戻る

スケジュール

講演者

Alterations of glutamate and γ-aminobutyric acid levels in patients with schizophrenia: proton magnetic resonance spectroscopy studies

Excitatory and inhibitory (E/I) imbalance is assumed to be implicated in the pathophysiology of various psychiatric disorders such as schizophrenia, depression, and autism spectrum disorder. Proton magnetic resonance spectroscopy (1H-MRS) is a modality to measure neurometabolite levels represented by glutamate and γ-aminobutyric acid (GABA) in the brain. I will present recent findings of our 1H-MRS studies focusing on treatment-resistant schizophrenia (TRS). The prevalence of schizophrenia is about 1% worldwide, and its main symptomatology comprises positive symptoms, negative symptoms, and cognitive dysfunction. Our recent meta-analysis noted that glutamate and GABA levels of the dorsal anterior cingulate cortex (dACC) were decreased in patients with schizophrenia-spectrum disorders compared with controls (Nakahara, Tsugawa, Honda, et al. Molecular Psychiatry). On the other hand, the mainstay of treatment of schizophrenia is antipsychotics, dopamine D2 receptor antagonists or partial agonists, supporting the dopamine hypothesis of the pathogenesis of schizophrenia. However, since approximately 30% of patients do not respond to antipsychotics (i.e., TRS), the pathophysiology of TRS may also involve disorders of the glutamate and GABA systems other than the dopamine system. In this context, we found that patients with severe TRS had higher glutamate + glutamine (Glx) levels in the dACC than controls (Tarumi, Tsugawa, Honda, et al. Neuropsychopharmacology). Furthermore, we noted that dACC GABA levels were higher in patients with TRS who also did not respond to clozapine, the only approved drug for TRS, compared with patients with TRS who responded well to clozapine (Ueno, Honda, et al. In submission). Therefore, 1H-MRS could be a useful modality to elucidate the relationships between E/I imbalance and antipsychotic treatment response in patients with schizophrenia, which may in turn stratify this population before treatment and help choose optimal treatment.

Spatially distinct neural mechanisms differentially linking tau aggregations, oxidative stress, and neuronal loss to apathic phenotypes in progressive supranuclear palsy

Although progressive supranuclear palsy (PSP) patients are known to exhibit apathy frequently, neuropathological processes leading to this phenotype remains elusive. The current study was aimed to examine the involvement of tau aggregations, oxidative stress (OS), and neuronal loss in the apathic manifestation of PSP patients.

Methods: Twenty PSP patients and 23 healthy controls (HCs) were enrolled. We evaluated tau depositions by PET with a specific probe, 18F-PM-PBB3, and brain volumes by MRI. Glutathione (GSH) levels as resilience measures against OS were also quantified by MRS in the anterior and posterior cingulate cortices (ACC and PCC).

Results: Tau pathologies were noted in the subcortical and cortical structures of the patient brains. Among these areas, tau accumulations were positively correlated with apathy scale (AS) in the angular gyrus (AG). Although PSP cases did not show alterations of GSH relative to HCs, GSH levels in PCC but not ACC were correlated with AS and tau depositions in AG. Marked atrophy was observed in the subcortical but not neocortical regions of PSP subjects, while gray matter (GM) volumes of the inferior frontal gyrus (IFG) and ACC were positively correlated with AS but had no relations to PET-detectable tau depositions and GSH. Finally, path analysis highlighted synergistic contributions of PET-detectable tau pathologies and GSH reductions in the posterior brain regions to AS, in parallel with associations of GM volume loss in the anterior brain regions with AS.

Conclusions: Our findings have indicated neural mechanisms underlying apathy in PSP may consist of PET-detectable tau aggregation and OS without marked neuronal loss in the posterior cortex and neuronal loss with neither PET-detectable tau pathologies nor OS in the anterior cortex.

Quantifying neurochemistry and hemodynamics in the human visual system using the combined fMRI-MRS sequence

The BOLD-response indirectly reflects neural activation, representing changes in blood flow during neu-ronal signaling. Although the BOLD-fMRI signal is widely used, it provides a limited description of these events1. The BOLD-fMRI signal cannot reveal what cellular events underlie the changes in blood flow. Neural activity is driven by excitatory or inhibitory neurotransmission. The only method that can non-invasively measure the major excitatory (glutamate) and inhibitory neurotransmitters (gamma-aminobutyric acid, GABA) in the human brain is proton magnetic resonance spectroscopy (MRS). The ability to capture both fMRI and MRS during brain function would provide a step towards building a more complete understanding of how the brain works2. In this talk, I will present recent research investigating the neurochemistry of the human visual system using the novel combined fMRI-MRS sequence at 7-Tesla. The advantage of the combined fMRI-MRS sequence is measurement of MRS and fMRI in the same time point. My research demonstrates the feasibility of tracking simultaneous BOLD-fMRI and glutamate sig-nals during visual stimulation, with glutamate increasing during 1-min visual stimulation blocks3. By vary-ing stimulation intensity, the glutamate response was shown to be intensity dependent 4. GABA was not modulated by visual stimulation. Instead, GABA was more sensitive to perceptual dynamics in the binocu-lar visual system, as shown by a correlation with perceptual eye dominance 5. The combined fMRI-MRS method is useful in understanding basic responses in the visual system and can be applied to further study the neurochemical signals underlying visual perception. By collecting simultaneous complementary sig-nals of the living human brain, we have the potential to address questions about cortical function that can-not be answered by separate application of either technique alone.  

1. Logothetis, N. K. What we can do and what we cannot do with fMRI. Nature 453, 869-878, doi:10.1038/nature06976 (2008). 
2. Stanley, J. A. & Raz, N. Functional Magnetic Resonance Spectroscopy: The "New" MRS for Cog-nitive Neuroscience and Psychiatry Research. Front Psychiatry 9, 76, doi:10.3389/fpsyt.2018.00076 (2018). 
3. Ip, I. B. et al. Combined fMRI-MRS acquires simultaneous glutamate and BOLD-fMRI signals in the human brain. NeuroImage 155, 113-119, doi:10.1016/j.neuroimage.2017.04.030 (2017). 
4. Ip, I. B., Emir, U. E., Parker, A. J., Campbell, J. & Bridge, H. Comparison of Neurochemical and BOLD Signal Contrast Response Functions in the Human Visual Cortex. The Journal of neurosci-ence : the official journal of the Society for Neuroscience 39, 7968-7975, doi:10.1523/JNEUROSCI.3021-18.2019 (2019). 
5. Ip, I. B., Emir, U. E., Lunghi, C., Parker, A. J. & Bridge, H. GABAergic inhibition in the human visual cortex relates to eye dominance.Scientific reports 11, doi:ARTN 17022 10.1038/s41598-021-95685-1 (2021).