Neural Correlates Of Episodic Memory Research Articles

Neural correlates of episodic memory in adults with Down syndrome and Alzheimer’s disease

BackgroundAdults with Down syndrome are at an ultra-high risk of developing early-onset Alzheimer’s disease. Episodic memory deficits are one of the earliest signs of the disease, but their association with regional brain atrophy in the population with Down syndrome has not been explored. We aimed to investigate the neuroanatomical correlates of episodic memory in adults with Down syndrome and symptomatic Alzheimer’s disease.MethodsSingle-center, cross-sectional study. A total of 139 adults with Down syndrome (85 asymptomatic and 54 with symptomatic Alzheimer’s disease) were included in the study (mean age 43.6 ± 10.9 years, 46% female). Episodic memory was assessed using the modified Cued Recall Test. Immediate (trial 1 free immediate recall, trial 3 free immediate recall, total free immediate recall score, and total immediate score) and delayed scores (free delayed recall score and total delayed score) were examined. Cortical thickness from magnetic resonance imaging was determined with surface-based morphometry using the FreeSurfer 6.0 software package. The clusters of reduced cortical thickness were compared between symptomatic and asymptomatic participants to create a cortical atrophy map. Then, the correlation between cortical thickness and the modified Cued Recall Test subscores were separately assessed in symptomatic and asymptomatic subjects, controlling for age, sex, and severity of intellectual disability.ResultsCompared with asymptomatic participants, those with symptomatic Alzheimer’s disease showed a pattern of cortical atrophy in posterior parieto-temporo-occipital cortices. In symptomatic subjects, trial 1 immediate free recall significantly correlated with cortical atrophy in lateral prefrontal regions. Trial 3 free immediate recall and total free immediate recall were associated with the most widespread cortical atrophy. Total immediate score was related to posterior cortical atrophy, including lateral parietal and temporal cortex, posterior cingulate cortex, precuneus, and medial temporal lobe areas. Delayed memory scores were associated with cortical atrophy in temporoparietal and medial temporal lobe regions. No significant relationships were observed between episodic memory measures and cortical atrophy in asymptomatic subjects.ConclusionsDifferent episodic memory measures were associated with cortical atrophy in specific brain regions in adults with Down syndrome and Alzheimer’s disease. These results overlap with those described in sporadic Alzheimer’s disease and further support the similarities between Down syndrome-associated Alzheimer’s disease and that in the general population.

Altered neural correlates of episodic memory for food and non-food cues in females with overweight/obesity

Episodic memory formation is fundamental to cognition and plays a key role in eating behaviors, indirectly promoting the maintenance and acceleration of weight gain. Impaired episodic memory function is a hallmark of people with overweight/obesity, nevertheless, little research has been conducted to explore the effects of overweight/obesity on neural networks associated with episodic memory. The current study aimed to unravel the behavioral responses and neurocognitive mechanisms underlying the episodic memory for food and non-food cues in females with overweight/obesity. To explore this issue, a group of females with overweight/obesity (n = 26) and a group of age-matched females with healthy weight (n = 28) participated in a functional magnetic resonance imaging (fMRI) event-related episodic memory paradigm, during which pictures of palatable food and pictures of neutral daily necessities were presented. Whole-brain analyses revealed differential engagement in several neural regions between the groups during an episodic memory task. Specifically, compared to the healthy weight controls, females with overweight/obesity exhibited reduced brain activity in the temporal, parietal, and frontal regions during episodic memory encoding and successful retrieval of both food and non-food cues. Additionally, activation patterns in the left hippocampus and right olfactory cortex of females with and without overweight/obesity suggested that item memory changed according to the type of stimuli presented during item memory. Specifically, females with overweight/obesity showed greater engagement of the left hippocampus and right olfactory cortex when processing food cues, but less activation of the left hippocampus and right olfactory cortex when presented with non-food cues. Consistent with the obesity and suboptimal food-related decision theoretical model, these findings provide evidence of dissociation of the neural underpinnings of episodic memory in females with overweight/obesity and underline important effects of overweight/obesity on brain functions related to episodic memory.

Imminent cognitive decline in normal elderly individuals is associated with hippocampal hyperconnectivity in the variant neural correlates of episodic memory.

The secondary prevention trials of Alzheimer's disease (AD) require an enrichment strategy to recruit individuals with imminent cognitive decline at the preclinical stage. Previously, we demonstrated a variant neural correlates of episodic memory (EM) function in apolipoprotein E (APOE) ε4 carriers. Herein, we investigated whether this variation was associated with longitudinal EM performance. This 3-year longitudinal study included 88 normal elderly subjects with EM assessment and resting-state functional MRI data at baseline; 48 subjects (27 ε3 homozygotes and 21 ε4 carriers) underwent follow-up EM assessment. In the identified EM neural correlates, multivariable regression models examined the association between hippocampal functional connectivity (HFC) and longitudinal EM change. Independent validation was performed using the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. At baseline, the EM neural correlates were characterized in the Papez circuit regions in the ε3 homozygotes, but in the sensorimotor cortex and cuneus in the ε4 carriers. Longitudinally, the ε4 carriers exhibited a negative association of the baseline HFC strength in the EM neural correlates with annual rate of EM change (R2 = 0.25, p = 0.05). This association also showed a trend in the ADNI dataset (R2 = 0.42, p = 0.06). These results indicate that hippocampal hyperconnectivity in the variant EM neural correlates is associated with imminent EM decline in ε4 carriers, which may serve as a promising enrichment strategy for secondary prevention trials of AD.

Brain Functional Correlates of Episodic Memory Using an Ecological Free Recall Task.

Episodic Memory (EM) allows us to revive a past event through mental time-travel. The neural correlates of memories recollection have been identified in hippocampal regions and multiple neocortical areas, but few neuroimaging studies have used an ecological task such as a free recall of a structured story. Using an ecological fMRI-free recall (FR) task, we aimed to investigate the relevant recruitment of the brain networks associated with the story recollection process and its performance. Fourteen healthy participants listened to a brief story and were tested for Immediate-Recall (IR), a task that is widely used in a neuropsychological evaluation. Then, the subjects underwent an fMRI session, where they had to perform a free recall (FR) of the story subvocally. Finally, the participants were tested for Delayed-Recall (DR). IR and DR scores were significantly (r = 0.942; p < 0.001) correlated. FR enhanced the activity of the Language, the Left Executive Control, the Default Mode and the Precuneus brain networks, with the strongest BOLD signal localized in the left Angular Gyrus (AG) (p < 0.05; FWE-corrected). Furthermore, the story recall performance covaried with specific network activation patterns and the recruitment of the left anterior/posterior AG correlated, respectively, with higher/lower performance scores (p > 0.05). FR seems to be a promising task to investigate ecologically the neural correlates of EM. Moreover, the recruitment of the anterior AG might be a marker for an optimal functioning of the recall process. Preliminary outcomes lay the foundation for the investigation of the brain networks in the healthy and pathological elderly population during FR.

Hippocampal correlates of episodic memory in Parkinson's disease: A systematic review of magnetic resonance imaging studies.

The present review asks whether magnetic resonance imaging (MRI) studies are able to define neural correlates of episodic memory within the hippocampus in Parkinson's disease (PD). Systematic searches were performed in PubMed, Web of Science, Medline, CINAHL, and EMBASE using search terms related to structural and functional MRI (fMRI), the hippocampus, episodic memory, and PD. Risk of bias was assessed for each study using the Newtown-Ottawa Scale. Thirty-nine studies met inclusion criteria; eight fMRI, seven diffusion MRI (dMRI), and 24 structural MRI (14 exploring whole hippocampus and 10 exploring hippocampal subfields). Critical analysis of the literature revealed mixed evidence from functional and dMRI, but stronger evidence from sMRI of the hippocampus as a biomarker for episodic memory impairment in PD. Hippocampal subfield studies most often implicated CA1, CA3/4, and subiculum volume in episodic memory and cognitive decline in PD. Despite differences in imaging methodology, study design, and sample characteristics, MRI studies have helped elucidate an important neural correlate of episodic memory impairment in PD with both clinical and theoretical implications. Natural progression of this work encourages future research on hippocampal subfield function as a potential biomarker of, or therapeutic target for, episodic memory dysfunction in PD.

Neural correlates of episodic memory modulated by temporally delayed rewards.

When a stimulus is associated with an external reward, its chance of being consolidated into long-term memory is boosted via dopaminergic facilitation of long-term potentiation in the hippocampus. Given that higher temporal distance (TD) has been found to discount the subjective value of a reward, we hypothesized that memory performance associated with a more immediate reward will result in better memory performance. We tested this hypothesis by measuring both behavioral memory performance and brain activation using functional magnetic resonance imaging (fMRI) during memory encoding and retrieval tasks. Contrary to our hypothesis, both behavioral and fMRI results suggest that the TD of rewards might enhance the chance of the associated stimulus being remembered. The fMRI data demonstrate that the lateral prefrontal cortex, which shows encoding-related activation proportional to the TD, is reactivated when searching for regions that show activation proportional to the TD during retrieval. This is not surprising given that this region is not only activated to discriminate between future vs. immediate rewards, it is also a part of the retrieval-success network. These results provide support for the conclusion that the encoding-retrieval overlap provoked as the rewards are more delayed may lead to better memory performance of the items associated with the rewards.

373 - Microanalysis of pointing gestures during psychotherapy with patients with social phobia

Some people remember events more completely and accurately than other people, but the origins of individual differences in episodic memory are poorly understood. One way to advance understanding is by identifying characteristics of individuals that reliably covary with memory performance. Recent research suggests motor behavior is related to memory performance, with individuals who consistently use a single preferred hand for unimanual actions performing worse than individuals who make greater use of both hands. This research has relied on self-reports of behavior. It is unknown whether objective measures of motor behavior also predict memory performance. Here, we tested the predictive power of bimanual coordination, an important form of manual dexterity. Bimanual coordination, as measured objectively on the Purdue Pegboard Test, was positively related to correct recall on the California Verbal Learning Test-II and negatively related to false recall. Furthermore, MRI data revealed that cortical surface area in right lateral prefrontal regions was positively related to correct recall. In one of these regions, cortical thickness was negatively related to bimanual coordination. These results suggest that individual differences in episodic memory may partially reflect morphological variation in right lateral prefrontal cortex and suggest a relationship between neural correlates of episodic memory and motor behavior.

Combining Behavior and EEG to Study the Effects of Mindfulness Meditation on Episodic Memory.

Although there has been recent interest in how mindfulness meditation can affect episodic memory as well as brain structure and function, no study has examined the behavioral and neural effects of mindfulness meditation on episodic memory. Here we present a protocol that combines mindfulness meditation training, an episodic memory task, and EEG to examine how mindfulness meditation changes behavioral performance and the neural correlates of episodic memory. Subjects in a mindfulness meditation experimental group were compared to a waitlist control group. Subjects in the mindfulness meditation experimental group spent four weeks training and practicing mindfulness meditation. Mindfulness was measured before and after training using the Five Facet Mindfulness Questionnaire (FFMQ). Episodic memory was measured before and after training using a source recognition task. During the retrieval phase of the source recognition task, EEG was recorded. The results showed that mindfulness, source recognition behavioral performance, and EEG theta power in right frontal and left parietal channels increased following mindfulness meditation training. In addition, increases in mindfulness correlated with increases in theta power in right frontal channels. Therefore, results obtained from combining mindfulness meditation training, an episodic memory task, and EEG reveal the behavioral and neural effects of mindfulness meditation on episodic memory.

Altered neural correlates of episodic memory in adolescents with severe obesity

Negative effects of obesity on memory and associated medial temporal circuitry have been noted in animal models, but the status in humans, particularly children, is not well established. Our study is the first to examine neural correlates of successful memory encoding of visual scenes and their associated context in adolescents with severe obesity (age 14–18 years, 43% male). Despite similar subsequent memory as adolescents without obesity (BMI for age and sex <95th percentile), those with severe obesity (BMI for age and sex 120% above the 95th percentile) showed reduced hippocampal, parahippocampal, frontal, and parietal engagement during encoding of remembered visual scenes and greater lateral temporal engagement during encoding of their associated context. Standardized testing revealed a trend level group difference in memory performance, with a larger magnitude of obesity-related difference in recollection-related memory that was mediated by individual differences in lateral temporal activation during contextual encoding. The observed widespread functional alterations are concerning in light of the importance of mnemonic processing for academic achievement and feeding behavior and underscore the need for prevention and intervention initiatives for pediatric obesity.

Detecting the neural correlates of episodic memory with mobile EEG: Recollecting objects in the real world

Episodic memory supports recognition of the details of complex real world experiences, providing a continuous record of events embedded within spatial and temporal context. Despite the inherently dynamic nature of real events, the bulk of neuroscientific research to date examines recognition in absence of the detailed contextual information that is known to be a defining characteristic. Given the importance of environmental context for episodic memory, examining ERP correlates of memory in more naturalistic settings is vital for progress in understanding how retrieval operates in daily life. The current study capitalized on recent advances in mobile EEG technology to address this issue and is the first to investigate ERP correlates of episodic retrieval in real world contexts. Participants were guided around a pre-defined route inside a building on campus, while performing a recognition memory task, which paired images of objects with actual physical locations in the building to provide context. Importantly, the findings clearly demonstrate that it is possible to observe reliable neural correlates of memory in real world contexts. Replicating two well established ERP correlates of episodic retrieval reported in prior laboratory based studies, we detected FN400 old/new effects traditionally associated with familiarity between 300 and 500 ms, and a late posterior negativity (LPN) often linked to reconstructive processing or evaluation of retrieval outcomes between 500 and 800 ms. Moreover, the FN400 effect was found to be sensitive to retrieval of context, with more sustained effects for objects encountered in a different context at study and test. Overall, the current work highlights the power of mobile EEG technology for examining complex cognitive functions in more naturalistic real world settings.

Distinct neural correlates of episodic memory among apolipoprotein E alleles in cognitively normal elderly.

The apolipoprotein E (APOE) ε4 and ε2 alleles are acknowledged genetic factors modulating Alzheimer's disease (AD) risk and episodic memory (EM) deterioration in an opposite manner. Mounting neuroimaging studies describe EM-related brain activity differences among APOE alleles but remain limited in elucidating the underlying mechanism. Here, we hypothesized that the APOE ε2, ε3, and ε4 alleles have distinct EM neural substrates, as a manifestation of degeneracy, underlying their modulations on EM-related brain activity and AD susceptibility. To test the hypothesis, we identified neural correlates of EM function by correlating intrinsic hippocampal functional connectivity networks with neuropsychological EM performances in a voxelwise manner, with 129 cognitively normal elderly subjects (36 ε2 carriers, 44 ε3 homozygotes, and 49 ε4 carriers). We demonstrated significantly different EM neural correlates among the three APOE allele groups. Specifically, in the ε3 homozygotes, positive EM neural correlates were characterized in the Papez circuit regions; in the ε4 carriers, positive EM neural correlates involved the lateral temporal cortex, premotor cortex/sensorimotor cortex/superior parietal lobule, and cuneus; and in the ε2 carriers, negative EM neural correlates appeared in the bilateral frontopolar, posteromedial, and sensorimotor cortex. Further, in the ε4 carriers, the interaction between age and EM function occurred in the temporoparietal junction and prefrontal cortex. Our findings suggest that the underlying mechanism of APOE polymorphism modulations on EM function and AD susceptibility is genetically related to the neural degeneracy of EM function across APOE alleles.

Bimanual coordination positively predicts episodic memory: A combined behavioral and MRI investigation

Some people remember events more completely and accurately than other people, but the origins of individual differences in episodic memory are poorly understood. One way to advance understanding is by identifying characteristics of individuals that reliably covary with memory performance. Recent research suggests motor behavior is related to memory performance, with individuals who consistently use a single preferred hand for unimanual actions performing worse than individuals who make greater use of both hands. This research has relied on self-reports of behavior. It is unknown whether objective measures of motor behavior also predict memory performance. Here, we tested the predictive power of bimanual coordination, an important form of manual dexterity. Bimanual coordination, as measured objectively on the Purdue Pegboard Test, was positively related to correct recall on the California Verbal Learning Test-II and negatively related to false recall. Furthermore, MRI data revealed that cortical surface area in right lateral prefrontal regions was positively related to correct recall. In one of these regions, cortical thickness was negatively related to bimanual coordination. These results suggest that individual differences in episodic memory may partially reflect morphological variation in right lateral prefrontal cortex and suggest a relationship between neural correlates of episodic memory and motor behavior.

Search and recovery of autobiographical and laboratory memories: Shared and distinct neural components

Functional neuroimaging evidence suggests that there are differences in the neural correlates of episodic memory for laboratory stimuli (laboratory memory) and for events from one’s own life (autobiographical memory). However, this evidence is scarce and often confounded with differences in memory testing procedures. Here, we directly compared the neural mechanisms underlying the search and recovery of autobiographical and laboratory memories while minimizing testing differences. Before scanning, participants completed a laboratory memory encoding task in which they studied four-word “chains” spread across three word pairs. During scanning, participants completed a laboratory memory retrieval task, in which they recalled the word chains, and an autobiographical memory retrieval task, in which they recalled specific personal events associated with word cues. Importantly, response times were similar in the two tasks, allowing for a direct comparison of the activation time courses. We found that during memory search (searching for the memory target), similar brain regions were activated during both the autobiographical and laboratory tasks, whereas during memory recovery (accessing the memory traces; i.e., ecphory), clear differences emerged: regions of the default mode network (DMN) were activated greater during autobiographical than laboratory memory, whereas the bilateral superior parietal lobules were activated greater during laboratory than autobiographical memory. Also, multivariate functional connectivity analyses revealed that regardless of memory stage, the DMN and ventral attention network exhibited a more integrated topology in the functional network underlying autobiographical (vs. laboratory) memory retrieval, whereas the fronto-parietal task control network exhibited a more integrated topology in the functional network underlying laboratory (vs. autobiographical) memory retrieval. These findings further characterize the shared and distinct neural components underlying autobiographical and laboratory memories, and suggest that differences in autobiographical vs. laboratory memory brain activation previously reported in the literature reflect memory recovery rather than search differences.

Family history and APOE4 risk for Alzheimer's disease impact the neural correlates of episodic memory by early midlife.

Episodic memory impairment is a consistent, pronounced deficit in pre-clinical stages of late-onset Alzheimer's disease (AD). Individuals with risk factors for AD exhibit altered brain function several decades prior to the onset of AD-related symptoms. In the current event-related fMRI study of spatial context memory we tested the hypothesis that middle-aged adults (MA; 40–58 yrs) with a family history of late onset AD (MA+ FH), or a combined + FH and apolipoprotein E ε4 allele risk factors for AD (MA+ FH + APOE4), will exhibit differences in encoding and retrieval-related brain activity, compared to − FH − APOE4 MA controls. We also hypothesized that the two at-risk MA groups will exhibit distinct patterns of correlation between brain activity and memory performance, compared to controls. To test these hypotheses we conducted multivariate task, and behavior, partial least squares analysis of fMRI data obtained during successful context encoding and retrieval. Our results indicate that even though there were no significant group differences in context memory performance, there were significant differences in brain activity and brain-behavior correlations involving the hippocampus, inferior parietal cortex, cingulate, and precuneus cortex in MA with AD risk factors, compared to controls. In addition, we observed that brain activity and brain-behavior correlations in anterior-medial PFC and in ventral visual cortex differentiated the two MA risk groups from each other, and from MAcontrols. Our results indicate that functional differences in episodic memory-related regions are present by early midlife in adults with + FH and + APOE-4 risk factors for late onset AD, compared to middle-aged controls.

Amyloid-independent functional neural correlates of episodic memory in amnestic mild cognitive impairment

Although amnestic mild cognitive impairment (aMCI) could have various biological characteristics, little attention has been given to the nature of episodic memory decline in aMCI with pathophysiologies other than Alzheimer's disease (AD), i.e., aMCI with low beta-amyloid (Aβ) burden. This study aimed to identify the functional neural basis of episodic memory impairment in aMCI with Aβ burden negative (aMCI-Aβ-) and to compare these results with aMCI with Aβ burden positive (aMCI-Aβ+). Individuals with aMCI (n = 498) were selected from the Alzheimer's Disease Neuroimaging Initiative database. Based on the mean florbetapir standard uptake value ratio, participants were classified as aMCI-Aβ- or aMCI-Aβ+. Correlations between memory scores and regional cerebral glucose metabolism (rCMglc) were analyzed separately for the two subgroups using a multiple regression model. For aMCI-Aβ-, significant positive correlations between memory and rCMglc were found in the bilateral claustrum, right thalamus, left anterior cingulate cortex, left insula, and right posterior cingulate. For aMCI-Aβ+, significant positive correlations between memory and rCMglc were found in the temporoparietal areas. These correlation patterns remained unchanged when clinical severity was added as a covariate Our findings indicate that memory impairment in aMCI-Aβ- is related to multimodal integrative processing and the attentional control system, whereas memory impairment in aMCI-Aβ+ is related to the typical brain memory systems and AD signature. These results suggest that although the two subgroups are clinically in the same category as aMCI, the memory impairment process depends on completely different functional brain regions according to their Aβ burden level.

Remembering the Past

Our ability to remember past events requires efficient encoding and successful “re-collection” of event features, such as the time, place, people, thoughts, and feelings associated with a past experience. Neuroimaging studies have demonstrated that episodic memory depends on specific brain mechanisms within the prefrontal cortex, medial temporal lobe, and ventral posterior parietal cortex that interact with the cortical sites that store event features. In this article, I present an analysis of the neural correlates of episodic memory, along with a theoretical framework, Cortical Binding of Relational Activity (CoBRA), that integrates the dynamic links between efficient encoding and successful retrieval of episodic memory.

Altered neural function during episodic memory encoding and retrieval in major depression

Memory impairments are common in major depression. Neural processing during non-emotional episodic memory in depressed patients has only sparsely been investigated, since the majority of studies have focused on emotional stimuli. The aim of this study was to explore neural correlates of episodic memory in depressive patients and to assess brain regions related to subsequent memory performance. Forty-six participants (23 depressed patients) performed a non-emotional episodic memory encoding and retrieval task while brain activation was measured with functional magnetic resonance imaging. Patients with depression showed decreased activation in the right prefrontal cortex and right cingulate cortex during memory encoding, but increased activation in the right inferior frontal gyrus (IFG) during recognition memory. While a strong association between hippocampal and parahippocampal activation during memory encoding with subsequent memory performance became evident in healthy controls, this relationship was absent in patients with depression. Taken together, these findings demonstrate that memory related brain regions are affected in their appropriate functioning during memory encoding in depressed patients. Therefore, patients with depression may rely to a greater degree on other brain regions such as the IFG during episodic memory retrieval.

Neural correlates of episodic memory: Associative memory and confidence drive hippocampus activations

The present study used a study-test recognition memory task to examine the brain regions engaged in episodic and associative memory processes. Participants evaluated on a six-point rating scale how confident they were on whether or not an item was presented in a previous study phase. Neural activations for high- and low-confidence decisions were examined in old and new items at two levels of between-item-associations. Items had different amounts of associations within the stimulus set, while associations were defined by co-occurrence statistics.The medial frontal gyrus, the posterior cingulate gyrus, the superior temporal gyrus and the right hippocampus revealed U-shaped activation functions with greater activations for high-confidence OLD and NEW decisions. This was independent of the associative memory manipulation, which suggests that not episodic memory, but rather processes related to confidence account for the activation in these brain regions. In contrast, left hippocampus followed a different activation pattern that was modulated by the amount of associations. This provides evidence for the role of the left hippocampus in associative memory.

MRI correlates of episodic memory in Alzheimer's disease, mild cognitive impairment, and healthy aging

Episodic memory is a core feature of Alzheimer's disease (AD) and mild cognitive impairment (MCI). Impaired episodic memory in AD results from the dysfunction of an integrated network and involves both gray and white matter pathologies. We explored the neural correlates of episodic memory in AD, MCI and healthy aging by correlating a measure of episodic memory with hippocampal volume and fractional anisotropy (FA) and mean diffusivity (MD) of the cingulum and fornix. Episodic memory was associated with hippocampal volume and MD of the cingulum and fornix. In contrast, there were fewer significant associations between episodic memory and FA. These findings support a relationship between episodic memory and hippocampal circuitry, and suggest that MD is a more sensitive marker of decreased white matter integrity in the study of AD and MCI than FA. Furthermore, MD was significantly associated with hippocampal volume, indicating that white matter pathology is not completely independent of gray matter pathology. However, the pattern of diffusivity differences in AD and MCI implies a more complex pathology than simply Wallerian degeneration.

Effects of cortisol on the laterality of the neural correlates of episodic memory

Alterations in the laterality of cortical activity have been shown in depressive illnesses. One possible pathophysiological mechanism for this is an effect of corticosteroids. We have previously demonstrated that endogenous cortisol concentrations correlate with the asymmetry of cortical activity related to episodic memory in healthy subjects and depressed patients. To further-examine whether this is due to a causal effect of cortisol on the laterality of episodic memory, we studied the effect of exogenous administration of cortisol in healthy subjects. Twenty-three right-handed healthy male volunteers were tested in a double-blind cross-over study. Event-related potentials (ERPs) were recorded during an episodic memory task following a four-day course of 160 mg/day cortisol or placebo. Low-resolution brain electromagnetic tomography (LORETA) was used to identify brain regions involved in the neurocognitive task. Cortisol levels were measured in saliva samples. ERP and LORETA analysis following placebo demonstrated significant left parahippocampal activation associated with successful retrieval. Cortisol led to a decrease in the mean early frontal ERP voltage and an increase in the late right ERP voltage. LORETA suggested this to be due to a significant increased late activation of the right superior frontal gyrus. There was no significant effect of cortisol on episodic memory performance. This study suggests that exogenous cortisol leads to more positive-going waveforms over the right than the left hemisphere, possibly due to increased monitoring of the products of retrieval. The results support the hypothesis of causal effects of cortisol on the laterality of cortical activity occurring during an episodic memory task.