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Table 2 Detailed findings of nonpharmacological 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
Baglio et al., 2015 [68] MST focused on AD and caregivers. ADperformed 30 sessions involving reality orientation, cognitive exercises, physical, recreational and occupational activities (2.5 h/day, 3 days/week). Caregivers underwent an educational program to favor a long-term positive interaction with patients at home. Control group: AD receiving usual care RCT single-blind 60 mild-moderate AD Verbal fluency task Pre-/Post-training Task-related whole-brain functional activity changes, performance improvement at cognitive assessment (ADAS-cog, FLSA, NPI, SF-36) and fMRI task, and their relationship Improvement on NPI and on language and memory assessed with ADAS-Cog in MST relative to the control group after 10 weeks. No changes on functional status and physical well-being after 10 weeks. No further changes after 22 weeks of training. No improvement at the task Increased Group X time, training vs control:Bilateral superior temporal gyrus, R insula and thalamus Increased brain activity; improvement at the ADAS-Cog total score
Belleville et al., 2011 [60] Group episodic memory encoding and retrieval training (6 sessions/week of 120 min each) consisting of interactive imagery, face-name associations, hierarchical organization and semantic organization NRCT single-blind 15 HC
15 MCI
Verbal memory encoding and retrieval task Pre-/Post-training Task-related whole-brain functional activity changes; performance improvement at fMRI task; performance at the Côte-des-Neiges Computerized Memory Battery (immediate and delayed word recall) Improvement on immediate and delayed word recall at the Côte-des-Neiges Computerized Memory Battery; performance improvement at the task for both encoding and retrieval Increased Pre-/post-training, MCI:Encoding: L superior temporal gyrus, insula and basal ganglia, R superior frontal and cerebellum. Retrieval: L postcentral, inferior parietal and superior temporal gyri, R superior temporal and middle frontal gyri, insula and precuneus Increased activity of the R inferior parietal lobule; improved performance on delayed word recall
Chirles et al., 2017 [66] Moderate intensity aerobic exercise on treadmill (12-week treatment, 30 min-walk, 4 times/week) NRCT open-label 16 HC
16 MCI
RS fMRI, seed-based (PCC/precuneus) connectivity Pre-/Post-training PCC/precuneus functional connectivity changes; performance improvement at cognitive and physical assessments Improvement on mean intensity of training, rate of perceived exertion, VO2 peak and RAVLT Increased Pre-/post-training, MCI:Connectivity between PCC/precuneus and bilateral frontal and parietal, R temporal and insular cortices and L cerebellum.
Group X time, MCI vs HC: connectivity between PCC/precuneus and inferior parietal lobule
Hampstead et al., 2011 [61] Mnemonic strategy training using face-name associations (3 total sessions/2 weeks) Case series 6 MCI Face-name association task Pre-/Post-training Task-related whole-brain functional activity changes; performance improvement at cognitive assessment Improvement on memory performance during the task Increased Pre-/post-training, MCI: Bilateral medial frontal, medial parietal, medial occipital cortex, L frontal operculum, temporo-parietal cortex. The L middle temporal gyrus was the primary “driver” of activation (effective connectivity)
Hampstead et al., 2012 [62] Mnemonic strategy training using object-location associations (3 total sessions/2 weeks) Control group: unspecific mnemonic training RCT single-blind 16 HC
18 MCI
Object-location association task Pre-/Post-training Task-related hippocampal functional activity changes; performance improvement at fMRI task; relationship between functional activity changes and performance improvement at fMRI task No improvement at the task Increased Pre-/post-training, trained MCI: Encoding: L hippocampal body during both the trained and untrained stimuli. Retrieval: L hippocampal body and tail during the untrained stimuli.
Group X time, trained MCI vs control: Retrieval: L hippocampal body and R hippocampus during trained stimuli; R hippocampal body during untrained stimuli
Rosen et al., 2011 [63] Average of 2-month computer-based, cognitive training program focused on auditory verbal discrimination (100 min/day for 24 sessions). Control group, computer-based unspecific activities (90 min/day for 24 sessions) RCT double-blind 12 MCI Auditory-verbal task Pre-/Post-training Task-related L hippocampal functional activity changes; performance improvement at fMRI task; performance at the RBANS Improvement on memory assessed with the RBANS. No improvement at the task Increased Group X time, training vs control: L hippocampus Increased activity L hippocampus-trend toward improvement at RBANS
Satoh et al., 2015 [59] Singing training (6-month training, 1 session/week). Control group: AD who did not perform the training NRCT open-label 20 mild-moderate AD Karaoke and Pitch tasks Pre-/Post-training Task-related whole-brain functional activity changes; performance improvement at the cognitive/behavioral assessment Improvement on disability, behavior and reasoning assessed with DAD, NPI, and RCPM, respectively Increased Pre-/post-training, AD: R angular gyrus and L lingual gyrus
Smith et al., 2013 [65] 12-week moderate intensity treadmill training (44 total sessions: 30 min each session, 4 sessions/week) NRCT open-label 18 HC
17 MCI (different subtypes)
Famous-name discrimination task Post-observation Task-related whole-brain functional activity changes; performance improvement at the cognitive, physical assessments and at the fMRI task Improvement on mean intensity of training, rate of perceived exertion, VO2 peak and RAVLT. No improvement at the task Unchanged No pre-/post-training or Group X time effect
Smith et al., 2011 [67] Low-physical activity (≤ 2 days/week of low-intensity physical activity); High-physical activity (≥ 3 days/week of moderate to vigorous physical activity) Case-control open-label 18 MCI Famous-name discrimination task Pre-/Post-training Task-related whole-brain functional activity changes; basal ganglia volume changes Increased Post-training/high vs low-physical activity: L caudate
Suo et al., 2016 [70] 26-week training (two sessions per week, each for 90 min). Four conditions: 1. PRT + CCT 2. PRT + sham-CCT 3. CCT + sham-PRT 4. Sham PRT + sham-CCT RCT double-blind 100 MCI RS fMRI, seed (bilateral hippocampus and PCC) connectivity Pre-/Post-training Bilateral hippocampi/PCC functional connectivity changes; cortical atrophy changes; performance improvement at the cognitive assessment (ADAS-Cog, Memory Awareness Rating Scale and Memory Complaint Score) Group X Time/PRT vs non-PRT: Improvement on ADAS-Cog Group X Time/CCT vs on-CCT: no decline on memory domain Decreased Group X time/PRT: connectivity between PCC, L inferior temporal lobe and anterior cingulate cortex; and between hippocampus and R inferior temporal lobe.
Group X time/CCT: connectivity between PCC, L superior frontal lobe and anterior cingulate cortex.
Group X time/combined vs single intervention: connectivity between PCC and anterior cingulate cortex
In CCT, increased connectivity between hippocampus and L superior frontal; higher memory performance
Increased Group X time/PRT: connectivity between hippocampus and R middle frontal.
Group X time/CCT: connectivity between hippocampus and L superior frontal lobe.
Group X time/combined vs single intervention: connectivity between hippocampus, anterior cingulate cortex, and R superior frontal lobe
Train the Brain Consortium 2016 [69] 7-month multidomain training, including cognitive, physical exercise and music therapy. Control group: MCI receiving usual care RCT single-blind 113 MCI (different subtypes) Visuo-spatial attention task At baseline At 7 months At 19 months Task-related whole-brain functional activity changes; hippocampal cortical atrophy changes; white matter hyperintensities changes; performance improvement at cognitive assessment (ADAS-Cog) Improvement on ADAS-Cog, on the immediate recall of the Rey-Osterrieth Complex Figure and on phonemic fluency. No improvement at the task Unchanged No pre-/post-training effect
Van Paasschen et al., 2013 [58] 8-week cognitive rehabilitation training (1 h sessions, 3 strategies for acquiring new information: verbal and visual mnemonics, semantic elaboration, and expanding rehearsal) Control: relaxing therapy and no training RCT open-label 19 mild AD Unfamiliar face-name pairs association task Pre-/Post-training Task-related whole-brain functional activity changes; performance improvement at fMRI task, occupational assessment and mood (COPM and HADS) Improvement on behavior assessed with the COPM. No improvement at the task Decreased Pre-/post-training, AD: Encoding: R insula
Increased Pre-/post-training, AD: Recognition: bilateral insula and angular gyrus, L middle frontal gyrus
Wells et al., 2013 [64] Mindfulness-based stress reduction (30 min/day, once a week for 8 weeks, 2 h each session + home practice). Control group: MCI receiving usual care RCT single-blind 14 MCI RS fMRI Pre-/Post-training DMN/hippocampal functional connectivity changes; hippocampal atrophy changes and changes on ADAS-Cog No significant changes on ADAS-Cog Increased Group X time, training vs control: connectivity between PCC and bilateral medial prefrontal cortex and between PCC and L hippocampus
  1. AD Alzheimer’s disease, ADAS-cog Alzheimer’s Disease Assessment Scale-cognitive subscale, COPM Canadian Occupational Performance Measure, CCT computerized cognitive training, DAD Disability Assessment for Dementia, DMN default mode network, FLSA functional living skills, fMRI functional magnetic resonance imaging, HADS Hospital Anxiety and Depression Scale, HC healthy controls, L left, MCI mild cognitive impairment, MST multidimensional stimulation group therapy, NPI Neuropsychiatric Inventory Scale, NRCT nonrandomized controlled trial, PCC posterior cingulate cortex, PRT progressive resistance training, R right, RAVLT Rey auditory verbal learning test, RBANS Repeatable Battery for the Assessment of Neuropsychological Status, RCPM Raven’s Colored Progressive Matrices, RCT randomized controlled trial, RS fMRI resting state fMRI, SF-36 Short Form 36 healthy survey questionnaire