Glutamate and Dysconnection in the Salience Network: Neurochemical, Effective Connectivity, and Computational Evidence in Schizophrenia

Limongi, Roberto; Jeon, Peter; Mackinley, Michael; Das, Tushar Kanti; Dempster, Kara; Théberge, Jean; Bartha, Robert; Wong, Dickson; Palaniyappan, Lena

doi:10.1016/j.biopsych.2020.01.021

Cited by 63 publications

(40 citation statements)

References 55 publications

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“…Specifically, connectivity-neurotransmitter coupling has been proposed and observed in healthy populations (28,29). Similarly, network dysconnectivity in schizophrenia has been associated with altered neurotransmission (30,31) involving dopaminergic, serotonergic, gamma-aminobutyric acid (GABA)-ergic, and glutamatergic pathways (32)(33)(34)(35). Here, it is interesting to note that current anti-psychotic drugs mainly targeting the dopamine system are primarily effective against positive rather than negative or cognitive symptoms (36,37).…”

Section: Introductionmentioning

confidence: 99%

Intrinsic Connectivity Patterns of Task-Defined Brain Networks Allow Individual Prediction of Cognitive Symptom Dimension of Schizophrenia and Are Linked to Molecular Architecture

Chen

Müller

Dukart

et al. 2021

Biological Psychiatry

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Section: Introductionmentioning

confidence: 99%

Intrinsic Connectivity Patterns of Task-Defined Brain Networks Allow Individual Prediction of Cognitive Symptom Dimension of Schizophrenia and Are Linked to Molecular Architecture

Chen

Müller

Dukart

et al. 2021

Biological Psychiatry

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“…Secondly, while the prevalence of C9ORF72 repeat expansion mutations is not known to be higher than expected among patients with schizophrenia, late onset cases (> 40 years of age) with family history of unknown degenerative illnesses or long-term psychiatric institutionalization should carry a low threshold for C9ORF72 evaluation. Third, we report an FDG-PET finding that shows striking hypometabolism in the Salience Network, a large-scale brain network that also has a critical role in the pathophysiology of schizophrenia [ 16 ], in addition to frontotemporal reduction characteristic of other variants of FTD. Of interest, bilateral insula, anterior cingulate cortex and thalamus constituting the Salience Network are also the most likely regions of grey matter reduction in schizophrenia [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Schizophrenia syndrome due to C9ORF72 mutation case report: a cautionary tale and role of hybrid brain imaging!

Burhan

Anazodo

Marlatt³

et al. 2021

BMC Psychiatry

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Background Frontal variant frontotemporal dementia is a common cause of presenile dementia. A hexanucleotide expansion on chromosome 9 has recently been recognized as the most common genetic mutation cause of this illness. This sub-type tends to present psychiatrically with psychosis being a common presenting symptom before the onset of cognitive changes or brain atrophy. A few case series have been published describing the prominence of early psychotic symptoms, and lack of clear brain atrophy on clinical brain imaging imposing a challenge in reaching early accurate diagnosis. In this report, we present a case whereby the diagnosis of Schizophrenia syndrome was made and the patient was treated for years with multiple interventions for that syndrome before reaching the accurate diagnosis of Frontal variant frontotemporal dementia due to hexanucleotide expansion on chromosome 9. This diagnosis was confirmed after genetic testing and findings on a hybrid Positron Emission Tomography/Magnetic Resonance Imaging scanning. Case summary A 60-year-old female diagnosed with schizophrenia at age 50 after presenting with delusions and hallucinations, which proved to be refractor to several lines of pharmacological and non-pharmacological interventions including electroconvulsive therapy. Patient had a history of post-partum psychosis in her 20s. She was referred to cognitive neurology due to progressive decline in function. While clinical structural brain imaging data were not adequate to support an alternative neurological diagnosis, careful inquiry elicited a history of psychotic illness followed by progressive decline in a sister. Genetic testing confirmed hexanucleotide expansion on chromosome 9 mutation. The patient was offered a state-of-the-art FD-Glucose Positron Emission Tomography/Magnetic Resonance Imaging scan available at our centre. While volumetric Magnetic Resonance Imaging scan did not show volume loss in frontotemporal areas, the hybrid scan showed regionally specific deficit in FD-Glucose Positron Emission Tomography affecting medial superior frontal, insula, inferior temporal, thalamus, and anterior cingulate cortex consistent with behavioral variant frontotemporal dementia. Conclusions This case highlights the importance of considering Frontal variant frontotemporal dementia due to hexanucleotide expansion on chromosome 9 when facing relatively late-onset, refractory schizophrenia-like syndrome. Careful history from all available sources to elicit family history of similar presentation is very important. Genetic testing and functional brain imaging can aid in confirming the diagnosis and potentially streamlining the management of these cases.

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“…From a neurobiological and neuropharmacological point of view, these results may implicate that the insular cortex represents a preferential site in which antipsychotics exert time-dependent effects, irrespective of the antipsychotic used. From a clinical point of view, the insular cortex has been considered a crucial region for the salience network, which is widely affected by dopaminergic and glutamatergic neurotransmission, and is involved in the ability to discriminate between self-generated and external information [74,75]. Alterations in the salience network and insula overactivations may underlie many of the clinical features of psychotic disorders [76,77].…”

Section: Discussionmentioning

confidence: 99%

The Effects of Antipsychotics on the Synaptic Plasticity Gene Homer1a Depend on a Combination of Their Receptor Profile, Dose, Duration of Treatment, and Brain Regions Targeted

Iasevoli

Buonaguro

Avagliano

et al. 2020

IJMS

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Background: Antipsychotic agents modulate key molecules of the postsynaptic density (PSD), including the Homer1a gene, implicated in dendritic spine architecture. How the antipsychotic receptor profile, dose, and duration of administration may influence synaptic plasticity and the Homer1a pattern of expression is yet to be determined. Methods: In situ hybridization for Homer1a was performed on rat tissue sections from cortical and striatal regions of interest (ROI) after acute or chronic administration of three antipsychotics with divergent receptor profile: Haloperidol, asenapine, and olanzapine. Univariate and multivariate analyses of the effects of topography, treatment, dose, and duration of antipsychotic administration were performed. Results: All acute treatment regimens were found to induce a consistently higher expression of Homer1a compared to chronic ones. Haloperidol increased Homer1a expression compared to olanzapine in striatum at the acute time-point. A dose effect was also observed for acute administration of haloperidol. Conclusions: Biological effects of antipsychotics on Homer1a varied strongly depending on the combination of their receptor profile, dose, duration of administration, and throughout the different brain regions. These molecular data may have translational valence and may reflect behavioral sensitization/tolerance phenomena observed with prolonged antipsychotics.

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Glutamate and Dysconnection in the Salience Network: Neurochemical, Effective Connectivity, and Computational Evidence in Schizophrenia

Cited by 63 publications

References 55 publications

Intrinsic Connectivity Patterns of Task-Defined Brain Networks Allow Individual Prediction of Cognitive Symptom Dimension of Schizophrenia and Are Linked to Molecular Architecture

Intrinsic Connectivity Patterns of Task-Defined Brain Networks Allow Individual Prediction of Cognitive Symptom Dimension of Schizophrenia and Are Linked to Molecular Architecture

Schizophrenia syndrome due to C9ORF72 mutation case report: a cautionary tale and role of hybrid brain imaging!

The Effects of Antipsychotics on the Synaptic Plasticity Gene Homer1a Depend on a Combination of Their Receptor Profile, Dose, Duration of Treatment, and Brain Regions Targeted

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