Donepezil Impairs Memory in Healthy Older Subjects: Behavioural, EEG and Simultaneous EEG/fMRI Biomarkers

Rising life expectancies coupled with an increasing awareness of age-related cognitive decline have led to the unwarranted use of psychopharmaceuticals, including acetylcholinesterase inhibitors (AChEIs), by significant numbers of healthy older individuals. This trend has developed despite very limited data regarding the effectiveness of such drugs on non-clinical groups and recent work indicates that AChEIs can have negative cognitive effects in healthy populations. For the first time, we use a combination of EEG and simultaneous EEG/fMRI to examine the effects of a commonly prescribed AChEI (donepezil) on cognition in healthy older participants. The short- and long-term impact of donepezil was assessed using two double-blind, placebo-controlled trials. In both cases, we utilised cognitive (paired associates learning (CPAL)) and electrophysiological measures (resting EEG power) that have demonstrated high-sensitivity to age-related cognitive decline. Experiment 1 tested the effects of 5 mg/per day dosage on cognitive and EEG markers at 6-hour, 2-week and 4-week follow-ups. In experiment 2, the same markers were further scrutinised using simultaneous EEG/fMRI after a single 5 mg dose. Experiment 1 found significant negative effects of donepezil on CPAL and resting Alpha and Beta band power. Experiment 2 replicated these results and found additional drug-related increases in the Delta band. EEG/fMRI analyses revealed that these oscillatory differences were associated with activity differences in the left hippocampus (Delta), right frontal-parietal network (Alpha), and default-mode network (Beta). We demonstrate the utility of simple cognitive and EEG measures in evaluating drug responses after acute and chronic donepezil administration. The presentation of previously established markers of age-related cognitive decline indicates that AChEIs can impair cognitive function in healthy older individuals. To our knowledge this is the first study to identify the precise neuroanatomical origins of EEG drug markers using simultaneous EEG/fMRI. The results of this study may be useful for evaluating novel drugs for cognitive enhancement

Uncovering the neural signature of lapsing attention: Electrophysiological predictors of human error are apparent up to 20 s in advance

The extent to which human error can be predicted by monitoring changes in brain activity is uncertain yet has important theoretical and practical implications. The present study examined changes in a range of electrophysiological signals preceding a lapse on a specially designed test of sustained attention. Twenty-one participants performed a continuous temporal expectancy task which involved monitoring a stream of regularly alternating patterned stimuli in order to detect a rarely occurring target stimulus whose duration was 40% longer. The task was designed to place continuous demands on attentional resources and hence to elicit frequent errors. Variations in a variety of attention-sensitive EEG and event-related potential measures were analysed in an epoch extending up to 30 s prior to target stimulus onset. Our results indicated that errors were consistently preceded by an endogenous increase in alpha band activity (8– 14 Hz) beginning approximately 20 s before the error actually occurred. Errors were also preceded by shorter-term decreases in the amplitude of two stimulus-related components: the frontal P3 which traces the timing of task stimuli and the contingent-negative variation which is sensitive to target anticipation and motor preparation. In contrast, visual evoked potentials did not distinguish between hits and misses in the pre-target interval suggesting that the efficacy of ongoing basic visual processing was unaffected by lapsing attention. Our results show that the specific neural signatures of attentional lapses are registered in the EEG up to 20 s prior to an error an identify new avenues for the development of novel feedback protocols

Lost in time: temporal monitoring elicits clinical decrements in sustained attention post-stroke

AbstractObjectiveMental fatigue, ‘brain fog’ and difficulties maintaining engagement are commonly reported issues in a range of neurological and psychiatric conditions. Traditional sustained attention tasks commonly measure this capacity as the ability to detect target stimuli based on sensory features in the auditory or visual domains. However, with this approach, discrete target stimuli may exogenously capture attention to aid detection, thereby masking deficits in the ability to endogenously sustain attention over time.MethodTo address this, we developed the continuous temporal expectancy test (CTET) where individuals continuously monitor a stream of patterned stimuli alternating at a fixed temporal interval (690ms) and detect an infrequently occurring target stimulus defined by a prolonged temporal duration (1020ms or longer). As such, sensory properties of target and non-target stimuli are perceptually identical and differ only in temporal duration. Using the CTET, we assessed stroke survivors with unilateral right hemisphere damage (N=14), a cohort in which sustained attention deficits have been extensively reported.ResultsStroke survivors had overall lower target detection accuracy compared to neurologically-healthy age-matched older controls (N=18). In addition, performance of the stroke survivors was characterised by significantly steeper within-block performance decrements which occurred within short temporal windows (~3 ½ minutes) and were restored by the break periods between blocks.ConclusionThese findings outline a precise measure of the endogenous processes hypothesized to underpin sustained attention deficits following right hemisphere stroke and suggest that continuous temporal monitoring taxes sustained attention process to capture clinical deficits in this capacity over time.</jats:sec

Dataset for: Self-initiated learning reveals memory performance and electrophysiological differences between younger, older and older adults with relative memory impairment

Older adults display difficulties in encoding and retrieval of information, resulting in poorer memory. This may be due to an inability of older adults to engage elaborative encoding strategies during learning. This study examined behavioural and electrophysiological effects of explicit cues to self-initiate learning during encoding and subsequent recognition of words in younger adults (YA), older control adults (OA) and older adults with relative memory impairment (OD). The task was a variation of the Old/New paradigm, some study items were preceded by a cue to learn the word (L) while others by a do not learn cue (X). Behaviourally, YA outperformed OA and OD on the recognition task, with no significant difference between OA and OD. Event-related potentials at encoding revealed enhanced early visual processing (70-140ms) for L-vs.X-words in young and old. Only YA exhibited a greater late posterior positivity (LPP) (200-500ms) for all words during encoding perhaps reflecting superior encoding strategy. During recognition, only YA differentiated L-vs.X-words with enhanced frontal P200 (150-250ms) suggesting impaired early word selection for retrieval in older groups, however OD had enhanced activity compared to OA during L-word. The LPP (250-500ms) was reduced in amplitude for L-words compared to both X- and New-words. However, YA and OD showed greater LPP amplitude for all words compared to OA. For older groups, we observed reduced left parietal hemispheric asymmetry apparent in YA during encoding and recognition, especially for OD. Findings are interpreted in light of models of compensation and dedifferentiation associated with age-related changes in memory function

Sustained attention in traumatic brain injury (tbi) and healthy controls: enhanced sensitivity with dual-task load

Poor sustained attention or alertness is a common consequence of traumatic brain injury (TBI) and has a considerable impact on the recovery and adjustment of TBI patients. Here, we describe the development of a sensitive laboratory task in healthy subjects (Experiment 1) and its enhanced sensitivity to sustained attention errors in TBI patients (Experiment 2). The task involves withholding a key press to an infrequent no-go target embedded within a predictable sequence of numbers (primary goal) and detecting grey-coloured targets within the sequence (secondary goal). In Experiment 1, we report that neurologically healthy subjects are more likely to experience a lapse of attention and neglect the primary task goal, despite ceiling performance on the secondary task. Further, attentional lapses on the task correlated with everyday attentional failures and variability of response time. In Experiment 2, the task discriminates between TBI patients and controls with a large effect size. The dual-task yields more errors in both groups than a simple task involving only the primary goal that is commonly used to detect sustained attention deficits in neurologically impaired groups. TBI patients' errors also correlated with everyday cognitive failures and variability of response time. This was not the case in the simple version of the task. We conclude that the dual-task demand associated with this task enhances its sensitivity as a measure of sustained attention in TBI patients and neurologically healthy controls that relates to everyday slips of attention

Impairments in Background and Event-Related Alpha-Band Oscillatory Activity in Patients with Schizophrenia

Studies show that patients with schizophrenia exhibit impaired responses to sensory stimuli, especially at the early stages of neural processing. In particular, patients’ alpha-band (8–14 Hz) event-related desynchronization (ERD) and visual P1 event-related potential (ERP) component tend to be significantly reduced, with P1 ERP deficits greater for visual stimuli biased towards the magnocellular system. In healthy controls, studies show that pre-stimulus alpha (background alpha) plays a pivotal role in sensory processing and behavior, largely by shaping the neural responses to incoming stimuli. Here, we address whether patients’ ERD and P1 deficits stem from impairments in pre-stimulus alpha mechanisms. To address this question we recorded electrophysiological activity in patients with schizophrenia and healthy controls while they engaged in a visual discrimination task with low, medium, and high contrast stimuli. The results revealed a significant decrease in patients’ ERDs, which was largely driven by reductions in pre-stimulus alpha. These reductions were most prominent in right-hemispheric areas. We also observed a systematic relationship between pre-stimulus alpha and the P1 component across different contrast levels. However, this relationship was only observed in healthy controls. Taken together, these findings highlight a substantial anomaly in patients’ amplitude-based alpha background activity over visual areas. The results provide further support that pre-stimulus alpha activity plays an active role in perception by modulating the neural responses to incoming sensory inputs, a mechanism that seems to be compromised in schizophrenia