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Infectious Disease and Neurocognition
T- cell lymphotropic virus type 1 and FM, these reports are robust with the Australian
study (Schierhout et al., 2020) involving more than 3000 subjects. In contrast, ndings supporting any relationship between ME/ CFS and lymphotropic viruses have
been withdrawn.
Our literature search also revealed a link between FM and a variety of chronic infections such as osteomyelitis, periodontitis, and rhinosinusitis. Such links were not
found in our literature search of ME/ CFS. We believe these ndings may be of assistance to clinicians in their eorts to diagnose FM and should the need arise to parse
their diagnosis between FM and ME/ CFS.
Relationship of cognitive dysfunction to chronic disease
Before evaluating the research ndings focused on the relationships between infectious agents and cognitive dysfunction in ME/ CFS and FM patients, we note that
research ndings support the concept of chronic infection causing cognitive dysfunction by documenting its occurrence in other diseases: (1) Damiano et al. (2022)
indicate a several decades- long discussion of the role of viral infections in the decline of mental cognitive processes associated with Alzheimer’s disease; (2) there is
larger support for the belief that bacterial infection is associated with cognitive decline among the elderly (Muzambi et al., 2019); and (3) there is general acceptance
of cognitive dysfunction as a consequence of infection with SARS- CoV- 2 virus— the
virus that causes Covid- 19 and long Covid (Delgado- Alonso et al., 2022; Muzambi
et al., 2019). Moreover, there is overlap of long Covid symptoms, including cognitive
dysfunction, with the symptoms of ME/ CFS (T. L. Wong & Weitzer, 2021) and FM
(Aaron et al., 2000). Other examples of altered cognition linked to infectious organisms include rabies (Soler- Rangel et al., 2020), syphilis (Davis et al., 2021), HIV
(Alford & Vera, 2018), and Chlamydia (Gérard et al., 2005).
Fibromyalgia and cognitive dysfunction
A text word search of PubMed for citations relevant to “bromyalgia and cognitive
dysfunction” yielded 229 citations, of which we selected 46 that explored the possible
relationship between the two. e studies were conducted in Asia, Europe, North
America, and South America, attesting to the worldwide interest in and reporting
of cognitive dysfunction as a symptom of FM. e countries in which these cited
studies have been conducted are displayed on a world map in Figure 22.4.
Our search of the literature suggests that cognitive dysfunction in FM patients has
been explored for approximately the last 25 years despite FM being a disease entity
for over 50 years. e delay in the investigation of FM- associated cognitive dysfunction suggests an initial reluctance to accept cognitive diculties as being a bona de
symptom of FM.
Fibromyalgia and Chronic Fatigue 369
Figure 22.4 Countries in which studies suggesting linkage of fibromyalgia to cognitive
impairment have been studied and which are cited in the manuscript are shown in dark grey.
Our summary table of cognitive impairment associated with FM (Table 22.3)
suggests a large variation in study design and the measures used to assess cognitive
function. e preponderance of studies utilized small numbers of subjects, making
such studies preliminary and promising but in need of duplication both elsewhere
and with larger numbers of participants to become conclusive. Table 22.3 lists the
criteria by which the patients were diagnosed as having FM upon enrollment in each
study where possible. We were not able to identify inclusion or selection criteria for
all studies. Since the same and current FM case denition has not been used in all
studies and because dierent case denitions permit the inclusion and/ or exclusion of some patients, there is a high probability that our table both includes and
excludes FM patients who satisfy the current FM case denition (Wolfe & Rasker,
2021). Caution is needed when comparing studies or drawing conclusions from
them under these circumstances. To assist the reader in determining how dierent
case denitions might inuence the results that have been found, we include a summary of the FM case denitions in Appendix 2.
Further making these studies dicult to compare or combine, the cognitive assessment tools used in these studies are not the same and oen are not fully described. ere are multiple assessment tools of cognition, and to fully understand
and compare the cognitive decits of patients, we and others (Gonzalez & Tadi,
2023) believe that all domains of cognition should be assessed. Some studies employ instruments that evaluate a single cognitive domain; others evaluate multiple
domains, and some employ a complete neuropsychological examination. Further,
some assessments may be better at identifying one or more domain decits than
others (Gonzalez & Tadi, 2023), and recent tools have improved abilities to identify
cognitive decits.
As shown in Table 22.3, a variety of cognitive assessment tools have been used
to characterize the cognitive impairment or dysfunction associated with FM.
Infectious Disease and Neurocognition
Table 22.3 Summary of cognitive impairments associated with fibromyalgia
Ref. Ye a r N Diagnostic
criteria
Location Results
a
Reviews and meta- analyses
1 2001 NA ACR 1990 USA Addresses the cognitive tasks that
are problematic for patients with
FM, the role of psychological factors
such as depression and anxiety, the
role of physical factors such as pain
and fatigue, the nature of patients’
perceptions of their cognitive
abilities, and whether patients can be
tested for cognitive dysfunction
2 2006 NA NA USA Proposes that the slow information
processing of CFS patients and the
impaired attention control of FM
patients is due to chronic pain
3 2009 NA No clinical
case denition
USA Most aected in FM are working
memory, episodic memory, and
semantic memory. ere is diculty
with attentional control. Cognitive
dysfunction is attributable to depression,
poor sleep, and possibly pain
4 2012 NA ACR 2010 Italy A meta- analysis literature evaluates
the ecacy of CBT and compares it
with physiotherapy, acupuncture,
and patient education programs for
the treatment of FM. CBT is no better
than other non- pharmacological
treatments and did not improve
outcomes for pain, fatigue, sleep
disturbance, and quality of life
5 2013 NA Prefers
Spain Reviews the literature from 1995
ACR 2010 to
ACR 1990
6 2018 NA NA UK
USA
to 2012. Few studies of cognitive
function in patients with FM were
found, and those found mostly
use small samples. e studies
demonstrate decits mainly in
working memory and complex
attentional function. Long- term
memory and executive functions are
also impaired. e degree of pain
seems directly related to cognitive
dysfunction
Meta- analysis that included 37
studies. FM was signicantly
and negatively associated with
performance on all domains of
cognitive function: inhibitory
control (g = 0.61), memory (g = 0.51
for short- term, 0.50 for long- term
memory), and set shiing (g = 0.30)
Table 22.3 Continued
Fibromyalgia and Chronic Fatigue 371
Ref. Ye a r N Diagnostic
criteria
a
7 2018 NA No clinical
case denition
cited
Location Results
Taiwan A meta- analysis with 23 case-
controlled studies with a total of 2096
participants. Cognitive function was
signicantly lower in individuals
with FM than in healthy controls.
Large eect sizes were found in
learning/ memory and attention/
psychomotor speed; medium eect
sizes found in executive function and
working memory
8 2020 NA No clinical
case denition
cited
USA A systematic review to evaluate the
relationship between pain conditions
and subsequent decline of cognitive
function. Positive associations found
for osteoarthritis and headaches/
migraines. Chronic pain symptoms
may accelerate cognitive decline
and increase risk for memory
impairment, Alzheimer’s disease,
and related disorders
9 2021 NA NA Netherlands A PubMed, keyword search limited
to the previous 5 years. Cognitive
dysfunction might be caused by
excessive pain perception, hormonal,
and metabolic changes.
10 2021 2493 ACR 2010
ACR 2011
ACR 2016
Germany
Netherlands
USA
FM is a pain syndrome. Severe
cognitive dysfunction parallels
severe FM symptoms
Characterizing cognitive dysfunction
11 2022 79,966 ACR 2010 Netherlands Cognitive task performance and
self- reported cognitive functioning
in CFS and FM patients are
investigated in a population- based
sample via survey instruments.
Objective task performance and
subjective cognitive symptoms
were assessed. Participants meeting
the criteria for FM reported more
subjective cognitive symptoms
compared with controls and
were independent of comorbid
mood or anxiety disorders and
physical symptom severity.
Conclusion: cognitive symptoms
and task performance were
suboptimal in CFS and FM patients
(continued)
Infectious Disease and Neurocognition
Table 22.3 Continued
Ref. Ye a r N Diagnostic
criteria
Location Results
a
12 2014 209 ACR 2010 USA Decit in lexical access speed
occurred at approximately twice
the frequency (48.3 percent versus
25.0 percent) in FM. e average
delay in speed of lexical access was
171 milliseconds in FM and 163
milliseconds in controls
13 2021 132 ACR 1990 Spain Patients with FM preserved their
working memory span and ability
to maintain and manipulate
information online for both
visuospatial and verbal domains.
Up to one- third of patients showed
impairment in tasks requiring
more short- term memory load,
divided attention, and information
processing ability. Cognitive
performance was spuriously related
to the level of pain experienced.
Linear regression analyses suggested
that sleep problems and fatigue
are the variables that best predict
working memory performance in
FM patients
14 2018 110 ACR 1990 Spain Short- term and working memory
and inattention measures were
only associated with symptoms of
depression. Selective attention was
associated with both depression and
FM. Conclusion: FM patients show
a cluster of cognitive impairment
in the attentional and executive
domains
15 2017 105 ACR 1990 Spain 84 percent of FM patients had
cognitive complaints with depression
scores, physical functioning, and
working memory performance
correlating with cognitive complaints
16 2008 67 ACR 1990 USA > 70 percent of FM patients
performed within one standard
deviation of the norm on ≥7 of
10 speeded measures. More than
49 percent of FM patients tested as
impaired on two speed tasks (reading
words and naming colors). Reading
speed impairment was two times
greater and naming color speed 1.6
times greater in FM patients
Table 22.3 Continued
Fibromyalgia and Chronic Fatigue 373
Ref. Ye a r N Diagnostic
criteria
a
17 2018 52 ACR 1990 Spain
Location Results
Executive functions assessed in FM
Aust ria
patients included updating, shiing
and inhibition, decision making, and
mental planning. Impairments were
found in updating, shiing inhibition,
decision making, and planning
18 2020 50 ACR 2016 USA FM patients in comparison to healthy
controls demonstrated poorer
cognitive functioning across three
United States National Institute of
Health Toolbox tests. ere were no
strong correlations between subjective
and objective cognitive functioning
in both the FM and control groups.
In the lived environment, the FM
group demonstrated poorer subjective
cognition and objective working
memory
19 2014 43 ACR 1990 USA Women with FM had poorer
executive function (Stroop Color/
Word) and one processing- speed
measure (measured by Digit Symbol
Substitution Coding)
20 2018 38 ACR 1990 Spain FM patients do not dier from healthy
controls in overall working memory
functioning. Poor performance was
found in a visuospatial working
memory only. FM patients displayed a
higher level of perception of cognitive
diculties, which appeared to be
mediated by depression and fatigue.
Cognitive complaints were only
associated with a lower verbal working
memory capacity
21 2015 30 ACR 2010 Italy Four domains of executive function
(shiing, inhibition, updating, and
access) using the Miyake model were
examined. Results conrmed the
presence of impairments of attention,
long- term memory, working memory,
and shiing and updating executive
functions
22 1995 25 Smythe (1979)
Yunus
et al. (1981)
ACR 1990
Norway FM patients share with depression
patients a nonspecic decit in
information processing capacity but
whereas that dysfunction resides in
the right hemisphere in patients with
depression it is not localized there in FM
patients. Conclusion: FM and depression
are probably dierent conditions
Infectious Disease and Neurocognition
Table 22.3 Continued
Ref. Ye a r N Diagnostic
criteria
23 2016 8 “Established
diagnosis”
Location Results
a
UK None of eight FM patients seen in a
cognitive disorder clinic diagnosed
as having cognitive impairment
Comparative studies
24 2004 57 ACR 1990 USA Compared to rheumatic disease
patients, FM patients have more
mental decline, mental confusion,
speech diculty, pain, stiness,
fatigue, and sleep diculty
25 2019 32 ACR 2010 USA Cognitive decits were observed in
FM (23.3 percent) and in rheumatoid
arthritis (34.5 percent). Most test
scores in aected individuals fell
in the mild to moderate ranges of
impairment. Psychological distress
was unrelated to cognition in both
groups
Correlations with brain electrical activity
26 2016 7 ACR 1990 Japan ree patients with FM as a
complication of frontotemporal
neurocognitive disorder and four
with Alzheimer’s disease studied.
No organic disorder explained
their chronic pain. Severe atrophic
changes in the temporal lobes
and hippocampus found. Severe
hypoperfusion on the right side
of the medial temporal lobe,
both sides of the anterior corpus
callosum, anterior cingulate gyrus,
and primary sensory area found.
Conclusion: central sensitization
may be a possible risk factor of
widespread pain in elderly patients
27 2018 42 ACR 2010 Spain
Aust ria
Study demonstrates lower pain
thresholds and pain tolerance
in FM patients than in healthy
individuals. Patients reported higher
pain intensity during pressure
stimulation. Results reect the
hyperalgesia that characterizes
the central pain sensitization
hypothesis: exaggerated pain
processing in FMS increases
demands on central nervous system
resources and thus reduces resources
for cognition
Table 22.3 Continued
Fibromyalgia and Chronic Fatigue 375
Ref. Ye a r N Diagnostic
criteria
a
Location Results
28 2019 19 ACR 1990 Spain e ndings suggest a reduction
in frontal brain activity during
performance of an interference
task, which was associated with
the patients’ cognitive complaints.
Decits in exibility in the allocation
of attentional resources and cognitive
control during complex tasks may
explain the cognitive problems
reported by chronic pain patients
29 2017 18 Diagnosis by a
Rheumatologist
Spain Electroencephalography results
suggest higher neural noise and
impaired local and distant neural
coordination in FM patients,
supporting the hypothesis that
neural “noise” correlates with
cognitive dysfunction
30 2017 20 ACR 1990 Italy Transcranial random noise
stimulation of primary motor
cortex in FM patients reduced
pain, depression, anxiety and
Fibromyalgia Impact Questionnaire
scores
31 2018 40 ACR 2010 Brazil
Portugal
Trans- direct current stimulation
and working memory training
administered over the dorsolateral
prefrontal cortex increased both
short- and long- term memory, and
increased orthographic and semantic
verbal uency scores
32 2017 20 ACR 2010 Brazil
USA
33 2018 11 ACR 1990 Taiwan
USA
e eect of a single application
of transcranial direct current
stimulation over dorsolateral
prefrontal cortex on three distinct
attentional networks (alertness
orienting and executive control)
led to increased performance in the
orienting and executive attention
networks but no dierence in the
alerting attentional network
NIRS was used to evaluate brain
function of FM patients. Reduced
brain activity was found in the
frontal regions of the FM patients.
NIRS is a potential tool for
evaluating FM brain function
(continued)
Infectious Disease and Neurocognition
Table 22.3 Continued
Ref. Ye a r N Diagnostic
criteria
Location Results
a
34 2005 36 ACR 1990 Tu rk e y Auditory event- related brain potentials
used to evaluate cognitive function
while the SF- 36 was used to determine
FM patient quality of life. FM patients
showed prolonged latencies and
reduced amplitudes of P300 and lower
scores across all SF- 36 subgroups
35 2016 16 ACR 1990 USA Functional magnetic resonance
imaging did not detect dierences in
working memory performance in FM
patients. However, their increased
perceived cognitive diculty was
positively correlated with the severity
of their symptoms
Biological modiers of cognitive dysfunction
36 2019 146 ACR 2010 Spain Authors conclude that olfactory
impairment is an early marker
of cognitive decline. FM patients
had signicantly lower perceptive
organization, processing speed, lower
verbal scale, manipulative scale, and
speed of odor identication, and odor
detection threshold. Lower scores
were achieved by hyposmic patients
37 2021 46 ACR
unspecied
China FM patients had worse performance
in attention, short- term memory,
orientation, object working memory,
and spatial reference memory.
Raised levels of cortisol and GnRH
protect general cognition, whereas
raised levels of cortisol and thyroidstimulating hormone will damage
spatial memory. Authors conclude
that the altered levels of cortisol,
thyrotropin- releasing hormone,
and GnRH may mediate cognitive
changes in FM
38 2021 44 ACR 2010 Taiwan FM patients performed
poorer: delayed recall in the Chinese
versions of the Verbal Learning Test,
Taylor Complex Figure Test, Boston
Naming Test, and Wisconsin Card
Sorting Test. Diurnal cortisol levels of
FM patients tended to be lower
39 2018 30 ACR 2010 Colombia FM patients had lower scores in
attention, memory, language, visualconstructive praxis, and executive
functions
Table 22.3 Continued
Fibromyalgia and Chronic Fatigue 377
Ref. Ye a r N Diagnostic
criteria
a
Location Results
40 2019 668 ACR 1990 USA 14.07 percent of the total patient
cohort were smokers. Smokers
reported greater perceived total
cognitive dysfunction and greater
subscale scores of perceived
diculty in language, verbal
memory, visuospatial memory, and
attention. Smokers reported greater
severity of FM- related symptoms,
worse quality- of- life index in the
mental component scale, greater
sleep problems, and increased
anxiety
41 2014 43 ACR 1990 Germany e impact of FM on tests that
predict driving ability was studied.
Visual orientation, concentration,
attention, vigilance, motor
coordination, performance under
stress, and reaction time were tested.
e driving ability of FM patients
was not inferior to that of healthy
volunteers
42 2021 668 ACR 1990 or
ACR 2010
USA Statin therapy for at least 1 month is
not a risk factor for worse symptom
burden in patients with FM as
measured by tender point count,
fatigue, cognition, mood, or sleep
issues
Anatomical correlates of cognitive dysfunction
43 2009 Review NA USA Proposes that the slow information
processing of CFS patients and the
impaired attention control of FM
patients is due to chronic pain
Attempts at therapy
44 2012 Review ACR 2010 Italy A meta- analysis literature
evaluates the efficacy of CBT
and compares it physiotherapy,
acupuncture, and patient
education programs for the
treatment of FM. CBT is no better
than other non- pharmacological
treatments and did not improve
outcomes for pain, fatigue, sleep
disturbance, and quality of life
(continued)