BDNF genotype is associated with hippocampal volume in mild traumatic brain injury.

The negative long-term effects of mild traumatic brain injury (mTBI) have been a growing concern in recent years, with accumulating evidence suggesting that mTBI combined with additional vulnerability factors may induce neurodegenerative-type changes in the brain. However, the factors instantiating risk for neurodegenerative disease following mTBI are unknown. This study examined the link between mTBI and brain-derived neurotrophic factor (BDNF) genotype, which has previously been shown to regulate processes involved in neurodegeneration including synaptic plasticity and facilitation of neural survival through its expression. Specifically, we examined nine BDNF single-nucleotide polymorphisms (SNPs; rs908867, rs11030094, rs6265, rs10501087, rs1157659, rs1491850, rs11030107, rs7127507 and rs12273363) previously associated with brain atrophy or memory deficits in mTBI. Participants were 165 white, non-Hispanic Iraq and Afghanistan war veterans between the ages of 19 and 58, 110 of whom had at least one mTBI in their lifetime. Results showed that the BDNF SNP rs1157659 interacted with mTBI to predict hippocampal volume. Furthermore, exploratory analysis of functional resting state data showed that rs1157659 minor allele homozygotes with a history of mTBI had reduced functional connectivity in the default mode network compared to major allele homozygotes and heterozygotes. Apolipoprotein E (APOE) was not a significant predictor of hippocampal volume or functional connectivity. These results suggest that rs1157659 minor allele homozygotes may be at greater risk for neurodegeneration after exposure to mTBI and provide further evidence for a potential role for BDNF in regulating neural processes following mTBI.

Medial Temporal Lobe Contributions to Episodic Future Thinking: Scene Construction or Future Projection?

Previous research has shown that the medial temporal lobes (MTL) are more strongly engaged when individuals think about the future than about the present, leading to the suggestion that future projection drives MTL engagement. However, future thinking tasks often involve scene processing, leaving open the alternative possibility that scene-construction demands, rather than future projection, are responsible for the MTL differences observed in prior work. This study explores this alternative account. Using functional magnetic resonance imaging, we directly contrasted MTL activity in 1) high scene-construction and low scene-construction imagination conditions matched in future thinking demands and 2) future-oriented and present-oriented imagination conditions matched in scene-construction demands. Consistent with the alternative account, the MTL was more active for the high versus low scene-construction condition. By contrast, MTL differences were not observed when comparing the future versus present conditions. Moreover, the magnitude of MTL activation was associated with the extent to which participants imagined a scene but was not associated with the extent to which participants thought about the future. These findings help disambiguate which component processes of imagination specifically involve the MTL.

Using future thinking to reduce temporal discounting: Under what circumstances are the medial temporal lobes critical?

The capacity to envision the future plays an important role in many aspects of cognition, including our ability to make optimal, adaptive choices. Past work has shown that the medial temporal lobe (MTL) is necessary for decisions that draw on episodic future thinking. By contrast, little is known about the role of the MTL in decisions that draw on semantic future thinking. Accordingly, the present study investigated whether the MTL contributes to one form of decision making, namely intertemporal choice, when such decisions depend on semantic consideration of the future. In an intertemporal choice task, participants must select either a smaller amount of money that is available in the present or a larger amount of money that would be available at a future date. Amnesic individuals with MTL damage and healthy control participants performed such a task in which, prior to making a choice, they engaged in a semantic generation exercise, wherein they generated items that they would purchase with the future reward. In experiment 1, we found that, relative to a baseline condition involving standard intertemporal choice, healthy individuals were more inclined to select a larger, later reward over a smaller, present reward after engaging in semantic future thinking. By contrast, amnesic participants were paradoxically less inclined to wait for a future reward following semantic future thinking. This finding suggests that amnesics may have had difficulty "tagging" the generated item(s) as belonging to the future. Critically, experiment 2 showed that when the generated items were presented alongside the intertemporal choices, both controls and amnesic participants shifted to more patient choices. These findings suggest that the MTL is not needed for making optimal decisions that draw on semantic future thinking as long as scaffolding is provided to support accurate time tagging. Together, these findings stand to better clarify the role of the MTL in decision making.

Does the hippocampus keep track of time?

In the present study, we examined the role of the medial temporal lobe (MTL) in prospective time estimation at short and long timescales using a novel behavioral paradigm adapted from rodent work. Amnesic patients with MTL damage and healthy control participants estimated the duration of nature-based video clips that were either short (≤ 90 s) or long (more than 4 min). Consistent with previous work in rodents, we found that amnesic patients were impaired at making estimations for long, but not for short durations. Critically, these effects were observed in patients who had lesions circumscribed to the hippocampus, suggesting that the pattern observed was not attributable to the involvement of extra-hippocampal structures. That the MTL, and more specifically the hippocampus, is critical for prospective temporal estimation only at long intervals suggests that multiple neurobiological mechanisms support prospective time estimation.

The neurological and cognitive sequelae of cardiac arrest.

BACKGROUND: Although cardiac arrest (CA) is commonly cited as a cause of amnesia, patients referred to the authors' center with a diagnosis of "amnesia" after CA rarely have isolated memory deficits. OBJECTIVE: To determine whether CA is a cause of pure amnesia and to assess patterns of cognitive deficits after CA. METHODS: The authors used cognitive assessment of 11 consecutive patients referred for memory deficits after CA, targeted at deficit domains identified in the literature reviews, and analysis of specific case reports and prospective studies of cognition after CA. RESULTS: The most common pattern of impairment in their patients was a combination of memory and motor deficits with variable executive impairment. No patient had isolated memory impairment. The case reports do not support the claim that isolated amnesia is a residual of CA; most cases of isolated amnesia are caused by subacute episodes of anoxia or excitotoxic injury. The prospective reports identify highly variable patterns of impairment, but isolated amnesia remains rare. CONCLUSIONS: Diffuse, sudden ischemic-hypoxic injury caused by cardiac arrest (CA) does not preferentially damage memory systems. Subacute or stepwise hypoxic or excitotoxic injury may cause isolated hippocampal injury and amnesia. The common pattern of impairment in the postacute phase after CA is a combination of memory, subtle motor, and variable executive deficits.

Memory systems of the brain: a cognitive neuropsychological analysis.

Neuropsychological studies of amnesic patients, cognitive studies of normal individuals, and functional neuroimaging studies have shaped our understanding of the cognitive and neural bases of various forms of human memory. This article reviews the functional and neural characteristics of working memory, declarative memory, and nondeclarative memory. In so doing, it highlights the pattern of impaired and preserved memory abilities that characterize different neurologic populations. This knowledge provides a framework for analyzing patients' neuropsychological deficits in terms of underlying cognitive processes.

Recognizing identical versus similar categorically related common objects: further evidence for degraded gist representations in amnesia.

Studies have shown lower false recognition of semantically related lure words in patients with global amnesia than in matched controls. This pattern has been interpreted as suggesting that medial temporal and diencephalic structures that are damaged in amnesia and that contribute to veridical memory also contribute to false recognition. It has been argued that whereas controls form and retain a well-organized representation of the semantic gist of studied items, patients with amnesia can retain only a degraded gist representation. However, these studies are subject to an alternative interpretation involving greater source confusions in controls. The authors used a categorized-pictures paradigm to test recognition under conditions in which source confusions were unlikely to occur. Relative to controls, patients with amnesia showed reduced false recognition of categorically related pictorial lures, thereby supporting the notion of degraded gist representations in amnesia.

The relationship between recall and recognition in amnesia: effects of matching recognition between patients with amnesia and controls.

To examine the relationship between recall and recognition memory in amnesia, the authors conducted 2 experiments in which recognition memory was equated between patients with amnesia and control participants. It was then determined whether recall was also similar across groups. In Experiment 1, recognition was equated by providing amnesic patients with additional study exposures; in Experiment 2, recognition was equated by testing controls following a longer delay. These different methods of equating recognition across groups led to divergent results because amnesic patients' recall performance was lower than controls' recall performance in Experiment 1 but not in Experiment 2. These findings are accounted for by considering the differential contribution of recollection and familiarity to the performance of amnesic patients and controls in the 2 experiments.

Recognition memory in amnesia: effects of relaxing response criteria.

In two experiments, using the remember/know paradigm, we examined whether recognition memory in amnesic patients can be improved by instructing patients to relax their response criterion. Experiment 1 was modeled after a study by Dorfman, Kihlstrom, Cork, and Misiaszek (1995), in which direct instructions to respond more leniently led to an increase in recognition accuracy in patients with ECT-induced amnesia. We failed to extend this finding to patients with global amnesia, but the manipulation was unsuccessful in control subjects as well. In Experiment 2, response criterion was manipulated indirectly by providing information about the alleged base rate of study items on the recognition test. This manipulation led to a criterion shift in control subjects and enhanced discriminability in amnesic patients. Analysis of "remember" and "know" responses suggests that improved accuracy in amnesia was associated with enhanced familiarity-based recognition.

The role of explicit memory processes in cross-modal priming: an investigation of stem completion priming in amnesia.

To clarify the role of explicit memory processes in cross-modal priming, two experiments examined the status of cross-modal stem completion priming in amnesia. Experiment 1 used a standard behavioral paradigm in which stems corresponding to studied and unstudied words were intermixed. Amnesic patients showed intact within- and cross-modal priming, but, in contrast to controls, they recognized very few of their completions as having been on the study list. This finding suggests that memorial awareness is not necessary for cross-modal priming to occur. Experiment 2 used a paradigm modeled after functional imaging studies, in which stems corresponding to studied and unstudied words were blocked. Amnesic patients showed intact within-modal priming, but impaired cross-modal priming. This finding is consistent with the notion that a blocked format induces voluntary retrieval strategies in normal participants.

Preserved priming in auditory perceptual identification in Alzheimer's disease.

To examine the status of auditory perceptual priming in Alzheimer's disease (AD), this study examined the performance of AD patients in auditory perceptual identification of words. In Experiment 1, the processing operations required to perform the tasks at study and test were matched, whereas in Experiment 2, processing operations at study and test were mismatched. AD patients showed normal priming in both experiments, despite impaired recognition memory. These findings extend to the auditory domain the finding of intact perceptual implicit memory in AD. Preserved auditory priming in AD may reflect the operation of a pre-semantic, phonological representation system, localized to posterior neocortical areas that are functionally spared in AD.

Role of perceptual and organizational factors in amnesics' recall of the Rey-Osterrieth complex figure: a comparison of three amnesic groups.

To examine the contribution of visual-perceptual and visual-organizational factors to visual memory in amnesia, Korsakoff, medial temporal, and anterior communicating artery (ACoA) aneurysm amnesics' copy, organization, and recall performance on the Rey-Osterrieth Complex Figure was assessed. Korsakoff patients were matched to medial temporal patients in terms of severity of amnesia, while the ACoA group, which was less severely amnesic, was matched to the Korsakoff patients on performance on executive tasks. Results indicated that while both the ACoA and Korsakoff groups had poorer copy accuracy and organization than controls, only the Korsakoff patients' copy accuracy was worse than the other two amnesic groups. While the Korsakoff patient's visuoperceptual deficits could partially explain this group's poor performance at immediate recall, the Korsakoff group's comparatively worse performance at delayed recall could not be accounted for by poor copy accuracy, reduced visual organization, or even the combined influence of these two factors.

Acquisition of novel semantic information in amnesia: effects of lesion location.

Two patients with severe global amnesia are described who differ in the extent to which they have acquired new semantic information. Patient SS, who has extensive medial temporal lobe damage including the hippocampus as well as surrounding cortical areas, has failed to acquire virtually any new information regarding vocabulary or famous faces that entered the public domain since the onset of his amnesia. In contrast, patient PS, who has a selective lesion of the hippocampus proper, has gained a sense of familiarity of novel vocabulary and famous people, even though her effortful retrieval of this new semantic knowledge remains impaired. These findings extend to amnesia of adult onset, the proposal of Vargha-Khadem and colleagues that in patients with selective hippocampal injury, cortical areas surrounding the hippocampus may play an important role in new semantic learning [Vargha-Khadem, F., Gadian, D.G., Watkins, K. E., Connelly, A., Van Paesschen, W. and Mishkin, M., regarding the importance of the subhippocampal cortices in the mediation of new semantic learning in children with hippocampal lesions, Science, 1997, 277, 376-380].

Fear recognition deficits after focal brain damage: a cautionary note.

OBJECTIVE: To test the hypothesis that fear recognition deficits in neurologic patients reflect damage to an emotion-specific neural network. BACKGROUND: Previous studies have suggested that the perception of fear in facial expressions is mediated by a specialized neural system that includes the amygdala and certain posterior right-hemisphere cortical regions. However, the neuropsychological findings in patients with amygdala damage are inconclusive, and the contribution of distinct cortical regions to fear perception has only been examined in one study. METHODS: We studied the recognition of six basic facial expressions by asking subjects to match these emotions with the appropriate verbal labels. RESULTS: Both normal control subjects (n = 80) and patients with focal brain damage (n = 63) performed significantly worse in recognizing fear than in recognizing any other facial emotion, with errors consisting primarily of mistaking fear for surprise. Although patients were impaired relative to control subjects in recognizing fear, we could not obtain convincing evidence that left, right, or bilateral lesions were associated with disproportionate impairments of fear perception once we adjusted for differences in overall recognition performance for the other five facial emotion categories. The proposed special role of the amygdala and posterior right-hemisphere cortical regions in fear perception was also not supported. CONCLUSIONS: Fear recognition deficits in neurologic patients may be attributable to task difficulty factors rather than damage to putative neural systems dedicated to fear perception.

A neuropsychological analysis of memory and amnesia.

Drawing on neuropsychological studies of amnesic patients, cognitive studies of normal individuals, and functional neuroimaging research, this article reviews recent developments in our understanding of the cognitive and neural bases of various forms of memory. This knowledge provides a foundation for a discussion of the clinical analysis of memory disorders. Different etiologies of selective memory impairment commonly seen in neurological practice are reviewed, followed by an overview of the clinical evaluation of memory disorders. In the evaluation of memory deficits, emphasis is placed on the identification of specific processing deficits that can be linked to underlying neuropathology.

Perceptual fluency as a cue for recognition judgments in amnesia.

This study investigated the extent to which amnesic patients use fluency of perceptual identification as a cue for recognition. Perceptual fluency was measured by having participants gradually unmask words before making recognition judgments. In Experiment 1, familiarity was the only possible basis for recognition because no words had been presented in the study phase. In Experiment 2, recollection provided an alternative basis for recognition because words had appeared in the study phase. Amnesic patients were as likely as normal controls to use perceptual fluency as a cue for recognition in Experiment 1 but were more likely than controls to do so in Experiment 2. For both groups, perceptual fluency affected judgments for studied and unstudied items to the same extent in Experiment 2. These findings suggest that amnesic patients do use perceptual fluency cues, but reliance on perceptual fluency does not necessarily elevate recognition accuracy.

When true recognition suppresses false recognition: evidence from amnesic patients.

False recognition occurs when people mistakenly claim that a novel item is familiar. After studying lists of semantically related words, healthy controls show extraordinarily high levels of false recognition to nonstudied lures that are semantic associates of study list words. In previous experiments, we found that both Korsakoff and non-Korsakoff amnesic patients show reduced levels of false recognition to semantic associates, implying that the medial temporal/diencephalic structures that are damaged in amnesic patients are involved in the encoding and/or retrieval of information that underlies false recognition. These data contrast with earlier results indicating greater false recognition in Korsakoff amnesics than in control subjects. The present experiment tests the hypothesis that greater or lesser false recognition of semantic associates in amnesic patients, relative to normal controls, can be demonstrated by creating conditions that are more or less conducive to allowing true recognition to suppress false recognition. With repeated presentation and testing of lists of semantic associates, control subjects and both Korsakoff and non-Korsakoff amnesics showed increasing levels of true recognition across trials. However, control subjects exhibited decreasing levels of false recognition across trials, whereas Korsakoff amnesic patients showed increases across trials and non-Korsakoff amnesics showed a fluctuating pattern. Consideration of signal detection analyses and differences between the two types of amnesic patients provides insight into how mechanisms of veridical episodic memory can be used to suppress false recognition.

Font-specific priming following global amnesia and occipital lobe damage.

Font-specificity in visual word-stem completion priming was examined in patients with global amnesia and Patient M.S., who had a right-occipital lobectomy. Word-stems appeared in the same or different font as study words. Amnesic patients showed normal font-specific priming (greater priming for words studied in the same than different font as test), despite impaired word-stem cued recall. Patient M.S. failed to exhibit font-specific priming, despite preserved declarative memory. Therefore, perceptual specificity in visual priming depends on visual processes mediated by the right-occipital lobe rather than medial temporal and diencephalic regions involved in declarative memory.

Illusory memories in amnesic patients: conceptual and perceptual false recognition.

Little is known about the neuropsychology of false recognition. D.L. Schacter, M. Verfaellie, and D. Pradere (1996) induced false recognition in amnesic patients and normal controls by exposing them to numerous semantic associates of a nonstudied word and found that amnesics showed significantly reduced levels of false recognition. To determine whether this outcome is specific to the semantic domain, the authors examined false recognition after exposure to lists of conceptually and perceptually related words. In the control group, conceptual false recognition was associated with "remember" responses and perceptual false recognition was associated with "know" responses. Amnesic patients showed reduced levels of conceptual and perceptual false recognition that were approximately equally divided between remember and know responses.

The neural basis of aware and unaware forms of memory.

Information regarding the nature of phenomenal awareness in memory comes from a direct comparison of explicit and implicit memory tasks. Explicit memory tasks require conscious awareness of a prior episode, whereas implicit memory tasks do not. This paper reviews evidence regarding the neural basis of aware and unaware forms of memory as obtained from patient studies and functional neuroimaging work. These studies suggest the existence of a memory system centered in the medial temporal and frontal lobes that is dedicated to the storage and retrieval of episodes and several neocortical memory systems that are dedicated to the processing and representation of perceptual and semantic information. Different hypotheses are discussed as to how the phenomenal awareness that accompanies episodic memories may arise within the hippocampal-frontal memory system. These views have in common the notion that various forms of information need to be bound together to be retrievable as an aware memory, and that the hippocampus is critical to this binding function.