Contributions of the Hippocampus and Prefrontal Cortex to the Spacing Effect

Evidence From Lesioned Patients

Li, Cuihong
Liu, Qi
Sun, Ke
Yu, Tao
Fan, Xiaotong
Wang, Jiangfei
Ren, Liankun
Yang, Jiongjiong

School of Mental Health and Psychological Sciences, Anhui Medical University
School of Psychological and Cognitive Sciences, Beijing Key Laboratory of Behavior and Mental Health, Peking University
Department of Pathology, The First Affiliated Hospital of Zhejiang University School of Medicine
Department of Functional Neurology, National Center for Children’s Health of China, Beijing Children’s Hospital, Capital Medical University
Department of Functional Neurosurgery, Beijing Institute of Functional Neurosurgery, Xuanwu Hospital, Capital Medical University
Department of Neurosurgery, Xuanwu Hospital, Capital Medical University
China International Neuroscience Institute, Beijing, China
Department of Neurosurgery, Tiantan Hospital, Capital Medical University
Department of Neurology, Xuanwu Hospital, Clinical Center for Epilepsy, Capital Medical University
National Center for Neurological Disorders, Beijing, China

Steven Paul Woods served as action editor.

Cuihong Li and Qi Liu contributed equally to this work. The data are available from the corresponding author on reasonable request. Sharing and reuse of data require the expressed written permission of the authors, as well as clearance from the Institutional Review Boards. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article.

The authors declare no competing financial interests. The work was supported by grants from the National Natural Science Foundation of China (32071027, Jiongjiong Yang), the National Natural Science Foundation of China (32200856, Cuihong Li), Natural Science Research Project of Anhui Educational Committee (KJ2021A0263, Cuihong Li), and Anhui Medical University Natural Science Foundation, Science Fund for Distinguished Young Scholars of Anhui Province (2121xkj022, Cuihong Li). The authors thank Tao Jiang from Tiantan Hospital, Capital Medical University, China, for his support on the study.

Cuihong Li contributed to conceptualization, methodology, data collection, formal analysis, visualization, and writing. Qi Liu contributed to data collection, methodology, and formal analysis. Ke Sun contributed to data collection and methodology. Tao Yu contributed to conceptualization and data collection. Xiaotong Fan contributed to data collection. Jiangfei Wang contributed to conceptualization, methodology, and data collection. Liankun Ren contributed to conceptualization, methodology, and data collection. Jiongjiong Yang contributed to supervision, conceptualization, methodology, formal analysis, visualization, and writing.

Cuihong Li played a lead role in data curation, formal analysis, methodology, visualization, and writing–original draft and an equal role in conceptualization. Qi Liu played an equal role in data curation, formal analysis, and methodology. Ke Sun played a supporting role in data curation and methodology. Tao Yu played a supporting role in conceptualization and data curation. Xiaotong Fan played a supporting role in data curation. Jiangfei Wang played a supporting role in conceptualization, data curation, and methodology. Liankun Ren played a supporting role in conceptualization, data curation, and methodology. Jiongjiong Yang played a lead role in supervision and an equal role in conceptualization, formal analysis, methodology, validation, and writing–review and editing.

Jiongjiong Yang, School of Psychological and Cognitive Sciences, Beijing Key Laboratory of Behavior and Mental Health, Peking University, Beijing 100871, P.R. China [email protected]

Received August 1, 2024

revised February 10, 2025

Accepted February 11, 2025

Neuropsychology 39(5):p 432-449, July 2025. | DOI: 10.1037/neu0001009

Objective: Although the hippocampus is critical for memory processes, recent studies have suggested that amnesic patients with hippocampal lesions can still acquire some types of memory by distributed learning rather than by massed learning. However, as these studies recruited patients with developmental amnesia, whether lesion onset influenced the spacing effect was unclear. In addition, the extent to which the prefrontal cortex (PFC) supports the spacing effect has not been explored. Method: Patients with hippocampal lesions at early onset and late onset and PFC lesions were enrolled. The participants learned face–scene pairs under single learning (i.e., once in 1 day), massed learning (i.e., four times in 1 day), and distributed learning (i.e., four times in 2 days, twice per day). Then, they performed associative recognition tasks 20 min and 1 day later. Results: The results showed that the spacing effect was significantly higher than baseline (d = 2.91) and comparable with the control groups for hippocampal lesions at early onset patients at 1 day. However, the spacing effect was significantly impaired for hippocampal lesions at late onset (d = −1.84) and PFC patients (d = −1.48) when compared with the normal groups. The repetition effect (massed vs. single learning) was significantly impaired for PFC patients at 20 min when compared with the controls (d = −1.15). Conclusions: These findings clarified the roles of the hippocampus and PFC in distributed learning and repetitive learning and suggest that early-onset hippocampal damage induces a significant reorganization in the human brain to support memory formation and retention.