Hippocampal Dysconnectivity and Altered Glutamatergic Modulation of the Default Mode Network: A Combined Resting-State Connectivity and Magnetic Resonance Spectroscopy Study in Schizophrenia

Nelson, Eric; Kraguljac, Nina; Maximo, Jose O.; Briend, Frederic; Armstrong, William P.; Hoef, Lawrence Ver; Lahti, Adrienne C.

doi:10.1016/j.bpsc.2020.04.014

Cited by 17 publications

(21 citation statements)

References 54 publications

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“…In parallel, we also found a reduction in hippocampal resting state connectivity to the anterior cingulate cortex, medial prefrontal cortex, insula, hippocampus, precuneus, posterior cingulate cortex and lingual gyrus. Spatial patterns of abnormalities here closely resemble those we observed in both unmedicated schizophrenia patients (27, 71) and antipsychotic medication-naïve first episode psychosis patients (71).…”

Section: Can Pharmacological Challenge Studies Provide a Framework Fosupporting

confidence: 83%

“…At rest, we initially did not detect a relationship between hippocampal glutamate and aberrant hippocampal connectivity to the precuneus in a small group of unmedicated schizophrenia patients (89). However, after expanding the sample size, we did observe that higher glutamate levels were correlated with higher hippocampus resting state connectivity to the anterior default mode network in healthy controls, but the relationship between measures was inverse in first episode psychosis patients (71). Taken together, our studies consistently demonstrated a link between glutamate levels and brain function, regardless of task condition and even in absence of a task in healthy subjects.…”

Section: Can Multimodal Brain Imaging Help Us Better Characterize Thementioning

confidence: 73%

“…In the overall group of antipsychotic medication-naïve patients, we note that hippocampus connectivity is disrupted. Spatial patterns of dysconnectivity resemble those in unmedicated, chronic schizophrenia patients ( 71 ). When examining dynamic connectivity, we found that quasi-periodic patterns had a greater impact of fronto-parietal control network connectivity in first episode patients compared to controls, suggesting that brain network dynamics are already altered in this patient group ( 70 ).…”

Section: Key Scientific Questions In Neuroimaging Research In Schizopmentioning

confidence: 91%

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Neuroimaging as a Window Into the Pathophysiological Mechanisms of Schizophrenia

Kraguljac

Lahti

2021

Front. Psychiatry

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Schizophrenia is a complex neuropsychiatric disorder with a diverse clinical phenotype that has a substantial personal and public health burden. To advance the mechanistic understanding of the illness, neuroimaging can be utilized to capture different aspects of brain pathology in vivo, including brain structural integrity deficits, functional dysconnectivity, and altered neurotransmitter systems. In this review, we consider a number of key scientific questions relevant in the context of neuroimaging studies aimed at unraveling the pathophysiology of schizophrenia and take the opportunity to reflect on our progress toward advancing the mechanistic understanding of the illness. Our data is congruent with the idea that the brain is fundamentally affected in the illness, where widespread structural gray and white matter involvement, functionally abnormal cortical and subcortical information processing, and neurometabolic dysregulation are present in patients. Importantly, certain brain circuits appear preferentially affected and subtle abnormalities are already evident in first episode psychosis patients. We also demonstrated that brain circuitry alterations are clinically relevant by showing that these pathological signatures can be leveraged for predicting subsequent response to antipsychotic treatment. Interestingly, dopamine D2 receptor blockers alleviate neural abnormalities to some extent. Taken together, it is highly unlikely that the pathogenesis of schizophrenia is uniform, it is more plausible that there may be multiple different etiologies that converge to the behavioral phenotype of schizophrenia. Our data underscore that mechanistically oriented neuroimaging studies must take non-specific factors such as antipsychotic drug exposure or illness chronicity into consideration when interpreting disease signatures, as a clear characterization of primary pathophysiological processes is an imperative prerequisite for rational drug development and for alleviating disease burden in our patients.

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Section: Can Pharmacological Challenge Studies Provide a Framework Fosupporting

confidence: 83%

Section: Can Multimodal Brain Imaging Help Us Better Characterize Thementioning

confidence: 73%

Section: Key Scientific Questions In Neuroimaging Research In Schizopmentioning

confidence: 91%

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Neuroimaging as a Window Into the Pathophysiological Mechanisms of Schizophrenia

Kraguljac

Lahti

2021

Front. Psychiatry

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“…In healthy participants, higher glutamate and glutamine levels could predict higher levels of functional connectivity from the hippocampus to the anterior default mode network. However, an inverse relationship was observed in medication-free individuals with first-episode psychosis ( Nelson et al, 2020 ). Furthermore, knockdown of S-SCAM, a unique synaptic scaffolding protein that localizes to both excitatory and GABAergic synapses in hippocampal neurons in vitro , causes a drastic loss of components in both GABAergic pre- and post-synapses, resulting in an attenuation of GABAergic synaptic transmission.…”

Section: Excitation-inhibition-related Microcircuit Deficits In Schizophreniamentioning

confidence: 99%

A Selective Review of the Excitatory-Inhibitory Imbalance in Schizophrenia: Underlying Biology, Genetics, Microcircuits, and Symptoms

Liu

Ouyang

Zheng

et al. 2021

Front. Cell Dev. Biol.

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Schizophrenia is a chronic disorder characterized by specific positive and negative primary symptoms, social behavior disturbances and cognitive deficits (e.g., impairment in working memory and cognitive flexibility). Mounting evidence suggests that altered excitability and inhibition at the molecular, cellular, circuit and network level might be the basis for the pathophysiology of neurodevelopmental and neuropsychiatric disorders such as schizophrenia. In the past decades, human and animal studies have identified that glutamate and gamma-aminobutyric acid (GABA) neurotransmissions are critically involved in several cognitive progresses, including learning and memory. The purpose of this review is, by analyzing emerging findings relating to the balance of excitatory and inhibitory, ranging from animal models of schizophrenia to clinical studies in patients with early onset, first-episode or chronic schizophrenia, to discuss how the excitatory-inhibitory imbalance may relate to the pathophysiology of disease phenotypes such as cognitive deficits and negative symptoms, and highlight directions for appropriate therapeutic strategies.

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“…The dataset here has subject overlap with our recent reports ( Briend et al, 2020 , Kraguljac et al, 2020 , Kraguljac et al, 2021 , Maximo et al, 2020 , Nelson et al, 2020 ). Data for NCT 034420101 is deposited to the NDA data archive and shared per NIMH agreement.…”

Section: Introductionmentioning

confidence: 99%

Salience network glutamate and brain connectivity in medication-naïve first episode patients – A multimodal magnetic resonance spectroscopy and resting state functional connectivity MRI study

Máximo

Briend

Armstrong

et al. 2021

NeuroImage: Clinical

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Highlights The pathophysiology of salience network in schizophrenia remains poorly understood. We found reduced connectivity, but no Glx alterations in psychosis patients. The relationship between Glx and connectivity was abnormal in psychosis patients. Findings suggest altered glutamatergic neurometabolism and connectivity in psychosis.

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Hippocampal Dysconnectivity and Altered Glutamatergic Modulation of the Default Mode Network: A Combined Resting-State Connectivity and Magnetic Resonance Spectroscopy Study in Schizophrenia

Cited by 17 publications

References 54 publications

Neuroimaging as a Window Into the Pathophysiological Mechanisms of Schizophrenia

Neuroimaging as a Window Into the Pathophysiological Mechanisms of Schizophrenia

A Selective Review of the Excitatory-Inhibitory Imbalance in Schizophrenia: Underlying Biology, Genetics, Microcircuits, and Symptoms

Salience network glutamate and brain connectivity in medication-naïve first episode patients – A multimodal magnetic resonance spectroscopy and resting state functional connectivity MRI study

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