Disturbing visual working memory: electrophysiological evidence for a role of the prefrontal cortex in recovery from interference

Single cell recordings in monkeys support the notion that the lateral prefrontal cortex (PFC) controls reactivation of visual working memory representations when rehearsal is disrupted. In contrast, recent fMRI findings yielded a double dissociation for PFC and the medial temporal lobe (MTL) in a letter working memory task. PFC was engaged in interference protection during reactivation while MTL was prominently involved in the retrieval of the letter representations. We present event-related potential data (ERP) that support PFC involvement in the top-down control of reactivation during a visual working memory task with endogenously triggered recovery after visual interference. A differentiating view is proposed for the role of PFC in working memory with respect to endogenous/exogenous control and to stimulus type. General implications for binding and retention mechanisms are discussed.     

Dissociation between explicit memory and configural memory in the human medial temporal lobe

Using functional magnetic resonance imaging, the current study explored the differential mnemonic contributions of the hippocampus and surrounding medial temporal lobe (MTL) cortices to explicit recognition memory and configural learning. Using a task that required processing of repeated and novel visuospatial contexts across multiple trials, we examined MTL activation in relation to 3 forms of learning in a single paradigm: 1) context-independent procedural learning, 2) context-dependent configural learning, and 3) explicit recognition memory. Activations in hippocampus and parahippocampal cortex were associated with explicit memory, differentiating between subsequently remembered and forgotten repeated contexts, but were unrelated to context-dependent configural learning. Activations in regions of perirhinal and entorhinal cortex were associated with configural learning of repeated contexts independent from explicit memory for those contexts. Procedural learning was unrelated to activation in any MTL region. The time course of activation across learning further differed in MTL subregions with MTL cortex demonstrating repetition-related decreases and hippocampus repetition-related increases. These repetition effects were differentially sensitive to recognition with only activation in hippocampus and parahippocampal cortex tracking recognized items. These imaging findings converge with studies of amnesia and indicate dissociable roles for hippocampus in learning that supports explicit recognition and for anterior MTL cortex in configural learning.     

Mechanisms of hierarchical reinforcement learning in cortico-striatal circuits 2: evidence from fMRI

The frontal lobes may be organized hierarchically such that more rostral frontal regions modulate cognitive control operations in caudal regions. In our companion paper (Frank MJ, Badre D. 2011. Mechanisms of hierarchical reinforcement learning in corticostriatal circuits I: computational analysis. 22:509-526), we provide novel neural circuit and algorithmic models of hierarchical cognitive control in cortico-striatal circuits. Here, we test key model predictions using functional magnetic resonance imaging (fMRI). Our neural circuit model proposes that contextual representations in rostral frontal cortex influence the striatal gating of contextual representations in caudal frontal cortex. Reinforcement learning operates at each level, such that the system adaptively learns to gate higher order contextual information into rostral regions. Our algorithmic Bayesian "mixture of experts" model captures the key computations of this neural model and provides trial-by-trial estimates of the learner's latent hypothesis states. In the present paper, we used these quantitative estimates to reanalyze fMRI data from a hierarchical reinforcement learning task reported in Badre D, Kayser AS, D'Esposito M. 2010. Frontal cortex and the discovery of abstract action rules. Neuron. 66:315--326. Results validate key predictions of the models and provide evidence for an individual cortico-striatal circuit for reinforcement learning of hierarchical structure at a specific level of policy abstraction. These findings are initially consistent with the proposal that hierarchical control in frontal cortex may emerge from interactions among nested cortico-striatal circuits at different levels of abstraction.     

Neural correlates of rule-based and information-integration visual category learning

An emerging theory of the neurobiology of category learning postulates that there are separate neural systems supporting the learning of categories based on verbalizeable rules (RB) or through implicit information integration (II). The medial temporal lobe (MTL) is thought to play a crucial role in successful RB categorization, whereas the posterior regions of the caudate are hypothesized to support II categorization. Functional neuroimaging was used to assess activity in these systems during category-learning tasks with category structures designed to afford either RB or II learning. Successful RB categorization was associated with relatively increased activity in the anterior MTL. Successful II categorization was associated with increased activity in the caudate body. The dissociation observed with neuroimaging is consistent with the roles of these systems in memory and dissociations reported in patient populations. Convergent evidence from these approaches consistently reinforces the idea of multiple neural systems supporting category learning.     

Dynamic changes in the medial temporal lobe during incidental learning of object-location associations

The role of the medial temporal lobe (MTL) in associative memory encoding has been the focus of many memory experiments. However, there has been surprisingly little investigation of whether the contributions of different MTL subregions (amygdala, hippocampus [HPC], parahippocampal [PHc], perirhinal cortex [PRc], and temporal polar cortex [TPc]) shift across multiple presentations during associative encoding. We examined this issue using event-related functional magnetic resonance imaging and a multivoxel pattern classification analysis. Subjects performed a visual search task, becoming faster with practice to locate objects whose locations were held constant across trials. The classification analysis implicated right HPC and amygdala early in the task when the speed-up from trial to trial was greatest. The same analysis implicated right PRc and TPc late in learning when speed-up was minimal. These results suggest that associative encoding relies on complex patterns of neural activity in MTL that cannot be expressed by simple increases or decreases of blood oxygenation level-dependent signal during learning. Involvement of MTL subregions during encoding of object-location associations depends on the nature of the learning phase. Right HPC and amygdala support active integration of object and location information, while right PRc and TPc are involved when object and spatial representations become unitized into a single representation.     

Learning-related neuronal responses in prefrontal cortex studied with functional neuroimaging

We assessed time-dependent neuronal activity accompanying learning using functional magnetic resonance imaging (fMRI). An artificial grammar learning paradigm enabled us to dissociate activations associated with individual item learning from those involved in learning the underlying grammar system. We show that a localized region of right prefrontal cortex (PFC) is preferentially sensitive to individual item learning during the early stages of the experiment, while the left PFC region is sensitive to grammar learning which occurred across the entire course of the experiment. In addition to dissociating these two types of learning, we were able to characterize the effect of rule acquisition on neuronal responses associated with explicit learning of individual items. This effect was expressed as modulation of the time-dependent right PFC activations such that the early increase in activation associated with item learning was attenuated as the experiment progressed. In a further analysis we used structural equation modelling to explore time-dependent changes in inter-regional connectivity as a function of both item and grammar rule learning. Although there were no significant effects of item learning on the measured path strengths, rule learning was associated with a decrease in right fronto-parietal connectivity and an increase in connectivity between left and right PFC. Further fronto-parietal path strengths were observed to change, with an increase in left fronto-parietal and a decrease in right fronto-parietal connectivity path strength from right PFC to left parietal cortex. We interpret our findings in terms of a left frontal system mediating the semantic analysis of study items and directly influencing a right fronto-parietal system associated with episodic memory retrieval.     

Temporal and cerebellar brain regions that support both declarative memory formation and retrieval

Using event-related fMRI, we scanned young healthy subjects while they memorized real-world photographs and subsequently tried to recognize them within a series of new photographs. We confirmed that activity in the medial temporal lobe (MTL) and inferior prefrontal cortex correlates with declarative memory formation as defined by the subsequent memory effect, stronger responses to subsequently remembered than forgotten items. Additionally, we confirmed that activity in specific regions within the parietal lobe, anterior prefrontal cortex, anterior cingulate and cerebellum correlate with recognition memory as measured by the conventional old/new effect, stronger responses for recognized old items (hits) than correctly identified new items (correct rejections). To obtain a purer measure of recognition success, we introduced two recognition effects by comparing brain responses to hits and old items misclassified as new (misses). The positive recognition effect (hits > misses) revealed prefrontal, parietal and cerebellar contributions to recognition, and in line with electrophysiological findings, the negative recognition effect (hits < misses) revealed an anterior medial temporal contribution. Finally, by inclusive masking, we identified temporal and cerebellar brain areas that support both declarative memory formation and retrieval. For matching operations during recognition, these areas may re-use representations formed and stored locally during encoding.     

Frontal and parietal lobe activation during transitive inference in humans

Cortical areas engaged in knowledge manipulation during reasoning were identified with functional magnetic resonance imaging (MRI) while participants performed transitive inference (TI) on an ordered list of 11 items (e.g. if A < B and B < C, then A < C). Initially, participants learned a list of arbitrarily ordered visual shapes. Learning occurred by exposure to pairs of list items that were adjacent in the sequence. Subsequently, functional MR images were acquired as participants performed TI on non-adjacent sequence items. Control tasks consisted of height comparisons (HT) and passive viewing (VIS). Comparison of the TI task with the HT task identified activation resulting from TI, termed 'reasoning', while controlling for rule application, decision processes, perception, and movement, collectively termed 'support processes'. The HT-VIS comparison revealed activation related to support processes. The TI reasoning network included bilateral prefrontal cortex (PFC), pre-supplementary motor area (preSMA), premotor area (PMA), insula, precuneus, and lateral posterior parietal cortex. By contrast, cortical regions activated by support processes included the bilateral supplementary motor area (SMA), primary motor cortex (M1), somatic sensory cortices, and right PMA. These results emphasize the role of a prefrontal-parietal network in manipulating information to form new knowledge based on familiar facts. The findings also demonstrate PFC activation beyond short-term memory to include mental operations associated with reasoning.     

Imagery and perception share cortical representations of content and location

Visual imagery allows us to vividly imagine scenes in the absence of visual stimulation. The likeness of visual imagery to visual perception suggests that they might share neural mechanisms in the brain. Here, we directly investigated whether perception and visual imagery share cortical representations. Specifically, we used a combination of functional magnetic resonance imaging (fMRI) and multivariate pattern classification to assess whether imagery and perception encode the "category" of objects and their "location" in a similar fashion. Our results indicate that the fMRI response patterns for different categories of imagined objects can be used to predict the fMRI response patters for seen objects. Similarly, we found a shared representation of location in low-level and high-level ventral visual cortex. Thus, our results support the view that imagery and perception are based on similar neural representations.     

Medial temporal lobe involvement in an implicit memory task: evidence of collaborating implicit and explicit memory systems from FMRI and Alzheimer's disease

We used a prototype extraction task to assess implicit learning of a meaningful novel visual category. Cortical activation was monitored in young adults with functional magnetic resonance imaging. We observed occipital deactivation at test consistent with perceptually based implicit learning, and lateral temporal cortex deactivation reflecting implicit acquisition of the category's semantic nature. Medial temporal lobe (MTL) activation during exposure and test suggested involvement of explicit memory as well. Behavioral performance of Alzheimer's disease (AD) patients and healthy seniors was also assessed, and AD performance was correlated with gray matter volume using voxel-based morphometry. AD patients showed learning, consistent with preserved implicit memory, and confirming that AD patients' implicit memory is not limited to abstract patterns. However, patients were somewhat impaired relative to healthy seniors. Occipital and lateral temporal cortical volume correlated with successful AD patient performance, and thus overlapped with young adults' areas of deactivation. Patients' severe MTL atrophy precluded involvement of this region. AD patients thus appear to engage a cortically based implicit memory mechanism, whereas their relative deficit on this task may reflect their MTL disease. These findings suggest that implicit and explicit memory systems collaborate in neurologically intact individuals performing an ostensibly implicit memory task.     

Computer-assisted instruction in otolaryngology: the use of a database for examination review.

A database of questions and answers has been developed to assist residents in reviewing current topics in otolaryngology-head and neck surgery. Each question/item has an associated answer, general category, specific category, and reference that allows cross-referencing on the computer system. The user can search the database for categories of interest and obtain a specific subset of questions. This allows an efficient means of knowledge acquisition and review for Board examinations. Additional data entry is also facilitated to expand the database as desired. Currently there are more than 2300 items in the database.     

Anterior prefrontal cortex mediates rule learning in humans

Despite a need for rule learning in everyday life, the brain regions involved in explicit rule induction remain undetermined. Here we use event-related functional magnetic resonance imaging to measure learning-dependent neuronal responses during an explicit categorization task. Subjects made category decisions, with feedback, to exemplar letter strings for which the rule governing category membership was periodically changed. Bilateral fronto-polar prefrontal cortices were selectively engaged following rule change. This activation pattern declined with improving task performance reflecting rule acquisition. The vocabulary of letters comprising the exemplars was also periodically changed, independently of rule changes. This exemplar change modulated activation in left anterior hippocampus. Our finding that fronto-polar cortex mediates rule learning supports a functional contribution of this region to generic reasoning and problem-solving behaviours.     

A teratoma of the third ventricle of the brain

A report is presented here of the total extirpation of a teratoma located in the third ventricle of a boy of eight. Since the tumour was made up of mature tissues (adult teratoma), its extirpation may be regarded as a cure. Although there are a few exceptions to the rule, other tumours located in the third ventricle of brain are mostly malignant, and they penetrate the tissues which constitute the wall of the third ventricle. For that reason the effects of a radical operation are doubtful. The adult teratoma is an exception. A tumour of this kind should be extirpated as a whole and removed from the third ventricle of brain.     

Distinct patterns of functional and effective connectivity between perirhinal cortex and other cortical regions in recognition memory and perceptual discrimination

Traditionally, the medial temporal lobe (MTL) is thought to be dedicated to declarative memory. Recent evidence challenges this view, suggesting that perirhinal cortex (PrC), which interfaces the MTL with the ventral visual pathway, supports highly integrated object representations in recognition memory and perceptual discrimination. Even with comparable representational demands, perceptual and memory tasks differ in numerous task demands and the subjective experience they evoke. Here, we tested whether such differences are reflected in distinct patterns of connectivity between PrC and other cortical regions, including differential involvement of prefrontal control processes. We examined functional magnetic resonance imaging data for closely matched perceptual and recognition memory tasks for faces that engaged right PrC equivalently. Multivariate seed analyses revealed distinct patterns of interactions: Right ventrolateral prefrontal and posterior cingulate cortices exhibited stronger functional connectivity with PrC in recognition memory; fusiform regions were part of the pattern that displayed stronger functional connectivity with PrC in perceptual discrimination. Structural equation modeling revealed distinct patterns of effective connectivity that allowed us to constrain interpretation of these findings. Overall, they demonstrate that, even when MTL structures show similar involvement in recognition memory and perceptual discrimination, differential neural mechanisms are reflected in the interplay between the MTL and other cortical regions.     

Interaction of working memory and long-term memory in the medial temporal lobe

Recent findings indicate that regions in the medial temporal lobe (MTL) do not only play a crucial role in long-term memory (LTM) encoding, but contribute to working memory (WM) as well. However, very few studies investigated the interaction between these processes so far. In a new functional magnetic resonance imaging paradigm comprising both a complex WM task and an LTM recognition task, we found not only that some items were successfully processed in WM but later forgotten, but also that a significant number of items which were not successfully processed in the WM task were subsequently recognized. Activation in the parahippocampal cortex (PHC) during successful WM was predictive of subsequent LTM, but was correlated with subsequent forgetting if the WM task was not successfully solved. The contribution of the PHC to LTM encoding thus crucially depends on whether an item was successfully processed in the WM task. Functional connectivity analysis revealed that across-trial fluctuations in PHC activity were correlated with activation in extensive regions if WM and LTM tasks were correctly solved, whereas connectivity broke down during unsuccessful attempts to do the task, suggesting that activity in the PHC during WM has to be well controlled to support LTM formation.     

The parahippocampal cortex mediates spatial and nonspatial associations

The parahippocampal cortex (PHC) has been implicated in the processing of place-related information. It has also been implicated in episodic memory, even for items that are not related to unique places. How could the same cortical region mediate such seemingly different cognitive processes? Both processes rely on contextual associations, and we therefore propose that the PHC should be viewed not as exclusively dedicated for analyzing place-related information, or as solely processing episodic memories, but instead as more generally playing a central role in contextual associative processing. To test this proposal, we created a novel learning paradigm to form new associations among meaningless visual patterns. These new associations were created to emulate either spatial or nonspatial contexts. Both spatial and nonspatial associations activated the PHC more than noncontextual items. Moreover, items from spatial contexts activated the posterior part of the PHC, whereas items from nonspatial contexts activated the anterior PHC. Therefore, we show that the PHC plays a role of processing contextual associations in general, and that these associations are not restricted to spatial information. By modifying the existing view of the PHC function accordingly, the seemingly contradicting processes that activate it can be reconciled under one overarching framework.     

Liver transplantation for status 1: the consequences of good intentions.

Status 1 is the listing category reserved for patients awaiting liver transplantation who are at risk of imminent death. This high allocation priority was intended to benefit patients with acute liver failure and children with severe chronic liver failure. However, the status 1 criteria were not well defined. The aims of this study, which used the Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients database for patients wait-listed between February 27, 2002, and September 30, 2003, were to determine the indication and numbers of children and adults at status 1 (including regional variations); examine death rates on the waiting list for children at vs. not at status 1; and examine time to death, transplant, or removal from the waiting list for both pediatric and adult status 1 candidates. During the study period, 40.3% of children and 6.1% of adults were transplanted at status 1. The indication was acute liver failure in 52.1% of adults and 31% of children. Among status 1 transplants, Regional Review Board exceptions were granted for 16.7% of children and 10.1% of adults. Death rates for children listed at status 1 by exception per patient-year at risk were substantially lower (0.51) than those of children with acute liver failure (4.06) or with chronic liver disease and Pediatric End-Stage Liver Disease score > or =25 (4.63). The percentage of adults who died while on the waiting list within 90 days of listing was more than twice that of children, whereas the percentages transplanted were similar. Patients listed and transplanted at status 1 were a heterogeneous population with an overrepresentation of children with varying degrees of chronic liver disease and other exceptions, and an associated wide variation in waiting list mortality. Recent changes in status 1 criteria provide stricter definitions, particularly for children, including the removal of the "by exception" category, with the intent that all candidates listed at status 1 share a similar mortality risk.     

Towards quantitative 3D imaging of the osteocyte lacuno-canalicular network

Osteocytes are the most abundant cells in bone and the only cells embedded in the bone mineral matrix. They form an extended, three-dimensional (3D) network, whose processes interconnecting the cell bodies reside in thin canals, the canaliculi. Together with the osteocyte lacunae, the canaliculi form the lacuno-canalicular network (LCN). As the negative imprint of the cellular network within bone tissue, the LCN morphology is considered to play a central role for bone mechanosensation and mechanotransduction. However, the LCN has neither been visualized nor quantified in an adequate way up to now. On this account, this article summarizes the current state of knowledge of the LCN morphology and then reviews different imaging methods regarding the quantitative 3D assessment of bone tissue in general and of the LCN in particular. These imaging methods will provide new insights in the field of bone mechanosensation and mechanotransduction and thus, into processes of strain sensation and transduction, which are tightly associated with osteocyte viability and bone quality.     

MELD Exceptions and Rates of Waiting List Outcomes

Model for End-stage Liver Disease (MELD)-based allocation of deceased donor livers allows exceptions for patients whose score may not reflect their true mortality risk. We hypothesized that organ procurement organizations (OPOs) may differ in exception practices, use of exceptions may be increasing over time, and exception patients may be advantaged relative to other patients. We analyzed longitudinal MELD score, exception and outcome in 88 981 adult liver candidates as reported to the United Network for Organ Sharing from 2002 to 2010. Proportion of patients receiving an HCC exception was 0-21.4% at the OPO-level and 11.9-18.8% at the region level; proportion receiving an exception for other conditions was 0.0%-13.1% (OPO-level) and 3.7-9.5 (region-level). Hepatocellular carcinoma (HCC) exceptions rose over time (10.5% in 2002 vs. 15.5% in 2008, HR = 1.09 per year, p<0.001) as did other exceptions (7.0% in 2002 vs. 13.5% in 2008, HR = 1.11, p<0.001). In the most recent era of HCC point assignment (since April 2005), both HCC and other exceptions were associated with decreased risk of waitlist mortality compared to nonexception patients with equivalent listing priority (multinomial logistic regression odds ratio [OR] = 0.47 for HCC, OR = 0.43 for other, p<0.001) and increased odds of transplant (OR = 1.65 for HCC, OR = 1.33 for other, p<0.001). Policy advantages patients with MELD exceptions; differing rates of exceptions by OPO may create, or reflect, geographic inequity.     

Longitudinal structure-function correlates in elderly reveal MTL dysfunction with cognitive decline

By integrating behavioral measures and imaging data, previous investigations have explored the relationship between biological markers of aging and cognitive functions. Evidence from functional and structural neuroimaging has revealed that hippocampal volume and activation patterns in the medial temporal lobe (MTL) may predict cognitive performance in old age. Most past demonstrations of age-related differences in brain structure-function were based on cross-sectional comparisons. Here, the relationship between 6-year intraindividual change in functional magnetic resonance imaging (fMRI) signal and change in memory performance over 2 decades was examined. Correlations between intraindividual change in fMRI signal during episodic encoding and change in memory performance measured outside of scanning were used as an estimate for relating brain-behavior changes. The results revealed a positive relationship between activation change in the hippocampus (HC) and change in memory performance, reflecting reduced hippocampal activation in participants with declining performance. Using a similar analytic approach as for the functional data, we found that individuals with declining performance had reduced HC volume compared with individuals with intact performance. These observations provide a strong link between cognitive change in older adults and MTL structure and function and thus provide insights into brain correlates of individual variability in aging trajectories.