30 Objective: Primary motor (M1) cortical excitability alterations are involved in the 31 development and maintenance of chronic pain. Less is known about M1-cortical 32 excitability implications in the acute phase of an orthopedic trauma. This study aims to 33 assess acute M1-cortical excitability in patients with an isolated upper limb fracture 34 (IULF) in relation to pain intensity.35 Methods: Eighty-four (56 IULF patients <14 days post-trauma and 28 healthy controls) 36 performed a single transcranial magnetic stimulation (TMS) session over M1 (resting 37 motor threshold (rMT); short-intracortical inhibition (SICI); intracortical facilitation 38 (ICF); long-interval cortical inhibition (LICI)). IULF patients were divided into two 39 subgroups according to pain intensity (mild versus moderate to severe pain). 40 Results: Reduced SICI and ICF were found in IULF patients with moderate to severe 41 pain, whereas mild pain was not associated with M1 alterations. Age, sex, and time since 42 the accident had no influence on TMS measures. 43 Discussion: These findings show altered M1 in the context of acute moderate to severe 44 pain, suggesting early signs of altered GABAergic inhibitory and glutamatergic 45 facilitatory activities. 46 47 48 65 [8,9]. More specifically, this non-invasive technique has made it possible to shed light on 66 the activity of the inhibitory and facilitatory interneuronal circuits of various targeted 67 systems [8,9]. In chronic pain studies, the primary motor cortex (M1) commonly serves 68 as the targeted brain region due to its connections with the nociceptive system and the 69 known effect of pain on motor function [10,11]. An added value of stimulating M1 is the 70 ability to establish a causal relationship between the administered stimulus (excitation or 71 inhibition) and the recorded output response (i.e. motor evoked potentials). Despite some 4 72 variability across TMS studies, there is extensive evidence of an altered balance between 73 inhibitory and facilitatory circuits of M1 in various chronic pain conditions (i.e. 74 fibromyalgia, neuropathic pain, complex regional pain syndrome, phantom limb pain, 75 chronic orofacial pain). These results highlight maladaptive plasticity within the motor 76 system, a consequence closely linked to central sensitization [12,13]. More precisely, a 77 state of disinhibition in M1 has been identified, mainly corresponding to a deficiency in 78 the GABAergic inhibition system as well as an upregulation of N-methyl-D-aspartate 79 (NMDA) receptors, glutamate receptors closely involved in facilitating peripheral and 80 central sensitization [14][15][16][17][18][19]. M1-cortical excitability alterations have been associated 81 with the severity of the clinical symptoms such as pain intensity, hyperalgesia, and 82 allodynia [20,21], pointing to the value of TMS as an objective tool that reflects 83 functional alterations. Moreover, cortical excitability restoration through repetitive TMS 84 (rTMS), a technique known to induce lasting modulation effec...