Thalamic-Medial Temporal Lobe Connectivity Underpins Familiarity Memory.

The neural basis of memory is highly distributed, but the thalamus is known to play a particularly critical role. However, exactly how the different thalamic nuclei contribute to different kinds of memory is unclear. Moreover, whether thalamic connectivity with the medial temporal lobe (MTL), arguably the most fundamental memory structure, is critical for memory remains unknown. We explore these questions using an fMRI recognition memory paradigm that taps familiarity and recollection (i.e., the two types of memory that support recognition) for objects, faces, and scenes. We show that the mediodorsal thalamus (MDt) plays a material-general role in familiarity, while the anterior thalamus plays a material-general role in recollection. Material-specific regions were found for scene familiarity (ventral posteromedial and pulvinar thalamic nuclei) and face familiarity (left ventrolateral thalamus). Critically, increased functional connectivity between the MDt and the parahippocampal (PHC) and perirhinal cortices (PRC) of the MTL underpinned increases in reported familiarity confidence. These findings suggest that familiarity signals are generated through the dynamic interaction of functionally connected MTL-thalamic structures.

Amount, not strength of recollection, drives hippocampal activity: A problem for apparent word familiarity-related hippocampal activation.

The role of the hippocampus in recollection and familiarity remains debated. Using functional magnetic resonance imaging (fMRI), we explored whether hippocampal activity is modulated by increasing recollection confidence, increasing amount of recalled information, or both. We also investigated whether any hippocampal differences between recollection and familiarity relate to processing differences or amount of information in memory. Across two fMRI tasks, we separately compared brain responses to levels of confidence for cued word recall and word familiarity, respectively. Contrary to previous beliefs, increasing confidence/accuracy of cued recall of studied words did not increase hippocampal activity, when unconfounded by amount recollected. In contrast, additional recollection (i.e., recollecting more information than the word alone) increased hippocampal activity, although its accuracy matched that of word recall alone. Unlike cued word recall, increasing word familiarity accuracy did increase hippocampal activity linearly, although at an uncorrected level. This finding occurred although cued word recall and familiarity memory seemed matched with respect to information in memory. The detailed characteristics of these effects do not prove that word familiarity is exceptional in having hippocampal neural correlates. They suggest instead that participants fail to identify some aspects of recollection, misreporting it as familiarity, a problem with word-like items that have strong and recallable semantic associates.

Material Specificity Drives Medial Temporal Lobe Familiarity But Not Hippocampal Recollection.

The specific role of the perirhinal (PRC), entorhinal (ERC) and parahippocampal cortices (PHC) in supporting familiarity-based recognition remains unknown. An fMRI study explored whether these medial temporal lobe (MTL) structures responded in the same way or differentially to familiarity as a function of stimulus type at recognition. A secondary aim was to explore whether the hippocampus responds in the same way to equally strong familiarity and recollection and whether this is influenced by the kind of stimulus involved. Univariate and multivariate analyses revealed that familiarity responses in the PRC, ERC, PHC and the amygdala are material-specific. Specifically, the PRC and ERC selectively responded to object familiarity, while the PHC responded to both object and scene familiarity. The amygdala only responded to familiarity memory for faces. The hippocampus did not respond to stimulus familiarity for any of the three types of stimuli, but it did respond to recollection for all three types of stimuli. This was true even when recollection was contrasted to equally accurate familiarity. Overall, the findings suggest that the role of the MTL neocortices and the amygdala in familiarity-based recognition depends on the kind of stimulus in memory, whereas the role of the hippocampus in recollection is independent of the type of cuing stimulus. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.

The hippocampus supports the representation of abstract concepts: Implications for the study of recognition memory.

Words, unlike images, are symbolic representations. The associative details inherent within a word's meaning and the visual imagery it generates, are inextricably connected to the way words are processed and represented. It is well recognised that the hippocampus associatively binds components of a memory to form a lasting representation, and here we show that the hippocampus is especially sensitive to abstract word processing. Using fMRI during recognition, we found that the increased abstractness of words produced increased hippocampal activation regardless of memory outcome. Interestingly, word recollection produced hippocampal activation regardless of word content, while the parahippocampal cortex was sensitive to concreteness of word representations, regardless of memory outcome. We reason that the hippocampus has assumed a critical role in the representation of uncontextualized abstract word meaning, as its information-binding ability allows the retrieval of the semantic and visual associates that, when bound together, generate the abstract concept represented by word symbols. These insights have implications for research on word representation, memory, and hippocampal function, perhaps shedding light on how the human brain has adapted to encode and represent abstract concepts.

A visual object stimulus database with standardized similarity information.

Although many visual stimulus databases exist, none has data on item similarity levels for multiple items of each kind of stimulus. We present such data for 50 sets of grayscale object photographs. Similarity measures between pictures in each set (e.g., 25 different buttons) were collected using a similarity-sorting method (Goldstone, Behavior Research Methods Instruments & Computers, 26(4):381-386, 1994). A validation experiment used data from 1 picture set and compared responses from standard pairwise measures. This showed close agreement. The similarity-sorting measures were then standardized across picture sets, using pairwise ratings. Finally, the standardized similarity distances were validated in a recognition memory experiment; false alarms increased when targets and foils were more similar. These data will facilitate memory and perception research that needs to make comparisons between stimuli with a range of known target-foil similarities.

Measuring recollection and familiarity: Improving the remember/know procedure.

The remember/know (RK) procedure is the most widely used method to investigate recollection and familiarity. It uses trial-by-trial reports to determine how much recollection and familiarity contribute to different kinds of recognition. Few other methods provide information about individual memory judgements and no alternative allows such direct indications of recollection and familiarity influences. Here we review how the RK procedure has been and should be used to help resolve theoretical disagreements about the processing and neural bases of components of recognition memory. Emphasis is placed on procedural weaknesses and a possible confound of recollection and familiarity with recognition memory strength. Recommendations are made about how to minimise these problems including using modified versions of the procedure. The proposals here are important for improving behavioural and lesion research, and vital for brain imaging work.

Impaired recollection but spared familiarity in patients with extended hippocampal system damage revealed by 3 convergent methods.

To understand recognition memory, the detection of stimulus repetition, it first is necessary to resolve the debate between 2 fundamentally different models of recognition. Contemporary single-process models assume that recognition memory relies solely on the neural system required for the recall of prior events. Dual-process models assume that recognition comprises 2 independent forms of memory: one supports recall, and the other detects repeated stimuli by signaling their familiarity, the feeling of previous occurrence without the recall of any associated information. These 2 models were contrasted in patients who had undergone surgical removal of a colloid cyst, a condition associated with memory loss when accompanied by fornix and/or mammillary body atrophy. Comparisons were made between 2 groups of 9 patients that differed only with respect to the extent of mammillary body atrophy. Only the more atrophied group was impaired on tests of recall, but both groups showed normal recognition levels on a task that equates recall and recognition performance in normal participants. To explore the nature of this spared recognition, we estimated recall-based recognition and familiarity-based recognition using 3 distinct methods: self-report, receiver operating characteristics, and structural equation modeling. All 3 methods showed impaired recall-based recognition accompanied by intact familiarity in the most atrophied group, as predicted only by dual-process models. When structural equation modeling was applied to all 62 colloid cyst patients, the recall/familiarity dual-process model best explained the patients' memory pattern. The convergent evidence that mammillary body atrophy impairs recall but spares familiarity-based recognition appears irreconcilable with single-process models.

A disproportionate role for the fornix and mammillary bodies in recall versus recognition memory.

Uncovering the functional relationship between temporal lobe amnesia and diencephalic amnesia depends on determining the role of the fornix, the major interlinking fiber tract. In this study relating fornix volume with memory, we made magnetic resonance imaging-based volume estimates of 13 brain structures in 38 individuals with surgically removed colloid cysts. Fornix status was assessed directly by overall volume and indirectly by mammillary body volume (which atrophies after fornix damage). Mammillary body volume significantly correlated with 13 out of 14 tests of episodic memory recall, but correlated poorly with recognition memory. Furthermore, as the volumes of the left fornix and the left mammillary bodies decreased, the difference between recall and recognition scores increased. No other structure was consistently associated with memory. These findings support models of diencephalic memory mechanisms that require hippocampal inputs for recall, but not for key elements of recognition.

Priming, recognition and autonomic discrimination in amnesia.

Six individuals with amnesia and matched healthy controls participated. There were two objectives. First, determine whether physiological activity at encoding relates to whether a word shows autonomic priming or is recognized. Second, propose a model for understanding relationships between recognition and autonomic priming. In amnesics, 'unrecognized' words were associated with better autonomic discrimination and lower levels of physiological activity at encoding. In healthy participants and amnesics, 'recognized' words were associated with poorer autonomic priming and higher levels of physiological activity at encoding. A state-dependent, activation-fractionation-inhibition model is proposed involving an orienting response elicited by preference and search and modulated by underlying memory strength.

The role of recollection and familiarity in the functional differentiation of the medial temporal lobes.

The components of the medial temporal lobes (MTL) receive different kinds of input. The perirhinal cortex receives primarily object/item information, the parahippocampal cortex receives contextual information, and the hippocampus receives high-level inputs that include object/item, context, and other information. Critically, the perirhinal and parahippocampal cortices have similar cytoarchitectonics, which differ considerably from that of the hippocampus and suggest that these cortices process their inputs differently from the way that the hippocampus processes its inputs. Much evidence indicates that the hippocampus is designed to rapidly bind together pattern-separated representations that support recall/recollection well. In contrast, the newer MTL cortices rapidly create poorly pattern-separated memories that support familiarity well, but recall/recollection very poorly. For over a decade, there has been disagreement about whether recall/recollection is primarily mediated by the hippocampus and familiarity by the evolutionarily newer MTL cortices or whether the MTL mediates these kinds of memory in an integrated, homogeneous fashion. Common misconceptions about familiarity, recollection, item, and associative memory are discussed as are methodological problems with MTL lesion and functional imaging research. The possible confound of familiarity with weaker memory and recollection with stronger memory is discussed and the implications of the Montaldi et al. (2006) functional Magnetic Resonance Imaging (fMRI) study, which matched memory strength between strong familiarity and recollection, finding that only recollection activated the hippocampus, are discussed. A suggestion is made about how the long-running conflict of findings in the human hippocampal lesion literature may be resolved.

British English norms for the spontaneous completion of three-letter word stems.

Word stem completion tasks involve showing participants a number of words and then later asking them to complete word stems to make a full word. If the stem is completed with one of the studied words, it indicates memory. It is a test widely used to assess both implicit and explicit forms of memory. An important aspect of stimulus selection is that target words should not frequently be generated spontaneously from the word stem, to ensure that production of the word really represents memory. In this article, we present a database of spontaneous stem completion rates for 395 stems from a group of 80 British undergraduate psychology students. It includes information on other characteristics of the words (word frequency, concreteness, imageability, age of acquisition, common part of speech, and number of letters) and, as such, can be used to select suitable words to include in a stem completion task. Supplemental materials for this article may be downloaded from http://brm.psychonomic-journals.org/content/supplemental.

Are there distinct forms of accelerated forgetting and, if so, why?

Whether accelerated long-term forgetting (ALF) and classic organic amnesia, particularly hippocampal-amnesia, differ qualitatively or merely quantitatively is disputed. Qualitative difference accounts postulate that ALF patients show normal recall memory for at least minutes, during which hippocampal-amnesics already show accelerated forgetting and impaired recall but, thereafter, ALF patients show accelerated forgetting and impaired delayed recall. These delayed impairments may be more severe than those shown by hippocampal-amnesics. In contrast, quantitative difference accounts postulate that ALF patients merely have mild hippocampal-amnesia, so their later forgetting rates and recall levels are sub-normal but always better than those of hippocampal-amnesics with worse initial recall levels (i.e., there is no cross-over in forgetting rates at longer delays). Many ALF studies in people with epilepsy have demonstrated evidence of a single dissociation-with accelerated delayed forgetting relative to healthy controls. Even when initial recall seems genuinely normal, uncompromised by patients needing more learning trials or showing below-average performance on more demanding recall tests, without further evidence, a quantitative interpretation remains possible. Resolution of the dispute requires evidence of a double dissociation between ALF patients and hippocampal-amnesics with more impaired initial recall in a comparison also involving matched controls. The only two studies that have made this comparison found that there was a cross-over interaction between initial and delayed recall in the ALF and amnesic patients, inconsistent with quantitative difference accounts. The functional and pathological conditions underlying this cross-over effect need to be systematically explored, controlling for potential methodological confounds, in temporal lobe epilepsy and transient epileptic amnesia as well as non-epileptic conditions. Future research must also explore under what conditions, if any, milder hippocampal-amnesics show relatively normal delayed forgetting of recall, and for how long, if at all, ALF patients show completely normal recall. Relatedly, the functional and pathological heterogeneity of ALF needs systematic exploration.

Feasibility of a randomized single-blind crossover trial to assess the effects of the second-generation slow-release dopamine agonists pramipexole and ropinirole on cued recall memory in idiopathic mild or moderate Parkinson's disease without cognitive impairment.

BACKGROUND: The aim was to assess the feasibility of a single-centre, single-blind, randomized, crossover design to explore the effects of two slow-release dopamine agonists, ropinirole and pramipexole, on cued recall in Parkinson's disease. As the design required a switch from the prescribed agonist (pramipexole-to-ropinirole, or ropinirole-to-pramipexole), the primary objectives were to (a) examine the efficacy of processes and procedures used to manage symptoms during the washout period and (b) to use cued recall estimates to inform a power calculation for a definitive trial. Secondary objectives were to assess consent and missing data rates, acceptability of clinical support for the OFF sessions, experience of the OFF sessions and of agonist switching, barriers-to-participation for patients and informal caregivers. METHODS: Patients were randomized in a 1:1 ratio to two treatment arms and stabilized on each agonist for 6 weeks. The arms differed only in the sequence in which the agonists were administered. Cued recall was assessed ON medication and, following a washout period resulting in 93.75% agonist elimination, OFF medication. RESULTS: A total of 220 patients were screened: 145 were excluded and 75 invitations to participate were sent to eligible patients. Fifty-three patients declined, 22 consented and 16 completed the study. There were no serious adverse events, and rates of non-serious adverse events were equivalent between the agonists. Using the largest standard deviation (SD) of the ON-OFF difference cued recall score (inflated by ~25% to give a conservative estimate of the SD in a definitive trial) and assuming an effect of at least 10% of the observed range of OFF medication cued recall scores for either agonist to be clinically important, a main trial requires a sample size of just under 150 patients. The consent and missing data rates were 29 and 27% respectively. The washout period and the preparation for the OFF sessions were acceptable, and the sessions were manageable. The experience of switching was also manageable. Barriers to participation included concerns about disease stability, side effects, research process, carer workload and accessibility of the information sheet. CONCLUSIONS: This study presented challenges to recruitment both in design and execution, and while it was a major aim of the study to assess this, evaluation of these challenges provided the opportunity to explore how they could be overcome for future studies. TRIAL REGISTRATION: EudraCT 2012-000801-64.

When memory does not fail: familiarity-based recognition in mild cognitive impairment and Alzheimer's disease.

Recognition can be guided by familiarity, a restricted form of retrieval devoid of contextual recall, or by recollection, which occurs when retrieval is sufficient to support the full experience of remembering an episode. Recollection and familiarity were disentangled by testing recognition memory using silhouette object drawings, high target-foil resemblance, and both yes-no and forced-choice procedures. Theoretically, forced-choice recognition could be mediated by familiarity alone. Alzheimer's disease and its preclinical stage, mild cognitive impairment (MCI), were associated with memory impairments that were greater on the yes-no test. Remarkably, forced-choice recognition was unequivocally normal in patients with MCI compared with age-matched controls. Neuropathology in hippocampus and entorhinal cortex, known to be present in MCI, presumably disrupted recollection while leaving familiarity-based recognition intact.

A deficit in familiarity-driven recognition in a right-sided mediodorsal thalamic lesion patient.

OBJECTIVE: According to a still-controversial view of recognition, projections between the perirhinal cortex and the medial subdivision of the mediodorsal thalamic nucleus (mMDT) support the mnemonic processes underlying familiarity, whereas a separate extended hippocampal system is critical for the recollection of episodic details during recognition. METHOD: In this study, we examined item recognition, familiarity, and recollection for faces and words in a patient (OG) with a right-sided lesion centered on the mMDT, which encroached on the central medial midline nucleus and may have resulted in partial disconnection of the mammillothalamic tract. On the basis of OG's neuropathology, the dual-process signal-detection (DPSD) high-threshold theory and the material-specific hypothesis of long-term memory together predicted a material-specific impairment in familiarity for novel facial memoranda, with a lesser decline in recollection of novel faces at short retention intervals. No abnormalities in either familiarity- or recollection-driven recognition of verbal memoranda were expected. RESULTS: Comparing the performance of OG and that of a group of 10 age-, sex-, and IQ-matched healthy controls, the remember-know procedure revealed the dissociations predicted by the material-specific and DPSD hypotheses: With recognition of previously novel faces, OG showed a deficit in familiarity-driven recognition that was significantly greater than the insignificant reduction in his recollection. All components of his word recognition were, however, preserved. CONCLUSION: A memory profile, marked by a dissociation between familiarity and recollection, fits naturally with the DPSD model and is incompatible with the idea that these kinds of memories reflect different degrees of trace strength.

Sparing of the familiarity component of recognition memory in a patient with hippocampal pathology.

Subject KN has a persistent anterograde amnesia as a result of brain injury following meningitis in 1993. MRI scans reveal a bilateral decrease in the volume of his hippocampal region (dentate gyrus, CA1-4, subicular cortices) of approximately 45% in both the right and left hemispheres, although the volume of his perirhinal cortex appears normal. Aside from some changes to his occipital lobe and bilateral shrinkage of the amygdala, the rest of his brain appears normal on recent quantitative MRI scans. A striking feature of his memory loss is his ability to perform at normal levels on some tests of recognition, despite his consistent deficit on tests of recall. Two tests designed specifically to distinguish performance of two putative divisions of recognition memory (the Remember/Know procedure and the use of receiver operating characteristics to distinguish familiarity and recollection), provide evidence for a selective sparing of the familiarity component of recognition. The dissociation within recognition memory supports dual-process models of recognition, and also supports proposals that anatomically linked regions within the medial temporal lobe make qualitatively different contributions to recognition.

Memory for between-list and within-list information in amnesic patients with temporal lobe and diencephalic lesions.

Patients with medial temporal lobe damage and diencephalic damage were compared on two tests of verbal temporal order memory: between-list discrimination and within-list discrimination. Both patient groups were impaired relative to a group of healthy control participants. In addition, despite comparable levels of item recognition, the diencephalic group was impaired relative to the medial temporal lobe group on both within-list and between-list discrimination. Temporal order memory for between-list information showed a significant correlation with a composite measure of recognition memory, and the results are discussed in terms of the patients' reliance on familiarity and distance-based processes to make temporal order judgments.

Evidence of an amnesia-like cued-recall memory impairment in nondementing idiopathic Parkinson's disease.

Medicated, non-dementing mild-to-moderate Parkinson's disease (PD) patients usually show recall/recollection impairments but have only occasionally shown familiarity impairments. We aimed to assess two explanations of this pattern of impairment. Recollection typically improves when effortful planning of encoding and retrieval processing is engaged. This depends on prefrontally-dependent executive processes, which are often disrupted in PD. Relative to an unguided encoding and retrieval of words condition (C1), giving suitable guidance at encoding alone (C2) or at encoding and retrieval (C3) should, if executive processes are disrupted, improve PD recollection more than control recollection and perhaps raise it to normal levels. Familiarity, being a relatively automatic kind of memory, whether impaired or intact, should be unaffected by guidance. According to the second explanation, PD deficits are amnesia-like and caused by medial temporal lobe dysfunction and although poorer recollection, which is caused by hippocampal disruption, may be improved by guidance, it should not improve more than control recollection. Familiarity impairment will also occur if the perirhinal cortex is disrupted, but will be unimproved by guidance. Without guidance, recollection/recall was impaired in thirty PD patients relative to twenty-two healthy controls and remained relatively equally impaired when full guidance was provided (C1 vs C3), both groups improving to broadly the same extent. Although impaired, and markedly less so than recollection, familiarity was not improved by guidance in both groups. The patients showed elevated rates of subclinical depressive symptoms, which weakly correlated with recall/recollection in all three conditions. PD executive function was also deficient and correlated with unguided/C1 recollection only. Our results are consistent with a major cause of the patients' recall/recollection impairments being hippocampal disruption, probably exacerbated by subclinical depressive symptoms. However, the results do not exclude a lesser prefrontal cortex contribution because patient executive functions were impaired and correlated solely with unguided overall recollection.