Journal of the Academy of Consultation-Liaison Psychiatry 2022:63:474–484

ª 2022 The Author(s). Published by Elsevier Inc. on behalf of Academy of Consultation-Liaison Psychiatry. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Original Research Article

Neuropsychological, Medical, and

Psychiatric Findings After Recovery From Acute
COVID-19: A Cross-sectional Study

Stephen J. Ferrando, M.D., Rhea Dornbush, Ph.D., M.P.H., Sean Lynch, M.D.,
Sivan Shahar, B.A., Lidia Klepacz, M.D., Carol L. Karmen, M.D., Donald Chen, M.D.,
Stephen A. Lobo, M.D., Dania Lerman, M.S.W.

Background: Persistent cognitive, medical and psychi- medical comorbidities, fatigue, and inversely with mea-
atric complaints have been extensively described after sures of executive function. C-reactive protein correlated
recovery from acute SARS-CoV-2 infection. Objective: with current COVID symptoms and depression score but
To describe neuropsychological, medical, psychiatric, inversely with quality of life. Conclusion: Results suggest
and functional correlates of cognitive complaints expe- the existence of extremely low neuropsychological test
rienced after recovery from acute COVID-19 infection. performance experienced by some individuals months
Methods: Sixty participants underwent neuropsycholog- after acute COVID-19 infection, affecting multiple
ical, psychiatric, medical, functional, and quality-of-life neurocognitive domains. This extremely low neuropsy-
assessments 6–8 months after acute COVID-19. Those chological test performance is associated with worse
seeking care for cognitive complaints in a post-COVID- acute COVID-19 symptoms, depression, medical
19 clinical program for post-acute symptoms of COVID- comorbidities, functional complaints, and subjective
19 (clinical group, N = 32) were compared with those cognitive complaints. Exploratory correlations with
recruited from the community who were not seeking care proinflammatory cytokines support further research into
(nonclinical, N = 28). A subset of participants under- inflammatory mechanisms and viable treatments.
went serological testing for proinflammatory cytokines (Journal of the Academy of Consultation-Liaison
C-reactive protein, interleukin-6, and tumor necrosis Psychiatry 2022; 63:474–484)
factor-a to explore correlations with neuropsychological,
psychiatric, and medical variables. Results: For the entire Key words: COVID-19, post-acute symptoms of
sample, 16 (27%) had extremely low test scores (less COVID-19 (PASC), neuropsychological testing,
than second percentile on at least 1 neuropsychological cognitive complaints, neuropsychiatry.
test). The clinical group with cognitive complaints scored
lower than age-adjusted population norms in tests of
attention, processing speed, memory, and executive
function and scored significantly more in the extremely Received October 11, 2021; revised January 7, 2022; accepted January
15, 2022. From the Department of Psychiatry (S.J.F., R.D., S.L., L.K.),
low range than the nonclinical group (38% vs. 14%, P , Westchester Medical Center Health System, Valhalla, NY; New York
0.04). The clinical group also reported higher levels of Medical College (S.J.F., R.D., S.L., S.S., lL.K., C.L.K., D.C., S.A.L.),
Valhalla, NY; and Department of Medicine (C.L.K., D.C., S.A.L.),
depression, anxiety, fatigue, posttraumatic stress disor-
Westchester Medical Center Health System, Valhalla, NY. Send corre-
der, and functional difficulties and lower quality of life. spondence and reprint requests to Stephen J. Ferrando, MD, Director,
In logistic regression analysis, scoring in the extremely Professor and Chairman, Department of Psychiatry, Westchester Med-
ical Center Health System, New York Medical College, 100 Woods
low range was predicted by acute COVID-19 symptoms, Road, Valhalla, New York 10595; e-mail: Stephen.Ferrando@
current depression score, number of medical comorbid- wmchealth.org
ities, and subjective cognitive complaints in the areas of ª 2022 The Author(s). Published by Elsevier Inc. on behalf of
Academy of Consultation-Liaison Psychiatry. This is an open access
memory, language, and executive functions. Interleukin- article under the CC BY-NC-ND license (http://creativecommons.org/
6 correlated with acute COVID symptoms, number of licenses/by-nc-nd/4.0/).

474 Journal of the Academy of Consultation-Liaison Psychiatry 63:5, September/October 2022

 Ferrando et al.

mouse model detected widespread microglial activa-

INTRODUCTION
tion, macrophage, and T-cell-dominated inflammatory
response with microglial apoptosis, suggesting an in-
Severe acute respiratory syndrome coronavirus 2, the flammatory mechanism.21
virus that causes COVID-19, has multiple neuropsy- Few studies have included NP screens or formal
chiatric manifestations in the acute stages, particularly testing. In a comprehensive review of 12 studies on
among severely ill hospitalized patients. These include cognitive impairment after recent COVID-19 infection
headache, fatigue, encephalopathy, encephalitis, (time frame 0–6 months), Daroische et al. (2021)
delirium, depression, anxiety, and psychosis.1–4 Respi- described global cognitive impairment in 15–80% of
ratory, cardiac, gastrointestinal, neuropsychiatric, and study participants, with impairment in memory, atten-
other symptoms may persist months after infection, tion, executive function and verbal fluency documented
giving rise to the terms “long COVID” or “post-acute in a small number of studies.22 Most of these studies were
sequelae of severe acute respiratory syndrome corona- conducted in the acute or subacute setting of COVID-19
virus 2 infection”.5 requiring hospitalization, used brief bedside assessments,
The neuropsychiatric symptoms of post-acute either the Montreal Cognitive Assessment or the Folstein
sequelae of severe acute respiratory syndrome corona- Mini-Mental State Examination, and few used formal
virus 2 infection include subjective cognitive complaints NP testing.22 In a longer term follow-up study, Pilotto
(colloquially described as “brain fog” by many patients) et al. (2020) found that 16% of hospitalized COVID-19
such as diminished focus and mental clarity, forgetful- patients screened positive for cognitive impairment via
ness, mental fatigue, and difficulty making decisions and the Montreal Cognitive Assessment at 6-month follow-
multitasking. These complaints often co-occur with fa- up, which was significantly correlated with COVID-19
tigue, sleep disorders, depression, and anxiety, among illness severity.23 Of 120 health-care workers recovered
others.6 Cognitive complaints have been studied in from mild-moderate COVID-19 illness assessed with a
multiple other clinical entities, including other infectious NP test battery 4 months after diagnosis, Mattioli et al.
disease states,7–9 postural orthostatic tachycardia syn- (2021) found no difference in general cognitive function
drome,10 patients receiving chemotherapy,11 those with or performance in specific cognitive domains compared
chronic fatigue syndrome,12 and neurological conditions with a COVID-negative comparison group.24 In
such as multiple sclerosis,13 among others. The specific contrast, 24 nonhospitalized COVID-19 patients tested
neuropsychological (NP) characteristics of post-acute in a specialized COVID-19 neurology clinic 5–6 months
sequelae of severe acute respiratory syndrome corona- after infection scored in the impaired range on measures
virus 2 infection, including course, risk factors, and of attention and working memory relative to population-
prognosis, have yet to be fully elucidated, leading to calls based norms.25
for large-scale, longitudinal studies.5,6 With this background, this cross-sectional study
Neuropsychiatric symptoms of COVID-19 may aimed to investigate longer term neuropsychiatric
occur through direct effects of the virus on the central sequelae of COVID-19 by assessing individuals recov-
nervous system and/or through other mechanisms, such ered from an acute COVID-19 illness with NP, psy-
as anoxia, inflammation (“cytokine storm”), or an chiatric, medical, and sociodemographic instruments.
autoimmune response.14 The virus may access the brain Study questions included,
by attaching to Angiotensin-Converting Enzyme-2
(ACE-2) receptors in the nasopharynx, traversing the 1. How frequent is NP test impairment, as defined by
olfactory nerve to the piriform cortex.15–17 ACE-2 ex- extremely low NP test scores, in individuals recov-
ists on blood vessel epithelial cells, the blood-brain ered from acute COVID-19 infection?
barrier, and in multiple brain structures, including 2. Do individuals seeking care for cognitive complaints
neurons and glial cells, all of which may influence have higher rates of NP impairment and psychiatric
neurotransmission.18,19 While there are isolated reports and medical symptoms than those not seeking care?
of severe acute respiratory syndrome coronavirus 2 3. Are there clinical predictors of extremely low NP
detected in CSF, clinical series have generally not found test scores that identify potential risk factors?
viral particles in CSF, even among patients with 4. Do elevations in proinflammatory cytokines
neurological complications.15,20 However, a transgenic interleukin-6 (IL-6), tumor necrosis factor-alpha

Journal of the Academy of Consultation-Liaison Psychiatry 63:5, September/October 2022 475

Neuropsychological Findings After Acute COVID-19

(TNF-a), or C-reactive protein (CRP) correlate with Medical measures included self-reported medical
NP or other post-COVID-19 symptoms? history, including a detailed history of COVID-19
illness with symptoms, treatment, and hospitalization,
METHODS time since diagnosis, and number of medical comor-
bidities. COVID-19 symptom severity at the time of
acute infection as well as at the time of the study
Data for this study were obtained from the baseline
appointment was determined by a score on an instru-
assessment of 60 participants enrolled in an ongoing
ment adapted from published Centers for Disease
longitudinal investigation of NP, medical, and psychi-
Control and Prevention COVID-19 symptoms, assess-
atric sequelae of COVID-19. Participants were
ing severity (absent, mild, moderate, severe) on 11
recruited from the Westchester County, New York,
COVID-19 symptoms, which is scored from 0 to 33.26
USA, community via social media, flyers, and word of
Participants were also administered the Lawton-Brody
mouth. In addition, a sample of patients seeking care
Instrumental Activities of Daily Living Scale (IADL),
for post-acute cognitive complaints were referred from
which measures increasing difficulty with practical as-
the Westchester Medical Center Health System
pects of everyday functioning on a scale of 0–8,27 and
(WMCHealth) Post-COVID-19 Recovery Program.
the 11-item Chalder Fatigue Scale, which measures
Interested persons were screened via telephone to
the severity of both mental and physical fatigue and is
determine eligibility, based on the following criteria: (1)
scored from 0 to 33. A cutoff score of .21 is considered
age at least 20 years; (2) a documented positive
clinically significant fatigue.28 Serological samples were
COVID-19 nasopharyngeal test or positive antibody
obtained from a subset of participants and assayed for
test before vaccination; (3) recovered from acute
CRP, IL-6, and TNF-a, as elevated levels of these
COVID-19 infection as per Centers for Disease Control
specific proinflammatory markers have been associated
and Prevention recommendations (10–20 days after
with neurocognitive and psychiatric disorders.29 Assays
symptom onset and 24 hours without fever); (4)
were performed by the Mayo Clinic Laboratories, and
completed minimum eighth grade education; (5) fluent
standardized reference ranges were used
in English; and (6) capable of signing informed consent.
(normal = CRP # 8.0 mg/L; IL-6 # 1.8 pg/ml; TNF-
Persons with a prior diagnosis of a major neuro-
a # 2.8 pg/ml).
cognitive disorder, traumatic brain injury with loss of
Psychiatric measures included pre-COVID-19 psy-
consciousness, uncorrected visual/hearing deficits, in-
chiatric and substance use disorder history, current
tellectual disability, or unstable psychiatric symptoms
psychiatric medication use, and self-report question-
were excluded.
naires to assess current psychiatric symptoms and dis-
At the baseline visit, eligible participants were
orders. Self-report questionnaires included the Patient
explained the risks and benefits and signed informed
Health Questionnaire-9 (PHQ-9), which queries Diag-
consent. The study was approved by the New York
nostic and Statistical Manual for Mental Disorders-5
Medical College Institutional Review Board as well as
Edition major depression criteria and has a maximum
the Westchester Medical Center Health System Clinical
score of 2730; the Endicott Quality of Life Enjoyment
Research Institute.
and Satisfaction Scale (Endicott QLESQ), which
Participants met with study assessors (S.L., S.S.),
queries overall life satisfaction in 14 areas and has a raw
who were trained to perform and score the assessment
score range of 0–7031; the Posttraumatic Stress
battery and were supervised by the study principal
Disorder Checklist for DSM-5, which has a
investigator (S.J.F.) and co-principal investigator
maximum score of 8032; and the Generalized Anxiety
(R.D.), the latter is a board-certified neuropsychologist.
Disorder-7 questionnaire, which is scored from 0 to
Participants were compensated with $40 for their time.
21.33 Scores on the questionnaires were categorized
Study Measurements and Instruments based on cutoff values in the medical literature. For
PHQ-9, a score of $11 may indicate clinically signifi-
Sociodemographic measures included age, gender, race, cant depressive symptoms30; for Generalized Anxiety
relationship status, years of education, and current Disorder-7, a score $10 indicates clinically significant
employment. anxiety symptoms33; for Posttraumatic Stress Disorder

476 Journal of the Academy of Consultation-Liaison Psychiatry 63:5, September/October 2022

 Ferrando et al.

Checklist for DSM-5, a score of $33 indicates clinically Recovery Program. The nonclinical group consisted
significant PTSD symptoms.32 of participants from the general community, none of
The NP battery consisted of measures assessing whom were seeking care for post-acute COVID-19
specific cognitive domains that have been implicated in symptoms.
other infectious and clinical disease states.7–11 The Data were analyzed using SPSS software.41 These
battery included the Test of Premorbid Function, to included descriptive statistics (frequency, mean, stan-
obtain an estimate of premorbid (i.e., pre-COVID-19) dard deviation); Chi-square for group comparisons on
intellectual function.34 Participants also completed the categorical variables; and independent and one-sample
Patient Assessment of Own Function (PAOF), which t-tests and analysis of covariance for group compari-
queries subjective cognitive complaints yielding an sons on continuous variables. Significant group differ-
average score of 0–5 for memory, language and ences in moderators such as age and number of medical
communication, handedness, sensory perception, and comorbidities were used as covariates in group com-
cognitive/intellectual functioning.35 For the study, the parisons. Pearson correlations were used to explore
PAOF subscales most associated with everyday cogni- associations between immune markers and clinical
tive functioning, including memory, language, and variables. Logistic regression was used to identify in-
cognitive/intellectual/executive functioning, served as dependent predictors of extremely low NP test scores,
measures of subjective cognitive complaints. Partici- using PAOF memory, language, and cognition scores,
pants were administered NP tests assessing attention; as well as medical and psychiatric variables that
auditory/verbal and visual immediate and delayed differed between clinical and nonclinical groups as
memory; visuospatial and constructional abilities; psy- predictors.
chomotor speed; language; and executive function. The RESULTS
battery included the Repeatable Battery for the
Assessment of Neuropsychological Status (RBANS) Characteristics of the Total Sample
Form A (total and 5 subscale scores), the Trail Making
Test Parts A and B, verbal fluency (letter and category), The participants had a mean age of 41 years, approxi-
and the Stroop Color-Word Test, yielding 11 test scores mately 67% were female, 75% were White or Hispanic,
per participant.36–39 67% were in a relationship, and 75% were employed.
NP test scores were converted to standardized t- On average, participants had a college level education
scores and analyzed in two ways: (1) as continuous (Table 1).
measures and (2) to categorize scores as unimpaired or From a medical standpoint (Table 2), the partici-
extremely low. For the first, to assess participants’ pants had acute COVID-19 illness on average 7 months
performance relative to a standardized comparison before the assessment. The most prevalent acute symp-
group without COVID-19, scores on each NP test were toms were fatigue (92%), respiratory symptoms (90%),
converted to t-scores according to their respective neurological symptoms (87%), anosmia (67%), and
manuals and compared with age- and education- memory/cognitive problems (57%). Seven participants
adjusted (where available) population-based norms. had been hospitalized for complications of COVID-19; 6
Thus, performance of the entire group and the sub- of them reported respiratory distress, 5 cognitive prob-
groups of interest could be compared with that of a lems or weakness, and 3 flu-like symptoms. None were
non-COVID-19 comparison population. For the sec- admitted to intensive care or required ventilator support.
ond, we applied accepted clinical practice for assessing Aside from COVID-19, participants reported on average
extremely low NP test performance, defined as $2 1.5 comorbid medical comorbidities, including obesity
standard deviations below (less than or equal to second (25%), asthma (23%), hypertension (17%), sleep apnea
percentile) the age- and education-adjusted norms on (15%), hypothyroidism (15%), migraines (10%), diabetes
one or more of the 11 tests.34,36,40 (7%), and hyperlipidemia (5%). Reported acute versus
Analyses were conducted on the entire sample of 60 current COVID-19 symptoms declined; however, half of
participants and on two subgroups—a “clinical group” the participants reported current clinically significant
and a “nonclinical group.” The clinical group included fatigue as measured by the Chalder Fatigue Scale. Fifty
participants seeking care for post-acute cognitive participants underwent serological testing for IL-6,
complaints from the WMCHealth Post-COVID-19 CRP, and TNF-a (Table 2). Availability of results

Journal of the Academy of Consultation-Liaison Psychiatry 63:5, September/October 2022 477

Neuropsychological Findings After Acute COVID-19

TABLE 1. Sociodemographic Characteristics

Measure Total sample Post-COVID nonclinical Post-COVID clinical Stat., df, sig. (P, 95%)*
N 60 28 32 -
Age, M (SD) 41.4 (13.5) 33.7 (11.0) 48.1 (12.8) t = 24.6, df = 58, P , 0.001
Female, N (%) 41 (68) 16 (57) 25 (78) Chi Sq. = 3.0, df = 1, P = 0.08
Race (%) Chi Sq. = 7.1, df = 4, P = 0.13
White 30 (56.6) 17 (65.4) 13 (48.1)
Hispanic 11 (20.8) 5 (19.2) 6 (22.2)
Asian 5 (9.4) 2 (7.6) 3 (11.1)
Black 5 (9.4) 0 (0.0) 5 (18.5)
Other 2 (3.8) 2 (7.7) 0 (0.0)
Education, yrs, M (SD) 16.0 (2.2) 16.4 (2.2) 15.8 (2.1) t = 1.1, df = 58, P = 0.28
Relationship status, N (%) in 38 (63) 18 (64) 20 (63) Chi Sq. = 0.02, df = 1, P = 0.89
relationship
Employed currently, N (%) 50 (83) 26 (93) 24 (75) Chi Sq. = 3.4, df = 1, P = 0.06

M = mean; SD = standard deviation.

* P value represents comparison of nonclinical and clinical COVID-19 groups.

varied by test and was based on participant refusal, marijuana and alcohol), all in remission. Twenty-five
insufficient sample volume, or sample degradation. Of percent were currently taking antidepressants, 8%
those with available results, approximately 40% had IL-6 stimulants, 7% benzodiazepines, and 6% hypnotics,
or CRP levels above the reference range, and 20% had lamotrigine, or gabapentin. Based on cutoff scores for
elevated TNF-a. the PHQ-9, Generalized Anxiety Disorder-7, and
Psychiatrically (Table 3), 39% reported a pre- Posttraumatic Stress Disorder Checklist for DSM-5,
COVID-19 psychiatric history, including depression 47% screened positive for clinically significant depres-
(30%), anxiety (25%), and attention deficit- sion, 28% for anxiety, and 20% for PTSD.
hyperactivity disorder (8%). Seventeen percent had a NP test findings (Table 4) indicated that the
history of substance use disorder (predominately sample had a high-normal estimated premorbid

TABLE 2. Medical Characteristics

Total sample Post-COVID Post-COVID Stat., df, sig. (P, 95%)*
nonclinical clinical
N N N
Number of medical comorbidities, M (SD) 1.5 (1.4) 60 1.0 (1.1) 28 1.9 (1.6) 32 t = 22.3, df = 59, P = 0.02
Days since diagnosis, M (SD) 209.3 (133.5) 60 172 (120) 28 250 (132) 32 t = 22.4, df = 59, P = 0.02
Acute illness CDC symptom score, M (SD) 16.5 (5.9) 60 13.7 (5.2) 28 18.9 (6.0) 32 F = 10.8, df = 3, P , 0.001†
Current CDC symptom score, M (SD) 5.7 (4.6) 60 2.5 (2.8) 28 8.4 (4.0) 32 F = 13.5, df = 3, P , 0.001†
Hospitalized during COVID illness, N (%) 7 (12) 60 1 (4) 28 6 (19) 32 Fishers Exact P = 0.11
Chalder Fatigue Scale, M (SD) 20.67 (7.71) 59 16.7 (7.6) 27 23.7 (6.5) 32 F = 5.8, df = 3, P = 0.002†
Clinical fatigue (Chadler Fatigue 30 (51) 59 8 (28) 27 22 (69) 32 Chi Sq = 8.9, df = 1, P = 0.003
Scale $ 21), N (%)
Instrumental activities of daily 7.6 (1.0) 60 8.0 (0) 28 7.3 (1.2) 32 F = 4.8, df = 3, P = 0.006†
living score, M (SD)
IL-6 above reference range, N (%) 18 (45) 40 5 (25) 20 12 (60) 20 Chi Sq = 4.4, df = 1, P = 0.04
TNF-a above reference range, N (%) 10 (20) 50 7 (29) 24 3 (14) 26 Chi Sq = 2.4, df = 1, P = 0.12
CRP above reference range, N (%) 14 (41) 40 5 (25) 22 9 (64) 18 Chi Sq = 7.9, df = 1, P = 0.02

CDC = Centers for Disease Control and Prevention; CRP = C-reactive protein; IL-6 = interleukin-6; M = mean; SD = standard deviation;
TNF-a = tumor necrosis factor-alpha.
* P value represents comparison of nonclinical and clinical COVID-19 groups.
†
Covariates include age and number of medical comorbidities.

478 Journal of the Academy of Consultation-Liaison Psychiatry 63:5, September/October 2022

 Ferrando et al.

TABLE 3. Psychiatric and Behavioral Measures

Total sample Post-COVID nonclinic Post-COVID clinic Stat., sig (P, 95%)
N 60 28 32 -
Prior psychiatric history, N (%) 24 (39) 11 (39) 13 (39) Chi Sq = 0.01, df = 1, P = 0.91
SUD history, N (%) 10 (17) 5 (18) 5 (16) Chi Sq = 0.05, df = 1, P = 0.82
PHQ-9, M (SD) 9.28 (6.17) 6.4 (5.2) 12.1 (5.8) F = 7.1, df = 3, P , 0.001*
GAD, M (SD) 6.17 (4.67) 5.59 (5.06) 6.77 (4.24) F = 2.8, df = 3, P = 0.05*
PCL-5, M (SD) 19.51 (14.45) 13.5 (14.1) 25.3 (12.5) F = 7.6, df = 3, P , 0.001*
Endicott QOL % score, M (SD) 47.5 (10.8) 70.0 (17.0) 51.3 (18.4) F = 7.5, df = 3, P , 0.001*
Depression (PHQ-9 $ 11), N (%) 28 (47) 6 (21) 22 (69) Chi Sq = 13.4, df = 1, P , 0.001
Anxiety (GAD-7 $ 10), N (%) 17 (28) 6 (21) 11 (34) Chi Sq = 1.2, df = 1, P = 0.27
PTSD (PCL-5 $ 33), N (%) 12 (20) 3 (10) 9 (28) Chi Sq = 2.8, df = 1, P = 0.09

GAD-7 = Generalized Anxiety Disorder-7; M = mean; PCL-5 = Posttraumatic Stress Disorder Checklist for DSM-5; PHQ-9 = Patient
Health Questionnaire-9; PTSD = posttraumatic stress disorder; QOL = quality of life; SD = standard deviation; SUD = substance use disorder.
P value represents comparison of nonclinical and clinical COVID-19 groups.
* Covariates include age and number of medical comorbidities.

intellectual function on the Test of Premorbid Func- differences in age and comorbid conditions, these
tion. Subjective cognitive function on the PAOF intrinsic patient characteristics that existed before the
indicated mild-moderate perceived cognitive problems COVID-19 illness were included as covariates in sub-
in the areas of memory, language, and cognition. sequent group comparisons on continuous assessment
Compared with age-adjusted norms, performance of measures (indicated in Tables 2–4). The clinical group
the overall sample on the RBANS total score as well was further from their COVID-19 diagnosis compared
as subtests of immediate and delayed memory and with the nonclinical group (8.3 vs. 5.7 months). They
language was significantly lower than normative reported significantly more acute and current COVID-
values. Based on study criteria, just over one fourth 19 symptoms, higher levels of fatigue, and diminished
(N = 16, 27%) had extremely low test scores (less IADLs. The clinical group also reported more current
than or equal to second percentile on at least one test). gastrointestinal symptoms (P , 0.04) and shortness of
Among those 16 individuals, mean IADL was signifi- breath (P , 0.02). They were also significantly more
cantly lower than that for the rest of the cohort (6.8 vs. likely to have CRP and IL-6 above the reference range.
7.9, respectively, P , 0.03), suggesting increased
functional difficulty, particularly in the areas of Psychiatric
medication management, handling money, shopping,
The two groups were nearly identical in terms of psy-
and cooking.
chiatric and substance use disorder history (Table 3).
However, the clinical group had higher levels of
Comparison of Nonclinical and Clinical Groups depressive symptoms on the PHQ-9 and were over three
Sociodemographics times more likely to screen positive for clinically signif-
icant depression (69% vs. 21%). They also reported
The clinical group was significantly older than the significantly more anxiety and PTSD symptoms, but the
nonclinical group but did not differ significantly on groups did not significantly differ in proportion with
other sociodemographic characteristics (Table 1). The clinically significant Generalized Anxiety or PTSD.
groups had nearly identical educational attainment and
relationship status. Neuropsychological

Medical The two groups were nearly identical in terms of esti-

mated premorbid intellectual function; however, the
The clinical group reported significantly more under- clinical group reported significantly more subjective
lying chronic comorbid conditions, but none were cognitive complaints in the areas of memory, language,
medically unstable (Table 2). Given the group and cognition (executive functions) on the PAOF

Journal of the Academy of Consultation-Liaison Psychiatry 63:5, September/October 2022 479

Neuropsychological Findings After Acute COVID-19

TABLE 4. Estimate of Premorbid Function, Patient Assessment of Their Current Cognitive Function and Neuropsychological Test Outcomes as
Compared to Published Normative Data
Total, N = 60 Post-COVID Post-COVID
nonclinical, N = 28 clinical, N = 32
Sig (P, 95%)*
Test of premorbid cognitive
function (TOPF), M (SD)
Scaled 108.9 (12.9) 108.7 (14.1) 108.8 (11.3) 0.33†
Predicted 107.4 (7.9) 109.3 (6.9) 106.3 (8.0) 0.72‡
Patient assessment of own
function (PAOF), M (SD)
Memory 1.88 (1.1) 1.4 (0.9) 2.3 (1.2) 0.002§
Language 1.47 (1.0) 1.1 (0.8) 1.8 (1.1) 0.006k
Cognition 1.50 (1.2) 0.8 (0.7) 2.2 (1.3) 0.001{
t, df, sig. t, df, sig. t, df, sig.
(P, 95%)# (P, 95%)# (P, 95%)#
RBANS total, M (SD)
Scaled score 94.3 (14.5) 23.0, 59, 0.004 9.46 (12.1) 20.24, 27, 0.82 2 2
Subgroups, M (SD) 21.1, 59, 0.29
Attention 97.8 (16.0) 21.1, 59, 0.29 103.6 (15.5) 1.2, 27, 0.22 92.6 (14.9) 22.8, 31, 0.009
Immediate memory 90.8 (15.0) 24.7, 59, ,0.001 94.3 (11.5) 22.6, 27, 0.01 87.8 (17.1) 24.0, 31, 0.001
Delayed memory 93.1 (14.3) 23.8, 59, ,0.001 97.0 (12.8) 21.2, 27, 0.23 89.6 (14.8) 24.0, 31, 0.001
Visuospatial 104 (16.4) 1.9, 59, 0.06 109.1 (10.7) 4.5, 27, 0.001** 99.6 (19.2) 20.12, 31, 0.91
Language 94.3 (16.2) 22.8, 59, 0.008 95.5 (17.3) 21.3, 27, 0.18 93.1 (15.3) 22.5, 31, 0.02
Trail Making Test, M (SD)
A (T) 47.3 (11.6) 21.8, 59, 0.08 48.6 (11.0) 20.67, 27,0.51 46.2 (12.2) 21.8, 31, 0.09
B (T) 45.6 (10.9) 23.1,59, 0.003 48.4 (11.6) 20.75, 27,0.46 43.1 (9.8) 24.0, 31, 0.001
Verbal fluency, M (SD)
Category mean (T) 49.3 (10.6) 20.5, 59, 0.62 51.0 (11.8) 0.47, 27, 0.65 47.8 (9.5) 21.3, 31, 0.20
Letter mean (T) 47.7 (10.8) 21.7, 59, 0.09 50.4 (10.7) 0.22, 27, 0.83 45.4 (9.5) 24.0, 31, 0.01
Stroop Color Word Score, 48.7 (11.9) 23.5, 59, 0.001 54.6 (12.1) 2.0, 27, 0.05** 43.6 (9.2) 23.9, 31, 0.001
M (SD) (T)
Extremely low Neuropsychological 16 (27%) 2 4 (14%) 2 12 (38%) Chi Square = 4.2,
Test Score(s) df = 1, P = 0.04

M = mean; RBANS = Repeatable Battery for the Assessment of Neuropsychological Status; SD = standard deviation.
* P value represents comparison of post-COVID-19 nonclinical group to clinical group.
†
Covariates include age and number of medical comorbidities: F = 1.2, df = 3, P = 0.33.
‡
Covariates include age and number of medical comorbidities: F = 7.6, df = 3, P = 0.72.
§
Covariates include age and number of medical comorbidities: F = 5.7, df = 3, P = 0.002.
k
Covariates include age and number of medical comorbidities: F = 4.6, df = 3, P = 0.006.
{
Covariates include age and number of medical comorbidities: F = 9.2, df = 3, P , 0.001.
#
P value represents statistical comparison of post-COVID-19 nonclinical group, clinical group, and total sample to published normative
data using one-sample t-test.
** Performance of the nonclinical group on the visuospatial subtests of the RBANS and Stroop Color Word Test was significantly better
than published norms.

(Tables 4 and 5). When the two groups were compared memory of the RBANS, as well as executive func-
with age- and education-adjusted normative values, the tioning as assessed by Letter Fluency, Trail Making
nonclinical group scored lower than normative values Test Part B, and Stroop Color-Word Test. Thus,
on only 1 test—immediate memory on the RBANS— decreased NP test performance noted for the entire
while scoring higher than expected on RBANS visuo- sample was primarily accounted for by the clinical
spatial functioning and Stroop Color Word tests. In group. Consistent with this, the clinical group had a
contrast, the clinical group scored significantly lower significantly higher proportion scoring with extremely
than normative values on 8 of 11 tests, including do- low NP scores (Table 4, n = 12, 38% clinical, vs. n = 4,
mains of attention, language, immediate and delayed 14% nonclinical, P = 0.04).

480 Journal of the Academy of Consultation-Liaison Psychiatry 63:5, September/October 2022

 Ferrando et al.

TABLE 5. Logistic Regression Analysis Predicting Neuropsychological Impairment by Key Clinical Variables
Statistic Wald statistic df Sig. (P, 95%)
Clinical variable
Acute COVID symptom score 3.89 1 0.05
Current COVID symptom score 3.55 1 0.06
PHQ-9 score 6.02 1 0.01
GAD-7 score 3.38 1 0.07
Chalder Fatigue Scale score 1.42 1 0.23
Number of medical comorbidities 4.93 1 0.03
Patient assessment of own functioning-cognition 8.45 1 0.004
Patient assessment of own functioning-memory 9.62 1 0.002
Patient assessment of own functioning-language 5.73 1 0.02

GAD-7 = Generalized Anxiety Disorder-7; PHQ-9 = Patient Health Questionnaire-9.

IADL and Quality of Life comorbidities (r = 0.58, P , 0.001) and Chalder Fatigue
Scale score (r = 0.42, P , 0.01), but inversely correlated
The clinical group had significantly more difficulty with with Stroop Color Word Test t-score (r = 20.38,
IADLs than the nonclinical group and significantly P , 0.02), and Trail Making Test Part B t-score
diminished quality of life on the Endicott QLESQ (r = 20.30, P , 0.05). CRP was correlated with current
(Tables 2 and 3). COVID illness score (r = 0.38, P , 0.01) and PHQ-9
score (r = 0.32, P , 0.05) but inversely correlated with
Predictors of NP Test Scores Endicott QLESQ (r = 20.32, P , 0.05). TNF-a had no
statistically significant correlations.
To determine which clinical factors might predict
extremely low NP scores, we conducted a logistic
DISCUSSION
regression analysis, with extremely low NP scores (#2nd
percentile) as the dependent variable (Table 5). Inde-
pendent variables included acute COVID-19 symptoms, Data from this sample suggest that individuals report-
current COVID-19 symptoms, PHQ-9 score, GAD-7 ing cognitive complaints months after acute COVID-19
score, Chalder Fatigue Scale score, number of medical may have extremely low NP test performance (scored
comorbidities, and PAOF memory, language, and less than or equal to the second percentile) relative to
cognition scores. Inflammatory markers were not those without such symptoms. These cognitive diffi-
included in this model as the smaller N would limit culties may lead such individuals to seek treatment.
predictive power. In the regression model, peak COVID- When comparing a clinical sample of individuals
19 symptoms, PHQ-9, number of medical comorbidities, seeking care for cognitive complaints and other post-
and PAOF memory, language, and cognition scores COVID symptoms, we found diminished performance
were significant predictors of extremely low NP scores, in multiple neurocognitive domains relative to age- and
correctly categorizing 78% (12/16, P = 0.004). education-adjusted norms that were not present in the
nonclinical group, including attention, processing
Exploratory Correlations of Proinflammatory speed, memory, and executive function. A significantly
Cytokines higher proportion of these individuals had extremely
low NP scores. This pattern and degree of performance
Because of the limited number of inflammatory marker difficulty is like that documented in prior studies of
results, we calculated Pearson correlation coefficients (r) COVID-19 with smaller sample sizes and shorter
to explore associations between IL-6, TNF-a, and CRP timeframe after acute illness, particularly among those
and medical, psychiatric, and NP variables of interest. who were hospitalized.6,23–25 We also found that the
IL-6 was significantly correlated with acute COVID clinical group had high levels of clinically significant
illness score (r = 0.32, P , 0.05), number of medical depression and fatigue, diminished quality of life, and

Journal of the Academy of Consultation-Liaison Psychiatry 63:5, September/October 2022 481

Neuropsychological Findings After Acute COVID-19

more limitations in IADLs than the nonclinical group, is possible that extremely low NP performance was
even after covarying for age and medical comorbidity. caused by depression, as depression is associated with
This suggests that group differences were both statisti- deficits in processing speed, memory, verbal fluency, and
cally and clinically significant, affecting function and executive function.44 Depression is also associated with
quality of life, and that these clinical symptoms or their later decline in cognition even in those with no baseline
combination appear to lead individuals to seek deficit.45 The fact that participants with a history of
treatment. depression before COVID-19 were not more likely to
The inclusion of a measure of subjective neuro- have extremely low test scores does not support this
cognitive complaints (the PAOF) allowed for investi- contention. It is also possible that the presence of neu-
gation of whether the perceived impairment correlates rocognitive decline, along with persistence of COVID-
with the actual impairment. It is important to note that 19-related symptoms and psychosocial stresses, causes
prior studies have found subjective cognitive com- depression. Finally, it is possible that depression and NP
plaints do not correlate reliably with NP test impair- dysfunction in COVID-19 co-occur and may be due to
ment,42 leading to skepticism about whether subjective the same underlying pathogenic mechanisms.
complaints are “real.” However, the current data sug- We investigated correlations between serum IL-6,
gest that perception of cognitive problems, even months TNF-a, and CRP levels and psychiatric, medical, and
after acute COVID-19, may be a reliable sign of actual neurocognitive measures to explore whether evidence of
cognitive difficulty and should be investigated. It could systemic inflammation might be associated with these
be argued that 38% with an extremely low NP test outcomes. The data indicated significant positive cor-
performance in a sample of individuals with cognitive relations between IL-6, COVID-19 symptoms at the
complaints is relatively low and that, conversely, 62% time of diagnosis, number of medical comorbidities,
were in the normal range. Nonetheless, the significant fatigue, and measures of executive function. Further-
differences found in the clinical group on individual NP more, the elevated IL-6 level was more prevalent in the
tests relative to published norms may indicate that in- clinical group. In contrast, CRP was significantly
dividuals with cognitive complaints may detect a correlated with current COVID-19 symptoms and
decline in NP function relative to what would be depressive symptoms but inversely correlated with
considered normal for their age and premorbid quality of life. It is not clear how to interpret these
functioning. disparate findings. IL-6 may be more associated with
When investigating a potential profile of risk fac- acute COVID severity and the underlying medical co-
tors for extremely low NP scores in the sample, inde- morbidity leading to fatigue and executive function
pendent predictors in a logistic regression model impairment, while CRP may be a marker of current
included severity of acute COVID-19 illness symptoms, COVID symptom burden and depression, leading to
depressive symptoms, number of medical comorbid- diminished perceived quality of life. IL-6 and CRP have
ities, and subjective perception of memory, language, been cited extensively as markers of COVID-19 illness
and cognitive (executive function) problems. It is not severity and prognosis.46 These proinflammatory cyto-
surprising that severity of acute COVID-19 illness kines may predict or cause the neuropsychiatric
would be associated with NP test scores as found in sequelae described here. While proinflammatory cyto-
previous research23,25; however, prior studies have not kines have been studied extensively in psychiatry,29
incorporated standardized measures of COVID-19 such research in COVID-19 is limited. Zhou et al.
symptoms, medical comorbidity, estimate of pre- (2020) found that CRP was correlated with elevated
morbid intellectual functioning and subjective cognitive reaction time in a sample of individuals recovered from
complaints. Medical comorbidities such as obesity, COVID-19, while IL-6 was not correlated with NP
hypertension, and diabetes are known to increase risk scores.47 These results are not consistent with the results
for NP dysfunction and severe COVID-19 illness hos- documented in this study, but study methodologies
pitalization and mortality.43 differed. Taken together, these preliminary results
It is important to note that, while current depressive support further research in this area.
symptoms were independently predictive of extremely Study strengths included standardized assessments
low NP test scores, the causal relationship is not clear. It across NP, medical, and psychiatric domains; however, the

482 Journal of the Academy of Consultation-Liaison Psychiatry 63:5, September/October 2022

 Ferrando et al.

study has important limitations. The study sample is rela- 2. Garrigues E, Janvier P, Kherabi Y, et al: Post-discharge
tively small and was skewed toward a clinical population, persistent symptoms and health-related quality of life after
hospitalization for COVID-19. J Infect 2020; 81
so the results may not be generalizable to the entire post-
3. Ferrando SJ, Klepacz L, Lynch S, et al: COVID-19 psy-
COVID population. While an estimate of premorbid in- chosis: a potential new neuropsychiatric condition Triggered
tellectual function was obtained, pre-COVID-19 NP per- by Novel Coronavirus infection and the inflammatory
formance was not available for comparison. The study did response? Psychosomatics 2020; 61:551–555
not include a COVID-19-negative comparison group 4. Ferrando SJ, Klepacz L, Lynch S, et al: Psychiatric emergen-
matched for age, medical, and other comorbidities. How- cies during the height of the COVID-19 pandemic in the sub-
urban New York City area. J Psychiatr Res 2021; 136:552–559
ever, comparison to age- and education-corrected norms is 5. NIH Announces research Opportunities to study “long
an accepted methodology in clinical practice and NP COVID” [Internet]. National Institute of Nursing research.
studies.48 Data for this study are cross-sectional, so the U.S. Department of health and human Services. Available
onset, course, and causal associations of clinical variables from: https://www.ninr.nih.gov/newsandinformation/
and extremely low NP test performance could not be newsandnotes/pasc-initiative
6. Ferrarese C, Silani V, Priori A, et al: An Italian multicenter
determined. Inflammatory markers were not available for
retrospective-prospective observational study on neurological
all participants and could not be included as predictors of manifestations of COVID-19 (NEUROCOVID). Neurol Sci
NP impairment in logistic regression analysis. The IADL, 2020; 41:1355–1359
while correlated with NP performance, is not an objective 7. Ferrando SJ: Diagnosis and treatment of HIV-associated
measure of occupational and social functioning. Neuro- neurocognitive disorders. New Dir Ment Health Serv 2000;
imaging, encephalographic, and other central nervous 2000:25–35
8. Stefano GB: Historical insight into infections and disorders
system studies were not uniformly available in study associated with neurological and psychiatric sequelae similar
participants. to long covid. Med Sci Monitor 2021; 27
Despite the limitations cited previously, these data 9. Bransfield RC, Aidlen DM, Cook MJ, Javia S: A clinical
support the existence of clinically relevant neuro- diagnostic system for late-stage neuropsychiatric Lyme Bor-
cognitive difficulty months after acute COVID-19 reliosis based upon an analysis of 100 patients. Healthcare
2020; 8:13
illness and that cognitive complaints warrant clinical
10. Ross AJ, Medow MS, Rowe PC, et al: What is brain fog? an
investigation. The results mirror our clinical experience evaluation of the symptom in postural tachycardia syndrome.
in caring for patients in the WMCHealth Post-COVID Clin Auton Res 2013; 23:305–311
Recovery Program where cognitive complaints are 11. Jansen CE, Miaskowski CA, Dodd MJ, et al: A meta-anal-
frequent and distressing. Despite finding significant ysis of the sensitivity of various neuropsychological tests used
correlations of clinical variables with inflammatory to detect chemotherapy-induced cognitive impairment in
patients with breast cancer. Oncol Nurs Forum 2007; 34:997–
markers, our results are preliminary. Longitudinal
1005
follow-up of this cohort is in progress. 12. Ocon AJ: Caught in the thickness of “Brain Fog”: Exploring
the cognitive symptoms of chronic fatigue syndrome. Front
Physiol 2013; 4
Funding: Funding for the present study is from the 13. Chiaravalloti ND, DeLuca J: Cognitive impairment in mul-
Edith Har Esh, M.D. Professorship Endowment Fund— tiple sclerosis. Lancet Neurol 2008; 7:1139–1151
New York Medical College. Funds were used to cover 14. DeSantis G, SARS-CoV-2: A new virus but a familiar inflam-
costs of participant reimbursement, laboratory assays, mation brain pattern. Brain Behav Immun 2020; 87:95–96
and NP test materials. 15. Huang YH, Jiang D, Huang JT: SARS-CoV-2 detected in
cerebrospinal fluid by PCR in a Case of COVID-19 en-
cephalitis. Brain Behav Immun 2020; 87:149
Disclosure: The authors declare that they have no
16. Shang J, Ye G, Shi K, et al: Structural basis of re-
known competing financial interests or personal re-
ceptor recognition by SARS-CoV-2. Nature 2020;
lationships that could have appeared to influence the 581:221–224
work reported in this paper.
17. Yan R, Zhang Y, Li Y, et al: Structural basis for the
recognition of SARS-CoV-2 by full-length human ACE2.
Science 2020; 367:1444–1448
References
18. Baig AM, Khaleeq A, Ali U, et al: Evidence of the COVID-
1. Paterson RW, Brown RL, Benjamin L, et al: The emerging 19 virus Targeting the CNS: Tissue Distribution, Host–virus
spectrum of COVID-19 neurology: clinical, radiological and Interaction, and Proposed Neurotropic mechanisms. ACS
laboratory findings. Brain 2020; 143:3104–3120 Chem Neurosci 2020; 11:995–998

Journal of the Academy of Consultation-Liaison Psychiatry 63:5, September/October 2022 483

Neuropsychological Findings After Acute COVID-19

19. Zubair AS, McAlpine LS, Gardin T, et al: Neuropatho- 34. Advanced Clinical Solutions for WAIS-IV and WMS-IV.
genesis and neurologic manifestations of the Coronaviruses Administration and Scoring Manual. San Antonio, Tx:
in the age of Coronavirus disease 2019. JAMA Neurol 2020; Pearson; 2009. p. 109–118
77:1018 35. Chelune GJ, Heaton RK, Lehman RA: Neuropsychological
20. Destras G, Bal A, Escuret V, et al: Systematic SARS-CoV-2 and Personality correlates of patients’ complaints of
screening in cerebrospinal fluid during the COVID-19 disability. Adv Clin Neuropsychol 1986:95–126
pandemic. The Lancet Microbe 2020; 1:e149 36. Randolph C, Tierney MC, Mohr E, et al: The Repeatable
21. Seehusen F, Clark JJ, Sharma P, et al: Viral neuroinvasion battery for the assessment of neuropsychological status
and neurotropism without neuronal damage in the hACE2 (RBANS): preliminary clinical Validity. J Clin Exp Neuro-
mouse model of COVID-19. medRXiv 2021:1–35. https://doi. psychol 1998; 20:310–319
org/10.1101/2021.04.16.440173 37. Lezak MD, Howieson DB, Loring DW, et al: Neuropsycho-
22. Daroische R, Hemminghyth MS, Eilertsen TH, Breitve MH, logical assessment. New York: Oxford University press; 2004
Chwiszczuk LJ: Cognitive impairment after covid-19—a re- 38. Gladsjo JA, Schuman CC, Evans JD, et al: Norms for letter
view on objective test data. Front Neurol 2021; 12 and category fluency: Demographic Corrections for age, ed-
23. Pilotto A, Cristillo V, Piccinelli SC, et al: Long-term neuro- ucation, and Ethnicity. Assessment 1999; 6:147–178
logical manifestations of COVID-19: prevalence and predic- 39. Golden CJ, Freshwater SM: Stroop color and word test: a
tive factors. Neurol Sci 2021; 42:4903–4907 manual for clinical and experimental uses. Illinois: Stoelting; 2002
24. Mattioli F, Stampatori C, Righetti F, et al: Neurological and 40. Van Gorp WG, Lamb DG, Schmitt FA: Methodologic issues
cognitive sequelae of Covid-19: a four month follow-up. in neuropsychological research with HIV-spectrum disease.
J Neurol 2021; 268:4422–4428 Arch Clin Neuropsychol 2013; 8:17–33
25. Graham EL, Clark JR, Orban ZS, et al: Persistent neurologic 41. IBM Corp: IBM SPSS Statistics for Windows, Version 27.0.
symptoms and cognitive dysfunction in non-hospitalized Armonk, NY: IBM Corp; 2020
Covid-19 “long haulers”. Ann Clin Translational Neurol 42. Petersen JZ, Porter RJ, Miskowiak KW: Clinical character-
2021; 8:1073–1085 istics associated with the discrepancy between subjective and
26. CDC: Coronavirus Disease 2019 (COVID-19) – Symptoms objective cognitive impairment in depression. J Affective
[Internet]. Centers for Disease Control and Prevention. Disord 2019; 246:763–774
Available from: http://www.CDC.gov/coronavirus/2019- 43. Liang W, Liang H, Ou L, et al: Development and Validation
ncov/symptoms-testing/symptoms.html; 2021 of a clinical risk score to predict the Occurrence of Critical
27. Graf C: The Lawton instrumental Activities of Daily Living illness in hospitalized patients with COVID-19. JAMA Intern
scale. AJN, Am J Nurs 2008; 108:52–62 Med 2020; 180:1081–1089
28. Jackson C: The Chalder fatigue scale (CFQ 11). Occup Med 44. Xu G, Lin K, Rao D, et al: Neuropsychological performance
2015; 65:86 in bipolar I, bipolar II and unipolar depression patients: a
29. Bauer ME, Teixeira AL: Inflammation in psychiatric disor- longitudinal, naturalistic study. J Affective Disord 2012;
ders: what comes first? Ann New York Acad Sci 2018; 136:328–339
1437:57–67 45. John A, Patel U, Rusted J, et al: Affective problems and
30. Kroenke K, Spitzer RL, Williams JB: The PHQ-9. J Gen decline in cognitive state in older adults: a systematic review
Intern Med 2001; 16:606–613 and meta-analysis. Psychol Med 2018; 49:353–365
31. Endicott J, Nee J, Harrison W, et al: Quality of life Enjoy- 46. Liu F, Li L, Xu MD, et al: Prognostic value of interleukin-6,
ment and satisfaction questionnaire. PsycTESTS Dataset C-reactive protein, and procalcitonin in patients with
1993; 29:321–326 COVID-19. J Clin Virol 2020; 127:104370
32. Blevins CA, Weathers FW, Davis MT, et al: The Post- 47. Zhou H, Lu S, Chen J, et al: The landscape of cognitive
traumatic stress disorder Checklist for DSM-5 (PCL-5): function in recovered COVID-positive Patients. J Psychiatr
Development and Initial Psychometric evaluation. Res 2020; 129:98–102
J Traumatic Stress 2015; 28:489–498 48. Heaton RK, Grant I, Matthews CG: Comprehensive norms
33. Spitzer RL, Kroenke K, Williams JB, et al: A brief measure for an expanded Halstead-Reitan battery: demographic cor-
for assessing generalized anxiety disorder. Arch Intern Med rections, research findings, and clinical applications. Florida:
2006; 166:1092 Psychological Assessment Resources; 1992

484 Journal of the Academy of Consultation-Liaison Psychiatry 63:5, September/October 2022