Review Article Cognitive Interventions in Older Persons…downloads.hindawi.com/journals/bmri/2015/438908.pdf · Review Article Cognitive Interventions in Older Persons: Do They Change

Review ArticleCognitive Interventions in Older Persons: Do They Changethe Functioning of the Brain?

Yindee van Os,1 Marjolein E. de Vugt,2 and Martin van Boxtel2

1Department of Medical Psychology, Elkerliek Hospital, Wesselmanlaan 25, 5507 HA Helmond, Netherlands2School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Department of Psychiatry and Neuropsychology,Maastricht University, P.O. Box 616, 6200 MDMaastricht, Netherlands

Correspondence should be addressed to Yindee van Os; [email protected]

Received 13 February 2015; Revised 5 May 2015; Accepted 18 May 2015

Academic Editor: Emmanuel Moyse

Copyright © 2015 Yindee van Os et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. Cognitive interventions for older persons that may diminish the burden of cognitive problems and could delayconversion to dementia are of great importance. The underlying mechanisms of such interventions might be psychologicalcompensation and neuronal plasticity. This review provides an overview of the literature concerning the evidence that cognitiveinterventions cause brain activation changes, even in damaged neural systems. Method. A systematic search of the literature wasconducted in several international databases, Medline, Embase, Cinahl, Cochrane, and Psychinfo. The methodological qualitywas assessed according to the guidelines of the Dutch Institute for Health Care Improvement (CBO). Results. Nineteen relevantarticles were included with variedmethodological quality. All studies were conducted in diverse populations from healthy elderly topatients with dementia and show changes in brain activation after intervention.Conclusions.The results thus far show that cognitiveinterventions cause changes in brain activation patterns.The exact interpretation of these neurobiological changes remains unclear.More study is needed to understand the extent to which cognitive interventions are effective to delay conversion to dementia. Futurestudies should more explicitly try to relate clinically significant improvement to changes in brain activation. Long-term follow-updata are necessary to evaluate the stability of the effects.

1. Introduction

Aging is accompanied by changes in our cognitive function-ing based on structural and functional changes in the brain [1,2]. Many older persons complain about diminished cognitivefunctioning [3]. Cognitive complaints and cognitive deficitsare often a burden for older persons and their family [4–6]. Cognitive deficits could also be a precursor for dementia.In that case it is important to intervene in an early stage toprevent or delay conversion to dementia and to minimizethe impact of these objective or perceived cognitive problems[5, 7].

Pharmacological interventions are of limited efficacy,may have serious side effects, and are only available forpatients with a clinical diagnosis of dementia [8]. Cognitiveinterventions have gained a lot of attention over the last

years.Themain goal of cognitive interventions is to stimulatethe cognitive system or offer compensatory methods toaddress difficulties with cognitive functioning [7, 9]. Clin-icians acknowledge the benefits of cognitive interventionssuch as changing a patient’s sets of beliefs, affective states, orbehavioural patterns and compensating for cognitive losses[10].

A literature review performed by Buschert and colleaguesin 2010 highlights the effectiveness of cognitive interventionsin improving global cognitive functioning, daily activities,quality of life, and diminishing behavioural problems inpatients withMild Cognitive Impairment (MCI) or dementia[8]. A review of randomized controlled trials on this topicin persons with MCI concluded that there is evidence forintervention success in overall cognition, overall self-ratings,episodic memory, and executive function/working memory.

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015, Article ID 438908, 14 pageshttp://dx.doi.org/10.1155/2015/438908

2 BioMed Research International

The quality of the evidence is limited due to several method-ological issues such as a small amount of long-term follow-upmeasures with generally small effect sizes. Moreover there aredifferences in design, sample sizes, and types of intervention[11].

Cognitive stimulation in a social setting such as remi-niscence with reality orientation is associated with benefitsin cognitive functioning as well as quality of life, well-being, communication, and social interaction skills [9].In healthy elderly, cognitive interventions lead to fewernegative emotional reactions towards cognitive functioning[3, 12, 13], improvement in coping with reported cognitivefailures [12, 13], and better objective cognitive functioning[13, 14]. Another important goal of cognitive interventionsis intervening at an early stage of cognitive decline to slowor prevent progression to dementia. Cognitive interventionscould even have the potential to delay the onset ofAlzheimer’sDementia (AD) by 5 years in those patients at risk for AD[8]. The evidence for the efficacy of cognitive interventionsis promising yet inconclusive due to differences in design,outcome measures, interventions, and sample sizes. The lowcosts, absence of adverse effects, and the possibility to delaythe onset of Alzheimer’s dementia make cognitive interven-tions attractive [8]. Some even stated that neurobiologicaloutcomes might be used as a sensitive biomarker for theefficacy of cognitive training [15].

Themechanisms underlying the effectiveness of cognitiveinterventions are not well understood. A better understand-ing of these mechanisms can help us tailor our cognitiveinterventions and possibly improve the effectiveness.

One mechanism might be psychological compensation.Cognitive interventions would then improve coping strate-gies to deal with the still existing cognitive problems [3].In clinical practice, the working mechanism and goalsof cognitive interventions are explained to participants interms of this psychological compensation. But recent neuralmodels suggest that neuronal plasticity may also underliethe effectiveness of cognitive interventions [5, 8, 16–18].Cognitive interventions might increase cognitive reserve thatis reflected in changes in brain activation patterns [4, 8].Cognitive reserve, the capacity of an adult brain to copewith brain pathology in order to minimize symptomatology,is linked to efficiency (less activation of brain networks) inhealthy elderly. On the other hand, in pathological aging,cognitive reserve enhances the recruitment of compensatingbrain networks particularly the frontal areas, hippocampus,and the precentral gyrus [1, 19].

The aim of this paper is to review the evidence that cog-nitive interventions cause brain activity changes. Eventually,early intervention in prodromal stages to delay conversion topathological aging is the ultimate goal.Therefore the effects ofcognitive interventions on brain activity changes are studiedin the brain of healthy older persons and in the brain of olderpersons suffering from pathological aging. To relate changesin brain activation to intervention effect, evidence of changesin performance, function, behaviour, and cognition are alsoreviewed.

2. Methods

2.1. Search Strategy. A systematic literature search of articlespublished from 1993 to March 2012 was conducted in Med-line, Embase, Cinahl, Psychinfo, and the Cochrane Database.Medical Subject Headings (MeSH) terms, thesaurus terms,and an age selection> 60 yearswere used in the search (searchterms used in selection of studies) as follows:

(1) Psychinfo: cognitive impairment OR dementia ORage selection set on > 60 years, Medline and Cinahl:cognition disorder OR dementia OR aged OR elderly,and Embase: cognitive defect OR dementia OR agedOR elderly;

(2) Psychinfo: behavioural therapy OR cognitive therapyMedline, Cinahl, Embase: behavior therapy OR cog-nitive therapy;

(3) Psychinfo: magnetic resonance imaging OR tomog-raphy OR electrophysiology, Medline and Cinahl:magnetic resonance imaging OR electroencephalog-raphyOR tomography, andEmbase: nuclearmagneticresonance imaging OR electroencephalogram ORtomography.

Reference lists of the retrieved studies were searched to iden-tify any relevant articles that had not yet been included. Tobe selected for this review, papers had to meet the followingcriteria: (i) the study had to involve the healthy elderly, thehealthy elderly with cognitive complaints, and the elderlywith Mild Cognitive Impairment or elderly with dementia;(ii) the study had to contain a cognitive intervention; (iii) thestudy had comparisons of brain activitymeasurements beforeand after the intervention; (iv) the study had a full reportavailable; (v) the articles were in English. A flowchart of theinclusion process is shown in Figure 1.

2.2. Selection of Studies. The search resulted in 735 papers.One reviewer (YvO) screened all titles and abstract forsuitability. Six hundred ninety-six studies were rejectedbecause of duplication, lack of full data, lack of brain activitymeasures, or lack of a cognitive intervention. The remaining39 studies were obtained in full text and assessed by tworeviewers (YvO, MdV). There was full agreement on theexclusion of 23 papers because they did not meet all inclusioncriteria. Amanual search of the reference lists of the includedstudies resulted in 3 additional papers. A total of 19 studiesmet all inclusion criteria. Figure 1 shows the flowchart of theselection process of the papers.

2.3. Methodological Quality. The methodological quality ofthe included studies was assessed according to the guidelinesof the Dutch Institute for Health Care Improvement (CBO).The CBO aims to improve healthcare by providing guide-lines for evidence-based interventions both nationally andinternationally (CBO, http://www.cbo.nl/). For randomizedcontrolled trials, the following aspects were evaluated: ran-domization, blinding of randomization, blinding of partici-pants, blinding of outcome assessors, baseline comparability,

BioMed Research International 3

Possible relevant studies from literature search in databases: 735

Rejected: 696, lack of (functional) neurobiological outcome measurements, lack of full data, lack of cognitive intervention, duplicates

Full text studies for further assessment: 39. Reviewers: YvO,MdV

A total of 16 studies met all inclusion criteria. A manual search of the references resulted in3 more articles that met all inclusion criteria. Reviewers: YvO, MdV

Studies included in this review: 19

Rejected: 23, lack of (functional) neurobiological outcome measurements, lack of full data, lack of a cognitive intervention, participants with acquired brain injury

Figure 1: Flowchart of the search strategy.

loss to follow, use of intent-to-treat analysis, comparability ofintervention, and a judgment of the validity and applicabilityof the study. Because it is impossible in cognitive interventiontrials to blind the therapists to the intervention, this item wasnot included as one of the quality criteria. With regard tostudies that did not contain a randomized controlled design,the following aspects were evaluated: definition of studypopulation, selection bias, intervention description, outcomedefinition, blinded outcome assessments, completeness ofthe dataset/follow-up, loss to follow, confounders, and ajudgment of the validity and applicability of the study.

Eventually, the overall quality of the individual studieswas rated in a level of evidence, ranging from A1 to D. A1 isa systematic review of at least two independent, randomizeddouble-blind studies of sufficient quality and size. A2 isa randomized double blind study of sufficient quality andsize. B is a comparative study, which does not meet all thecriteria of an A2 study. C is a noncomparative study and D isthe opinion of experts (http://www.cbo.nl/). Two reviewers(YvO and MdV) independently assessed the methodologicalquality of the studies. The level of agreement was 96%. Aftera consensus meeting, both reviewers reached full agreementon the quality ratings. The quality ratings of the studies aredisplayed in Tables 1 and 2.

3. Results

3.1. The Healthy Elderly

3.1.1. Study Characteristics. Six studies focused on healthyolder adults [18, 20–23, 30]. Two studies investigated theeffect of the method of loci, a mnemonic technique, onbrain activation [18, 30]. The intervention duration variedbetween these two studies from one day [30] to five weeks[18]. The neurobiological outcomes were different; the one-day intervention used Positron Emission Tomography (PET)measures and a memory test as outcomes [30]. The otherstudy used magnetic resonance imaging (MRI), MagneticResonance Spectroscopy (MRS), performance on a memorytest, and level of depression and anxiety as outcomes. Onestudy lacked a control group [30], and the other study hada randomized controlled trial (RCT) design with a smallsample size.

A third study [20] used a RCT design and studiedthe effect of a multicomponent intervention in 17 olderpersons with mild subjective memory complaints. Eight ofthem took part in the intervention that consisted of a diet,relaxation exercises, brain-teasers, memory strategies, andcardiovascular physical training. The PET and MRI data,performance on cognitive tasks, and scores on the subscale


Table1:Metho

dologicalqualityof

rand

omized

controlledtrials.

RCT

Theh

ealth

yeld

erly

MCI

Dem

entia

Valenzuela

etal.2003

[18]

Small

etal.200

6[20]

Erickson

etal.2007

[21]

Brehmer

etal.2011

[22]

Belleville

etal.2014

[23]

Rosen

etal.2011

[16]

Ham

pstead

etal.2012

[24]

Heiss

etal.1994

[25]

Akanu

ma

etal.2011

[26]

Forster

etal.2011

[27]

vanPaasschen

etal.2013

[28]

Baglio

etal.2014

[29]

Rand

omized

11

11

11

11

11

11

Blindedrand

omization

00

10

11

10

10

01

Blindedparticipants

00

01

11

10

00

00

Blindedou

tcom

eassessors

00

00

01

00

11

01

Baselin

ecom

parability

01

11

11

11

11

11

Lossto

follo

w1

11

11

11

11

01

1Intention-to-tr

eatanalysis

01

00

01

10

11

10

Com

parabilityinterventio

n0

00

11

11

10

10

1Va

lidity

andapplicability

11

11

11

11

11

11

Total

35

56

79

85

76

56

CBOcla

ssificatio

nB

BB

BA2

A2

BB

BB

BB

TheCB

Ocla

ssificatio

nreflectsthe

levelo

fevidence.A1isa

syste

maticreview

ofatleasttwoindepend

entrando

mized

doub

leblindstu

dies

ofsufficientq

ualityandsiz

e.A2isarand

omized

doub

leblindstu

dyof

sufficientq

ualityandsiz

e.Bisac

omparativ

estudy,w

hich

does

notm

eetallthec

riteriaof

anA2stu

dy.C

isan

oncomparativ

estudy

andDistheo

pinion

ofexperts(http://www.cbo.nl/).


Table 2: Methodological quality of observational studies.

Observational studiesThe healthyelderly MCI Dementia

Nyberg et al.2003 [30]

Clare et al.2009 [31]

Hampstead2011 [32]

Belleville etal. 2011 [33]

Nagaya etal. 2005 [34]

Tanaka et al.2007 [35]

Spironelli etal. 2013 [36]

Definition study population 0 1 1 1 0 1 1Selection bias 0 0 0 1 0 0 0Intervention description and allocation 1 1 1 1 1 1 1Outcome definition 1 1 1 1 1 1 1Blinded outcome assessments 0 0 0 1 0 0 0Completeness dataset/follow-up 0 1 1 1 0 1 1Loss to follow 0 1 1 1 1 1 1Confounders 1 0 0 1 0 0 0Validity and applicability 0 1 0 1 0 0 1Total 3 6 5 9 3 5 6CBO classification C C C B C C CThe CBO classification reflects the level of evidence. A1 is a systematic review of at least two independent randomized double blind studies of sufficient qualityand size. A2 is a randomized double blind study of sufficient quality and size. B is a comparative study, which does not meet all the criteria of an A2 study. C isa noncomparative study and D is the opinion of experts (http://www.cbo.nl/).

self-awareness of memory ability of the Mood and FeelingsQuestionnaire (MFQ) were collected.

A fourth study [22] evaluated the benefits of 25 sessions ofcomputerized workingmemory training on neuropsycholog-ical tests varying in level of similarity to those practiced in thetraining. FMRImeasures were studied to evaluate differencesin brain activity post intervention. The strength of this studyis the use of an active control group that also received aworkingmemory training but with a fixed low level task load.The intervention group received an adaptive training withincreasing task load.

Two studies [21, 23] studied the effect of repeated practicewith performance feedback on brain activity. Both usedsingle and dual tasks to study focused and divided attention.Belleville and collaborators [23] added a condition in whichparticipants were instructed on themodulation of their atten-tion to the tasks. They were interested if the training formatwould influence brain activity patterns after intervention.To investigate this hypothesis, all 48 community dwellingolder adults were randomly assigned to one of the threeintervention conditions, for example, single task, dual task,or top down control of attention. In the other study the 34older participants were randomly assigned to either a waitinglist or the intervention.

The intervention consists of 5 [21] or 6 [23] sessions.Both used fMRI and MRI as neurobiological outcomes. Thereaction time and accuracy of the task performances werecollected and served in both studies as behavioural data.Moreover both studies statistically examined the relationbetween performance gains and brain activity changes afterintervention.

3.1.2. Findings. The six studies differ in the type of inter-vention, sample size, design, neurobiological outcomes, andthe presence of more clinically relevant outcomes to measure

intervention success (Table 2). All six studies found brainactivity differences after intervention.

Participants in the study of Valenzuela et al. learned thesame mnemonic (method of loci). They showed increases inbrain activation in the hippocampus [18] and the left occipitalparietal cortex and left retrosplenial cortex [30]. These areasare known to be associated with the cognitive domains thatwere targeted in the intervention. Post hoc relation betweenperformance improvement and brain activity changes wasidentified in the Nyberg study. Only the older adults whoalso improved on a memory test showed these brain activityincreases [30].

The study of Small and colleagues (2006) demonstrateddecrease in the dorsolateral brain activation after interven-tion and an improvement in verbal fluency. There was nosignificant intervention effect on subjective measures of self-awareness of memory performance and a memory task [20].

There are three studies that explicitly tried to linkintervention related performance gains to brain activationchanges. Participants that profit the most from an adaptiveworking memory training showed the largest activationdecreases in regions known to be involved in memoryand attention processes (e.g., right inferior frontal, rightinferior parietal, left fusiform region, and insula) and thelargest activation increases in the caudate [22]. Anotherstudy provided evidence that training induced dual taskperformance improvement was related to increased activityin the left ventral prefrontal cortex and decreased activity inthe dorsolateral prefrontal cortex. Compared with an adultsample, age related differences in brain activity were reducedafter intervention [21]. The study of Belleville and colleagues[23] found significant correlations between performance andtraining related activity. They provide evidence that type ofintervention influenced the loci and type of brain activity.Repeated practice in single tasking was associated with a


decreased activity in the inferior and middle frontal gyribilaterally and the left thalamus. The computed correlationsrevealed that a better performance in single tasking wascorrelated with decreased activity in the right inferior andmiddle frontal gyrus. Repeated training in dual taskingresulted in greater activity in the prefrontal cortex during dualtasking. There were no significant correlations between per-formance gains and brain activity changes for this condition.For the strategic control of attention condition, dependenton the type of instruction, increased activity after training inthe right middle frontal gyrus or the right cerebellum wasseen. An improved ability to modulate attention accordingto task instruction was correlated with a greater activity inBrodmann area 10 [23].

However, how the brain activity changes in all studieswere related to clinical relevant improvement is not clear, dueto a lack of such outcomes and a fail to link brain activationchanges to clinically meaningful improvement [18, 20–23,30]. The stability of the intervention effects was unclear andlong-term follow-up measures were lacking [18, 20–23, 30].

3.2. Patients with MCI

3.2.1. Study Characteristics. All five studies [16, 24, 31–33]that focused on MCI patients used fMRI to investigatethe influence of a cognitive intervention on brain activity.However the targets of the cognitive intervention as well asthe design of the studies differed.

The most recent study with an RCT design evaluated theeffects of a mnemonic strategy training on object locationassociations and brain activation in the hippocampus viafMRI. Amatched control group was also exposed to the samelists of object location associations, but without learning themnemonic. Eighteen participants had a diagnosis of amnesticMCI. A group of 16 healthy controls were allocated to thesame treatment conditions. Both diagnostic groups werecomparable in terms of prognostic factors, and interventionsuccess was evaluated by amodified change score for learningobject location associations [32].

One study used an episodic memory training of 6 weeks(mnemonics and psychoeducation) with proven effectivenessfor a MCI population. Fifteen participants with the diagnosisamnestic MCI and 15 matched healthy controls took partin the intervention. The data on visual memory, MRI, andfMRI were collected at baseline and after intervention. Brainactivity was studied during encoding and retrieval of amemory test. A double baseline was used to study the pos-sibility of a repetition effect. Furthermore preexisting brainactivation differences between both groups were investigatedby comparing fMRI data at baseline [33].

Another study [16] randomly assigned 12 MCI patientsto a cognitive intervention or an active control group. Thecomputer-based cognitive intervention aimed to improveprocessing speed and accuracy of auditory processing. Itwas a time consuming intervention. Participants used thecognitive training five days a week for a hundred minutesper day for two months. The active control group madecomputer-based exercises with comparable time intensity.

Pre- and postintervention fMRI data and a memory test wereadministered [16].

A face-name association learning task was used as anintervention in an earlier study of Hampstead and colleagues[32]. They studied the effect of this face-name associationlearning in six amnestic multidomain MCI patients. ThefMRI was administered before and after the 5 training ses-sions. They compared fMRI results of trained with untrainedlists in different sessions to compensate for repetition effectsof fMRI. Furthermore they computed a functional connectiv-ity analysis [32].

In a single case design, the effect of a goal oriented cogni-tive rehabilitationwas studied in a personwith amnesticMCI.Besides fMRI data, performance on a memory tests and ananxiety and depression questionnaire were collected. Finally,the progress in personal rehabilitation goals was evaluated. Aface-name association learning task was administered duringthe fMRI [31].

3.2.2. Findings. Despite the differences in methodologies,types of intervention, and sample sizes in the studies (seeTable 3), all investigations found evidence for neurobiologicalchanges in brain activation after intervention.

In an RCT study with an active control group, an inter-vention related increase in brain activity in the hippocam-pus was seen, whereas the active control group showeda decreased activity in the hippocampus. Participants thatunderwent the auditory processing training also improved ona memory test and the training tasks [16].

The other RCT study that evaluated amnemonic training,found evidence for an intervention related increased activityin the left hippocampal body and the right hippocampusduring retrieval of the trained stimuli. For retrieval of theuntrained stimuli there was an intervention related increasedactivity in the right hippocampal. Performance improvedafter training for the trained stimuli, not for untrained stimuli[24].

In an earlier multiple cases study by the same author,increased connectivity and increased activity in frontal, pari-etal, temporoparietal areas and precuneus were seen after aface-name association learning training. The six participantsalso improved on trained and untrained memory tasks [32].

A study that evaluated the effect of an episodic memorytraining found increased activity in frontal, temporal, andparietal areas. Some areas were already active at baseline;other areas were new, alternative areas. Only increasedactivity in the right inferior parietal lobe correlated withimprovement on a memory test [33].

A single case study found evidence for a pattern ofbrain activity increases and decreases after a goal orientedcognitive training. Decreases were seen in sensory areasduring both encoding and retrieval, such as the highervisual areas, left fusiform gyrus, left medial occipital gyrus.Increased activity was seen in frontal areas, temporoparietaljunction, parahippocampal gyrus, and right globus pallidus.Both subjective memory satisfaction and subjective memoryperformance improved after the intervention [31].


Table3:Maincharacteris

ticso

fsele

cted

studies.

Stud

y

Design

Duration

Long

-term

follo

w-u

p𝑛

Interventio

nRe

sultneurob

iologicaloutcomes

Resultbehaviou

raloutcomes

Health

yTh

eelderly

Valenzuelaetal.

(2003)

[18]

RCT

5weeks

Nofollo

w-up

n=20

Metho

dof

loci

Increasedcreatin

eand

cholineinhipp

ocam

pus

Improvem

entinreprod

uctio

nmem

orytask

Noeffecto

ndepressio

nor

anxietyscores

Nybergetal.

(2003)

[30]

Prospectivec

ohort

1day

Nofollo

w-up

n=24

Metho

dof

loci

Acqu

isitio

n:no

grou

pdifferences

Use

phase:adultsandim

proved

elderlyincreased

activ

ityin

interventio

nrelated

areas

8of

16olderp

ersons

noim

provem

entinmem

ory

task

(theu

nimproved

elderly

).8of

16olderp

ersons

andall8

adultsim

proved

inmem

orytask

Smalletal.(200

6)[20]

RCT

14days

Nofollo

w-up

n=17

Multic

ompo

nent

health

prom

otion

Interventio

ngrou

p:decreasedactiv

ityprefrontalcortex

Bette

rverbalfl

uencyin

interventio

ngrou

pno

significanteffecton

mem

orytask

and

subjectiv

emem

oryability

Erickson

etal.

(2007)

[21]

RCT

2-3weeks

Nofollo

w-up

n=65

Attentionaltraining

Improvem

entindu

altask

perfo

rmance

iscorrelated

with

increasedactiv

ityin

leftventral

prefrontalcortex

anddecreasedactiv

ityin

the

dorsolateralprefrontalcortex

Both

reactio

ntim

eand

accuracy

improved

most

inthed

ualtaskinterventio

ngrou

pYo

ungandoldadultsshow

edthes

amed

egreeo

fperfo

rmance

improvem

entafterintervention.

Brehmer

etal.

(2011)[22]

RCT

5weeks

Nofollo

w-up

n=24

Adaptiv

eworking

mem

orytraining

.Con

trolgroup

:low

levelfi

xedworking

mem

orytraining

Allparticipantsdecreasedbrainactiv

ityParticipantswho

profi

tthe

mostsho

wedthe

largestd

ecreases

ininterventio

nrelated

brain

areasa

ndlargestincreaseincaud

ate

Both

grou

psIm

proved

inspan

boardbackward,

digitspanbackward,PA

SAT,RA

VLT

Nointerventio

nrelated

perfo

rmance

gainsfor

inscannertask

Interventio

ngrou

pshow

edtraining

related

improvem

entinspan

boardbackwardtask

and

PASA

Tcomparedto

controls

Belleville

etal.

(2014)

[23]

RCT

3weeks

Nofollo

w-up

n=46

Attentionaltraining

Bette

rperform

ance

insin

gletasking

correlated

with

decreasedactiv

ityin

right

inferio

rand

middlefrontalgyrus

Inthes

trategiccontrolofatte

ntioncond

ition

,abette

rabilityto

mod

ulatea

ttentionaccordingto

task

instructioncorrela

tedwith

increasedactiv

ityin

Brod

mannarea

10

Allinterventio

ngrou

psim

proved

inreactio

ntim

eandaccuracy

fora

lphanu

merictask,noeffectfor

visualdetectiontask

Both

dualtask

cond

ition

sbetterp

erform

ance

dualtaskingcomparedto

singletaskinterventio

ngrou

pStrategicc

ontro

lofatte

ntioncond

ition

significant

effecto

ftaskinstr

uctio

n.Th

eywerea

bleto

mod

ifyattentionaccordingto

instr

uctio

n.Mild

Cognitiv

eIm

pairm

ent

Claree

tal.(2009)

[31]

Sing

lecase

study

8weeks

Nofollo

w-up

n=1

Goalorie

nted

cogn

itive

interventio

n

Encoding

:increased

activ

ityin

interventio

nrelated

brainareas,decreasedactiv

ityhigh

ervisualareas,andfro

ntalareas

Recogn

ition

:increased

activ

ityin

interventio

nrelated

brainareas,decreasedactiv

ityhigh

ervisualareas,andfro

ntalareas

Bette

rsub

jectivem

emoryperfo

rmance,m

emory

satisfaction


Table3:Con

tinued.

Stud

y

Design

Duration

Long

-term

follo

w-u

p𝑛

Interventio

nRe

sultneurob

iologicaloutcomes

Resultbehaviou

raloutcomes

Ham

pstead

etal.

(2011)[32]

Multip

lesin

glec

ases

2weeks

Nofollo

w-up

n=6

Face-nam

eassociationlearning

Encoding

:increased

activ

ityin

defaultn

etwork

Effectiv

econ

nectivity

chan

ges:increased

conn

ectiv

ity

Sign

ificant

improvem

entinperfo

rmance

trainedandun

trainedmem

orytask

Belleville

etal.

(2011)[33]

Case

control

6weeks

Nofollo

w-up

n=15

Episo

dicm

emory

training

Encoding

healthye

lderly:decreased

activ

ityin

brainareasrelated

tointerventio

n.En

coding

MCI

:increased

activ

ityin

brainareas

relatedto

interventio

nRe

trievalh

ealth

yelderlyan

dMCI

:increased

activ

itynewbrainareasa

ndaccumulated

activ

ityin

specialized

areasb

othrelated

tointerventio

n.

Both

grou

psim

proved

onam

emorytest

Rosenetal.(2011)

[16]

RCT

2mon

ths

Nofollo

w-up

n=12

Auditory

processin

gtraining

Increasedactiv

ityhipp

ocam

pusininterventio

ngrou

pdecreasedactiv

ityhipp

ocam

pusincontrol

grou

p

Interventio

ngrou

pim

proved

inmem

orytestand

training

tasks

Ham

pstead

etal.

(2012)

[24]

RCT

2weeks

Nofollo

w-up

n=34

Mnemon

ictraining

Encoding

MCI

:increased

activ

ityleft

hipp

ocam

palbod

yRe

trievalM

CI:increased

activ

ityhipp

ocam

pal

body

andtailbilaterally

Health

ycon

trols:decreasedactiv

ityrig

hthipp

ocam

palbod

y

MCI

grou

pandhealthycontrolsim

proved

inencoding

andretrieving

trainedob

jectlocatio

ns.

Nointerventio

neffectfor

untrainedob

ject

locatio

ns.

Dem

entia

Heissetal.(1994)

[25]

RCT

6mon

ths

Nofollo

w-up

n=80

(1)S

ocialsup

port

(2)C

ognitiv

etraining

(3)C

ognitiv

etraining

+pyritinol

(4)C

ognitiv

etraining

+ph

osph

atidylserin

e

EEG:increased

glob

alpo

wer

gr3+4Decreased

delta

power

gr4

PET:

significantcorrelationMMSE

scorea

ndglucosem

etabolism

tempero-parietalcortex.

Gr.4increasedactiv

ityprim

aryvisualcortex

durin

ginterventio

n,bu

tnot

atthee

ndof

the

interventio

n

Gr4

morer

espo

ndersa

ndsig

nificanth

igher

scores

onorientationthan

gr1+

2in

week8+16.

Atthee

ndof

theintervention(6

mon

ths)there

weren

odifferences.

Nagayae

tal.

(2005)

[34]

With

insubjects

Unk

nown

Nofollo

w-up

n=11

Recreatio

nal

rehabilitation

Respon

ders:decreased

activ

ityfro

ntalregion

sNon

respon

ders:decreased

activ

ityallregions

Respon

ders:improved

3MMSE

points

Tanaka

etal.

(2007)

[35]

Sing

lecase

2mon

ths

Follo

w-upfor6

mon

ths

n=1

Reminisc

ence

increasedactiv

ityfro

ntalareas,po

stcingu

late

gyrus,andprecun

eus

Improvem

entincogn

ition

,vita

lity,volition,

and

daily

lifea

ctivities


Table3:Con

tinued.

Stud

y

Design

Duration

Long

-term

follo

w-u

p𝑛

Interventio

nRe

sultneurob

iologicaloutcomes

Resultbehaviou

raloutcomes

Forstere

tal.(2011)

[27]

RCT

6mon

ths

Nofollo

w-up

n=36

Multip

urpo

se

MCI

controls:

decreasedactiv

ityin

brainregion

stypically

impaire

din

AD

MCI

interventio

n:no

declines

ADcontrols:

decreasedactiv

ityin

brainregion

stypically

impaire

din

AD

ADinterventio

n:decreasedactiv

ityin

2clu

sters;

lingualgyrus,leftinferio

rtem

poralgyrus

Nochanges

Akanu

mae

tal.

(2011)[26]

RCT

3mon

ths

Nofollo

w-up

n=24

Reminisc

ence

with

reality

orientation

Interventio

ngrou

p:increasedactiv

ityanterio

rcing

ulateb

ilateral,leftinferio

rtem

poralcortex.

Correlationbetweenincreasedactanterior

cing

ulatea

ndim

provem

entsocialand

commun

icationscales

brse

Interventio

ngrou

p:im

proved

insocialand

commun

icationscales

(brse)

Spiro

nelli

etal.

(2013)

[36]

Observatio

nalstudy

5weeks

Nofollo

w-up

n=11

Cognitiv

etraining

Thea

mplitu

deso

fthe

recogn

ition

potential

(negativep

otentia

l)weres

ignificantly

increased

ontheleft

sides

ofpo

sterio

rregions

forh

igh

frequ

ency

words

Amarginally

significantimprovem

ento

nthe

verbalreason

ingscore

Nosig

nificanttreatmenteffecton

thed

ementia

screeningtests

,fou

rout

offivec

ognitiv

etasks,

andtheind

ependent

functio

ning

questio

nnaires.

vanPaasschenet

al.(2013)[28]

RCT

8weeks

Nofollo

w-up

n=19

Tailo

redcogn

itive

rehabilitation

Interventio

ngroup

Encoding

:nosig

nificantchanges.

Recogn

ition

:significantincreased

activ

itybilateralprefro

ntalareasa

ndtheb

ilateralinsula

Controlg

roup

Recogn

ition

:decreased

activ

ityin

bilateral

prefrontalareasa

ndtheb

ilateralinsula

Interventio

ngrou

pim

proved

onsatisfactionand

perfo

rmance

ofindividu

algoals(CO

PM)

Notre

atmenteffecton

theinscannerface-name

associationtask

Baglio

etal.(2014)

[29]

RCT

10weeks

Follo

w-upfor2

2weeks𝑛=60,𝑛=30

Follo

w-up

Multid

imensio

nal

stim

ulationprogram

Postinterventio

n:increasedactiv

itybilateral

superio

rtem

poralgyrus

(right>left),right

lentifo

rmnu

cleus,and

thalam

us

Interventio

ngrou

pshow

edclinicalrele

vant

improvem

entinNPI,language,andmem

ory

scales

ofADAS-cog

Nosig

nificantchangeinfunctio

nalstatuso

rph

ysicalwell-b

eing

Long

-term

follo

w-up

:improvem

entinthe

lang

uage

andmem

oryscales

oftheA

DAS-cogis

preserved

Legend

a:qo

l:qu

ality

oflife.

MMSE

:minim

entalstateexam

ination.

ADAScog:dementia

screeningtest.

BRSE

:scaleforsocialand

commun

icationskills.

GDS:geria

tricdepressio

nscale.


In conclusion, mostly an increase in brain activationspecifically in areas typically involved in intervention relatedcognitive processes [16, 24, 31, 33] was seen, as well asactivation of the default network [24, 32]. In several studies,the authors claimed that normalisation of the pattern of brainactivation after intervention had occurred as a possible resultof restoration [24, 31–33] whereas the activation of additionalareas was interpreted as a compensatory mechanism [24, 32].

Most of the studies tried to relate the changes in brainactivation to intervention success.Most studies formulate thisintervention success as performance improvement on a cog-nitive task that was the target of the intervention. One singlecase study also studied subjective complaints of cognition,mood, and anxiety. These authors reported improvement insubjectivemeasures ofmemory performance and satisfaction[31].

3.3. Patients with Dementia

3.3.1. Study Characteristics. Eight studies [25–29, 34–36]focused on patients with dementia. Four of the studies useda RCT design [25–27, 29]. Study population, interventiontargets, and outcome measures differed.

The most recent RCT study [29] aimed to improvecognition, behaviour, andmotor functioning with an intense,multidimensional stimulation program. The effectivenessof this program was studied in 60 persons with AD ona questionnaire for behavioural and psychiatric problems(NPI), language, and memory scales of the Alzheimer’s Dis-easeAssessment Scale-Cognitive subscale (ADAS-cog), func-tional status, physical well-being, and fMRI.The interventiongroupwas compared to awaiting list. Twenty healthy controlsserved as a reference for the typical activation pattern whileperforming the in-scanner verbal fluency task. The strengthof this study was a long-term follow-up measurement [29].

In another RCT study [27] the effect of a six-monthcognitive intervention program designed to improve globalcognitive functioning, mood, and quality of life in patientswith MCI and mild AD was investigated. To study disease-related brain activation differences at baseline, PET dataof the MCI and AD group were compared with PET dataof a group of eleven healthy elderly. In the active controlcondition, participants made pencil and paper assignmentsfocused on sustained attention (mostly intact in MCI andAD). A specific PET method was used that is known tobe more sensitive in detecting disease related metabolicdisturbances inmild tomoderate stages of neurodegenerativediseases [27].

The RCT study of Heiss et al. [25] also used a six-monthintervention for 80 participants with AD. The content oftheir intervention was different. The 17 participants receivedsocial support (group 1), 18 participants received cognitivetraining twice a week (group 2), 18 participants received acombination of the cognitive training and the drug pyritinolthat is used for symptomatic treatment of AD (group 3),and finally 18 participants received cognitive training andthe dietary supplement phosphatidylserine. At baseline andat several times during intervention and postintervention

neuropsychological tasks, the quantitative EEG, resting statePET, and stimulation PET were administered [25].

The fourth RCT study [26] investigated 24 residents of ageriatric nursing home with a diagnosis of vascular dementia(VaD). They were randomly assigned to reminiscence withreality approach condition or were treated to the standard ofcare.Theduration of the interventionwas 3months. Reminis-cence with reality approach claimed to invokememories withthe aid of materials and generated a better awareness of the“here and now.” Scores on a cognitive screening test (MMSE),a mood questionnaire (GDS), a behavioural observationalquestionnaire (BRSE), and PET data were all collected. Aregion of interest analysis (anterior cingulate left and right)was conducted with the PET data. [26].

The efficacy of tailored cognitive rehabilitation in 19people with early stage AD or mixed AD/VaD was evaluatedby van Paasschen et al. [28]. The goal of this study wasto relate clinically relevant improvement and differences inbrain activity. A passive control group with no treatment aswell as an active control group with relaxation therapy wasused. In 8 weekly sessions, personalized goals concerningmemory were targeted in the cognitive rehabilitation. Themain outcome measure was the Canadian OccupationalPerformanceMeasure (COPM) that rated the satisfaction andperformance of participants on several goals with respect todaily living. Brain activity was studied with fMRI [28].

Whereas most studies selected fMRI to study brainactivation, Spironelli et al. [36] used Event Related Potentials(ERP) to evaluate possible changes in brain functioning aftercognitive training in 11 people with mild to moderate AD.Their intervention aimed to stimulate different cognitivedomains based on everyday activities and exercises. The 11matched healthy controls underwent one experimental ERPsession to serve as a reference for possible altered responsepatterns. The intervention success was also evaluated withneuropsychological tests and questionnaires of everydayactivities [36].

Two studies used PET data as the neurobiological out-come. One study was a single case design on the effect ofeight weekly reminiscence sessions on activities of daily liv-ing, cognition, volition, vitality, behavioural problems, well-being, caregiver burden, and PET data. A comprehensivegeriatric assessment was also administered six months afterintervention [35]. The other study provided 11 VaD patientswith recreational rehabilitation. They used PET to studyblood flow differences after intervention. The group of 11patients was divided into responders (improved more than3 points on the MMSE) and nonresponders [34].

3.3.2. Findings. The eight studies that investigated cognitiveintervention effects on brain functioning of people sufferingfrom dementia differed in design, type of intervention,duration of the intervention, type of neurobiological andbehavioural outcomes, and the presence of follow-up mea-sures (Table 3). Despite those differences, all studies foundneurobiological changes after intervention.

In the most recent RCT study, an increased activity inthe superior temporal gyrus bilaterally, the thalamus and the


right lentiform nucleus was seen after a multidimensionalstimulation program. The intervention group also showedclinical relevant improvement in neuropsychiatric symptoms,language, and memory scales of a cognitive screening.There is a significant correlation between the magnitudeof increased activity in the left superior temporal gyrus,precuneus and left thalamus, and the change in cognitivescreening performance. The improvement in these scalesof the cognitive screening is preserved at 22 weeks afteintervention [29].

Another multidimensional intervention found evidencethat participants with AD showed decreased activity in twoclusters (lingual gyrus, left inferior temporal gyrus), whereasthe active control group showed decreased activity in a largernetwork prefrontal, parieto-occipital and parieto-temporal.However, therewere no significant changes in the behaviouraloutcomes [27].

Another RCT study showed that tailored cognitive reha-bilitation induced increased activity in prefrontal areas andinsula bilaterally, whereas both active and waiting list controlgroups showed decreased activity in those areas. The inter-vention group improved on satisfaction and performance ofindividual goals; both control groups showed no improve-ment [28].

A RCT study that evaluated the effect of reminiscencewith reality orientation found that intervention relatedincreased activity in the anterior cingulate correlated signifi-cantly with improvement in social and communication scales[26].

A single case study on the effect of reminiscence reportedincreased activity in frontal areas, precuneus and poste-rior cingulate gyrus after intervention. The participant alsoimproved on measures of cognition, vitality, volition, anddaily life activities [35].

In a RCT study hat evaluated the effect of four dif-ferent interventions, global EEG power increased in bothintervention groups that combined cognitive training witha dietary supplement or a symptomatic drug for dementia.There were no significant changes in brain metabolism afterintervention in predetermined target regions. Additionalregions of interest were analysed; this revealed an increase inmetabolism in the visual association area during functionalactivation for the cognitive training and phosphatidylserinegroup. For this intervention group there was also an increasein resting state metabolism in temporal regions, but only forthe participants in this particular intervention group thathad initial metabolism values below 90% of normal in thetemporal region. There were also some behavioural benefitsfor this intervention group. In weeks 8 and 16, the group thatreceived cognitive training and phosphatidylserine scoredsignificantly better on orientation than the other interventiongroups. This effect was no longer present at the end of theintervention [25].

An increased amplitude of the recognition potential forhigh frequency words on the left sides of posterior regionsafter cognitive training was demonstrated in an ERP study.Most behavioural outcomes fail to show a significant inter-vention effect, despite a marginally significant improvementon verbal reasoning [36].

Responders of a recreational rehabilitation interventionshowed decreased activity in frontal areas after intervention.The nonresponders showed activity decreases in a largenetwork of brain areas after intervention [34].

Thus, most studies found an increase in brain activationafter intervention or less decrease in activation versus thecontrol group.One study reported that the responders in theirintervention showed a significant decrease in cerebral bloodflow in the frontal regions, whereas nonresponders showeda decrease in a larger network of brain areas. Their study,however, is the least quality of all the included studies [34].According to one study [25], the changes in neuropsycho-logical measurements and brain activity were temporary anddisappeared at the end of the six-month intervention. Twostudies however demonstrated a behavioural interventionsuccess of 22 weeks and six months after intervention.Both studies did not follow up with the neurobiologicalchanges [29, 35]. The three most recent studies [28, 29, 36]and the study of Tanaka and colleagues [35] tried to linkclinical improvement to changes in brain activation by usingbehavioural outcomes that were not only cognitive tasks butmore related to daily functioning, individual goals, subjectivecomplaints, or social skills. Baglio and colleagues took thisone step further to statistically relate the brain activationchanges to the behavioural outcomes [29].

3.4. Methodological Quality. The selected 19 studies werequite heterogeneous in terms of design, sample size, popu-lation, intervention methods, and neurobiological outcomemeasurements. Therefore, it was decided to not statisticallypool the data to perform a quantitative meta-analysis. Eightstudies were comprised of patients with a diagnosis ofdementia; five studies involved patients with Mild CognitiveImpairment; and six studies included healthy elderly. Of theselected studies there were 13 randomized controlled trials,3 prospective studies, 1 study using a within-subjects design,and 2 single case studies.

Theoverallmethodological quality of the included studiesvaried. For the RCTs, the overall score of the methodologicalquality varied from 3 to 9 (maximum 9) with a level ofevidence ranging from A2 to B according to the CBO(Table 1). The overall score for the methodological quality ofthe observational studies varied from 3 to 9 (maximum 9).The CBO level of evidence ranged from B to C (Table 2).

Six of the 13 RCT studies lacked an intention to treatanalysis. Randomization was blind in only six of the 13 RCTstudies. In more than half of the studies the outcome assessorwas not blind to the treatment condition. In the observationalstudies, almost none of the studies had blinded outcomeassessors and almost every study had a selection bias.

A hierarchy of quality was composed based on the designand methodology. With regard to the studies that focusedon healthy elderly, the study of Belleville et al. [23] had thehighest methodological quality. For the studies that comprisepatients with MCI, the studies of Belleville and Bherer [15]and Erickson et al. [21] had the highest methodologicalquality. The study with the highest methodological qualitythat involved patients with dementia was that of Baglio et al.


[29]. Akanuma et al. [26] was limited in the informative valuedue to a lack of detailed methods and results.

4. Discussion

In this paper, the literature was reviewed to investigatewhether cognitive interventions in elderly lead to changesin brain activation suggestive of neural plasticity even indamaged neural systems. The methodological quality ofthe 19 studies was rated according to the guidelines ofthe Dutch Institute for Health Care Improvement (CBO,http://www.cbo.nl/).

The results illustrate that all studies, conducted in diversepopulations from healthy elderly to patients with dementia,show changes in brain activation post intervention. Themethodological quality of the studies varied with the CBOlevel of evidence ranging from A2 to C (Tables 1 and 2).

All four studies in healthy elderly found brain activationdifferences after intervention. Two studies found increases inbrain activation post intervention, primarily in the occipitalparietal cortex and retrosplenial cortex [30] as well as inthe hippocampus [18]. Post hoc only the older participantsthat improved on a memory test showed these brain activityincreases [30]. However, this could not be documented bymore clinical outcomes due to a lack of such outcomes or afail to link brain activation changes to clinically meaningfulimprovement.

On the contrary, another study found a decrease afterintervention in the dorsolateral brain activity [20]. Therelationship between this decreased activity dorsolateral andclinically relevant improvement was not evident. Only animprovement in verbal fluency was found, but no sig-nificant intervention effects were found on the subjectivemeasurements of self-awareness of memory performanceand other cognitive tasks [20]. Three studies successfullylinked intervention-related performance gains to brain acti-vation changes by statistical analyses. One study foundperformance-related brain activity decreases in the corticalregions known to be involved in cognitive functions tar-geted by the intervention and performance related brainactivity increases in subcortical areas [22]. Another studyprovided evidence that training induced dual task perfor-mance improvement was related to increased activity inthe left ventral prefrontal cortex and decreased activity inthe dorsolateral prefrontal cortex. Compared with an adultsample, age related differences in brain activity were reducedafter intervention [21]. The study of Belleville and colleagues[23] concluded that the type of intervention influenced theloci and type of brain activity. A better performance insingle tasking was correlated with decreased activity in theright inferior and middle frontal gyrus. An improved abilityto modulate attention according to task instruction wascorrelated with a greater activity in Brodmann area 10 [23].

Two studies argued that the decreases in brain activitycould be explained by an increased cognitive efficiency, thusdemanding less effort [20, 22]. The increase in subcorticalbrain activity was, according to these authors, evidence thatthe performance was becoming less executively demanding

andmore proceduralized as the training proceeded [22].Thisis in line with the theory of Bartres-Faz and Arenaza-Urquijoon cognitive efficiency [19]. In addition, the study with thehighest methodological quality highlighted the importanceof the type of intervention format. Intervention format haseffect on the loci and type of brain activation changes afterintervention. They refer to the framework of Lorden andtheir own theoretical framework named INTERACTIVE[21]. These models state that repeated practice would leadto decreased activity in the brain areas involved in the task,indicating increased cognitive efficiency. Interventions thataim to learn participants new strategies will lead to increasedactivity in alternative networks involved in learning thosestrategies [21].

Another study interpreted the performance related brainactivity pattern of increased activity in the left ventralprefrontal cortex and decreased activity in the dorsolateralprefrontal cortex, as evidence conflicting with views of com-pensation related reduced brain activity asymmetry. Whilebrain activity differences between adults and older adultswere significantly reduced after training, they interpreted thisas evidence that cognitive training can modulate age relatedpatterns of brain activity [23].

All of the reviewed studies of cognitive interventions inMCI patients found neurobiological changes in brain acti-vation after intervention despite differences in methodology.There was mostly an increase in brain activation, in areastypically involved in intervention related cognitive processes.This was seen as well as activation of the default network.In several studies, even normalisation of the pattern ofbrain activation after intervention was claimed. The studyof Rosen et al. had the highest methodological quality inthis review and showed that even brain structures known tobe injured in patients with MCI such as the hippocampusretained sufficient brain plasticity to benefit from cognitiveinterventions [16]. This activation of the default networkand hippocampus is in line with Bartres’ assumption that,in pathological aging, the cognitive reserve enhances therecruitment of compensating brain networks particularlythe frontal areas, hippocampus, and the precentral gyrus[19]. Cognitive behavioural interventions might increasethis cognitive reserve [4, 8]. Functionally relevant clinicalimprovement has been given little attention in these studies.A statistical approach to the relationship between interven-tion success on behavioural measures and brain activationchanges was only made by one study [26]. Long-term follow-up measures to determine the stability of the interventionsuccess were not included.

Studies in dementia patients also found neurobiologicalchanges after intervention. Most of the studies found anincrease in brain activation or a diminished decrease inactivation after intervention. The study of Forster et al. [27]was the only one that found a decrease in activation postintervention, but the construct of this study has poormethod-ology with little detailed information about the methodsand results. According to one study that used a six-monthintervention, the increased brain activity and improvementon neuropsychological tests were temporary in persons with


AD and then disappear over time [35]. Other studies demon-strated a preserved improvement in the clinical outcomessuch as cognitive tasks, daily life activities, and vitality at22 weeks and six months after intervention. However, theydid not follow up the neurobiological outcomes [26, 32].Thus, it remained unclear if the changes in brain functioningwere temporary. The study with the highest methodologicalquality correlated improvement in social and communicationscales with increased activity in the anterior cingulate, an areaknown to be involved in social behaviour [26].

One study excluded [27]; all of the authors interpretedtheir findings as evidence for brain plasticity. Some evenstated that cognitive interventions activate compensatingbrain networks in pathological ageing and could possiblyrestore brain activation. However, the stability of this effectremains unclear.

Overall, these results suggest that cognitive interventionslead to neurobiological changes even in potentially damagedneural systems. However, the interpretation of changes inactivation patterns is complicated. For instance, a decrease inbrain activation can indicate increased cognitive efficiency assuggested in the cognitive reserve hypotheses of Bartres-Fazand Arenaza-Urquijo [19] and the learning phases model ofDoyon in Lustig et al. [37]. On the other hand, a decrease inbrain activation might reflect exhaustion of neural resourcesaccompanied by a decline in clinical performance as sug-gested by the CRUNCHmodel [37].

Moreover, the type of intervention would influence theloci and type of activation changes after intervention [21].

The complexity of interpreting these neurobiological dataunderlines the importance of including clinical measure-ments to gain insight into the clinical relevance of neu-robiological changes. Unfortunately, in several studies, thisinformation is lacking or neurobiological data is interpretedas evidence for plasticity/restoration of function in theabsence of a demonstrated intervention success on clinicaloutcomes. In the more recent studies, there is increasedattention for the clinical relevance of neurobiological changeswith promising results. In five studies [21–23, 26, 32] per-formance gains were linked to brain activation. Four studiesused correlations to correlate improvement on a dementiascreening test [22], social and communication scales [26]and changes in performance on different attentional tasks[21, 23] to relevant changes in brain activation. A fourth studyused the maximum gain score on working memory tasks as acovariate in statistical analysis [32].

These studies focus on relating performance improve-ment to brain activity changes. However, the transfer of theseperformance gains to untrained tasks and more importantlyto daily life functioning is a great issue [21].

The heterogeneity in populations, outcome measuresand interventions as well as the small sample sizes andrelatively large amount of case studies further complicate thecomparability of the findings between studies.

We recommend that future studies should include mea-sures of clinically meaningful improvement as well as long-term follow-up data to evaluate the stability of the effects.Theinfluence of task demands, premorbid cognitive reserve, andlearning phases on brain activation should be considered to

increase comparability between studies. The results thus farindicate that the elderly show changes in brain activation aftercognitive interventions. However, the exact interpretationand stability of these changes remain unclear just like towhat extent cognitive interventions are effective to reach theultimate goal: to delay conversion to or prevent progressionof dementia.

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper.

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