In a random-assignment, active-placebo experiment with MCI participants, cognitive training positively affected memory ability and memory-related left hippocampal function. The small number of participants in the study warrants a conservative interpretation of the findings. In regards to MTL activation, the benefit for the experimental group appeared to reflect less of the continuing decline that was expected in MCI and was evident in the MCI control group. The hippocampal changes in function were, however, consistent at a single-patient level: There was virtually no overlap in pre-post activation changes between the experimental group (with 5/6 participants showing increased activation) and the control group (with all 6 participants showing decreased activation and with all decreases larger than the single decrease in the experimental group). Thus, these findings suggest that despite presumed injury to the hippocampus in MCI that typically leads to AD, the hippocampus in MCI retains sufficient neuroplasticity to benefit from cognitive remediation
The behavioral and imaging findings are consistent with and extend previous work in older adults and participants at risk for dementia showing that mental activity is associated with brain plasticity. MTL chemistry was modified by prolonged cognitive training in a study of healthy older adults that demonstrated changes in hippocampus using MR spectroscopy [36
]. A longitudinal study found that self-reported histories of higher life-span cognitive activity were associated with a reduced rate of hippocampal volume atrophy [37
]. A small cohort of older adults (8 experimental, 9 control) with memory difficulty performed a variety of healthy lifestyle changes over the course of 2 weeks, including performing “brain teasers” and verbal mnemonic memory training [38
]. Improved verbal fluency was associated with decreased dorsolateral pre-frontal metabolism, but there was no improvement in verbal memory.
Cognitive training in the present study appeared to enhance hippocampal function despite the fact that the training focused on auditory-verbal perception rather than memory per se. The finding that increased hippocampal activation was associated with better memory performance on neuropsychological testing is consistent with correlational evidence that increased hippocampal fMRI activation in MCI participants is compensatory [39
]. Although it is expected that a gain, or reduced loss of, memory function in MCI would be associated with MTL plasticity, it is unknown as to why this training program was associated with MTL functional plasticity and not functional plasticity in auditory neocortex. Both frontal and hippocampal regions, as opposed to inferior parietal, superior temporal, and anterior cingulate regions, have exhibited upregulation in choline acetyletransferase activity in MCI relative to healthy older adults, and thus both regions may be particularly amenable to intervention [40
]. Also, although MTL functional plasticity was observed, that plasticity could reflect a functional benefit of primary, structural plasticity in other brain regions; however, in this study only MTL plasticity was robust enough to detect with fMRI.
A question of interest is what psychological and neural mechanisms translate training that focuses on auditory perception to gains in auditory memory and hippocampal function. One possibility is suggested by animal studies of neuroplasticity showing that degraded brain processing of perceptual inputs can degrade the quality of mental representations, and that perceptual training can improve the accuracy of higher order mental representations [18
]. Improved auditory representations of the words heard in the scanner may have enhanced experience-dependent plasticity. Several studies of aging have shown surprisingly strong correlations between basic sensory and memory declines (e.g. [42
]). These could reflect a shared mechanism that is related to performance on both sensory and memory tests, such as attention. Alternatively, it may be that improved perceptual processing enhances memory performance in that modality. Some studies have found, for example, that cataract surgery improving vision also improves broader cognition [43
]. We did not observe training-related alterations of activation in auditory temporal-lobe regions that could mediate perceptual training, but this may reflect the limited sample size.
There were several limitations to the current study beyond the small sample. The study was conducted prior to current MCI subtyping so it is uncertain how many participants would now be classified as amnestic-MCI. The baseline test scores suggest that the majority of the participants had significant memory dysfunction, with low standardized scores on delayed tests of memory, but average scores on visual construction, language, and attention indices (). Overall, this would be consistent with an amnestic-MCI subtype. The present study was not designed to examine the duration of benefits from cognitive training. In healthy adults, gains achieved via cognitive training were sustained over a 3-month no-contact period [1
]. In the present study, imaging occurred days to weeks after training was completed, so benefits do not appear to end immediately after training. It seems likely, however, that benefits from a cognitive training program in the face of a degenerative brain disease would not last long without continued application (as would be the case with physical exercise or medications). We attempted to match exact time spent training between the groups, but the control group self-reported their training times (in contrast automatic data downloading for the experimental group) so that training times of the control group may be less accurate. Future studies should automatically track training times in all conditions.
Because of the relatively small group of participants, subtle individual differences may have an impact on our results and we address these differences here. One participant in the study had chronic, well controlled, temporal lobe epilepsy, but this participant’s memory performance and activation pattern were typical for the treatment group and did not alter the overall outcomes. Also, the control group was slightly but significantly better educated than the experimental group. It is not possible to know the impact of this difference in education on the failure of the control group to benefit from training because so few studies of cognitive training in MCI have been conducted. A previous meta-analysis of 19 studies (30 training groups) comparing healthy older adults above and below 14 years of education (a median split) failed to find an effect of education on cognitive training outcome [44
]. Education has also been found to be unrelated to disease progression in dementia, but is related to relatively higher cognitive functioning [45
]. Thus, the available evidence suggests that the small but significant difference in education between the two groups is unlikely to account for the findings.
With the caveats noted above, however, the present findings report that cognitive training in a random-assignment, double-blinded, active-placebo design was associated with less loss of memory ability and growth of hippocampal activation in MCI. These findings ought to motivate larger studies to more definitively determine whether such cognitive training can slow memory loss and functional hippocampal degeneration and extend a higher quality of life in MCI.