1. Neurocognitive Manifestations in ME/CFS Gudrun Lange, PhD Professor Department of Physical Medicine and Rehabilitation, Rutgers-NJMS

2. Outline Why is it important to talk about cognitive function in ME/CFS? What is the clinical presentation? How can cognitive dysfunction in ME/CFS be understood? What is an effective neuropsychological battery? What is the research evidence? Final thoughts

3. Brainfog: Common and Disabling Experienced as difficulties with attention, concentration and multi-tasking Recognized as important: Listed as symptom in all ME/CFS case definitions Serves as objective criterion for disability: lack of validated physiological markers

4. Clinical Presentations “I feel like I’m loosing my mind…” “I feel like having the brain of an 80-year old in the body of a 36-year old…” “I feel stupid…”

5. Conceptualization of Cognitive Dysfunction Possible etiology of cognitive dysfunction Genetic Acquired Severity of cognitive dysfunction Severe Moderate Mild

6. Determination of Severity of Cognitive Dysfunction Subjective Patient and family report Perception of degree of loss of cognitive function Objective Neuropsychological evaluation Statistical determination of degree of loss of cognitive function Behavioral observations during testing should be taken into consideration

7. An effective neuropsychological battery for ME/CFS patients Has to include standardized and normed measures that Sufficiently and repeatedly challenge complex information processing and multi- tasking reliably demonstrate areas of cognitive resilience assess mood and anxiety ascertain adequate effort

8. Intellectual profiles in ME/CFS WAIS-IV profile: Scores discrepant from expected levels Case 1 Case 2

9. Case 1

10. Case 2

11. Clinical Interview  Wechsler Adult Intelligence Scale - Fourth Edition (WAIS- IV)  Test of Premorbid Functioning (TOPF) Beck Depression Inventory II (BDI II)  Spielberger State Trait Anxiety Questionnaire (STAI)  Gordon Diagnostic Test  Stroop Test  DKEFS Trails Verbal Fluency Test Paced Auditory Serial Attention Test (PASAT)  Wisconsin Card Sorting Test (WCST)  California Verbal Learning Test II (CVLT-II)  Wechsler Memory Scale - Fourth Edition (WMS-IV)  Boston Naming Test (BNT)  Rey Osterrieth Complex Figure (ROCF)  Judgment of Line Orientation Test (JOL)  Hooper Visual Organization Test  Hand Dynamometer  Grooved Pegboard  Finger Tapping Test (FTT)  Validity Indicator Profile (VIP)

12. Findings on neuropsychological exam Decreased attention, concentration and slowed processing speed Problems sequencing pieces of information and prioritizing their use for quick decision making Limited working memory, less information available “online” Learning difficulties: Changes in learning strategy Poor absorption and recall

13. Neuropsychological Profile in ME/CFS Profile suggests mild, subtle deficits Evaluation of impairment relative to expected level of intellectual function necessary to uncover true deficiencies Profile not consistent with dementia Generally no frank memory problem Profile can be differentiated from conditions of a more focal nature

14. Brain Abnormalities in ME/CFS Lange et al., 2005 Used verbal working memory task to probe brain function using fMRI simultaneously assessing efficient information processing behaviorally Statistically controlled for age, mood, anxiety, self-reported mental fatigue score Equated on prior behavioral test performance on same task

15. Brain Abnormalities in ME/CFS Controls versus ME/CFS: No differences in brain activity during simple condition When task demands get more complex, ME/CFS increased involvement of Anterior Cingulate BA 24/32 Left DLF BA 10/44/45/47 Bilateral supplemental and premotor BA6/8 Parietal regions BA 7/40

16. Brain Abnormalities in ME/CFS

17. Increased signal change was significantly accounted for by ME/CFS report of mental fatigue Perceived mental fatigue is reflected by increased functional recruitment of Left superior parietal region (BA7) Responsible for shifts in attention Bilateral supplementary and premotor regions (BA6/8) Associated with automatic information processing maintenance of temporal order

18. Brain Abnormalities in ME/CFS No lack of effort accounted for the differences in signal change To achieve behavioral performance similar to Controls Brains of ME/CFS work harder when tasks are c omplex Require efficient and quick information processing Require effective online sequencing and prioritization

19. Consequences of cognitive dysfunction in ME/CFS Automaticity of cognitive function is often lost Mundane tasks become effortful Multi-tasking often impossible Considered by patients as affecting every aspect of their lives Mental exertion can last for a long time

20. Is there an effective cognitive screen for ME/CFS patients? Dementia screens and typical brief bedside memory tests are not appropriate i.e. MMSE, Mini-Cog Suggestions: Serial 7s, Digit Span Sequencing May work if done for at least a few minutes Quickly give a 6-or-7 step set of complex driving directions and request repetition

21. Final thoughts If evaluation of cognitive function is needed Refer to Clinical Neuropsychologist knowledgeable about ME/CFS Much more work is needed to familiarize Neuropsychologists with ME/CFS to provide valid and reliable neuropsychological assessments.