Imaging & Neuroscience

Imaging & Neuroscience

Pathophysiology of posterior fossa syndrome

Group lead: Mina Langhein, MD · Co-lead: Stuart McAfee, PhD

Which brain structures does surgery injure in posterior fossa syndrome (PFS), and how does that injury produce its symptoms? This page summarizes the current evidence, from lesion mapping in children to basic neuroscience.

What surgery injures

Anatomic substrates

The neuronal structures compromised during surgery that initiate the disease process of posterior fossa syndrome.

How injury becomes symptoms

Mechanisms

The neurofunctional changes that unfold during the disease process and lead to the expression of its core symptoms.

Anatomic substrates

Only a handful of studies have measured surgical injury directly, mapping the location and extent of resection against which children developed the syndrome.1, 2, 3 Together they converge on a small set of nuclear, peri-nuclear, and lobular regions that process information in the medial cerebellum, as well as axonal transection injuries that disrupt cerebellar outflow.

  • Deep cerebellar nuclei. In 195 children, severe postoperative cognitive and affective disturbance mapped to the fastigial nuclei, where the association peaked, and to the interposed and medial dentate nuclei.1 Complete mutism was linked to damage of the right fastigial nucleus in particular.2
  • Superior cerebellar peduncles. The same mapping implicated the superior cerebellar peduncles, which Albazron and colleagues described as an anatomic bottleneck: because all cerebellar output passes through them, small lesions can disrupt connections serving many functions at once.1 Damage to the proximal peduncles, just beyond the nuclei, was associated with complete mutism.2
  • Inferior vermis. Lesions of the inferior vermis, lobules VIII to X, were associated with the syndrome, both in the original lesion-symptom map and in children with complete mutism.1, 2
  • Extent matters. The rate of the syndrome rises progressively with the degree to which a lesion overlaps the cerebellar outflow pathway.3

How these injuries appear on MRI is covered on our radiology page.

Mechanisms

The exact mechanisms at play are not known. The delayed onset, in which children wake from surgery speaking and become mute hours or days later, suggests that the surgical injury does not produce the symptoms directly. Instead, it appears to trigger secondary changes in the brain regions that depend on cerebellar output, and those changes produce the symptoms. Therefore, most pathophysiology research focuses on connections the cerebellum makes with other brain regions, and the functions those other regions mediate. Five mechanisms, not mutually exclusive, have been proposed:

Cerebello-cerebral diaschisis

Injury to the dentato-thalamo-cortical tract may leave connected regions of the cerebral cortex underactive.

The dentato-thalamo-cortical tract carries output from the cerebellum to wide areas of the cerebral cortex, including motor, premotor, and prefrontal regions, supporting both cognition and goal-directed action.4, 5 Injury to the tract is thought to leave connected cortex underactive, a phenomenon called diaschisis. This is consistent with the reduced frontal perfusion seen on SPECT, arterial spin labeling, and DSC imaging,6, 7 with parallels to supplementary motor area syndrome.8 Diffusion imaging studies have shown the pathway to be compromised in patients with PFS,4, 9, 10, 11, 12 and the laterality of tract changes strongly predicts the laterality of motor deficits.12

Disordered gating of movement and speech

Loss of cerebellar output to the midbrain may suppress the drive to speak and move.

Disrupted vermal and fastigial output to the periaqueductal gray, a midbrain hub that gates vocalization and movement, may inhibit the execution of speech and movement.2 Functional MRI has revealed that children with PFS show impaired coordination between cortical speech regions and the periaqueductal gray.13 In animal models, fastigial neurons excite periaqueductal gray neurons that drive freezing,14 and periaqueductal gray neurons gate vocalization, integrating forebrain signals that promote or suppress calls.15 Stimulating cerebellar output through the superior cerebellar peduncle in mice suppresses social vocalization through the periaqueductal gray, even without overt motor impairment, apparently by acting on the decision to vocalize rather than the mechanics of producing sound.16

Dysregulated defensive learning

Loss of vermal and fastigial regulation may bias how defensive responses are learned, consolidated, and extinguished.

The same circuits implicated in vocal gating also shape how fear responses are learned and maintained. Vermal lobule VIII is a key node linking the periaqueductal gray to fear-evoked freezing.17 Fastigial output to the periaqueductal gray regulates how strongly fear associations form and how readily they are extinguished,18, 19 its projection to the mediodorsal thalamus supports fear extinction,20 and the vermis contributes to consolidating fear memories over several days.21 In mice, even brief suppression of fastigial output altered innate fear responses a day later.22 Because surgical injury removes this regulation, it could bias children toward stronger, longer-lasting, and harder-to-extinguish defensive states such as freezing and vocal suppression, consistent with the delayed onset of mutism and apraxia.

Emotional dysregulation through a vermal–parabrachial pathway

Loss of vermal inhibition of a forebrain-projecting brainstem hub may disrupt emotional regulation.

In mice, Purkinje cells of the posterior vermis, chiefly lobules VIII to X, directly inhibit parabrachial nucleus neurons23, 24, 25 that project to forebrain regions involved in emotion and arousal, including the amygdala, basal forebrain, and septum. They provide about half of all inhibitory (GABAergic) synapses in the parabrachial nucleus.25 This route bypasses the deep nuclei, and suppressing it is aversive.25 Injury to the inferior vermis could therefore cause a substantial loss of inhibition in the parabrachial nucleus, contributing to the affective symptoms of the syndrome.

Maladaptive cerebellar plasticity

Disrupted teaching signals may cause the cerebellar cortex to send abnormal output through tracts that remain intact.

Cerebellar learning depends on teaching signals carried by climbing fibers from the inferior olive, which is itself held in check by inhibitory feedback from the deep cerebellar nuclei. Injury to the dentate nucleus or superior cerebellar peduncle can remove that feedback, and the resulting hypertrophic olivary degeneration is significantly associated with PFS.26, 27, 28 There is evidence that PFS diagnosis leads to plasticity in the cerebellar cortex which feeds the dentato-thalamo-cortical pathway,29 which may result in sustained abnormal signaling between cerebellum and cerebrum in patients with intact dentato-thalamo-cortical tracts.13, 29 Disrupted olivary signals may drive this plasticity over weeks to months, contributing mainly to chronic features. Whether loss of signaling and abnormal signaling affect outcomes differently remains an open question.

Selected references

  1. Albazron FM, Bruss J, Jones RM, et al. Pediatric postoperative cerebellar cognitive affective syndrome follows outflow pathway lesions. Neurology. 2019;93(16):e1561–e1571. Link
  2. McAfee SS, Zhang S, Zou P, et al. Fastigial nuclei surgical damage and focal midbrain disruption implicate PAG survival circuits in cerebellar mutism syndrome. Neuro Oncol. 2023;25(2):375–385. Link
  3. Skye J, Bruss J, Toescu S, et al. Neuroanatomy of cerebellar mutism syndrome: the role of lesion location. Brain Commun. 2024;6(4):fcae197. Link
  4. Morris EB, Phillips NS, Laningham FH, et al. Proximal dentatothalamocortical tract involvement in posterior fossa syndrome. Brain. 2009;132(Pt 11):3087–3095. Link
  5. Krimmel SR, Laumann TO, Chauvin RJ, et al. The brainstem's red nucleus was evolutionarily upgraded to support goal-directed action. Nat Commun. 2025;16:3398. Link
  6. Miller NG, Reddick WE, Kocak M, et al. Cerebellocerebral diaschisis is the likely mechanism of postsurgical posterior fossa syndrome in pediatric patients with midline cerebellar tumors. AJNR Am J Neuroradiol. 2010;31(2):288–294. Link
  7. Ahmadian N, van Baarsen KM, Robe P, Hoving EW. Association between cerebral perfusion and paediatric postoperative cerebellar mutism syndrome after posterior fossa surgery: a systematic review. Childs Nerv Syst. 2021;37(9):2743–2751. Link
  8. Grønbæk J, Molinari E, Avula S, et al. The supplementary motor area syndrome and the cerebellar mutism syndrome: a pathoanatomical relationship? Childs Nerv Syst. 2020;36(6):1197–1204. Link
  9. Avula S, Kumar R, Pizer B, et al. Diffusion abnormalities on intraoperative magnetic resonance imaging as an early predictor for the risk of posterior fossa syndrome. Neuro Oncol. 2015;17(4):614–622. Link
  10. Vedantam A, Stormes KM, Gadgil N, et al. Association between postoperative DTI metrics and neurological deficits after posterior fossa tumor resection in children. J Neurosurg Pediatr. 2019;24(4):364–370. Link
  11. Toescu SM, Bruckert L, Jabarkheel R, et al. Spatiotemporal changes in along-tract profilometry of cerebellar peduncles in cerebellar mutism syndrome. NeuroImage Clin. 2022;35:103000. Link
  12. Ji Q, McAfee SS, Scoggins M, et al. Cerebellar mutism syndrome and dentato-thalamo-cortical tract disruption in diffusion tractography following surgery for medulloblastoma. Radiology. 2024;311(2):e232521. Link
  13. McAfee SS, Robinson G, Gajjar A, et al. Cerebellar mutism is linked to midbrain volatility and desynchronization from speech cortices. Brain. 2023;146(11):4755–4765. Link
  14. Vaaga CE, Brown ST, Raman IM. Cerebellar modulation of synaptic input to freezing-related neurons in the periaqueductal gray. eLife. 2020;9:e54302. Link
  15. Michael V, Goffinet J, Pearson J, et al. Circuit and synaptic organization of forebrain-to-midbrain pathways that promote and suppress vocalization. eLife. 2020;9:e63493. Link
  16. Brandenburg C, Srivastava S, Rey Hipolito AG, Lin T, Arenkiel BR, Sillitoe RV. Frequency-dependent cerebellar circuits independently gate social vocalizations and movement. iScience. 2026;29:117706. Link
  17. Koutsikou S, et al. Neural substrates underlying fear-evoked freezing: the periaqueductal grey–cerebellar link. J Physiol. 2014. Link
  18. Frontera JL, Baba Aissa H, Sala RW, et al. Bidirectional control of fear memories by cerebellar neurons projecting to the ventrolateral periaqueductal grey. Nat Commun. 2020;11:5207. Link
  19. Lawrenson C, et al. Cerebellar modulation of memory encoding in the periaqueductal grey and fear behaviour. eLife. 2022;11:e76278. Link
  20. Frontera JL, et al. The cerebellum regulates fear extinction through thalamo-prefrontal cortex interactions in male mice. Nat Commun. 2023. Link
  21. Sacchetti B, Baldi E, Lorenzini CA, Bucherelli C. Cerebellar role in fear-conditioning consolidation. Proc Natl Acad Sci USA. 2002;99(12):8406–8411. Link
  22. McGann RA, et al. Optogenetic stimulation of Purkinje cells in the cerebellar vermis disrupts innate freezing behaviors and is highly aversive [preprint]. bioRxiv. 2026. Link
  23. Hashimoto M, Yamanaka A, Kato S, Tanifuji M, Kobayashi K, Yaginuma H. Anatomical evidence for a direct projection from Purkinje cells in the mouse cerebellar vermis to medial parabrachial nucleus. Front Neural Circuits. 2018;12:6. Link
  24. Novello M, Bosman LWJ, De Zeeuw CI. A systematic review of direct outputs from the cerebellum to the brainstem and diencephalon in mammals. Cerebellum. 2024;23(1):210–239. Link
  25. Chen CH, Newman LN, Stark AP, et al. A Purkinje cell to parabrachial nucleus pathway enables broad cerebellar influence over the forebrain. Nat Neurosci. 2023;26(11):1929–1941. Link
  26. Khan RB, Patay Z, Klimo P, et al. Clinical features, neurologic recovery, and risk factors of postoperative posterior fossa syndrome and delayed recovery: a prospective study. Neuro Oncol. 2021;23(9):1586–1596. Link
  27. Avula S, Spiteri M, Kumar R, et al. Post-operative pediatric cerebellar mutism syndrome and its association with hypertrophic olivary degeneration. Quant Imaging Med Surg. 2016;6(5):535–544. Link
  28. Pinto SN, Scoggins MA, Patni T, et al. Longitudinal signal changes in the dentato-rubro-olivary pathway of patients with posterior fossa syndrome. Neuro-Oncol Pract. 2026. Link
  29. McAfee SS, Robinson G, Gajjar A, et al. Secondary cerebro-cerebellar and intra-cerebellar dysfunction in cerebellar mutism syndrome. Neuro Oncol. 2024;26(9):1700–1711. Link

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Society members can join this group by contacting the Imaging & Neuroscience lead or co-lead or writing to info@posteriorfossasociety.org. Not yet a member? Membership is open to clinicians and researchers working on posterior fossa syndrome.

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