Emilie T. Reas

Animal model of methylphenidate's long-term memory-enhancing effects

Methylphenidate (MPH), introduced more than 60 years ago, accounts for two-thirds of current prescriptions for attention deficit hyperactivity disorder (ADHD). Although many studies have modeled MPHs effect on executive function, almost none have directly modeled its effect on long-term memory (LTM), even though improvement in LTM is a critical target of therapeutic intervention in ADHD. We examined the effects of a wide range of doses of MPH (0.01-10 mg/kg, i.p.) on Pavlovian fear learning, a leading model of memory. MPHs effects were then compared to those of atomoxetine (0.1-10 mg/kg, i.p.), bupropion (0.5-20 mg/kg, i.p.), and citalopram (0.01-10 mg/kg, i.p.). At low, clinically relevant doses, MPH enhanced fear memory; at high doses it impaired memory. MPHs memory-enhancing effects were not confounded by its effects on locomotion or anxiety. Further, MPH-induced memory enhancement seemed to require both dopamine and norepinephrine transporter inhibition. Finally, the addictive potential of MPH (1 mg/kg and 10 mg/kg) was compared to those of two other psychostimulants, amphetamine (0.005 mg/kg and 1.5 mg/kg) and cocaine (0.15 mg/kg and 15 mg/kg), using a conditioned place preference and behavioral sensitization paradigm. We found that memory-enhancing effects of psychostimulants observed at low doses are readily dissociable from their reinforcing and locomotor activating effects at high doses. Together, our data suggest that fear conditioning will be an especially fruitful platform for modeling the effects of psychostimulants on LTM in drug development.

Retrieval search and strength evoke dissociable brain activity during episodic memory recall

Neuroimaging studies of episodic memory retrieval have revealed activations in the human frontal, parietal, and medial-temporal lobes that are associated with memory strength. However, it remains unclear whether these brain responses are veritable signals of memory strength or are instead regulated by concomitant subcomponents of retrieval such as retrieval effort or mental search. This study used event-related fMRI during cued recall of previously memorized word-pair associates to dissociate brain responses modulated by memory search from those modulated by the strength of a recalled memory. Search-related deactivations, dissociated from activity due to memory strength, were observed in regions of the default network, whereas distinctly strength-dependent activations were present in superior and inferior parietal and dorsolateral PFC. Both search and strength regulated activity in dorsal anterior cingulate and anterior insula. These findings suggest that, although highly correlated and partially subserved by overlapping cognitive control mechanisms, search and memory strength engage dissociable regions of frontoparietal attention and default networks.

Erratum: search-related suppression of hippocampus and default network activity during associative memory retrieval

Episodic memory retrieval involves the coordinated interaction of several cognitive processing stages such as mental search, access to a memory store, associative re-encoding, and post-retrieval monitoring. The neural response during memory retrieval is an integration of signals from multiple regions that may subserve supportive cognitive control, attention, sensory association, encoding, or working memory functions. It is particularly challenging to dissociate contributions of these distinct components to brain responses in regions such as the hippocampus, which lies at the interface between overlapping memory encoding and retrieval, and “default” networks. In the present study, event-related functional magnetic resonance imaging (fMRI) and measures of memory performance were used to differentiate brain responses to memory search from subcomponents of episodic memory retrieval associated with successful recall. During the attempted retrieval of both poorly and strongly remembered word pair associates, the hemodynamic response was negatively deflected below baseline in anterior hippocampus and regions of the default network. Activations in anterior hippocampus were functionally distinct from those in posterior hippocampus and negatively correlated with response times. Thus, relative to the pre-stimulus period, the hippocampus shows reduced activity during intensive engagement in episodic memory search. Such deactivation was most salient during trials that engaged only pre-retrieval search processes in the absence of successful recollection or post-retrieval processing. Implications for interpretation of hippocampal fMRI responses during retrieval are discussed. A model is presented to interpret such activations as representing modulation of encoding-related activity, rather than retrieval-related activity. Engagement in intensive mental search may reduce neural and attentional resources that are otherwise tonically devoted to encoding an individual’s stream of experience into episodic memory.

Effortful retrieval reduces hippocampal activity and impairs incidental encoding

Functional imaging studies frequently report that the hippocampus is engaged by successful episodic memory retrieval. However, considering that concurrent encoding of the background environment occurs during retrieval and influences medial temporal lobe activity, it is plausible that hippocampal encoding functions are reduced with increased attentional engagement during effortful retrieval. Expanding upon evidence that retrieval efforts suppress activity in hippocampal regions implicated in encoding, this study examines the influence of retrieval effort on encoding performance and the interactive effects of encoding and retrieval on hippocampal and neocortical activity. Functional magnetic resonance imaging was conducted while subjects performed a word recognition task with incidental picture encoding. Both lower memory strength and increased search duration were associated with encoding failure and reduced hippocampal and default network activity. Activity in the anterior hippocampus tracked encoding, which was more strongly deactivated when incidental encoding was unsuccessful. These findings highlight potential contributions from background encoding processes to hippocampal activations during neuroimaging studies of episodic memory retrieval.

Effects of Sex and Education on Cognitive Change Over a 27-Year Period in Older Adults: The Rancho Bernardo Study

OBJECTIVE This study investigated how cognitive function changes with age and whether rates of decline vary by sex or education in a large, homogenous longitudinal cohort characterized by high participation rates, long duration of follow-up, and minimal loss to follow-up. DESIGN/SETTING/PARTICIPANTS Between 1988 and 2016, 2,225 community-dwelling participants of the Rancho Bernardo Study, aged 31 to 99 years at their initial cognitive assessment, completed neuropsychological testing approximately every 4 years, over a maximum 27-year follow-up. MEASUREMENTS Linear mixed effects regression models defined sex-specific cognitive trajectories, adjusting for education and retest effects. RESULTS Significant decline across all cognitive domains began around age 65 years and accelerated after age 80 years. Patterns of decline were generally similar between sexes, although men declined more rapidly than women on the global function test. Higher education was associated with slower decline on the tests of executive and global functions. After excluding 517 participants with evidence of cognitive impairment, accelerating decline with age remained for all tests, and women declined more rapidly than men on the executive function test. CONCLUSIONS Accelerating decline with advancing age occurs across multiple cognitive domains in community-dwelling older adults, with few differences in rates of decline between men and women. Higher education may provide some protection against executive and global function decline with age. These findings better characterize normal cognitive aging, a critical prerequisite for identifying individuals at risk for cognitive impairment, and lay the groundwork for future studies of health and behavioral factors that affect age-related decline in this cohort.

Sensitivity of restriction spectrum imaging to memory and neuropathology in Alzheimer’s disease

BackgroundDiffusion imaging has demonstrated sensitivity to structural brain changes in Alzheimer’s disease (AD). However, there remains a need for a more complete characterization of microstructural alterations occurring at the earliest disease stages, and how these changes relate to underlying neuropathology. This study evaluated the sensitivity of restriction spectrum imaging (RSI), an advanced diffusion magnetic resonance imaging (MRI) technique, to microstructural brain changes in mild cognitive impairment (MCI) and AD.MethodsMRI and neuropsychological test data were acquired from 31 healthy controls, 12 individuals with MCI, and 13 individuals with mild AD, aged 63–93 years. Cerebrospinal fluid amyloid-β levels were measured in a subset (n = 38) of participants. RSI measures of neurite density (ND) and isotropic free water (IF) were computed in fiber tracts and in hippocampal and entorhinal cortex gray matter, respectively. Analyses evaluated whether these measures predicted memory performance, correlated with amyloid-β levels, and distinguished impaired individuals from controls. For comparison, analyses were repeated with standard diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA) and mean diffusivity.ResultsBoth RSI and DTI measures correlated with episodic memory and disease severity. RSI, but not DTI, measures correlated with amyloid-β42 levels. ND and FA in the arcuate fasciculus and entorhinal cortex IF most strongly predicted recall performance. RSI measures of arcuate fasciculus ND and entorhinal cortex IF best discriminated memory impaired participants from healthy participants.ConclusionsRSI is highly sensitive to microstructural changes in the early stages of AD, and is associated with biochemical markers of AD pathology. Reduced ND in cortical association fibers and increased medial temporal lobe free-water diffusion predicted episodic memory, distinguished cognitively impaired from healthy individuals, and correlated with amyloid-β. Although further research is needed to assess the sensitivity of RSI to preclinical AD and disease progression, these results suggest that RSI may be a promising tool to better understand neuroanatomical changes in AD and their association with neuropathology.

Imbalance of incidental encoding across tasks: An explanation for non-memory-related hippocampal activations?

Functional neuroimaging studies have increasingly noted hippocampal activation associated with a variety of cognitive functions--such as decision making, attention, perception, incidental learning, prediction, and working memory--that have little apparent relation to declarative memory. Such findings might be difficult to reconcile with classical hippocampal lesion studies that show remarkable sparing of cognitive functions outside the realm of declarative memory. Even the oft-reported hippocampal activations during confident episodic retrieval are not entirely congruent with evidence that hippocampal lesions reliably impair encoding but inconsistently affect retrieval. Here we explore the conditions under which the hippocampus responds during episodic recall and recognition. Our findings suggest that anterior hippocampal activity may be related to the imbalance of incidental encoding across tasks and conditions rather than due to retrieval per se. Incidental encoding and hippocampal activity may be reduced during conditions where retrieval requires greater attentional engagement. During retrieval, anterior hippocampal activity decreases with increasing search duration and retrieval effort, and this deactivation corresponds with a coincident impaired encoding of the external environment (Israel, Seibert, Black, & Brewer, 2010; Reas & Brewer, 2013; Reas, Gimbel, Hales, & Brewer, 2011). In light of this emerging evidence, we discuss the proposal that some hippocampal activity observed during memory retrieval, or other non-memory conditions, may in fact be attributable to concomitant encoding activity that is regulated by the attentional demands of the principal task.

Amyloid and Tau Pathology in Normal Cognitive Aging

Detecting deviations from healthy brain aging is critical for identifying individuals at greatest risk for developing dementia. Yet because there is substantial overlap in patterns of cognitive decline and neural changes between those with dementia and nondemented older adults, dissociating normal

Mean signal and response time influences on multivoxel signals of contextual retrieval in the medial temporal lobe.

The medial temporal lobe supports integrating the “what,” “where,” and “when” of an experience into a unified memory. However, it remains unclear how representations of these contextual features are neurally encoded and distributed across medial temporal lobe subregions.

Dietary Patterns and Cognitive Function among Older Community-Dwelling Adults

Diet may be an important modifiable risk factor for maintenance of cognitive health in later life. This study aimed at examining associations between common dietary indices and dietary patterns defined by factor analysis and cognitive function in older community-dwelling adults. Dietary information for 1499 participants from the Rancho Bernardo Study was collected in 1988–1992 and used to calculate the alternate Mediterranean diet score, Alternate Healthy Eating Index (AHEI)-2010 score and factor scores derived from factor analysis of nutrients. Global cognitive function, executive function, verbal fluency and episodic memory were assessed at approximate four-year intervals from 1988–2016. Linear mixed models were used to examine associations between dietary patterns and cognitive trajectories. Estimates for the highest vs. lowest tertile in models adjusting for age, sex, education, energy intake, lifestyle variables and retest effect showed greater adherence to the Mediterranean score was associated with better baseline global cognitive function (β (95% CI) = 0.33 (0.11, 0.55)). The AHEI-2010 score was not significantly associated with cognitive performance. Higher loading on a plant polyunsaturated fatty acid (PUFA)/vitamin E factor was associated with better baseline global cognitive function and executive function (β = 0.22 (0.02, 0.42) and β = −7.85 (−13.20, −2.47)). A sugar/low protein factor was associated with poorer baseline cognitive function across multiple domains. Dietary patterns were not associated with cognitive decline over time. Adherence to a healthy diet with foods high in PUFA and vitamin E and a low sugar to protein ratio, as typified by a Mediterranean diet, may be beneficial for cognitive health in late life.