Nicholas R Livingston, Amanda Kiemes, Owen O'Daly, Samuel R Knight, Paulina B Lukow, Luke A Jelen, Thomas J Reilly, Aikaterini Dima, Maria A Nettis, Cecilia Casetta, Gabriel A Devenyi, Thomas Spencer, Andrea De Micheli, Paolo Fusar-Poli, Anthony A Grace, Steve C R Williams, Philip McGuire, M Mallar Chakravarty, Alice Egerton, Gemma Modinos
{"title":"安定调节精神病临床高危人群海马CA1功能连通性","authors":"Nicholas R Livingston, Amanda Kiemes, Owen O'Daly, Samuel R Knight, Paulina B Lukow, Luke A Jelen, Thomas J Reilly, Aikaterini Dima, Maria A Nettis, Cecilia Casetta, Gabriel A Devenyi, Thomas Spencer, Andrea De Micheli, Paolo Fusar-Poli, Anthony A Grace, Steve C R Williams, Philip McGuire, M Mallar Chakravarty, Alice Egerton, Gemma Modinos","doi":"10.1017/S0033291725101268","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Preclinical evidence suggests that diazepam enhances hippocampal γ-aminobutyric acid (GABA) signalling and normalises a psychosis-relevant cortico-limbic-striatal circuit. Hippocampal network dysconnectivity, particularly from the CA1 subfield, is evident in people at clinical high-risk for psychosis (CHR-P), representing a potential treatment target. This study aimed to forward-translate this preclinical evidence.</p><p><strong>Methods: </strong>In this randomised, double-blind, placebo-controlled study, 18 CHR-P individuals underwent resting-state functional magnetic resonance imaging twice, once following a 5 mg dose of diazepam and once following a placebo. They were compared to 20 healthy controls (HC) who did not receive diazepam/placebo. Functional connectivity (FC) between the hippocampal CA1 subfield and the nucleus accumbens (NAc), amygdala, and ventromedial prefrontal cortex (vmPFC) was calculated. Mixed-effects models investigated the effect of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on CA1-to-region FC.</p><p><strong>Results: </strong>In the placebo condition, CHR-P individuals showed significantly lower CA1-vmPFC (<i>Z</i> = 3.17, <i>P</i><sub>FWE</sub> = 0.002) and CA1-NAc (<i>Z</i> = 2.94, <i>P</i><sub>FWE</sub> = 0.005) FC compared to HC. In the diazepam condition, CA1-vmPFC FC was significantly increased (<i>Z</i> = 4.13, <i>P</i><sub>FWE</sub> = 0.008) compared to placebo in CHR-P individuals, and both CA1-vmPFC and CA1-NAc FC were normalised to HC levels. In contrast, compared to HC, CA1-amygdala FC was significantly lower contralaterally and higher ipsilaterally in CHR-P individuals in both the placebo and diazepam conditions (lower: placebo <i>Z</i> = 3.46, <i>P</i><sub>FWE</sub> = 0.002, diazepam <i>Z</i> = 3.33, <i>P</i><sub>FWE</sub> = 0.003; higher: placebo <i>Z</i> = 4.48, <i>P</i><sub>FWE</sub> < 0.001, diazepam <i>Z</i> = 4.22, <i>P</i><sub>FWE</sub> < 0.001).</p><p><strong>Conclusions: </strong>This study demonstrates that diazepam can partially restore hippocampal CA1 dysconnectivity in CHR-P individuals, suggesting that modulation of GABAergic function might be useful in the treatment of this clinical group.</p>","PeriodicalId":20891,"journal":{"name":"Psychological Medicine","volume":"55 ","pages":"e230"},"PeriodicalIF":5.5000,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12360692/pdf/","citationCount":"0","resultStr":"{\"title\":\"Diazepam modulates hippocampal CA1 functional connectivity in people at clinical high-risk for psychosis.\",\"authors\":\"Nicholas R Livingston, Amanda Kiemes, Owen O'Daly, Samuel R Knight, Paulina B Lukow, Luke A Jelen, Thomas J Reilly, Aikaterini Dima, Maria A Nettis, Cecilia Casetta, Gabriel A Devenyi, Thomas Spencer, Andrea De Micheli, Paolo Fusar-Poli, Anthony A Grace, Steve C R Williams, Philip McGuire, M Mallar Chakravarty, Alice Egerton, Gemma Modinos\",\"doi\":\"10.1017/S0033291725101268\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Preclinical evidence suggests that diazepam enhances hippocampal γ-aminobutyric acid (GABA) signalling and normalises a psychosis-relevant cortico-limbic-striatal circuit. Hippocampal network dysconnectivity, particularly from the CA1 subfield, is evident in people at clinical high-risk for psychosis (CHR-P), representing a potential treatment target. This study aimed to forward-translate this preclinical evidence.</p><p><strong>Methods: </strong>In this randomised, double-blind, placebo-controlled study, 18 CHR-P individuals underwent resting-state functional magnetic resonance imaging twice, once following a 5 mg dose of diazepam and once following a placebo. They were compared to 20 healthy controls (HC) who did not receive diazepam/placebo. Functional connectivity (FC) between the hippocampal CA1 subfield and the nucleus accumbens (NAc), amygdala, and ventromedial prefrontal cortex (vmPFC) was calculated. Mixed-effects models investigated the effect of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on CA1-to-region FC.</p><p><strong>Results: </strong>In the placebo condition, CHR-P individuals showed significantly lower CA1-vmPFC (<i>Z</i> = 3.17, <i>P</i><sub>FWE</sub> = 0.002) and CA1-NAc (<i>Z</i> = 2.94, <i>P</i><sub>FWE</sub> = 0.005) FC compared to HC. In the diazepam condition, CA1-vmPFC FC was significantly increased (<i>Z</i> = 4.13, <i>P</i><sub>FWE</sub> = 0.008) compared to placebo in CHR-P individuals, and both CA1-vmPFC and CA1-NAc FC were normalised to HC levels. In contrast, compared to HC, CA1-amygdala FC was significantly lower contralaterally and higher ipsilaterally in CHR-P individuals in both the placebo and diazepam conditions (lower: placebo <i>Z</i> = 3.46, <i>P</i><sub>FWE</sub> = 0.002, diazepam <i>Z</i> = 3.33, <i>P</i><sub>FWE</sub> = 0.003; higher: placebo <i>Z</i> = 4.48, <i>P</i><sub>FWE</sub> < 0.001, diazepam <i>Z</i> = 4.22, <i>P</i><sub>FWE</sub> < 0.001).</p><p><strong>Conclusions: </strong>This study demonstrates that diazepam can partially restore hippocampal CA1 dysconnectivity in CHR-P individuals, suggesting that modulation of GABAergic function might be useful in the treatment of this clinical group.</p>\",\"PeriodicalId\":20891,\"journal\":{\"name\":\"Psychological Medicine\",\"volume\":\"55 \",\"pages\":\"e230\"},\"PeriodicalIF\":5.5000,\"publicationDate\":\"2025-08-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12360692/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Psychological Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1017/S0033291725101268\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PSYCHIATRY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Psychological Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1017/S0033291725101268","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PSYCHIATRY","Score":null,"Total":0}
Diazepam modulates hippocampal CA1 functional connectivity in people at clinical high-risk for psychosis.
Background: Preclinical evidence suggests that diazepam enhances hippocampal γ-aminobutyric acid (GABA) signalling and normalises a psychosis-relevant cortico-limbic-striatal circuit. Hippocampal network dysconnectivity, particularly from the CA1 subfield, is evident in people at clinical high-risk for psychosis (CHR-P), representing a potential treatment target. This study aimed to forward-translate this preclinical evidence.
Methods: In this randomised, double-blind, placebo-controlled study, 18 CHR-P individuals underwent resting-state functional magnetic resonance imaging twice, once following a 5 mg dose of diazepam and once following a placebo. They were compared to 20 healthy controls (HC) who did not receive diazepam/placebo. Functional connectivity (FC) between the hippocampal CA1 subfield and the nucleus accumbens (NAc), amygdala, and ventromedial prefrontal cortex (vmPFC) was calculated. Mixed-effects models investigated the effect of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on CA1-to-region FC.
Results: In the placebo condition, CHR-P individuals showed significantly lower CA1-vmPFC (Z = 3.17, PFWE = 0.002) and CA1-NAc (Z = 2.94, PFWE = 0.005) FC compared to HC. In the diazepam condition, CA1-vmPFC FC was significantly increased (Z = 4.13, PFWE = 0.008) compared to placebo in CHR-P individuals, and both CA1-vmPFC and CA1-NAc FC were normalised to HC levels. In contrast, compared to HC, CA1-amygdala FC was significantly lower contralaterally and higher ipsilaterally in CHR-P individuals in both the placebo and diazepam conditions (lower: placebo Z = 3.46, PFWE = 0.002, diazepam Z = 3.33, PFWE = 0.003; higher: placebo Z = 4.48, PFWE < 0.001, diazepam Z = 4.22, PFWE < 0.001).
Conclusions: This study demonstrates that diazepam can partially restore hippocampal CA1 dysconnectivity in CHR-P individuals, suggesting that modulation of GABAergic function might be useful in the treatment of this clinical group.
期刊介绍：
Now in its fifth decade of publication, Psychological Medicine is a leading international journal in the fields of psychiatry, related aspects of psychology and basic sciences. From 2014, there are 16 issues a year, each featuring original articles reporting key research being undertaken worldwide, together with shorter editorials by distinguished scholars and an important book review section. The journal''s success is clearly demonstrated by a consistently high impact factor.
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