Cognitive Dysfunction in Fibromyalgia Patients
Cognitive Dysfunction in Fibromyalgia Patients
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.
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

 Exclusion Criteria:

 1. History of head trauma

 2. Any significant neurological disorder that may confound neuro-cognitive testing