Measurement of Functional Brain Network Connectivity in People with Orthostatic Tremor.

Orthostatic tremor is a rare movement disorder characterized by a sensation of unsteadiness and leg tremor while standing. It has been hypothesized that the disorder is attributable to dysregulation of a central oscillatory network in the brain. This putative network includes primary motor cortex, supplementary motor area, cerebellum, thalamus, and pontine tegmentum. We studied this brain network by recording resting-state functional MRI data from individuals with orthostatic tremor. For each participant, we measured resting-state functional connectivity using a seed-based approach. Regions of interest included were components of the putative central oscillatory network and a primary motor thumb region (identified via transcranial magnetic stimulation). A non-central oscillatory network region of interest-posterior cingulate cortex-was included for comparative analysis of a well-characterized intrinsic network, the default mode network. Demographic information, medical history, and tremor characteristics were collected to test associations with functional connectivity. For normative context, data from the 1000 Functional Connectomes Project were analyzed using an identical approach. We observed that tremor and demographic variables were correlated with functional connectivity of central oscillatory network components. Furthermore, relative to healthy comparison participants, patients with orthostatic tremor exhibited qualitatively different patterns of cerebellar resting state functional connectivity. Our study enhances the current understanding of brain network differences related to orthostatic tremor and is consistent with a hypothesized selective decoupling of cerebellum. Additionally, associations observed between functional connectivity and factors including medical history and tremor features may suggest targets for treatment of orthostatic tremor.

Hippocampal Resting State Functional Connectivity Associated with Physical Activity in Periadolescent Children.

Periadolescence is a neurodevelopmental period characterized by structural and functional brain changes that are associated with cognitive maturation. The development of the functional connectivity of the hippocampus contributes to cognitive maturation, especially memory processes. Notably, hippocampal development is influenced by lifestyle factors, including physical activity. Physical activity has been associated with individual variability in hippocampal functional connectivity. However, this relationship has not been characterized in a developmental cohort. In this study, we aimed to fill this gap by investigating the relationship between physical activity and the functional connectivity of the hippocampus in a cohort of periadolescents aged 8-13 years (N = 117). The participants completed a physical activity questionnaire, reporting the number of days per week they performed 60 min of physical activity; then, they completed a resting-state functional MRI scan. We observed that greater physical activity was significantly associated with differences in hippocampal functional connectivity in frontal and temporal regions. Greater physical activity was associated with decreased connectivity between the hippocampus and the right superior frontal gyrus and increased connectivity between the hippocampus and the left superior temporal sulcus. Capturing changes in hippocampal functional connectivity during key developmental periods may elucidate how lifestyle factors including physical activity influence brain network connectivity trajectories, cognitive development, and future disease risk.

Stimulating Memory: Reviewing Interventions Using Repetitive Transcranial Magnetic Stimulation to Enhance or Restore Memory Abilities.

Human memory systems are imperfect recording devices that are affected by age and disease, but recent findings suggest that the functionality of these systems may be modifiable through interventions using non-invasive brain stimulation such as repetitive transcranial magnetic stimulation (rTMS). The translational potential of these rTMS interventions is clear: memory problems are the most common cognitive complaint associated with healthy aging, while pathological conditions such as Alzheimer's disease are often associated with severe deficits in memory. Therapies to improve memory or treat memory loss could enhance independence while reducing costs for public health systems. Despite this promise, several important factors limit the generalizability and translational potential of rTMS interventions for memory. Heterogeneity of protocol design, rTMS parameters, and outcome measures present significant challenges to interpretation and reproducibility. However, recent advances in cognitive neuroscience, including rTMS approaches and recent insights regarding functional brain networks, may offer methodological tools necessary to design new interventional studies with enhanced experimental rigor, improved reproducibility, and greater likelihood of successful translation to clinical settings. In this review, we first discuss the current state of the literature on memory modulation with rTMS, then offer a commentary on developments in cognitive neuroscience that are relevant to rTMS interventions, and finally close by offering several recommendations for the design of future investigations using rTMS to modulate human memory performance.

Resting-state functional connectivity of the human hippocampus in periadolescent children: Associations with age and memory performance.

The hippocampus is necessary for declarative (relational) memory, and the ability to form hippocampal-dependent memories develops through late adolescence. This developmental trajectory of hippocampal-dependent memory could reflect maturation of intrinsic functional brain networks, but resting-state functional connectivity (rs-FC) of the human hippocampus is not well-characterized for periadolescent children. Measuring hippocampal rs-FC in periadolescence would thus fill a gap, and testing covariance of hippocampal rs-FC with age and memory could inform theories of cognitive development. Here, we studied hippocampal rs-FC in a cross-sectional sample of healthy children (N = 96; 59 F; age 9-15 years) using a seed-based approach, and linked these data with NIH Toolbox measures, the Picture-Sequence Memory Test (PSMT) and the List Sorting Working Memory Test (LSWMT). The PSMT was expected to rely more on hippocampal-dependent memory than the LSWMT. We observed hippocampal rs-FC with an extensive brain network including temporal, parietal, and frontal regions. This pattern was consistent with prior work measuring hippocampal rs-FC in younger and older samples. We also observed novel, regionally specific variation in hippocampal rs-FC with age and hippocampal-dependent memory but not working memory. Evidence consistent with these findings was observed in a second, validation dataset of similar-age healthy children drawn from the Philadelphia Neurodevelopment Cohort. Further, a cross-dataset analysis suggested generalizable properties of hippocampal rs-FC and covariance with age and memory. Our findings connect prior work by describing hippocampal rs-FC and covariance with age and memory in typically developing periadolescent children, and our observations suggest a developmental trajectory for brain networks that support hippocampal-dependent memory.

Accuracy analysis of fMRI and MEG activations determined by intraoperative mapping.

OBJECTIVE: By looking at how the accuracy of preoperative brain mapping methods vary according to differences in the distance from the activation clusters used for the analysis, the present study aimed to elucidate how preoperative functional neuroimaging may be used in such a way that maximizes the mapping accuracy. METHODS: The eloquent function of 19 patients with a brain tumor or cavernoma was mapped prior to resection with both functional MRI (fMRI) and magnetoencephalography (MEG). The mapping results were then validated using direct cortical stimulation mapping performed immediately after craniotomy and prior to resection. The subset of patients with equivalent MEG and fMRI tasks performed for motor (n = 14) and language (n = 12) were evaluated as both individual and combined predictions. Furthermore, the distance resulting in the maximum accuracy, as evaluated by the J statistic, was determined by plotting the sensitivities and specificities against a linearly increasing distance threshold. RESULTS: fMRI showed a maximum mapping accuracy at 5 mm for both motor and language mapping. MEG showed a maximum mapping accuracy at 40 mm for motor and 15 mm for language mapping. At the standard 10-mm distance used in the literature, MEG showed a greater specificity than fMRI for both motor and language mapping but a lower sensitivity for motor mapping. Combining MEG and fMRI showed a maximum accuracy at 15 mm and 5 mm-MEG and fMRI distances, respectively-for motor mapping and at a 10-mm distance for both MEG and fMRI for language mapping. For motor mapping, combining MEG and fMRI at the optimal distances resulted in a greater accuracy than the maximum accuracy of the individual predictions. CONCLUSIONS: This study demonstrates that the accuracy of language and motor mapping for both fMRI and MEG is heavily dependent on the distance threshold used in the analysis. Furthermore, combining MEG and fMRI showed the potential for increased motor mapping accuracy compared to when using the modalities separately.Clinical trial registration no.: NCT01535430 (clinicaltrials.gov).

Eye tracking in cytotechnology education: "visualizing" students becoming experts.

INTRODUCTION: This study reports the potential of eye-tracking technology in determining screening skills of cytotechnology (CT) students while examining digital images (DI). MATERIALS AND METHODS: Twenty-five static DI of gynecologic cytology specimens were serially displayed on a computer monitor for evaluation by 16 CT students and 3 cytotechnologists at 3 locations. During evaluation, participant's eye movements were monitored with a Mirametrix S2 eye tracker (iMotions, Boston, MA) and EyeWorks software (Eyetracking, Solana Beach, CA). Students completed the protocol at: Period1 (P1)-4 months, Period2 (P2)-7 months, Period3 (P3)-11 months during their 1-year training; and the cytotechnologists only once. A general linear mixed model was used to analyze the results. RESULTS: The proportion of agreement on interpretations for cytotechnologists, students during P1, and students during P3 were 0.83, 0.62, and 0.70 respectively. The mean task duration in seconds for cytotechnologists, students during P1, and students during P3 were 21.1, 34.6, and 24.9 respectively. The mean number of fixation points for cytotechnologists, students during P1, and students during P3 were 14.5, 52.2, and 35.3, respectively. The mean number of gaze observations of cytotechnologists, students during P1, and students during P3 on region of interest (ROI) 1 were 77.93, 181.12, and 123.83, respectively; and, ROI 2 were 38.90, 142.79, and 92.46, respectively. CONCLUSIONS: This study demonstrated that students had decreased time, number of fixation points, gaze observations on ROI, and increased agreement with the reference interpretations at the end of the training program, indicating that their screening skills were progressing towards the level of practicing cytotechnologists.

Fast mappers, slow learners: Word learning without hippocampus is slow and sparse irrespective of methodology.

Rapid word learning without the hippocampus is an alluring prospect - it holds the promise of remediating a common learning deficit associated with aging (healthy or pathological) and certain neurological conditions. Despite recent reports indicating rapid, non-hippocampal word learning by amnesic adults after contrastive 'fast-mapping' exposure, several replications have failed. These failures stand in contrast to successful but slow learning by amnesic patients under other conditions, and this pattern suggests that rapid word learning in adulthood is hippocampus-dependent and relational irrespective of learning format. However, much remains to be studied, and important methodological and theoretical considerations are highlighted here.

Cross-Situational Statistical Learning of New Words Despite Bilateral Hippocampal Damage and Severe Amnesia.

Word learning requires learners to bind together arbitrarily-related phonological, visual, and conceptual information. Prior work suggests that this binding can be robustly achieved via incidental cross-situational statistical exposure to words and referents. When cross-situational statistical learning (CSSL) is tested in the laboratory, there is no information on any given trial to identify the referent of a novel word. However, by tracking which objects co-occur with each word across trials, learners may acquire mappings through statistical association. While CSSL behavior is well-characterized, its brain correlates are not. The arbitrary nature of CSSL mappings suggests hippocampal involvement, but the incremental, statistical nature of the learning raises the possibility of neocortical or procedural learning systems. Prior studies have shown that neurological patients with hippocampal pathology have word-learning impairments, but this has not been tested in a statistical learning paradigm. Here, we used a neuropsychological approach to test whether patients with bilateral hippocampal pathology (N = 3) could learn new words in a CSSL paradigm. In the task, patients and healthy comparison participants completed a CSSL word-learning task in which they acquired eight word/object mappings. During each trial of the CSSL task, participants saw two objects on a computer display, heard one novel word, and selected the most likely referent. Across trials, words were 100% likely to co-occur with their referent, but only 14.3% likely with non-referents. Two of three amnesic patients learned the associations between objects and word forms, although performance was impaired relative to healthy comparison participants. Our findings show that the hippocampus is not strictly necessary for CSSL for words, although it may facilitate such learning. This is consistent with a hybrid account of CSSL supported by implicit and explicit memory systems, and may have translational applications for remediation of (word-) learning deficits in neurological populations with hippocampal pathology.

Ventromedial Prefrontal Cortex Is Necessary for Normal Associative Inference and Memory Integration.

The ability to flexibly combine existing knowledge in response to novel circumstances is highly adaptive. However, the neural correlates of flexible associative inference are not well characterized. Laboratory tests of associative inference have measured memory for overlapping pairs of studied items (e.g., AB, BC) and for nonstudied pairs with common associates (i.e., AC). Findings from functional neuroimaging and neuropsychology suggest the ventromedial prefrontal cortex (vmPFC) may be necessary for associative inference. Here, we used a neuropsychological approach to test the necessity of vmPFC for successful memory-guided associative inference in humans using an overlapping pairs associative memory task. We predicted that individuals with focal vmPFC damage (n = 5; 3F, 2M) would show impaired inferential memory but intact non-inferential memory. Performance was compared with normal comparison participants (n = 10; 6F, 4M). Participants studied pairs of visually presented objects including overlapping pairs (AB, BC) and nonoverlapping pairs (XY). Participants later completed a three-alternative forced-choice recognition task for studied pairs (AB, BC, XY) and inference pairs (AC). As predicted, the vmPFC group had intact memory for studied pairs but significantly impaired memory for inferential pairs. These results are consistent with the perspective that the vmPFC is necessary for memory-guided associative inference, indicating that the vmPFC is critical for adaptive abilities that require application of existing knowledge to novel circumstances. Additionally, vmPFC damage was associated with unexpectedly reduced memory for AB pairs post-inference, which could potentially reflect retroactive interference. Together, these results reinforce an emerging understanding of a role for the vmPFC in brain networks supporting associative memory processes.SIGNIFICANCE STATEMENT We live in a constantly changing environment, so the ability to adapt our knowledge to support understanding of new circumstances is essential. One important adaptive ability is associative inference which allows us to extract shared features from distinct experiences and relate them. For example, if we see a woman holding a baby, and later see a man holding the same baby, then we might infer that the two adults are a couple. Despite the importance of associative inference, the brain systems necessary for this ability are not known. Here, we report that damage to human ventromedial prefrontal cortex (vmPFC) disproportionately impairs associative inference. Our findings show the necessity of the vmPFC for normal associative inference and memory integration.

Brain Network Theory Can Predict Whether Neuropsychological Outcomes Will Differ from Clinical Expectations.

OBJECTIVE: Theories of brain-network organization based on neuroimaging data have burgeoned in recent years, but the predictive power of such theories for cognition and behavior has only rarely been examined. Here, predictions from clinical neuropsychologists about the cognitive profiles of patients with focal brain lesions were used to evaluate a brain-network theory (Warren et al., 2014). METHOD: Neuropsychologists made predictions regarding the neuropsychological profiles of a neurological patient sample (N = 30) based on lesion location. The neuropsychologists then rated the congruence of their predictions with observed neuropsychological outcomes, in regard to the "severity" of neuropsychological deficits and the "focality" of neuropsychological deficits. Based on the network theory, two types of lesion locations were identified: "target" locations (putative hubs in a brain-wide network) and "control" locations (hypothesized to play limited roles in network function). RESULTS: We found that patients with lesions of target locations (N = 19) had deficits of greater than expected severity that were more widespread than expected, whereas patients with lesions of control locations (N = 11) showed milder, circumscribed deficits that were more congruent with expectations. CONCLUSIONS: The findings for the target brain locations suggest that prevailing views of brain-behavior relationships may be sharpened and refined by integrating recently proposed network-oriented perspectives.

What relates newspaper, definite, and clothing? An article describing deficits in convergent problem solving and creativity following hippocampal damage.

Creativity relies on a diverse set of cognitive processes associated with distinct neural correlates, and one important aspect of creativity, divergent thinking, has been associated with the hippocampus. However, hippocampal contributions to another important aspect of creativity, convergent problem solving, have not been investigated. We tested the necessity of hippocampus for convergent problem solving using a neuropsychological method. Participants with amnesia due to hippocampal damage (N = 5) and healthy normal comparison participants (N = 5) were tested using a task that promoted solutions based on existing knowledge (Bowden and Jung-Beeman, 2003). During each trial, participants were given a list of three words (e.g., fly, man, place) and asked to respond with a word that could be combined with each of the three words (e.g., fire). The amnesic group produced significantly fewer correct responses than the healthy comparison group. These findings indicate that the hippocampus is necessary for normal convergent problem solving and that changes in the status of the hippocampus should affect convergent problem solving in the context of creative problem-solving across short intervals. This proposed contribution of the hippocampus to convergent problem solving is consistent with an expanded perspective on hippocampal function that acknowledges its role in cognitive processes beyond declarative memory. © 2016 Wiley Periodicals, Inc.

Impaired acquisition of new words after left temporal lobectomy despite normal fast-mapping behavior.

Word learning has been proposed to rely on unique brain regions including the temporal lobes, and the left temporal lobe appears to be especially important. In order to investigate the role of the left temporal lobe in word learning under different conditions, we tested whether patients with left temporal lobectomies (N=6) could learn novel words using two distinct formats. Previous research has shown that word learning in contrastive fast mapping conditions may rely on different neural substrates than explicit encoding conditions (Sharon et al., 2011). In the current investigation, we used a previously reported word learning task that implemented two distinct study formats (Warren and Duff, 2014): a contrastive fast mapping condition in which a picture of a novel item was displayed beside a picture of a familiar item while the novel item's name was presented aurally ("Click on the numbat."); and an explicit encoding (i.e., control) condition in which a picture of a novel item was displayed while its name was presented aurally ("This is a numbat."). After a delay, learning of the novel words was evaluated with memory tests including three-alternative forced-choice recognition, free recall, cued recall, and familiarity ratings. During the fast-mapping study condition both the left temporal lobectomy and healthy comparison groups performed well, but at test only the comparison group showed evidence of novel word learning. Our findings indicate that unilateral resection of the left temporal lobe including the hippocampus and temporal pole can severely impair word learning, and that fast-mapping study conditions do not promote subsequent word learning in temporal lobectomy populations.

Dissociable contributions of amygdala and hippocampus to emotion and memory in patients with Alzheimer's disease.

The amygdala and the hippocampus are associated with emotional processing and declarative memory, respectively. Studies have shown that patients with bilateral hippocampal damage caused by anoxia/ischemia, and patients with probable Alzheimer's disease (AD), can experience emotions for prolonged periods of time, even when they cannot remember what caused the emotion in the first place (Feinstein et al. (2010) Proc Natl Acad Sci USA 107:7674-7679; Guzmán-Vélez et al. (2014) Cogn Behav Neurol 27:117-129). This study aimed to investigate, for the first time, the roles of the amygdala and hippocampus in the dissociation between feelings of emotion and declarative memory for emotion-inducing events in patients with AD. Individuals with probable AD (N = 12) and age-matched healthy comparisons participants (HCP; N = 12) completed a high-resolution (0.44 × 0.44 × 0.80 mm) T2-weighted structural MR scan of the medial temporal lobe. Each of these individuals also completed two separate emotion induction procedures (sadness and happiness) using film clips. We collected real-time emotion ratings at baseline and multiple times postinduction, and administered a test of declarative memory shortly after each induction. Consistent with previous research, hippocampal volume was significantly smaller in patients with AD compared with HCP, and was positively correlated with memory for the film clips. Sustained feelings of emotion and amygdala volume did not significantly differ between patients with AD and HCP. Follow-up analyses showed a significant negative correlation between amygdala volume and sustained sadness, and a significant positive correlation between amygdala volume and sustained happiness. Our findings suggest that the amygdala is important for regulating and sustaining an emotion independent of hippocampal function and declarative memory for the emotion-inducing event. © 2015 Wiley Periodicals, Inc.

Investigating the Neural Correlates of Schemas: Ventromedial Prefrontal Cortex Is Necessary for Normal Schematic Influence on Memory.

Schemas, as memory representations of typical contexts, allow for generalization from previous experiences while often improving memory organization and accuracy. However, these advantageous characteristics of schematic memory may come at the cost of episode-specific information. In the human brain, this tradeoff between general and specific knowledge has been linked to differential contributions of the medial temporal lobes (MTL) to episode-specific memory and the ventromedial prefrontal cortex (vmPFC) to generalized, schematic memory. Here, we used a neuropsychological approach to test whether participants with focal vmPFC damage (n = 6) would show a reduced influence of schematic memory relative to healthy normal comparison participants (n = 12) in a recognition task that presented schematically congruent or incongruent contexts at study. As predicted, normal comparison participants were more likely to identify items as old after studying them in congruent contexts, and this effect was reflected in increased true and false recognition. These effects of prior context on recognition were not observed in the vmPFC group, suggesting that vmPFC damage reduced the influence of schematic memory. These findings are consistent with the proposition that the vmPFC plays an important role in integrating previous experience into ongoing memory processes while acting as part of a larger memory network. SIGNIFICANCE STATEMENT: In the human brain, new memories are strongly influenced by existing knowledge of relevant context (sometimes called "schemas"). Schemas can benefit memory by expediting learning and increasing capacity in familiar contexts, but these benefits may simultaneously reduce episode-specific memory. Here we show that damage to the human ventromedial prefrontal cortex (vmPFC) reduced the influence of existing knowledge on new memories. Our findings suggest that the vmPFC plays a key role in schematic memory processes by integrating previous experiences and contextual information to influence memory. These findings provide novel insight into the brain regions necessary for normal schematic memory and enhance our understanding of the brain networks supporting memory processes.

Damage to the Ventromedial Prefrontal Cortex Impairs Learning from Observed Outcomes.

Individuals learn both from the outcomes of their own internally generated actions ("experiential learning") and from the observation of the consequences of externally generated actions ("observational learning"). While neuroscience research has focused principally on the neural mechanisms by which brain structures such as the ventromedial prefrontal cortex (vmPFC) support experiential learning, relatively less is known regarding how learning proceeds through passive observation. We explored the necessity of the vmPFC for observational learning by testing a group of patients with damage to the vmPFC as well as demographically matched normal comparison and brain-damaged comparison groups--and a single patient with bilateral dorsal prefrontal damage--using several value-learning tasks that required learning from direct experience, observational learning, or both. We found a specific impairment in observational learning in patients with vmPFC damage manifest in the reduced influence of previously observed rewards on current choices, despite a relatively intact capacity for experiential learning. The current study provides evidence that the vmPFC plays a critical role in observational learning, suggests that there are dissociable neural circuits for experiential and observational learning, and offers an important new extension of how the vmPFC contributes to learning and memory.

Hippocampus contributes to the maintenance but not the quality of visual information over time.

The hippocampus has recently been implicated in the brief representation of visual information, but its specific role is not well understood. We investigated this role using a paradigm that distinguishes quantity and quality of visual memory as described in a previous study. We found that amnesic patients with bilateral hippocampal damage (N = 5) were less likely to remember test stimuli than comparison participants despite a brief maintenance interval (900 msec). However, estimates of memory quality were similar for all groups. Our findings suggest that the hippocampus contributes to brief maintenance of visual information but does not contribute to the quality of that information.

Network measures predict neuropsychological outcome after brain injury.

Hubs are network components that hold positions of high importance for network function. Previous research has identified hubs in human brain networks derived from neuroimaging data; however, there is little consensus on the localization of such hubs. Moreover, direct evidence regarding the role of various proposed hubs in network function (e.g., cognition) is scarce. Regions of the default mode network (DMN) have been frequently identified as "cortical hubs" of brain networks. On theoretical grounds, we have argued against some of the methods used to identify these hubs and have advocated alternative approaches that identify different regions of cortex as hubs. Our framework predicts that our proposed hub locations may play influential roles in multiple aspects of cognition, and, in contrast, that hubs identified via other methods (including salient regions in the DMN) might not exert such broad influence. Here we used a neuropsychological approach to directly test these predictions by studying long-term cognitive and behavioral outcomes in 30 patients, 19 with focal lesions to six "target" hubs identified by our approaches (high system density and participation coefficient) and 11 with focal lesions to two "control" hubs (high degree centrality). In support of our predictions, we found that damage to target locations produced severe and widespread cognitive deficits, whereas damage to control locations produced more circumscribed deficits. These findings support our interpretation of how neuroimaging-derived network measures relate to cognition and augment classic neuroanatomically based predictions about cognitive and behavioral outcomes after focal brain injury.

False recall is reduced by damage to the ventromedial prefrontal cortex: implications for understanding the neural correlates of schematic memory.

Schematic memory, or contextual knowledge derived from experience (Bartlett, 1932), benefits memory function by enhancing retention and speeding learning of related information (Bransford and Johnson, 1972; Tse et al., 2007). However, schematic memory can also promote memory errors, producing false memories. One demonstration is the "false memory effect" of the Deese-Roediger-McDermott (DRM) paradigm (Roediger and McDermott, 1995): studying words that fit a common schema (e.g., cold, blizzard, winter) often produces memory for a nonstudied word (e.g., snow). We propose that frontal lobe regions that contribute to complex decision-making processes by weighting various alternatives, such as ventromedial prefrontal cortex (vmPFC), may also contribute to memory processes by weighting the influence of schematic knowledge. We investigated the role of human vmPFC in false memory by combining a neuropsychological approach with the DRM task. Patients with vmPFC lesions (n = 7) and healthy comparison participants (n = 14) studied word lists that excluded a common associate (the critical item). Recall and recognition tests revealed expected high levels of false recall and recognition of critical items by healthy participants. In contrast, vmPFC patients showed consistently reduced false recall, with significantly fewer intrusions of critical items. False recognition was also marginally reduced among vmPFC patients. Our findings suggest that vmPFC increases the influence of schematically congruent memories, a contribution that may be related to the role of the vmPFC in decision making. These novel neuropsychological results highlight a role for the vmPFC as part of a memory network including the medial temporal lobes and hippocampus (Andrews-Hanna et al., 2010).

Very mild Alzheimer׳s disease is characterized by increased sensitivity to mnemonic interference.

Early pathology and tissue loss in Alzheimer׳s disease (AD) occurs in the hippocampus, a brain region that has recently been implicated in relational processing irrespective of delay. Thus, tasks that involve relational processing will especially tax the hippocampal memory system, and should be sensitive to even mild dysfunction typical of early AD. Here we used a short-lag, short-delay memory task previously shown to be sensitive to hippocampal integrity in an effort to discriminate cognitive changes due to healthy aging from those associated with very mild AD. Young adults, healthy older adults, and individuals with very mild AD (N=30 for each group) participated in our investigation, which entailed attempting to find an exact match to a previously presented target among a series of stimuli that varied in perceptual similarity to the target stimulus. Older adults with very mild AD were less accurate than healthy older adults, who, in turn, were impaired relative to young adults. Older adults with very mild AD were also particularly susceptible to interference from intervening lure stimuli. A measure based on this finding was able to explain additional variance in differentiating those in the very mild stage of AD from healthy older adults after accounting for episodic memory and global cognition composite scores in logistic regression models. Our findings suggest that cognitive changes in early stage AD reflect aging along with an additional factor potentially centered on sensitivity to interference, thereby supporting multifactorial models of aging.

Not so fast: hippocampal amnesia slows word learning despite successful fast mapping.

The human hippocampus is widely believed to be necessary for the rapid acquisition of new declarative relational memories. However, processes supporting on-line inferential word use ("fast mapping") may also exercise a dissociable learning mechanism and permit rapid word learning without the hippocampus (Sharon et al. (2011) Proc Natl Acad Sci USA 108:1146-1151). We investigated fast mapping in severely amnesic patients with hippocampal damage (N = 4), mildly amnesic patients (N = 6), and healthy comparison participants (N = 10) using on-line measures (eye movements) that reflected ongoing processing. All participants studied unique word-picture associations in two encoding conditions. In the explicit-encoding condition, uncommon items were paired with their names (e.g., "This is a numbat."). In the fast mapping study condition, participants heard an instruction using a novel word (e.g., "Click on the numbat.") while two items were presented (an uncommon target such as a numbat, and a common distracter such as a dog). All groups performed fast mapping well at study, and on-line eye movement measures did not reveal group differences. However, while comparison participants showed robust word learning irrespective of encoding condition, severely amnesic patients showed no evidence of learning after fast mapping or explicit encoding on any behavioral or eye-movement measure. Mildly amnesic patients showed some learning, but performance was unaffected by encoding condition. The findings are consistent with the following propositions: the hippocampus is not essential for on-line fast mapping of novel words; but is necessary for the rapid learning of arbitrary relational information irrespective of encoding conditions.