[show abstract][hide abstract] ABSTRACT: A well-documented dissociation between memory encoding and retrieval concerns the role of attention in the two processes. The typical finding is that divided attention (DA) during encoding impairs future memory, but retrieval is relatively robust to attentional manipulations. However, memory research in the past 20 years had demonstrated that retrieval is a memory-changing process, in which the strength and availability of information are modified by various characteristics of the retrieval process. Based on this logic, several studies examined the effects of DA during retrieval (Test 1) on a future memory test (Test 2). These studies yielded inconsistent results. The present study examined the role of memory consolidation in accounting for the after-effect of DA during retrieval. Initial learning required a classification of visual stimuli, and hence involved incidental learning. Test 1 was administered 24 hours after initial learning, and therefore
required retrieval of consolidated information. Test 2 was administered either immediately following Test 1 or after a 24-hour delay. Our results show that the effect of DA on Test 2 depended on this delay. DA during Test 1 did not affect performance on Test 2 when it was administered immediately, but improved performance when Test 2 was given 24-hours later. The results are consistent with other findings showing long-term benefits of retrieval difficulty. Implications for theories of reconsolidation in human episodic memory are discussed.
PLoS ONE 03/2014; 9(3):e91309. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Chemotherapy, used for the treatment of cancer, often produces cognitive impairment that has been related to suppression of neurogenesis. Physical exercise, which promotes neurogenesis, is known to improve cognitive function in neurologically challenged animals and humans. It is unknown whether exercise similarly protects against chemotherapy-induced cognitive impairment and whether recovery of neurogenesis is a critical factor.
The present study investigated the relationship between hippocampal neurogenesis and cognitive performance in chemotherapy-treated rats that engaged in different amounts of physical activity.
Groups of rats, housed individually in standard cages or in specially designed cages that allowed unlimited access to a running wheel, received three injections of the chemotherapeutic drugs methotrexate and 5-flourouracil, or equal volumes of saline. They were then administered the following cognitive tests in a water maze: (1) spatial memory (SM), (2) cued memory, (3) non-matching to sample (NMTS) rule learning; (4) delayed NMTS (DNMTS). Hippocampal neurogenesis was quantified by counting doublecortin-expressing cells in the dentate gyrus.
Chemotherapy administered to rats in standard cages resulted in a significant reduction in hippocampal neurogenesis and impaired performance on the SM, NMTS, and DNMTS tasks. In rats receiving chemotherapy and housed in exercise cages, neurogenesis was not suppressed and cognitive performance was similar to controls.
Physical exercise can reduce cognitive deficits that result from chemotherapy and this effect is mediated, at least in part, by preventing suppression of drug-induced hippocampal neurogenesis. The results suggest benefits of exercise in preventing or treating cognitive impairment associated with chemotherapy.
[show abstract][hide abstract] ABSTRACT: Recent developments reveal that memories relying on the hippocampus are relatively resistant to interference, but sensitive to decay. The hippocampus is vital to recollection, a form of memory involving reinstatement of a studied item within its spatial-temporal context. An additional form of memory known as familiarity does not involve contextual reinstatement, but a feeling of acquaintance with the studied items. Familiarity depends more on extrahippocampal structures that do not have the properties promoting resistance to interference. These notions led to the novel hypothesis that the causes of forgetting depend on the memories' nature: memories depending on recollection are more vulnerable to decay than interference, whereas for memories depending on familiarity, the reverse is true. This review provides comprehensive evidence for this hypothesis.
Trends in Cognitive Sciences 11/2013; · 16.01 Impact Factor
[show abstract][hide abstract] ABSTRACT: This review evaluates three current theories - Standard Consolidation (Squire & Wixted, 2011), Overshadowing (Sutherland, Sparks, & Lehmann, 2010), and Multiple Trace- Transformation (Winocur, Moscovitch, & Bontempi, 2010a) - in terms of their ability to account for the role of the hippocampus in recent and remote memory in animals. Evidence, based on consistent findings from tests of spatial memory and memory for acquired food preferences, favours the transformation account, but this conclusion is undermined by inconsistent results from studies that measured contextual fear memory, probably the most commonly used test of hippocampal involvement in anterograde and retrograde memory. Resolution of this issue may depend on exercising greater control over critical factors (e.g., contextual environment, amount of pre-exposure to the conditioning chamber, the number and distribution of foot-shocks) that can affect the representation of the memory shortly after learning and over the long-term. Research strategies aimed at characterizing the neural basis of long-term consolidation/transformation, as well as other outstanding issues are discussed.
Neurobiology of Learning and Memory 10/2013; · 3.33 Impact Factor
[show abstract][hide abstract] ABSTRACT: The relationship of higher order problem solving to basic neuropsychological processes likely depends on the type of problems to be solved. Well-defined problems (e.g., completing a series of errands) may rely primarily on executive functions. Conversely, ill-defined problems (e.g., navigating socially awkward situations) may, in addition, rely on medial temporal lobe (MTL) mediated episodic memory processes. Healthy young (N = 18; M = 19; SD = 1.3) and old (N = 18; M = 73; SD = 5.0) adults completed a battery of neuropsychological tests of executive and episodic memory function, and experimental tests of problem solving. Correlation analyses and age group comparisons demonstrated differential contributions of executive and autobiographical episodic memory function to well-defined and ill-defined problem solving and evidence for an episodic simulation mechanism underlying ill-defined problem solving efficacy. Findings are consistent with the emerging idea that MTL-mediated episodic simulation processes support the effective solution of ill-defined problems, over and above the contribution of frontally mediated executive functions. Implications for the development of intervention strategies that target preservation of functional independence in older adults are discussed. (JINS, 2013, 19, 1-10).
Journal of the International Neuropsychological Society 09/2013; · 2.70 Impact Factor
[show abstract][hide abstract] ABSTRACT: Objective:To determine the feasibility of recruitment and retention of healthy older adults and the effectiveness of an intervention designed to manage age-related executive changes.Design:A pilot randomized controlled trial.Setting:Research centre and participants' homes.Participants:Nineteen healthy, community dwelling older adults with complaints of cognitive difficulties and everyday problems, but no evidence of mild cognitive impairment, dementia or depression on objective testing.Interventions:Seventeen hours of group and individual training. Participants in the experimental arm received education about self-management, successful aging and an occupation-based meta-cognitive strategy-training program. Participants in the control arm received education about brain health and participated in cognitively stimulating exercises.Main measures:Changes on untrained, everyday life goals were identified using the Canadian Occupational Performance Measure. Generalization of benefits was measured using the Stanford Chronic Disease Questionnaire, general self-efficacy and changes in executive function (Delis-Kaplan Executive Function System Tower Test, Word Fluency and Trail-Making Test).Results:20% (19/96) of healthy older adults approached were eligible, consented and were enrolled in the study, 90% (17/19) were retained to three-month follow-up. Participants in the experimental arm reported significantly more improvement on untrained goals (11/22 compared with 9/46, χ(2)=4.92, p<0.05), maintenance of physical activity (p<0.05) and better preparation for doctors' visits (p<0.05) relative to the control group. There were no significant between group differences on objective measures of executive function.Conclusions:These data support the feasibility of a larger trial where a sample of 72 (36 participants in each arm) would be required to confirm or refute these findings.
[show abstract][hide abstract] ABSTRACT: Functional magnetic resonance imaging (fMRI) was used to compare brain activity during the retrieval of coarse- and fine-grained spatial details and episodic details associated with a familiar environment. Long-time Toronto residents compared pairs of landmarks based on their absolute geographic locations (requiring either coarse or fine discriminations) or based on previous visits to those landmarks (requiring episodic details). An ROI analysis of the hippocampus showed that all three conditions activated the hippocampus bilaterally. Fine-grained spatial judgments recruited an additional region of the right posterior hippocampus, while episodic judgments recruited an additional region of the right anterior hippocampus, and a more extensive region along the length of the left hippocampus. To examine whole-brain patterns of activity, Partial Least Squares (PLS) analysis was used to identify sets of brain regions whose activity covaried with the three conditions. All three comparison judgments recruited the default mode network including the posterior cingulate/retrosplenial cortex, middle frontal gyrus, hippocampus, and precuneus. Fine-grained spatial judgments also recruited additional regions of the precuneus, parahippocampal cortex and the supramarginal gyrus. Episodic judgments recruited the posterior cingulate and medial frontal lobes as well as the angular gyrus. These results are discussed in terms of their implications for theories of hippocampal function and spatial and episodic memory.
[show abstract][hide abstract] ABSTRACT: Clinical studies indicate that up to 70% of patients with cancer who receive chemotherapy experience cognitive impairment. The present study used a prospective longitudinal design to assess short- and long-term effects of commonly used anticancer drugs on cognitive performance in a mouse model.
Normal mice received three weekly injections of a combination of methotrexate + 5-fluorouracil (CHEMO group) or an equal volume of saline (SAL group). Cognitive tests, measuring different aspects of learning and memory, were administered before treatment, immediately after treatment, and three months later. Structural MRI scanning was conducted at each stage of cognitive testing.
The CHEMO group exhibited deficits on cognitive tasks acquired pretreatment [spatial memory, nonmatching-to-sample (NMTS) learning, and delayed NMTS], as well as impaired new learning on two tasks (conditional associative learning, discrimination learning) introduced posttreatment. Consistent with clinical evidence, cognitive deficits were pronounced on tests that are sensitive to hippocampal and frontal lobe dysfunction, but the CHEMO group's poor performance on the discrimination learning problem suggests that impairment is more widespread than previously thought. Cognitive deficits persisted for at least three months after treatment but some recovery was noted, particularly on tests thought to be under frontal lobe control. The MRI tests did not detect brain changes that could be attributed to treatment.
Chemotherapeutic agents can have adverse effects on information acquired pretreatment as well as new learning and memory and, despite some recovery, impairment is long lasting.
Clinical Cancer Research 03/2012; 18(11):3112-21. · 7.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: The ability to acquire and retain spatial memories in order to navigate in new environments is known to decline with age, but little is known about the effect of aging on representations of environments learned long ago, in the remote past. To investigate the status of remote spatial memory in old age, we tested healthy young and older adults on a variety of mental navigation tests based on a large-scale city environment that was very familiar to participants but rarely visited by the older adults in recent years. We show that whereas performance on a route learning test of new spatial learning was significantly worse in older than younger adults, performance was comparable or better in the older adults on mental navigation tests based on a well-known environment learned long ago. An exception was in the older adults' ability to vividly re-experience the well-known environment, and recognize and represent the visual details contained within it. The results are seen as analogous to the pattern of better semantic than episodic memory that has been found to accompany healthy aging.
Frontiers in Aging Neuroscience 01/2012; 4:25. · 5.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Deep brain stimulation has been investigated as a treatment for memory disturbance but its mechanisms remain elusive. We show that anterior thalamic nucleus (ATN) stimulation administered to corticosterone-treated rats one month prior to testing improved performance on a delayed non-matching to sample task and increased hippocampal neurogenesis. In contrast, no behavioral changes were observed in animals that were tested a few days after surgery. Results of this study suggests that the behavioral effects of ATN stimulation in corticosterone-treated animals was likely dependent on long-term plastic changes, including the development of newly borne dentate gyrus cells of sufficient functional maturity.
[show abstract][hide abstract] ABSTRACT: Adjuvant cancer chemotherapy often causes cognitive impairment that can be long-lasting and adversely affect quality of life. The present study sought to determine if the cognitive enhancing drug, donepezil, can reduce cognitive impairment induced by a combination of methotrexate +5-fluorouracil, two drugs commonly used in cancer chemotherapy. Four groups of mice: (1) chemotherapy-only; (2) chemotherapy+donepezil; (3) saline-only; (4) saline+donepezil, were administered the following learning and memory tests: (1) standard spatial memory (SM); (2) non-spatial cued memory (CM); (3) non-matching-to-sample (NMTS) rule-learning; (4) delayed-NMTS (DNMTS). The chemotherapy-only group was impaired on the SM, NMTS, and DNMTS tasks. Chemotherapy-induced cognitive deficits were significantly reduced in the chemotherapy+donepezil group whose performance on some measures was very similar to that of the saline-only group. There was no evidence that donepezil improved the performance of saline-treated mice. The results confirm the adverse effects of chemotherapy on cognitive function and demonstrate that they can be ameliorated by donepezil, which is widely used to treat cognitive impairment in other clinical populations (e.g., Alzheimer's disease).
[show abstract][hide abstract] ABSTRACT: Rats, subjected to low-dose irradiation that suppressed hippocampal neurogenesis, or a sham treatment, were administered a visual discrimination task under conditions of high, or low interference. Half of the rats engaged in running activity and the other half did not. In the non-runners, there was no effect of irradiation on learning, or remembering the discrimination response under low interference, but irradiation treatment increased their susceptibility to interference, resulting in loss of memory for the previously learned discrimination. Irradiated rats that engaged in running activity exhibited increased neuronal growth and protection from memory impairment. The results, which show that hippocampal cells generated in adulthood play a role in differentiating between conflicting, context-dependent memories, provide further evidence of the importance of neurogenesis in hippocampus-sensitive memory tasks. The results are consistent with computational models of hippocampal function that specify a central role for neurogenesis in the modulation of interfering influences during learning and memory.
Behavioural brain research 06/2011; 227(2):464-9. · 3.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: With time and experience, memories undergo a process of reorganization that involves different neuronal networks, known as systems consolidation. The traditional view, as articulated in standard consolidation theory (SCT), is that (episodic and semantic) memories initially depend on the hippocampus, but eventually become consolidated in their original forms in other brain regions. In this study, we review the main principles of SCT and report evidence from the neuropsychological literature that would not be predicted by this theory. By comparison, the evidence supports an alternative account, the transformation hypothesis, whose central premise is that changes in neural representation in systems consolidation are accompanied by corresponding changes in the nature of the memory. According to this view, hippocampally dependent, episodic, or context-specific memories transform into semantic or gist-like versions that are represented in extra-hippocampal structures. To the extent that episodic memories are retained, they will continue to require the hippocampus, but the hippocampus is not needed for the retrieval of semantic memories. The transformation hypothesis emphasizes the dynamic nature of memory, as well as the underlying functional and neural interactions that must be taken into account in a comprehensive theory of memory.
Journal of the International Neuropsychological Society 06/2011; 17(5):766-80. · 2.70 Impact Factor
[show abstract][hide abstract] ABSTRACT: Functional magnetic resonance imaging (MRI) was used to investigate the hypothesis that memory for a large-scale environment is initially dependent on the hippocampus but is later supported by extra-hippocampal structures (e.g., precuneus, posterior parahippocampal cortex, and lingual gyrus) once the environment is well-learned. Participants were scanned during mental navigation tasks initially when they were newly arrived to the city of Toronto, and later after having lived and navigated within the city for 1 yr. In the first session, activation was observed in the right hippocampus, left precuneus, and postcentral gyrus. The second session revealed activation in the caudate and lateral temporal cortex, but not in the right hippocampus; additional activation was instead observed in the posterior parahippocampal cortex, lingual gyrus, and precuneus. These findings suggest that the right hippocampus is required for the acquisition of new spatial information but is not needed to represent this information when the environment is highly familiar.
[show abstract][hide abstract] ABSTRACT: Medial-temporal, parietal, and pFC regions have been implicated in recollection and familiarity, but existing evidence from neuroimaging and patient studies is limited and conflicting regarding the role of specific regions within pFC in these memory processes. We report a study of 20 patients who had undergone resection of right frontal lobe tumors and 20 matched healthy control participants. The location and extent of lesions were traced on the patients' scans. A process dissociation procedure was employed to yield estimates of the contributions of recollection and familiarity in verbal recognition performance. Group comparisons revealed deficits in recollection but not familiarity in the patient group relative to their healthy counterparts. We found a positive relationship between estimates of familiarity and lesion sizes in the right inferior pFC (BA 11, 47) which was significant upon bootstrap resampling. These results are discussed in terms of prior work linking this area to an overextended sense of familiarity.
Journal of Cognitive Neuroscience 05/2011; 23(12):3804-16. · 4.49 Impact Factor
[show abstract][hide abstract] ABSTRACT: In previous work, we showed that adult rats that were reared socially for 3 months in a complex (village) environment retained allocentric spatial memory for that environment following hippocampal lesions (Winocur et al., (2005) Nat Neurosci 8:273–275). In the present series of experiments, we showed that 3 months of postoperative rearing did not confer the same benefits (Experiment 1), although hippocampal groups, with or without rearing experience, exhibited spatial learning after extensive training (Experiments 1 and 2). Experiment 3 showed that as little as 2 weeks of preoperative rearing in the village was sufficient to retain acquired spatial memories after hippocampal lesions. Probe testing revealed that, although rats with hippocampal lesions exhibited remarkably good memory for preoperatively learned locations in the village, they were impaired when changes in task demands required flexible use of existing spatial representations. In a direct test of flexibility (Experiment 4), preoperatively reared rats were administered a blockedroutes task in the original learning environment, in which on designated trials, a barrier was placed across one of the direct paths to the goal compartment. On encountering the barrier, control rats consistently selected the next most direct route, whereas rats with hippocampal lesions, despite using spatial strategies, made more errors and took longer to find the goal. The present results confirm that allocentric spatial memories can survive hippocampal damage but they are schematic in nature and less cohesive than those associated with cognitive maps in intact brains. As well, there was evidence that, although different processes are involved in their formation, the schematic memories that were acquired preoperatively and survived hippocampal lesions are essentially the same as those laboriously formed postoperatively after extensive training.
[show abstract][hide abstract] ABSTRACT: Historically, the hippocampus has been viewed as a temporary memory structure. Consistent with the central premise of standard consolidation theory (SCT), a memory is initially hippocampus-dependent but, over time, it undergoes a consolidation process and eventually becoming represented in a distributed cortical network independent of the hippocampus. In this paper, we review evidence that is incompatible with each of the following essential features of SCT that are derived from its central premise: (1) Hippocampal damage reliably produces temporally graded retrograde amnesia, (2) all declarative explicit memories are equivalent with respect to consolidation, (3) consolidation entails a process of duplication in which a particular cortically based memory is identical to the hippocampus-dependent memory from which it derived, (4) consolidated memories are permanent and immutable. We propose an alternative hypothesis that assumes a transformation process and changes in the memory over time. Building on multiple trace theory (Nadel & Moscovitch, 1997), the transformation hypothesis contains three key elements that differentiate it from SCT: (1) An initially formed memory, which is assumed to be episodic and context-bound, remains dependent on the hippocampus for as long as it is available, (2) with time and experience, a hippocampal memory supports the development, in neocortex, of a less integrated, schematic version, which retains the gist of the original memory, but few of its contextual details, (3) there is a dynamic interplay between the two types of memory such that one or another may be dominant, depending on the circumstances at retrieval. Evidence is provided in support of the transformation hypothesis, which is advanced as a framework for unifying the seemingly disparate results of studies of anterograde and retrograde memory in the animal and human literatures.