Fibromyalgia Clinical Trial
Official title:
Cognitive Dysfunction in Fibromyalgia Patients: Specific Neuro-psychological Dysfunctions, Psychiatric Comorbidity and Integrative Assessments
Fibromyalgia is a common rheumatologic disorder. Many patients complain of cognitive
dysfunction as part of their symptoms.
The investigators aim to assess this cognitive dysfunction through extensive neuro-cognitive
testing.
Cognitive dysfunction in Fibromyalgia patients: specific neuro-psychological dysfunctions,
psychiatric comorbidity and integrative assessments - Can the investigators help them?
Scientific and Technological Background
1. General Clinical characteristics FM is a common rheumatologic disorder (ranges from
2%-12% in the general population) with complex symptom presentation that include:
chronically painful, soft tissue pain. Those affected suffer widespread pain and
tenderness at anatomically defined tender points in soft tissue musculoskeletal
structures. Associated symptoms include depression, anxiety, fatigue, sleep
disturbances, and other somatic complaints (headaches, irritable bowel or bladder,
morning stiffness, dysesthesia) and severe cognitive impairment. Cognitive impairment
in FM has both subjective elements: "forgetfulness", "concentration difficulties" or "a
failing memory".
2. Cognitive impairment in FM 2.1 Subjective Cognitive impairment in FM The subjective
cognitive impairments have been described in several studies. Zachrisson and colleagues
reported a 95% incidence rate for ''Concentration Difficulties'' and a 93% incidence
rate for ''Failing Memory'' on their Fibro-Fatigue scale. Additionally, patients who
have FM report more cognitive problems and dissociative states than other rheumatology
patients. Arnold and colleagues reported the results of patient focus groups that
assessed important symptoms and the impact of these symptoms from a patient
perspective. Patients reported that memory and concentration problems were very
disruptive—affecting their ability to express themselves due to word-finding
difficulties, their ability to organize and plan ahead, their ability to respond
quickly to questions, and their ability to drive.
2.2 Objective Cognitive impairment in FM Objective cognitive dysfunction is assessed
through a broad range of neuro-cognitive testing. The mechanisms found to have the most
marked impairment in FM are: working memory, followed by episodic memory and access to
semantic memory. In addition findings points to a particular difficulty in dealing with
distracting information so that patients have an enhanced sensitivity to distraction
and difficulty in filtering sensory stimuli.
2.2.1 Working memory Working memory is a system of short-term memory storage system (on
the order of seconds) combined with other mental processes, that allows for example, to
briefly remember two numbers and add them together mentally. A quick assessment of
working memory function is: how many digits an individual can listen to and then repeat
in backward order. Working memory is a basic cognitive mechanism that underlies
successful performance on many other cognitive tasks. There are now several studies
that have reported impairment in this important cognitive function in subjects who have
FM, using a variety of different tests of working memory.
(A) Paced auditory serial attention test (PASAT): Most studies using the PASAT found
lower performance in subjects who have FM compared with controls although Suhr did not
find differences.
(B) Auditory Consonant Trigram (ACT) test: Both Leavitt and Katz and Dick and
colleagues found that subjects who have FM recalled fewer of the trigrams correctly,
and many performed in the impaired range compared with the control participants.
(C) Reading Span Task is a working memory test used extensively to study age-related
decline in working memory : Park and colleagues and Dick and colleagues found that
subjects who have FM perform more poorly than age-matched controls. Furthermore, Park
and colleagues found that performance in the subjects who have FM was not different
from control subjects who were 20 years older.
(D) Test of Everyday Attention (TEA) showed that subjects who have FM had lower scores
on the working memory component of the TEA.
The wide variety of working memory tests that demonstrate lower performance in FM is
striking, suggesting that this impairment is quite robust. Because deficits in working
memory ability have repercussive effects on other aspects of cognition, a small deficit
in working memory may have a large impact on performance on complex tasks. A busy work
environment requires an employee to hold some information in mind while using that
information for further processing.
2.2.2 Episodic Memory
Episodic memory refers specifically to the ability to remember specific events or
episodes from one's life (Remembering your first day at school or the name of your
teacher). Several researchers have found deficits in episodic memory in subjects who
have FM using a wide variety of standardized neuro-psychological tests and some
laboratory tests. Several of these results are presented:
(A) Grace and colleagues found significant differences on the general memory, verbal
memory, and delayed recall components of the Wechsler Memory Scale-Revised (WMS-R), but
not on the visual memory or attention/concentration components.
(B) Leavitt and Katz found that subjects who have FM, performed slightly below the norm
on logical memory and paired associates.
(C) Glass and colleagues found that subjects who have FM recalled fewer words in a list
learning task, and their memory was most impaired when combined with a distracting
secondary task at both list learning and recall.
These and other findings suggest a mild impairment in episodic memory in FM patients.
However, the results of episodic memory testing do not seem to be as robust as the
working memory results. In addition, Leavitt and Katz suggest that memory function in
FM may be strong enough to perform well under ideal conditions (neuro-cognitive
testing), but performance decrements may be observed in the presence of distraction.
2.2.3 Semantic memory Semantic memory is the knowledge of words and facts that have
been learned, such as knowing that eggs and milk are sources of protein (21). It can be
measured in a number of ways. One method uses verbal fluency to measure how quickly and
efficiently stored knowledge about words can be accessed. Several studies indicate
impairment in verbal fluency in FM.
(A) Park and colleagues found that FM subjects produced fewer words during a fluency
test compared to age-matched controls.
(B) Landro and colleagues and Munguia-Izquierdo and Legaz-Arrese) also reported similar
findings.
(C) Suhr did not find any difference between subjects who have FM and controls on a
fluency test.
(D) Park and colleagues and Glass and colleagues also found that FM subjects perform
more poorly than education- matched controls on tests of vocabulary (another test of
semantic memory).
(E) Leavitt and Katz reported a naming speed deficit in FM, consistent with the verbal
fluency results.
Thus, patients who have FM seem to have a deficit in accessing stored knowledge. This
deficit can make it difficult for patients to think quickly and to come up with the
right word for a given situation. Several patients indicated this kind of word-finding
difficulty while interviewed in a patient focus group.
2.2.4 Attention, concentration and executive functions Attention and working memory are
very closely linked because attention mechanisms are used to control the items that are
accessed, stored and processed in working memory. The working memory problems found in
FM patients may be due to the management of the contents of working memory, using
attention and concentration.
(A) Leavitt and Katz suggest that the cognitive impairment in FM patients is more
prominent on tasks where distraction from a competing source of information was
prominent (PASAT, ACT) in contrast to tasks without distraction (digit span, logical
memory, paired associate).
(B) Others found that distraction reduced memory abilities in FM subjects when
attention was divided during the learning.
(C) Dick and colleagues reported that FM subjects perform at a lower level than healthy
controls on the TEA test of attention.
(D) In a recent study performed by Verdejo-Garcia and colleagues, executive functions
and decision making were assessed in FM using the Wisconsin Card Sorting Task (WCST)
and the Iowa Gambling Task (IGT). FM subjects achieved a lower number of categories and
made more non-perseverative errors on the WCST. On the IGT, subjects who have FM showed
an altered learning curve that suggested a hypersensitivity to reward. These new data
on executive functions fit well with the attention control difficulties.
Dealing with distraction or controlling what is attended to, are particular problems in
FM and come under the category of executive functions. Planning a goal-directed
behavior and monitoring it are also under that category. Taken together, these results
strongly suggest that executive functions are impaired in FM patients.
3. Possible causes of cognitive dysfunction in FM
3.1 Other mental symptoms Mental symptoms such as depression and anxiety are suspected
to play an important role in the development of cognitive dysfunction in FM. Sephton et
al found depressive symptoms to be negatively correlated with verbal recall and Surh
found them to be related to memory. Grace et al reported an association between anxiety
and measures of memory and concentration. An important question was whether these
dysfunctions remained after correcting for depression and anxiety. Indeed, Dick et al
reported a significant difference between controls and FM patients even after
correcting for depression and anxiety. Park et al and Verdejo-Garcia et al did not find
a significant correlation between these mental symptoms and performance on cognitive
measures. In summary, depressive symptoms and anxiety can contribute to cognitive
dysfunction but they do not entirely explain it.
3.2 Fatigue and sleep disturbances Impaired sleep is known to negatively affect
cognitive performance. Cote -Moldofsky and Suhr attempted to explain the possible
relationship between altered sleep architecture and cognitive performance. Suhr
specifically reported that fatigue was related to psychomotor speed. Dick et al
reported that the differences between control and FM patients remained even after
controlling for sleep disturbances. Thus, as is the case in mental symptoms, fatigue
and sleep disturbances can not fully explain the cognitive deficit in FM patients.
3.3 Pain Chronic pain is known to negatively affect cognitive performance. Various
cognitive tasks including, impaired attention, impaired learning on a decision-making
task and an attentional bias to pain-related stimuli, were found in chronic pain
patient and in FM patients specifically. These patients were found to selectively
attend to pain words. In many studies of FM patients specifically, self-reported levels
of pain were associated with cognitive performance. These suggest that pain in itself
may disrupt the normal function of attention. As apposed to the case with depression,
anxiety and sleep disturbances, Dick et al, observed that the differences between
controls and FM patients cognitive functions disappeared when controlled for pain.
4. Recent experience in our psychiatric clinic Over the past few months the investigators
have been evaluating FM patients for cognitive dysfunction. Nearly 10 patients have
undergone the above mentioned extensive assessment. In our assessment the investigators
also added a more specific assessment of executive function; the "six elements" task.
This task directs participants to perform several tasks while under both a time
limitation and under specific rules. Thus, they are required to use: planning and
organization, initiation, and monitoring. These processes are usually not taken under
consideration during formal neuro-psychological tests because of their very structured
nature. Our preliminary findings suggest that fibromyalgia patients show a pattern of
executive dysfunction compared to the healthy population. The investigators hypothesize
a similar pattern will be found in our more extensive research and suggest that
significant executive dysfunction lie in the basis of cognitive dysfunction found in
fibromyalgia patients.
5. Cognitive rehabilitation - Treatment options Cognitive rehabilitation, a behavioral
treatment approach for individuals with cognitive dysfunction, is designed to reduce
functional impairment and increase engagement in daily adaptive activities; vocational,
social, and adaptive daily living skills. Originally developed to improve cognitive
functioning after traumatic brain injury (TBI), cognitive rehabilitation programs have
recently been adapted for other neurological conditions. Subsets of cognitive training
programs have been developed to target improvement in specific cognitive domains
including: attention, working memory, and executive functioning, which are all
essential cognitive skills to complete daily living tasks.
For example, TBI patients' who underwent attention training, consisting of direct attention
and metacognitive training to promote development of compensatory and problem solving
strategies, showed improvement on complex attention measures. When it comes to mild memory
impairment, compensatory strategies are recommended. Adults with chronic TBI, who were
trained to use compensatory strategies for personally-relevant memory problems through
errorless learning or didactic strategy instruction, reported greater use of strategies
after training.
Metacognitive training (self monitoring and self regulation) for executive functions include
problem solving strategies with application to everyday activities. The awareness training
protocol incorporates feedback to increase participants' awareness of their abilities, with
experiential exercises requiring participants to predict, self-monitor, and self-evaluate
their performance. Improvement in awareness, performance of everyday tasks and overall
function were evident for both TBI and stroke patients.
Cognitive decline and executive dysfunction are also common among Parkinson's disease
patients. As in FM, executive dysfunction/attention and memory impairment are the most
prevalent deficits reported. A computerized cognitive rehabilitation program focused on
improving attention, abstract reasoning, and visuospatial abilities showed PD patients had
significantly improved verbal fluency, immediate and delayed logical memory, and
visuospatial reasoning compared with their baseline assessments; these gains were maintained
after 6 months. Improvement on measures of executive skills were shown after completing an
intervention consisted of in-person training with practice exercises and worksheets on
attention tasks. Daily at-home practice exercises were also encouraged.
Similar cognitive impairment is also common among multiple sclerosis (MS) patients,
reporting mainly attention and memory complaints. In a double-blinded, randomized, placebo
controlled trial of an intervention to improve learning and memory, MS patients were taught
to use a modified "story memory technique" which used context and imagery to improve
learning and, therefore, recall. Participants who had moderate to severe learning
impairments showed a significant improvement in learning abilities. The use of the modified
story memory technique is recommended as a practice guideline for the remediation of
learning and memory in MS patients.
In summary:
Altogether, these reports demonstrate quite conclusively the salience of cognitive
dysfunction and its impact on daily life for patients who have FM. Comorbid symptoms
(depression, anxiety, fatigue and disturbed sleep) can negatively impact on cognitive
function, but can not fully explain the findings. In one study, pain did have a robust
effect on cognitive function and could explain the dysfunction found in FM. There is a need
to further assess cognitive function in FM along with the possible comorbid symptoms. Based
on our preliminary findings there is also a need to broaden assessment of executive
functions. In addition, cognitive rehabilitation has proved to be successful in a variety of
conditions involve cognitive impairment. One may suggest that if a specific cognitive
impairment pattern can be identified in FM patients, a cognitive rehabilitation plan can
then be tailored to fit these patients' needs.
Research Objectives
The objects of the proposed research are to perform:
1. A broad neuro-cognitive testing battery on a large population of Fibromyalgia patients.
Previous testing did not fully evaluate executive functions; therefore the
investigators are adding specific testing for these functions.
2. A broad assessment for Axis I psychiatric co-morbidity in the FM population.
3. A broad assessment for FM additional symptoms: depressive symptoms, anxiety, fatigue,
pain, sleep disturbances.
4. An attempt to identify "pure" cognitive deficits that are unique to FM patients and can
be directly attributed to FM. Therefore, possible correlation between neuro-cognitive
impairments, Axis I psychiatric diagnoses, additional FM symptoms and motivation levels
will be performed and data will be analyzed while controlling for these confounders.
5. Develop a cognitive rehabilitation program based on the cognitive dysfunction the
investigators discover in the study.
6. Based on the cognitive dysfunction the investigators discover in the study the
investigators hope to compile a shorter neuro-cognitive battery for clinical use in FM
patients.
- Research Plan________________________________ A. Methodology and plan of operation
A.1 Overview This is an open study in which a large number of fibromyalgia patients will
undergo an extensive neuro-cognitive assessment. All consenting participants will be
assessed using well validated neuro-cognitive tests. Current Axis I, psychiatric comorbidity
will be assessed using a well validated questionnaires. Finally, other symptoms associated
with FM will also be assessed (depression, anxiety, fatigue, sleep and pain) with the
appropriate rating scales. This assessment will be performed by a trained neuro-psychologist
and will take place in the psychiatric clinic during two consecutive sessions.
A.2 Patient selection A.2.1 Inclusion criteria 1. Primary fibromyalgia as defined by the
American College of Rheumatology 2. Age 18-70 years 3. Male or female 4. Competent and
willing to give written informed consent 4.A.2.2 Exclusion Criteria
1. History of head trauma
2. Any significant neurological disorder that may confound neuro-cognitive testing
A.3 Sample size The investigators plan to recruit 100 fibromyalgia patients over a period of
18 months. This is an exceptionally large number of patients. It is large enough to fully
assess the neuro-cognitive dysfunction in FM patients while controlling for psychiatric
symptoms and other additional FM symptoms.
A.4 Assessment of patients
A.4.1 Neuro-cognitive testing
1. Adult Intelligence Scale - WAIS III - relevant subtests from Wechsler Adult Intelligence
Scale-III 2. Verbal memory - Rey AVLT - adapted for Hebrew speakers 3. Motor ability and
visual memory
1. Rey Complex Figure Test
2. Bender Gestalt II 4. Executive function assessment
1. Wisconsin Card Sorting Test
2. Verbal Fluency - adapted for Hebrew speakers
3. Six Elements
4. Clock drawing test
A.4.2 Psychiatric rating scales and questionnaire
Axis I comorbidity -general -
1. Structured Clinical Interview for Axis I DSM-IV disorders (SCID) - Hebrew version
Depression
1. Hamilton Depression Scale, 21 items (HAM-D)
2. Beck Depression Inventory (BDI)
3. 100mm Visual Analog Scale (VAS) for depression Anxiety
1. Hamilton Anxiety Scale (HAM-A)
A.4.3 Assessment of associated symptoms; FM, Pain, fatigue and sleep disturbances
Fibromyalgia severity
1. Fibromyalgia Impact Questionnaire (FIQ)-Hebrew version
2. Fibromyalgia rating scale (FRS)
3. Clinical Global Impression of Severity (CGI) (for fibromyalgia) Pain
1. 100mm Visual Analog Scale (VAS) for pain
2. Brief Pain Inventory (BPI) Fatigue
1. Fatigue Severity Scale 2. Brief Fatigue Inventory Sleep disturbance
1. Insomnia Severity Scale
B. Time schedule The investigators plan on recruiting the patients over a period of 18
months. The analysis of the data will take a further 6 months.
C. Expected results The investigators expect to find extensive but specific pattern of
cognitive dysfunction in the FM patients, compared to the norms found in the healthy
population. The investigators expect to find cognitive dysfunction in the field of:
working memory, episodic memory, semantic memory. The investigators are expanding the
assessment to include executive functions and expect to find significant dysfunction in
this area. The investigators do expect to find psychological factors such as depression
and anxiety and additional FM symptoms such as pain and fatigue. The investigators mean
to control for these symptoms in order to expose the "pure" cognitive dysfunction
characteristic of FM, that which can not be explained by these active symptoms.
D. Significance FM is a common disabling disorder with many complex symptoms. Evidence
continues to mount that cognitive dysfunction is a real and troubling symptom with
working memory, episodic memory and semantic memory mostly affected. In addition, FM
patients seem particularly sensitive to distraction and in our preliminary data they
appear specifically to have executive dysfunction. This study aims to broadly assess
neuro-cognitive function in FM patients for possible neuro-cognitive deficits with a
specific focus on executive functions.
Since Axis I psychiatric disorders, mental symptoms (depression and anxiety) and
additional FM symptoms (fatigue, pain and sleep disturbances) may all affect cognitive
function, the investigators will also assess these factors. In the analysis of our
expected data the investigators will "control" for these possible confounders in hope
of finding a unique neuro-cognitive dysfunction pattern specific for FM patients. The
investigators than intend on compiling a shorter, "user friendly", neuro-cognitive
battery, that may serve clinicians in their routine assessment of FM patients.
The investigators aim to develop a cognitive rehabilitation program that will
specifically address the cognitive dysfunction the investigators expect to discover in
this study. Munguia-Izquierdo and Lagaz-Arrese found that aquatic therapy (exercise in
warm water) indirectly improved many symptoms in FM, including cognitive function.
Leavitt and Katz found that rehearsal helped subjects with FM overcome the effects of
distraction in a memory test. Based on these studies, but more on the extensive
knowledge from cognitive rehabilitation programs in other clinical states, the
investigators are determined to develop our own cognitive rehabilitation program that
will supplement other pharmacological and non-pharmacological interventions in FM
patients. By this the investigators will offer a unique and novel intervention for Fm
patients.
;
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