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Table 1 Detailed findings of pharmacological fMRI studies

From: Effects of pharmacological and nonpharmacological treatments on brain functional magnetic resonance imaging in Alzheimer’s disease and mild cognitive impairment: a critical review

Reference

Treatment

Design

Sample

fMRI protocol/scan timing

Outcome measures

Clinical findings

Direction fMRI changes

Brain areas involved

Clinical-fMRI relationship

Bakker et al., 2015 [40]

Levetiracetam (different doses: 62.5 mg twice/day, 125 mg twice/day, and 250 mg twice/day) and placebo

RCT double-blind for patients and single-blind for HC

17 HC

54 MCI

Three-choice recognition memory task Pre-/post-treatment

Task-related medial temporal, temporal-polar, and hippocampal functional activity changes; performance improvement at fMRI task and cognitive assessment

Improvement on recognition memory task in the group on low-dose treatment. No changes at the BSRT, Verbal Pair Associate test, or BVRT

Decreased

Post-treatment vs placebo: L CA3 and DG of hippocampus

Decreased activity; higher memory performance during task

Increased

Post-treatment vs placebo:L entorhinal cortex

Bakker et al., 2012 [41]

Levetiracetam (125 mg twice/day) and placebo

RCT double-blind for patients and single-blind for HC

17 HC

17 MCI

Three-choice recognition memory task Pre-/post-treatment

Task-related hippocampal functional activity changes; performance improvement at fMRI task and cognitive assessment

Improvement on recognition memory task. No changes at the BSRT, Verbal Pair Associate test, and BVRT

Decreased

Post-treatment vs placebo: L CA3 and DG of hippocampus

Decreased activity; higher memory performance during task

Bentley et al., 2008 [26]

Physostigmine (infusion at a rate of 1 mg/1 h) and placebo (an equivalent volume of saline), in both groups 25 min prior to scan

NRCT double-blind

17 HC

16 mild AD

Visuo-attentional task Post-treatment

Task-related parietal functional activity changes; performance improvement at fMRI task

Improvement on RT for the ‘deeper’ task in AD

Increased

Group X time, treated vs placebo: R precuneus and posterior parahippocampal cortex; R parietal and PFC

Decreased

Group X time, treated vs placebo: R fusiform gyrus

Bentley et al., 2009 [27]

Physostigmine (infusion at a rate of 1 mg/1 h) and placebo (an equivalent volume of saline), in both groups 25 min prior to scan

NRCT double-blind

18 HC

13 mild AD

Face-encoding task Post-treatment

Task-related fusiform functional activity changes and their relationship with performance improvement at fMRI task

Task-independent (‘shallow’ vs ‘deeper’) improvement in confident memory

Increased

Group X time, treated vs placebo: Bilateral fusiform cortex

Increased activity; higher face recognition post-scanning

Blautzik et al., 2016 [55]

Galantamine (6-month treatment: 8 mg/day for the first month; 16 mg/day for the second month; 24 mg/day for the other months) or placebo, followed by 6 months galantamine (24 mg/day) – open label period

RCT double-blind and open-label

11 HC

13 mild-moderate AD

RS fMRI At baseline At 6 months At 12 months

DMN functional connectivity changes; performance improvement at cognitive assessment

No changes at the CEREAD

Increased

Post-treatment vs HC (12-month follow-up):Posterior DMN (PCC, precuneus, L > R); Post-treatment vs placebo (12-month follow-up):Hippocampal sub-component (anterior division of hippocampus, R > L)

Bokde et al., 2016 [47]

Rivastigmine (3-month treatment: 3 mg/day for the first month; 6 mg/day for the second month; 9 mg/day for the third month) or placebo, followed by 9 months rivastigmine (9 mg/day) – open label period

RCT double-blind and open-label

12 MCI

Face- and location-matching task At baseline At 3 months At 6 months

Task-related whole-brain functional activity changes and performance improvement at cognitive assessment

After 3 and 6 months: lower performances at the verbal fluency; stable performances at the CERAD and at the task

Increased

Pre-/post-treatment (3-month follow-up): Face-matching task: bilateral lingual and fusiform gyrus, L angular gyrus and cerebellum. Location matching task: L inferior temporal gyrus, R precuneus, R angular and inferior frontal gyri

Pre-/post-treatment (6-month follow-up): Location matching task: R inferior parietal and supramarginal gyrus, L precuneus and paracentral lobule, L medial frontal gyrus

Bokde et al., 2009 [32]

Galantamine (3-month treatment: 8 mg/day for the first month; 16 mg/day for the second month; 24 mg/day for the last month)

Case series

5 mild AD

Face- and location-matching task Pre-/post-treatment

Task-related ventral and dorsal visual pathway changes; performance improvement at fMRI task and cognitive assessment

No changes at the task or at the CEREAD

Decreased

Pre-/post-treatment:Location-matching task: bilateral dorsal pathway (from occipital to parietal and frontal cortices)

Dhanjal et al., 2013 [29]

Donepezil (6-week treatment: 5 mg/day for the first 2 weeks; 10 mg until the end of the study)

Case series

9 mild AD

Auditory sentence encoding and retrieval with auditory working memory suppressors Pre-/post-treatment

Task-related primary auditory, ventro-lateral temporal, pars triangularis and angular gyri functional activity changes; performance improvement at fMRI task

Increased percentage of retrieved trials during task

Increased

Pre-/post-treatment: L anterior ventral temporal cortex and pars triangularis

Dhanjal et al., 2014 [30]

Donepezil (6-week treatment: 5 mg/day for the first 2 weeks; 10 mg until the end of the study)

Cohort study

18 HC

18 mild AD

Auditory sentence encoding and retrieval with auditory working memory suppressors Pre-/post-treatment

Task-related functional activity changes within the executive and salience networks; performance improvement at fMRI task

Increased percentage of retrieved trials during task

Increased

Pre-/post-treatment: Fronto-parietal executive network: L lateral posterior parietal cortex and lateral frontal cortex. Higher-order cortex: L parahippocampal gyrus and anterior ventral temporal cortex

Goekoop et al., 2004 [39]

Galantamine (oral intake, single dose: 8 mg; and after prolonged exposure: 4 mg day 1, 8 mg next 4 days, 4 mg on day 6). Washout period: 2 days

Cross-over

28 MCI

Episodic face-encoding and N-letter back task Pre-/post-treatment

Task-related whole-brain functional activity changes

N-letter back: task accuracy increased and latency decreased, mainly after single dose intake

Increased

Pre-/post-treatment (prolonged exposure): Face encoding: L middle frontal and occipital cortices, L posterior hippocampus and R anterior cingulate cortex. N-letter back: R precuneus and middle frontal cortex

Goekoop et al., 2006 [31]

Galantamine (acute (8 mg) and prolonged 5 days exposure (4 mg the first day, 8 mg the following 4 days, 4 mg the last day))

Cross-over

18 mild AD

28 MCI

Face-recognition task Pre-/post-treatment

Task-related whole-brain functional activity changes

No changes at the task

Increased

Pre-/post-treatment (acute exposure): MCI: L PCC, anterior and temporal lobe, L superior parietal, R frontal lobe and cerebellum. AD: vermis of cerebellum, R inferior temporal and parahippocampal gyri

Decreased

Pre-/post-treatment (prolonged exposure): MCI: bilateral superior frontal cortices, L PCC, R middle frontal gyrus. AD: R parahippocampal cortex

Goveas et al., 2011 [50]

Donepezil (3-month treatment: 5 mg/day for 4 weeks; 10 mg/day until the end of the study)

Cohort study

14 HC

18 mild AD

RS fMRI, seed-based (hippocampus) connectivityPre-/post-treatment

Hippocampal functional connectivity changes; performance improvement at cognitive assessment

Improvement on ADAS-cog but not on MMSE

Increased

Pre-/post-treatment: Positively correlated hippocampal functional connectivity network: L middle frontal and precentral gyri, L parahippocampus, insula and thalamus, R PCC

Increased hippocampal connectivity strength in the L dorsolateral PFC and middle frontal gyrus; improvement on ADAS-cog

Decreased

Pre-/post-treatment: Negatively correlated hippocampal functional connectivity network: L inferior parietal cortex/supramarginal gyrus, L posterior middle temporal gyrus, and R dorsolateral PFC

Griffanti et al., 2016 [52]

Donepezil (12-week treatment: 5 mg/day for the first 4 weeks, followed by 10 mg/day until the end of the study)

Case series

18 mild-moderate AD

RS fMRIPre-/post-treatment

Relationship between whole-brain functional connectivity changes and performance improvement at cognitive assessment

Greater improvement on MMSE and MoCA in responders compared to nonresponders

Increased

Pre-/post-treatment: Orbitofrontal network: precuneus, PCC and R dorsolateral frontal cortex (responders > nonresponders)

Increased connectivity of anterior and posterior cingulate cortices, precuneus, and R dorsolateral frontal regions within the orbitofrontal network; improvement on MoCA

Grön et al., 2006 [38]

Galantamine (4 mg twice a day for 7 days)

Case series

10 MCI

Spatial navigation taskPre-/post-treatment

Task-related hippocampal functional activity changes and performance improvement at cognitive assessment

Improvement on verbal episodic memory but not at the task

Increased

Pre-/post-treatment: R middle occipital and temporal gyri, R PCC, R hippocampus and parahippocampal gyrus; L anterior hippocampus

Haller et al., 2014 [45]

Caffeine (one capsule containing caffeine 200 mg or placebo) 30 min before testing

NRCT double-blind

15 HC

13 MCI

2-back (vs 0-back) working memory taskPre-/post-treatment

Task-related whole-brain functional activity changes

No effect on task RT neither on accuracy

Increased

Post-treatment vs placebo: Task-related: bilateral striatum, temporal and parietal cortices. TICA: L working memory network including PFC, supplementary motor area, ventral premotor and parietal cortices

Kircher et al., 2005 [28]

Donepezil (10-week treatment: 5 mg/day for the first 4 weeks; 10 mg/day until the end of the study)

Cohort study

10 HC

10 mild-moderate AD

Face memory encoding taskPre-/post-treatment

Task-related fusiform gyrus functional activity

Improvement on ADAS-cog total score and on the memory subscale. No changes at the task

Increased

Pre-/post-treatment/Post-treatment vs HC: R fusiform gyrus

Li et al., 2012 [51]

Donepezil (12-week treatment: 5 mg/day for the first 4 weeks; 10 mg/day until the end of the study)

Case series

12 mild AD

RS fMRI, seed based (MCC and PCC) connectivityPre-/post-treatment

MCC and PCC functional connectivity changes; cerebral blood flow changes; performance improvement at cognitive assessment

Improvement on ADAS-cog but not on MMSE, NPI, or IADL

Increased

Pre-/post-treatment: Middle cingulate and PCC network connectivity

Increased connectivity between the middle cingulate cortex and the ventral anterior cingulate cortex and PFC; and between the PCC and the ventral anterior cingulate cortex-changes in ADAS-cog

Lorenzi et al., 2011 [56]

Memantine (6-month treatment: 5 mg/day, increasing by 5 mg/day to a final dose of 20 mg/day) or placebo

RCT double-blind

15 moderate AD

RS fMRI Pre-/post-treatment

DMN functional connectivity changes; performance improvement at cognitive assessment

No changes at the cognitive assessment

Increased

Pre-/post-treatment/Group X time, treated vs placebo: R precuneus and calcarine gyrus within DMN

McGeown et al., 2010 [36]

Donepezil (20-week treatment: 10 mg/day)

Cohort study

9 HC

12 mild AD

Semantic association and N-back (1-back) task Pre-/post-treatment

Task-related whole-brain functional activity changes; performance improvement at fMRI task

No changes at the cognitive assessment (including ADAS-cog, NPI and ADL) or at the task

Decreased

Pre-/post-treatment: Semantic association: L superior parietal, middle temporal, medial and inferior frontal gyrus, and R superior temporal gyrus. Working memory: L caudate, L middle and superior temporal gyri, and R inferior frontal gyrus. Post-treatment vs HC: Semantic association: bilateral middle frontal gyrus, R superior occipital, cuneus and anterior cingulate cortex. Working memory: L thalamus, L parahippocampal gyrus, R inferior frontal gyrus

Increased activity in non-task relevant regions (such as bilateral inferior parietal lobe, PCC and precuneus); higher accuracy at the semantic association task

McGeown et al., 2008 [34]

Rivastigmine (20-week treatment: 6 mg twice/day)

Cohort study

9 HC

11 mild AD

Semantic association and N-back (1-back) task Pre-/post-treatment

Task-related whole-brain functional activity changes; performance improvement at cognitive assessment

Improvement on ADAS-cog. No further changes at the cognitive assessment or at the task

Increased

Pre-/post-treatment: Semantic association: bilateral middle frontal and paracentral gyri, parahippocampal and fusiform gyri. Working memory: R superior, middle, medial and inferior frontal gyrus, and R precentral gyrus. Post-treatment vs HC: Semantic association: R inferior frontal and L anterior cingulate cortex. Working memory: R middle frontal, postcentral and supramarginal gyri

Decreased

Pre-/post-treatment: Working memory: L middle frontal, precentral and cingulate gyrus, L insula and thalamus. Post-treatment vs HC: Working memory: L PCC and angular gyrus

Miettinen et al., 2011 [24]

A single oral dose of rivastigmine (3 mg, acute); and 1.5 mg of rivastigmine twice a day for 4 weeks (chronic); a single oral dose of placebo

NRCT double-blind

20 mild AD

Face recognition memory task Post-treatment

Task-related whole-brain functional activity changes and their relationship with baseline cognitive assessment

No changes at the task

Increased

Post-treatment vs placebo (acute): bilateral PFC, R middle and superior temporal gyrus.

Post-treatment vs placebo (chronic): bilateral PFC, L middle temporal and anterior cingulate cortices, and L parietal gyrus

Increased PFC activity after chronic treatment; poorer MMSE at baseline

Pa et al., 2013 [42]

Donepezil (3-month treatment: 5 mg/day for 1 month and 10 mg/day for 2 months) or placebo

RCT double-blind

27 MCI

Face recognition task Pre-/post-treatment

Task-related prefrontal, parietal and hippocampal functional activity changes; performance improvement at cognitive assessment

Improvement on task RT and accuracy. No changes at the cognitive assessment

Increased

Group X time, treated vs placebo: L fusiform face area and its connectivity with R hippocampus and inferior frontal junction

Increased connectivity between L fusiform face and R hippocampus; reduced RT for face recognition in treated patients

Petrella et al., 2009 [44]

Donepezil (12- or 24- week treatment: 5 mg/day for 42 days, followed by 10 mg/day until the end of the study)

RCT double-blind

13 MCI

Novel face visual memory task Pre-/post-treatment

Task-related whole-brain functional activity changes; performance improvement at cognitive assessment

No improvement at the cognitive assessment or at the task

Increased

Post-treatment vs placebo: Bilateral dorsal e ventrolateral PFC.

Group X time,treated vs placebo: L inferior frontal gyrus

Risacher et al., 2013 [43]

Donepezil (3-month treatment: 5 mg/day for 4 weeks, 10 mg/day until the end of study)

NRCT open-label

20 HC

18 MCI

Verbal episodic encoding task Pre-/post-treatment

Task-related whole-brain functional activity changes and their relationship with patient performances at cognitive assessment before and after treatment

Improvement on CVLT. Mild accuracy decline during task

Increased

Group X time/treated vs HC: R hippocampus and parahippocampal gyrus, R middle frontal gyrus. Increased deactivation of the medial parietal lobe

Changes on medial parietal lobe activity-changes in CVLT. Increased connectivity of the L frontal lobe and L caudate; improved task accuracy

Rombouts et al., 2002 [25]

Single dose (3 mg) of rivastigmine, 3 h before the first vs the second scanning

NRCT single-blind

11 mild AD

Face encoding and working memory task Pre-/post-treatment

Task-related whole-brain functional activity changes

No changes at the task

Increased

Post-treatment vs placebo: Face encoding: bilateral fusiform gyrus. Simple working memory: L middle and superior frontal gyrus. Increased working memory load: L middle frontal gyrus, R inferior and superior frontal gyrus.

Decreased

Post-treatment vs placebo: Increased working memory load: R middle and superior frontal gyrus

Saykin et al., 2004 [46]

Donepezil (5 mg/day for 4 weeks; 10 mg/day for 5.67 ± 1.66 weeks on average)

NRCT open-label

9 HC

9 MCI

Auditory N-back task Pre-/post-treatment

Task-related whole-brain functional activity changes; performance improvement at cognitive assessment and fMRI task

Improvement on accuracy during task and on TMT-B. Reduction of subjective cognitive concerns

Increased

Group X time, treated vs HC: L dorsolateral PFC and L superior frontal cortex

Increased activity of the L anterior prefrontal-improved task accuracy

Shanks et al., 2007 [35]

Galantamine (20-week treatment: 16 mg twice/day)

Cohort study

9 HC

9 mild AD

Semantic association and target detection task Pre-/post treatment

Task-related frontal and parieto-temporal functional activity changes

No improvement at the cognitive assessment or at the tasks. Increased awareness in patient self-assessment with respect to problems during daily activities

Increased

Pre-/post-treatment: Semantic association: L paracentral lobule, L caudate and R lingual gyrus. Target detection: bilateral postcentral, L inferior parietal lobule.

Post-treatment vs HC: Semantic association: bilateral superior temporal gyri and insula, R medial frontal gyrus, L inferior frontal. Target detection: bilateral middle frontal, L superior temporal and precuneus

Solé-Padullés et al., 2013 [49]

Donepezil (3-month treatment: 5 mg/day for 1 month and 10 mg/day for 2 months) or no treatment

RCT single-blind

15 mild-moderate AD

RS fMRI andvisual scene encoding task Pre-/post-treatment

RS whole-brain functional connectivity and task-related activity changes; performance improvement at fMRI task

Improvement on semantic fluency. No further changes at the cognitive assessment or at the task

Increased

Post-treatment vs untreated: R parahippocampal gyrus within the DMN. No task-related changes were observed

Thiyagesh et al., 2010 [33]

Donepezil (23-week treatment: 5 mg/day)

Cohort study

11 HC

10 mild AD

Visuospatial tasks Pre-/Post-treatment

Task-related functional activity changes in brain regions subtending visuospatial abilities

Improvement on MMSE, ADAS-cog, and Present Functioning Questionnaire. No changes at the task

Increased

Pre-/post-treatment: L precuneus

Increased activity of the L precuneus-improvement atthe Present Functioning Questionnaire

Venneri et al., 2009 [37]

AchEI treatment (20-week treatment: at the maximum guideline-recommended dosage)

Cohort study

9 HC

26 mild AD

Semantic association and N-back (1-back) task Pre-/post-treatment

Task-related whole-brain functional activity changes and performance improvement at cognitive assessment in responders compared with nonresponders

Improvement of the responders on ADAS-cog. No further changes at the cognitive assessment or at the task

Increased

Pre-/post-treatment/Group X time, responders vs nonresponders: Semantic association: bilateral inferior and medial frontal gyri, L precentral and postcentral gyri, L insula, middle temporal and inferior parietal gyri and anterior cingulate cortex; R inferior temporal gyrus, precuneus and caudate. Working memory: R precentral, precuneus, inferior parietal and thalamus, L inferior and superior frontal gyrus

Increased activity of the L frontal cortex during the semantic association task; poorer performance at the baseline semantic fluency

Wang et al., 2014 [54]

Stable dose of AchEIs (donepezil, rivastigmine, or galantamine) for at least 15 days and for almost 18 months

Case-control

25 mild treated AD

19 mild untreated AD

RS fMRI Post-treatment

Functional connectivity changes and interaction with the APOE genotype

Increased

Pre-/post-treatment/ApoEε4 treated vs ApoEε4 untreated: Greater composite scores in dorsal attention, control and salience networks

Zaidel et al., 2012 [53]

Donepezil (8-week treatment: 5 mg/day for 28 days; 10 mg/day until the end of the study)

Case series

11 mild AD

RS fMRI, L hemisphere seed-based connectivity Pre-/post-treatment

RS functional changes in the interhemispheric connectivity

Increased

Pre-/post-treatment: L-R dorsolateral PFC

Zhang et al., 2016 [57]

Bushen capsule (24-month treatment: 4 capsules 3 times a day) or placebo

RCT double-blind

60 MCI

RS fMRI At baseline At 12 months At 24 months

DMN functional connectivity and performance improvement at cognitive assessment, and their relationship

Improvement on MMSE, RAVLT, and digit span

Increased

Group X time, treated vs placebo:R precuneus within the DMN

No relationship was observed between connectivity and cognitive changes

Zhang et al., 2014 [48]

CCRC (3-month treatment: 3 capsules per day) or placebo

RCT double-blind

39 MCI

N-back (0-1-and 2 back) working-memory task Pre-/Post-treatment

Task-related whole-brain functional activity changes; performance improvement at cognitive assessment

Improvement on MMSE and digit span. No further changes on other cognitive scores or on task

Increased

Group X time, treated vs placebo and vs HC: Increased negative activation of L PCC and R fusiform gyrus

Increased negative activity in L PCC; changes on MMSE and digit span scores

  1. AchEI acetyl-cholinesterase inhibitor, AD Alzheimer’s disease, ADAS-cog Alzheimer's Disease Assessment Scale-cognitive subscale, ADL activities of daily living, APOE apolipoprotein E, BSRT Buschke Selective Reminding Test, BVRT Benton Visual Retention Test, CCRC Compound Congrongyizhi Capsule, CEREAD Consortium to Establish a Registry for Alzheimer's Disease, CVLT California Verbal Learning Test, DG dentate gyrus, DMN default mode network, fMRI functional MRI, HC healthy controls, IADL instrumental activities of daily living, L left, MCC middle cingulate cortex, MCI mild cognitive impairment, MMSE Mini mental state examination, MoCA The Montreal Cognitive Assessment, NPI Neuropsychiatric Inventory, NRCT nonrandomized controlled trial, PCC posterior cingulate cortex, PFC prefrontal cortex, R right, RAVLT Rey auditory verbal learning test, RCT randomized controlled trial, RS fMRI resting state functional MRI, RT reaction time, shallow low-demanding, TICA tensorial-independent component analysis, TMT-B Trail Making Test, part B