. Me...

Background and hypothesis: Active inference has become an influential concept in psychopathology. We apply active inference to investigate conceptual disorganization in first-episode schizophrenia. We conceptualize speech production as a decision-making process affected by the latent "conceptual organization"-as a special case of uncertainty about...

Schizophrenia is believed to be a developmental disorder with one hypothesis suggesting that symptoms arise due to abnormal interactions (or disconnectivity) between different brain regions. While some major deep white matter pathways have been extensively studied (e.g. arcuate fasciculus), studies of short-ranged, “U”-shaped tracts have been limit...

https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1144281/abstract

Computational semantics, a branch of computational linguistics, involves automated meaning analysis that relies on how words occur together in natural language. This offers a promising tool to study schizophrenia. At present, we do not know if these word-level choices in speech are sensitive to the illness stage (i.e., acute untreated vs. stable es...

Abstract Cholinergic dysfunction has been implicated in the pathophysiology of psychosis and 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...

Introduction Symptoms of schizophrenia are closely related to aberrant language comprehension and production. Macroscopic brain changes seen in some patients with schizophrenia are suspected to relate to impaired language production, but this is yet to be reliably characterized. Since heterogeneity in language dysfunctions, as well as brain structu...

Background and HypothesisActive inference has become an influential concept in psychopathology. We apply active inference to investigate language behaviour in first-episode schizophrenia. We conceptualize speech production as a decision-making process affected by the latent “conceptual organization” during the selection of words. We consider concep...

In the clinical linguistics of schizophrenia, syntactic complexity has received much attention. In this study, we address whether syntactic complexity deteriorates within the six months following the first episode of psychosis in those who develop a diagnosis of schizophrenia. We collected data from a cohort of twenty-six first-episode psychosis an...

Background and hypothesis: Following the first episode of psychosis, some patients develop poor social and occupational outcomes, while others display a pattern of preserved functioning. Evidence from preclinical, genetic, and biochemical studies suggest a role for high oxidative stress in poor functional outcomes among patients. The measurement o...

Network-level dysconnectivity has been studied in positive and negative symptoms of schizophrenia. Conceptual disorganization (CD) is a symptom subtype that predicts impaired real-world functioning in psychosis. Systematic reviews have reported aberrant connectivity in formal thought disorder, a construct related to CD. However, no studies have inv...

Myo-inositol is mainly found in astroglia and its levels has been shown to be reduced in the anterior cingulate cortex (ACC) of patients with schizophrenia. We investigate the status of astroglial integrity indexed by ACC myo-inositol at the onset and over the first 6 months of treatment of first episode schizophrenia. We employed 7 T magnetic reso...

Computational semantics, a branch of computational linguistics, involves automated meaning analysis that relies on how words occur together in natural language. This offers a promising tool to study schizophrenia. At present, we do not know if these word level choices in speech are sensitive to illness stage (i.e. acute untreated vs. stable establi...

Following the first episode of psychosis, some patients develop poor social and occupational outcomes, while others display a pattern of preserved functioning. Several lines of evidence from preclinical, genetic and biochemical studies suggest a role for high oxidative stress in poor functional outcomes. The measurement of intracortical glutathione...

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...

A substantial number of individuals with clinical high-risk (CHR) mental state do not transition to psychosis. However, regardless of future diagnostic trajectories, many of these individuals develop poor social and occupational functional outcomes. The levels of glutathione, a crucial cortical antioxidant, may track variations in functional outcom...

Failures in spoken language production can be captured through an analysis of not only its content (what is said) but also of its form (how it is said). Focused on the clinical impression of formal thought disorder (FTD) in schizophrenia (SZ), we apply the concept of analytic thinking as a marker of the linguistic style in SZ speech. ➢ The analysis...

This study aimed to shed light on the linguistic style affecting the communication-discourse in First Episode Schizophrenia (FES) by investigating the analytic thinking index in relation to clinical scores of conceptual and thought disorganisation (Positive and Negative Syndrome Scale, PANSS-P2 and Thought and Language Index, TLI). Using robust Bay...

This study aimed to shed light on the linguistic style affecting the communication-discourse in First Episode Schizophrenia (FES) by investigating the analytic thinking index in relation to clinical scores of conceptual and thought disorganisation (Positive and Negative Syndrome Scale, PANSS-P2 and Thought and Language Index, TLI). Using robust Bay...

Disrupted serotonergic and glutamatergic signaling interact and contribute to the pathophysiology of schizophrenia, which is particularly relevant for the hippocampus where diverse expression of serotonin receptors is noted. Hippocampal atrophy is a well-established feature of schizophrenia, with select subfields hypothesized as particularly vulner...

Astroglial pathology has been long suspected in schizophrenia. Myo-inositol, a metabolic marker particularly abundant in astroglia, is reduced in the anterior cingulate cortex (ACC) of patients with schizophrenia. We investigate the status of astroglial integrity indexed by ACC myo-inositol at the onset and over the first 6 months of treatment of f...

Progressive reduction in glutamatergic transmission has been proposed as an important component of the illness trajectory of schizophrenia. Despite its popularity, to date, this notion has not been convincingly tested in patients in early stages of schizophrenia. In a longitudinal 7T magnetic resonance spectroscopy (1H-MRS), we quantified glutamate...

Repetitive transcranial magnetic stimulation (rTMS), when applied to left dorsolateral prefrontal cortex (LDLPFC), reduces negative symptoms of schizophrenia, but has no effect on positive symptoms. In a small number of cases, it appears to worsen the severity of positive symptoms. It has been hypothesized that high frequency rTMS of the LDLPFC mig...

This study aimed to shed light on the linguistic style affecting the communication-discourse in First Episode Schizophrenia (FES) by investigating the analytical thinking index in relation to clinical scores of conceptual and thought disorganization (Positive and Negative Syndrome Scale, PANSS-P2 and Thought and Language Index, TLI). By using robus...

A substantial number of individuals with clinical high-risk (CHR) mental state do not transition to psychosis. However, regardless of future diagnostic trajectories, many of these individuals develop poor social and occupational functional outcomes. The levels of glutathione, a crucial cortical antioxidant, may track variations in functional outcom...

Background:Network level dysconnectivity has been studied in positive and negative symptoms of schizophrenia. Conceptual disorganization (CD) is a symptom subtype which predicts impaired real-world functioning in psychosis. Systematic reviews have reported aberrant connectivity in formal thought disorder, a construct related to CD. However, no stud...

Progressive reduction in glutamatergic transmission has been proposed as an important component of the illness trajectory of schizophrenia. Despite its popularity, to date, this notion has not been convincingly tested in patients in early stages schizophrenia. In a longitudinal 7T magnetic resonance spectroscopy (1H-MRS), we quantified glutamate at...

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...

Objectives Aberrant cortical development, inferred from cortical folding, is linked to the risk of schizophrenia. Cortical folds develop in a time-locked fashion during fetal growth. We leveraged this temporal specificity of sulcation to investigate the timing of the prenatal insult linked to schizophrenia and the cognitive impairment seen in this...

Aim: Thought disorder is a core feature of schizophrenia but assessment of disordered thinking is challenging, which may contribute to the paucity of mechanistic understanding of disorganization in early psychosis. We studied the use of linguistic connectives in relation to clinically quantified dimensions of thought disorder using automated speec...

Repetitive transcranial magnetic stimulation (rTMS), when applied to left dorsolateral prefrontal cortex (LDLPFC), reduces negative symptoms of schizophrenia, but has no effect on positive symptoms. In a small number of cases, it appears to worsen the severity of positive symptoms. It has been hypothesized that high frequency rTMS of the LDLPFC mig...

Background: Functional dysconnection in schizophrenia is underwritten by a pathophysiology of the glutamate neurotransmission that affects the excitation-inhibition balance in key nodes of the salience network. Physiologically, this manifests as aberrant effective connectivity in intrinsic connections involving inhibitory interneurons. In computat...

Background: Disturbances in the expression of thought is a core feature of schizophrenia but assessment of disordered thinking is challenging, relying on clinical intuition which may contribute to the paucity of mechanistic understanding of disorganization seen in early stages of psychosis. We studied the use of linguistic connectives in relation t...

Objectives: Aberrant cortical development, inferred from cortical folding measures, is linked to the risk of schizophrenia. Cortical folds develop in a time-locked fashion during fetal growth. We leveraged this temporal specificity of sulcation to investigate the approximate timing of the prenatal insult linked to schizophrenia as well as the cogni...

Objective The 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...

In the dysconnection hypothesis, psychosis is caused by NMDA hypofunction resulting in aberrant network connectivity. Combining a cognitive-control task, functional magnetic resonance spectroscopy, and functional magnetic resonance imaging, we tested this hypothesis in the salience network of 20 first-episode psychosis (FEP) and 20 healthy control...

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...

Background: The diagnosis of schizophrenia is thought to embrace several distinct subgroups. The manifold entities in a single clinical patient group increases the variance of biological measures, deflates the group-level estimates of causal factors and masks the presence treatment effects. However, reliable neurobiological boundaries to differenti...

Background Predictive coding and active inference framework states that subjects with psychotic disorders overly ascribe confidence (precision) to both sensory information and prior beliefs, leading to delusions and hallucinations. When considered in terms of brain connectivity, we predict that this computational aberrance should map onto strong fo...

Background The hippocampus and its subfields are considered putative markers in schizophrenia. In particular, earliest volume deficits in select subfields have been demonstrated in multiple studies and extending to the rest later in the disease. Recently, there is increasing interest in studying the white matter projections from the hippocampus inc...

Background Ultra-high field 7T imaging greatly enhances the estimation of altered structure-function correspondence in disease states and provides unprecedented access to estimate neurometabolites with high specificity. Glutathione and glutamate have emerged as promising therapeutic targets for patients showing inadequate response. Nevertheless, th...

Background Of the various symptom complexes of established psychosis, network level dysconnectivity has been widely studied in association with positive and negative symptoms. Very few studies have focused on studying the dysconnectivity patterns associated with disorganization, specifically conceptual disorganization (CD), which explains the impai...

Background The structural integrity of the anterior cingulum has been repeatedly observed to be abnormal in psychosis. Cingulum tract carries fibers that connect medial prefrontal structures with precuneus, thus serving as the major pathway within the default mode network (DMN), critical for self-related processing. Persistent disorganization (or f...

Background In addition to positive and negative symptoms, patients with schizophrenia have notable disturbances in their ability to produce integrated, complex thoughts. Clinical quantification of thought disorder is a challenging process, contributing to the paucity of mechanistic understanding of disorganization seen in early stages of psychosis....

Background Structural neuroimaging studies report disrupted morphological relationship in the grey matter volume (structural covariance) in patients with schizophrenia, indicating an impairment in functional and/or developmental plasticity. To our knowledge, no studies have examined the alterations in structural covariance across the entire brain i...

Background Structural neuroimaging studies report distributed grey matter volume (GMV) deficits in drug-naïve first episode psychosis (FEP), though their relevance to symptom burden and cognitive deficits is currently unclear. When compared to studies in medicated patients and/or patients with established later-stage of psychosis, the GMV deficits...