Effects of a cognitive training on spatial learning and associated functional brain activations

Aging in humans is accompanied by a decline of performance in a wide range of cognitive functions, along with structural and functional changes in several brain regions [1]. Because life expectancy has increased dramatically in industrialized societies within the last decades, it is of particular importance to identify successful strategies for maintaining and enhancing cognitive flexibility and plasticity throughout the lifespan. Mental abilities in childhood [2] and genetic variations [3] are reliable predictors of cognitive functioning in older age. However, the lifestyle of an individual substantially modulates cognitive aging, even in older adults. Different interventions for successful aging have been suggested, for example the control of cardiovascular risk factors [4], caloric restriction [5], or a Mediterranean diet [6], as well as physical exercise [7] and cognitive interventions [8]. The present paper focuses on the effects of a combined physical and cognitive intervention on cognitive functions and their neural correlates.

Prospective epidemiological studies have repeatedly provided evidence for a positive relationship between physical activity and a reduced risk of dementia [9, 10]. Cross-sectional studies have demonstrated a positive relationship between physical activity, in particular cardiovascular fitness, and a large number of different cognitive variables [11–15]. In controlled longitudinal intervention studies, the most consistent finding has been a positive effect of cardiovascular fitness on executive functions in older adults [16–19]. These improvements were accompanied by functional changes in associated frontal brain regions, most likely indicating more efficient neuronal processing [16]. Moreover, less age-related decline of grey and white matter volume, especially in the frontal cortex, has been reported after an aerobic exercise training compared to a stretching control training [17].

Recent studies have demonstrated an impact of physical exercise on memory functions as well. Based on their interventional study, Ruscheweyh et al. [20] reported a positive association between the increase in overall physical activity and episodic memory regardless of the exercise intensity. Hötting et al. [21] found a positive correlation between the increase in cardiovascular fitness and verbal memory after a six-month exercise training, suggesting a direct relation between physical exercising success and cognitive gains. Furthermore, older adults with subjective memory impairments have been shown to benefit from physical activity [22]. Moreover, visual-spatial memory [23] and immediate verbal memory [24] in young adults was reported to increase after a few weeks of physical exercise. The latter studies, however, have some methodological weaknesses as they compared data of the physical exercise group to a passive control group [23] or used a pre-posttest design without control group [24]. Thus, these results have to be confirmed in randomized trials.

On the neural level, physical exercise has been shown to increase the hippocampal volume [25] and blood flow in the dentate gyrus [24]. Moreover, changes in the functional connectivity of medial temporal lobe structures have been reported after exercise interventions [26, 27].

Cognitive interventions, on the other hand, are specific protocols of tasks developed to improve cognitive functions or to prevent age-related declines. A positive effect of cognitive interventions has been demonstrated in various domains, including working memory (e.g. [28]), processing speed (e.g. [29]), reasoning (e.g. [30]) and executive functions (e.g. [31]). While some authors have postulated that the training effects are rather specific for the practiced domain [8], others have demonstrated considerable transfer to untrained tasks (summarized in [32]).

The effects of an extensive spatial training on spatial skills and associated brain systems have hardly been studies in humans [33–35]. In a study by Lövdén et al. [36] healthy young and healthy old men participated in a four-month virtual reality navigation training. Improved performance in the navigation task compared to a control group was found. Moreover, participants of the spatial training group showed stable hippocampal volumes during and four months after the end of the intervention. By contrast, age-related volume decrements were found for the control group. Thus, a spatial navigation training seems to enhance navigation performance and to protect the hippocampal volume in humans from age-related decline [36]. This conclusion is further supported by a recent longitudinal study in a more natural setting: trainee London taxi drivers who had successfully learned the map of the city of London within four years showed an increase in posterior hippocampal volume compared to participants who failed to acquire this spatial knowledge [37].

Functional brain imaging studies on learning-induced neural plasticity found several different patterns of change after cognitive interventions. An increase in activity after training has been linked to the recruitment of additional cortical tissue or the strengthening of responses within a brain region [38]. Other studies have reported a decrease in brain activity after training. This result has been interpreted as an improved neuronal efficiency and specialization of neural networks [39]. Moreover, shifts of activated brain regions from pre-to posttest have been observed as well. Such functional reallocations have been interpreted as a qualitative change in the cognitive processes recruited for a specific task [39]. To our knowledge, there are no functional MRI studies on the effects of an extensive spatial training on neuronal processing in humans so far. Some spatial navigation studies showed changes with practice within one session. For example, Iaria, Petrides, Dagher, Pike, and Bohobot [34] provided fMRI evidence for a switch in strategy during a spatial navigation learning session. Studies correlating individual differences in performance with fMRI activations during navigation tasks found both positive [40, 41] and negative correlations [41] for neural networks associated with spatial navigation. Thus, it seems to depend on the task and instructions used whether improvements in spatial navigation resulted in an increase, a decrease or a reorganization of brain functions. Animal research has suggested that the hippocampus and spatial learning abilities are especially sensitive to both physical exercise and cognitive training. In rodents, wheel running and hippocampus-dependent learning tasks have been shown to enhance neurogenesis [42, 43], to increase the release of neurotrophins [44, 45] and to improve spatial memory [46, 47]. The neuronal mechanisms mediating gains from physical exercise and cognitive stimulation seem to differ: while physical exercise increased especially the proliferation of precursor cells in the subgranular zone of the dentate gyrus, cognitive stimulation promoted the survival of new neurons [48].

Based on these results in rodents, Kempermann [49] proposed the idea that a combination of physical activity and cognitive challenge might be most effective in inducing beneficial and permanent effects on the brain’s structure and function. Results in mice have supported this hypothesis: animals that had access to a running wheel before they were exposed to an enriched environment showed a more pronounced increase in neurogenesis compared to animals exposed to only running or only to an enriched environment [50]. Hence, it could be hypothesized that physical activity might boost the effects of a cognitive intervention in humans, too. To our knowledge only one study has tried to test this hypothesis in humans: Fabre et al. [51] showed that a combination of an aerobic endurance training and a cognitive training targeting various cognitive functions (e.g. memory, attention, spatial skills) was more effective in improving cognitive variables in older adults than any of the trainings alone or no training at all. Middle-aged adults have hardly been included in such studies. Thus, it is unknown whether cognitive, physical or a combined cognitive and physical intervention is beneficial in younger age groups as well. Interventions targeting middle-aged individuals, however, might be especially important to prevent age-related cognitive decline, since midlife physical activity has been found to determine brain structure and function at later ages [52].

In the present controlled interventional study, sedentary 40 to 55 year old adults were randomly assigned to either a six-month long aerobic endurance training (‘cycling’) or a non-endurance control training (‘stretching’). In addition, participants took part in a cognitive intervention during the last month of the physical intervention. They were randomly assigned to either a spatial training (‘spatial training’) or a non-spatial control training (‘perceptual training’) group. Spatial learning and functional brain activation (fMRI) were measured during a spatial maze task (see Wolbers et al. [53]) before and after the interventions. Recently, we reported that cardiovascular fitness modulated brain activation during successful spatial learning [54]. In the present report we focus on the effects of the physical and cognitive interventions on spatial learning and associated brain activity. Based on previous results in animals [50] and humans [51] it was hypothesized that both, a physical training and a cognitive training, has beneficial effects on spatial learning. We predicted additive effects, both at the behavioral level and in neural structures associated with spatial learning, including the hippocampus and parahippocampal gyrus (e.g. [55]), the inferior and superior parietal cortex and the retrosplenial cortex (e.g. [56, 57]), the caudate nucleus (e.g. [58]), and the cuneus and medial frontal gyrus (e.g. [59]). Due to inconsistent reports in the literature, we did not make explicit predictions about the direction of training induced changes in the BOLD signal.

The present controlled interventional study examined the effects of a cognitive intervention (spatial training vs. perceptual control training) and a physical intervention (endurance training vs. non-endurance training) on spatial learning and associated functional brain activations in healthy middle-aged adults. Spatial learning of a virtual maze tended to improve after a spatial training involving viewpoint shifting and path integration. Only the spatial training group showed significant changes in brain activation in the right middle and superior temporal gyrus and medial temporal lobe from pretest to posttest. At posttest, participants of the spatial training group showed lower activation levels than participants in the perceptual training group in a network of brain regions associated with spatial learning such as the hippocampus and parahippocampal gyrus. In contrast, the type of physical intervention did neither increase spatial training gains nor performance and associated brain activity in the virtual maze task. Thus, we did not find support for our hypothesis that cognitive and physical training would result in additive or even supra-additive gains for cognitive functioning.

Based on the findings in animals that both physical exercise and spatial training increased neuronal plasticity particularly in the hippocampus and performance in spatial memory tasks (e.g. [43]), performance in a spatial learning and navigation paradigm was chosen as the dependent variable in the present intervention study. This task was realized in a virtual maze task and required participants to build up a cognitive map of a virtual town. Only participants who took part in the spatial training, which involved viewpoint shifting and path integration tasks, were able to solve the virtual maze task at posttest and showed reduced brain activations at posttest compared to pretest. To successfully solve the virtual maze task, participants had to integrate the position of landmarks into a cognitive representation of the town and to continuously update their position in the environment by making use of visual motion cues. Thus, participants of the spatial learning group were able to transfer their newly acquired spatial abilities to the test task, i.e. the virtual maze task. This type of transfer has been called “near transfer” [75] and means that an ability is generalized from the training task, involving different stimuli and tasks, to a more complex test task of the same functional domain. In contrast, participants of the spatial training group did not outperform participants of the perceptual training group in tests of verbal learning and executive functions (‘far’ transfer). This result is in line with previous studies in humans (e.g. [36]) and animals [76], and suggests that spatial training induced changes limited to spatial processing systems. Furthermore, our results are in line with training studies in other cognitive domains, suggesting that a transfer from training to test is mainly observed when the training task and the test task depend on overlapping functions associated with similar brain regions [28]. It remains to be determined whether spatial skills acquired in a virtual environment would generalize to the real world as well, although there is evidence that virtually acquired spatial knowledge transfers at least to real-world settings that are similar to the learned virtual environment [77].

On the neuronal level, the spatial training group, as compared to the perceptual training group, showed significant activation changes from pre- to posttest in the superior and middle temporal gyri and the medial temporal lobe of the right hemisphere.

Lateral temporal cortex has been shown to be involved in declarative memory, both during encoding and retrieval [78]. Moreover, the middle and superior temporal gyri have been discussed as parts of a neural network which encodes spatial relations; especially the right temporal areas seem to be involved in calculating spatial coordinates [79]. Activations in these temporal lobe structures have been shown to correlate with participants’ performance during spatial navigation [40, 58]. It might be speculated that brain activations in lateral temporal regions in the present study were involved in encoding the spatial relationship between buildings in the virtual maze tasks. A reduced activity in these areas at posttest for the spatial learning group might reflect a more efficient encoding of the spatial layout compared to posttest [38, 39].

Furthermore, a comparison of the spatial and perceptual training group at posttest revealed a reduced activation in the spatial training group in a network of brain areas associated with spatial learning, including the hippocampus and parahippocampal gyrus.

Hippocampal and parahippocampal activity have been shown to correlate with navigation abilities [41], navigation strategies [80] and increasing practice [34]. Moreover, interindividual differences in navigational expertise have been linked to structural properties of the human hippocampus [81, 82], at least in young adults [83]. Previous data using a similar spatial paradigm as in the present fMRI sessions had shown decreasing hippocampal activity with increasing knowledge of the environment [53].

Thus, as seen in the present study, the reduced activity in the spatial training group (as compared to the perceptual group) might reflect a better elaborated spatial knowledge.

Participants in the present sample (middle-aged men and women), however, did not reach a performance in the virtual maze task that was as high as the performance of the participants of Wolbers and Büchel [53]. We think this is mainly due to the age difference of the participants. Moreover, Wolbers and Büchel had recruited only male adults while both men and women were recruited for the present study. Although Wolbers and Büchel [53] provided evidence for reduced hippocampal activity along with superior spatial performance, it has to be noted that there are other studies which demonstrated increased hippocampal activity in participants with more successful spatial navigation skills (e.g. [84, 85]). Moreover, age-related decline in spatial navigation performance has been associated with reduced hippocampal and parahippocampal activation [85, 86]. Thus, future studies are necessary to disentangle more precisely how age, navigation performance and strategies affect functional brain activation patterns in the medial temporal lobe.

Reduced activations in the spatial training group, as compared to the perceptual group, were seen in the frontal cortex as well. The medial frontal gyrus has been associated with spatial short-term memory [66]. Moreover, the prefrontal cortex seems to play an important role for ‘higher cognitive processes’ in general and has been linked to the difficulty of a task [87]. A reduced activity in prefrontal areas subsequent to practice is a well known correlate of learning and has been interpreted as an increase in neural efficiency [39].

Although the spatial training group tended to improve in the virtual maze task, and showed significant changes in associated brain activations from pre- to posttest, the aerobic endurance training group did not gain more than the non-endurance control group. This held true for the learning improvements across training sessions as well. The result differs from reports of previous studies in older adults. They reported enhanced cognitive performance after an aerobic endurance training as compared to a non-endurance training (e.g. [17, 19]). The sample in the present study was younger (40 to 55 years) than the samples of most previous studies (mostly older than 65 years). It has been discussed that beneficial effects of physical fitness on cognition increase with increasing age. In a meta-analysis, Colcombe and Kramer [18] provided evidence that participants between 66 and 70 years of age benefit more from exercise interventions than adults between 55 and 65 years of age. It might be speculated that beneficial effects of aerobic exercise on spatial learning are not yet observable in middle-aged adults, and may become evident only when these functions have already been subject of a larger degree of age-related decline. Although brain activations were not modulated by physical exercise on the group level, individual cardiovascular fitness and training induced fitness gains were positively correlated with brain activations during the virtual maze task for participants who took part in an additional spatial training (reported in [54]). The present results, together with our previous report, suggest that a spatial training has an immediate effect on neural networks associate with spatial learning (at least in middle-aged adults), whereas the influence of an endurance training might cause only subliminal effects on neurocognitive functioning, which are detected only in older age after age-related decline has further progressed. Indeed, prospective studies provided evidence that physical activity in midlife correlated with gray matter volume 20 years later [52] and participants that reported regular physical activity in midlife had a reduced risk of dementia at follow-up [10].

Another reason for the lack of a significant difference between the endurance and non-endurance training group might be that the stretching and coordination exercise in the present study promoted functions supporting spatial learning. Indeed Ruscheweyh et al. [20] demonstrated that physical activity has beneficial effects on memory functions independent of exercising intensity. Moreover, Voelcker-Rehage et al. [88] reported higher performance in older adults in a visual search task and in an executive task after a coordination training compared to a control group. FMRI data revealed changes in frontal and parietal areas, both after a cardiovascular training and a coordination training, suggesting that besides cardiovascular trainings, other types of exercise might have beneficial effects on cognition as well [89].

The sample size in the present study was rather small. On the behavioral level, effects of the spatial training showed only trends in the predicted direction. Moreover, null effects such as the non-significant interaction of physical and cognitive training must be interpreted with caution. The present results, together with our previous report of cardiovascular fitness modulating brain activations during a virtual spatial learning task [54], however, provide first empirical support in humans that the combination of a cognitive training with a physical intervention might promote neuronal plasticity in midlife. More studies with larger sample sizes should further address the question of additive or supraadditive effects of cognitive and physical trainings on cognitive functions in humans. Another limiting factor of the present study might be the rather overall low performance of participants in the maze task. This was unexpected given the results of previous studies with this paradigm [53, 66] and, as discussed above, is most likely due to age differences between study samples. Spatial memory has been shown to decrease as early as in midlife [90]. Nevertheless, middle-aged adults still outperformed participants older than 55 years of age [91]. Future studies should use a test task better adapted for the age group under investigation.

The present study demonstrated that a training of spatial abilities, compared to a perceptual training, modulated brain activations during spatial learning in a virtual maze task. After the cognitive intervention, brain activations were lower in the spatial training group than in the perceptual training group in a network of brain areas associated with spatial navigation, possibly demonstrating a more efficient neural processing. Moreover, the spatial training group tended to improve in the virtual maze task of spatial learning more than the perceptual training group. Hence, specific cognitive programs might be a useful tool to maintain and improve cognitive functions already in middle-aged adults.

^aAs mentioned in the section "Participants", the fMRI data reported here was part of a larger intervention study investigating the effect of a physical training on cognition in humans. When analyzing data of all participants who took part in the spatial training (N = 34, N = 18 cycling group, N = 16 stretching group), the same pattern of results emerged: participants improved in viewpoint shifting and path integration across training sessions, but there was no difference between the cycling group and the stretching group (Training day × Physical intervention all p > 0.4). Thus, the lack of a significant interaction of group and time does not seem to be due to the small sample size of the fMRI sample.

^bLearning score of the Auditory Verbal Learning Test: for the spatial training group: M = 60.0 (SD = 5.6) pretest vs. M = 65.9 (SD = 4.9) posttest; for the perceptual training group: M = 57.8 (SD = 8.7) pretest vs. M = 64.1 (SD = 7.1) posttest.

Reading time in sec for the Stroop task: for the spatial training group: M = 76.3 (SD = 13.2) pretest vs. M = 74.3 (SD = 17.6) posttest; for the perceptual training group: M = 74.8 (SD = 14.2) vs. M = 69.6 (SD = 11.7) posttest.