CClinicalTrials.gg
RecruitingNCT04439552Updated Dec 19, 2025

fMRI and IVCM Cornea Microscopy of CXL in Keratoconus

An observational study in Pain, Postoperative, Pain, Chronic and Pain, Acute, sponsored by Boston Children's Hospital. Recruiting at 1 site in United States. Open to participants aged 8 Years to 35 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2025-12-19.

Sponsored by Boston Children's Hospital · Observational

Study type
Observational
Model
Cohort
Time perspective
Prospective
Enrollment
60
Ages
8 Years to 35 Years
Sex
All
01

Study summary

Evaluation of neuroplasticity of pain pathways and corneal afferent nerve regeneration following corneal crosslinking (CXL) in keratoconus patients using fMRI and corneal In Vivo Confocal Microscopy (IVCM).

Read the detailed description

Our long-term goal is to evaluate the transition from acute to chronic pain that sometimes occurs following CXL in keratoconus patients. This study will determine whether these changes can be structurally and functionally quantified using functional neuroimaging and in vivo corneal microscopy (IVCM), and whether they can be predicted based on predisposing biological and psychological factors. Our central hypothesis is that CXL produces acute pain through activation of trigeminal afferents, and that post-operative chronic pain outcomes are related to neuroplastic changes in trigeminal circuitry, corneal afferent regeneration, and psychological factors.

02

Conditions studied

  • Pain, Postoperative
  • Pain, Chronic
  • Pain, Acute
  • Surgical Injury
  • Surgical Wound
  • Cornea Injury
  • Cornea
  • Keratoconus

Keywords

  • fMRI
  • Corneal Microscopy
  • IVCM
  • Neuroimaging
03

Who can participate

Ages eligible
8 Years to 35 Years
Sexes eligible
All
Accepts healthy volunteers
Yes
Sampling method
Non-probability sample

Study population

The population under study are patients with keratoconus who are undergoing a corneal cross-linking (CXL) procedure. Keratoconus is an eye condition where the cornea progressively develops abnormally into a cone shape, which can lead to distorted vision and irreversible vision loss The CXL procedure is designed to restore and maintain the shape of the cornea to avoid these complications.

Inclusion criteria

CXL Group

  • Age 8-35 years
  • Clinical diagnosis of keratoconus and seeking CXL treatment
  • English speaking ability sufficient to comprehend consent with parental assistance
  • MRI compatible
  • Ability to lie still for an MRI session (60 minutes)

Control Group

  • Age 8-35 years
  • No diagnosis of keratoconus
  • English speaking ability sufficient to comprehend consent with parental assistance
  • MRI compatible
  • Ability to lie still for an MRI session (60 minutes)

Exclusion criteria

Exclusion Criteria (Both Groups):

  • Claustrophobic
  • Weight > 285 lbs (weight limit of the MRI table)
  • Significant medical history, including:

Current DSM-IV-TR axis I psychiatric disorders. Chronic pain Significant head injury Seizures Brain tumor Cerebrovascular accident Neurological disease aside from migraine HIV-AIDs Prescription medication strongly implicated in causing dry eyes

  • Magnetic implants or metal-containing tattoos on their chest or above
  • Pregnancy
  • History of contact lens wear
  • Any allergic response to a numbing eyedrop in the past
04

Study design

Observational model
Cohort
Time perspective
Prospective
Enrollment
60 participants (estimated)
Patient registry
No

Groups and cohorts

  • CXL group

    Patients who are about to undergo a corneal cross-linking (CXL) surgery to treat keratoconus.

  • Control group

    Healthy volunteers age and sex matched to the CXL group.

05

What researchers measure

Primary outcomes

  1. Neural activity related to pain.

    Pain-related brain activation measured with fMRI.

    Time frame: 1 year

  2. Corneal nerve morphology.

    Afferent nerve fiber morphology measured with IVCM.

    Time frame: 1 year

06

Study locations

1 of 1 sites recruiting
07

References and documents

Publications

  • Belmonte C, Acosta MC, Merayo-Lloves J, Gallar J. What Causes Eye Pain? Curr Ophthalmol Rep. 2015;3(2):111-121. doi: 10.1007/s40135-015-0073-9. PubMed 26000205 ↗
  • Borsook D, Youssef AM, Simons L, Elman I, Eccleston C. When pain gets stuck: the evolution of pain chronification and treatment resistance. Pain. 2018 Dec;159(12):2421-2436. doi: 10.1097/j.pain.0000000000001401. PubMed 30234696 ↗
  • Cruzat A, Qazi Y, Hamrah P. In Vivo Confocal Microscopy of Corneal Nerves in Health and Disease. Ocul Surf. 2017 Jan;15(1):15-47. doi: 10.1016/j.jtos.2016.09.004. Epub 2016 Oct 19. PubMed 27771327 ↗
  • Downie LE, Naranjo Golborne C, Chen M, Ho N, Hoac C, Liyanapathirana D, Luo C, Wu RB, Chinnery HR. Recovery of the sub-basal nerve plexus and superficial nerve terminals after corneal epithelial injury in mice. Exp Eye Res. 2018 Jun;171:92-100. doi: 10.1016/j.exer.2018.03.012. Epub 2018 Mar 14. PubMed 29550279 ↗
  • Ghanem VC, Ghanem RC, de Oliveira R. Postoperative pain after corneal collagen cross-linking. Cornea. 2013 Jan;32(1):20-4. doi: 10.1097/ICO.0b013e31824d6fe3. PubMed 22547128 ↗
  • Hruschak V, Cochran G. Psychosocial predictors in the transition from acute to chronic pain: a systematic review. Psychol Health Med. 2018 Dec;23(10):1151-1167. doi: 10.1080/13548506.2018.1446097. Epub 2018 Feb 28. PubMed 29490476 ↗
  • Hasenbring MI, Chehadi O, Titze C, Kreddig N. Fear and anxiety in the transition from acute to chronic pain: there is evidence for endurance besides avoidance. Pain Manag. 2014;4(5):363-74. doi: 10.2217/pmt.14.36. PubMed 25350076 ↗
  • Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet. 2006 May 13;367(9522):1618-25. doi: 10.1016/S0140-6736(06)68700-X. PubMed 16698416 ↗
  • Kennedy RH, Bourne WM, Dyer JA. A 48-year clinical and epidemiologic study of keratoconus. Am J Ophthalmol. 1986 Mar 15;101(3):267-73. doi: 10.1016/0002-9394(86)90817-2. PubMed 3513592 ↗
  • Kinard KI, Smith AG, Singleton JR, Lessard MK, Katz BJ, Warner JE, Crum AV, Mifflin MD, Brennan KC, Digre KB. Chronic migraine is associated with reduced corneal nerve fiber density and symptoms of dry eye. Headache. 2015 Apr;55(4):543-9. doi: 10.1111/head.12547. Epub 2015 Mar 31. PubMed 25828778 ↗
  • Larbig W, Andoh J, Huse E, Stahl-Corino D, Montoya P, Seltzer Z, Flor H. Pre- and postoperative predictors of phantom limb pain. Neurosci Lett. 2019 May 29;702:44-50. doi: 10.1016/j.neulet.2018.11.044. Epub 2018 Nov 29. PubMed 30503915 ↗
  • Moulton EA, Becerra L, Borsook D. An fMRI case report of photophobia: activation of the trigeminal nociceptive pathway. Pain. 2009 Oct;145(3):358-363. doi: 10.1016/j.pain.2009.07.018. Epub 2009 Aug 11. PubMed 19674842 ↗
  • Moulton EA, Borsook D. C-Fiber Assays in the Cornea vs. Skin. Brain Sci. 2019 Nov 12;9(11):320. doi: 10.3390/brainsci9110320. PubMed 31718074 ↗
  • Rosenthal P, Borsook D, Moulton EA. Oculofacial Pain: Corneal Nerve Damage Leading to Pain Beyond the Eye. Invest Ophthalmol Vis Sci. 2016 Oct 1;57(13):5285-5287. doi: 10.1167/iovs.16-20557. PubMed 27723896 ↗
  • Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of the Ocular Surface Disease Index. Arch Ophthalmol. 2000 May;118(5):615-21. doi: 10.1001/archopht.118.5.615. PubMed 10815152 ↗
  • Simone DA, Nolano M, Johnson T, Wendelschafer-Crabb G, Kennedy WR. Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: correlation with sensory function. J Neurosci. 1998 Nov 1;18(21):8947-59. doi: 10.1523/JNEUROSCI.18-21-08947.1998. PubMed 9787000 ↗
  • Sjoberg J, Kanje M. The initial period of peripheral nerve regeneration and the importance of the local environment for the conditioning lesion effect. Brain Res. 1990 Oct 8;529(1-2):79-84. doi: 10.1016/0006-8993(90)90812-p. PubMed 2282506 ↗
  • Tervo K, Latvala TM, Tervo TM. Recovery of corneal innervation following photorefractive keratoablation. Arch Ophthalmol. 1994 Nov;112(11):1466-70. doi: 10.1001/archopht.1994.01090230080025. PubMed 7980137 ↗
  • Pondelis NJ, Moulton EA. Supraspinal Mechanisms Underlying Ocular Pain. Front Med (Lausanne). 2022 Feb 8;8:768649. doi: 10.3389/fmed.2021.768649. eCollection 2021. PubMed 35211480 ↗
  • van der Valk Bouman ES, Pump H, Borsook D, Severinsky B, Wisse RP, Saeed HN, Moulton EA. Pain mechanisms and management in corneal cross-linking: a review. BMJ Open Ophthalmol. 2021 Nov 29;6(1):e000878. doi: 10.1136/bmjophth-2021-000878. eCollection 2021. PubMed 34901466 ↗
  • Dieckmann G, Borsook D, Moulton E. Neuropathic corneal pain and dry eye: a continuum of nociception. Br J Ophthalmol. 2022 Aug;106(8):1039-1043. doi: 10.1136/bjophthalmol-2020-318469. Epub 2021 Apr 30. PubMed 33931393 ↗

Individual participant data

Plan to share: Yes — All IPD that underlie results in a publication

Supporting information: Study protocol, Sap, Icf, Csr, Analytic code

08

Registry details

Key details

Study ID
NCT04439552
Lead sponsor
Boston Children's Hospital
Responsible party
Eric Moulton (Assistant Professor of Anesthesia, Boston Children's Hospital) — Principal investigator
First posted
Jun 19, 2020
Start date
Oct 4, 2021
Primary completion
Aug 2027 (estimated)
Completion
Dec 2027 (estimated)
Last update
Dec 19, 2025

Study contacts

Eric A Moulton, OD PhD
Contact
eric.moulton@childrens.harvard.edu
617-919-6827
Nicholas J Pondelis, BA
Contact
nicholas.pondelis@childrens.harvard.edu
617-919-1895
Eric A Moulton, OD PhD
principal investigator · Boston Children's Hospital

Oversight

Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

Interested in this study?

Eligibility is decided by the study team. Share this record with your doctor or contact the team directly.

Contact study team

Follow this study

Get an email when the registry record changes — status, dates, results — or when someone posts here.

Sign in to follow

Discussion

Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.

Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

Start the discussion