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      Septal stimulation attenuates hippocampal seizure with subregion specificity

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          Abstract

          Objective

          Deep brain stimulation (DBS) is a promising approach for the treatment of epilepsy. However, the optimal target for DBS and underlying mechanisms are still not clear. Here, we compared the therapeutic effects of DBS on distinct septal subregions, aimed to find the precise targets of septal DBS and related mechanisms for the clinical treatment.

          Methods

          Assisted by behavioral test, electroencephalography (EEG) recording and analyzing, selectively neuronal manipulation and immunohistochemistry, we assessed the effects of DBS on the three septal subregions in kainic acid (KA)‐induced mouse seizure model.

          Results

          DBS in the medial septum (MS) not only delayed generalized seizure (GS) development, but reduced the severity; DBS in the vertical diagonal band of Broca (VDB) only reduced the severity of GS, while DBS in the horizontal diagonal band of Broca (HDB) subregion showed no anti‐seizure effect. Notably, DBS in the MS much more efficiently decreased abnormal activation of hippocampal neurons. EEG spectrum analysis indicated that DBS in the MS and VDB subregions mainly increased the basal hippocampal low‐frequency (delta and theta) rhythm. Furthermore, ablation of cholinergic neurons in the MS and VDB subregions blocked the anti‐seizure and EEG‐modulating effects of septal DBS, suggesting the seizure‐alleviating effect of DBS was dependent on local cholinergic neurons.

          Significance

          DBS in the MS and VDB, rather than HDB, attenuates hippocampal seizure by activation of cholinergic neurons‐augmented hippocampal delta/theta rhythm. This may be of great therapeutic significance for the clinical treatment of epilepsy with septal DBS.

          Plain Language Summary

          The optical target of deep brain stimulation in the septum is still not clear. This study demonstrated that stimulation in the medial septum and vertical diagonal band of Broca subregions, but not the horizontal diagonal band of Broca, could alleviate hippocampal seizure through cholinergic neurons‐augmented hippocampal delta/theta rhythm. This study may shed light on the importance of precise regulation of deep brain stimulation therapy in treating epileptic seizures.

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          Most cited references54

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          Modification of seizure activity by electrical stimulation: II. Motor seizure

          Ronald J Racine (1972)
          Article 0 comments Cited 509 times – based on 0 reviews     Review now
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            Early identification of refractory epilepsy.

            Patrick Kwan, Martin J Brodie (2000)
            More than 30 percent of patients with epilepsy have inadequate control of seizures with drug therapy, but why this happens and whether it can be predicted are unknown. We studied the response to antiepileptic drugs in patients with newly diagnosed epilepsy to identify factors associated with subsequent poor control of seizures. We prospectively studied 525 patients (age, 9 to 93 years) who were given a diagnosis, treated, and followed up at a single center between 1984 and 1997. Epilepsy was classified as idiopathic (with a presumed genetic basis), symptomatic (resulting from a structural abnormality), or cryptogenic (resulting from an unknown underlying cause). Patients were considered to be seizure-free if they had not had any seizures for at least one year. Among the 525 patients, 333 (63 percent) remained seizure-free during antiepileptic-drug treatment or after treatment was stopped. The prevalence of persistent seizures was higher in patients with symptomatic or cryptogenic epilepsy than in those with idiopathic epilepsy (40 percent vs. 26 percent, P=0.004) and in patients who had had more than 20 seizures before starting treatment than in those who had had fewer (51 percent vs. 29 percent, P<0.001). The seizure-free rate was similar in patients who were treated with a single established drug (67 percent) and patients who were treated with a single new drug (69 percent). Among 470 previously untreated patients, 222 (47 percent) became seizure-free during treatment with their first antiepileptic drug and 67 (14 percent) became seizure-free during treatment with a second or third drug. In 12 patients (3 percent) epilepsy was controlled by treatment with two drugs. Among patients who had no response to the first drug, the percentage who subsequently became seizure-free was smaller (11 percent) when treatment failure was due to lack of efficacy than when it was due to intolerable side effects (41 percent) or an idiosyncratic reaction (55 percent). Patients who have many seizures before therapy or who have an inadequate response to initial treatment with antiepileptic drugs are likely to have refractory epilepsy.
            Article 0 comments Cited 501 times – based on 0 reviews     Review now
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              The cholinergic system in aging and neuronal degeneration.

              Reinhard Schliebs, Thomas Arendt (2011)
              The basal forebrain cholinergic complex comprising medial septum, horizontal and vertical diagonal band of Broca, and nucleus basalis of Meynert provides the mayor cholinergic projections to the cerebral cortex and hippocampus. The cholinergic neurons of this complex have been assumed to undergo moderate degenerative changes during aging, resulting in cholinergic hypofunction that has been related to the progressing memory deficits with aging. However, the previous view of significant cholinergic cell loss during aging has been challenged. Neuronal cell loss was found predominantly in pathological aging, such as Alzheimer's disease, while normal aging is accompanied by a gradual loss of cholinergic function caused by dendritic, synaptic, and axonal degeneration as well as a decrease in trophic support. As a consequence, decrements in gene expression, impairments in intracellular signaling, and cytoskeletal transport may mediate cholinergic cell atrophy finally leading to the known age-related functional decline in the brain including aging-associated cognitive impairments. However, in pathological situations associated with cognitive deficits, such as Parkinsons's disease, Down-syndrome, progressive supranuclear palsy, Jakob-Creutzfeld disease, Korsakoff's syndrome, traumatic brain injury, significant degenerations of basal forebrain cholinergic cells have been observed. In presenile (early onset), and in the advanced stages of late-onset Alzheimer's disease (AD), a severe loss of cortical cholinergic innervation has extensively been documented. In contrast, in patients with mild cognitive impairment (MCI, a prodromal stage of AD), and early forms of AD, apparently no cholinergic neurodegeneration but a loss of cholinergic function occurs. In particular imbalances in the expression of NGF, its precursor proNGF, the high and low NGF receptors, trkA and p75NTR, respectively, changes in acetylcholine release, high-affinity choline uptake, as well as alterations in muscarinic and nicotinic acetylcholine receptor expression may contribute to the cholinergic dysfunction. These observations support the suggestion of a key role of the cholinergic system in the functional processes that lead to AD. Malfunction of the cholinergic system may be tackled pharmacologically by intervening in cholinergic as well as neurotrophic signaling cascades that have been shown to ameliorate the cholinergic deficit at early stages of the disease, and slow-down the progression. However, in contrast to many other, dementing disorders, in AD the cholinergic dysfunctions are accompanied by the occurrence of two major histopathological hallmarks such as β-amyloid plaques and neurofibrillary tangles, provoking the question whether they play a particular role in inducing or mediating cholinergic dysfunction in AD. Indeed, there is abundant evidence that β-amyloid may trigger cholinergic dysfunction through action on α7 nicotinic acetylcholine receptors, affecting NGF signaling, mediating tau phosphorylation, interacting with acetylcholinesterase, and specifically affecting the proteome in cholinergic neurons. Therefore, an early onset of an anti β-amyloid strategy may additionally be potential in preventing aging-associated cholinergic deficits and cognitive impairments. Copyright © 2010 Elsevier B.V. All rights reserved.
              Article 0 comments Cited 324 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Yeping Ruan: ruanyp@zcmu.edu.cn
                Jiajia Fang: fangjiajia6926@163.com
                Fan Fei:
                ORCID: https://orcid.org/0000-0001-8035-5001
                fei-fan@zju.edu.cn
                Journal
                Journal ID (nlm-ta): Epilepsia Open
                Journal ID (iso-abbrev): Epilepsia Open
                Journal ID (doi): 10.1002/(ISSN)2470-9239
                Journal ID (publisher-id): EPI4
                Title: Epilepsia Open
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Electronic): 2470-9239
                Publication date (Electronic): 03 June 2024
                Publication date Collection: August 2024
                Volume: 9
                Issue: 4 ( doiID: 10.1002/epi4.v9.4 )
                Pages: 1445-1457
                Affiliations
                [ 1 ] Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, Department of Neurology, The First Affiliated Hospital, School of Pharmaceutical Sciences Zhejiang Chinese Medical University Hangzhou China
                [ 2 ] Chinese Medicine Plant Essential Oil Zhejiang Engineering Research Center, School of Pharmaceutical Sciences Zhejiang Chinese Medical University Hangzhou China
                [ 3 ] Department of Neurology, The Fourth Affiliated Hospital, School of Medicine Zhejiang University Yiwu China
                Author notes
                [*] [* ] Correspondence

                Yeping Ruan and Fan Fei, Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, Department of Neurology, The First Affiliated Hospital, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.

                Email: ruanyp@ 123456zcmu.edu.cn and fei-fan@ 123456zju.edu.cn

                Jiajia Fang, Department of Neurology, The Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, China.

                Email: fangjiajia6926@ 123456163.com

                Author information
                https://orcid.org/0000-0001-8035-5001
                Article
                Publisher ID: EPI412983 Other ID: EPI4-0053-2024.R1
                DOI: 10.1002/epi4.12983
                PMC ID: 11296123
                PubMed ID: 38831626
                SO-VID: 37804c2d-37d9-44f4-a4fc-f8f8ac3ead42
                Copyright © © 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date revision received : 06 May 2024
                Date received : 22 February 2024
                Date accepted : 18 May 2024
                Page count
                Figures: 5, Tables: 0, Pages: 13, Words: 7700
                Funding
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                Award ID: 82022071
                Award ID: 82304460
                Award ID: 82330116
                Categories
                Subject: Original Article
                Subject: Original Article
                Custom metadata
                source-schema-version-number 2.0
                cover-date August 2024
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.4.6 mode:remove_FC converted:02.08.2024

                Keywords: cholinergic neuron,deep brain stimulation,hippocampal rhythm,seizure,septum
                Data availability:
                Keywords: cholinergic neuron, deep brain stimulation, hippocampal rhythm, seizure, septum

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