Persistent smell loss that can include diminished or distorted smell function is a commonsymptom of long COVID syndrome. There are limited treatment options for longCOVID-related smell loss. This study aims to determine the efficacy of two at-hometreatments, smell training and non-invasive trigeminal nerve stimulation. This studyrequires participants to conduct daily at-home treatment sessions, attend three in-personstudy visits at the MUSC Department of Psychiatry and Behavioral Sciences, and completeelectronic questionnaires over the 12-week trial, and again at the six-month timepoint.Participants in this trial may benefit directly with an improvement in sense of smell.However, participation may also help society more generally, as this study will providenew information about long COVID-related smell loss and its treatment.
Sudden smell loss (SL), a hallmark feature of Severe Acute Respiratory Syndrome
Coronavirus 2 (SARS-coV-2/COVID), frequently persists well past the initial recovery;
rates of unresolved anosmia (total loss) are 21%, with unresolved hyposmia (reduced
smell) or parosmia (distorted smell) higher at nearly 50%. SL is now recognized as a core
symptom of "long COVID" (LC), which also includes other impairments in mood, cognition,
and sleep. Given that SL itself can negatively impact many of the same problems being
recognized in the symptomatology of LC, it is likely that SL is both a symptom of LC and
a contributing factor that worsens other LC symptoms (i.e. mood, cognition, sleep, etc.).
As such, successful treatment of SL could also help to improve these other LC symptoms.
Smell/olfactory training (ST) is currently being studied as a treatment for COVID-related
SL. Classic ST requires twice daily practice of sniffing odorants over the course of 3
months to regenerate olfactory neurons, engage smell-related cognitive functions, and
retrain the brain to smell. ST is promising as a stand-alone treatment. However, its
limitations include the burden of many months of daily practice that often leads to
sub-optimal compliance and dropout.
The current study aims to determine whether the benefits of ST can be accelerated and
enhanced by using a novel, adjunct neuromodulatory intervention to conventional ST.
Trigeminal nerve stimulation (TNS) is a non-invasive, pain-free, method of
neuromodulation that delivers low levels of electrical stimulation to the trigeminal
circuit, having potential to enhance smell function through activation of the highly
connected olfactory-intranasal trigeminal systems. Prior work demonstrated TNS-enhanced
psychophysical detection of odorants. Yet the effects of TNS are extensive, i.e. improved
executive functioning (e.g. attention), sleep quality, and daytime sleepiness, as well as
therapeutic efficacy across a number of neuropsychiatric disorders. Thus, TNS-as an
adjunct to ST-may not only improve overall efficacy and speed of recovery of SL, but may
help to treat some of the other symptoms of LC that ST, and improvement in smell
function, may not fully resolve.
This randomized, controlled trial (RCT) of ST and combination TNS and ST in adults with
COVID-related SL will use a 3- group design: Group 1) Active ST (N=60), Group 2) Placebo
ST (PBO, N=60), and Group 3) Active TNS plus Active ST (N=60). Our primary objectives are
to 1) determine the efficacy of ST versus potential natural gains in function, 2)
determine the TNS-enhanced effects of ST on SL, and 3) determine whether TNS+ST is more
efficacious than ST in treating the other symptoms of LC.
Device: Trigeminal Nerve Stimulation (TNS)
Non-invasive, pain-free, low-level electrical stimulation to the forehead to modulate the
trigeminal nerve and enhance smell function through activation of the highly connected
olfactory-intranasal trigeminal brain circuits.
Other Name: Transcutaneous Electrical Nerve Stimulation
Other: Active Smell Training (ST)
Sniffing various higher intensity odorant chemicals while performing odor-related
cognitive tasks. 16 odorant chemicals will be used for training including: 2 phenyl
ethanol, eugenol, lemon, eucalyptus, cinnamon, peppermint, coffee, mandarin, lavender,
vanilla, lilac, ginger, chocolate, thyme, banana, and bacon.
Other Name: Olfactory Training
Other: Placebo Smell Training (PBO)
Sniffing the same lower intensity odorant chemicals (i.e. N-butanol and 2-phenyl ethanol)
over the course of the trial and performing no odor-related cognitive tasks.
Inclusion Criteria:
- treatment-seeking for COVID-related persistent SL (anosmia, hyposmia, phantosmia or
parosmia)
- SARS-coV-2 PCR-positive test prior to April 2021
- normal sense of smell prior to COVID
- naïve to both smell training (ST) and trigeminal nerve stimulation (TNS)
- able to comprehend English and provide informed consent
Exclusion Criteria:
- history of head injury (e.g. sport, accident, combat blast)
- sinonasal condition (e.g. upper respiratory infection, rhinosinusitis, polyps)
- neurological disorder (e.g. epilepsy, neurodegenerative disorder, narcolepsy)
- serious mental illness (e.g. schizophrenia, bipolar, or other psychotic disorder)
- suicidal ideation within the last month
- current (≤6 months) heavy cigarette smoker (heavy defined as ≥ 10 pack-years)
- oral/nasal steroids or other intranasal medications within the last month
- immunomodulatory medications
- pregnant or trying to become pregnant
Medical University of South Carolina
Charleston, South Carolina, United States
Investigator: Bernadette Cortese, PhD
Contact: 843-792-6922
corteseb@musc.edu
Bernadette M. Cortese, Ph.D.
843-792-6922
corteseb@musc.edu
Bashar W. Badran, Ph.D.
843-792-6076
badran@musc.edu
Not Provided