Rationale and protocol of the ENGAGE study: a double-blind randomized controlled preference trial using a comprehensive cohort design to measure the effect of a cognitive and leisure-based intervention in older adults with a memory complaint.

BACKGROUND: Leisure activities can be both enjoyable and cognitively stimulating, and participation in such activities has been associated with reduced age-related cognitive decline. Thus, integrating stimulating leisure activities in cognitive training programs may represent a powerful and innovative approach to promote cognition in older adults at risk of dementia. The ENGAGE study is a randomized controlled, double-blind preference trial with a comprehensive cohort design that will test the efficacy and long-term impact of an intervention that combines cognitive training and cognitively stimulating leisure activities. METHODS: One hundred and forty-four older adults with a memory complaint will be recruited in Montreal and Toronto. A particular effort will be made to reach persons with low cognitive reserve. Participants will be randomly assigned to one of two conditions: cognitive + leisure training (ENGAGE-MUSIC/SPANISH) or active control (ENGAGE-DISCOVERY). The ENGAGE-MUSIC/SPANISH training will include teaching of mnemonic and attentional control strategies, casual videogames selected to train attention, and classes in music or Spanish as a second language. The ENGAGE-DISCOVERY condition will comprise psychoeducation on cognition and the brain, low-stimulating casual videogames and documentary viewing with discussions. To retain the leisure aspect of the activities, participants will be allowed to exclude either music or Spanish at study entry if they strongly dislike one of these activities. Participants randomized to ENGAGE-MUSIC/SPANISH who did not exclude any activity will be assigned to music or Spanish based on a second random assignment. Training will be provided in 24 2-h sessions over 4 months. Outcomes will be measured at baseline, at 4-month follow-up, and at 24-month follow-up. The primary outcome will be cognitive performance on a composite measure of episodic memory (delayed recall scores for words and face-name associations) measured at baseline and at the 4-month follow-up. Secondary outcomes will include a composite measure of attention (speed of processing, inhibition, dual tasking, and shifting), psychological health, activities of daily living, and brain structure and function and long-term maintenance measured at the 24-month follow-up. Information on cognitive reserve proxies (education and lifestyle questionnaires), sex and genotype (apolipoprotein (Apo)E4, brain-derived neurotrophic factor (BDNF), and catechol-O-methyltransferase (COMT)) will be collected and considered as moderators of training efficacy. DISCUSSION: This study will test whether a program combining cognitive training with stimulating leisure activities can increase cognition and reduce cognitive decline in persons at risk of dementia. TRIAL REGISTRATION: NCT03271190 . Registered on 5 September 2017.

Finding of increased caudate nucleus in patients with Alzheimer's disease.

OBJECTIVES: A recently published study using an automated MRI volumetry method (NeuroQuant®) unexpectedly demonstrated larger caudate nucleus volume in patients with Alzheimer's disease dementia (AD) compared to patients with subjective and mild cognitive impairment (SCI and MCI). The aim of this study was to explore this finding. MATERIALS & METHODS: The caudate nucleus and the hippocampus volumes were measured (both expressed as ratios of intracranial volume) in a total of 257 patients with SCI and MCI according to the Winblad criteria and AD according to ICD-10 criteria. Demographic data, cognitive measures, and APOE-ɛ4 status were collected. RESULTS: Compared with non-dementia patients (SCI and MCI), AD patients were older, more of them were female, and they had a larger caudate nucleus volume and smaller hippocampus volume (P<.001). In multiple linear regression analysis, age and female sex were associated with larger caudate nucleus volume, but neither diagnosis nor memory function was. Age, gender, and memory function were associated with hippocampus volume, and age and memory function were associated with caudate nucleus/hippocampus ratio. CONCLUSIONS: A larger caudate nucleus volume in AD patients was partly explained by older age and being female. These results are further discussed in the context of (1) the caudate nucleus possibly serving as a mechanism for temporary compensation; (2) methodological properties of automated volumetry of this brain region; and (3) neuropathological alterations. Further studies are needed to fully understand the role of the caudate nucleus in AD.

Impact of video games on plasticity of the hippocampus.

The hippocampus is critical to healthy cognition, yet results in the current study show that action video game players have reduced grey matter within the hippocampus. A subsequent randomised longitudinal training experiment demonstrated that first-person shooting games reduce grey matter within the hippocampus in participants using non-spatial memory strategies. Conversely, participants who use hippocampus-dependent spatial strategies showed increased grey matter in the hippocampus after training. A control group that trained on 3D-platform games displayed growth in either the hippocampus or the functionally connected entorhinal cortex. A third study replicated the effect of action video game training on grey matter in the hippocampus. These results show that video games can be beneficial or detrimental to the hippocampal system depending on the navigation strategy that a person employs and the genre of the game.

Rat spatial memory tasks adapted for humans: characterization in subjects with intact brain and subjects with selective medial temporal lobe thermal lesions.

In the present paper we describe five tests, 3 of which were designed to be similar to tasks used with rodents. Results obtained from control subjects, patients with selective thermo-coagulation lesions to the medial temporal lobe and results from non-human primates and rodents are discussed. The tests involve memory for spatial locations acquired by moving around in a room, memory for objects subjects interacted with, or memory for objects and their locations. Two of the spatial memory tasks were designed specifically as analogs of the Morris water task and the 8-arm radial-maze tasks used with rats. The Morris water task was modeled by hiding a sensor under the carpet of a room (Invisible Sensor Task). Subjects had to learn its location by using an array of visual cues available in the room. A path integration task was developed in order to study the non-visual acquisition of a cognitive representation of the spatial location of objects. In the non-visual spatial memory task, we blindfolded subjects and led them to a room where they had to find 3 objects and remember their locations. We designed an object location task by placing 4 objects in a room that subjects observed for later recall of their locations. A recognition task, and a novelty detection task were given subsequent to the recall task. An 8-arm radial-maze was recreated by placing stands at equal distance from each other around the room, and asking subjects to visit each stand once, from a central point. A non-spatial working memory task was designed to be the non-spatial equivalent of the radial maze. Search paths recorded on the first trial of the Invisible Sensor Task, when subjects search for the target by trial and error are reported. An analysis of the search paths revealed that patients with lesions to the right or left hippocampus or parahippocampal cortex employed the same type of search strategies as normal controls did, showing similarities and differences to the search behavior recorded in rats. Interestingly, patients with lesions that included the right parahippocampal cortex were impaired relative to patients with lesions to the right hippocampus that spared the parahippocampal cortex, when recall of the sensor was tested after a 30 min delay (Bohbot et al. 1998). No differences were obtained between control subjects and patients with selective thermal lesions to the medial temporal lobe, when tested on the radial-maze, the non-spatial analogue to the radial-maze and the path integration tasks. Differences in methodological procedures, learning strategies and lesion location could account for some of the discrepant results between humans and non-human species. Patients with lesions to the right hippocampus, irrespective of whether the right parahippocampal cortex was spared or damaged, had difficulties remembering the particular configuration and identity of objects in the novelty detection of the object location task. This supports the role of the human right hippocampus for spatial memory, in this case, involving memory for the location of elements in the room; learning known to require the hippocampus in the rat.

Consolidation of memory.

Animal studies have proven useful in addressing aspects of memory formation and consolidation that cannot be readily answered in research with humans. In particular, they offer the possibility of controlling both the extent and locus of brain lesions, and the exact nature of the experiences to be remembered. Taking advantage of these possibilities, recent studies indicated that the graded retrograde amnesia often seen after lesions to the hippocampal system is not uniform across lesion site and task, nor is it an indication that all of the remembered information available in intact subjects becomes available after hippocampal system lesions made a long time after learning. Rather, these studies support the notion that information is stored in both hippocampal and extrahipocampal sites, and that retrieval from different sites involves access to different kinds of information. The strongest evidence in support of this view is the set of findings indicating that when remote memories are retrieved, in either human or animal subjects that have suffered hippocampal system damage, these memories are not qualitatively the same as remote memories retrieved in intact subjects. In sum, memory appears to be rather more dynamic than most current conceptions allow, such that retrieval events trigger new encodings, and these new encodings engage the hippocampal system once again. As a result, older, reactivated memories become more resistant to disruption, and this mechanism helps to explain why graded retrograde amnesia is sometimes seen after brain damage. The use of new neuroimaging techniques, coupled with more sensitive neuropsychological tests in lesioned subjects, should further illuminate the complex nature of memory in coming years. It is likely that animal studies will continue to prove important in these developments.

Memory deficits characterized by patterns of lesions to the hippocampus and parahippocampal cortex.

Spatial and nonspatial memory tests were given to patients with small thermal lesions administered to the medial temporal lobes in an attempt at alleviating pharmacologically resistant epilepsy. In all three spatial memory experiments presented in this paper, patients with lesions that included the right parahippocampal cortex were seriously impaired. Their impairment, together with the performance of patients with lesions to the right hippocampus (sparing the right parahippocampal cortex), provides the different patterns of deficits that lead to different interpretations of the function of the parahippocampal cortex. The distinction between the effects of functional damage in hippocampus and the effects of a lesion to the hippocampus or to regions surrounding the hippocampus, such as the parahippocampal cortex, is emphasized. We conclude that the right parahippocampal cortex participates in spatial memory beyond serving as a gateway to the hippocampus.

Impaired preference conditioning after anterior temporal lobe resection in humans.

Research with animals suggests that structures within the amygdaloid nuclear complex (ANC) are critical for acquiring associations between rewarding events and neutral stimuli, a form of conditioning often manifested in a subsequent preference for those (conditioned) stimuli. In this study, we investigated the relationship between the ANC and preference learning in humans. Three abstract monochrome patterns were presented to each subject over 180 trials in the context of a counting task requiring working memory. One pattern was paired with food reward on 90% of the trials in which it was presented and with no food reward on the other 10% of trials. The other patterns were similarly reinforced, but at ratios of 50:50% and 10:90% with reward and nonreward, respectively. Subsequently, a group of 21 normal participants preferred the pattern paired most often with reward to that paired least often with reward, and they did not explicitly relate their preferences to the conditioning procedure, but instead attributed them to the characteristics of the patterns themselves. Unlike the normal controls, a group of patients with unilateral surgical lesions that included the ANC (15 left, 18 right) did not show conditioned preferences, but performed normally on a measure of working memory. In contrast, 13 patients with unilateral damage confined to frontal cortex exhibited normal conditioned preferences but were impaired on the working memory task. This double dissociation provides clear evidence that, in humans as in other animals, reward-related learning (conditioned reward) critically depends on a circuit involving inferotemporal cortex and the ANC.

Spatial memory deficits in patients with lesions to the right hippocampus and to the right parahippocampal cortex.

Spatial memory tasks, performance of which is known to be sensitive to hippocampal lesions in the rat, or to medial temporal lesions in the human, were administered in order to investigate the effects of selective damage to medial temporal lobe structures of the human brain. The patients had undergone thermo-coagulation with a single electrode along the amygdalo-hippocampal axis in an attempt to alleviate their epilepsy. With this surgical technique, lesions to single medial temporal lobe structures can be carried out. The locations of the lesions were assessed by means of digital high-resolution magnetic resonance imaging and software allowing a 3-D reconstruction of the brain. A break in the collateral sulcus, dividing it into the anterior collateral sulcus and the posterior collateral sulcus is reported. This division may correspond to the end of the entorhinal/perirhinal cortex and the start of the parahippocampal cortex. The results confirmed the role of the right hippocampus in visuo-spatial memory tasks (object location, Rey-Osterrieth Figure with and without delay) and the left for verbal memory tasks (Rey Auditory Verbal Learning Task with delay). However, patients with lesions either to the right or to the left hippocampus were unimpaired on several memory tasks, including a spatial one, with a 30 min delay, designed to be analogous to the Morris water maze. Patients with lesions to the right parahippocampal cortex were impaired on this task with a 30 min delay, suggesting that the parahippocampal cortex itself may play an important role in spatial memory.

Electroconvulsive shock and lidocaine reveal rapid consolidation of spatial working memory in the water maze.

Head trauma leading to concussion and electroconvulsive shock (ECS) in humans causes amnesia for events that occurred shortly before the injury (retrograde amnesia). The present experiment investigated the amnesic effect of lidocaine and ECS in 25 rats trained on a working memory version of the Morris water task. Each day, the escape platform was moved to a new location; learning was evidenced by a decrease in the latency to find the platform from the first to the second trial. "Consolidation" of this newly encoded spatial engram was disrupted by bilateral inactivation of the dorsal hippocampus with 1 microliter of 4% lidocaine applied as soon as possible after the first trial. When trial 2 was given after recovery from the lidocaine (30 min after the injection), a normal decrease in latency indicated that the new engram was not disrupted. When trial 2 was given under the influence of lidocaine (5 min after injection), absence of latency decrease demonstrated both the success of the inactivation and the importance of hippocampus for the task. To examine the role of events immediately after learning, ECS (30 or 100 mA, 50 Hz, 1.2 sec) was applied 0 sec to 45 sec after a single escape to the new platform location. A 2-h delay between ECS and trial 2 allowed the effects of ECS to dissipate. ECS applied 45 sec or 30 sec after trial 1 caused no retrograde amnesia: escape latencies on trial 2 were the same as in control rats. However, ECS applied 0 sec or 15 sec after trial 1 induced clear retrograde amnesia: escape latencies on trial 2 were no shorter than on trial 1. It is concluded that the consolidation of a newly formed memory for spatial location can only be disrupted by ECS within 30 sec after learning.