Binary mechanisms underlying seizure initiation and symptom manifestation in mesial temporal lobe epilepsy: research progress based on subregion pathology and functional network alterations_Journal of Epilepsy

Authors：

TIAN Youjia ¹ , TANG Chongyang ^1,2 , XU Ke ² , DENG Jiahui ² ,  ZHOU Jian ^1,2,3

1. Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing 100093, China;
2. Laboratory for Clinical Medicine, Capital Medical University, Beijing 100093, China;
3. Department of Neurology, Sanbo Brain Hospital, Capital Medical University, Beijing 100093, China;

Corresponding?author：

ZHOU Jian, Email: zhouj@ccmu.edu.cn

Keywords：

Epilepsy; Amygdala; Anatomy; Subregions; Neural Networks

DOI：

10.7507/2096-0247.202605008

Video：

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The amygdala, a core limbic structure, plays a critical role in epilepsy due to its structural and functional heterogeneity. Its major subnuclei—the basolateral, centromedial, and superficial cortical nuclei—differ in cellular composition, connectivity, and function, and form extensive circuits with the prefrontal cortex, hippocampus, and hypothalamus. In epilepsy, the amygdala may become a hyperexcitable microcircuit through impaired GABAergic inhibition, ion channel dysfunction, altered synaptic plasticity, and neuroinflammation, thereby lowering seizure threshold. Abnormal amygdalar activity can propagate to the frontotemporal cortex via the uncinate fasciculus or influence autonomic centers through the stria terminalis. Theta/gamma coupling and high-frequency oscillations within the amygdala–hippocampal network are key electrophysiological markers of seizure spread. Clinically, different subnuclei are associated with distinct seizure symptoms: the basolateral nucleus is linked to affective auras such as fear, the centromedial nucleus to autonomic symptoms such as palpitations, and the superficial cortical nuclei to olfactory or gustatory auras. Stereotactic electroencephalography and multimodal neuroimaging improve epileptogenic zone localization and support precise surgical or neuromodulatory treatment targeting the amygdala. Future research should further clarify subnucleus-specific mechanisms, developmental dynamics, and cross-species differences to advance targeted therapies for amygdala-related epilepsy.

Citation： TIAN Youjia, TANG Chongyang, XU Ke, DENG Jiahui, ZHOU Jian. Binary mechanisms underlying seizure initiation and symptom manifestation in mesial temporal lobe epilepsy: research progress based on subregion pathology and functional network alterations. Journal of Epilepsy, 2026, 12(4): 331-336. doi: 10.7507/2096-0247.202605008 Copy

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2.	Li Y, Xue YZ, Zhao WT, et al. Correlates of intelligence via resting-state functional connectivity of the amygdala in healthy adults. Brain research, 2021, 1751: 147176.
3.	Harms A, Bauer T, Fischbach L, et al. Shape description and volumetry of hippocampus and amygdala in temporal lobe epilepsy - a beneficial combination with a clinical perspective. Epilepsy & behavior, 2022, 128: 108560.
4.	Kuru Bektasoglu P, Ghare A, Elias C, et al. Afferent and efferent fiber systems of the human amygdala: anatomical, pathophysiological, and clinical significance. Journal of neurosurgery, 2025, 143(5): 1202-1216.
5.	Weiss A, Di Carlo DT, Di Russo P, et al. Microsurgical anatomy of the amygdaloid body and its connections. Brain structure & function, 2021, 226(3): 861-874.
6.	Liu Z, Sun W, Ng YH, et al. The cortical amygdala consolidates a socially transmitted long-term memory. Nature, 2024, 632(8024): 366-374.
7.	Braga MFM, Juranek J, Eiden LE, et al. GABAergic circuits of the basolateral amygdala and generation of anxiety after traumatic brain injury. Amino acids, 2022, 54(9): 1229-1249.
8.	Wank I, Pliota P, Badurek S, et al. Central amygdala circuitry modulates nociceptive processing through differential hierarchical interaction with affective network dynamics. Communications biology, 2021, 4(1): 732.
9.	McDonald AJ. Functional neuroanatomy of monoaminergic systems in the basolateral nuclear complex of the amygdala: Neuronal targets, receptors, and circuits. Journal of neuroscience research, 2023, 101(9): 1409-1432.
10.	Prakash N, Abu Irqeba A, Corbin JG. Development and function of the medial amygdala. Trends in neurosciences, 2025, 48(1): 22-32.
11.	Auer H, Cabalo DG, Rodríguez-Cruces R, et al. From histology to macroscale function in the human amygdala. eLife, 2025, 13: 15780.
12.	Ambron R. Experiencing pain: electromagnetic waves, consciousness, and the mind. Frontiers in human neuroscience, 2025, 19: 1568019.
13.	Hagihara KM, Bukalo O, Zeller M, et al. Intercalated amygdala clusters orchestrate a switch in fear state. Nature, 2021, 594(7863): 403-407.
14.	Li Z, Jiang K, Zhu Y, et al. Happy people are always similar: the evidence from brain morphological and functional inter-subject correlations. NeuroImage, 2024, 297: 120690.
15.	Fernández de Gamarra-Oca L, Lucas-Jiménez O, Onta?ón JM, et al. Amygdala structure and function and its associations with social-emotional outcomes in a low-risk preterm sample. Brain structure & function, 2024, 229(2): 477-488.
16.	Yang T, Yu K, Zhang X, et al. Plastic and stimulus-specific coding of salient events in the central amygdala. Nature, 2023, 616(7957): 510-519.
17.	Li T, Xia H, Zhao S, et al. Alterations of structural-functional connectivity coupling in older adults with depressive symptoms. Psychological medicine, 2025, 55: e293.
18.	Zhang L, Lu L, Bu X, et al. Alterations in hippocampal subfield and amygdala subregion volumes in posttraumatic subjects with and without posttraumatic stress disorder. Human brain mapping, 2021, 42(7): 2147-2158.
19.	Shakhatreh L, Sinclair B, McLean C, et al. Amygdala enlargement in temporal lobe epilepsy: histopathology and surgical outcomes. Epilepsia, 2024, 65(6): 1709-1719.
20.	Sun YH, Hu BW, Tan LH, et al. Posterior basolateral amygdala is a critical amygdaloid area for temporal lobe epilepsy. Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2024, 11(48): e2407525.
21.	Stefanits H, Milenkovic I, Mahr N, et al. Alterations in GABAA receptor subunit expression in the amygdala and entorhinal cortex in human temporal lobe epilepsy. Journal of Neuropathology and Experimental Neurology, 2019, 78(11): 1022-1048.
22.	Ferro M, Ramos JN, Visani E, et al. Temporal lobe epilepsy with isolated amygdala enlargement: anatomo-electro-clinical features and long-term outcome. Journal of Neurology, 2025, 272(2): 130.
23.	Fournier NM, Brandt LE, Kalynchuk LE. The effect of left and right long-term amygdala kindling on interictal emotionality and Fos expression. Epilepsy & Behavior, 2020, 104(Pt A): 106910.
24.	Guo Z, Zhao B, Hu W, et al. Effective connectivity among the hippocampus, amygdala, and temporal neocortex in epilepsy patients: a cortico-cortical evoked potential study. Epilepsy & Behavior, 2021, 115: 107661.
25.	Feng T, Yang Y, Wang Y, et al. Delineating structural and metabolic abnormalities in amygdala and hippocampal subfields for different seizure-onset patterns via stereotactic electroencephalography. CNS Neuroscience & Therapeutics, 2024, 30(9): 15478.
26.	Nasrullah N, Kerr WT, Stern JM, et al. Amygdala subfield and prefrontal cortex abnormalities in patients with functional seizures. Epilepsy & Behavior, 2023, 145: 109278.
27.	Guex R, Méndez-Bértolo C, Moratti S, et al. Temporal dynamics of amygdala response to emotion- and action-relevance. Scientific reports, 2020, 10(1): 11138.
28.	Ives-Deliperi V, Butler JT, Jokeit H. Left or right? Lateralizing temporal lobe epilepsy by dynamic amygdala fMRI. Epilepsy & Behavior, 2017, 70(Pt A): 118-124.
29.	Aung T, Tang LW, Ho J, et al. Differential functional connectivity of amygdala in drug-resistant temporal lobe epilepsy. Epilepsia, 2025, 66(6): 1945-1958.
30.	McDonald AJ, Mott DD. Functional neuroanatomy of amygdalohippocampal interconnections and their role in learning and memory. Journal of Neuroscience Research, 2017, 95(3): 797-820.
31.	Yu B, Zhang Q, Lin L, et al. Molecular and cellular evolution of the amygdala across species analyzed by single-nucleus transcriptome profiling. Cell Discovery, 2023, 9(1): 19.
32.	Gunther KE, Petrie D, Pérez-Edgar K, et al. Relations between executive functioning and internalizing symptoms vary as a function of frontoparietal-amygdala resting state connectivity. Research On Child and Adolescent Psychopathology, 2023, 51(6): 775-788.
33.	Pine DS, Wise SP, Murray EA. Evolution, emotion, and episodic engagement. The American Journal of Psychiatry, 2021, 178(8): 701-714.
34.	Kalhan S, McFadyen J, Tsuchiya N, et al. Neural and computational processes of accelerated perceptual awareness and decisions: a 7T fMRI study. Human Brain Mapping, 2022, 43(12): 3873-3886.
35.	Mahjoob M, Heravian Shandiz J, et al. Characterizing the visual cortex function in cognitive task-induced mental load: an functional magnetic resonance imaging study. Brain Connectivity, 2024, 14(3): 189-197.

1. Gurevitch G, Lubianiker N, Markovits T, et al. Amygdala self-neuromodulation capacity as a window for process-related network recruitment. Philosophical transactions of the Royal Society of London Series B, Biological sciences, 2024, 379(1915): 20240186.
2. Li Y, Xue YZ, Zhao WT, et al. Correlates of intelligence via resting-state functional connectivity of the amygdala in healthy adults. Brain research, 2021, 1751: 147176.
3. Harms A, Bauer T, Fischbach L, et al. Shape description and volumetry of hippocampus and amygdala in temporal lobe epilepsy - a beneficial combination with a clinical perspective. Epilepsy & behavior, 2022, 128: 108560.
4. Kuru Bektasoglu P, Ghare A, Elias C, et al. Afferent and efferent fiber systems of the human amygdala: anatomical, pathophysiological, and clinical significance. Journal of neurosurgery, 2025, 143(5): 1202-1216.
5. Weiss A, Di Carlo DT, Di Russo P, et al. Microsurgical anatomy of the amygdaloid body and its connections. Brain structure & function, 2021, 226(3): 861-874.
6. Liu Z, Sun W, Ng YH, et al. The cortical amygdala consolidates a socially transmitted long-term memory. Nature, 2024, 632(8024): 366-374.
7. Braga MFM, Juranek J, Eiden LE, et al. GABAergic circuits of the basolateral amygdala and generation of anxiety after traumatic brain injury. Amino acids, 2022, 54(9): 1229-1249.
8. Wank I, Pliota P, Badurek S, et al. Central amygdala circuitry modulates nociceptive processing through differential hierarchical interaction with affective network dynamics. Communications biology, 2021, 4(1): 732.
9. McDonald AJ. Functional neuroanatomy of monoaminergic systems in the basolateral nuclear complex of the amygdala: Neuronal targets, receptors, and circuits. Journal of neuroscience research, 2023, 101(9): 1409-1432.
10. Prakash N, Abu Irqeba A, Corbin JG. Development and function of the medial amygdala. Trends in neurosciences, 2025, 48(1): 22-32.
11. Auer H, Cabalo DG, Rodríguez-Cruces R, et al. From histology to macroscale function in the human amygdala. eLife, 2025, 13: 15780.
12. Ambron R. Experiencing pain: electromagnetic waves, consciousness, and the mind. Frontiers in human neuroscience, 2025, 19: 1568019.
13. Hagihara KM, Bukalo O, Zeller M, et al. Intercalated amygdala clusters orchestrate a switch in fear state. Nature, 2021, 594(7863): 403-407.
14. Li Z, Jiang K, Zhu Y, et al. Happy people are always similar: the evidence from brain morphological and functional inter-subject correlations. NeuroImage, 2024, 297: 120690.
15. Fernández de Gamarra-Oca L, Lucas-Jiménez O, Onta?ón JM, et al. Amygdala structure and function and its associations with social-emotional outcomes in a low-risk preterm sample. Brain structure & function, 2024, 229(2): 477-488.
16. Yang T, Yu K, Zhang X, et al. Plastic and stimulus-specific coding of salient events in the central amygdala. Nature, 2023, 616(7957): 510-519.
17. Li T, Xia H, Zhao S, et al. Alterations of structural-functional connectivity coupling in older adults with depressive symptoms. Psychological medicine, 2025, 55: e293.
18. Zhang L, Lu L, Bu X, et al. Alterations in hippocampal subfield and amygdala subregion volumes in posttraumatic subjects with and without posttraumatic stress disorder. Human brain mapping, 2021, 42(7): 2147-2158.
19. Shakhatreh L, Sinclair B, McLean C, et al. Amygdala enlargement in temporal lobe epilepsy: histopathology and surgical outcomes. Epilepsia, 2024, 65(6): 1709-1719.
20. Sun YH, Hu BW, Tan LH, et al. Posterior basolateral amygdala is a critical amygdaloid area for temporal lobe epilepsy. Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2024, 11(48): e2407525.
21. Stefanits H, Milenkovic I, Mahr N, et al. Alterations in GABAA receptor subunit expression in the amygdala and entorhinal cortex in human temporal lobe epilepsy. Journal of Neuropathology and Experimental Neurology, 2019, 78(11): 1022-1048.
22. Ferro M, Ramos JN, Visani E, et al. Temporal lobe epilepsy with isolated amygdala enlargement: anatomo-electro-clinical features and long-term outcome. Journal of Neurology, 2025, 272(2): 130.
23. Fournier NM, Brandt LE, Kalynchuk LE. The effect of left and right long-term amygdala kindling on interictal emotionality and Fos expression. Epilepsy & Behavior, 2020, 104(Pt A): 106910.
24. Guo Z, Zhao B, Hu W, et al. Effective connectivity among the hippocampus, amygdala, and temporal neocortex in epilepsy patients: a cortico-cortical evoked potential study. Epilepsy & Behavior, 2021, 115: 107661.
25. Feng T, Yang Y, Wang Y, et al. Delineating structural and metabolic abnormalities in amygdala and hippocampal subfields for different seizure-onset patterns via stereotactic electroencephalography. CNS Neuroscience & Therapeutics, 2024, 30(9): 15478.
26. Nasrullah N, Kerr WT, Stern JM, et al. Amygdala subfield and prefrontal cortex abnormalities in patients with functional seizures. Epilepsy & Behavior, 2023, 145: 109278.
27. Guex R, Méndez-Bértolo C, Moratti S, et al. Temporal dynamics of amygdala response to emotion- and action-relevance. Scientific reports, 2020, 10(1): 11138.
28. Ives-Deliperi V, Butler JT, Jokeit H. Left or right? Lateralizing temporal lobe epilepsy by dynamic amygdala fMRI. Epilepsy & Behavior, 2017, 70(Pt A): 118-124.
29. Aung T, Tang LW, Ho J, et al. Differential functional connectivity of amygdala in drug-resistant temporal lobe epilepsy. Epilepsia, 2025, 66(6): 1945-1958.
30. McDonald AJ, Mott DD. Functional neuroanatomy of amygdalohippocampal interconnections and their role in learning and memory. Journal of Neuroscience Research, 2017, 95(3): 797-820.
31. Yu B, Zhang Q, Lin L, et al. Molecular and cellular evolution of the amygdala across species analyzed by single-nucleus transcriptome profiling. Cell Discovery, 2023, 9(1): 19.
32. Gunther KE, Petrie D, Pérez-Edgar K, et al. Relations between executive functioning and internalizing symptoms vary as a function of frontoparietal-amygdala resting state connectivity. Research On Child and Adolescent Psychopathology, 2023, 51(6): 775-788.
33. Pine DS, Wise SP, Murray EA. Evolution, emotion, and episodic engagement. The American Journal of Psychiatry, 2021, 178(8): 701-714.
34. Kalhan S, McFadyen J, Tsuchiya N, et al. Neural and computational processes of accelerated perceptual awareness and decisions: a 7T fMRI study. Human Brain Mapping, 2022, 43(12): 3873-3886.
35. Mahjoob M, Heravian Shandiz J, et al. Characterizing the visual cortex function in cognitive task-induced mental load: an functional magnetic resonance imaging study. Brain Connectivity, 2024, 14(3): 189-197.

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