{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/395156"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/395156","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Suppressing What Hurts: The Role of Prefrontal-Thalamic Pathways in Inhibitory Control of Intrusive Thoughts and Conditioned Fear","abstract":"Humans possess cognitive mechanisms which enable them to control the retrieval of unwanted thoughts. Such inhibitory control becomes extremely important when an individual is confronted with unwanted thoughts and intrusive memories. Prior research has implicated prefrontal-hippocampal interactions mediating suppression in humans; however, the precise neural pathway(s) remain unknown. Converging anatomical and functional evidence in rodents and more recently in primates suggests that the Nucleus Reuniens (NRe), a small but vital nucleus situated in the ventral midline of the thalamus plays an important role in mediating such top-down control. Further, fear extinction which forms the basis of exposure therapy has been hypothesized to employ retrieval stopping processes. If this holds true, humans may be capable of extinguishing fear by suppressing its retrieval. In rodents, the NRe has been widely implicated in fear extinction. However, to this date, there have been very few attempts to study this nucleus in the human brain, possibly due to its tiny size and lack of delineation. This thesis primarily investigates the role of the NRe in memory suppression in the human brain along with studying whether memory suppression and fear extinction share common neural pathways. Chapter 1 and Chapter 2 lay the foundation for this thesis by reviewing evidence across species demonstrating that memory suppression and fear extinction may both rely on shared prefrontal-thalamic-hippocampal mechanisms with the NRe being the thalamic hub which mediates this control. Chapter 3 consists of a meta-analysis of fMRI data (n=330) using the Think/No-Think (TNT) task which revealed that the NRe is functionally active during retrieval suppression, showing task-specific activation and connectivity with the right dorsolateral prefrontal cortex (rDLPFC) and hippocampus (HpC). Building on these findings, Chapter 4 delves into a new segmentation protocol developed for localizing the NRe in individual human brains, informed by anatomy in rodents and primates. Chapter 5 and 6 apply this segmentation to a within-subject fMRI design to study whether memory suppression and fear extinction share common neural pathways and whether the NRe plays a role in these mechanisms. Specifically, chapter 5 provides subject specific evidence that the NRe is involved during retrieval suppression, especially during reactive control as tested via the TNT task. Chapter 6 investigates fear extinction and evaluates if the NRe along with regions involved in the broader inhibitory control network are engaged during extinction. Finally, chapter 7 summarises findings from all chapters as part of this thesis and makes recommendations about future research avenues. Taken together, this thesis offers the first anatomically grounded evidence that the NRe is involved in memory suppression in humans and provides a within-subject test of the hypothesis that memory suppression and fear extinction share common neural pathways. The findings from these studies lay groundwork for future research into thalamic contributions to the regulation of maladaptive memory and emotion thus opening translational avenues for treating disorders characterised by intrusive thoughts.","abstract_html":"Humans possess cognitive mechanisms which enable them to control the retrieval of unwanted thoughts. Such inhibitory control becomes extremely important when an individual is confronted with unwanted thoughts and intrusive memories. Prior research has implicated prefrontal-hippocampal interactions mediating suppression in humans; however, the precise neural pathway(s) remain unknown. Converging anatomical and functional evidence in rodents and more recently in primates suggests that the Nucleus Reuniens (NRe), a small but vital nucleus situated in the ventral midline of the thalamus plays an important role in mediating such top-down control. Further, fear extinction which forms the basis of exposure therapy has been hypothesized to employ retrieval stopping processes. If this holds true, humans may be capable of extinguishing fear by suppressing its retrieval. In rodents, the NRe has been widely implicated in fear extinction. However, to this date, there have been very few attempts to study this nucleus in the human brain, possibly due to its tiny size and lack of delineation. This thesis primarily investigates the role of the NRe in memory suppression in the human brain along with studying whether memory suppression and fear extinction share common neural pathways. Chapter 1 and Chapter 2 lay the foundation for this thesis by reviewing evidence across species demonstrating that memory suppression and fear extinction may both rely on shared prefrontal-thalamic-hippocampal mechanisms with the NRe being the thalamic hub which mediates this control. Chapter 3 consists of a meta-analysis of fMRI data (n=330) using the Think/No-Think (TNT) task which revealed that the NRe is functionally active during retrieval suppression, showing task-specific activation and connectivity with the right dorsolateral prefrontal cortex (rDLPFC) and hippocampus (HpC). Building on these findings, Chapter 4 delves into a new segmentation protocol developed for localizing the NRe in individual human brains, informed by anatomy in rodents and primates. Chapter 5 and 6 apply this segmentation to a within-subject fMRI design to study whether memory suppression and fear extinction share common neural pathways and whether the NRe plays a role in these mechanisms. Specifically, chapter 5 provides subject specific evidence that the NRe is involved during retrieval suppression, especially during reactive control as tested via the TNT task. Chapter 6 investigates fear extinction and evaluates if the NRe along with regions involved in the broader inhibitory control network are engaged during extinction. Finally, chapter 7 summarises findings from all chapters as part of this thesis and makes recommendations about future research avenues. Taken together, this thesis offers the first anatomically grounded evidence that the NRe is involved in memory suppression in humans and provides a within-subject test of the hypothesis that memory suppression and fear extinction share common neural pathways. The findings from these studies lay groundwork for future research into thalamic contributions to the regulation of maladaptive memory and emotion thus opening translational avenues for treating disorders characterised by intrusive thoughts.","abstract_has_math":false,"creators":["Kirpalani, Mahek"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Anderson, Michael"],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-08-21","date_published":"2025-08-21","updated_at":"2026-07-22T22:24:00Z","subjects":["Emotional regulation","Fear extinction","Inhibitory control","Intrusive thoughts","Memory inhibition","Memory suppression","Mental health","Nucleus reuniens","PTSD","Retrieval stopping","Thalamus"],"languages":["eng"],"rights":[],"rights_urls":["https://www.repository.cam.ac.uk/bitstreams/d30792df-47ba-4d09-8d2b-170677e05943/download","http://purl.org/NET/rdflicense/allrightsreserved"],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.124753","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Anderson, Michael"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["Cambridge Trust, Medical Research Council, Centrum Foundation, Cambridge Philosophical Society"]},{"key":"dc:creator","label":"Author","values":["Kirpalani, Mahek"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2025-08-21"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/395156"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Emotional regulation","Fear extinction","Inhibitory control","Intrusive thoughts","Memory inhibition","Memory suppression","Mental health","Nucleus reuniens","PTSD","Retrieval stopping","Thalamus"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["https://www.repository.cam.ac.uk/bitstreams/d30792df-47ba-4d09-8d2b-170677e05943/download","http://purl.org/NET/rdflicense/allrightsreserved"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.17863/CAM.124753"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://www.repository.cam.ac.uk/bitstreams/d9df33fe-ad10-4dfa-bf62-8ad75ed5d5dc/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Humans possess cognitive mechanisms which enable them to control the retrieval of unwanted thoughts. 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This thesis primarily investigates the role of the NRe in memory suppression in the human brain along with studying whether memory suppression and fear extinction share common neural pathways. Chapter 1 and Chapter 2 lay the foundation for this thesis by reviewing evidence across species demonstrating that memory suppression and fear extinction may both rely on shared prefrontal-thalamic-hippocampal mechanisms with the NRe being the thalamic hub which mediates this control. Chapter 3 consists of a meta-analysis of fMRI data (n=330) using the Think/No-Think (TNT) task which revealed that the NRe is functionally active during retrieval suppression, showing task-specific activation and connectivity with the right dorsolateral prefrontal cortex (rDLPFC) and hippocampus (HpC). Building on these findings, Chapter 4 delves into a new segmentation protocol developed for localizing the NRe in individual human brains, informed by anatomy in rodents and primates. Chapter 5 and 6 apply this segmentation to a within-subject fMRI design to study whether memory suppression and fear extinction share common neural pathways and whether the NRe plays a role in these mechanisms. Specifically, chapter 5 provides subject specific evidence that the NRe is involved during retrieval suppression, especially during reactive control as tested via the TNT task. Chapter 6 investigates fear extinction and evaluates if the NRe along with regions involved in the broader inhibitory control network are engaged during extinction. Finally, chapter 7 summarises findings from all chapters as part of this thesis and makes recommendations about future research avenues. Taken together, this thesis offers the first anatomically grounded evidence that the NRe is involved in memory suppression in humans and provides a within-subject test of the hypothesis that memory suppression and fear extinction share common neural pathways. 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This thesis primarily investigates the role of the NRe in memory suppression in the human brain along with studying whether memory suppression and fear extinction share common neural pathways. Chapter 1 and Chapter 2 lay the foundation for this thesis by reviewing evidence across species demonstrating that memory suppression and fear extinction may both rely on shared prefrontal-thalamic-hippocampal mechanisms with the NRe being the thalamic hub which mediates this control. Chapter 3 consists of a meta-analysis of fMRI data (n=330) using the Think/No-Think (TNT) task which revealed that the NRe is functionally active during retrieval suppression, showing task-specific activation and connectivity with the right dorsolateral prefrontal cortex (rDLPFC) and hippocampus (HpC). Building on these findings, Chapter 4 delves into a new segmentation protocol developed for localizing the NRe in individual human brains, informed by anatomy in rodents and primates. Chapter 5 and 6 apply this segmentation to a within-subject fMRI design to study whether memory suppression and fear extinction share common neural pathways and whether the NRe plays a role in these mechanisms. Specifically, chapter 5 provides subject specific evidence that the NRe is involved during retrieval suppression, especially during reactive control as tested via the TNT task. Chapter 6 investigates fear extinction and evaluates if the NRe along with regions involved in the broader inhibitory control network are engaged during extinction. Finally, chapter 7 summarises findings from all chapters as part of this thesis and makes recommendations about future research avenues. Taken together, this thesis offers the first anatomically grounded evidence that the NRe is involved in memory suppression in humans and provides a within-subject test of the hypothesis that memory suppression and fear extinction share common neural pathways. 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