Table 2 Detailed findings of nonpharmacological fMRI studies
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 | – |