Long COVID and the Brain: A Retrospective Study of the Neuropsychological Manifestations of Long COVID

Abstract

Background: The purpose of this study was to investigate the incidence and impact of neuropsychological symptoms related to long COVID syndrome to better understand, characterize, and treat symptoms. Methods: A retrospective chart review was performed utilizing de-identified patient data obtained from UConn Health’s Long COVID Clinic and Recovery Center within the Department of Pulmonary, Critical Care, and Sleep Medicine in Farmington, CT between March 2020 and August 2022. A total of 155 patients were included, and data was collected via standardized patient questionnaires. These included a review of systems, followed by physical examination and further diagnostic testing and treatment as indicated. Results: Of the 155 patients, many were female (females n = 102 versus males n = 53) and more than 60% of patients were between 41 and 60 years of age. This was despite higher hospitalization rates in males (n = 24, 45.3%) and those over the age of 71 (n = 7, 70.0%). Most patients did report experiencing neuropsychological symptoms attributed to long COVID syndrome, which unfortunately did not correlate with diagnostic modalities such as brain imaging in most cases. Conclusions: In the aftermath of the COVID-19 pandemic, patients have been left with lingering symptoms now defined as long COVID syndrome. Our study highlights the extent of neuropsychiatric symptom burden in the setting of long COVID syndrome. Pathophysiological mechanisms in the development of long COVID syndrome in certain patient cohorts are not well understood, and are believed to be secondary to immune system dysregulation leading to chronic inflammation.

1. Introduction

Long COVID syndrome, also known as post-acute sequelae of SARS-CoV-2 infection, has emerged as an impactful public health concern affecting approximately 6% to 7.3% of the adult population [1,2]. While most individuals recover from the acute phase of infection, a substantial portion experience persistent or recurrent symptoms weeks to years after initial infection, even regardless of illness severity [3]. Per the Centers for Disease Control and Prevention (CDC), long COVID is defined as new, recurring, or ongoing symptoms lasting beyond 28 days after the initial infection [4].

Symptoms of long COVID vary widely and may include fatigue, headache, abdominal pain, myalgias, arthralgias, sleep disturbance, alteration in mood, cognitive impairment, and brain fog. These symptoms may be persistent, intermittent, or relapsing. Important risk factors include older age and female sex. Additional risk factors include pre-existing medical conditions, including diabetes mellitus, history of chronic lung disease, hospitalization during the acute phase, need for mechanical ventilation during acute infection, high viral load, vaccination status, and additional lifestyle factors [5,6].

Diagnosing long COVID syndrome is based on a prior clinical diagnosis of COVID-19. However, patients may not always present with a positive PCR or antigen test [4]. This can make diagnosis challenging. Distinguishing whether symptoms may be related to long COVID syndrome as opposed to a new acute SARS-CoV-2 infection or other pre-existing condition may also pose a significant challenge.

This study sought to focus on neuropsychiatric manifestations of long COVID syndrome, which are particularly concerning due to their impact on cognitive function, sleep, and mental health. Symptoms such as cognitive dysfunction, sleep disturbances, anxiety, and depression are commonly reported and have been shown to affect up to 25% of non-hospitalized individuals, and up to 90% of hospitalized individuals [6,7]. The underlying pathophysiology has not been fully elucidated, however. Suggested hypotheses include possible immune dysregulation, neuroinflammation, or dysfunction of the blood–brain barrier. This may in turn impair neurogenesis, cause alterations in cerebral perfusion, and cause oxidative stress [8,9,10,11,12].

Given the significant impact of long COVID syndrome on both quality of life and ability to perform daily activities, early recognition and diagnosis is crucial. A deeper understanding of its underlying pathophysiology is essential to develop targeted interventions aimed at improving symptoms and enhancing overall functioning [12]. The aim of this study was to investigate the incidence of long-COVID-related symptoms, particularly neuropsychological symptoms, and objectively correlate symptoms with an appropriate diagnostic modality when applicable to better understand, characterize, and potentially treat these symptoms.

2. Materials and Methods

A retrospective chart review was performed utilizing de-identified patient data obtained from the Long COVID Clinic and Recovery Center within UConn Health’s Department of Pulmonary, Critical Care, and Sleep Medicine in Farmington, CT. Data was collected between March 2020 and August 2022. A total of 171 patients were referred by providers outside of this clinic during this timeframe. A total of 155 patients were included in the study. Inclusion criteria included the development of symptoms after SARS-CoV-2 infection, the persistence of symptoms for at least four weeks after infection, and age greater than 18 years. Infection was confirmed by a documented positive COVID test either via molecular polymerase chain reaction testing or rapid antigen testing. Sixteen patients were excluded, either because they did not present for their initial appointment or because of a lack of a positive COVID test on file.

On initial presentation, patients were provided a standardized questionnaire that detailed each patient’s date of positive COVID test, any need for hospitalization (with duration of stay if applicable), COVID-related therapies and complications, and a detailed 13-point review of systems. This review of systems documented a structured set of questions to systematically review and identify any symptoms across various organ systems. Psychiatric symptoms were assessed via the four-item patient health questionnaire for anxiety and depression (PHQ-4). Prior psychiatric history, including need for treatment and any changes to medication regimen following SARS-CoV-2 infection was also included. A full physical examination was then performed. Additional treatments, testing, and/or referrals were provided as indicated based on the above gathered information to assist with the array of clinical concerns. The primary outcomes of this study were the self-reported symptoms, particularly neuropsychological symptoms, following documented SARS-CoV-2 infection persisting for 4 weeks or longer. Additional data points, including age, gender, ethnicity, and need for hospitalization were also obtained.

3. Results

Of the 155 patients eligible for inclusion in this study, 102 were female, and 53 were male (65.8% versus 34.2%, respectively). Patients ranged from 20 to 81 years of age, with a mean age of 51. More than 60% of patients were between 41 and 60 years of age. Most patients were white. A total of 47 patients were hospitalized for SARS-CoV-2 infection, 23 of whom were female (22.5% of all females) and 24 of whom were male (45.3% of all males). Those older than 71 years of age had the highest rates of hospitalization (n = 7, 70.0%). Both white and African American patients had the highest rates of hospitalization by percentage (

Table 1. Demographics of Long COVID Clinic Patients at UConn Health.

Total Patients n = 155 Total Patients Included in Study		Patients Requiring Hospitalization n = 47 of Total Patients
	n = Number of Total Patients (% of Patients Stratified by Demographic)	n = Number of Patients Requiring Hospitalization (% of Patients Stratified by Demographic)
Age
20–30	13 (8.4%)	1 (7.7%)
31–40	15 (9.7%)	3 (20.0%)
41–50	40 (25.8%)	10 (25.0%)
51–60	54 (34.8%)	20 (37.0%)
61–70	23 (14.8%)	6 (26.1%)
71+	10 (6.5%)	7 (70.0%)
Sex
Male	53 (65.8%)	24 (45.3%)
Female	102 (34.2%)	23 (22.5%)
Race/Ethnicity
African American	21 (13.5%)	7 (33.3%)
Asian	4 (2.6%)	1 (25.0%)
Latino	31 (20.0%)	8 (25.8%)
Native American	1 (0.6%)	0 (0.0%)
Pacific Islander	2 (1.3%)	0 (0.0%)
White	81 (52.3%)	27 (33.3%)
Other	15 (9.7%)	4 (26.7%)

). The average timeframe from positive COVID test to date of initial evaluation was 6.9 months, with the shortest time to presentation being 2 months and the longest time to presentation being 24 months.

Of 155 patients, 110 (70.9%) reported neurological symptoms. These included issues with memory and concentration, brain fog, headaches, dizziness/vertigo, myalgias, neuropathy, generalized weakness, and alteration/loss of taste and/or smell. The most prevalent symptoms reported included issues with memory and concentration (n = 50, 45.5%) and brain fog (n = 43, 39.1%) (

Table 2. Summary of Neuropsychological Symptoms Reported by Long COVID Clinic Patients at UConn Health.

Total Patients n = 171 Total Patients Referred n = 155 Total Patients Included in Study
	n = Number of Total Patients (% of Patients)
Neurological symptoms	110 (70.9%)
Memory/concentration	50 (45.5%)
Brain fog	43 (39.1%)
Headaches	34 (30.9%)
Dizziness/vertigo	14 (12.7%)
Myalgias	11 (10.0%)
Neuropathy of extremities	11 (10.0%)
Generalized weakness	9 (8.2%)
Alteration/loss of taste and/or smell	7 (6.4%)
Psychological symptoms	121 (78.1%)
Fatigue	99 (81.8%)
New/worsened anxiety	55 (45.5%)
New/worsened depression	15 (12.4%)
Sleep disorder/insomnia	35 (29.0%)

). Of these 110 patients, 39 were male (73.6% of all males) and 71 were female (69.6% of all females). Neurologic symptoms were most prevalent in individuals aged 51–60 (

Table 3. Summary of Neuropsychological Symptoms Reported by Long COVID Clinic Patients at UConn Health Stratified by Age and Sex.

	n = Number of Total Patients by Demographic (% of Patients)
Neurological symptoms (n = 110, 70.9%)
Age
20–30 (n = 13)	10 (9.1%)
31–40 (n = 15)	10 (9.1%)
41–50 (n = 40)	27 (24.5%)
51–60 (n = 54)	42 (38.2%)
61–70 (n = 23)	14 (12.7%)
71+ (n = 10)	7 (6.4%)
Sex
Males (n = 53)	39 (73.6%)
Females (n = 102)	71 (69.6%)
Psychological symptoms (n = 121, 78.1%)
Age
20–30 (n = 13)	7 (5.8%)
31–40 (n = 15)	12 (9.9%)
41–50 (n = 40)	33 (27.3%)
51–60 (n = 54)	45 (37.2%)
61–70 (n = 23)	19 (15.7%)
71+ (n = 10)	5 (4.1%)
Sex
Males (n = 53)	31 (58.5%)
Females (n = 102)	90 (88.2%)

).

For further evaluation, patients with neurological complaints were referred for appropriate imaging, then referred to neurology for further evaluation and treatment, as indicated. Brain imaging was ordered when applicable, and 30 of the above patients with neurologic symptoms underwent imaging. Twenty-nine patients had MRIs of the brain and one patient had a CT scan of the head. Only two brain MRIs revealed minimal white matter hyperintensity on T2 sequence. The remaining imaging either revealed no acute findings or incidental chronic findings deemed unrelated to presenting symptoms. Fifty-nine patients were referred to neurology and five were referred to ENT, particularly for alterations in taste or smell.

Of 155 patients, 121 (78.1%) reported new or worsened psychiatric complaints including fatigue, anxiety, depression, and/or sleep dysfunction such as insomnia (Table 2). Of these 121 patients, 31 were male (58.5% of all males) and 90 were female (88.2% of all females). Psychiatric symptoms were also most prevalent in individuals aged 51–60 by percentage (Table 3). Fatigue was the most common complaint, being reported in 99 of the 155 patients (63.9%). When stratified by sex, fatigue was reported in 31 males (58.5% of all males) and 68 females (66.7% of all females), and this symptom was most prevalent in individuals aged 51–60 years as well. Sixteen patients were referred to a mental health specialist: a psychologist, psychiatrist, and/or a therapist. Seventeen patients were already established with a mental health provider.

Treatment was tailored to each patient based upon the recommendations of psychiatry and neurology as applicable. For fatigue specifically, it is notable that amantadine was utilized on a case-by-case basis with notable impact. Supplementation with riboflavin (vitamin B2), magnesium, and coenzyme Q10 was also used. In cases of severe and persistent fatigue, IV steroid infusions were utilized in seven cases. Five patients were also prescribed continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea. In select cases, central nervous system stimulants such as modafinil were also prescribed. Referrals to physical therapy were also utilized. With respect to psychiatric concerns, in addition to patients being referred to mental health specialists as indicated, new or increased dosages of prescription medications, such as selective serotonin reuptake inhibitors, were provided for 42 patients for worsening symptoms including fatigue, anxiety, depression, and insomnia.

It is important to note that further work-up also revealed new diagnoses of type 2 diabetes in four patients, Graves’ disease in two patients, hypothyroidism in one patient, adrenal insufficiency in one patient, and fibromyalgia in two patients. In addition, one patient provided a positive antinuclear antibody (ANA) test (1:130 speckled) of undetermined significance, while another was found to have positive rheumatoid factor which may be indicative of an underlying autoimmune disorder.

4. Discussion

Most patients who presented to UConn Health’s Long COVID Clinic reporting neuropsychological symptoms attributed to long COVID syndrome were female, and more than 60% of patients were aged between 41 and 60 years, despite hospitalization rates being higher in males and those over the age of 71 (Table 1). These findings are consistent with demographic data reported by the Centers for Disease Control and Prevention’s National Center for Health Statistics for adults with long COVID [13], and are also consistent with prior case series [14].

The average timeframe from positive COVID test to date of initial evaluation was 6.9 months. It is our clinical opinion that most individuals experienced a slow recovery or general persistence of their long COVID symptoms as opposed to an emergence of new symptoms over time. This is in light of the fact that some studies have suggested that neuropsychological symptoms potentially increase, rather than resolve over time [6]. However, our experience of patients presenting for initial evaluation for persistent symptoms up to 24 months following the date of a positive COVID test does highlight the relentless nature of neuropsychological manifestations of the disease.

Specifically, the most prevalent neurological symptoms included issues with memory and concentration in 45.5% of patients and brain fog in 39.1% of patients (Table 2). This is consistent with a metanalysis by Premjaj et al., which looked at over 10,000 patients from 18 different publications. Within three months of acute infection, these features were predominant in almost up to one-third of patients [6]. Many of these patients were male (73.6%), however, when fatigue was not accounted for. This is unique, as female sex has typically been identified as a risk factor for post-acute neuropsychiatric symptoms [7]. Moreover, most patients did not have findings on diagnostic modalities such as MRI of the brain or CT scan of the head that could explain symptoms.

New or worsened psychiatric complaints were experienced by 78.1% of patients (Table 2), as evaluated with the four-item patient health questionnaire for anxiety and depression (PHQ-4). While 88.2% of these patients were female, fatigue was most reported by 63.9% of all patients, both male and female. Fatigue has also been noted to be a key feature of disease in prior studies [6,7]. Prior psychiatric illness also appeared to be a risk factor for new or worsening symptoms.

The exact pathophysiology of long COVID syndrome remains to be completely understood. Nonetheless, SARS-CoV-2 infection has been observed to cause immune dysregulation. Imbalances in immune regulation have previously been reported, including declines in lymphocyte counts such as CD4+ and CD8+ T cells, B cells, and natural killer cells. Concomitantly, increases in the number of immunosuppressive regulatory T cells as well as an upregulation of interleukins, such as IL-6, have been observed. These play a large role in immune reactions and inflammation. Such alterations have been found to be reliable indicators of more severe acute infection and thus may have a role in long-term sequalae [8].

Proposed mechanisms for prolonged neuropsychiatric symptoms include immune dysregulation of the various inflammatory mediators resulting in neuroinflammation and blood–brain barrier dysfunction. This may result in the entry of inflammatory molecules such as cytokines into the brain itself. This may then contribute to impairment in neuronal development and growth and, further, to microvascular dysfunction [9,10,11,12] which may in turn contribute to cerebral hypoperfusion and oxidative stress [12]. It has been suggested that mitochondrial dysfunction may also contribute to hypoxic neuronal injury [15,16].

An additional proposed mechanism of long COVID syndrome includes viral persistence. It is possible that viral remnants may remain in CNS tissue, contributing to chronic inflammation and neurotoxicity at the cellular level [7]. Reactivation of latent viruses may also play a role. For example, with respect to human immunodeficiency virus (HIV), microglia, monocytes, and macrophages have been known to harbor this virus [17]. This suggests that they could also act as reservoirs for the SARS-CoV-2 virus. Furthermore, autoimmunity may be a contributing factor, as antibodies formed post-infection may target neuronal tissue [18].

Potential limitations of this study include the fact that this was a single-center study with a high percentage of predominantly white patients, which may limit generalizability. This study may also be limited by its retrospective-cohort design. Strengths of this study include the fact that reliable data collection methods were conducted using standardized questionnaires during patient encounters with the intention of diagnosing and treating symptoms. Rigorous attempts were made to include patients meeting criteria to assess incidence and prevalence of neurological symptoms and disease burden. Patients also acted as their own controls, allowing for a comparison of symptoms both before and after SARS-CoV-2 infection, helping to reduce possible confounding variables. However, the coexistence of additional disease states, which could also have contributed to symptomatology, cannot always be excluded. We believe that this study adds to a growing body of knowledge regarding neuropsychiatric manifestations of long COVID syndrome, and highlights the risk factors that contribute to long-term social and psychological impacts.

5. Conclusions

In the aftermath of the COVID-19 pandemic, many patients, predominantly females and individuals of middle age, were left with long-term neuropsychiatric symptoms, as seen in this cohort of long COVID patients. The mechanisms of development and persistence of such symptoms are poorly understood. Consequently, therapeutic options have been—and remain—limited. However, some neuromodulatory medications have been tried, with varying degrees of success. While this study highlights the long-term neuropsychological impacts of long COVID syndrome, further research and data is needed to better understand this debilitating sequela of disease.