Medial Temporal Lobe Damage Impairs Temporal Integration in Episodic Memory.

Although the role of the medial temporal lobe (MTL) and the hippocampus in episodic memory is well established, there is emerging evidence that these regions play a broader role in cognition, specifically in temporal processing. However, despite strong evidence that the hippocampus plays a critical role in sequential processing, the involvement of the MTL in timing per se is poorly understood. In the present study, we investigated whether patients with MTL damage exhibit differential performance on a temporal distance memory task. Critically, we manipulated context shifts, or boundaries, which have been shown to interfere with associative binding, leading to increases in subjective temporal distance. We predicted that patients with MTL damage would show impaired binding across boundaries and thus fail to show temporal expansion. Consistent with this hypothesis, unilateral patients failed to show a temporal expansion effect, and bilateral patients actually exhibited the reverse effect, suggesting a critical role for the MTL in binding temporal information across boundaries. Furthermore, patients were impaired overall on both the temporal distance memory task and recognition memory, but not on an independent, short-timescale temporal perception task. Interestingly, temporal distance performance could be independently predicted by performance on recognition memory and the short temporal perception task. Together, these data suggest that distinct mnemonic and temporal processes may influence long interval temporal memory and that damage to the MTL may impair the ability to integrate episodic and temporal information in memory.

The Medial Temporal Lobe Is Critical for Spatial Relational Perception.

The medial temporal lobe (MTL) is traditionally considered to be a system that is specialized for long-term memory. Recent work has challenged this notion by demonstrating that this region can contribute to many domains of cognition beyond long-term memory, including perception and attention. One potential reason why the MTL (and hippocampus specifically) contributes broadly to cognition is that it contains relational representations-representations of multidimensional features of experience and their unique relationship to one another-that are useful in many different cognitive domains. Here, we explore the hypothesis that the hippocampus/MTL plays a critical role in attention and perception via relational representations. We compared human participants with MTL damage to healthy age- and education-matched individuals on attention tasks that varied in relational processing demands. On each trial, participants viewed two images (rooms with paintings). On "similar room" trials, they judged whether the rooms had the same spatial layout from a different perspective. On "similar art" trials, they judged whether the paintings could have been painted by the same artist. On "identical" trials, participants simply had to detect identical paintings or rooms. MTL lesion patients were significantly and selectively impaired on the similar room task. This work provides further evidence that the hippocampus/MTL plays a ubiquitous role in cognition by virtue of its relational and spatial representations and highlights its important contributions to rapid perceptual processes that benefit from attention.

Human Dorsolateral Prefrontal Cortex Is Not Necessary for Spatial Working Memory.

A dominant theory, based on electrophysiological and lesion evidence from nonhuman primate studies, posits that the dorsolateral prefrontal cortex (dlPFC) stores and maintains working memory (WM) representations. Yet, neuroimaging studies have consistently failed to translate these results to humans; these studies normally find that neural activity persists in the human precentral sulcus (PCS) during WM delays. Here, we attempt to resolve this discrepancy. To test the degree to which dlPFC is necessary for WM, we compared the performance of patients with dlPFC lesions and neurologically healthy controls on a memory-guided saccade task that was used in the monkey studies to measure spatial WM. We found that dlPFC damage only impairs the accuracy of memory-guided saccades if the damage impacts the PCS; lesions to dorsolateral dlPFC that spare the PCS have no effect on WM. These results identify the necessary subregion of the frontal cortex for WM and specify how this influential animal model of human cognition must be revised.

Parahippocampal and Entorhinal Resection Extent Predicts Verbal Memory Decline in an Epilepsy Surgery Cohort.

The differential contribution of medial-temporal lobe regions to verbal declarative memory is debated within the neuroscience, neuropsychology, and cognitive psychology communities. We evaluate whether the extent of surgical resection within medial-temporal regions predicts longitudinal verbal learning and memory outcomes. This single-center retrospective observational study involved patients with refractory temporal lobe epilepsy undergoing unilateral anterior temporal lobe resection from 2007 to 2015. Thirty-two participants with Engel Class 1 and 2 outcomes were included (14 left, 18 right) and followed for a mean of 2.3 years after surgery (±1.5 years). Participants had baseline and postsurgical neuropsychological testing and high-resolution T1-weighted MRI scans. Postsurgical lesions were manually traced and coregistered to presurgical scans to precisely quantify resection extent of medial-temporal regions. Verbal learning and memory change scores were regressed on hippocampal, entorhinal, and parahippocampal resection volume after accounting for baseline performance. Overall, there were no significant differences in learning and memory change between patients who received left and right anterior temporal lobe resection. After controlling for baseline performance, the extent of left parahippocampal resection accounted for 27% (p = .021) of the variance in verbal short delay free recall. The extent of left entorhinal resection accounted for 37% (p = .004) of the variance in verbal short delay free recall. Our findings highlight the critical role that the left parahippocampal and entorhinal regions play in recall for verbal material.

Toward a neuropsychology of political orientation: exploring ideology in patients with frontal and midbrain lesions.

How do people form their political beliefs? In an effort to address this question, we adopt a neuropsychological approach. In a natural experiment, we explored links between neuroanatomy and ideological preferences in two samples of brain lesion patients in New York City. Specifically, we compared the political orientations of patients with frontal lobe lesions, patients with amygdala lesions and healthy control subjects. Lesion type classification analyses revealed that people with frontal lesions held more conservative (or less liberal) beliefs than those with anterior temporal lobe lesions or no lesions. Additional analyses predicting ideology by extent of damage provided convergent evidence that greater damage in the dorsolateral prefrontal cortex-but not the amygdala-was associated with greater conservatism. These findings were robust to model specifications that adjusted for demographic, mood, and affect-related variables. Although measures of executive function failed to mediate the relationship between frontal lesions and ideology, our findings suggest that the prefrontal cortex may play a role in promoting the development of liberal ideology. Our approach suggests useful directions for future work to address the issue of whether biological developments precede political attitudes or vice versa-or both. This article is part of the theme issue 'The political brain: neurocognitive and computational mechanisms'.

Pre-existing antitherapeutic antibodies against the Fc region of the hu14.18K322A mAb are associated with outcome in patients with relapsed neuroblastoma.

PURPOSE: Patients with cancer receiving tumor-reactive humanized monoclonal antibody (mAb) therapy can develop a human antihuman antibody (HAHA) response against the therapeutic mAb. We evaluated for HAHA in patients with neuroblastoma treated in a phase I study of humanized anti-GD2 mAb (immunoglobulin (Ig)G1 isotype), hu14.18K322A (NCT00743496). The pretreatment sera (collected prior to mAb treatment) from 9 of 38 patients contained antitherapeutic antibodies, even though they had no prior mAb exposure. We sought to characterize these pre-existing antitherapeutic antibodies (PATA). EXPERIMENTAL DESIGN: The PATA+ pretreatment samples were characterized via ELISA; clinical associations with PATA status were evaluated. RESULTS: Pretreatment sera from eight of nine PATA+ patients also bound rituximab and demonstrated preferential ELISA reactivity against the Fc portions of hu14.18K322A and rituximab as compared with the Fab portions of these mAbs. These PATA+ sera also recognized dinutuximab (human IgG1 isotype) and mouse IgG2a isotype mAbs, but not a mouse IgG1 isotype or the fully human panitumumab (IgG2 isotype) mAb. Of the 38 treated patients, only 4 patients (all in the PATA+ cohort) demonstrated no disease progression for >2.5 years without receiving further therapy (p=0.002). CONCLUSIONS: This study demonstrates an association between clinical outcome and the presence of PATA against determinant(s) on the Fc component of the therapeutic mAb, suggesting that the PATA may be playing a role in augmenting mAb-based antitumor effects. Further analyses for the presence of PATA in a larger cohort of patients with relapsed neuroblastoma, analyses of their clinical correlates, identification of their immunological targets, and potential antitumor mechanisms are warranted.

Patients with dorsolateral prefrontal cortex lesions are capable of discriminatory threat learning but appear impaired in cognitive regulation of subjective fear.

Humans are able to cognitively regulate emotions by changing their thoughts. Neuroimaging studies show correlations between dorsolateral prefrontal cortex (dlPFC) activity and cognitive regulation of emotions. Here our objective was to investigate whether dlPFC damage is associated with impaired cognitive regulation of emotion. We therefore tested the ability of patients with dlPFC lesions (N = 6) and matched control participants (N = 19) to utilize a laboratory version of cognitive regulation training (CRT) to regulate subjective fear and autonomic threat responses following Pavlovian threat conditioning. We found that patients with dlPFC lesions were able to acquire conditioned threat but seemed impaired in their ability to utilize CRT to cognitively regulate subjective fear to a threatening stimulus. Despite inclusion of a limited number of lesion patients, our results suggest that the dlPFC is important for the cognitive regulation of subjective fear.

Hippocampal Contributions to Model-Based Planning and Spatial Memory.

Little is known about the neural mechanisms that allow humans and animals to plan actions using knowledge of task contingencies. Emerging theories hypothesize that it involves the same hippocampal mechanisms that support self-localization and memory for locations. Yet limited direct evidence supports the link between planning and the hippocampal place map. We addressed this by investigating model-based planning and place memory in healthy controls and epilepsy patients treated using unilateral anterior temporal lobectomy with hippocampal resection. Both functions were impaired in the patient group. Specifically, the planning impairment was related to right hippocampal lesion size, controlling for overall lesion size. Furthermore, although planning and boundary-driven place memory covaried in the control group, this relationship was attenuated in patients, consistent with both functions relying on the same structure in the healthy brain. These findings clarify both the neural mechanism of model-based planning and the scope of hippocampal contributions to behavior.

Understanding perirhinal contributions to perception and memory: Evidence through the lens of selective perirhinal damage.

Although a memory systems view of the medial temporal lobe (MTL) has been widely influential in understanding how memory processes are implemented, a large body of work across humans and animals has converged on the idea that the MTL can support various other decisions, beyond those involving memory. Specifically, recent work suggests that perception of and memory for visual representations may interact in order to support ongoing cognition. However, given considerations involving lesion profiles in neuropsychological investigations and the correlational nature of fMRI, the precise nature of representations supported by the MTL are not well understood in humans. In the present investigation, three patients with highly specific lesions to MTL were administered a task that taxed perceptual and mnemonic judgments with highly similar face stimuli. A striking double dissociation was observed such that I.R., a patient with a cyst localized to right posterior PRc, displayed a significant impairment in perceptual discriminations, whereas patient A.N., an individual with a lesion in right posterior parahippocampal cortex and the tail of the right hippocampus, and S.D., an individual with bilateral hippocampal damage, did not display impaired performance on the perceptual task. A.N. and S.D. did, however, show impairments in memory performance, whereas patient I.R. did not. These results causally implicate right PRc in successful perceptual oddity judgments, however they suggest that representations supported by PRc are not necessary for correct mnemonic judgments, even in situations of high featural overlap.

Dissociable contributions of the prefrontal cortex in group-based cooperation.

The success of our political institutions, environmental stewardship and evolutionary fitness all hinge on our ability to prioritize collective-interest over self-interest. Despite considerable interest in the neuro-cognitive processes that underlie group cooperation, the evidence to date is inconsistent. Several papers support models of prosocial restraint, while more recent work supports models of prosocial intuition. We evaluate these competing models using a sample of lesion patients with damage to brain regions previously implicated in intuition and deliberation. Compared to matched control participants (brain damaged and healthy controls), we found that patients with dorsolateral prefrontal cortex (dlPFC) damage were less likely to cooperate in a modified public goods game, whereas patients with ventromedial prefrontal cortex (vmPFC) damage were more likely to cooperate. In contrast, we observed no association between cooperation and amygdala damage relative to controls. These findings suggest that the dlPFC, rather than the vmPFC or amygdala, plays a necessary role in group-based cooperation. These findings suggest cooperation does not solely rely on intuitive processes. Implications for models of group cooperation are discussed.

Validity of the Clock Drawing Test in predicting reports of driving problems in the elderly.

BACKGROUND: This study examined the use of the Folstein Mini Mental Status Exam (MMSE) and the Clock Drawing Test (CDT) in predicting retrospective reports of driving problems among the elderly. The utility of existing scoring systems for the CDT was also examined. METHODS: Archival chart records of 325 patients of a geriatric outpatient clinic were reviewed, of which 162 had CDT results (including original clock drawings). T-test, correlation, and regression procedures were used to analyze the data. RESULTS: Both CDT and MMSE scores were significantly worse among non-drivers than individuals who were currently or recently driving. Among current or recent drivers, scores on both instruments correlated significantly with the total number of reported accidents or near misses, although the magnitude of the respective correlations was small. Only MMSE scores, however, significantly predicted whether or not any accidents or near misses were reported at all. Neither MMSE nor CDT scores predicted unique variance in the regressions. CONCLUSIONS: The overall results suggest that both the MMSE and CDT have limited utility as potential indicators of driving problems in the elderly. The demonstrated predictive power for these instruments appears to be redundant, such that both appear to assess general cognitive function versus more specific abilities. Furthermore, the lack of robust prediction suggests that neither are sufficient to serve as stand-alone instruments on which to solely base decisions of driving capacity. Rather, individuals who evidence impairment should be provided a more thorough and comprehensive assessment than can be obtained through screening tools.

WITHDRAWN: Cognitive effects of androgen deprivation therapy in an older cohort of men with prostrate cancer.

This article has been withdrawn from Critical Reviews in Oncology/Hematology. With the permission of the authors, it has been published in Volume1, issue 1 of the Journal of Geriatric Oncology (www.geriatriconcology.net). The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

Cognitive effects of androgen deprivation therapy in an older cohort of men with prostate cancer.

OBJECTIVE: To determine the baseline prevalence of cognitive impairment in older men treated with ADT and to assess changes in cognitive performance over time. METHODS AND RESULTS: Thirty-two patients (median age of 71 years, range 51-87) were administrated an extensive neuropsychological testing battery prior to ADT initiation, with 21 (65%) completing post-treatment evaluations 6 months later. At baseline, 45% scored >1.5 standard deviations below the mean on > or = 2 neuropsychological measures. Using standardized inferential statistics, no change in cognition was documented following treatment. The Reliable Change Index revealed that, on a case-by-case basis, 38% demonstrated a decline in measures of executive functioning and 48% showed improvement on measures of visuospatial abilities. Within exploratory analyses, patients who scored below expectation at baseline displayed no change in cognition, while patients with average or better scores at baseline displayed improvements in visuospatial planning and timed tests of phonemic fluency. CONCLUSIONS: We found a high prevalence of lower than expected cognitive performance among a sample of patients just starting ADT for prostate cancer. Assessment of baseline cognitive function should be taken into account for future research and to inform clinical management.