Impaired modulation of hippocampal glutamate during memory consolidation in schizophrenia: Evidence from ¹H fMRS
Jeffrey A. Stanley1, Patricia Thomas1, Dalal Khatib1, Asadur Chowdury1, Usha Rajan1, Luay Haddad1, Amirsadri Alireza1, and Vaibhav A. Diwadkar1

1Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, United States


Schizophrenia is one of the most debilitating, life-long mental illnesses where treatment has a limited impact in restoring real-life functions such as deficits in learning and memory. The hippocampus is particularly rich in glutamatergic neurons and altered neuroplasticity related to glutamate has been proposed as a critical mechanism mediating learning and memory in schizophrenia. Understanding glutamate-related dysfunction in schizophrenia may therefore, elucidate mechanisms underlying the illness as well as help tailor intervention strategies. Here we provide the first ever evidence of a dysfunctional modulation of hippocampal glutamate during memory encoding in schizophrenia using ¹H fMRS.


Glutamate plays a central role in frontal-hippocampal mechanisms of learning and memory. The hippocampus is particularly rich in glutamatergic neurons and N-methyl-D-aspartate (NMDA) mediated synaptic plasticity is central for subserving learning. Unsurprisingly, altered neuroplasticity related to glutamate has been proposed as a critical mechanism mediating learning and memory deficits in schizophrenia. Understanding glutamate-related hippocampal dysfunction in schizophrenia may therefore, elucidate not only mechanisms underlying the illness, but may subsequently help in tailoring intervention strategies. However in vivo studies have largely relied on hemodynamic signals based on fMRI to assess hippocampal function (and dysfunction) in schizophrenia, or on quantitating static levels of glutamate with ¹H MRS. These signals are not informative of functional modulation of hippocampal glutamate. Here we provide the first ever application of in vivo ¹H functional MRS (fMRS) to assess dysfunctional modulation of hippocampal glutamate in schizophrenia. fMRS is a highly novel method for quantitating functional neurochemistry and can provide direct evidence of normal and impaired hippocampal function (Stanley et al., 2017).


Fifteen early course DSM-V schizophrenia patients (10M + 5F; 25.9±3.7yrs) and 13 healthy, young adults (8M + 5F; 25.8±3.9yrs) participated in the ¹H fMRS study at 3T. The associative learning and memory previously assessed in schizophrenia using fMRI (Wadehra et al., 2013) involved epochs of encoding (9 unique object-location pairs) and cued-retrieval (of those associated memoranda) and interspersed with rest epochs (Stanley et al., 2017) (Figure 1). Eight encoding-retrieval cycles were employed to allow learning to asymptote. Mixed rest epochs of either 27s (64% of data) or 9s were interspersed between task blocks. A visual flashing checkerboard task was introduced prior to the onset of the learning task to provide a non-hippocampal task as a non-memory baseline condition. A total of 19 consecutive single-voxel, short-TE ¹H spectra of 16 averages each were acquired from the right head/body of the hippocampus (voxel:1.7x3.0x1.2cm or 6.12 cm3, PRESS, TE=23ms). The resulting ¹H spectra from the 8 encoding/rest epochs and 8 retrieval/rest epochs as well the 3 ¹H spectra from the baseline condition were quantified using LCModel (Figure 2). Performance on task was estimated by modeling the behavioral data (expressed as a percent correct by epoch) using the three-parameter Gompertz function (learning rate, asymptote and inflection point). The statistical analyses assessed changes in glutamate across task conditions (encoding, retrieval) relative to baseline for each group as well as a group-by-task condition interaction for glutamate using the repeated measure GEE approach with task (encoding, retrieval) and time (epoch number) as within subject factors, and age and sex as covariates.


Regarding performance, both groups showed negatively accelerated learning with no statistical group differences on the learning rate, asymptote or inflection point (all p>.20). Independent of time, the task condition for glutamate was significant in controls (Χ2= 7.70; p=0.021) with post-hoc tests demonstrating a significant increase in hippocampal glutamate during both encoding (5.9%; p<.0001) and retrieval (3.7%, p=.028) compared to baseline (Figure 3). In contrast, there were no significant differences in glutamate across conditions in schizophrenia patients. Additionally, the group-by-task interaction was not significant (Χ2= 1.45; p=.23); however, post-hoc analyses indicated a significantly higher glutamate modulation during encoding in controls compared to schizophrenia (p=0.025), while glutamate modulation during retrieval was not significant between groups (p=.64).


The results indicate that even as schizophrenia subjects were engaged in the task, modulation of hippocampal glutamate was absent during encoding and retrieval. These results provide the first assessment, and evidence of impaired functional neurochemistry of the hippocampus in schizophrenia. In healthy controls, the increased levels of hippocampal glutamate observed during encoding and retrieval may be driven by the influx of oxidative metabolism related to increased neuronal activity (Schaller et al., 2014), but assessed independently of the confounds of hemodynamics. By inference, therefore, impaired glutamate modulation in schizophrenia may reflect a lack of neuronal engagement during learning. Though further studies are warranted (and are ongoing), our results provide the first direct evidence of a hippocampal dysfunction related to glutamatergic neurotransmission during processes of memory consolidation in schizophrenia.


This study was supported by NIMH under award number R01 MH111177 (JAS and VAD) and by the Lycaki-Young Funds from the State of Michigan.


Schaller, B., Xin, L., O&apos;Brien, K., Magill, A.W., Gruetter, R., 2014. Are glutamate and lactate increases ubiquitous to physiological activation? A (1)H functional MR spectroscopy study during motor activation in human brain at 7Tesla. NeuroImage 93 Pt 1, 138-145.

Stanley, J.A., Burgess, A., Khatib, D., Ramaseshan, K., Arshad, M., Wu, H., Diwadkar, V.A., 2017. Functional dynamics of hippocampal glutamate during associative learning assessed with in vivo (1)H functional magnetic resonance spectroscopy. NeuroImage 153, 189-197.

Wadehra, S., Pruitt, P., Murphy, E.R., Diwadkar, V.A., 2013. Network dysfunction during associative learning in schizophrenia: Increased activation, but decreased connectivity: an fMRI study. Schizophr Res 148, 38-49.


Figure 1: (A) Schematic illustration of the associative learning and memory paradigm depicts the two-dimensional grid and example objects presented during encoding, and the cued locations during retrieval. The intervening rest epoch is depicted by fixation marker. The figure highlights the encoding and retrieval trials within their respective epochs, and the interspersed rest epochs. (B) A total of eight encoding and retrieval epochs were employed and the timing of the individual ¹H MRS measurements is depicted along the bottom.

Figure 2: A typical ¹H MRS spectrum acquired with 16 averages yielding a 54s temporal resolution. The acquired spectrum in black is superimposed on the LCModel fitted spectrum in red. Below includes the glutamate signal (Glu) in blue and the residual of the fitting in grey. The chemical shift axis in ppm is depicted at the bottom.

Figure 3: The bars for each of the task conditions (encoding and retrieval) represent mean % levels of hippocampal glutamate relative to the control condition for schizophrenia patients (red) and controls (blue). *Significant increase in glutamate modulation during task compared to the control condition (p<.03). **Significant difference in glutamate modulation during encoding between individuals with schizophrenia and controls (p=0.025).

Proc. Intl. Soc. Mag. Reson. Med. 26 (2018)