behavioral approaches to cognitive rehabilitation in multiple sclerosis · 2015-10-26 ·...

Behavioral Approaches to Cognitive Rehabilitation in Multiple Sclerosis

John DeLuca, Ph.D.

Vice President for Research

Kessler Foundation Research Center

West Orange, New Jersey, USA

Professor, Department of Physical Medicine & Rehabilitation

Department of Neurology and Neurosciences

UMDNJ- New Jersey Medical School

Newark, New Jersey, USA

Cognitive Deficits in MS

• Information processing speed/ efficiency

• Executive functions

• planning, organization, initiation

• Perceptual processing

• Memory

• Retrieval failure hypothesis

• Acquisition hypothesis

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ospat

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erce

ptio

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emory

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verb

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emory

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visu

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emor

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iate

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visu

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emor

y (d

elay

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king

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ory

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conc

ept f

orm

atio

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cognitive domain

pe

rce

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air

ed

Frequency of Impairment (adapted from Benedict, et al., 2006)

Chiaravalloti & DeLuca, 2008

Cognitive Problems and Everyday Life

Functioning

• Cognitive deficits in MS have been shown to negatively affect daily life including:

– Employment

– Social and vocational activities

– Household activities

– Sexual functioning

– Family activities

– Overall QOL

– Increased psychiatric illness

• Beyond physical disability alone

Rao et al., 1991

Evidenced-Based Cognitive Rehabilitation for Persons with Multiple Sclerosis: A Review of

the Literature

Amanda R. O’Brien, Ph.D

Nancy Chiaravalloti, Ph.D

Yael Goverover, OT, Ph.D

John DeLuca, Ph.D.

Archives of Physical Medicine & Rehabilitation

2008, 89, 761-769

Review Methodology

Articles were eliminated according to criteria from Cicerone et al. (2000; 2005), e.g.:

1) did not specifically study an intervention

2) was a theoretical article or general overview

3) was a review article

4) the article did not focus specifically on adults with MS

5) was non peer-reviewed (also excludes book chapters)

6) was a pharmacological intervention

7) was not in English

Methodology of Review

• Final acceptance of evidence classification was based on total agreement between the two reviewers.

• If there was a disagreement

– The disagreement was discussed by the two reviewers and in all cases agreement was reached

Based on the exclusion criteria

• 224 articles were identified

– 16 of these were appropriate

– randomly assigned for review among 4 reviewers

Level Criteria

Class I Well designed, prospective, randomized controlled trials

Class Ia Well designed, prospective “quasi-randomized assignment to treatment

conditions (e.g. alternating conditions)

Class II Prospective, nonrandomized cohort studies

Retrospective, nonrandomized case-control studies

Clinical series with well-designed controls that permitted between

subjects comparisons of treatment conditions

Class III Clinical series without concurrent controls

Studies reporting one or more case study that used appropriate single

subject methods (e.g. multiple baselines)

Class IV Evidence from uncontrolled studies, case series, case reports, or expert

opinions

Levels of Evidence

Evidenced-Based Cognitive Rehabilitation Review

• 16 studies identified

– 4 class I

– 5 class II

– 2 class III

– 5 class IV

• Attention

• Executive Functions

• Learning and Memory

• Non-specific Cognitive Rehabilitation

O’Brien et al., 2008

Overall Results

Studies

included YES NO

Learning &

Memory 7 5 2

Executive

functions 2 1 1

attention 4 1 3

Non-specific 4 2 2


Practice Standards

Practice Guidelines

Practice Options

Based on at least 1, well designed Class I study or overwhelming Class II evidence, that directly addresses the effectiveness of the treatment in question …

Based on well-designed Class II studies that directly address the effectiveness of the treatment in question …

Based on Class II or Class III studies, with additional grounds to support a recommendation …

Conclusions Evidenced-Based Cognitive Rehabilitation Review

• MS received little attention to effective rehabilitation of cognitive impairment

– Yielded only 16 studies

– Contrasts with TBI reviewed 258 studies

• Only 1 practice guideline recommended

– Single technique, based on 1 study

• Missing are studies on processing speed


General Limitations of Studies

• Subject selection:

– Self-reports of cognitive impairments

– Participants with and without cognitive impairments included

• Treatment often not impairment specific

• Frequency of treatment often not reported

• Duration of treatment often not reported

• Specific treatment details often not reported

General Limitations of Studies

• Poor outcome measurement – i.e., “Positive clinical response.”

– Self-reports of cognition as outcome measure

• Greater need for focus on functional outcomes – Social functioning

– Occupational functioning

– IADL’s

Methodological Aspects of Randomized Controlled Trials on Cognitive

Interventions

Alessandra Solari

Neurological Science, published online 2010

Method and Results: Solari 2010

• Examined methodological challenges of RCT on cognitive symptoms in MS

• Bibliographic search of 7 databases

• 5 methodological criteria for inclusion

• 12 RCT published between 1996-2010

– 5 pharmacological (3 symptom tx, 2 disease modifying)

– 7 rehabilitation (6 pc based)

Conclusions: Solari 2010

• “…quality are overall insufficient”

• Methodological problems include:

– Choosing study sample

– Choosing outcome measures

– Interventions are complex

– Training of clinicians can vary

– Blinding difficult if not impossible

– Resources necessary are very high

Review for Current Position Paper

• Learning and memory

• Information Processing speed

Position paper on treatment of

cognitive impairment in MS

• Define & assign 4 subtopics to Sc. Committee

• Sc. Com. provide guidance on literature searches (key words and search criteria)

• SSIF conduct literature review - list of paper

• SSIF drafts summaries for each subtopic

• Sc. Com. Identify key papers to review

• SSIF drafts preliminary position paper

• At SSIF symposium position statements are proposed to participants, to collect feed back

• Sc. Com. revise/fine tune position paper

• Submit to Multiple Sclerosis Journal

General Procedure: Processing Speed

• No studies specifically designed to improve processing speed found

General Procedure: Learning and Memory

• 44 potential papers identified

– Not all of these assessed memory

• 17 considered for inclusion

– Intervention was memory-based

– Memory was an outcome measure

• Reviewed independently by 2 experts

Methodological Problems with many Existing

Behavioral Studies

• Small sample size

• Lack of control group, or inadequate control (e.g., “historic controls”)

• Interventions are multifaceted and difficult to quantify

• Inadequate selection of targeted sample – e.g., cognitively intact patients often included

• Inclusion criteria for cognitive impairment based on self-report rather than objective assessment

• Treatment is often not impairment specific (e.g., “improve cognition”)

• Frequency and intensity of treatment often not reported

• Specific details of how treatment was delivered often not reported – (e.g., non-specific cognitive training)

• Unsupervised training sessions (compliance not monitored)

• Use of poor outcome measures (e.g., “positive clinical response”)

• Outcome measurements lack relevance to everyday life

• Lack of long-term follow-up

Study Designs Employed

Design Studies

MS vs. HC 8

RCT 5

Non-randomized, matched control

2

w/in group 1

No control 1

Behavioral Treatment and Learning and Memory in MS

12 5

Support No Support

1 weak support

RCT Results

3 2

Support No Support

1 weak support

Intervention Type

Targeted

Intervention

Non-specific

training

14 3

Intervention Format Computerized interventions

Behavioral interventions

Mendozzi, 1998 RehaCom Jonsson, 1993 NP rehab

Solari, 2004 RehaCom Allen, 1998 Story memory Tech

Tesar, 2005 RehaCom Chiaravalloti, 2002 Generated learning

Hildebrandt, 2007 VILAT-G 1.0 Chiaravalloti, 2005 Story memory Tech

Brenk, 2008 Brain Gym Basso, 2006 Generated learning

Vogt, 2009 Brain Stim Goverover, 2008 Generated learning

Shatil, 2010 CogniFit Personal Coach

Goverover, 2009 Spaced learning

Sumowski, 2010 Spaced retrieval

Goverover, 2011 GE/SE

Example Targeted Interventions

Self-generation to improve learning and memory of functional activities in multiple sclerosis: Meal

preparation and managing finances

Yael Govereover, Ph.D.


John DeLuca, Ph.D.

Archives of Physical Medicine & Rehabilitation

2008, 89, 1514-1521

Tasks

• Participants were asked to complete two tasks:

– Meal preparation

– Financial management

Generation Effect and Everyday Life Activities

• Instructions on how to perform tasks were presented in two conditions:

– provided condition

– generated condition

• Within group design

Food Preparation Results -MS

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immediate 30 min 1 week

Generated

Provided

Goverover et al., 2008

Managing Finances Results - MS

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14

16

18

20

immediate 30 min 1 week

Generated

Provided


Spacing Effect

New learning in healthy individuals is significantly improved when trials:

• are SPACED or distributed over time

compared to

• MASSED or consecutive learning trials

Ebbinghaus, 1885/1994

A functional application of the spacing effect to improve learning and memory in persons with

multiple sclerosis

Yael Govereover, Ph.D.

Frank H. Hillary, Ph.D.


Juan Carlos Arango,, Ph.D

John DeLuca, Ph.D.

Journal of Clinical Experimental Neuropsychology, 2009, 31, 513-522

Paragraph from Newspaper in MS

6.4

6.6

6.8

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immediate 30 min

Spaced

Massed


Combined Spaced and Self-generation:

Mean Recall of Appointments

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Sp-Gen spaced massed

Chart Title

immediate

30 min delay

Goverover, Basso, Wood Chiaravalloti & DeLuca, (in press)

“Testing Effect” Spaced retrieval”

Retrieval Practice Improves Memory in Multiple Sclerosis: Clinical Application

of the Testing Effect

James F. Sumowski, Ph.D.


John DeLuca, Ph.D.

Neuropsychology, 2010, 24, 267-272

Testing Effect in MS

3

5

7

9

Massed Restudy Spaced Restudy Spaced Testing

Sumowski, DeLuca et al., 2010

Mean Words recalled

Testing Effect in MS

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Memory Impaired Memory Intact

Massed Restudy

Spaced Restudy

Spaced Testing

Sumowski, DeLuca et al., 2010

Mean Words recalled

Sumowski et al., unpublished data

77% 25% 15%

Sumowski et al., unpublished data

1.3% 5.0% 27.5%

Example RCT Interventions

Cognitive Training in MS: Effects and

Relations to Brain Atrophy

Helmut Hildebrandt Michael Lanza Horst K. Hahnc

Ebba Hoffmanna Bjorn Schwarzed

Gunther Schwendemanna Jurgen A. Krausa

Restorative Neurology and Neuroscience, 25 (2007) 33–43

Hildebrandt, H. et al. (2007). Cognitive Training in MS: Effects and relation to brain atrophy. Restorative Neurology and Neuroscience, 25, 330-42.

Cognitive Remediation as a Treatment for New Learning Deficits in Multiple Sclerosis

Nancy D. Chiaravalloti, Ph.D.

John DeLuca, Ph.D.

Nancy B. Moore, M.A.

Joseph H. Ricker, Ph.D.

Multiple Sclerosis, 2005, 11, 58-68

Funded by NMSS grant PP0752

Context and Imagery

Memory Retraining in MS

• 28 participants with MS – with objective impairment in new learning

• Method – Random assignment into two groups:

• memory retraining group • control group

– 8 sessions • 2x per week for 4 weeks • 30-90 minutes in duration

– Double blinded conditions

• Baseline • Treatment (4 weeks) • Immediate follow-up • Long-term follow-up (5 weeks following end of tx)

HVLT-R Mod/Severe vs. Control baseline to immediate change score

-3

-2

-1

0

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2

3

HVLT-R Change Score

mod/severe imp Control Group

p<.01

HVLT-R Mod/Severe vs. Control baseline to long-term change score

-3

-2

-1

0

1

2

3

HVLT-R Change Score

mod/severe imp Control Group

p<.05

Self-report Memory Impairment (n=28) Baseline to immediate follow-up

-3

-2

-1

0

1

2

3

Remember things that occur in everyday life

Treatment Group Control Group

p<.01

Self-report Memory Impairment (n=28) Baseline to Long-term follow-up

-3

-2

-1

0

1

2

3

Remember things that occur in everyday life

Treatment Group Control Group

p<.001

Cognitive Remediation as a Treatment for New Learning Deficits in Multiple Sclerosis

Nancy D. Chiaravalloti, Ph.D.

John DeLuca, Ph.D.

Nancy B. Moore, M.A.

Unpublished preliminary data

Funded by NIH R01

Demographics

Variable Treatment

Group

N=47

Placebo Group

N=47

t p

Age 48.17 (9.97) 49.93 (8.76) -.86 ns

Education 15.68 (2.55) 15.79 (2.34) -.21 ns

Months since Dx 172 (119) 168 (98) .17 ns

SRT Trials to Criterion at

Screening

12.15 (3.12) 13 (3.04) -1.34 ns

Ambulation Index 2.64 (2.42) 3.14 (2.29) -.97 ns

WASI Vocab (T Score) 52.13 (9.6) 51.83 (12.55) .13 ns

WASI Block Design (T Score) 46.45 (9.2) 48.26 (9.2) -.93 ns

WASI Similarities 52.56 (8.62) 51.76 (8.85) .44 ns

WASI Matrix Reasoning 54.93 (8.45) 54.33 (9.12) .33 ns

Learning Performance by Group CVLT

learn

ing s

lope

(T1-5

)

Sam

ple

base

d Z

sco

res

Follow-up

-0.3

-0.2

-0.1

0.0

0.1

0.2

0.3

Control Treatment

Baseline

p=.02, controlling for baseline

Learning by Group: Post-treatment*

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12

Trial 1 Trial 2 Trial 3 Trial 4 Trial 5

Treatment Control

CVLT Learning Trials

p=.02, controlling for baseline * No significant group difference at baseline

Learning by Group (post-treatment*)

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12

13

14


4

5

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Treatment ControlCVLT Learning Trials

PS Intact PS Impaired

* No significant group difference pre-treatment

p=.006

Imaging data and Rehabilitation

• Brain changes after treatment

– Functional: fMRI

– Structural: DTI

• Does this 10 session behavioral treatment change brain structure or function?

Preliminary analysis

Chiaravalloti, DeLuca, et al., unpublished data

Rehabilitation of Learning and Memory:

fMRI

• Pre-training (treatment group – placebo group)

• No group differences in patterns of activation


Rehabilitation of Learning and Memory: fMRI

Post-training: treatment group significantly more activity in the hippocampus, occipital regions, and parietal regions vs. placebo group (p<.05)


Rehabilitation of Learning and Memory: fMRI: fMRI

Post-training: treatment group significantly more activity in

frontal regions vs placebo group (p<.05)


DTI Results

3 clusters of increased FA were identified after memory training:

1. Body of the corpus collosum

2. Fornix

3. Right inferior longitudinal fasciculus

Preliminary data

Leavitt, Chiaravalloti, DeLuca, et al., unpublished data

Results Group x time interaction (corpus collosum)

0.35

0.4

0.45

0.5

pre- post-

Non-treatment

Treatment

FA

Leavitt et al., unpublished

2 clusters of significance emerged when

threshold was set at >200 contiguous voxels,

all significant at p<.01

1. Left inferior longitudinal fasciculus (ILF)

= 445 significant voxels

2. Right superior longitudinal fasciculus

(SLF) = 204 significant voxels

24% increase in FA (274 voxels at p<.05)


Cluster 1: Body of corpus collosum

Results

Group x time interaction (fornix)

0.35

0.4

0.45

0.5

pre- post-

Non-treatment

Treatment

FA


Cluster 2: Fornix


Results

Group x time interaction (right ILF)

0.35

0.4

0.45

0.5

pre- post-

Non-treatment

Treatment

FA


Cluster 3: Right inferior longitudinal fasciculus



Overall Conclusions

• Overall quality moderate to poor • Numerous methodological problems • Relatively small sample size • Yet majority show positive results • Both computer-based and behavioral

interventions used • Results viewed preliminary and with caution • No studies found to address processing

speed • Future RCT are needed

Thank you

Yael Goverover James Sumowski

Victoria Leavitt Helen Genova

Jean Lengenfelder Glen Wylie

Nancy Chiaravalloti Nancy Moore

National Multiple Sclerosis Society:

Pilot Grant #P0782

NIH Grants (NCMRR):

1R01HD045798

1R01HD045798 S

Treatment Protocol Study #2: NIH RO1

• Currently concluding clinical trial

• 100+ participants

• Follow-up 6 months post treatment

• Examines additional outcomes

– Everyday life

– Neuroimaging (on a subset of participants)

behavioral approaches to cognitive rehabilitation in multiple sclerosis · 2015-10-26 ·...

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