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Post-COVID olfactory dysfunction (OD) – including anosmia, hyposmia, and qualitative disorders such as parosmia and phantosmia – is not merely a peripheral consequence of infection, but a “bridging” symptom spanning sensory, emotional, and cognitive dimensions. In long COVID, persistent OD can reduce quality of life, compromise safety and nutrition, diminish hedonic experience, and perpetuate distress and social withdrawal. Recent evidence indicates that, at least in a subset of patients, persistence is not solely dependent on peripheral regenerative processes but also involves central and network alterations, with potential neuropsychological correlates. In this chapter, we propose an integrated neurological, psychological, and neuropsychological interpretation of post-COVID OD and an assessment framework focused on multidimensional outcomes. Olfactory training remains the primary therapeutic approach; however, in persistent or refractory cases, combined strategies that enhance plasticity have shown promising results in controlled trials. Neuromodulation is discussed as a promising approach to enhancing olfactory rehabilitation, and advancing personalised, mechanism-informed interventions, including a clinical vignette reporting proof-of-concept observations following prefrontal repetitive transcranial magnetic stimulation (rTMS) in persistent post-COVID anosmia.
Department of Psychology, University of Turin, Turin, Italy
Neuroradiology Unit, Diagnostic and Technology Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Neurologico Carlo Besta, Milan, Italy
Neuroscience Institute of Turin (NIT), Turin, Italy
Chiara Di Fazio
Department of Psychology, University of Turin, Turin, Italy
International School of Advanced Studies, University of Camerino, Camerino, Italy
*Address all correspondence to: sara.palermo@unito.it
1. Introduction
The WHO definition of post-COVID-19 condition describes a syndrome that typically appears three months after infection and persists for at least two months, with symptoms that cannot be explained by other diagnoses [1, 2]. In this context, olfactory dysfunction (anosmia, hyposmia, and qualitative disorders such as parosmia and phantosmia) is not simply a “peripheral symptom”: it is often an experience that alters habits, confidence, and quality of life, and can intensify fatigue, distress, and social withdrawal [3, 4].
Many patients recover, but some retain olfactory alterations for months or years, with slow and variable courses; prolonged follow-up shows that recovery may remain incomplete even after considerable time, and that olfactory training is an important determinant of prognosis [5]. In a volume on long COVID, therefore, persistent anosmia warrants attention because it represents a clinical bridge between sensory perception, emotions, and cognitive functioning.
Accordingly, this chapter aims to: (i) review current hypotheses regarding the persistence of post-COVID olfactory dysfunction, with particular emphasis on central and network-level mechanisms; (ii) propose an integrated neurological, psychological, and neuropsychological framework for multidimensional assessment; and (iii) discuss the rationale and emerging role of neuromodulation as a strategy to support olfactory rehabilitation and promote network plasticity.
2. From the epithelium to the brain: What we know (and what we hypothesize) about persistence
In “classic” post-viral cases, attention is often focused on damage or inflammation of the olfactory epithelium and regenerative processes; in post-COVID cases, however, persistence appears more frequently to involve central and network components, especially in refractory cases or those with significant parosmia [3, 4].
A key point, also useful from an educational perspective, is to remember that smell is not a “linear” sense: the olfactory pathways intertwine early with limbic structures (amygdala, hippocampus) and with orbitofrontal and insular areas, which encode meaning, salience, hedonic valence, and guide attention towards stimuli. When smell is lost, we do not simply lose an input: we lose part of our “connections” to autobiographical memory, pleasure, sociality, and emotional regulation.
Functional neuroimaging studies and network analysis in patients with persistent post-COVID olfactory dysfunction have shown alterations in the global and local properties of the olfactory network and associations with cognitive measures, suggesting that – at least in some cases – persistence is linked to a reorganisation of connections rather than being an exclusively peripheral problem [6].
The literature discussed in this chapter was identified through a narrative, non-systematic search of PubMed, Scopus, and Google Scholar, focusing on studies published between 2020 and early 2026. Search terms included combinations of “COVID-19”, “long COVID”, “olfactory dysfunction”, “anosmia”, “parosmia”, “neuromodulation”, “rTMS”, “tDCS”, “olfactory training”, “brain fog”, and “quality of life”. Priority was given to longitudinal studies, controlled trials, and investigations addressing neuropsychological correlates and network-level alterations associated with persistent olfactory dysfunction
3. Psychological consequences: Beyond mood symptoms – loss of pleasure, salience, and sensory identity
In clinical practice, patients with persistent anosmia often report experiences not fully captured by anxiety or depression screening alone: they describe a “flatter life,” reduced enjoyment of food, diminished desire for socialising, and less pleasure in daily routines. This is particularly evident in studies measuring hedonic experiences and quality of life, which show that the impact can arise specifically in these areas even when “classic” anxiety and depression scores do not differ significantly [7].
Another crucial aspect – well worth mentioning – is that the risk of depressive symptoms depends not only on the extent of the olfactory deficit, but also on specific subjective distress. A study in Scientific Reports shows that distress related to smell can mediate the relationship between the duration of dysfunction and depressive symptoms, with a particularly notable effect in the post-COVID group [8]. To understand who will suffer most, it is not enough to measure “how much” they can smell; we also need to understand “how much” that loss affects their life.
4. Neuropsychological implications: When smell is intertwined with brain fog and fatigue
In long COVID, reported cognitive disorders (“brain fog”) are common and often affect attention, processing speed, and executive functions. In individuals with persistent olfactory dysfunction, the relationship is not necessarily linear or universal, but some data indicate that in subgroups with chronic olfactory dysfunction, associations are observed between the severity of the deficit, network alterations, and neuropsychological performance [6]. Furthermore, longitudinal studies of people with persistent olfactory dysfunction document a significant neuropsychiatric burden (depression, anxiety, subjective cognitive symptoms) over time, reinforcing the idea that care should be integrated [9].
Persistent anosmia is a “cross-cutting” risk factor. It can increase fatigue (due to compensation and hypervigilance), reduce motivation and pleasure (with repercussions on cognitive efficiency), and in some cases be an indicator of broader cerebral networks involvement.
5. What to really evaluate: From the olfactory threshold to functional impact
In long COVID, olfactory dysfunction is often overlooked if assessed only with a generic question (“Have you regained your sense of smell?”) or, conversely, if evaluation is limited to a psychophysical test without considering functional impact. Clinical experience and the literature indicate that the same degree of deficit can have very different consequences depending on phenotype (anosmia vs parosmia), specific distress, anhedonia, and the co-occurrence of fatigue and “brain fog” [6–9]. This highlights the need for an integrated assessment that combines measurement of the deficit, subjective experience, and impact on daily life, to guide both clinical management and study design realistically.
To make this approach immediately usable, we propose two concise and complementary tools: Box 1 translates the assessment into a checklist for clinical use (what to ask and what to measure to ensure crucial points are not missed), while Box 2 suggests a minimum set of outcomes for research, designed to capture not only olfactory recovery in the strict sense, but also factors that often determine disability in long COVID – quality of life, specific distress, anhedonia, and participation [7, 8, 10–12].
Phenotyping olfactory dysfunction
Anosmia/hyposmia vs qualitative distortions (parosmia/phantosmia).
Course: stable, fluctuating, with “windows” of recovery.
Impact on nutrition, safety, and social life.
Olfactory measures: objective and subjective
Psychophysical tests when available (e.g. Sniffin’ Sticks, UPSIT; even identification alone in outpatient settings).
Patient-reported outcomes: VAS smell; olfactory distress and quality of life questionnaires (e.g. QOD).
6. Treatments: What is established and what is emerging
6.1 The basis: Olfactory Training (OT)
Consensus recommendations identify olfactory training as the intervention with the best risk/benefit profile and the most consistent empirical support for post-infectious olfactory dysfunction, including post-COVID cases [3, 4]. The “classic” form involves repeated exposure to a set of odours twice daily for several weeks, with extended variations and protocols adapted for parosmia [13].
6.2 Why combined approaches are needed in persistent cases
A systematic review of therapies for COVID-19-associated olfactory dysfunction highlights a landscape of heterogeneous interventions (topical or systemic drugs in selected settings, PRP, supplements, and other approaches), with variable study quality and a need for comparable randomised controlled trials [5]. Considering a biopsychosocial perspective, this point should be linked with the clinical data: OT is the foundation; the rest is still being consolidated, and for this reason it is reasonable to explore strategies that enhance plasticity and learning, especially when olfactory dysfunction becomes chronic [5].
7. Neuromodulation: Rationale and state of evidence
If we accept that, at least in some patients, the persistence of OD is supported by network reorganisation (top-down attention, salience, limbic-prefrontal integration), then non-invasive neuromodulation becomes plausible as a booster of plasticity and as support for OT-induced learning [6] (Figure 1).
Figure 1.
Multilevel mechanisms of persistent post-COVID olfactory dysfunction and neuromodulation rationale.
Schematic illustration of the multilevel processes involved in persistent olfactory dysfunction in long COVID. Peripheral damage and inflammatory processes affecting the olfactory epithelium and bulb may be accompanied by alterations along central olfactory pathways and their integration with limbic and prefrontal networks involved in salience, emotion, and top-down attentional control. Prefrontal neuromodulation, targeting the left dorsolateral prefrontal cortex, can be considered a network-level intervention, aimed at modulating top-down control and supporting plasticity and perceptual recalibration, particularly in combination with olfactory training. Figure created by the authors.
7.1 tDCS + OT: Currently the most trial-based approach
An initial double-blind, sham-controlled study investigated the use of anodal tDCS in individuals with persistent post-COVID hyposmia, reporting signs of improvement compared to sham treatment [10].
Subsequently, a more recent randomised controlled trial evaluated the combination of OT and anodal tDCS versus OT and sham in patients with persistent post-COVID anosmia, demonstrating improvement in both subjective and psychophysical measures, with effects maintained at follow-up [11]. The suggestion is straightforward: tDCS does not replace OT, but can enhance it when the aim is to increase the likelihood of perceptual recalibration and functional recovery [11].
7.2 Prefrontal rTMS: Network hypotheses and clinical perspectives
The use of repetitive transcranial magnetic stimulation (rTMS) in post-COVID olfactory dysfunction is still in the early stages of exploration [6], but it is based on a solid neurofunctional rationale. Unlike other add-on interventions, rTMS allows for repeated, dose-dependent modulation of the prefrontal and fronto-limbic circuits involved in top-down control, salience, and emotional-cognitive integration [7]. In chronic and refractory cases, olfactory dysfunction seems to reflect not only a peripheral deficit but also an alteration in the balance between bottom-up and top-down processes, with repercussions on distress, motivation, and cognitive performance [6, 8]. From this perspective, rTMS can be understood as a “network” intervention: it does not target the sensory channel exclusively, but aims to restore neurophysiological conditions conducive to perceptual recalibration and the reactivation of motivational and attentional processes [8].
High-frequency stimulation of the left DLPFC, widely used in neuropsychiatry to modulate fronto-striatal and limbic circuits, is also a plausible target for persistent olfactory disorders [7, 9]. This approach is based on the hypothesis that chronic loss of smell involves functional decoupling between sensory areas and frontal control networks, which neuromodulation could help to re-establish [6–8]. Furthermore, rTMS offers a pragmatic advantage: it is already implemented in clinical settings, with standardised protocols and an established safety profile [9], factors that make its transfer to post-COVID rehabilitation pathways realistic.
Consistent with this rationale, our preliminary clinical observations in one individual with persistent olfactory dysfunction, unresponsive to olfactory training and other treatments showed clinically consistent signs of progressive recovery of olfactory perception during a course of prefrontal rTMS, accompanied by improvements in executive-attentional domains (Box 3) [11]. Although these observations do not permit inferences about efficacy, they provide clinical proof of concept supporting the design of sham-controlled studies with multidimensional outcomes (psychophysical and subjective measures of smell, quality of life and specific distress, anhedonia, and cognitive functions) and stratification by phenotype (anosmia vs parosmia, high vs low distress, presence or absence of “brain fog”). Looking ahead, rTMS could be evaluated both as a second-line option in refractory cases and as a priming or enhancement intervention in combination with olfactory training, aiming to increase network plasticity and optimise olfactory learning processes [6–9, 11].
In long COVID, persistent anosmia is often described by patients as a “global” experience: it not only affects the perception of smells, but also involves attention to stimuli, motivation and reward, mood, and sometimes brain fog. In this context, we present a clinical vignette as proof of concept: it does not demonstrate efficacy (single case, no control), but it clarifies the rationale that prefrontal modulation – acting on executive control, top-down attention, and integration with limbic systems – can accompany the re-emergence of olfactory perception and, in parallel, support vulnerable cognitive domains.
The clinical vignette presented below refers to one of the individuals included in these preliminary observations.
Patient: adult woman (aged 65), medium-high level of education, no significant neurological or psychiatric history.
Index event: SARS-CoV-2 infection (year 2021) with onset of severe loss of smell (with transient taste alteration) and persistence of symptoms for several months without significant spontaneous recovery.
Baseline assessment (T0): overall cognitive profile in the normal to low- normal range, with signs of fragility in executive and attentional efficiency; low anxiety and depressive symptoms; mild fatigue (MMSE 25; ACE-R 85; TMT-B 65 s; phonemic fluency 20; BDI-II and BAI in the low range).
Intervention: high-frequency rTMS on the left DLPFC, 12-week protocol (36 sessions), 10 Hz, approximately 800 pulses per session, intensity 120% of resting motor threshold. No structured olfactory training was administered before or during the rTMS intervention.
Clinical monitoring: structured diary of olfactory perception, with repeated assessments of categories of odours in everyday life.
Course: after an initial phase without obvious changes, the first signs appear in the intermediate phase (around the 10th–12th session) with the re-emergence of more salient/pungent odours; in the following weeks, a progressive expansion towards commonly used odours is observed and, in the final phase, towards more subtle scents.
Post-treatment outcome (T36): improvement in overall cognitive functioning and executive efficiency (MMSE 27; ACE-R 90; TMT-B 56 s), with no clinically relevant adverse events.
Box 3.
Clinical vignette.
Note: The clinical vignette is presented in anonymised form, and written informed consent for publication was obtained from the patient in accordance with institutional ethical standard.
Nevertheless, rTMS requires appropriate safety screening and clinical supervision. Contraindications include a history of epilepsy or seizures, unstable neurological conditions, and the presence of certain implanted electronic or ferromagnetic devices. Although generally well tolerated, rTMS may be associated with transient adverse effects such as headache, scalp discomfort, or fatigue and, more rarely, seizures, which should be considered when evaluating its applicability in post-COVID populations.
Persistent post-COVID anosmia is a clinical problem associated with other aspects of long COVID – not necessarily because it shares a single cause, but because it sits at the intersection of perception, meaning, emotion, and daily functioning. In this context, the issue is not whether olfactory dysfunction is “peripheral” or “central”; rather, it is to recognise that, when persistent, it almost always becomes multidimensional [2, 6–9].
From a clinical perspective, three practical choices emerge. First, olfactory training remains the preferred treatment and should be started early and continued over time, supported by adherence strategies and psychoeducation [3, 4, 13]. Second, the outcome that matters is not only the olfactory threshold, but also quality of life, loss of pleasure, specific distress, and the possibility of returning to full participation in daily life [7, 8]. Third, for persistent cases, the concept of a “package” treatment is becoming more established: OT as the foundation, with additional interventions aimed at enhancing plasticity when appropriate. In this context, neuromodulation should be considered in a rigorous, rather than sensationalistic, manner: tDCS as an adjunct to OT already has a clear rationale and controlled data supporting further investigation with larger samples and multidimensional endpoints [11].
From a research perspective, three priorities also emerge: improved phenotyping (anosmia vs parosmia; high vs low distress; presence vs absence of brain fog), integration of network biomarkers and ecological measures, and the design of pragmatic trials that genuinely address real long COVID – not only asking whether interventions work, but also for whom they work best.
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Written By
Sara Palermo and Chiara Di Fazio
Submitted: 20 January 2026Reviewed: 29 May 2026Published: 20 July 2026
Open access peer-reviewed chapter - ONLINE FIRST
