Acute thalamic connectivity precedes chronic post-concussive symptoms in mild traumatic brain injury
Authors: Woodrow Rebecca E , Winzeck Stefan , Luppi Andrea I , Kelleher-Unger Isaac R , Spindler Lennart R B , Wilson J T Lindsay , Newcombe Virginia F J , Coles Jonathan P ,   CENTER-TBI MRI Substudy Participants and Investigators, Amrein Krisztina , Andelic Nada , Andreassen Lasse , Anke Audny , Azouvi Philippe , Bellander Bo-Michael , Benali Habib , Buki Andras , Caccioppola Alessio , Calappi Emiliana , Carbonara Marco , Citerio Giuseppe , Clusmann Hans , Coburn Mark , Coles Jonathan , Correia Marta , Czeiter Endre , De Keyser Véronique , Degos Vincent , Depreitere Bart , Eikenes Live , Ezer Erzsébet , Foks Kelly , Frisvold Shirin , Ghuysen Alexandre , Galanaud Damien , Glocker Ben , Haberg Asta , Haitsma Iain , Helseth Eirik , Hutchinson Peter J , Kornaropoulos Evgenios , Kovács Noémi , Kowark Ana , Laureys Steven , Ledoux Didier , Lingsma Hester , Maas Andrew I R , Manley Geoffrey , Menon David K , Menovsky Tomas , Misset Benoit , Muraleedharan Visakh , Nakken Ingeborg , Newcombe Virginia , Nordhøy Wibeke , Nyirádi József , Ortolano Fabrizio , Parizel Paul M , Perlbarg Vincent , Persona Paolo , Peul Wilco , Posti Jussi P , Puybasset Louis , Richter Sophie , Roe Cecilie , Roise Olav , Rossaint Rolf , Rossi Sandra , Rueckert Daniel , Skandsen Toril , Sorinola Abayomi , Stamatakis Emmanuel , Steyerberg Ewout W , Stocchetti Nino , Takala Riikka , Tamás Viktória , Tenovuo Olli , Vámos Zoltán , Van der Steen Gregory , Van Hecke Wim , Vyvere Thijs Vande , Verheyden Jan , Vik Anne , Volovici Victor , Westlye Lars T , Williams Guy , Winzeck Stefan , Ylén Peter , Zoerle Tommaso , Menon David K , Stamatakis Emmanuel A 
Published: February 2023

Abstract
Chronic post-concussive symptoms are common after mild traumatic brain injury (mTBI) and are difficult to predict or treat. Thalamic functional integrity is particularly vulnerable in mTBI and may be related to long-term outcomes but requires further investigation.
We compared structural MRI and resting state functional MRI in 108 patients with a Glasgow Coma Scale (GCS) of 13–15 and normal CT, and 76 controls. We examined whether acute changes in thalamic functional connectivity were early markers for persistent symptoms and explored neurochemical associations of our findings using PET data.
Of the mTBI cohort, 47% showed incomplete recovery 6 months post-injury. Despite the absence of structural changes, we found acute thalamic hyperconnectivity in mTBI, with specific vulnerabilities of individual thalamic nuclei. Acute fMRI markers differentiated those with chronic post-concussive symptoms, with time- and outcome-dependent relationships in a sub-cohort followed longitudinally. Moreover, emotional and cognitive symptoms were associated with changes in thalamic functional connectivity to known serotonergic and noradrenergic targets, respectively.
Our findings suggest that chronic symptoms can have a basis in early thalamic pathophysiology. This may aid identification of patients at risk of chronic post-concussive symptoms following mTBI, provide a basis for development of new therapies and facilitate precision medicine application of these therapies.