{"paper_id":"c26511ae-76d3-4bcf-ab81-1628fcf0490e","body_text":"Diazepam modulates hippocampal CA1 func6onal connec6vity in \npeople at clinical high-risk for psychosis \n \nNicholas R. Livingston, MSc1*; Amanda Kiemes, PhD1; Owen O’Daly, PhD2; Samuel R. Knight, \nMSc1; Paulina B. Lukow, PhD3; Luke A. Jelen, PhD1; Thomas J. Reilly, MD4,5; Aikaterini Dima, \nMD5,6; Maria AntonieFa NeGs, PhD 5,6; Cecilia CaseFa, MD 5,6; Gabriel A. Devenyi, PhD7,8; \nThomas Spencer, PhD5,9; Andrea De Micheli, PhD10,9; Paolo Fusar-Poli, PhD10,11,9,; Anthony A. \nGrace, PhD12; Steve C.R. Williams, PhD2; Philip McGuire, PhD4; M. Mallar Chakravarty, PhD7,8; \nAlice Egerton, PhD5; Gemma Modinos, PhD1,13 \n \n1Department of Psychological Medicine, Institute of Psychiatry, Psychology, and Neuroscience, King’s College \nLondon, UK \n2Department of Neuroimaging, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, \nUK  \n3Institute of Cognitive Neuroscience, University College London, UK \n4Department of Psychiatry, University of Oxford, UK \n5Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King’s College \nLondon, UK  \n6South London and Maudsley National Health Service Foundation Trust, London, UK \n7Department of Psychiatry, McGill University, Montreal, QC, Canada \n8Cerebral Imaging Centre, Douglas Mental Health University Institute, Montreal, QC, Canada \n9Outreach and Support in South-London (OASIS) service, South London and Maudsley National Health Service \nFoundation Trust, London, UK \n10Early Psychosis: IntervenOons and Clinical-detecOon (EPIC) Lab, Department of Psychosis Studies, InsOtute of \nPsychiatry, Psychology & Neuroscience, King's College London, London, UK \n11Department of Brain and Behavioural Sciences, University of Pavia, Italy \n12Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA, USA \n13MRC Centre for Neurodevelopmental Disorders, King’s College London, UK \n \n* Corresponding author: \n Nicholas.livingston@kcl.ac.uk \nShort/running Ttle: Diazepam and CA1 dysconnecTvity in psychosis risk \nKeywords: schizophrenia; benzodiazepine; neuroimaging; pharmacological MRI; resTng-\nstate; early intervenTon \n \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 21, 2024. ; https://doi.org/10.1101/2024.12.20.24319330doi: medRxiv preprint \nNOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.\n\nAbstract \n \nBackground: Preclinical evidence suggests that diazepam enhances hippocampal γ-\naminobutyric acid (GABA) signalling and normalises a psychosis -relevant corTco -limbic-\nstriatal circuit. Hippocampal network dysconnecTvity, parTcularly from the CA1 subfield,  is \nevident in people at clinical high-risk for psychosis (CHR-P), represenTng a potenTal treatment \ntarget. This study aimed to forward-translate this preclinical evidence. \nMethods: In this randomised, double-blind, placebo-controlled study, 18 CHR-P individuals \nunderwent resTng-state funcTonal magneTc resonance imaging twice, once following a 5mg \ndose of diazepam and once following a placebo. They were compared to 20 healthy controls \n(HC) who did not receive diazepam/placebo . FuncTonal connecTvity (FC) between the \nhippocampal CA1 subfield  and the nucleus accumbens (NAc), amygdala, and ventromedial \nprefrontal cortex (vmPFC) was calculated . Mixed-effects models invesTgated the effect of \ngroup (CHR-P placebo/diazepam vs. HC) and condiTon (CHR-P diazepam vs. placebo) on CA1-\nto-region FC.  \nResults: In the placebo condiTon, CHR-P individuals showed significantly lower CA1-vmPFC \n(Z=3.17, PFWE=0.002) and CA1-NAc (Z=2.94, PFWE=0.005) FC compared to HC. In the diazepam \ncompared to placebo condiTon , CA1 -vmPFC FC was significantly increased  (Z=4.13, \nPFWE=0.008) in CHR-P individuals, and both CA1 -vmPFC and CA1-NAc FC w ere normalised to \nHC levels. In contrast, compared to HC, CA1-amygdala FC was significantly lower \ncontralaterally and higher ipsilaterally in CHR-P individuals in both the placebo and diazepam \ncondiTons (lower: placebo Z=3.46, PFWE=0.002, diazepam Z=3.33, PFWE=0.003; higher: placebo \nZ=4.48, PFWE<0.001, diazepam Z=4.22, PFWE<0.001).  \nConclusions: This study demonstrates that diazepam can parTally restore hippocampal CA1 \ndysconnecTvity in CHR-P individuals, suggesTng that modulaTon of GABAergic funcTon might \nbe useful in the treatment of this clinical group. \n \n \n \n \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 21, 2024. ; https://doi.org/10.1101/2024.12.20.24319330doi: medRxiv preprint \n\nIntroduc6on \nIdenTfying novel pharmacological intervenTons to reduce symptom severity  and prevent \ntransiTon to psychosis in individuals at clinical high -risk for psychosis (CHR-P) is a significant \nunmet clinical need1,2. Current neurobiological theories of psychosis development idenTfy the \nhippocampus as a central hub  of pathophysiology47,59,107 and a promising pharmacological \ntarget6. Several neuroimaging studies in individuals at CHR -P have idenTfied increased \nhippocampal cerebral blood flow/volume compared to healthy controls (HC) 3–5. The cornu \nammonis 1 (CA1) subfield is proposed to be the origin of hippocampal dysfuncTon in the CHR-\nP state, in terms of volume loss 7 and hyperacTvity8,9, which then spreads to the subiculum \nfollowing psychosis onset 9. The CA1 and subiculum have  a high number of glutamatergic \nefferent projecTons 10, and  anterior projecTons innervate a corTco -limbic-striatal circuit \nencompassing the nucleus accumbens (NAc) of the striatum, amygdala, and the ventromedial \nprefrontal cortex (vmPFC)11. These regions are highly interconnected11–19 and are associated \nwith posiTve, negaTve, and cogniTve symptoms of schizophrenia, respecTvely20–22. Therefore, \nhippocampal dysfuncTon preceding the onset of psychosis may disrupt downstream corTco-\nlimbic-striatal regions, contribuTng to circuit dysfuncTon and the emergence of psychosis11.  \n \nCircuit dysfuncTon can be invesTgated in terms of the funcTonal connecTvity (FC) between \nbrain regions measured using resTng-state funcTonal magneTc resonance imaging (rs-fMRI)23. \nrs-fMRI studies have idenTfied altered hippocampal FC with the corTco -limbic-striatal circuit \nin individuals with a first episode of psychosis or chronic schizophrenia compared to HC. More \nspecifically, these studies reported lower hippocampal FC with the striatum 24–30 and \nvmPFC24,26,28,29,29,31–40, and either lower 38,41, higher42, or unaltered42 hippocampal FC to the \namygdala. The paFern is  less clear  in subclinical psychosis spectrum individuals  (although \nthere are far fewer studies) : lower hippocampal -striatal FC has been shown in healthy \nindividuals with high schizotypy traits 43,44, while both lower 25,34 and normal 33,45,46 \nhippocampal-striatal and hippocampal -PFC FC ha ve been observed in individuals at CHR -P \ncompared to HC. To our knowledge , no studies in CHR -P individuals have invesTgated \nhippocampal-amygdala FC, or FC  alteraTons from specific hippocampal subfields  to the \ncorTco-limbic-striatal circuit. Given that hippocampal dysfuncTon may be localised to the CA1 \nsubfield in the CHR -P stage 8, alteraTons in FC may may not be present  across the whole \nhippocampus.  \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 21, 2024. ; https://doi.org/10.1101/2024.12.20.24319330doi: medRxiv preprint \n\nGABAergic dysfuncTon has been proposed as a key  mechanism underlying hippocampal \nhyperacTvity in psychosis47. Studies in rats exposed to the mitotoxin  methylazoxymethanol \nacetate (MAM) during neurodevelopment showed that reduced PV+ interneuron number in \nthe hippocampus was associated with an increased firing rate of local excitatory neurons and \nexcitatory/inhibitory imbalance48. This hyperacTvity is found to drive funcTonal alteraTons of \ndownstream regions  in MAM -treated rats, evidenced by experiments where  chemical48 or \npharmacological inacTvaTon of the hippocampus  (with a nonspecific GABA A-enhancing \nbenzodiazepine49 or an α5-GABAA specific compound49,50) normalised midbrain dopaminergic \nneuron firing. Furthermore, this mechanism is proposed to underlie the findings that repeated \nperipubertal diazepam administraTon in MAM -treated rats  prevented the emergence of \nschizophrenia-related neurophysiological and behavioural phenotypes in adulthood . Such \nphenotypes included prevenTon of midbrain dopamine hyperacTvity and hyperlocomoTon \nresponse to amphetamine (posiTve symptoms), amygdala hyperacTvity (negaTve symptoms), \nand PFC dysfuncTon (cogniTve symptoms)51–53.  \n \nThis preclinical evidence suggests that GABA-enhancing compounds  may be an effecTve \nstrategy for psychosis prevenTon by downregulaTng hippocampal hyperacTvity and \nnormalising downstream circuit dysfuncTon. In healthy individuals, prior rs-fMRI studies using \nan acute, non -sedaTng dose of a GABA -enhancing compound report increases in FC under \nbenzodiazepine (or other GABA -enhancing drugs e.g., Z -drugs such as zopiclone/zolpidem ) \ncompared to placebo  across the hippocampal-amygdala-PFC circuit 54, the default mode \nnetwork55,56, and a wider brain network including visual, auditory, sensorimotor , and \nprefrontal regions57. In CHR -P individuals, w e recently demonstrated that an acute, non -\nsedaTng dose of diazepam normalised elevated hippocampal and subfield cerebral blood flow \ntowards levels seen in healthy controls 58. However, whether this is  accompanied by a \nnormalisaTon of the FC between the hippocampus and downstream corTco -limbic-striatal \nregions was not known .  \n \nTherefore, the current study examined the effects of an acute dose of diazepam vs. placebo \non FC between the hippocampus and this corTco -limbic-striatal circuit in the same cohort of \nCHR-P individuals58. Each condiTon was also compared to  HC data  collected on the same \nscanner. We focussed on the CA1 subfield as a seed, g iven its proposed role in psychosis \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 21, 2024. ; https://doi.org/10.1101/2024.12.20.24319330doi: medRxiv preprint \n\ndevelopment59 and the substanTal number of anatomical connecTons to output regions of \ninterest (NAc, amygdala, and vmPFC60,61). On the basis of previous findings in hippocampal FC \nacross the psychosis spectrum 16–26,29–32,34–36,41,43, we hypothesised that individuals at CHR -P \n(in the placebo condiTon) would display lower CA1-NAc and CA1-vmPFC FC and altered CA1-\namygdala FC compared to HC . Based on prior benzodiazepine challenge rs -fMRI studies in \nhealthy individuals50–53, we hypothesise d that a single dose of diazepam would increase CA1 \nFC within this circuit, to the extent that it would no longer differ  from HC. For completeness, \nthe following supplementary analyses were included : i) using the anterior hippocampus as a \nseed (given it is specifically the anterior porTon of the CA1 implicated  in psychosis \ndevelopment8,9) and ii) exploring broader effects of diazepam on CA1/anterior hippocampus \nFC with the rest of the brain. \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 21, 2024. ; https://doi.org/10.1101/2024.12.20.24319330doi: medRxiv preprint \n\nMethods  and Materials  \nStudy design, par0cipants, and procedure \nThis experimental medicine study was conducted at King’s College London. The study received \nethical approval from the NaTonal Health Service UK Research Ethics CommiFee \n(18/LO/0618), and each parTcipant gave wriFen informed consent. While the study received \nethical clearance as ‘not a Clinical Trial of an InvesTgaTonal Medicinal Product’ by the EU \ndirecTve 2001/20/EC, it was registered on clinicaltrials.gov (NCT06190483). Full study details, \nincluding inclusion/exclusion criteria, can be found  in our recent publicaTon describing the \nhippocampal cerebral blood flow findings in the same parTcipants58. Briefly, this study used a \nrandomised, double-blind, placebo-controlled, crossover design, whereby 24 anTpsychoTc -\nnaïve individuals at CHR-P underwent MRI scanning on two occasions, once following a single \noral dose of diazepam (5mg) and once following an oral  placebo (50mg ascorbic acid). The \ndiazepam/placebo capsule was administered 60 minutes before MRI scanning, and there was \na minimum 3-week washout period between scans. Data from a group of 22 HC from a prior \nstudy (PSYAUD17/25) acquired with the same MRI scanner, scanning sequences, and \nacquisiTon parameters were used as a comparison group65.  \n \nMRI acquisi0on \nMRI data were acquired on a General Electric MR750 3.0T MR scanner with an 8-channel head \ncoil at the Centre for Neuroimaging Sciences, KCL. A 3D T1-weighted scan was acquired using \na SPGR sequence and rs-fMRI data was acquired using a mulT -echo echo planar imaging \nsequence (full acquisiTon details in Supplementary Methods) . During the rs -fMRI scan, \nparTcipants were instructed to remain awake with their eyes open , while a fixaTon cross was \ndisplayed in the centre of the screen. \n \nNeuroimaging data processing \nPreprocessing \nThe structural and rs -fMRI data were preprocessed using fMRIPrep (version 23. 1.3)66, \nSPM1267, CONN 68, and FSL 69. Structural images from both sessions were corrected for \nintensity non-uniformity using N4, skull-stripped, segmented, and averaged across sessions to \ngenerate a singular parTcipant structural image which was then normalised to MNI space \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 21, 2024. ; https://doi.org/10.1101/2024.12.20.24319330doi: medRxiv preprint \n\n(1mm3 resoluTon)66. For the rs -fMRI data, volume re -alignment and slice -Tming correcTon \nparameters were calculated using the first echo and applied to all echoes66. ParTcipants were \nexcluded if they moved >3mm on any translaTon/rotaTon parameter or had a mean \nframewise displacement of >0.5mm, as advised by prior methodological invesTgaTons70. The \nthree echoes in naTve space underwent TE -dependent ICA -based denoising and were \nopTmally-combined using T2* weighted averaging via TEDANA71, before being normalised to \nMNI space (2mm 3 resoluTon) with transformaTons generated during fMRIPrep  (see \nsupplementary materials for full boiler plate) 66. The denoised, opTmally combined , \nnormalised funcTonal data was then spaTally smoothed in SPM 1267 with a 6mm FWHM \nGaussian kernel, and further denoised by removing white maFer and CSF signal using the first \n5 components of aCompCor, despiking, scrubbing, and band -pass filtering (0.008-0.09 Hz) in \nCONN68.  \n \nGenera/on of seed and region -of-interest masks \nHippocampal and subfield seed masks were generated for each parTcipant from their \npreprocessed structural scan collected during their first scanning visit using the MAGeT Brain \n(mulTple automaTcally generated templates of different brains)  toolbox72 (see previous \npublicaTon for further details58). Using all parTcipants’ CA1 segmentaTons, study-specific lew \nand right CA1 masks were generated by using majority vote (ANTs/2.5.0; Figure 1). ROI masks \nfor the corTco -limbic-striatal circuit  (NAc, amygdala, and vmPFC) were derived from \nNeurosynth ( hFps://www.neurosynth.org/ ) using the search terms ‘nucleus accumbens’, \n‘amygdala’, and ‘vmPFC’ (uniformity tests). The resulTng images were thresholded, binarised, \nand dilated (MINC toolkit; hFps://bic -mni.github.io/).  \n   \nNeuroimaging data analysis \nTo control for the number of models , FDR correcTon was performed  on all FWE-corrected \nsecond-level analyses described below.  \nFirst- and second-level analysis \nTo generate parTcipant -level seed -to-voxel Z-maps, the mean funcTonal Tme series was \nextracted from the lew and right  CA1 and used in first-level analysis models as regressors of \ninterest in FSL. These first -level seed-to-voxel Z-maps were then entered into second -level \nanalysis models using FLAME -1 (FMRIB’s Local Analysis of Mixed Effects) 69, which employs \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 21, 2024. ; https://doi.org/10.1101/2024.12.20.24319330doi: medRxiv preprint \n\nBayesian modelling and a weighted least -squares approach to perform  a mixed-effects \nanalysis. FLAME-1 was chosen as mixed-effects modelling is opTmal for within-subject designs \n(i.e., CHR-P diazepam vs. placebo) to account for within -subject correlaTons, and FLAME-1 is \nable to esTmate different variances for different groups of subjects within a model, which is \nadvantageous for unpaired two -sample comparison (i.e., CHR -P vs. HC) 73. All models below \nuse an FWE-corrected (P<0.05) threshold of Z>2.3. This threshold with FLAME -1 models has \nbeen shown to produce  FWE rates lower than 5% , and is therefore similar to tradiTonal FSL \nordinary least square analyses using a threshold of Z>3.174. \n \nWithin-group CA1 res/ng -state FC analyses \nBefore comparing differences between groups/condiTons, we first validated within -group \nresTng-state FC networks for the CA1 to the whole brain to ensure they matched expected \nnetworks (one-sample contrast for each group independently)75.  \n \nGroup and condi/on s eed-to-ROI analyses \nTo invesTgate the effect of group (CHR -P placebo/diazepam vs. HC) and condiTon (CHR -P \ndiazepam vs. placebo) on FC differences between CA1 and corTco -limbic-striatal circuit \nregions, we conducted seed -to-ROI analysis. Second-level models were run per seed -to-ROI \nper hemisphere for each group/condiTon comparison using a small volume adjustment \napproach by applying a pre-threshold ROI mask  generated from Neurosynth as described \nabove. Models were run both contralaterally (e.g., lew CA1 to the right amygdala) and \nipsilaterally (e.g., lew CA1 to the lew amygdala), as disrupTons to both have been found across \nthe psychosis spectrum  within this circuit 76. Voxel-level thresholding was used ( Z>2.3) for \ninference, which was FWE-corrected (P<0.05) for mulTple comparisons. Again, this threshold \nhas been demonstrated to be quite conservaTve when using voxel-level inference in FLAME-\n1 models74. For CHR-P placebo/diazepam vs. HC models, age (mean centred) and sex were \nadded in as covariates of no interest. For CHR-P diazepam vs. placebo, change in pre-post scan \nfaTgue score from the Bodily Symptoms Scale77 for each condiTon was included as a covariate \nof no interest to control for drug effects of sedaTon/faTgue.  \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 21, 2024. ; https://doi.org/10.1101/2024.12.20.24319330doi: medRxiv preprint \n\n \nSupplementary / exploratory analyses \nFor completeness, supplementary analyses  explored the effect of group/condiTon on FC \nbetween 1) anterior hippocampus and the corTco-limbic-striatal circuit (seed-to-ROI), and 2) \nhippocampal seeds (CA1 and anterior hippocampus) and the rest of the brain on a voxel-wise \nbasis. Anterior hippocampal masks were generated by masking the study -specific averaged \nwhole hippocampus segmentaTon with a hippocampus head mask derived from the Allen \nhuman reference atlas 78, then thresholded, binarized, and dilated . IdenTcal second -level \nmodels were run as described above , and for the seed -to-voxel analyses an inclusive grey \nmaFer mask was used during the pre-threshold masking.  \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 21, 2024. ; https://doi.org/10.1101/2024.12.20.24319330doi: medRxiv preprint \n\nResults \nDemographics and Clinical Assessments \nFollowing data quality checks, 6 CHR-P parTcipants were excluded (n=2 missing rs-fMRI data, \nn=1 poor data quality, n=3 excessive moTon), along with 2 HC parTcipants (n=1 missing rs -\nfMRI data, n=1 poor data quality) . This resulted in a final sample of 18 CHR -P and 20 HC  for \nanalyses. ParTcipant details can be found in Table 1.  \n \n \n \n \n CHR-P \n(n = 18)  \nHC \n(n = 20) \nComparison t/χ2 p \nDemographic \nAge (years; mean ±SD) 24.1 ±4.6 26.5 ±5.1 CHR-P vs. HC 1.5 0.136 \nSex (male/female; n) 5/13 9/11 CHR-P vs. HC 1.2 0.272 \nEthnicity (n) CHR-P vs. HC 11.2 0.024 \n Asian 1 6 - - - \n Black  4 0 - - - \n Mixed or multiple 2 0 - - - \n Other 1 0 - - - \n White 10 14 - - - \nIQ (WAIS-III short version81; mean ±SD) 96.0 ±22.1 122.9 ±13.9 CHR-P vs. HC 4.4 <0.001 \nCurrent daily cigarette use, n (%)  4 (22) 2 (10) CHR-P vs. HC 1.1 0.302 \nCurrent alcohol use, n (%) 14 (77) 18 (90) CHR-P vs. HC 1.1 0.302 \nCurrent cannabis use, n (%)  5 (28) 3 (15) CHR-P vs. HC 1.8 0.181 \nClinical characteristics \nCAARMS83 score (mean ±SD) \n Positive symptoms 47.5 ±12.9 NA - - - \n Negative symptoms (n=21) 29.5 ±25.3 NA - - - \n Total (n=21) 77.9 ±28.2 NA - - - \nGlobal functioning score 85 (mean ±SD) \n Social 6.3 ±1.5 NA - - - \n Role 6.1 ±1.7 NA - - - \nHamilton scale score (mean ±SD) \n Anxiety87 (n=22) 17.6 ±9.3 NA - - - \n Depression89 (n=21) 13.5 ±6.9 NA - - - \nCurrent antidepressant medication, n (%)  7 (38) NA - - - \nCurrent or prior antipsychotic medication, n (%)  0 (0) NA - - - \nCurrent benzodiazepine/hypnotic medication, n (%)  0 (0) NA - - - \nHead motion \nFractional displacement in mm (mean ±SD) \n Total group 0.148 ±0.08 0.146 ±0.07 CHR-P vs. HC 0.05 0.957 \n Placebo condition 0.156 ±0.10 - CHR-P placebo vs. HC 0.36 0.724 \n Diazepam condition 0.139 ±0.07 - CHR-P diazepam vs. HC -0.35 0.722 \n  - - CHR-P diazepam vs. placebo 0.62 0.544 \nBodily Symptoms Scale \nFatigue scores post-scan (mean ±SD) \n Placebo condition 0.944 ±0.93 - CHR-P diazepam vs. placebo 1.51 0.148 \n Diazepam condition 1.38 ±1.58 - - - - \nTable 1. Par;cipant demographic informa;on, clinical characteris;cs, head mo;on parameters \nand fa;gue scores  \nCAARMS: comprehensive assessment of at -risk mental states; CHR -P: clinical high -risk for psychosis; HC: healthy \ncontrol; IQ: intelligent quoBent; WAIS: Weschler adult intelligence scale  \n \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 21, 2024. ; https://doi.org/10.1101/2024.12.20.24319330doi: medRxiv preprint \n\nCHR-P individuals had a significantly lower IQ (as is owen observed in this clinical populaTon79) \nand differed in terms of ethnicity  compared to the HC group (which was driven by a  high \nproporTon of white ethnicity in the HC group ). There were no significant differences in head \nmoTon parameters or change between pre - and post-scan Bodily Symptom Scale 77 scores \nbetween the placebo and diazepam condiTons. \n \nRes0ng-State Func0onal Connec0vity \nWithin-group CA1 res/ng -state FC \nWithin each group/condiTon, as expected75, the CA1 showed  significant FC with the rest of \nthe hippocampus, extending to the temporal lobe, amygdala, precuneus, posterior cingulate \ncortex, mPFC, and parieto-occipital regions (Z>2.3, PFWE<0.05; Figure 1). \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n CA1-to-voxel funcOonal connecOvity networks averaged across each group \nindependently (healthy controls, CHR-P placebo, and CHR-P diazepam) for the leX and \nright CA1 subfield using study-specific mask (Z > 2.3, PFWE < 0.05). \nCHR-P: clinical high-risk for psychosis \n \nFigure 1. Within-group CA1-to-voxel func8onal connec8vity \nnetworks  \nCHR-P \nplacebo\nCHR-P \ndiazepam\nRight\nLeft\nCA1\nCHR-P \nplacebo\nCHR-P \ndiazepam\nHealthy \ncontrols\nHealthy \ncontrols\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 21, 2024. ; https://doi.org/10.1101/2024.12.20.24319330doi: medRxiv preprint \n\nCA1-to-ROI \nCompared to HC, individuals at CHR-P in the placebo condiTon showed significantly lower FC \nbetween the lew CA1 and the right NAc (Figure 2A, Table 2), and between the right CA1 and \nthe lew NAc, lew amygdala, and lew vmPFC (Figure 2B, Table 2).  \n  \nFigure 2. Region-of-interest func8onal connec8vity results for the CA1 \nLeft CA1\nA\nRight CA1\nB\nParameter esOmates of funcOonal connecOvity strength between leX (A) and right (B) CA1 and \noutput regions (nucleus accumbens, amygdala, and ventromedial prefrontal cortex) displayed for \nhealthy controls and individuals at clinical high -risk for psychosis (in the placebo and diazepam \ncondiOons) at peak coordinate of significant effect of group/condiOon (Z > 2.3, PFWE < 0.05). CA1 \n(green), amygdala (red), nucleus accumbens (yellow), and vmPFC (purple) are visualised on the \nbrain using masks. \nCHR-P clinical high -risk for psychosis; Amy: amygdala; NAc: nucleus accumbens; vmPFC: \nventromedial prefrontal cortex; *** < 0.001; * < 0.05, ns not significant \n \nLeft CA1\nA\nRight CA1\nB\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 21, 2024. ; https://doi.org/10.1101/2024.12.20.24319330doi: medRxiv preprint \n\nAddiTonally, the right CA1 showed higher FC to the right amygdala (Figure 2B, Table 2). In the \ndiazepam condiTon, these differences observed in the placebo condiTon compared to  HC \nwere ameliorated  (no significant difference) , apart from the right CA1 to lew and right \namygdala, which sTll showed significantly lower and higher FC compared to HC, respecTvely \n(Figure 2B, Table 2). We observed a significant drug effect on CA1-vmPFC FC, where diazepam \n(compared to placebo) significantly increased the FC strength from the lew CA1 to lew vmPFC \nand right CA1 to bilateral vmPFC (Figure 2, Table 2).  \n \n \n \n \n \nSupplementary / exploratory analyses \nAt the whole -brain level, compared to HC, individuals at CHR -P in the placebo condiTon  \nshowed significantly higher FC between the right CA1 and a right medial temporal network \nincluding the hippocampus, insula, and inferior/medial temporal gyri (Figure 3A, \nSupplementary Table 1). Conversely, lower FC was observed between the right CA1 and a lew \nmedial temporal network that extended to include key regions of the default mode network \n(bilateral mPFC, anterior cingulate cortex , and posterior cingulate cortex) . In the diazepam \ncondiTon, higher FC between right CA1 and a right medial temporal lobe network was also \nContrast Seed  ROI Peak Z x y z pFDR \nvalue \n# \nvoxels \nCHR-P placebo > HC  \n Right CA1 Right amygdala 4.48 30 -8 20 <0.001 93 \nCHR-P diazepam > HC \n Right CA1 Right amygdala 4.22 28 -8 -22 <0.001 129 \nHC > CHR-P placebo \n Right CA1 Left amygdala 3.46 -20 -6 -24 <0.001 42 \nLeft NAc 2.94 -14 10 -8 0.004 78 \nLeft vmPFC 3.17 -8 48 -2 0.002 135 \n Left CA1 Right NAc 2.57 16 12 -4 0.011 12 \nHC > CHR-P diazepam \n Right CA1 Left amygdala 3.33 -20 -6 -22 0.002 44 \nCHR-P diazepam > placebo \n Right CA1 Right vmPFC 4.42 10 46 -6 <0.001 79 \nLeft vmPFC 3.25 -10 48 0 0.002 3 \n Left CA1 Left vmPFC 3.20 -4 38 -12 0.002 8 \nCHR-P: clinical high-risk for psychosis; FDR: false discovery rate; HC: healthy control; NAc: nucleus accumbens; \nvmPFC: ventromedial prefrontal cortex  \n \nTable 2. Summary sta;s;cs of region-of-interest func;onal connec;vity results for the CA1   \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 21, 2024. ; https://doi.org/10.1101/2024.12.20.24319330doi: medRxiv preprint \n\nFigure 3. Voxel-wise whole-brain func8onal connec8vity results for the CA1 \nSignificant clusters showing differences (Z > 2.3, PFWE < 0.05) in funcOonal connecOvity between healthy \ncontrols and CHR -P placebo (A) and CHR -P diazepam (B) for the CA1. Areas showing funcOonal \nhyperconnecOvity (CHR-P placebo/diazepam > HC) are displayed in red colourbar, whilst areas displaying \nfuncOonal hypoconnecOvity are displayed in blue. N.B., no significant differences were found for the \nanterior hippocampus, nor for any of the regions (CA1 or anterior hippocampus) when contrasOng CHR-P \ndiazepam vs. CHR-P placebo.  \nCHR-P clinical high-risk for psychosis; HC healthy controls \nobserved compared to HC, and addiTonally extended to parieto-occipital regions such as the \nangular gyrus  (Figure 3B, Supplementary Table 1 ). When comparing CHR -P diazepam vs. \nplacebo condiTons directly, no significant differences in whole -brain FC were observed for \neither the right or lew CA1. Finally, there were no significant differences between groups (CHR-\nP placebo/diazepam vs. HC) or condiTons (CHR -P diazepam vs. placebo) in FC strength using \nthe anterior hippocampus as a seed on a ROI or whole-brain level. \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 21, 2024. ; https://doi.org/10.1101/2024.12.20.24319330doi: medRxiv preprint \n\nDiscussion  \nThe main finding of the current study was that a single, non -sedaTng dose of the GABA -\nenhancing drug diazepam parTally normalised CA1 dysconnecTvity to a corTco-limbic-striatal \ncircuit in individuals at CHR-P. More specifically, CHR-P individuals in the placebo condiTon  \n(compared to HC) showed lower CA1-vmPFC and CA1 -NAc FC. Diazepam significantly \nincreased CA1-vmPFC FC compared to placebo , and the lower CA1-vmPFC and CA1-NAc FC \nobserved in the placebo condiTon  was normalised  to HC levels. We observed more complex \nresults for CA1-amygdala FC, as CHR-P individuals in the placebo condiTon showed lower and \nhigher FC compared to HC, which were sTll present in the diazepam condiTon. Previously, we \ndemonstrated that diazepam normalised increased hippocampal and subfield regional \ncerebral blood flow in the same CHR-P individuals, and here we extend this work by showing \nthat diazepam can also parTally normalise CA1 dysconnecTvity to a downstream circuit. Taken \ntogether, these results indicate that GABA-enhancing compounds can rescue brain funcTon in \na psychosis -relevant circuit in CHR -P individuals , and therefore show promise as a novel \ntreatment strategy for clinical intervenTon in this group.  \n \nOur finding of lower CA1-vmPFC and CA1-NAc FC contralaterally (but normal FC ipsilaterally) \nin CHR-P individuals in the placebo condiTon (vs. HC) is consistent with prior rs -fMRI reports \nof subtle dysconnecTvity in sub-clinical psychosis populaTons25,33,34,41,43–46. In contrast, studies \nin first-episode and chronic schizophrenia samples consistently report lower FC between these \nregions24–28,28–40. This may suggest that in psychosis vulnerability stages , as hippocampal \nhyperacTvity begins to drive glutamatergic input to the corTco -limbic-striatal circuit11,20,21, \nthere is preserved temporal coherence (i.e., FC) between the hippocampus and these regions. \nAs CHR-P symptoms persist, hippocampal hyperacTvity and dysrhythmia may lead to \nuncoupling between the hippocampus and downstream circuitry, which may further \ndeteriorate following the onset of psychosis. For example, experiments in MAM-treated rats \ndemonstrated that NAc hyperacTvity  due to  hippocampal dysfuncTon , drives a striatal -\nmidbrain circuit loop48 which increases phasic dopamine efflux in the NAc itself80. Importantly, \nthis increase in phasic dopamine can potenTate the hippocampal drive on the NAc 82, which \nmay result in reduced hippocampal -NAc FC. This inverse relaTonship of hippocampal \nhyperacTvity and reduced hippocampal-striatal FC has been observed previously in individuals \nat CHR-P , as higher hippocampal glutamate levels (indicaTve of hyperacTvity) was associated \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 21, 2024. ; https://doi.org/10.1101/2024.12.20.24319330doi: medRxiv preprint \n\nwith reduced hippocampal-striatal FC45. In accordance with this, reduced CA1-NAc FC was the \nmost robust finding in our sample of individuals at CHR -P (i.e., it was observed bilaterally in \nthe CA1), in whom we have previously demonstrated hippocampal hyperacTvity 58. Beyond \nillness chronicity, the more pronounced reducTons observed in hippocampal FC in individuals \nwith psychoTc disorders  compared to those at CHR -P might be related to anTpsychoTc \ntreatment. For instance, we observed reducTons in right, but not lew, CA1-vmPFC FC in our \nsample of anTpsychoTc-naïve individuals at CHR-P compared to the more robust observaTons \nin anTpsychoTc-treated individuals with schizophrenia 26,28,31–35. Whilst cogniTve symptoms \nwhich are present in the prodrome may worsen following the onset of psychosis84,86,88, chronic \nanTpsychoTc treatment may also play a role in further cogniTve impairment related to \nhippocampal-PFC FC uncoupling90,91.  \n \nWe found both higher and lower CA1-amygdala FC in individuals at CHR -P in the placebo \ncondiTon compared to HC. Prior rs -fMRI studies have found lower 38,41 and normal 42 \nhippocampal-amygdala FC in individuals with psychoTc disorders. However, hippocampal -\namygdala FC was increased in people with schizophrenia with paranoia vs. no paranoia42, and \nhigher hippocampal-amygdala-PFC FC was associated with higher fear/anxiety in individuals \nwith early psychosis92. Whilst amygdala dysfuncTon is associated with negaTve symptoms of \nschizophrenia21, it is also implicated in clinically disTnct comorbid anxiety /mood disorders, \nwhich are more common in those at CHR -P93,94. This increased affecTve component might \nexplain the higher hippocampal-amygdala FC observed in our sample of individuals at CHR -P \ncompared to HC. Furthermore, the findings in our study appeared hemisphere dependent \n(i.e., the right CA1 showed increased FC to the right amygdala and decreased FC to the lew \namygdala). This was also observed at the whole -brain level, whereby the right CA1 showed \nhyperconnecTvity with a right medial temporal network, including the amygdala, but \nhypoconnecTvity with a lew hippocampal network and frontal regions of the lew default mode \nnetwork. Increased hippocampal FC with the medial temporal lobe  has been observed \npreviously in the psychosis spectrum26,95,96, and could therefore be driving hyperconnecTvity \nto the amygdala given the close proximity and number of bidirecTonal connecTons 97. \nFurthermore, this paFern of intra -hemispheric hyperconnecTvity and inter -hemispheric \nhypoconnecTvity has been found previously in individuals with psychoTc disorders, indicaTng \nincreased local network segregaTon and decreased remote network integraTon98.  \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 21, 2024. ; https://doi.org/10.1101/2024.12.20.24319330doi: medRxiv preprint \n\nThe main effect of diazepam vs. placebo in CHR-P individuals on CA1 FC to the corTco-limbic-\nstriatal network was a bilateral increase in CA1-vmPFC FC. Furthermore, all decreases in CA1-\nvmPFC and CA1-NAc FC in CHR-P individuals in the  placebo condiTon compared to HC were \nnot present in the diazepam condiTon. The general direcTon of the drug effect  (that is, \nincreasing FC) is in line with our predicTons and with prior pharmacological rs -fMRI studies \nusing acute doses of GABA -enhancing drugs  in healthy in dividuals54–57,64. GABA -enhancing \ndrugs, such as diazepam, are posiTve allosteric modulators  of the GABA A receptors via the \nbenzodiazepine site 99. Most commonly, benzodiazepine binding leads to increased \nhyperpolarisaTon of post-synapTc glutamatergic pyramidal cells99, reducing their acTvity 100. \nThe mechanism by which inhibiTon of neural acTvity in one brain region can result in \nincreased FC to another has been recently elucidated by chemogeneTc fMRI study in mice. \nRocchi and colleagues101 demonstrated that either acute or chronic inhibiTon of the PFC led \nto increases in FC with direct thalamo-corTcal output regions. The spiking acTvity was reduced \nbut became more rhythmic and phase -locked to low -frequency oscillatory rhythms, leading \nto an increase in FC with connecTng regions. Therefore, through this mechanism, it is likely \nthat downregulaTon of hippocampal hyperacTvity under diazepam (which we have \ndemonstrated previously in this sample) led to increases in FC with connecTng output regions.  \n \nInteresTngly, the effect of diazepam on CA1 -vmPFC FC showed the least inter -individual \ndifferences between people at CHR -P , whilst the effects in the amygdala and NAc were more \nvaried. This may be due to the fact that the vmPFC , similar to the hippocampus , contains a \nhigh number of benzodiazepine receptors 102. ConsequenTally, similar local effects on neural \nacTvity in the hippocampus and vmPFC might have also contributed to a more robust increase \nin temporal coherence between them. Increases in hippocampal -PFC FC under \nbenzodiazepine vs. placebo have previously been reported54, along with increases in FC to \nsomatosensory and occipital regions 103,104 which also have high number of benzodiazepine \nbinding sites 102. Furthermore, as noted earlier, the largest alteraTons in hippocampal FC \nobserved in individuals at CHR -P in the  placebo condiTon compared to HC were with the \namygdala. This suggests that hippocampal-amygdala FC was the most perturbed out of the \ncorTco-limbic-striatal regions. Given the proposed role of the amygdala in the iniTaTon of \nhippocampal hyperacTvity 105 and PV+ interneuron loss 106, and the high number of \nconnecTons between these regions97, a single dose of diazepam may not have been sufficient \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 21, 2024. ; https://doi.org/10.1101/2024.12.20.24319330doi: medRxiv preprint \n\nto regulate altered hippocampal -amygdala FC in individuals at CHR -P . In support of this, \nbenzodiazepines have been shown to either increase 54 or decrease55 hippocampal-amygdala \nFC in healthy individuals. This suggests the pharmacological effects of GABA -enhancing \ncompounds on this circuity are inherently complex, without the presence of potenTal \nalteraTons to the GABAergic system in individuals at CHR-P.   \n \nFinally, we found no differences in FC strength between groups or drug condiTons for the \nanterior hippocampus to the corTco -limbic-striatal circuit. This was unexpected, based on \npreclinical evidence22 and current theories  about the pathophysiology of psychosis 47,59,107. \nHowever, the anterior hippocampus contains subfields beyond the CA1 and subiculum, such \nas the CA2/3, which largely only have intra -hippocampal projecTons108. Therefore, inclusion \nof this signal may increase noise , making it difficult to detect subtle FC alteraTons between \nthe anterior hippocampus and the corTco-limbic-striatal circuit within individuals at CHR-P . In \nline with this, whilst preclinical evidence focuses on the anterior hippocampus, it specifically \nidenTfies the anterior CA1 as the site of dysfuncTon109. \n \nThis study had several strengths. We used a gold standard randomised, double-blind, placebo-\ncontrolled, crossover study design in a sample of anTpsychoTc naïve individuals at CHR-P.  The \nhippocampus and CA1 subfield were segmented with a high degree of accuracy using novel \ncomputaTonal methods72, allowing the generaTon of study-specific hippocampal and subfield \nmasks. We acquired rs -fMRI data using an advanced mulT -echo sequence, allowing robust \ndata cleaning and removal of non -physiological noise with advanced methodological \ntechniques such as TEDANA71. This led to high quality data as within-group/condiTon resTng-\nstate FC networks for the CA1 to the rest of the brain replicated those found previously75. We \nwere able to contextualise baseline differences and direcTon of drug effects in the CHR -P \ngroup by comparing them with data from a HC group. Finally, we used advanced staTsTcal \nmixed-effects modelling, which is opTmal for examining both inter-group differences without \nassuming uniform variance and also for invesTgaTng within -subject effects73. This study also \nhad some limitaTons. Our sample size of CHR-P individuals was reduced from 24 down to 18 \nawer quality control , but retrospecTve power analysis  demonstrated that the diazepam vs. \nplacebo analyses (mean Cohen’s d=0.83) had an achieved power of 91%. AddiTonally, this \nstudy was not powered to invesTgate relaTonship between FC alteraTons and symptoms, \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 21, 2024. ; https://doi.org/10.1101/2024.12.20.24319330doi: medRxiv preprint \n\nwhich would require a much larger CHR-P sample. Due to limitaTons with the resoluTon of rs-\nfMRI, we were not able to invesTgate differences in FC from specifically the anterior CA1 which \nis of parTcular relevance for psychosis22.  \n \nIn conclusion, this study provides evidence that a single dose of a non -specific GABA -\nenhancing drug, such as diazepam, can normalise CA1 FC alteraTons with the vmPFC and NAc \nin individuals at CHR-P.  C o n v e r s e l y,  C A 1-amygdala FC was greatly perturbed in people at CHR-\nP under placebo compared to HC and was largely unaffected by diazepam challenge. Given \nthis mechanisTc evidence, future research is warranted with extended treatment duraTons to \nlink these neurobiological changes to symptoms and clinical outc omes, including psychosis \nprevenTon. \n \n \nAcknowledgments  \nThis research was funded by the Wellcome Trust  and The Royal Society  (202397/Z/16/Z to \nGM) and the NaTonal InsTtute for Health and Care Research (NIHR) Maudsley Biomedical \nResearch Centre (BRC). The views expressed are those of the authors and not necessarily \nthose of the Welcome Trust, NIHR or the Department of Health and Social Care. For the \npurpose of open access, the author has applied a CC-BY public copyright licence to any Author \nAccepted Manuscript version arising from this submission.  NRL was fund ed by a n MRC DTP \nPhD studentship at the Tme of data collecTon and analysis. PBL was in receipt of a PhD \nstudentship funded by the NIHR Maudsley BRC at the Tme of data collecTon. OO is funded by \nthe Maudsley BRC.  LAJ was supported by an MRC Clinical Research  Training Fellowship \n(MR/T028084/1) at the Tme of data collecTon. TJR is supported by an MRC Clinical Research \nTraining Fellowship (MR/W015943/1). PFP is supported by the European Union funding within \nthe MUR PNRR Extended Partnership iniTaTve on Neuroscience and Neuropharmacology \n(Project no. PE00000006 CUP H93C22000660006 “MNESYS, A mulTscale integrated approach \nto the study of the nervous system in health and disease”). AAG received funding from USPHS \nNIMH MH57440. MMC receives salary support from the Fonds de Recherche Québec – Santé \nand from a James McGill Professorship.  MMC also receives research support from Canadian \nInsTtutes of Health Research, Natural Sciences and Engineering Research Council – Canada, \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 21, 2024. ; https://doi.org/10.1101/2024.12.20.24319330doi: medRxiv preprint \n\nMcGill University’s Health Brains for Health Lives (a Canada Research Excellence Fund IniaTve), \nand TRIDENT (a New FronTers in Research Fund program).  \n \n \nDisclosures \nAAG has received consulTng fees from Alkermes, Lundbeck, Takeda, Roche, Lyra, Concert, \nNewron and SynAgile, and research funding from Newron and Merck. SCRW has recently \nreceived research funding from Boehringer Ingelheim and GE Healthcare to perform \ninvesTgator-led research. AE has received consultancy fees from Leal TherapeuTcs. GM has \nreceived consulTng fees from Boehringer Ingelheim . 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CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 21, 2024. ; https://doi.org/10.1101/2024.12.20.24319330doi: medRxiv preprint","source_license":"CC-BY-4.0","license_restricted":false}