Disorder of ConsciousnessNCT05747170
Olfactory Stimulation in Severe Brain Injury
A study testing Olfactory sstimulation in people with Disorder of Consciousness, run by Fondazione Policlinico Universitario Agostino Gemelli IRCCS at 1 site in Italy.
Trial summary
The management of patients with disorders of consciousness (DoC) represents a topic of great importance and topicality in the medical-scientific field because of the complexity and extent of associated disabilities and the difficulty in identifying effective therapeutic approaches. Read more about this study
- Who is it for?
- Ages 18 to 90 yearsHealthy volunteers can take part
- Conditions the study is for
- Disorder of Consciousness
- What is being tested?
- Olfactory sstimulation
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 1 siteItaly
- Study dates
- 15 Oct 2021to 30 Jun 2024
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 90 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Age between 18 and 90 years;
- Glasgow Come Scale (GCS) score between 8 and 13;
- Level of Cognitive Function (LCF) score between 2 and 3;
- Latency from the acute event of not more than 2 months;
- Spontaneous eye opening.
Who cannot join
- Documented history of brain injury prior to the one that resulted in hospitalization;
- Documented history of uncorrected visual or hearing impairment;
- Documented history of chronic rhinosinusitis with or without the presence of naso-sinus polyps;
- Previous history of psychiatric and/or neurological disorders that resulted in significant disability prior to the acute event;
- Acute pathology at the time of recruitment, head injury, or ischemic or expansive injury with suspected peripheral olfactory tract involvement.
Trial locations and contacts
1 site in 1 country.
Italy1 site
Fondazione Policlinico Universitario A. Gemelli IRCCS
Roma, RM, 00168
About this study
Official title: Effects of Olfactory Stimulation in Patients with Severe Acquired Brain Injury
The management of patients with disorders of consciousness (DoC) represents a topic of great importance and topicality in the medical-scientific field because of the complexity and extent of associated disabilities and the difficulty in identifying effective therapeutic approaches. Despite significant advances in neuroscience, much remains to be elucidated about the mechanisms that regulate consciousness, and which of these to act on to stimulate plasticity and thus promote responsiveness and functional recovery in patients. Evidence on treatments that promote arousal and communication skills in individuals with DoC is still limited.
Among the possible interventions proposed in the literature, sensory stimulation would act by stimulating synaptic plasticity, counteracting the sensory deprivation to which these patients are exposed.
Published studies on the topic have produced results that are not unique and difficult to compare across different stimulation protocols (content, intensity, frequency, modality), settings and patient populations.
Read the detailed description
Smell is a primitive and complex sense related to emotions, memory and language. When we smell an odor, its molecules reach the nasal cavity and bind to the receptors of olfactory neurons, which transform the chemical information into an electrical signal that reaches the olfactory bulb and is then transmitted to the brain areas (piriform cortex, amygdala, thalamus, hypothalamus, insula, anterior cingulate cortex, orbitofrontal cortex) deputed to the emotional perception of smell and its storage. Studies in the literature have demonstrated the ability of the olfactory stimulus to influence emotional and cognitive processes (attention, memory, language), motor gesture, and autonomic nervous system response in healthy subjects. The use of stimuli with emotional and familiar content for the subject has also been shown to increase the likelihood of observing a behavioral response in patients with DoC.
In DoC patients, the use of the olfactory stimulus (intensity, modality, timing, measurement tools) in the recovery process is still limited, and it has not yet been clarified what effect it has on awakening and neurovegetative nervous system response.
This study aims to investigate, in both healthy subjects and patients with obsessive compulsive disorder (DoC) resulting from severe Acquired Brain Injury (sABI), the effects that odors of various types produce at the level of the autonomic nervous system (ANS) and brain connectivity.
More specifically, this study aims to evaluate, in healthy subjects and in patients with DoC, the effects of neutral, pleasant, and unpleasant olfactory stimuli on ANS, brain connectivity, reactivity, and the possible onset of habituation following repeated administration of the same olfactory stimulus.
- Conditions
- Disorder of Consciousness
- Being tested
- Olfactory sstimulation
- Keywords
- Acquired Brain Injury, Disorder of Consciousness, Olfactory stimulation
- Medical subject headings
- Consciousness Disorders, Brain Injuries
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Olfactory sstimulationOther
The odors being tested (natural odor, neutral odor, chemical odor) are part of the 40 fragrances made by International Flavors and Fragrances (IFF) and each is contained in an approximately 15-mL glass bottle. The selected odors will be administered using a small paper strip (15 cm length and 0.7 cm width) that will be soaked in the selected odor and placed under the subject's nose at a minimum distance to prevent direct contact of the strip with the skin; the strip will be moved alternately from one nostril to the other.
Stimulation will have, for each odor the duration of 5 minutes. It will always be carried out within the same time slot (between 8:00 am and 4:00 pm) for 5 consecutive days for 2 weeks. Before and after the administration of each odor, a neutral odor (water) will be administered as a control in the same manner as described above.
The sequence of odor administration will be randomized according to a computer-generated sequence.
| Study group | Role | What they receive |
|---|---|---|
| Group natural_neutral_chemical | Experimental | The recruited subjects (DoC patients and healthy subjects) will be evaluated inside a quiet, well-ventilated room and will be subjected to olfactory stimulation using odors with different characteristics a "natural" type odor, e.g., mint, a "chemical" type odor, e.g., gasoline, and a "neutral" type odor, e.g., water.
Stimulation will have, for each odor the duration of 5 minutes. It will always be carried out within the same time slot (between 8:00 am and 4:00 pm) for 5 consecutive days for 2 weeks. Before and after the administration of each odor, a neutral odor (water) will be administered as a control in the same manner as described above.
The sequence of odor administration will be: natural odor (mint) for 5 minutes, neutral odor (water) for 5 minutes, chemical odor (gasoline) for 5 minutes. Receives: Other: Olfactory sstimulation |
| Group chemical:neutral_natural | Experimental | The recruited subjects (DoC patients and healthy subjects) will be evaluated inside a quiet, well-ventilated room and will be subjected to olfactory stimulation using odors with different characteristics a "natural" type odor, e.g., mint, a "chemical" type odor, e.g., gasoline, and a "neutral" type odor, e.g., water.
Stimulation will have, for each odor the duration of 5 minutes. It will always be carried out within the same time slot (between 8:00 am and 4:00 pm) for 5 consecutive days for 2 weeks. Before and after the administration of each odor, a neutral odor (water) will be administered as a control in the same manner as described above.
The sequence of odor administration will be: chemical odor (gasoline) for 5 minutes, neutral odor (water) for 5 minutes, natural odor (mint) for 5 minutes. Receives: Other: Olfactory sstimulation |
What is being measured
The primary outcome is the main question the study is designed to answer.
Sympathetic Skin Response (SSR)
SSR is a physiologic measurement to record the electrical potential through an electrode placed on the palm of the hand after median nerve stimulation. The test is based on the temporary change in skin electrical resistance in response to activation of the sweat glands when exposed to a stimulus. It allows assessment of the ANS response through the study of sympathetic cholinergic efferent pathways
Measured: Change from baseline SSR at 2 weeks
Secondary outcomes (4)
Electrodermal Activity (EDA)
The E4 wereable medical devide (Empatica) will be used to assess the electrodermal activity (EDA).
Fluctuations in some electrical properties of the skin will be recorded; the online software Empatica (https://www.empatica.com/en-eu/) will the export the recorded data.
A higher EDA value corresponds to a higher stress level.
Measured: Change from baseline EDA at 2 weeks
Heart Rate Variability (HRV)
HRV, that is, the assessment of heart rate variability, is evaluated using an electrocardiographic (ECG) device with normal surface electrodes applied at the level of the heart and special software for data analysis.
Measured: Change from baseline HRV at 2 weeks
Electrocortical activity
The information inherent in the assessment of electrocortical activity, will be recorded using 64-channel high density electroencephalogram (EEG-HD). The presence of a cortical potential in motor area will be assessed by following the somatotopic organization, by reconstructing a brain map in amplitude.
Measured: Change from baseline EEG-HD at 2 weeks
Coma Recovery Scale-revised
CRS-r is an assessment tool that examines 6 functions: auditory, visual, oral-verbal motor, communicative and vigilance.
Its different items are organized hierarchically (low scores represent reflex activities, hig scores decribe cognitively mediated behaviours).
For each function examined, the diagnosis of Vegetative State, Minimal Consciousness State, Emergence from Minimal Consciousness State can be made.
Measured: Change from baseline CRS-r at 2 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Feb 2023
- Study start15 Oct 2021
- Primary completion30 Apr 2022
- Study completion30 Jun 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Disorder of ConsciousnessStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 24 participants (actual)
Sponsor and investigators
- Lead sponsor
- Fondazione Policlinico Universitario Agostino Gemelli IRCCS
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, PADUA LUCA, Fondazione Policlinico Universitario Agostino Gemelli IRCCS
- Investigators
- Luca Padua, MD, phD, Principal investigator, Fondazione Policlinico Universitario Agostino Gemelli IRCCS
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05747170
- Sponsor's protocol ID
- 4376
- Status last verified
- Feb 2024
- First submitted
- 17 Feb 2023
- Last updated
- 20 Mar 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 20 Mar 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effects of Olfactory Stimulation in Patients with Severe Acquired Brain Injury
- ClinicalTrials.gov ID
- NCT05747170
- Acronym / sponsor ID
- 4376
- Conditions
- Disorder of Consciousness
- Keywords
- Acquired Brain Injury, Disorder of Consciousness, Olfactory stimulation
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 24 participants (actual)
- Lead sponsor
- Fondazione Policlinico Universitario Agostino Gemelli IRCCSUniversity, hospital or other
- Study start
- 15 Oct 2021 (actual)
- Primary completion
- 30 Apr 2022 (actual)
- Study completion
- 30 Jun 2024 (actual)
- First posted
- 28 Feb 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The management of patients with disorders of consciousness (DoC) represents a topic of great importance and topicality in the medical-scientific field because of the complexity and extent of associated disabilities and the difficulty in identifying effective therapeutic approaches. Despite significant advances in neuroscience, much remains to be elucidated about the mechanisms that regulate consciousness, and which of these to act on to stimulate plasticity and thus promote responsiveness and functional recovery in patients. Evidence on treatments that promote arousal and communication skills in individuals with DoC is still limited.
Among the possible interventions proposed in the literature, sensory stimulation would act by stimulating synaptic plasticity, counteracting the sensory deprivation to which these patients are exposed.
Published studies on the topic have produced results that are not unique and difficult to compare across different stimulation protocols (content, intensity, frequency, modality), settings and patient populations.
Detailed description
Smell is a primitive and complex sense related to emotions, memory and language. When we smell an odor, its molecules reach the nasal cavity and bind to the receptors of olfactory neurons, which transform the chemical information into an electrical signal that reaches the olfactory bulb and is then transmitted to the brain areas (piriform cortex, amygdala, thalamus, hypothalamus, insula, anterior cingulate cortex, orbitofrontal cortex) deputed to the emotional perception of smell and its storage. Studies in the literature have demonstrated the ability of the olfactory stimulus to influence emotional and cognitive processes (attention, memory, language), motor gesture, and autonomic nervous system response in healthy subjects. The use of stimuli with emotional and familiar content for the subject has also been shown to increase the likelihood of observing a behavioral response in patients with DoC.
In DoC patients, the use of the olfactory stimulus (intensity, modality, timing, measurement tools) in the recovery process is still limited, and it has not yet been clarified what effect it has on awakening and neurovegetative nervous system response.
This study aims to investigate, in both healthy subjects and patients with obsessive compulsive disorder (DoC) resulting from severe Acquired Brain Injury (sABI), the effects that odors of various types produce at the level of the autonomic nervous system (ANS) and brain connectivity.
More specifically, this study aims to evaluate, in healthy subjects and in patients with DoC, the effects of neutral, pleasant, and unpleasant olfactory stimuli on ANS, brain connectivity, reactivity, and the possible onset of habituation following repeated administration of the same olfactory stimulus.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Group natural_neutral_chemical | Experimental | Other: Olfactory sstimulationThe recruited subjects (DoC patients and healthy subjects) will be evaluated inside a quiet, well-ventilated room and will be subjected to olfactory stimulation using odors with different characteristics a "natural" type odor, e.g., mint, a "chemical" type odor, e.g., gasoline, and a "neutral" type odor, e.g., water. Stimulation will have, for each odor the duration of 5 minutes. It will always be carried out within the same time slot (between 8:00 am and 4:00 pm) for 5 consecutive days for 2 weeks. Before and after the administration of each odor, a neutral odor (water) will be administered as a control in the same manner as described above. The sequence of odor administration will be: natural odor (mint) for 5 minutes, neutral odor (water) for 5 minutes, chemical odor (gasoline) for 5 minutes. |
| Group chemical:neutral_natural | Experimental | Other: Olfactory sstimulationThe recruited subjects (DoC patients and healthy subjects) will be evaluated inside a quiet, well-ventilated room and will be subjected to olfactory stimulation using odors with different characteristics a "natural" type odor, e.g., mint, a "chemical" type odor, e.g., gasoline, and a "neutral" type odor, e.g., water. Stimulation will have, for each odor the duration of 5 minutes. It will always be carried out within the same time slot (between 8:00 am and 4:00 pm) for 5 consecutive days for 2 weeks. Before and after the administration of each odor, a neutral odor (water) will be administered as a control in the same manner as described above. The sequence of odor administration will be: chemical odor (gasoline) for 5 minutes, neutral odor (water) for 5 minutes, natural odor (mint) for 5 minutes. |
Who may qualify
- Ages
- 18 to 90 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Age between 18 and 90 years;
- Glasgow Come Scale (GCS) score between 8 and 13;
- Level of Cognitive Function (LCF) score between 2 and 3;
- Latency from the acute event of not more than 2 months;
- Spontaneous eye opening.
Key exclusion criteria (5 listed)
- Documented history of brain injury prior to the one that resulted in hospitalization;
- Documented history of uncorrected visual or hearing impairment;
- Documented history of chronic rhinosinusitis with or without the presence of naso-sinus polyps;
- Previous history of psychiatric and/or neurological disorders that resulted in significant disability prior to the acute event;
- Acute pathology at the time of recruitment, head injury, or ischemic or expansive injury with suspected peripheral olfactory tract involvement.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Olfactory sstimulationThe odors being tested (natural odor, neutral odor, chemical odor) are part of the 40 fragrances made by International Flavors and Fragrances (IFF) and each is contained in an approximately 15-mL glass bottle. The selected odors will be administered using a small paper strip (15 cm length and 0.7 cm width) that will be soaked in the selected odor and placed under the subject's nose at a minimum distance to prevent direct contact of the strip with the skin; the strip will be moved alternately from one nostril to the other. Stimulation will have, for each odor the duration of 5 minutes. It will always be carried out within the same time slot (between 8:00 am and 4:00 pm) for 5 consecutive days for 2 weeks. Before and after the administration of each odor, a neutral odor (water) will be administered as a control in the same manner as described above. The sequence of odor administration will be randomized according to a computer-generated sequence. | Other | Group chemical:neutral_natural, Group natural_neutral_chemical |
Primary outcome
Sympathetic Skin Response (SSR)
Time frame: Change from baseline SSR at 2 weeks
SSR is a physiologic measurement to record the electrical potential through an electrode placed on the palm of the hand after median nerve stimulation. The test is based on the temporary change in skin electrical resistance in response to activation of the sweat glands when exposed to a stimulus. It allows assessment of the ANS response through the study of sympathetic cholinergic efferent pathways
4 secondary outcomes
Electrodermal Activity (EDA)
Time frame: Change from baseline EDA at 2 weeks
Heart Rate Variability (HRV)
Time frame: Change from baseline HRV at 2 weeks
Electrocortical activity
Time frame: Change from baseline EEG-HD at 2 weeks
Coma Recovery Scale-revised
Time frame: Change from baseline CRS-r at 2 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Mar 2025.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Luca Padua, MD, phD principal investigator
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Olfactory sstimulation in people with Disorder of Consciousness, run by Fondazione Policlinico Universitario Agostino Gemelli IRCCS at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Mar 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Sympathetic Skin Response (SSR) (time frame: Change from baseline SSR at 2 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Mar 2025.