Decreased hippocampal volume on MRI is associated with increased extracellular glutamate in epilepsy patients
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Summary: Purpose: Temporal lobe epilepsy (TLE) is associated with smaller hippocampal volume and with elevated extracellular (EC) glutamate levels. We investigated the relationship between the hippocampal volume and glutamate in refractory TLE patients. Methods: We used quantitative MRI volumetrics to measure the hippocampal volume and zero‐flow microdialysis to measure the interictal glutamate, glutamine, and GABA levels in the epileptogenic hippocampus of 17 patients with medication‐resistant epilepsy undergoing intracranial EEG evaluation. The relationships between hippocampal volume, neurochemical levels, and relevant clinical factors were examined. Results: Increased EC glutamate in the epileptogenic hippocampus was significantly related to smaller ipsilateral (R 2= 0.75, p < 0.0001), but not contralateral hippocampal volume when controlled for glutamine and GABA levels, and for clinical factors known to influence hippocampal volume. Glutamate in the atrophic hippocampus was significantly higher (p = 0.008, n = 9), with the threshold for hippocampal atrophy estimated as 5 μM. GABA and glutamine levels in the atrophic and nonatrophic hippocampus were comparable. Decreased hippocampal volume was related to higher seizure frequency (p = 0.008), but not to disease duration or febrile seizure history. None of these clinical factors were related to the neurochemical levels. Conclusions: We provide evidence for a significant association between increased EC glutamate and decreased ipsilateral epileptogenic hippocampal volume in TLE. Future work will be needed to determine whether the increase in glutamate has a causal relationship with hippocampal atrophy, or whether another, yet unknown factor results in both. This work has implications for the understanding and treatment of epilepsy as well as other neurodegenerative disorders associated with hippocampal atrophy.
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A human imaging study found that higher extracellular glutamate levels were associated with smaller hippocampal volumes, although this has not yet been studied in major depressive disorder samples.
“a human imaging study noted associations between increased extracellular glutamate levels and hippocampal volume reductions (130).”
From The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology (2019) · cites this paper as [130]
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- Authors
- Cavus, I., Pan, J. W., Hetherington, H. P., Abi‐Saab, W., Zaveri, H. P., Vives, K. P., Krystal, J. H., Spencer, S. S., & Spencer, D. D.
- Affiliations
- Yale University (US)
- ORCID
- Venue
- Epilepsia
- Publisher
- Wiley
- Published
- 2008-07-28
- Volume
- 49
- Issue
- 8
- Pages
- 1358-1366
- ISSN
- 0013-9580 (ISSN-L)
- 1528-1167
- OpenAlex
- W1982409010
- Cited by
- 89
- References
- 66
- Citations by year
- 2025: 4 · 2024: 3 · 2023: 4 · 2022: 3 · 2021: 4 · 2020: 3 · 2019: 7 · 2018: 10 · 2017: 8 · 2016: 7 · 2015: 4 · 2014: 3 · 2013: 4 · 2012: 6
- FWCI
- 4.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Epilepsia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Yale University
- National Institutes of Health
- U.S. Public Health Service (000473)
- National Institute on Drug Abuse (1K12DA14038-01, K12DA014038)
- National Institute of Neurological Disorders and Stroke (P01NS-39092, R01NS040550, R01NS054038, P01NS039092)
- National Institute of Biomedical Imaging and Bioengineering (EB-005438, R21EB005438, R01EB011639)
- National Center for Complementary and Integrative Health (R21AT002984)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Keywords
- temporal lobe epilepsy, hippocampal volume, hippocampal atrophy, extracellular glutamate, glutamine, GABA, drug-resistant epilepsy, seizure frequency, hippocampal volumetry
- MeSH terms
- Adolescent, Adult, Atrophy, Chromatography, High Pressure Liquid, Electroencephalography, Epilepsy, Temporal Lobe, Extracellular Space, Female, gamma-Aminobutyric Acid, Hippocampus, Humans, Functional Laterality, Magnetic Resonance Imaging, Male, Middle Aged, Severity of Illness Index, Microdialysis, Glutamic Acid
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