Towards an Integrated View of Early Molecular Changes Underlying Vulnerability to Social Stress in Psychosis

Barron, Henry; Hafizi, Sina; Mizrahi, Romina

doi:10.1159/000470810

Cited by 5 publications

(4 citation statements)

References 96 publications

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“…Neuroinflammation is proposed to play a role in the pathogenesis of schizophrenia 1–3 . This idea is supported by several preclinical 4 , epidemiological 5 , and genome wide association studies 6 .…”

Section: Introductionmentioning

confidence: 99%

TSPO expression and brain structure in the psychosis spectrum

Hafizi

Guma

Koppel

et al. 2018

Brain, Behavior, and Immunity

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Psychosis is associated with abnormal structural changes in the brain including decreased regional brain volumes and abnormal brain morphology. However, the underlying causes of these structural abnormalities are less understood. The immune system, including microglial activation, has been implicated in the pathophysiology of psychosis. Although previous studies have suggested a connection between peripheral proinflammatory cytokines and structural brain abnormalities in schizophrenia, no in-vivo studies have investigated whether microglial activation is also linked to brain structure alterations previously observed in schizophrenia and its putative prodrome. In this study, we investigated the link between mitochondrial 18 kDa translocator protein (TSPO) and structural brain characteristics (i.e. regional brain volume, cortical thickness, and hippocampal shape) in key brain regions such as dorsolateral prefrontal cortex and hippocampus of a large group of participants (N = 90) including individuals at clinical high risk (CHR) for psychosis, first-episode psychosis (mostly antipsychotic-naïve) patients, and healthy volunteers. The participants underwent structural brain MRI scan and [F]FEPPA positron emission tomography (PET) targeting TSPO. A significant [F]FEPPA binding-by-group interaction was observed in morphological measures across the left hippocampus. In first-episode psychosis, we observed associations between [F]FEPPA V (total volume of distribution) and outward and inward morphological alterations, respectively, in the dorsal and ventro-medial portions of the left hippocampus. These associations were not significant in CHR or healthy volunteers. There was no association between [F]FEPPA V and other structural brain characteristics. Our findings suggest a link between TSPO expression and alterations in hippocampal morphology in first-episode psychosis.

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Section: Introductionmentioning

confidence: 99%

TSPO expression and brain structure in the psychosis spectrum

Hafizi

Guma

Koppel

et al. 2018

Brain, Behavior, and Immunity

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“…The unique metabolic demands of PV-INs might suggest a particular susceptibility to oxidative stress ( Steullet et al, 2017 ) and antioxidants depletion-induced oxidative stress, leading to PV immunoreactivity downregulation in PV-INs ( Cabungcal et al, 2013b ; Hasam-Henderson et al, 2018 ; Rossetti et al, 2018 ). The observed reduced PV expression might result from altered PV-INs neurodevelopment ( Cabungcal et al, 2013b ; Barron et al, 2017 ), such as neuronal immaturity, which appears to be directly correlated to reduced PV expression ( Gandal et al, 2012 ). This is of particular relevance from a functional perspective considering that reduced PV expression is considered as a surrogate biomarker for the activity of PV-INs.…”

Section: Discussionmentioning

confidence: 99%

The Neurometabolic Basis of Mood Instability: The Parvalbumin Interneuron Link—A Systematic Review and Meta-Analysis

Pinna

Colasanti

2021

Front. Pharmacol.

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The neurobiological bases of mood instability are poorly understood. Neuronal network alterations and neurometabolic abnormalities have been implicated in the pathophysiology of mood and anxiety conditions associated with mood instability and hence are candidate mechanisms underlying its neurobiology. Fast-spiking parvalbumin GABAergic interneurons modulate the activity of principal excitatory neurons through their inhibitory action determining precise neuronal excitation balance. These interneurons are directly involved in generating neuronal networks activities responsible for sustaining higher cerebral functions and are especially vulnerable to metabolic stress associated with deficiency of energy substrates or mitochondrial dysfunction. Parvalbumin interneurons are therefore candidate key players involved in mechanisms underlying the pathogenesis of brain disorders associated with both neuronal networks’ dysfunction and brain metabolism dysregulation. To provide empirical support to this hypothesis, we hereby report meta-analytical evidence of parvalbumin interneurons loss or dysfunction in the brain of patients with Bipolar Affective Disorder (BPAD), a condition primarily characterized by mood instability for which the pathophysiological role of mitochondrial dysfunction has recently emerged as critically important. We then present a comprehensive review of evidence from the literature illustrating the bidirectional relationship between deficiency in mitochondrial-dependent energy production and parvalbumin interneuron abnormalities. We propose a mechanistic explanation of how alterations in neuronal excitability, resulting from parvalbumin interneurons loss or dysfunction, might manifest clinically as mood instability, a poorly understood clinical phenotype typical of the most severe forms of affective disorders. The evidence we report provides insights on the broader therapeutic potential of pharmacologically targeting parvalbumin interneurons in psychiatric and neurological conditions characterized by both neurometabolic and neuroexcitability abnormalities.

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“…Early clinical evidence arose from epidemiological studies of the 1957 influenza pandemic in which maternal infection during pregnancy was found to correlate with the development of schizophrenia in the offspring in later life (Brown and Patterson,2011;Mednick et al,1988). A growing body of experimental and clinical evidence supports the role of neuroinflammation in the pathophysiology of psychosis and schizophrenia (Doorduin et al, 2009), with theories pinpointing parvalbumin interneuron development impacted by inflammation and NMDAR hypofunction (Barron et al, 2017;Najjar et al, 2018). These parvalbumin interneurons are fast spiking GABAergic neurons that synchronise the pyramidal neurons in the cortex and contribute to the generation of cognitive processes and working memory (Zandi et al, 2011).…”

Section: Psychosismentioning

confidence: 99%

Inflammatory neuropsychiatric disorders and COVID-19 neuroinflammation

Tang

Helmeste

Leonard

2021

Acta Neuropsychiatr.

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Neuropsychiatric sequalae to COVID-19 infection are beginning to emerge, like previous Spanish influenza and SARS episodes. Streptococcal infection in pediatric patients causing OCD (PANDAS) is another recent example of an infection-based psychiatric disorder. Inflammation associated with neuropsychiatric disorders has been previously reported but there is no standard clinical management approach established. Part of the reason is that it is unclear what factors determine the specific neuronal vulnerability and the efficacy of anti-inflammatory treatment in neuroinflammation. The emerging COVID-19 data suggested that in the acute stage, wide-spread neuronal damage appears to be the result of abnormal and overactive immune responses and cytokine storm is associated with poor prognosis. It is still too early to know if there are long term specific neuronal or brain regional damages associated with COVID-19, resulting in distinct neuropsychiatric disorders. In several major psychiatric disorders where neuroinflammation is present, patients with abnormal inflammatory markers may also experience less than favorable response or treatment resistance when standard treatment is used alone. Evidence regarding the benefits of co-administered anti-inflammatory agents such as COX-2 inhibitor is encouraging in selected patients though may not benefit others. Disease modifying therapies are increasingly being applied to neuropsychiatric diseases characterized by abnormal or hyperreactive immune responses. Adjunct anti-inflammatory treatment may benefit selected patients and is definitely an important component of clinical management in the presence of neuroinflammation.

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Towards an Integrated View of Early Molecular Changes Underlying Vulnerability to Social Stress in Psychosis

Cited by 5 publications

References 96 publications

TSPO expression and brain structure in the psychosis spectrum

TSPO expression and brain structure in the psychosis spectrum

The Neurometabolic Basis of Mood Instability: The Parvalbumin Interneuron Link—A Systematic Review and Meta-Analysis

Inflammatory neuropsychiatric disorders and COVID-19 neuroinflammation

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