Noninvasive Brain Stimulation Promising for COVID-Related Smell Loss

Lolita Osorio

June 24, 2022

Noninvasive brain stimulation may help restore a sense of smell in patients with chronic anosmia or hyposmia related to COVID-19, early research suggests.

Results of a small, double-blind, sham-controlled study showed anodal transcranial direct current stimulation (A-tDCS) combined with olfactory training (OT) provided notable and durable improvement in seven patients with persistent COVID-19–related hyposmia or anosmia.

"We are proud and very excited about these results. Although seven patients is a small sample, it is still notable," lead investigator Fabio Bandini, MD, head of the Department of Neurology, ASL 3 Genovese, Genoa, Italy, told Medscape Medical News.

tDCS is cheap, safe, accessible, and very easy to administer. It has been used in rehabilitative treatment for 15 years, but this is the first time it has been used for this kind of problem, Bandini added.

The study was published online May 23 in the Journal of Neurology, Neurosurgery and Psychiatry.

First Study of Its Kind

Approximately 1% of patients with COVID will suffer from long-term smell loss, and given the widespread global impact of COVID, this represents a substantial number who have experienced or will potentially experience chronic smell loss because of the disease.

Loss of smell associated with COVID may last anywhere from 15 to 180 days after a SAR-CoV-2 infection, the researchers note. Research suggests there is central nervous system involvement in COVID anosmia, mostly in the orbitofrontal cortex — the neural substrate for conscious olfactory perception.

"Smell loss has important consequences in everyday life for food, for hazards, for socialization. Usually, you recover from smell loss after 2 or 3 months, but after 6 months, that is considered permanent," said Bandini.

Some research has pointed to the activation of the orbital frontal cortex for control of olfactory perception, so Bandini and colleagues wanted to explore whether stimulating this area could improve smell disturbances in post-COVID patients.

The study included seven consecutive patients with hyposmia or anosmia from COVID-19 lasting at least 6 months and who had a score of less than 12 on the Sniffin' Sticks identification subtest. Exclusion criteria included severe mood disorder, rhinologic diseases, epilepsy, and sensitive scalp. No medications for alleviating olfactory symptoms were permitted.

Patients' smell performances were assessed immediately prior to stimulation (t0) and rated on a scale of 0-10, with a score of 0 indicating a complete loss of smell and a score of 10 indicating a full sense of smell as the subjective measure. Sniffin' Sticks, a validated test that assesses smell threshold, discrimination, and validation, was used as an objective measure.

In the 20-minute OT session, patients had to sniff 10 odors (rose, eucalyptus, lemon, star anise, rosemary, strawberry, coconut, vanilla, pine tree, and bergamot) in a random order for 10 seconds each then were asked to identify the smell and rate its intensity. The training was applied once in each session.

A-tDCS or sham-transcranial direct current stimulation (S-tDCS) was administered at the same time. In the active stimulation the anode was placed over the left prefrontal cortex because the orbitofrontal cortex is not directly accessible by A-tDCS.

The patients participated in olfactory training with S-tDCS for the first 2 weeks. In the second 2 weeks of the study, they received OT with A-tDCS.

The order of sham and A-tDCS stimulation was not counterbalanced to avoid potential carryover effects if A-tDCS had been applied first. The patients and assessors collecting the data were blinded.

The smell assessment was repeated immediately after S-tDCS (t1), A-tDCS (t2) and 3 months from the end of stimulation (t3), using the same odors and the same order of the first assessment.

The Wilcoxon test was used to compare each assessment (t1, t2, and t3) with baseline, indicating a two-sided alpha < 0.05, which was considered statistically significant.

Both the subjective and objective measures showed a statistically significant improvement at t2 and t3, with average measurements doubled or even tripled compared with t0 and t1. In addition, all patients demonstrated notable improvement in smell performance.

This study, said Bandini, is the first to use A-tDCS to treat patients with persistent smell loss due to COVID. Not only did the results show significant improvement in all study participants compared with baseline but the beneficial effect lasted up to 3 months after treatment, demonstrating a durable effect.

Bandini noted that the study's small sample size is a major limitation of the research so he hopes to enlarge it in future research testing A-tDCS for COVID-related smell loss and work toward providing this therapy on an outpatient basis.

Encouraging Results Offer New Hope

Commenting on the research for Medscape Medical News, Cheng-Ying Ho, MD, associate professor of pathology at the Johns Hopkins University School of Medicine, Baltimore, Maryland, described the study as "interesting and encouraging."

"Even though there is a small percentage of patients that suffer persistent smell loss from COVID, it's still a large number of people who have smell dysfunction and are unable to recover."

"So far, there is no treatment for COVID-related or viral-infection–related smell loss. The only thing that can be done is olfactory training, but the effect is very limited. There is no drug or other type of therapy for smell loss so far," said Ho whose areas of expertise include neuromuscular pathology, pediatric neuropathology, and neuropathology of infectious diseases.

"Even though it's a small study with only seven patients, the results are very encouraging. After 2 weeks of stimulation, almost all had smell recovery that lasted several months. The weakness of the study is that they didn't have a control group. The next step would be to expand the study to include more participants and have an adequate control group that received the sham stimuli to see if their results still stand when they have more participants.

"This very encouraging and relatively noninvasive treatment modality can give patients with smell loss some hope that this therapy can help them recover their sense of smell to some degree. The study seems to suggest that either the tDCS can stimulate nerve regrowth or that it actually can correct the rewiring of the brain," added Ho.

The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors. No competing interests were declared.

J Neurol Neurosurg Psychiatry. May 23, 2022. Full text

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