Structural and functional neuroimaging of hippocampus to study adult neurogenesis in long COVID-19 patients with neuropsychiatric symptoms: a scoping review

Identifying the research question

The principal research question was “What is the current evidence on the impact of long COVID/PASC on adult neurogenesis and its association with neuropsychiatric symptoms?”

The principal research question was broken down into the following:

1. What type of studies have been conducted on adult neurogenesis in patients with long COVID-19/PASC?

2. What neuropsychiatric symptoms are commonly reported in patients with long COVID-19/PASC?

3. What are the proposed mechanisms linking long COVID-19/PASC to changes in adult neurogenesis?

4. How are changes in adult neurogenesis measured in patients with long COVID-19/PASC?

5. What interventions or treatments have been studied to address changes in adult neurogenesis in patients with long COVID-19/PASC?

6. What are the gaps that exist in the current literature on this topic?

Identifying relevant studies

The scoping review followed the Population, Concept, Context (PCC) format to identify relevant studies for answering the research questions with population being patients diagnosed with long COVID-19 with neuropsychiatric sequalae, and concept being adult neurogenesis.

The current scoping review was conducted in accordance with the JBI methodology for scoping reviews (Peters et al., 2020). A preliminary limited search was conducted in PubMed to identify articles published on the topic. The keywords and Mesh terms from the identified topics were used to develop the search strategy for PubMed, Web of Science, Embase, and SCOPUS. Studies published in the English language with no restriction on the time of publication were searched using the keywords “Neurogenesis [Mesh]”, “Adult neurogenesis[tiab]”, “Post-acute COVID-19 Syndrome [Mesh]”, long COVID-19[tiab], and SARS-CoV-2[tiab] using the search strategy as given in Table S1.

This scoping review included a range of study designs, incorporating both experimental and quasi-experimental approaches such as randomized controlled trials, non-randomized controlled trials, before-and-after studies, and interrupted time-series studies. Additionally, it encompassed analytical observational studies including prospective and retrospective cohort studies, case-control studies, and analytical cross-sectional studies. Descriptive observational study designs such as case series, individual case reports, and descriptive cross-sectional studies, were also considered for inclusion. However, opinion articles, as well as systematic reviews were excluded from this scoping review.

Selection of eligible studies

All identified articles obtained from the database search were collated and uploaded to Nested Knowledge AutoLit semi-automated systematic review platform and duplicates were removed. Following a pilot test, two reviewers (IS & JS) independently screened the titles and abstracts against the inclusion criteria for the scoping review.

Only original research articles conducted on human subjects with focusing on adult neurogenesis in long COVID-19 patients were included in the review. While review articles, opinion papers, and studies where full-text articles could not be retrieved were excluded. Full texts of potentially relevant sources were retrieved, and their citation details were imported into the JBI System for the Unified Management, Assessment, and Review of Information (JBI SUMARI) (JBI, Adelaide, Australia) (Munn et al., 2019). Two independent reviewers (IS & JS) thoroughly evaluated the complete texts of chosen articles against the specified eligibility criteria. The studies that did not meet these criteria were documented and included in the scoping review report as excluded evidence. Disagreements among the reviewers during the selection process were resolved through discussion.

Charting the data

A draft version of data extraction tool was created and the preliminary data extraction tool underwent adjustments and refinements as needed throughout the data extraction process for each included source of evidence. These modifications were documented within the scoping review. Any discrepancies between reviewers were addressed through discussion.

Collating, summarising, and reporting the results

The extracted data were summarised and reported as tables (Tables 1 and 2). A narrative format is used to describe the results in relation to the review questions and study purpose.

Overview of results

Database search revealed 707 studies and after removal of duplicates 408 unique studies remained. Following title and abstract screening, 288 studies were excluded, and 120 studies were sought for full-text retrieval and screening. 103 studies were excluded after full-text screening and 17 studies published between 2020 to 2023 which adhered to the eligibility criteria were included in this review (Fig. 1) (Balsak et al., 2023; Barnden et al., 2023; Besteher et al., 2022; Carroll et al., 2020; Cattarinussi et al., 2022; Díez-Cirarda et al., 2023; Du et al., 2022; Ergül et al., 2022; Esposito et al., 2022; Franke et al., 2023; Lu et al., 2020; Muccioli et al., 2023; Rothstein, 2023; Taskiran-Sag et al., 2023; Tu et al., 2021; Wingrove et al., 2023; Yousefi-Koma et al., 2021). Three studies each were conducted in Italy (Cattarinussi et al., 2022; Esposito et al., 2022; Muccioli et al., 2023), China (Du et al., 2022; Lu et al., 2020; Tu et al., 2021), and Turkey (Balsak et al., 2023; Ergül et al., 2022; Taskiran-Sag et al., 2023). Two studies were conducted in Germany (Besteher et al., 2022; Franke et al., 2023) and the United States of America (Carroll et al., 2020; Rothstein, 2023), and one study was conducted in Spain (Díez-Cirarda et al., 2023), Iran (Yousefi-Koma et al., 2021), UK (Wingrove et al., 2023), and Australia (Barnden et al., 2023). The studies varied in sample size with the median being 49 patients. The studies with the smallest sample size were case reports with one sample (Carroll et al., 2020; Yousefi-Koma et al., 2021) and the largest sample size was 252 (126 each in the study group and control group) (Tu et al., 2021). The total number of patients studied in all the studies put together was 1,114 with 687 in the study group and 427 in the control group. Gender distribution varied between studies. The case reports were on females (n = 1) (Carroll et al., 2020; Yousefi-Koma et al., 2021) and the remaining studies included both male and female participants. The median of the percentage of male participants across the studies was 35.6%. The age of the participants ranged between 28 and 69 years with the mean (±SD) age of 44.07 ± 8.96 years (Table 3).

Criteria for selecting long COVID-19 patients

There were minor disparities in the criteria for defining long COVID-19 by the selected studies. Most studies defined long COVID (LC) using WHO or NICE guidelines (Barnden et al., 2023; Franke et al., 2023; Muccioli et al., 2023; Rothstein, 2023), while others included participants based on persistent symptoms beyond 12 weeks (Díez-Cirarda et al., 2023; Wingrove et al., 2023) or broader post-acute symptom duration (Balsak et al., 2023; Besteher et al., 2022; Cattarinussi et al., 2022; Du et al., 2022; Ergül et al., 2022; Esposito et al., 2022; Lu et al., 2020; Taskiran-Sag et al., 2023; Tu et al., 2021; Yousefi-Koma et al., 2021) WHO defines long COVID-19 as “the continuation or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with the symptoms lasting for at least 2 months with no other explanation” (WHO, 2022). NICE guidelines give two definitions of post-acute COVID-19 including “(1) ongoing symptomatic COVID-19 for people who still have symptoms between 4 and 12 weeks after the start of acute symptoms; and (2) post-COVID-19 syndrome for people who still have symptoms for more than 12 weeks after the start of acute symptoms” (Venkatesan, 2021). Taking into consideration the participant characteristics, symptomology, and day of the scan/study post-infection, those studies conducted on COVID-19 patients with persistent symptoms for a minimum of 4 weeks were also included in the review even though the authors did not exclusively mention the study to be conducted on long COVID-19 patients (Balsak et al., 2023; Carroll et al., 2020; Cattarinussi et al., 2022; Du et al., 2022; Ergül et al., 2022; Esposito et al., 2022; Lu et al., 2020; Taskiran-Sag et al., 2023; Tu et al., 2021; Yousefi-Koma et al., 2021) (Table 3). The common challenge faced by the authors is linking the complaints to COVID-19 after recovery from the disease and considering the patients to be COVID-19 long haulers. Using matching controls was one of the ways employed by the authors to overcome this challenge. Except the study by Franke et al. (2023) and Rothstein (2023) which was conducted on a cohort of long COVID-19 patients with self-reported cognitive deficits and in COVID-19 patients with long term neurologic symptoms, the remaining research articles were case control studies (Balsak et al., 2023; Cattarinussi et al., 2022; Du et al., 2022; Ergül et al., 2022; Esposito et al., 2022; Lu et al., 2020; Taskiran-Sag et al., 2023; Tu et al., 2021). The day of the brain scan post infection across the studies are given in Table S2.

Clinical type of COVID-19 in the included studies

Majority of the studies were conducted in non-critical COVID-19 patients though the severity of COVID-19 experienced by the study participants were not mentioned in a few studies (34.06% of study group) (Cattarinussi et al., 2022; Díez-Cirarda et al., 2023; Ergül et al., 2022; Franke et al., 2023; Yousefi-Koma et al., 2021). In the participants for whom the COVID-19 severity was reported, 78.14% were of the mild or mild to moderate type severity of COVID-19, 16.78% were moderate to worse or severe type and 0.66% had critical type of COVID-19 (WHO, 2020) (Table S2).

Neuropsychiatric manifestations in long COVID-19

Neuropsychiatric symptoms were commonly reported across the studies involving long COVID-19 (LC) patients (Dataset D1). The most frequently observed manifestations included cognitive impairment, memory deficits, fatigue, depression, anxiety, sleep disturbances, and olfactory or gustatory dysfunction. These symptoms were assessed using a range of validated psychometric instruments.

Cognitive impairment and memory dysfunction were among the most consistent findings. Studies using the Montreal Cognitive Assessment (MOCA) demonstrated that LC patients frequently scored below the threshold for normal cognition, indicating both subjective and objectively measurable deficits (Besteher et al., 2022; Esposito et al., 2022; Franke et al., 2023; Muccioli et al., 2023). Other tools used included the Stroop Test (Barnden et al., 2023) and additional neurocognitive batteries to assess executive function, processing speed, and attention (Díez-Cirarda et al., 2023).

Mood disorders, including depression and anxiety, were assessed using Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), Depression Anxiety Stress Scale (DASS-21), Montgomery-Asberg Depression Rating Scale (MADRS), and the Hospital Anxiety and Depression Scale (HADS). These tools consistently indicated higher levels of emotional distress in LC patients compared to controls (Besteher et al., 2022; Cattarinussi et al., 2022; Du et al., 2022; Muccioli et al., 2023). Notably, some studies also reported correlations between mood symptoms and neuroimaging findings; for instance, Cattarinussi et al. (2022) found an association between right hippocampal connectivity and depression severity (Cattarinussi et al., 2022).

Fatigue and sleep-related issues were also prominent. Fatigue was assessed through the Modified Fatigue Impact Scale (Díez-Cirarda et al., 2023; Muccioli et al., 2023) and the Multidimensional Fatigue Inventory (Cattarinussi et al., 2022). Sleep disturbances were evaluated using tools such as the Athens Insomnia Scale (Du et al., 2022) and the Pittsburgh Sleep Quality Index (Díez-Cirarda et al., 2023), both revealing significantly poorer sleep quality in LC patients.

Post-traumatic stress symptoms (PTSS) were specifically assessed by Tu et al. (2021) using the PTSD Checklist for DSM-5. Their findings indicated elevated PTSS scores in LC patients, with females showing higher levels of distress and an increase in symptoms over time (Tu et al., 2021). Sensory dysfunctions, particularly involving smell and taste, were measured using the Brief Smell Identification Test (BSIT) and the University of Pennsylvania Smell Identification Test (UPSIT) (Díez-Cirarda et al., 2023; Wingrove et al., 2023). Persistent olfactory and gustatory issues were common and were sometimes associated with functional changes in the hippocampus and related brain regions (Esposito et al., 2022).

While several studies attempted to link neuropsychiatric symptoms with hippocampal structure or function, the findings were mixed. Some, like Cattarinussi et al. (2022), reported positive associations, while others, such as Besteher et al. (2022), did not find significant correlations. This inconsistency may stem from variations in study design, timing of assessment post-infection, or differences in patient selection criteria (Table 3 and Dataset D1).

Overall, the reviewed studies support the conclusion that neuropsychiatric symptoms are a prominent and persistent feature of long COVID-19. The use of standardized neuropsychological assessment tools lends validity to these observations, although further research is needed to better understand the underlying mechanisms and their potential associations with hippocampal alterations.

Hippocampus in long COVID-19

The interpretation of data from neuroimaging studies and their extrapolation to AN should be tread with caution as there are various limitations to them. The variability in imaging techniques, including macrostructural, microstructural, and connectivity analyses, introduces significant assumptions and potential pitfalls (Calamante, 2019; Gatto, 2020). Specifically, variations in hardware and clinical imaging protocols across institutions pose challenges to the interpretation of diffusion MRI (dMRI) data (Gatto, 2020). Therefore, in vivo validation of AN requires a comprehensive approach, combining multimodal MR parameter correlations with biomarkers in cerebrospinal fluid or blood (e.g., doublecortin, BDNF) (Erickson et al., 2011; Just, Chevillard & Migaud, 2022), neurocognitive assessments, and clinical parameters. While neurocognitive assessments can offer indirect insights, their reliability is limited, as cognitive changes are influenced by a complex interplay of factors beyond AN, including psychological (depression, anxiety, PTSD), pharmacological (antiepileptics, antidepressants), and lifestyle factors (sleep disturbances, substance abuse) antidepressants (Corney et al., 2024; Gooden et al., 2023; Son & Larson, 2023; Su & Xiao, 2022). Thus, none of the correlates given in the Table 1 denotes adult neurogenesis by itself. However, the current review includes findings from the studies which has any one or more of the in vivo correlates of AN. Findings that may help detect AN in the current review are given in Table 1.

The majority of the reviewed studies (15/17) had performed structural MRI of the hippocampus including Voxel-based morphometry (VBM), which analyzes brain images to detect regional differences in tissue composition, diffusion tensor imaging (DTI), which is utilized to visualize and quantify white matter tracts in the brain, and cerebral blood volume (CBV), which measures blood volume changes associated with brain activation (Balsak et al., 2023; Besteher et al., 2022; Carroll et al., 2020; Cattarinussi et al., 2022; Díez-Cirarda et al., 2023; Ergül et al., 2022; Esposito et al., 2022; Franke et al., 2023; Lu et al., 2020; Muccioli et al., 2023; Rothstein, 2023; Taskiran-Sag et al., 2023; Tu et al., 2021; Wingrove et al., 2023; Yousefi-Koma et al., 2021) while 8/17 studies had included functional MRI of the hippocampus in long COVID-19 patients (Dataset D1) (Barnden et al., 2023; Cattarinussi et al., 2022; Díez-Cirarda et al., 2023; Du et al., 2022; Esposito et al., 2022; Muccioli et al., 2023; Tu et al., 2021; Wingrove et al., 2023). Resting state fMRI was performed in seven studies (Cattarinussi et al., 2022; Díez-Cirarda et al., 2023; Du et al., 2022; Esposito et al., 2022; Muccioli et al., 2023; Tu et al., 2021; Wingrove et al., 2023) while Barnden et al. (2023) studied fMRI while the participants performed activity (Stroop task). Six studies included both structural and functional MRI study of the hippocampus in long COVID-19 patients (Cattarinussi et al., 2022; Díez-Cirarda et al., 2023; Esposito et al., 2022; Muccioli et al., 2023; Tu et al., 2021; Wingrove et al., 2023). Franke et al. (2023) used indirect immunofluorescence on the mouse model to study anti-neuronal and anti-glial autoantibodies in serum and CSF of PCS patients with self-reported cognitive deficits in addition to structural MRI (Table S4).

Correlation with long COVID-19 symptoms

Several studies explored the relationship between hippocampal alterations and symptom severity in long COVID (LC) patients (Table 2). Díez-Cirarda et al. (2023) linked reduced hippocampal subfield volumes and perfusion with poorer cognitive performance, particularly in memory and executive functions. Similarly, Tu et al. (2021) found that lower left hippocampal volume was associated with higher post-traumatic stress symptoms. Lu et al. (2020) also reported a negative correlation between bilateral hippocampal grey matter volume and memory loss.

However, findings were not consistent across all studies. Besteher et al. (2022) reported no association between hippocampal volume and mood or cognitive scores. Ergül et al. (2022) found no significant correlation between hippocampal volume and sensory dysfunction. Taskiran-Sag et al. (2023) noted increased hippocampal thickness in anxious patients but no correlation with inflammatory markers. These discrepancies suggest that while hippocampal changes may contribute to LC symptoms, the relationship is not yet clearly defined (Table 2 and Table S4).

Correlation with biomarkers

Several studies explored the relationship between hippocampal alterations and biomarkers of inflammation and neurodegeneration (Table 2). Díez-Cirarda et al. (2023) identified elevated levels of glial fibrillary acidic protein (GFAP), myelin oligodendrocyte glycoprotein (MOG), and neurofilament light chain (NfL) in LC patients, which were significantly associated with reduced hippocampal volume and perfusion, particularly in patients who had been hospitalized. These biomarkers are linked to axonal injury, astrocyte reactivity, and myelin damage (Hol & Pekny, 2015; Lorenzo et al., 2019; Solly et al., 1996).

In the same study, higher levels of the chemokine eotaxin-1 (CCL11)—known to inhibit hippocampal neurogenesis—were observed in LC patients with cognitive symptoms and were negatively correlated with the volume of hippocampal subfields including the dentate gyrus, CA3 head, and CA4 head (Díez-Cirarda et al., 2023). These findings suggest a potential biological mechanism linking inflammation to hippocampal dysfunction and cognitive decline in LC.

However, not all studies reported such associations. Taskiran-Sag et al. (2023) did not find significant correlations between hippocampal thickness or volume and common inflammatory markers such as C-reactive protein (CRP) or the neutrophil-to-lymphocyte ratio (NLR). Similarly, Du et al. (2022) observed no relationship between hippocampal activation and systemic inflammation markers in their cohort, despite increased left hippocampal activity on fMRI.

The variability in results may reflect differences in biomarker selection, sample size, severity of acute infection, or the time elapsed since recovery. While findings from Díez-Cirarda et al. (2023) suggest a link between neuroinflammation and hippocampal damage in LC, the absence of consistent biomarker associations across studies indicates a need for more standardized and targeted investigations, particularly those integrating neuroimaging with biomolecular profiling.

Analysis of included studies

Strengths and limitations of the review

As a planned scoping review, we adhered to established guidelines such as PRISMA-ScR (Tricco et al., 2018) and the Joanna Briggs Institute (Peters et al., 2020). However, due to the scoping review format, a risk of bias assessment was not included, hence caution should be exercised when interpreting the findings. Nevertheless, we have detected crucial methodological limitations prevalent in many included studies, offering a synthesized and current overview of in vivo correlates of adult neurogenesis in long COVID-19 patients with neuropsychiatric sequelae. We detected both consistent and inconsistent findings and helped arbitrate the feasibility of a future systematic review. Additionally, as only peer-reviewed material was included, there is a possibility of overlooking relevant findings from sources not readily available (e.g., conference abstracts), potentially introducing publication bias. A more extensive and rigorous systematic review would be warranted to capture relevant findings possibly missed in the current review. Furthermore, because of the limited number of studies examined and their substantial variability concerning demographic and clinical variables, their impact could not be thoroughly assessed in the current review. Methodologically, the included studies showed significant heterogeneity, with most being cross-sectional, small-scale, and single-centre. This limits causal inference, generalizability, and the ability to track recovery over time. Neuropsychiatric assessment tools varied widely, with few studies evaluating specific adult neurogenesis-related functions or conducting power analyses. Importantly, many studies lacked appropriate control groups—particularly recovered COVID-19 individuals without long-term symptoms—making it difficult to isolate the unique effects of LC from general post-infection outcomes. Conceptually, several confounding factors such as unreported psychiatric history, lockdown-related stress, comorbidities, and medication use were inadequately addressed. Furthermore, alternative mechanisms unrelated to adult neurogenesis (e.g., inflammation, structural remodeling, or blood–brain barrier dysfunction) were rarely considered. These gaps hinder definitive conclusions about the specific impact of LC on hippocampal structure and function.

Nonetheless, this scoping review provides a comprehensive overview of the current literature on hippocampal alterations and neuropsychiatric symptoms in long COVID-19 (LC), identifying key methodological gaps and underexplored domains. It offers direction for future research by highlighting the need for standardized assessment tools, longitudinal designs, and integrative approaches linking behavioural, imaging, and biomarker data. Finally, as mentioned earlier in the introduction, given that direct visualisation or detection of AN is practically not possible in humans, we included articles that studied the in vivo correlates of AN using structural and functional neuroimaging of the hippocampus in long COVID-19 patients. Future technological improvements in the field of neuroimaging may help to overcome this challenge.

Future directions

Future research should prioritize longitudinal studies with extended follow-up to monitor changes in adult neurogenesis in individuals with long COVID-19 and neuropsychiatric symptoms, helping to elucidate its trajectory and clinical relevance.

Mechanistic studies are also essential to determine how SARS-CoV-2 infection and its associated neuroinflammation affect AN. Evidence suggests both direct viral effects and immune-mediated responses may disrupt neurogenesis (Ryan & Nolan, 2016; Song et al., 2021), highlighting the need to identify key pathological drivers as potential therapeutic targets. Identifying biomarkers linked to altered AN could significantly enhance diagnosis and treatment monitoring. Promising candidates include brain-derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP), cytokines (e.g., IL-6, TNF-α), and microglial markers (e.g., CD68, Iba-1) (Zhang & Jiao, 2015). Peripheral or CSF biomarkers, including microRNAs and neurotrophic factors, offer accessible tools for assessing neurogenic activity (DeKosky & Golde, 2016). Additionally, doublecortin (DCX) and polysialylated neuronal cell adhesion molecule (PSA-NCAM) are specific to the proliferation and survival of new hippocampal neurons (Moreno-Jiménez et al., 2021; Von Bohlen und Halbach, 2011). Integrating these with neuroimaging biomarkers (Table 1) may provide a more comprehensive view of AN.

Multi-modal imaging approaches—combining fMRI, structural MRI, and PET—can further clarify the role of AN in long COVID. FLAIR MRI findings such as white matter hyperintensities (WMH), although not definitive, may be explored as neural correlates of AN (Cho et al., 2015; Debette & Markus, 2010; Montini et al., 2021; Wallin & Fladby, 2010). PET studies have revealed bilateral hypermetabolic areas in the hippocampus post-COVID-19, correlating with neurologic symptoms and severity (Debs et al., 2023; Morand et al., 2022). The possible link between brain metabolism and AN is debatable and has gained traction in the past decade. However, studies linking PET metabolic profile of the brain to adult neurogenesis are rather insufficient. Given the high metabolic demands of neurogenesis—including lipogenesis, glycolysis, and mitochondrial activity—this connection warrants deeper investigation (Garone, De Giorgio & Carli, 2024; Landry & Huang, 2021; Rumpf, Sanal & Marzano, 2023).

Finally, interventions that promote neurogenesis and neuroplasticity, such as serotonergic agents, atypical antipsychotics, cognitive training, or exercise, should be explored to improve outcomes in long COVID patients with neuropsychiatric symptoms. Overall, addressing these future directions could contribute to a better understanding of the role of adult neurogenesis in the pathophysiology of neuropsychiatric symptoms in long COVID-19 patients and facilitate the development of effective interventions to improve patient outcomes.