The sensation of smell is influenced by the somatosensory and chemesthetic sensati¬ons of the nose: for example, the cooling sensation of menthol or the prickle of carbon dioxide from carbonated drinks. These sensations are mediated in the nose by the trigeminal nerve and there is increasing evidence that trigeminal and olfactory functions are closely linked and potentially interdependent. In addition, trigeminal activation is crucial to the perception of nasal airflow. Some researchers speculate about the impact of trigeminal nerve on the entire olfactory sensation and about the presence of some specific "trigeminal cells" into the nose.Patients with Multiple sclerosis (MS) can suffer from quantitative olfactory disorders that generally are of light entity and do not interfere with daily life activities but it is important to underline that olfactory loss can be an onset sign of the MS. Considering the "trigeminal component" in the olfaction, because trigeminal nerve inflammation is quite common in MS patients due to central and peripheral inflammation, it could be possible that these patients suffer from changes in the quantitative, but more in the qualitative smell functions that are generally not identified because poorly investigated.

From a theoretically point of view pain in the trigeminal nerve increases the surrounding perception, including the perception of the odors. It has been shown that by using sweet food it is possible to reduce the level of pain; on the other side, sweet food in contrast to the bitter one was able to reduce the sensation of odor unpleasantness present with pain increase.

To date no studies have investigated the relationship between trigeminal inflammation, odors and pain in a cohort of patients with MS. This study aims at investigating the possible correlation between alteration in trigeminal functions and perception of odors using Sniffin' Stick Threshold, Detection and Identification test and quality smell questionnaire in a sample of healthy patients compared to MS patients.

Inclusion Criteria:

Adult women (age 18 to 55) diagnosed with multiple sclerosis using the 2017 McDonald Criteria under treatment with Disease Modifying Therapy (DMTs) with or without trigeminal concerns, or newly diagnosed with MS

Exclusion Criteria:

• Chronic rhinosinusitis with and without nasal polyposis; current allergic rhinitis; other nasal issues that lead to olfactory dysfunction
• anamnestic COVID with incomplete recovery
• Neurodegenerative disorders (Parkinson, Alzheimer, Fronto-temporal Dementia, cognitive impairment and brain vascular diseases)
• History of stroke in the last three years
• Depression or any psychiatric condition
• intake of drugs with sedating side effects
• major health issues that might affect olfactory function (e.g., significant renal insufficiency, uncontrolled diabetes)
• Chronic alcoholism / drug abuse
• Severe head trauma
• Severe facial injuries
• Smoker over 20 cigarettes day or smoking from more than 15 years

Number of participants: 400, 200 healthy controls, and 200 patients diagnosed with multiple sclerosis divided as follow: 100 with manifest trigeminal pain 100 without known trigeminal pathology.

History collection

Magnetic Resonance Imaging (MRI) 1.5-T Signal scanner; Whole brain scan; T2 FLAIR and double-echo long-TR axial, 3-mm axial and 1mm coronal slices; Olfactory bulb volumetrics

"Sniffin' Sticks" Threshold and Identification Test Perform monorhinal

Visual Analogue Scale Ratings Smell ability (How is your sense of smell right now? 0 cannot smell, 1-3 severe impairment, 4-6 moderate impairment, 7-9 mild impairment, 10 normal) Nasal breathing (How well can you breathe through your nose right now? 0 complete nasal obstruction, 1-3 severe impairment, 4-6 moderate impairment, 7-9 mild impairment, 10 normal)

Quality of smell Questionnaire

Cognitive Evaluation by Montreal Cognitive Assessment

Anxiety and Depression questionnaire

Trigeminal Lateralization