Greater accelerometer-measured physical activity is associated with better cognition and cerebrovascular health in older adults.

OBJECTIVES: Physical activity (PA) may help maintain brain structure and function in aging. Since the intensity of PA needed to effect cognition and cerebrovascular health remains unknown, we examined associations between PA and cognition, regional white matter hyperintensities (WMH), and regional cerebral blood flow (CBF) in older adults. METHOD: Forty-three older adults without cognitive impairment underwent magnetic resonance imaging (MRI) and comprehensive neuropsychological assessment. Waist-worn accelerometers objectively measured PA for approximately one week. RESULTS: Higher time spent in moderate to vigorous PA (MVPA) was uniquely associated with better memory and executive functioning after adjusting for all light PA. Higher MVPA was also uniquely associated with lower frontal WMH volume although the finding was no longer significant after additionally adjusting for age and accelerometer wear time. MVPA was not associated with CBF. Higher time spent in all light PA was uniquely associated with higher CBF but not with cognitive performance or WMH volume. CONCLUSIONS: Engaging in PA may be beneficial for cerebrovascular health, and MVPA in particular may help preserve memory and executive function in otherwise cognitively healthy older adults. There may be differential effects of engaging in lighter PA and MVPA on MRI markers of cerebrovascular health although this needs to be confirmed in future studies with larger samples. Future randomized controlled trials that increase PA are needed to elucidate cause-effect associations between PA and cerebrovascular health.

The Retrograde Memory for News Events Test (RM-NET) and the relationship between news event memory and performance on standard neuropsychological tests.

Novel tests of semantic memory (SM)-for example, memory for news events (NE; news facts) or famous personalities-are useful for estimating the severity of retrograde amnesia. Individuals with mild cognitive impairment exhibit relatively intact SM/language on traditional neuropsychological tests but exhibit consistent impairment on novel tests of SM, suggesting novel SM tests are dissimilar from traditional SM tests. To identify the relationship between NE memory and traditional cognitive measures, older adults (N = 51) completed a traditional neuropsychological battery and the Retrograde Memory News Events Test (RM-NET; a new test that robustly measures NE memory across the adult life span with high temporal resolution), and the relationship between performance on these tests was examined. Total RM-NET scores were more closely aligned with episodic memory scores than SM scores. The strength of the association between NE scores and episodic memory scores decreased as the age of NE memory increased. Tests of news events appear to reflect performance on traditional tests of episodic memory rather than SM, especially when recent news events are tested.

Impaired Behavioral Pattern Separation in Refractory Temporal Lobe Epilepsy and Mild Cognitive Impairment.

OBJECTIVE: Episodic memory impairment and hippocampal pathology are hallmark features of both temporal lobe epilepsy (TLE) and amnestic mild cognitive impairment (aMCI). Pattern separation (PS), which enables the distinction between similar but unique experiences, is thought to contribute to successful encoding and retrieval of episodic memories. Impaired PS has been proposed as a potential mechanism underling episodic memory impairment in aMCI, but this association is less established in TLE. In this study, we examined behavioral PS in patients with TLE and explored whether profiles of performance in TLE are similar to aMCI. METHOD: Patients with TLE, aMCI, and age-matched, healthy controls (HCs) completed a modified recognition task that relies on PS for the discrimination of highly similar lure items, the Mnemonic Similarity Task (MST). Group differences were evaluated and relationships between clinical characteristics, California Verbal Learning Test-Second Edition scores, and MST performance were tested in the TLE group. RESULTS: Patients with TLE and aMCI demonstrated poorer PS performance relative to the HCs, but performance did not differ between the two patient groups. Neither the side of seizure focus nor having hippocampal sclerosis affected performance in TLE. However, TLE patients with clinically defined memory impairment showed the poorest performance. CONCLUSION: Memory performance on a task that relies on PS was disrupted to a similar extent in TLE and aMCI. The MST could provide a clinically useful tool for measuring hippocampus-dependent memory impairments in TLE and other neurological disorders associated with hippocampal damage.

Pregabalin for Recurrent Seizures in Critical Illness: A Promising Adjunctive Therapy, Especially for cyclic Seizures.

BACKGROUND: Pregabalin (PGB) is an effective adjunctive treatment for focal epilepsy and acts by binding to the alpha2-delta subunit of voltage-gated calcium channels to reduce excitatory neurotransmitter release. Limited data exist on its use in the neurocritical care setting, including cyclic seizures-a pattern of recurrent seizures occurring at nearly regular intervals. Although the mechanism underpinning cyclic seizures remains elusive, spreading excitation linked to spreading depolarizations may play a role in seizure recurrence and periodicity. PGB has been shown to increase spreading depolarization threshold; hence, we hypothesized that the magnitude of antiseizure effect from PGB is more pronounced in patients with cyclic versus noncyclic seizures in a critically ill cohort with recurrent seizures. METHODS: We conducted a retrospective case series of adults admitted to two academic neurointensive care units between January 2017 and March 2019 who received PGB for treatment of seizures. Data collected included demographics, etiology of brain injury, antiseizure medications, and outcome. Continuous electroencephalogram recordings 48 hours before and after PGB administration were reviewed by electroencephalographers blinded to the administration of antiseizure medications to obtain granular data on electrographic seizure burden. Cyclic seizures were determined quantitatively (i.e., < 50% variation of interseizure intervals for at least 50% of consecutive seizures). Coprimary outcomes were decrease in hourly seizure burden in minutes and decrease in seizure frequency in the 48 hours after PGB initiation. We used nonparametric tests for comparison of seizure frequency and burden and segmented linear regression to assess PGB effect. RESULTS: We included 16 patients; the median age was 69 years, 11 (68.7%) were women, three (18.8%) had undergone a neurosurgical procedure, and five (31%) had underlying epilepsy. All seizures had focal onset; ten patients (62.5%) had cyclic seizures. The median hourly seizure burden over the 48 hours prior to PGB initiation was 1.87 min/hour (interquartile range 1.49-8.53), and the median seizure frequency was 1.96 seizures/hour (interquartile range 1.06-3.41). In the 48 hours following PGB (median daily dose 300 mg, range 75-300 mg), the median number of seizures per hour was reduced by 0.80 seizures/hour (95% confidence interval 0.19-1.40), whereas the median hourly seizure burden decreased by 1.71 min/hour (95% confidence interval 0.38-3.04). When we compared patients with cyclic versus noncyclic seizures, there was a relative decrease in hourly seizure frequency (- 86.7% versus - 2%, p = 0.04) and hourly seizure burden (- 89% versus - 7.8%, p = 0.03) at 48 hours. CONCLUSIONS: PGB was associated with a relative reduction in seizure burden in neurocritically ill patients with recurrent seizures, especially those with cyclic seizures, and may be considered in the therapeutic arsenal for refractory seizures. Whether this effect is mediated via modulation of spreading depolarization requires further study.

Awareness of what is learned as a characteristic of hippocampus-dependent memory.

We explored the relationship between memory performance and conscious knowledge (or awareness) of what has been learned in memory-impaired patients with hippocampal lesions or larger medial temporal lesions. Participants viewed familiar scenes or familiar scenes where a change had been introduced. Patients identified many fewer of the changes than controls. Across all of the scenes, controls preferentially directed their gaze toward the regions that had been changed whenever they had what we term robust knowledge about the change: They could identify that a change occurred, report what had changed, and indicate where the change occurred. Preferential looking did not occur when they were unaware of the change or had only partial knowledge about it. The patients, overall, did not direct their gaze toward the regions that had been changed, but on the few occasions when they had robust knowledge about the change they (like controls) did exhibit this effect. Patients did not exhibit this effect when they were unaware of the change or had partial knowledge. The findings support the idea that awareness of what has been learned is a key feature of hippocampus-dependent memory.

Eye movements support the link between conscious memory and medial temporal lobe function.

When individuals select the recently studied (and familiar) item in a multiple-choice memory test, they direct a greater proportion of viewing time toward the to-be-selected item when their choice is correct than when their choice is incorrect. Thus, for both correct and incorrect choices, individuals indicate that the chosen item is old, but viewing time nevertheless distinguishes between old and new items. What kind of memory supports this preferential viewing effect? We recorded eye movements while participants made three-alternative, forced-choice recognition memory judgments for scenes. In experiment 1 (n = 30), the magnitude of the preferential viewing effect was strongly correlated with measures of conscious, declarative memory: recognition accuracy as well as the difference in confidence ratings and in response times for correct and incorrect choices. In four analyses that minimized the contribution of declarative memory in order to detect a possible contribution from other processes, the preferential viewing effect was absent. In experiment 2, five memory-impaired patients with medial temporal lobe lesions exhibited a diminished preferential viewing effect. These patients also exhibited poor recognition accuracy and reduced differences in confidence ratings and response times for correct and incorrect choices. We propose that the preferential viewing effect is a phenomenon of conscious, declarative memory and is dependent on the medial temporal lobe. The findings support the link between medial temporal lobe function and declarative memory. When the effects of experience depend on the medial temporal lobe, the effects reflect conscious memory.

When eye movements express memory for old and new scenes in the absence of awareness and independent of hippocampus.

Eye movements can reflect memory. For example, participants make fewer fixations and sample fewer regions when viewing old versus new scenes (the repetition effect). It is unclear whether the repetition effect requires that participants have knowledge (awareness) of the old-new status of the scenes or if it can occur independent of knowledge about old-new status. It is also unclear whether the repetition effect is hippocampus-dependent or hippocampus-independent. A complication is that testing conscious memory for the scenes might interfere with the expression of unconscious (unaware), experience-dependent eye movements. In experiment 1, 75 volunteers freely viewed old and new scenes without knowledge that memory for the scenes would later be tested. Participants then made memory judgments and confidence judgments for each scene during a surprise recognition memory test. Participants exhibited the repetition effect regardless of the accuracy or confidence associated with their memory judgments (i.e., the repetition effect was independent of their awareness of the old-new status of each scene). In experiment 2, five memory-impaired patients with medial temporal lobe damage and six controls also viewed old and new scenes without expectation of memory testing. Both groups exhibited the repetition effect, even though the patients were impaired at recognizing which scenes were old and which were new. Thus, when participants viewed scenes without expectation of memory testing, eye movements associated with old and new scenes reflected unconscious, hippocampus-independent memory. These findings are consistent with the formulation that, when memory is expressed independent of awareness, memory is hippocampus-independent.

Comparison of explicit and incidental learning strategies in memory-impaired patients.

Declarative memory for rapidly learned, novel associations is thought to depend on structures in the medial temporal lobe (MTL), whereas associations learned more gradually can sometimes be supported by nondeclarative memory and by structures outside the MTL. A recent study suggested that even rapidly learned associations can be supported by structures outside the MTL when an incidental encoding procedure termed "fast mapping" (FM) is used. We tested six memory-impaired patients with bilateral damage to hippocampus and one patient with large bilateral lesions of the MTL. Participants saw photographs and names of animals, plants, and foods that were previously unfamiliar (e.g., mangosteen). Instead of asking participants to study name-object pairings for a later memory test (as with traditional memory instructions), participants answered questions that allowed them to infer which object corresponded to a particular name. In a second condition, participants learned name-object associations of unfamiliar items by using standard, explicit encoding instructions (e.g., remember the mangosteen). In FM and explicit encoding conditions, patients were impaired (and performed no better than a group that was given the same tests but had not previously studied the material). The same results were obtained in a second experiment that used the same procedures with modifications to allow for more robust learning and more reliable measures of performance. Thus, our results with the FM procedure and memory-impaired patients yielded the same deficits in learning and memory that have been obtained by using other more traditional paradigms.

When recognition memory is independent of hippocampal function.

Hippocampal damage has been thought to result in broad memory impairment. Recent studies in humans, however, have raised the possibility that recognition memory for faces might be spared. In five experiments we investigated face recognition in patients with hippocampal lesions (H) or large medial temporal lobe (MTL) lesions, including patients where neurohistological information was available. Recognition of novel faces was unequivocally intact in H patients but only at a short retention interval. Recognition memory for words, buildings, inverted faces, and famous faces was impaired. For MTL patients, recognition memory was impaired for all materials and across all retention intervals. These results indicate that structures other than the hippocampus, perhaps the perirhinal cortex, can support face recognition memory in H patients under some conditions. The fact that the faces were novel when recognition memory was intact does not fully account for our findings. We propose that the role of the hippocampus in recognition memory is related to how recognition decisions are accomplished. In typical recognition tasks, participants proceed by forming an association between a study item and the study list, and the recognition decision is later made based on whether participants believe the item was on the study list. We suggest that face recognition is an exception to this principle and that, at short retention intervals, participants can make their recognition decisions without making explicit reference to the study list. Important features of faces that might make face recognition exceptional are that they are processed holistically and are difficult to verbally label.

True and false memories, parietal cortex, and confidence judgments.

Recent studies have asked whether activity in the medial temporal lobe (MTL) and the neocortex can distinguish true memory from false memory. A frequent complication has been that the confidence associated with correct memory judgments (true memory) is typically higher than the confidence associated with incorrect memory judgments (false memory). Accordingly, it has often been difficult to know whether a finding is related to memory confidence or memory accuracy. In the current study, participants made recognition memory judgments with confidence ratings in response to previously studied scenes and novel scenes. The left hippocampus and 16 other brain regions distinguished true and false memories when confidence ratings were different for the two conditions. Only three regions (all in the parietal cortex) distinguished true and false memories when confidence ratings were equated. These findings illustrate the utility of taking confidence ratings into account when identifying brain regions associated with true and false memories. Neural correlates of true and false memories are most easily interpreted when confidence ratings are similar for the two kinds of memories.