Altered functional connectivity and hyperactivity of the caudal hippocampus in schizophrenia Compared with Bipolar Disorder：a resting state fMRI study

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Further, these abnormalities are often associated with specific symptom profiles. we examined basal activation state and functional connectivity (FC) in four subregions of the bilateral Hipp: left caudal (cHipp_L), right caudal (cHipp_R), left rostral (rHipp_L), and right rostral (rHipp_R). Resting-state functional magnetic resonance images were obtained from 62 schizophrenia patients, 57 bipolar disorder (BD) patients, and 45 healthy controls (HCs), and analyzed for fractional amplitude of low-frequency fluctuations (fALFF) as a measure of basal neural activity and for whole-brain FC with the aforementioned hippocampal subregions as seeds. The schizophrenia group exhibited greater fALFF in bilateral cHipp and rHipp subregions compared to BD and HC groups as well as greater FC between the bilateral cHipp and multiple brain regions, including the thalamus, putamen, middle frontal gyrus, parietal cortex, and precuneus. Moreover, fALFF values of the bilateral cHipp were positively correlated with the severity of clinical symptoms as measured by the Positive and Negative Syndrome Scale. These findings confirm a crucial contribution of hippocampal dysfunction, especially of the cHipp, in schizophrenia. Further, hyper-connectivity and hyperactivity of the cHipp could serve as a biomarker for therapeutic development. schizophrenia resting state functional magnetic resonance caudal hippocampus Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction Schizophrenia is a severe neuropsychiatric disorder that afflicts 1% of the global population and incurs major socio-economic costs [ 1 ]. A highly heritable disorder, schizophrenia results from deficits in brain development and maturation, and symptoms frequently emerge between late adolescence and early adulthood[ 2 ]. While not directly fatal, schizophrenia is associated with a 15-year reduction in life expectancy compared to the general population, in part due to a 5–10% lifetime risk of death by suicide[ 3 ]. Despite treatment advances, the prognosis for many schizophrenia patients is poor, especially those with negative symptoms and cognitive impairments. Limitations in treatment result from an incomplete understanding of disease pathogenesis, necessitating continued basic research into structural and functional impairments at the network, cellular, and molecular levels. Hippocampus is involved in multiple cognitive functions, such as emotion regulation, stress responses, visuospatial orientation and memory[ 4 ], also correlated with the formation of psychotic symptoms in schizophrenia or bipolar disorder[ 5 , 6 ]. Moreover, a general reduction in hippocampal volume has been reported among asymptomatic individuals that eventually develop psychosis [ 7 ]. Functional magnetic resonance imaging (fMRI) have revealed dysconnectivity with other regions of the central nervous system[ 8 , 9 ]potentially associated with dysregulation of synaptic development and synaptic protein expression[ 10 , 11 ]. In addition, other functional imaging modalities have revealed higher resting metabolism and blood flow in the hippocampus of patients with schizophrenia [ 12 ]. The magnitudes of these structural and functional abnormalities often correlate with clinical symptom severity and predict clinical progression from a prodromal to psychotic state [ 13 ]. Hippocampal dysfunction in schizophrenia is associated with impaired habituation (i.e., an inability to modulate responses after repeated presentations of sensory stimuli), specific memory deficits, and dopaminergic system hyperactivity [ 14 , 15 ]. There seemed to be a small alteration in hippocampal structure and function in BD[ 16 ]. So far, the role of the hippocampus in psychotic symptoms of schizophrenia or bipolar disorder neuropathology is not understood. With substantial advances in magnetic resonance imaging (MRI) tools, new hippocampal segmentation algorithms have made it possible to label hippocampal subfields according to the Human Brainnetome Atlas identified by a connectivity-based parcellation framework [ 17 ]. Functional dissociations between rostral and caudal hippocampus have also been observed in humans and animals[ 18 ], including in the processing of novel versus repeated stimuli, emotional versus non-emotional stimuli, and encoding versus retrieval [ 19 , 20 ].The posterior hippocampus has been implicated in the retrieval of memories associated with spatial context, while the anterior hippocampus mediates less context-dependent relational memory processes [ 21 ]. Basic behavioral and cognitive neuroscience studies have revealed important functional differences across the rostral-to-caudal axis of the hippocampus. However, it is unclear whether rostral and caudal subregions are differentially affected in schizophrenia or bipolar disorder. Therefore, additional studies are required to elucidate the precise relationships of axial subregions and the pathophysiology of schizophrenia to encourage more region-specific research. In this study, we compared fractional amplitude of low-frequency fluctuations (fALFF) and FC of 4 axial regions of the bilateral hippocampus among schizophrenia (SCH), bipolar disorder (BD), and healthy control (HC) groups. We hypothesized that the SCH group would show specific FC and activity abnormalities in each hippocampal subregion compared to BD and HC groups. These findings could provide potential biomarkers and novel treatment targets for schizophrenia. 2. Materials and methods 2.1 Participants Sixty-two patients with schizophrenia and 57 with BP were recruited from the Anhui Mental Health Center between July 1, 2021 and September 20, 2023. All patients met the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, criteria for schizophrenia or bipolar disorder. The exclusion criteria were as follows: (1) younger than 18 or older than 50 years; (2) electroconvulsive therapy in the previous 3 months; (3) history or current neurological illness; (4) head motion exceeding 2 mm in translation or 2 mm in rotation during the fMRI scan; (5) any contraindications for MRI. On the day of MRI scans, patients completed the Positive and Negative Syndrome Scale (PANSS)[ 22 ]. We also recruited 45 healthy control (HC) participants who met the same exclusion criteria as patients. The study protocol was approved by the Anhui Mental Health Centre Ethics Committee. All participants or their legal guardians provided written informed consent after receiving a full explanation of the study. 2.2 MRI data acquisition All participants were scanned by a General Electric (GE) 3-T scanner (Discovery GE750w) at the University of Science and Technology of China (USTC) or Anhui Mental Health Center. Participants were required to remain still with their eyes closed and stay awake during the scan. Earplugs and foam pads were used to reduce scanning noise and minimize head motion, respectively. High spatial resolution T1-weighted anatomic images were acquired in the sagittal orientation with the following settings: repetition time [TR] = 8.16 ms; field of view = 256 × 256 mm 2 ; voxel size = 1 × 1 × 1 mm 3 ; flip angle = 12°; number of slices = 188; echo time = 3.18 ms and slice thickness = 1 mm. The resting-state functional images consisting of 217 echo-planar imaging volumes were collected with the following parameters: repetition time, 2400 ms; echo time, 30 ms; flip angle, 90°; matrix size, 64 × 64; field of view, 192 × 192 mm 2 ; slice thickness, 3 mm and 46 continuous axial slices covering the whole brain. (one voxel = 3 × 3 × 3 mm 3 ). 2.3 MRI processing Resting-state (rs)-fMRI images were processed with the Data Processing Assistant for Resting-State Functional MR Imaging toolkit (DPARSF, http://rfmri.org/DPARSF ) [ 23 ]. The following processing steps were applied to each patient dataset: removing the first 10 volumes to achieve a steady state; correcting for different slice acquisition timing and head motion; deriving images co-registered with the corresponding structural images which were segmented and normalized to the Montreal Neurological Institute (MNI) space using the Diffeomorphic Anatomical Registration Through Exponentiated Lie algebra (DARTEL); removing linear trends; regressing out of white matter signals, cerebrospinal fluid signals, and 24 Friston head-motion parameters; spatially smoothing with a 6-mm isotropic Gaussian kernel. Additionally, participants with head movement (max > 2mm) or head rotation (max > 2 degree) were removed from the following analysis. 2.4 Defining axial subregions of the bilateral hippocampus The bilateral hippocampus was segmented into four axial subregions according to the Human Brainnetome Atlas identified by a connectivity-based parcellation framework[ 17 ] (Fig. 1): the left rostral hippocampus, the left caudal hippocampus, the right rostral hippocampus, and the right caudal hippocampus. These subregions were then used as seed areas for resting-state functional connectivity analyses. 2.5. Fractional amplitude of low-frequency fluctuations (fALFF) and functional connectivity analyses For fALFF measurement, we first converted the filtered time series to a frequency domain power spectrum by fast Fourier transform. The fALFF of each subregion was then calculated as the average power in the range 0.01–0.1 Hz relative to the entire frequency spectrum. The fALFF of each voxel was normalized to the Z value. Then average normalized fALFF values were extracted from the rostral and caudal hippocampal regions of interest (ROIs) separately in each hemisphere and entered into statistical analyses as described below. We then extracted the mean time series of each hippocampal subregion. The FC values between each subregion and the whole brain regions was calculated. Pearson’s correlation coefficients between the averaged time series for each hippocampal subregion and voxels in the rest of the brain represented the strength of the FC values. Subsequently, Fisher’s z transformation was applied to normalize the correlation coefficients for further analysis. 2.6 Correlation Analyses Pearson’s correlation coefficients were calculated between spontaneous neural activity of hippocampal subregions at rest (fALFF) and the severity of clinical symptoms were assessed by the PANSS. Additionally, we also calculated Pearson’s correlation coefficients between statistically significant FC values and PANSS scores. The threshold of significance was set at p < 0.05. 2.7 Statistical analysis We compared normally distributed demographic variables among groups by one-way analysis of covariance (ANCOVA). The sex ratio was compared among groups by chi-squared test. Regional fALFF values were compared among groups by one-way ANCOVA with age, sex, and years of education as covariates, followed by post hoc two-sample t-tests for comparisons. Functional connectivity maps (FCMs) for each hippocampal subregion were compared among groups by voxel-based one-way analysis of covariance (ANCOVA) with age, sex, and years of education as covariates. All image analyses were conducted using Statistical Parametric Mapping (SPM)12 ( http://www.fil.ion.ucl.ac.uk/spm ). To control for multiple comparisons, statistical maps were thresholded using the Gaussian random field correction with a voxel-level threshold of p < 0.001 and cluster-level threshold of p < 0.05. Post hoc two-sample t-tests were performed to assess differences in FC between groups within a mask showing group FCM differences from the ANCOVA analysis. 3. Results 3.1 Demographic and clinical characteristics of the study population There were no significant differences in age, sex ratio, or years of education among groups. Sixty-two patients with schizophrenia, 57 with bipolar disorder and 45 HCs were recruited. The details about demographic and clinical characteristics of the three groups were presented in Table 1. As expected, schizophrenia patients scored higher on the PANSS than HCs, while bipolar disorder patients scored higher on both the HAMD and YMRS compared to HCs. 3.2 Group differences in fALFF within each subregion of the hippocampus Average fALFF was less negative in all four hippocampal subregions of the schizophrenia group compared to both BP and HC groups (left caudal hippocampus [cHipp_L]: (F(2,161) = 52.47, p < 0.001), right caudal hippocampus [cHipp_R]: (F(2,161) = 69.95, p < 0.001), left rostral hippocampus [rHipp_L]: (F(2,161) = 35.57, p < 0.001), and right rostral hippocampus [rHipp_R]: (F(2,161) = 29.11, p 0.05) (Fig. 2). 3.3 Functional connectivity differences with each hippocampal subregion among groups Whole-brain FC analyses revealed significantly stronger connections of the left caudal hippocampus (Fig. 3) and right caudal hippocampus (Fig. 4) with the thalamus, putamen, frontal cortex, and parietal cortex among schizophrenia patients. In contrast, FC values of bilateral caudal hippocampal subregions and the frontal cortex were lower in the BD group compared to schizophrenia and HC groups. There were no significant differences in FC between bilateral rostral hippocampus and other regions among the three groups. The locations and sizes of voxel clusters with significant FC to the seed region are listed in Table 2 and Table 3. 3.4 Correlation analyses Pearson’s correlation analysis revealed a positive association between PANSS scores and fALFF values in bilateral cHipp subregions (left: r = 0.531, p < 0.001; right: r = 0.380, p = 0.002) (Fig. 5) but not in bilateral rHipp subregions among schizophrenia patients after multiple comparisons correction. There were no significant correlations between FC and PANSS scores after multiple comparisons correction in any group. 4. Discussion The schizophrenia group exhibited less negative fALFF in both the caudal and rostral regions of the bilateral hippocampus compared to bipolar disorder patients and healthy matched controls. In addition, schizophrenia patients demonstrated stronger FC from bilateral caudal hippocampus to the thalamus, putamen, middle frontal gyrus, parietal cortex, and precuneus. Moreover, the fALFF values of the bilateral cHipp were positively correlated with the severity of clinical symptoms (higher PANSS scores) in the schizophrenia group. Consistent with our primary hypothesis, these findings suggest that functionally dissociated regions of the hippocampus along the rostral–caudal axis are differentially disturbed in schizophrenia and that these disturbances manifest as schizophrenia symptoms. We observed higher fALFF values in both rostral and caudal subregions of bilateral hippocampus in the schizophrenia group compared to BD and HC groups, suggesting hyperactivity of hippocampal neurons in schizophrenia. Due to metabolic coupling, neuronal hyperactivity is usually associated with greater metabolic activity and blood flow[ 24 ], and the severity of delusions in schizophrenia was found to be strongly associated with greater blood volume in the hippocampus[ 13 ]. Basic studies have also shown that abnormally heightened hippocampal activity leads to a hyperdopaminergic state, which may contribute to the psychotic features of schizophrenia. A hyperdopaminergic state in turn can further enhance hippocampal activity via reciprocal connections between the hippocampal formation and midbrain dopamine neurons[ 25 ]. Indeed, several studies have reported hippocampal hyperactivity in schizophrenia patients that correlated with psychosis. Likewise, we found the fALFF values in the caudal hippocampus of schizophrenia patients were positively correlated with severity of clinical symptoms as measured by PANSS scores[ 26 , 27 ]. Post-mortem studies have also suggested the caudal hippocampus may be particularly vulnerable to the pathophysiology of schizophrenia[ 28 ]. In addition to hyperactivity within the caudal hippocampus, we found increased FC between the bilateral cHipp and multiple brain regions, including the thalamus, putamen, middle frontal gyrus, parietal cortex, and precuneus, suggesting wide dissemination of this hyperactive state. The thalamus has long been implicated in schizophrenia pathophysiology, mainly due to its strong reciprocal FC with the hippocampus and prefrontal cortex[ 29 ]. Abnormal resting-state FC between the thalamus and hippocampus has been reported in both schizophrenia patients and individuals at-risk for schizophrenia, and further may predict conversion to psychosis among at-risk individuals[ 30 , 31 ]. Some studies have even suggested that the thalamus may serve as a hub for wide-scale network dysfunction in schizophrenia[ 32 ]. Cortical–basal ganglia–thalamocortical circuits contribute to multiple aspects of motor, executive/associative, and emotional/motivational function[ 33 ]. The putamen receives extensive dopaminergic innervation from various cortical regions, and sends output to the cortex via the thalamus[ 34 ]. Dysfunction of the putamen may be associated with the excessive and inappropriate dopamine signaling underlying schizophrenia[ 35 ]. The middle frontal gyrus of the prefrontal cortex is part of a mesocorticolimbic dopaminergic pathway that functions in reward-dependent behaviors, and previous studies have suggested impaired reward mechanisms in schizophrenia[ 35 ]. The middle frontal gyrus itself is associated to language processing and the appreciation phase of humor[ 36 ]. We found increased FC between the bilateral cHipp and the middle frontal gyrus, and speculate that this abnormality may contribute to the impaired intrinsic motivation frequently observed in schizophrenia patients. In contrast, the bipolar disorder group showed decreased FC between bilateral caudal hippocampus and frontal cortex compared to both the schizophrenia and HC groups. These distinct FC abnormalities may explain the difference in behavioral motivation between BD and schizophrenia patients. The precuneus and parietal cortex are the key nodes of the default mode network (DMN), which shows greater metabolic activity during rest and contributes to a wide range of higher-order functions including self-referential cognition, memory-based problem solving, cognitive flexibility, mind-wandering, autobiographical memory, and theory of mind[ 37 , 38 ]. Increased FC within the DMN has been reported repeatedly in schizophrenia and associated with increased positive symptom severity[ 39 ]. Thus, hyper-connectivity of the DMN may contribute to the cognitive deficits and other clinical symptoms observed in schizophrenia. This study has several limitations. First, the sample size was relatively small, so more subtle effects of schizophrenia or BD on fALFF may have been missed. Further, significant effects must be validated in a larger cohort. Second, this was a cross-sectional study without longitudinal follow-up, so no causal inferences are possible. Third, medication may have been a major confound as nearly all of the patients were receiving pharmacotherapy. However, this was unavoidable given the ethical considerations of keeping patients medication-free. Further studies using a prospective design are needed to address these issues. Fourth, some of our results are inconsistent with previous studies, possibly due to subject heterogeneity, such as observed between first-episode, chronic, and acute episode patients[ 40 ]. 5. Conclusion Patients with schizophrenia show neural hyperactivity within the bilateral hippocampus and hyperconnectivity of the bilateral caudal hippocampus with the thalamus, putamen, middle frontal gyrus, parietal cortex, and precuneus. Increased activity in the bilateral cHipp was positively correlated clinical symptom severity. Collectively, these findings strongly implicate hippocampal dysfunction in the pathophysiology of schizophrenia, especially the caudal hippocampus. These abnormalities may be useful biomarkers for disease progression or serve as treatment targets. Additional studies are required to clarify the longitudinal relationship between regional hippocampal abnormalities and disease progression. Declarations Ethical Approval The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration. All procedures involving human subjects/patients were approved by Anhui Mental Health Centre Ethics Committee. All subjects or their guardians volunteered to participate in the study and signed a written informed consent form after receiving a full written and verbal explanation of the study. They received information on the rationale of the research and were informed that they are free to withdraw from the study at any time. Clinical trial number: not applicable. Competing interests None of the authors have a conflict of interest to declare Funding This work was supported by National Clinical Key Specialty Construction Project of China, the Scientific research project of Anhui Health Committee (grant number: AHWJ2023A20217 to L.Z.), the National Natural Science Foundation of China (grant number. 81671354, and 32071054). Author Contribution Li Zhang: data acquisition, data analysis and the manuscript writing Wenli Wang: clinical evaluation and data acquisitionZhiyong Li：data analysis and data interpretationRuan Yuan: clinical evaluation and data acquisitionLe Sun: data analysis and clinical evaluationGong_jun Ji: data analysis and data interpretationKai Wang：study design and critical revision of the article.Yanghua Tian: study design and critical revision of the article.all authors have read the final version of the manuscript and approved the final article were true. 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Hyperactivity of the default mode network in schizophrenia and free energy: A dialogue between Freudian theory of psychosis and neuroscience. Front Hum Neurosci. 2022;16:956831. McHugo M, Talati P, Armstrong K, Vandekar SN, Blackford JU, Woodward ND, Heckers S. Hyperactivity and Reduced Activation of Anterior Hippocampus in Early Psychosis. Am J Psychiatry. 2019;176(12):1030–8. Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files table1.pdf table2.pdf table3.pdf Cite Share Download PDF Status: Published Journal Publication published 27 Feb, 2025 Read the published version in BMC Psychiatry → Version 1 posted Editorial decision: Revision requested 10 Oct, 2024 Editor assigned by journal 08 Oct, 2024 Submission checks completed at journal 08 Oct, 2024 First submitted to journal 30 Sep, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5179111","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":364483979,"identity":"7de02748-09c5-41db-985b-15b9abc43117","order_by":0,"name":"Li Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyklEQVRIiWNgGAWjYLACxgYgwc7Y+ICB4QApWpgZmw1I1cLAJkGUFv725ocPf+6wy5N3Zm6r/FFxJ7GB/fDRDfi0SJw5ZmwgeSa52PAwY9ttnjPPEht40tJu4NNiIJHDJmHYxpy4sRmohbHtcGKDBI8ZYS2JbfVgLYU/idZyEKhyPjNjGwMvMVpAfjFsbDueuAEYyNI8Zw4btxHyCyTE2qoT57e3P/z4o+KwbD/74WN4tSBceADKYCNKOQjINxCtdBSMglEwCkYaAAA3RE5n4u7lFAAAAABJRU5ErkJggg==","orcid":"","institution":"Psychological Hospital of Anhui Medical University","correspondingAuthor":true,"prefix":"","firstName":"Li","middleName":"","lastName":"Zhang","suffix":""},{"id":364483981,"identity":"38924449-ecdd-4876-9888-664d3ec0e539","order_by":1,"name":"Wenli Wang","email":"","orcid":"","institution":"Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Wenli","middleName":"","lastName":"Wang","suffix":""},{"id":364483983,"identity":"229dc3d6-0332-4c56-a294-72c8191ed19a","order_by":2,"name":"Yuan Ruan","email":"","orcid":"","institution":"Psychological Hospital of Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuan","middleName":"","lastName":"Ruan","suffix":""},{"id":364483984,"identity":"a984a5b4-2773-4988-801c-be545d358f18","order_by":3,"name":"Zhiyong Li","email":"","orcid":"","institution":"Psychological Hospital of Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhiyong","middleName":"","lastName":"Li","suffix":""},{"id":364483985,"identity":"8d24009a-b053-4b49-8cba-846ea0a84a68","order_by":4,"name":"Le Sun","email":"","orcid":"","institution":"Psychological Hospital of Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Le","middleName":"","lastName":"Sun","suffix":""},{"id":364483988,"identity":"63162e17-aefd-4226-a8f6-deaa22f6c434","order_by":5,"name":"Gong-Jun Ji","email":"","orcid":"","institution":"Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Gong-Jun","middleName":"","lastName":"Ji","suffix":""},{"id":364483992,"identity":"132707b6-a3e1-4110-975d-832873138111","order_by":6,"name":"Yanghua Tian","email":"","orcid":"","institution":"Second Hospital of Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yanghua","middleName":"","lastName":"Tian","suffix":""},{"id":364483993,"identity":"22e77733-6d12-412b-b683-37d32f99202e","order_by":7,"name":"Kai Wang","email":"","orcid":"","institution":"First Affiliated Hospital of Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Kai","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2024-09-30 08:38:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5179111/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5179111/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12888-025-06632-7","type":"published","date":"2025-02-27T15:57:23+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":72281967,"identity":"d7ae6dc5-d460-4522-b79f-1e36c6ff186c","added_by":"auto","created_at":"2024-12-24 16:35:37","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":62422,"visible":true,"origin":"","legend":"\u003cp\u003eThe four subregions defined along the rostral-caudal axis of the bilateral hippocampus: left caudal hippocampus (green), right caudal hippocampus (purple), left rostral hippocampus (red), and right rostral hippocampus (blue). Regions are rendered on sagittal and ventral views.\u003c/p\u003e","description":"","filename":"figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5179111/v1/1f37d4a57b878639dec7fcc7.jpg"},{"id":72281323,"identity":"d43e5735-9231-460c-9ea2-c4a6bb7ced2f","added_by":"auto","created_at":"2024-12-24 16:27:37","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":53731,"visible":true,"origin":"","legend":"\u003cp\u003eLess negative fALFF in both rostral and caudal subregions of the bilateral hippocampus among schizophrenia patients (SCH group) compared to bipolar disorder patients (BD group) and healthy matched controls (HC group). cHipp_L: left caudal hippocampus, cHipp_R: right caudal hippocampus, rHipp_L: left rostral hippocampus, rHipp_R: right rostral hippocampus. *p \u0026lt; 0.05 and **p \u0026lt; 0.01\u003c/p\u003e","description":"","filename":"figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5179111/v1/d82d262bbf2b3c2d51329e98.jpg"},{"id":72283691,"identity":"fc4df3ca-1604-4e62-a280-95ffc63cfc13","added_by":"auto","created_at":"2024-12-24 16:43:37","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":203519,"visible":true,"origin":"","legend":"\u003cp\u003eFunctional connectivity to the left caudal hippocampus (cHipp_L) in schizophrenia (SCH), bipolar disorder (BD), and healthy control (HC) groups. (a) Voxel clusters with significant FC are color-coded. A–D show selected slices in the sagittal plane (left column), coronal plane (middle column), and axial plane (right column). (b) Bar plot of average FC values with the cHipp_L for the three groups.\u003c/p\u003e","description":"","filename":"figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5179111/v1/aa828c789a5fc77d2585cd30.jpg"},{"id":72281329,"identity":"930cd7cb-8bf1-41a0-8dc1-468b85c8e197","added_by":"auto","created_at":"2024-12-24 16:27:37","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":196735,"visible":true,"origin":"","legend":"\u003cp\u003eFunctional connectivity to the right caudal hippocampus (cHipp_R) in schizophrenia (SCH), bipolar disorder (BD), and healthy control (HC) groups. (a) Voxel clusters with significant FC are color-coded. A–D show selected slices in the sagittal plane (left column), coronal plane (middle column), and axial plane (right column). (b) Bar plot of average FC values with the cHipp_R for the three groups\u003c/p\u003e","description":"","filename":"figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5179111/v1/a5f3ddccce2cfb69dbe1356f.jpg"},{"id":72281325,"identity":"5efcd270-7e6d-4b69-a315-93ebd9535376","added_by":"auto","created_at":"2024-12-24 16:27:37","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":50378,"visible":true,"origin":"","legend":"\u003cp\u003eAssociation between schizophrenia symptom severity as measured by PANSS score and fALFF in the bilateral caudal hippocampus of three groups. cHipp_L: the left caudal hippocampus, cHipp_R: the right caudal hippocampus The significant was set at p \u0026lt; 0.05.\u003c/p\u003e","description":"","filename":"figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5179111/v1/fbf025bd674e8b3ce59d03c7.jpg"},{"id":77622452,"identity":"796befa4-dc9e-4ec5-9d0d-46186a463973","added_by":"auto","created_at":"2025-03-03 16:07:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1259620,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5179111/v1/895f21c9-4cc7-4a79-bdec-2f22b16c03ef.pdf"},{"id":72281326,"identity":"04cf700f-3f43-4a21-88d5-8e3bed2fe7d3","added_by":"auto","created_at":"2024-12-24 16:27:37","extension":"pdf","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":111260,"visible":true,"origin":"","legend":"","description":"","filename":"table1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5179111/v1/54c3eb3472fe2b022a63bf9b.pdf"},{"id":72281968,"identity":"e6f8a79a-1d74-453d-89ae-6504e21f2b10","added_by":"auto","created_at":"2024-12-24 16:35:37","extension":"pdf","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":115660,"visible":true,"origin":"","legend":"","description":"","filename":"table2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5179111/v1/f0a6e416bf06fee7c5425161.pdf"},{"id":72281330,"identity":"8c385c5f-3bf9-4a5c-98e6-dede8e285f13","added_by":"auto","created_at":"2024-12-24 16:27:37","extension":"pdf","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":128626,"visible":true,"origin":"","legend":"","description":"","filename":"table3.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5179111/v1/4086dab4584d997cce2a32d3.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Altered functional connectivity and hyperactivity of the caudal hippocampus in schizophrenia Compared with Bipolar Disorder：a resting state fMRI study","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eSchizophrenia is a severe neuropsychiatric disorder that afflicts 1% of the global population and incurs major socio-economic costs [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. A highly heritable disorder, schizophrenia results from deficits in brain development and maturation, and symptoms frequently emerge between late adolescence and early adulthood[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. While not directly fatal, schizophrenia is associated with a 15-year reduction in life expectancy compared to the general population, in part due to a 5\u0026ndash;10% lifetime risk of death by suicide[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Despite treatment advances, the prognosis for many schizophrenia patients is poor, especially those with negative symptoms and cognitive impairments. Limitations in treatment result from an incomplete understanding of disease pathogenesis, necessitating continued basic research into structural and functional impairments at the network, cellular, and molecular levels.\u003c/p\u003e \u003cp\u003eHippocampus is involved in multiple cognitive functions, such as emotion regulation, stress responses, visuospatial orientation and memory[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], also correlated with the formation of psychotic symptoms in schizophrenia or bipolar disorder[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Moreover, a general reduction in hippocampal volume has been reported among asymptomatic individuals that eventually develop psychosis [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Functional magnetic resonance imaging (fMRI) have revealed dysconnectivity with other regions of the central nervous system[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]potentially associated with dysregulation of synaptic development and synaptic protein expression[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In addition, other functional imaging modalities have revealed higher resting metabolism and blood flow in the hippocampus of patients with schizophrenia [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe magnitudes of these structural and functional abnormalities often correlate with clinical symptom severity and predict clinical progression from a prodromal to psychotic state [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Hippocampal dysfunction in schizophrenia is associated with impaired habituation (i.e., an inability to modulate responses after repeated presentations of sensory stimuli), specific memory deficits, and dopaminergic system hyperactivity [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. There seemed to be a small alteration in hippocampal structure and function in BD[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSo far, the role of the hippocampus in psychotic symptoms of schizophrenia or bipolar disorder neuropathology is not understood. With substantial advances in magnetic resonance imaging (MRI) tools, new hippocampal segmentation algorithms have made it possible to label hippocampal subfields according to the Human Brainnetome Atlas identified by a connectivity-based parcellation framework [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Functional dissociations between rostral and caudal hippocampus have also been observed in humans and animals[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], including in the processing of novel versus repeated stimuli, emotional versus non-emotional stimuli, and encoding versus retrieval [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].The posterior hippocampus has been implicated in the retrieval of memories associated with spatial context, while the anterior hippocampus mediates less context-dependent relational memory processes [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBasic behavioral and cognitive neuroscience studies have revealed important functional differences across the rostral-to-caudal axis of the hippocampus. However, it is unclear whether rostral and caudal subregions are differentially affected in schizophrenia or bipolar disorder. Therefore, additional studies are required to elucidate the precise relationships of axial subregions and the pathophysiology of schizophrenia to encourage more region-specific research.\u003c/p\u003e \u003cp\u003eIn this study, we compared fractional amplitude of low-frequency fluctuations (fALFF) and FC of 4 axial regions of the bilateral hippocampus among schizophrenia (SCH), bipolar disorder (BD), and healthy control (HC) groups. We hypothesized that the SCH group would show specific FC and activity abnormalities in each hippocampal subregion compared to BD and HC groups. These findings could provide potential biomarkers and novel treatment targets for schizophrenia.\u003c/p\u003e"},{"header":"2. Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003e2.1 Participants\u003c/h2\u003e\n\u003cp\u003eSixty-two patients with schizophrenia and 57 with BP were recruited from the Anhui Mental Health Center between July 1, 2021 and September 20, 2023. All patients met the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, criteria for schizophrenia or bipolar disorder. The exclusion criteria were as follows: (1) younger than 18 or older than 50 years; (2) electroconvulsive therapy in the previous 3 months; (3) history or current neurological illness; (4) head motion exceeding 2 mm in translation or 2 mm in rotation during the fMRI scan; (5) any contraindications for MRI. On the day of MRI scans, patients completed the Positive and Negative Syndrome Scale (PANSS)[\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e]. We also recruited 45 healthy control (HC) participants who met the same exclusion criteria as patients.\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the Anhui Mental Health Centre Ethics Committee. All participants or their legal guardians provided written informed consent after receiving a full explanation of the study.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n\u003ch2\u003e2.2 MRI data acquisition\u003c/h2\u003e\n\u003cp\u003eAll participants were scanned by a General Electric (GE) 3-T scanner (Discovery GE750w) at the University of Science and Technology of China (USTC) or Anhui Mental Health Center. Participants were required to remain still with their eyes closed and stay awake during the scan. Earplugs and foam pads were used to reduce scanning noise and minimize head motion, respectively.\u003c/p\u003e\n\u003cp\u003eHigh spatial resolution T1-weighted anatomic images were acquired in the sagittal orientation with the following settings: repetition time [TR]\u0026thinsp;=\u0026thinsp;8.16 ms; field of view\u0026thinsp;=\u0026thinsp;256 \u0026times; 256 mm\u003csup\u003e2\u003c/sup\u003e; voxel size\u0026thinsp;=\u0026thinsp;1 \u0026times; 1 \u0026times; 1 mm\u003csup\u003e3\u003c/sup\u003e; flip angle\u0026thinsp;=\u0026thinsp;12\u0026deg;; number of slices\u0026thinsp;=\u0026thinsp;188; echo time\u0026thinsp;=\u0026thinsp;3.18 ms and slice thickness\u0026thinsp;=\u0026thinsp;1 mm. The resting-state functional images consisting of 217 echo-planar imaging volumes were collected with the following parameters: repetition time, 2400 ms; echo time, 30 ms; flip angle, 90\u0026deg;; matrix size, 64 \u0026times; 64; field of view, 192 \u0026times; 192 mm\u003csup\u003e2\u003c/sup\u003e; slice thickness, 3 mm and 46 continuous axial slices covering the whole brain. (one voxel\u0026thinsp;=\u0026thinsp;3 \u0026times; 3 \u0026times; 3 mm\u003csup\u003e3\u003c/sup\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003e2.3 MRI processing\u003c/h2\u003e\n\u003cp\u003eResting-state (rs)-fMRI images were processed with the Data Processing Assistant for Resting-State Functional MR Imaging toolkit (DPARSF, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://rfmri.org/DPARSF\u003c/span\u003e\u003c/span\u003e) [\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e]. The following processing steps were applied to each patient dataset: removing the first 10 volumes to achieve a steady state; correcting for different slice acquisition timing and head motion; deriving images co-registered with the corresponding structural images which were segmented and normalized to the Montreal Neurological Institute (MNI) space using the Diffeomorphic Anatomical Registration Through Exponentiated Lie algebra (DARTEL); removing linear trends; regressing out of white matter signals, cerebrospinal fluid signals, and 24 Friston head-motion parameters; spatially smoothing with a 6-mm isotropic Gaussian kernel. Additionally, participants with head movement (max\u0026thinsp;\u0026gt;\u0026thinsp;2mm) or head rotation (max\u0026thinsp;\u0026gt;\u0026thinsp;2 degree) were removed from the following analysis.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n\u003ch2\u003e2.4 Defining axial subregions of the bilateral hippocampus\u003c/h2\u003e\n\u003cp\u003eThe bilateral hippocampus was segmented into four axial subregions according to the Human Brainnetome Atlas identified by a connectivity-based parcellation framework[\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e] (Fig.\u0026nbsp;1): the left rostral hippocampus, the left caudal hippocampus, the right rostral hippocampus, and the right caudal hippocampus. These subregions were then used as seed areas for resting-state functional connectivity analyses.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003e2.5. Fractional amplitude of low-frequency fluctuations (fALFF) and functional connectivity analyses\u003c/h2\u003e\n\u003cp\u003eFor fALFF measurement, we first converted the filtered time series to a frequency domain power spectrum by fast Fourier transform. The fALFF of each subregion was then calculated as the average power in the range 0.01\u0026ndash;0.1 Hz relative to the entire frequency spectrum. The fALFF of each voxel was normalized to the Z value. Then average normalized fALFF values were extracted from the rostral and caudal hippocampal regions of interest (ROIs) separately in each hemisphere and entered into statistical analyses as described below.\u003c/p\u003e\n\u003cp\u003eWe then extracted the mean time series of each hippocampal subregion. The FC values between each subregion and the whole brain regions was calculated. Pearson\u0026rsquo;s correlation coefficients between the averaged time series for each hippocampal subregion and voxels in the rest of the brain represented the strength of the FC values. Subsequently, Fisher\u0026rsquo;s z transformation was applied to normalize the correlation coefficients for further analysis.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003e2.6 Correlation Analyses\u003c/h2\u003e\n\u003cp\u003ePearson\u0026rsquo;s correlation coefficients were calculated between spontaneous neural activity of hippocampal subregions at rest (fALFF) and the severity of clinical symptoms were assessed by the PANSS. Additionally, we also calculated Pearson\u0026rsquo;s correlation coefficients between statistically significant FC values and PANSS scores. The threshold of significance was set at \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n\u003ch2\u003e2.7 Statistical analysis\u003c/h2\u003e\n\u003cp\u003eWe compared normally distributed demographic variables among groups by one-way analysis of covariance (ANCOVA). The sex ratio was compared among groups by chi-squared test. Regional fALFF values were compared among groups by one-way ANCOVA with age, sex, and years of education as covariates, followed by post hoc two-sample t-tests for comparisons.\u003c/p\u003e\n\u003cp\u003eFunctional connectivity maps (FCMs) for each hippocampal subregion were compared among groups by voxel-based one-way analysis of covariance (ANCOVA) with age, sex, and years of education as covariates. All image analyses were conducted using Statistical Parametric Mapping (SPM)12 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.fil.ion.ucl.ac.uk/spm\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eTo control for multiple comparisons, statistical maps were thresholded using the Gaussian random field correction with a voxel-level threshold of \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and cluster-level threshold of \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Post hoc two-sample t-tests were performed to assess differences in FC between groups within a mask showing group FCM differences from the ANCOVA analysis.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003ch2\u003e3.1 Demographic and clinical characteristics of the study population\u003c/h2\u003e\n\u003cp\u003eThere were no significant differences in age, sex ratio, or years of education among groups. Sixty-two patients with schizophrenia, 57 with bipolar disorder and 45 HCs were recruited. The details about demographic and clinical characteristics of the three groups were presented in Table\u0026nbsp;1. As expected, schizophrenia patients scored higher on the PANSS than HCs, while bipolar disorder patients scored higher on both the HAMD and YMRS compared to HCs.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003ch2\u003e3.2 Group differences in fALFF within each subregion of the hippocampus\u003c/h2\u003e\n\u003cp\u003eAverage fALFF was less negative in all four hippocampal subregions of the schizophrenia group compared to both BP and HC groups (left caudal hippocampus [cHipp_L]: (F(2,161)\u0026thinsp;=\u0026thinsp;52.47, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), right caudal hippocampus [cHipp_R]: (F(2,161)\u0026thinsp;=\u0026thinsp;69.95, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), left rostral hippocampus [rHipp_L]: (F(2,161)\u0026thinsp;=\u0026thinsp;35.57, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and right rostral hippocampus [rHipp_R]: (F(2,161)\u0026thinsp;=\u0026thinsp;29.11, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), but did not differ between BP and HC groups (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Fig.\u0026nbsp;2).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n\u003ch2\u003e3.3 Functional connectivity differences with each hippocampal subregion among groups\u003c/h2\u003e\n\u003cp\u003eWhole-brain FC analyses revealed significantly stronger connections of the left caudal hippocampus (Fig.\u0026nbsp;3) and right caudal hippocampus (Fig.\u0026nbsp;4) with the thalamus, putamen, frontal cortex, and parietal cortex among schizophrenia patients. In contrast, FC values of bilateral caudal hippocampal subregions and the frontal cortex were lower in the BD group compared to schizophrenia and HC groups. There were no significant differences in FC between bilateral rostral hippocampus and other regions among the three groups. The locations and sizes of voxel clusters with significant FC to the seed region are listed in Table\u0026nbsp;2 and Table\u0026nbsp;3.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n\u003ch2\u003e3.4 Correlation analyses\u003c/h2\u003e\n\u003cp\u003ePearson\u0026rsquo;s correlation analysis revealed a positive association between PANSS scores and fALFF values in bilateral cHipp subregions (left: r\u0026thinsp;=\u0026thinsp;0.531, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; right: r\u0026thinsp;=\u0026thinsp;0.380, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002) (Fig.\u0026nbsp;5) but not in bilateral rHipp subregions among schizophrenia patients after multiple comparisons correction. There were no significant correlations between FC and PANSS scores after multiple comparisons correction in any group.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThe schizophrenia group exhibited less negative fALFF in both the caudal and rostral regions of the bilateral hippocampus compared to bipolar disorder patients and healthy matched controls. In addition, schizophrenia patients demonstrated stronger FC from bilateral caudal hippocampus to the thalamus, putamen, middle frontal gyrus, parietal cortex, and precuneus. Moreover, the fALFF values of the bilateral cHipp were positively correlated with the severity of clinical symptoms (higher PANSS scores) in the schizophrenia group. Consistent with our primary hypothesis, these findings suggest that functionally dissociated regions of the hippocampus along the rostral\u0026ndash;caudal axis are differentially disturbed in schizophrenia and that these disturbances manifest as schizophrenia symptoms.\u003c/p\u003e \u003cp\u003eWe observed higher fALFF values in both rostral and caudal subregions of bilateral hippocampus in the schizophrenia group compared to BD and HC groups, suggesting hyperactivity of hippocampal neurons in schizophrenia. Due to metabolic coupling, neuronal hyperactivity is usually associated with greater metabolic activity and blood flow[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], and the severity of delusions in schizophrenia was found to be strongly associated with greater blood volume in the hippocampus[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Basic studies have also shown that abnormally heightened hippocampal activity leads to a hyperdopaminergic state, which may contribute to the psychotic features of schizophrenia. A hyperdopaminergic state in turn can further enhance hippocampal activity via reciprocal connections between the hippocampal formation and midbrain dopamine neurons[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Indeed, several studies have reported hippocampal hyperactivity in schizophrenia patients that correlated with psychosis. Likewise, we found the fALFF values in the caudal hippocampus of schizophrenia patients were positively correlated with severity of clinical symptoms as measured by PANSS scores[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Post-mortem studies have also suggested the caudal hippocampus may be particularly vulnerable to the pathophysiology of schizophrenia[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn addition to hyperactivity within the caudal hippocampus, we found increased FC between the bilateral cHipp and multiple brain regions, including the thalamus, putamen, middle frontal gyrus, parietal cortex, and precuneus, suggesting wide dissemination of this hyperactive state.\u003c/p\u003e \u003cp\u003eThe thalamus has long been implicated in schizophrenia pathophysiology, mainly due to its strong reciprocal FC with the hippocampus and prefrontal cortex[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Abnormal resting-state FC between the thalamus and hippocampus has been reported in both schizophrenia patients and individuals at-risk for schizophrenia, and further may predict conversion to psychosis among at-risk individuals[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Some studies have even suggested that the thalamus may serve as a hub for wide-scale network dysfunction in schizophrenia[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCortical\u0026ndash;basal ganglia\u0026ndash;thalamocortical circuits contribute to multiple aspects of motor, executive/associative, and emotional/motivational function[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. The putamen receives extensive dopaminergic innervation from various cortical regions, and sends output to the cortex via the thalamus[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Dysfunction of the putamen may be associated with the excessive and inappropriate dopamine signaling underlying schizophrenia[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe middle frontal gyrus of the prefrontal cortex is part of a mesocorticolimbic dopaminergic pathway that functions in reward-dependent behaviors, and previous studies have suggested impaired reward mechanisms in schizophrenia[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. The middle frontal gyrus itself is associated to language processing and the appreciation phase of humor[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. We found increased FC between the bilateral cHipp and the middle frontal gyrus, and speculate that this abnormality may contribute to the impaired intrinsic motivation frequently observed in schizophrenia patients. In contrast, the bipolar disorder group showed decreased FC between bilateral caudal hippocampus and frontal cortex compared to both the schizophrenia and HC groups. These distinct FC abnormalities may explain the difference in behavioral motivation between BD and schizophrenia patients.\u003c/p\u003e \u003cp\u003eThe precuneus and parietal cortex are the key nodes of the default mode network (DMN), which shows greater metabolic activity during rest and contributes to a wide range of higher-order functions including self-referential cognition, memory-based problem solving, cognitive flexibility, mind-wandering, autobiographical memory, and theory of mind[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Increased FC within the DMN has been reported repeatedly in schizophrenia and associated with increased positive symptom severity[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Thus, hyper-connectivity of the DMN may contribute to the cognitive deficits and other clinical symptoms observed in schizophrenia.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, the sample size was relatively small, so more subtle effects of schizophrenia or BD on fALFF may have been missed. Further, significant effects must be validated in a larger cohort. Second, this was a cross-sectional study without longitudinal follow-up, so no causal inferences are possible. Third, medication may have been a major confound as nearly all of the patients were receiving pharmacotherapy. However, this was unavoidable given the ethical considerations of keeping patients medication-free. Further studies using a prospective design are needed to address these issues. Fourth, some of our results are inconsistent with previous studies, possibly due to subject heterogeneity, such as observed between first-episode, chronic, and acute episode patients[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003ePatients with schizophrenia show neural hyperactivity within the bilateral hippocampus and hyperconnectivity of the bilateral caudal hippocampus with the thalamus, putamen, middle frontal gyrus, parietal cortex, and precuneus. Increased activity in the bilateral cHipp was positively correlated clinical symptom severity. Collectively, these findings strongly implicate hippocampal dysfunction in the pathophysiology of schizophrenia, especially the caudal hippocampus. These abnormalities may be useful biomarkers for disease progression or serve as treatment targets. Additional studies are required to clarify the longitudinal relationship between regional hippocampal abnormalities and disease progression.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eEthical Approval\u003c/strong\u003e \u003cp\u003eThe authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration. All procedures involving human subjects/patients were approved by Anhui Mental Health Centre Ethics Committee. All subjects or their guardians volunteered to participate in the study and signed a written informed consent form after receiving a full written and verbal explanation of the study. They received information on the rationale of the research and were informed that they are free to withdraw from the study at any time. Clinical trial number: not applicable.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eNone of the authors have a conflict of interest to declare\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003e This work was supported by National Clinical Key Specialty Construction Project of China, the Scientific research project of Anhui Health Committee (grant number: AHWJ2023A20217 to L.Z.), the National Natural Science Foundation of China (grant number. 81671354, and 32071054).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eLi Zhang: data acquisition, data analysis and the manuscript writing Wenli Wang: clinical evaluation and data acquisitionZhiyong Li：data analysis and data interpretationRuan Yuan: clinical evaluation and data acquisitionLe Sun: data analysis and clinical evaluationGong_jun Ji: data analysis and data interpretationKai Wang：study design and critical revision of the article.Yanghua Tian: study design and critical revision of the article.all authors have read the final version of the manuscript and approved the final article were true.\u003c/p\u003e\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e \u003cp\u003eSixty-two patients with schizophrenia and 57 with BP were recruited from the Anhui Mental Health Center. 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Ann N Y Acad Sci. 2014;1316(1):29\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTran The J, Ansermet JP, Magistretti PJ, Ansermet F. Hyperactivity of the default mode network in schizophrenia and free energy: A dialogue between Freudian theory of psychosis and neuroscience. Front Hum Neurosci. 2022;16:956831.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcHugo M, Talati P, Armstrong K, Vandekar SN, Blackford JU, Woodward ND, Heckers S. Hyperactivity and Reduced Activation of Anterior Hippocampus in Early Psychosis. Am J Psychiatry. 2019;176(12):1030\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bpsy","sideBox":"Learn more about [BMC Psychiatry](http://bmcpsychiatry.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bpsy/default.aspx","title":"BMC Psychiatry","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"schizophrenia, resting state functional magnetic resonance, caudal hippocampus","lastPublishedDoi":"10.21203/rs.3.rs-5179111/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5179111/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSchizophrenia patients frequently present with structural and functional abnormalities of the hippocampus (Hipp). Further, these abnormalities are often associated with specific symptom profiles. we examined basal activation state and functional connectivity (FC) in four subregions of the bilateral Hipp: left caudal (cHipp_L), right caudal (cHipp_R), left rostral (rHipp_L), and right rostral (rHipp_R). Resting-state functional magnetic resonance images were obtained from 62 schizophrenia patients, 57 bipolar disorder (BD) patients, and 45 healthy controls (HCs), and analyzed for fractional amplitude of low-frequency fluctuations (fALFF) as a measure of basal neural activity and for whole-brain FC with the aforementioned hippocampal subregions as seeds. The schizophrenia group exhibited greater fALFF in bilateral cHipp and rHipp subregions compared to BD and HC groups as well as greater FC between the bilateral cHipp and multiple brain regions, including the thalamus, putamen, middle frontal gyrus, parietal cortex, and precuneus. Moreover, fALFF values of the bilateral cHipp were positively correlated with the severity of clinical symptoms as measured by the Positive and Negative Syndrome Scale. These findings confirm a crucial contribution of hippocampal dysfunction, especially of the cHipp, in schizophrenia. Further, hyper-connectivity and hyperactivity of the cHipp could serve as a biomarker for therapeutic development.\u003c/p\u003e","manuscriptTitle":"Altered functional connectivity and hyperactivity of the caudal hippocampus in schizophrenia Compared with Bipolar Disorder：a resting state fMRI study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-24 16:27:32","doi":"10.21203/rs.3.rs-5179111/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-10-10T09:31:27+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-08T09:47:19+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-08T09:27:50+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Psychiatry","date":"2024-09-30T08:25:20+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bpsy","sideBox":"Learn more about [BMC Psychiatry](http://bmcpsychiatry.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bpsy/default.aspx","title":"BMC Psychiatry","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ce173d74-546a-457e-8187-cc92e71fef98","owner":[],"postedDate":"December 24th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-03-03T16:00:42+00:00","versionOfRecord":{"articleIdentity":"rs-5179111","link":"https://doi.org/10.1186/s12888-025-06632-7","journal":{"identity":"bmc-psychiatry","isVorOnly":false,"title":"BMC Psychiatry"},"publishedOn":"2025-02-27 15:57:23","publishedOnDateReadable":"February 27th, 2025"},"versionCreatedAt":"2024-12-24 16:27:32","video":"","vorDoi":"10.1186/s12888-025-06632-7","vorDoiUrl":"https://doi.org/10.1186/s12888-025-06632-7","workflowStages":[]},"version":"v1","identity":"rs-5179111","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5179111","identity":"rs-5179111","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}