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Reduced cerebello-thalamo-cortical functional connectivity during traumatic memory retrieval in PTSD

Nature Mental Health volume 3, pages 1057–1069 (2025)Cite this article

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Abstract

Traumatic memory retrieval is marked by vivid sensations, temporal fragmentation and a sense of reliving the past. Here we apply an unrestricted, whole-brain connectome approach to examine neutral and traumatic memory retrieval using functional magnetic resonance imaging in 90 individuals: those with post-traumatic stress disorder (PTSD, n = 46) and its dissociative subtype (PTSD + DS, n = 19) versus trauma-exposed controls (n = 25). Both PTSD and PTSD + DS exhibited hypoconnectivity in cerebrocerebellar and basal ganglia–cerebellar circuits alongside increased intracerebellar connectivity during traumatic memory retrieval only, reflecting a segregated cerebellar topology and a breakdown in long-range cortical connections. Brainstem–cerebellar hyperconnectivity was observed in PTSD + DS relative to controls during traumatic memory retrieval and in all participants with PTSD when directly comparing traumatic versus neutral memory retrieval. PTSD + DS exhibited additional hypoconnectivity between occipital regions and the thalamus and basal ganglia. These findings suggest a disruption to subcortical–cortical ‘vertical’ integration during traumatic memory retrieval, where cerebellar-based predictive processes may be markedly altered.

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Fig. 1: PTSD and PTSD + DS versus trauma-exposed controls during neutral and traumatic memory retrieval.
Fig. 2: Brain-behavior latent factor analysis for all participants with PTSD.
Fig. 3: Schematic of large-scale functional connectivity alterations in PTSD and PTSD + DS during traumatic memory retrieval.

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Data availability

The group data (SPM files) from the ROI-to-ROI large-scale analyses reported in this article will be made available upon request and are not openly available due to ethical and privacy concerns. Please direct any such request to the corresponding author via email. We will make our best attempt to respond to any inquiries within 14 days.

Code availability

All analyses used standard SPM12, CONN (version 21a) analysis pipelines and MATLAB R2022a implementations of openly available algorithms. No custom code was used in this study.

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Acknowledgements

We thank all the individuals who participated, as well as Homewood Health in Guelph, Ontario, Canada, who facilitated referrals. We are also grateful to our dedicated research and clinical team, without whom we could not have done this work. This work was supported by infrastructure funds from the Canada Foundation for Innovation Grant (grant no. 31724 to J.T.) and Lawson Research Institute, as well as operating funds from Innovation for Defense Excellence and Security (IDEaS) (grant no. CovCA-0642 to R.A.L.), the Canadian Institute for Military and Veteran Health Research, Green Shield Canada, the Centre of Excellence on PTSD, Canada, and the Canadian Institutes of Health Research (grant no. 148784 to M.C.M. and R.A.L.). B.E.K. is supported by the Jonathan and Joshua Memorial Scholarship and Homewood Research Institute in Guelph, Ontario. R.A.L. is supported by the Harris-Woodman Chair in Psyche and Soma at Western University, and M.C.M. is supported by the Homewood Chair in Mental Health and Trauma at McMaster University.

Author information

Author notes

  1. These authors jointly supervised this work: Saurabh B. Shaw, Ruth A. Lanius.

Authors and Affiliations

  1. Neuroscience Program, Western University, London, Ontario, Canada

    Breanne E. Kearney & Ruth A. Lanius

  2. Department of Psychiatry, Western University, London, Ontario, Canada

    Maria Densmore, Jean Théberge, Saurabh B. Shaw & Ruth A. Lanius

  3. Imaging Program, Lawson Research Institute, London, Ontario, Canada

    Maria Densmore, Jean Théberge & Ruth A. Lanius

  4. Department of Medical Biophysics, Western University, London, Ontario, Canada

    Jean Théberge

  5. Institute of Mental Health Research, University of Ottawa, Ottawa, Ontario, Canada

    Rakesh Jetly

  6. Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada

    Margaret C. McKinnon

  7. Mood Disorders Program, St. Joseph’s Healthcare, Hamilton, Ontario, Canada

    Margaret C. McKinnon

  8. Homewood Research Institute, Guelph, Ontario, Canada

    Margaret C. McKinnon

  9. London Health Sciences Centre Research Institute, London, Ontario, Canada

    Ruth A. Lanius

Authors
  1. Breanne E. Kearney
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  2. Maria Densmore
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  3. Jean Théberge
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  4. Rakesh Jetly
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  5. Margaret C. McKinnon
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  6. Saurabh B. Shaw
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  7. Ruth A. Lanius
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Contributions

B.E.K.: conceptualization (analysis), methodology, data analysis and writing. M.D.: data curation and methodology. J.T.: data curation, methodology, funding acquisition and editing. R.J.: funding acquisition and conceptualization (experimental). M.C.M: conceptualization (experimental) and funding acquisition. S.B.S: conceptualization (analysis), data collection and curation, methodology, writing, editing and supervision. R.A.L.: conceptualization (experimental and analysis), data collection and curation, methodology, editing, funding acquisition and supervision.

Corresponding author

Correspondence to Ruth A. Lanius.

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Extended data

Extended Data Fig. 1 ROI-to-ROI Connectome Ring for PTSD (n = 46) > Control (n = 25) during Traumatic Memory Retrieval.

Two-sided t-tests were conducted to compare ROI-to-ROI functional connectivity strength between groups. The t-statistic bar is presented in the bottom left corner, with warm colors denoting increased and cool colors denoting decreased functional connectivity strength. The connection threshold was set to p < 0.05 uncorrected, and the cluster threshold was set to p < 0.05 cluster-level pFDR corrected (MVPA omnibus test). AAN= Ascending arousal network; AC= Anterior cingulate; AG= Angular gyrus; aITG= Inferior temporal gyrus, anterior division; aPaHC= Parahippocampal gyrus, anterior division; aSMG= Supramarginal gyrus, anterior division; aTFusC= Temporal fusiform cortex, anterior division; Cereb=Cerebellum; CO= Central operculum; FOrb= Frontal orbital cortex; FP= Frontal pole; HG= Heschl’s gyrus; IFGtri= Inferior frontal gyrus, pars triangularis; IFGoper= Inferior frontal gyrus, pars opercularis; iLOC= Inferior lateral occipital cortex; LC= Locus coeruleus; LDTg= Laterodorsal tegmental nucleus; LG= Lingual gyrus; medFC= Frontal medial cortex; mesRF= Mesencephalic reticular formation; MidFG= Middle frontal gyrus; OFusG= Occipital fusiform gyrus; OP= Occipital pole; PBC= Parabrachial complex; PaCiG= Paracingulate gyrus; PAG= Periaqueductal gray; PC= Posterior cingulate; pITG= Inferior frontal gyrus, posterior division; pMTG= Middle Temporal Gyrus, posterior division; PO= Parietal operculum; PostCG= Postcentral gyrus; pSMG= Supramarginal gyrus, posterior division; PreCG= Precentral gyrus; PT= Planum temporale; pTFusC= Temporal fusiform cortex, posterior division; ROI= Region of Interest; SMA= Supplementary motor area; sLOC= Lateral occipital cortex, superior division; SFG= Superior frontal gyrus; SPL= Superior parietal lobule; TOFusC= Temporal occipital fusiform cortex; toITG= Inferior temporal gyrus, temporooccipital part; toMTG= Middle Temporal Gyrus, temporooccipital part; TP= Temporal pole; Ver=Vermis; VTA= Ventral tegmental area.

Extended Data Fig. 2 ROI-to-ROI Connectome Ring for PTSD + DS (n = 19) > Control (n = 25) during Traumatic Memory Retrieval.

Two-sided t-tests were conducted to compare ROI-to-ROI functional connectivity strength between groups. The t-statistic bar is presented in the bottom left corner, with warm colors denoting increased and cool colors denoting decreased functional connectivity strength. The connection threshold was set to p < 0.05 uncorrected, and the cluster threshold was set to p < 0.05 cluster-level pFDR corrected (MVPA omnibus test). AAN= Ascending arousal network; AC= Anterior cingulate; AG= Angular gyrus; aITG= Inferior temporal gyrus, anterior division; aPaHC= Parahippocampal gyrus, anterior division; aSMG= Supramarginal gyrus, anterior division; aTFusC= Temporal fusiform cortex, anterior division; Cereb=Cerebellum; Cuneal= Cuneal cortex; FP= Frontal pole; ICC= Intracalcarine cortex; IFGtri= Inferior frontal gyrus, pars triangularis; iLOC= Lateral occipital cortex, inferior division; LC= Locus coeruleus; LG= Lingual gyrus; MedRaphe= Median raphe; mesRF= Mesencephalic reticular formation; OFusG= Occipital fusiform gyrus; OP= Occipital pole; PaCiG= Paracingulate gyrus; PAG= Periaqueductal gray; pITG= Inferior temporal gyrus, posterior division; pMTG= Middle Temporal Gyrus, posterior division; PO= Parietal operculum; pPaHC= Parahippocampal gyrus, posterior division; PontRF= Pontine reticular formation; PPN= Pedunculopontine nucleus; PreCG= Precentral gyrus; PostCG= Postcentral gyrus; pSTG= Superior temporal gyrus, posterior division; pTFusC= Temporal fusiform cortex, posterior division; ROI= Region of Interest; SCC= Supracalcarine cortex; sLOC= Lateral occipital cortex, superior division; TOFusC= Temporal occipital fusiform cortex; toITG= inferior temporal gyrus, temporooccipital part; toMTG= Middle Temporal Gyrus, temporooccipital part; Ver=Vermis; VTA= Ventral tegmental area.

Extended Data Fig. 3 Traumatic Memory Retrieval > Neutral Memory Retrieval in all PTSD individuals (PTSD + PTSD + DS; n = 65) vs Controls (n = 25).

Corresponding to Supplementary Table 2b. Two-sided t-tests were conducted to compare ROI-to-ROI functional connectivity strength between groups. Blue denotes decreased and red denotes increased functional connectivity strength; colours are non-thresholded and thus are for visualization purposes. The connection threshold was set to p < 0.05 uncorrected, and the cluster threshold was set to p < 0.05 cluster-level pFDR corrected (MVPA omnibus test). ROI= Region of Interest.

Extended Data Fig. 4 ROI-to-ROI Connectome Ring for Traumatic Memory Retrieval > Neutral Memory Retrieval in all PTSD individuals (PTSD + PTSD + DS; n = 65) vs Controls (n = 25).

Corresponding to Supplementary Table 2b. Two-sided t-tests were conducted to compare ROI-to-ROI functional connectivity strength between groups. No significant differences emerged for this contrast for trauma-exposed controls (n = 25). The t-statistic bar is presented in the bottom left corner, with warm colors denoting increased and cool colors denoting decreased functional connectivity strength. The connection threshold was set to p < 0.05 uncorrected, and the cluster threshold was set to p < 0.05 cluster-level pFDR corrected (MVPA omnibus test). AAN= Ascending arousal network; AC= Anterior cingulate; AG= Angular gyrus; aITG= Inferior temporal gyrus, anterior division; aMTG= Middle temporal gyrus, anterior division; aPaHC= Parahippocampal gyrus, anterior division; aSMG= Supramarginal gyrus, anterior division; aSTG= Superior temporal gyrus, anterior division; aTFusC= Temporal fusiform cortex, anterior division; Cereb=Cerebellum; CO= Central operculum; FO= Frontal operculum; FP= Frontal pole; HG= Heschl’s gyrus; IC= Insular cortex; IFGtri= Inferior frontal gyrus, pars triangularis; IFGoper= Inferior frontal gyrus, pars opercularis; LC= Locus coeruleus; LDTg= Laterodorsal tegmental nucleus; medRaphe= Median Raphe; mesRF= Mesencephalic reticular formation; MidFG= Middle frontal gyrus; PBC= Parabrachial complex; PaCiG= Paracingulate gyrus; PAG= Periaqueductal gray; PontRF= Pontine reticular formation; PC= Posterior cingulate; pITG= Inferior frontal gyrus, posterior division; pMTG= Middle Temporal Gyrus, posterior division; PO= Parietal operculum; PostCG= Postcentral gyrus; PP= Planum Polare; PPN= Pedunculopontine nucleus; ROI= Region of Interest; pSMG= Supramarginal gyrus, posterior division;; PreCG= Precentral gyrus; pSTG= Superior temporal gyrus, posterior division; PreCG= Precentral gyrus; PT= Planum temporale; pTFusC= Temporal fusiform cortex, posterior division; SMA= Supplementary motor area; sLOC= Lateral occipital cortex, superior division; SFG= Superior frontal gyrus; SPL= Superior parietal lobule; TOFusC= Temporal occipital fusiform cortex; toITG= Inferior temporal gyrus, temporooccipital part; toMTG= Middle Temporal Gyrus, temporooccipital part; TP= Temporal pole; Ver=Vermis.

Extended Data Fig. 5 Traumatic Memory Retrieval > Neutral Memory Retrieval in PTSD alone (n = 46) vs Controls (n = 25).

Corresponding to Supplementary Table 2c. Two-sided t-tests were conducted to compare ROI-to-ROI functional connectivity strength between groups. No significant differences emerged for this contrast for trauma-exposed controls (n = 25) or PTSD + DS (n = 19). Blue denotes decreased and red denotes increased functional connectivity strength; colours are non-thresholded and thus are for visualization purposes. The connection threshold was set to p < 0.05 uncorrected, and the cluster threshold was set to p < 0.05 cluster-level pFDR corrected (MVPA omnibus test). ROI= Region of Interest.

Extended Data Fig. 6 ROI-to-ROI Connectome Ring for Traumatic Memory Retrieval > Neutral Memory Retrieval in PTSD alone (n = 46) vs Controls (n = 25).

Corresponding to Supplementary Table 2c. Two-sided t-tests were conducted to compare ROI-to-ROI functional connectivity strength between groups. No significant differences emerged for this contrast for trauma-exposed controls (n = 25) or PTSD + DS (n = 19). The t-statistic bar is presented in the bottom left corner, with warm colors denoting increased and cool colors denoting decreased functional connectivity strength. The connection threshold was set to p < 0.05 uncorrected, and the cluster threshold was set to p < 0.05 cluster-level pFDR corrected (MVPA omnibus test). AAN= Ascending arousal network; AC= Anterior cingulate; AG= Angular gyrus; aSMG= Supramarginal gyrus, anterior division; Cereb=Cerebellum; FP= Frontal pole; IFGtri= Inferior frontal gyrus, pars triangularis; LC= Locus coeruleus; MedRaphe= Median raphe; midFG= Middle frontal gyrus; PaCiG= Paracingulate gyrus; PAG= Periaqueductal gray; PBC= Parabrachial complex; pPaHC= Parahippocampal gyrus, posterior division; PPN= Pedunculopontine nucleus; pSMG= Supramarginal gyrus, posterior division; ROI= Region of Interest; sLOC= Lateral occipital cortex, superior division; SPL= Superior parietal lobule; toITG= inferior temporal gyrus, temporooccipital part; toMTG= Middle Temporal Gyrus, temporooccipital part; Ver=Vermis.

Extended Data Fig. 7 fMRI paradigm.

Eight-minute resting-state scans were conducted before and after the experimental conditions. For the experimental conditions, participants were instructed to recall their neutral and traumatic memories when presented visually and aurally with their predetermined, personalized script. Scripts were presented one sentence at a time, for a total of eight sentences per memory. After sentence presentation (five seconds), participants spent 25 seconds retrieving that part of their memory in as vivid of detail as possible. Each sentence and its memory retrieval were followed by presentation of a virtual avatar with direct or averted gaze followed by a fixation cross for the purposes of separate analyses. Figure is adapted from previous work21 and was created using BioRender.com.

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Kearney, B.E., Densmore, M., Théberge, J. et al. Reduced cerebello-thalamo-cortical functional connectivity during traumatic memory retrieval in PTSD. Nat. Mental Health 3, 1057–1069 (2025). https://doi.org/10.1038/s44220-025-00476-6

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