Nadine Külzow

Relationship between excitability, plasticity and thickness of the motor cortex in older adults

The relationship between brain structure, cortical physiology, and learning ability in older adults is of particular interest in understanding mechanisms of age-related cognitive decline. Only a few studies addressed this issue so far, yielding mixed results. Here, we used comprehensive multiple regression analyses to investigate associations between brain structure on the one hand, i.e., cortical thickness (CT), fractional anisotropy (FA) of the pyramidal tract and individual coil-to-cortex distance, and cortical physiology on the other hand, i.e. motor cortex excitability and long-term potentiation (LTP)-like cortical plasticity, in healthy older adults (mean age 64 years, 14 women). Additional exploratory analyses assessed correlations between cortical physiology and learning ability in the verbal domain. In the regression models, we found that cortical excitability could be best predicted by CT of the hand knob of the primary motor cortex (CT-M1HAND) and individual coil-to-cortex distance, while LTP-like cortical plasticity was predicted by CT-M1HAND and FA of the pyramidal tract. Exploratory analyses revealed a significant inverse correlation between cortical excitability and learning ability. In conclusion, higher cortical excitability was associated with lower CT and lower learning ability in a cohort of healthy older adults, in line with previous reports of increased cortical excitability in patients with cortical atrophy and cognitive deficits due to Alzheimers Disease. Cortical excitability may thus be a parameter to identify individuals at risk for cognitive decline and gray matter atrophy, a hypothesis to be explored in future longitudinal studies.

Impact of Omega-3 Fatty Acid Supplementation on Memory Functions in Healthy Older Adults

As the process of Alzheimers disease (AD) begins years before disease onset, searching for prevention strategies is of major medical and economic importance. Nutritional supplementation with long-chain polyunsaturated omega-3 fatty acids (LC-n3-FA) may exert beneficial effects on brain structure and function. However, experimental evidence in older adults without clinical dementia is inconsistent, possibly due to low sensitivity of previously employed test batteries for detecting subtle improvements in cognition in healthy individuals. Here we used LOCATO, recently described as a robust and sensitive tool for assessing object-location memory (OLM) in older adults, to evaluate the impact of LC-n3-FA supplementation on learning and memory formation. In a double-blind placebo-controlled proof-of-concept study, 44 (20 female) cognitively healthy individuals aged 50-75 years received either LC-n3-FA (2,200 mg/day, n = 22) or placebo (n = 22) for 26 weeks. Before and after intervention, memory performance in the OLM-task (primary) was tested. As secondary outcome parameters, performance in Rey Auditory Verbal Learning Test (AVLT), dietary habits, omega-3-index, and other blood-derived parameters were assessed. Omega-3 index increased significantly in the LC-n3-FA group compared with the placebo group. Moreover, recall of object locations was significantly better after LC-n3-FA supplementation compared with placebo. Performance in the AVLT was not significantly affected by LC-n3-FA. This double-blind placebo-controlled proof-of-concept study provides further experimental evidence that LC-n3-FA exert positive effects on memory functions in healthy older adults. Our findings suggest novel strategies to maintain cognitive functions into old age.

Impact of tDCS on cerebral autoregulation in aging and in patients with cerebrovascular diseases

Following seminal articles on the technique and underlying mechanisms of transcranial direct current stimulation (tDCS) at the turn of this century,1 tDCS has gained special attention in neurorehabilitative research, given its ability to modulate brain function in a polarity-specific manner in stroke patients together with an excellent safety profile.2 However, an important safety concern emerged recently with regard to its impact on cerebral autoregulation, given a report on decreased autoregulation after 15 minutes anodal tDCS (atDCS) over primary motor cortex (M1) in young healthy subjects.3 Cerebral autoregulation, assessed by vasomotor reactivity (VMR), reflects the autonomic ability of cerebral arterioles to dilate following a vasodilatory stimulus. It is consistently decreased in patients with cerebrovascular diseases,4 and has been linked to stroke risk.5 Thus, a decrease of VMR after atDCS may be harmful to patients with already impaired VMR, such as stroke patients.4 Importantly, >40 ongoing trials with stroke patients and atDCS are registered on www.clinicaltrials.gov as of May 2014. Thus, the concerns raised by Vernieri et al.3 may carry important clinical implications.

Brain stimulation during an afternoon nap boosts slow oscillatory activity and memory consolidation in older adults

Sleep-related consolidation of declarative memories, as well as associated neurophysiological events such as slow oscillatory and spindle activity, deteriorate in the course of aging. This process is accelerated in neurodegenerative disease. Transcranial slow oscillatory stimulation (so-tDCS) during sleep has been shown to enhance slow oscillatory brain activity and thereby improve memory consolidation in young subjects. Here, we investigated whether so-tDCS applied to older adults during an afternoon nap exerts similar effects. Eighteen older human subjects were assessed using visuo-spatial (picture memory, primary, and location memory) and verbal memory tasks before and after a 90-min nap either comprising weak so-tDCS at 0.75Hz over fronto-central location or sham (no) stimulation in a within-subject design. Electroencephalographic activity was recorded throughout the naps and immediate effects of stimulation on brain activity were evaluated. Here, spectral power within three frequency bands of interest were computed, i.e., slow oscillatory activity, slow spindle and fast spindle activity; in 1-min stimulation-free intervals following 5 stimulation blocks. So-tDCS significantly increased frontal slow oscillatory activity as well as fast spindle activity, and significantly improved picture memory retention after sleep. Retention in the location memory subtask and in the verbal memory task was not affected. These findings may indicate a novel strategy to counteract cognitive decline in aging in a convenient manner during brief daytime naps.

Promoting sleep oscillations and their functional coupling by transcranial stimulation enhances memory consolidation in mild cognitive impairment

Alzheimers disease (AD) not only involves loss of memory functions, but also prominent deterioration of sleep physiology, which is already evident at the stage of mild cognitive impairment (MCI). Cortical slow oscillations (SO; 0.5–1 Hz) and thalamocortical spindle activity (12–15 Hz) during sleep, and their temporal coordination, are considered critical for memory formation. We investigated the potential of slow oscillatory transcranial direct current stimulation (so-tDCS), applied during a daytime nap in a sleep-state-dependent manner, to modulate these activity patterns and sleep-related memory consolidation in nine male and seven female human patients with MCI. Stimulation significantly increased overall SO and spindle power, amplified spindle power during SO up-phases, and led to stronger synchronization between SO and spindle power fluctuations in EEG recordings. Moreover, visual declarative memory was improved by so-tDCS compared with sham stimulation and was associated with stronger synchronization. These findings indicate a well-tolerated therapeutic approach for disordered sleep physiology and memory deficits in MCI patients and advance our understanding of offline memory consolidation. SIGNIFICANCE STATEMENT In the light of increasing evidence that sleep disruption is crucially involved in the progression of Alzheimers disease (AD), sleep appears as a promising treatment target in this pathology, particularly to counteract memory decline. This study demonstrates the potential of a noninvasive brain stimulation method during sleep in patients with mild cognitive impairment (MCI), a precursor of AD, and advances our understanding of its mechanism. We provide first time evidence that slow oscillatory transcranial stimulation amplifies the functional cross-frequency coupling between memory-relevant brain oscillations and improves visual memory consolidation in patients with MCI.

Hippocampal Pathway Plasticity Is Associated with the Ability to Form Novel Memories in Older Adults

White matter deterioration in the aging human brain contributes to cognitive decline. The fornix as main efferent hippocampal pathway is one of the tracts most strongly associated with age-related memory impairment. Its deterioration may predict conversion to Alzheimer’s dementia and its precursors. However, the associations between the ability to form novel memories, fornix microstructure and plasticity in response to training have never been tested. In the present study, 25 healthy older adults (15 women; mean age (SD): 69 (6) years) underwent an object-location training on three consecutive days. Behavioral outcome measures comprised recall performance on the training days, and on 1-day and 1-month follow up assessments. MRI at 3 Tesla was assessed before and after training. Fornix microstructure was determined by fractional anisotropy and mean diffusivity (MD) values from diffusion tensor imaging (DTI). In addition, hippocampal volumes were extracted from high-resolution images; individual hippocampal masks were further aligned to DTI images to determine hippocampal microstructure. Using linear mixed model analysis, we found that the change in fornix FA from pre- to post-training assessment was significantly associated with training success. Neither baseline fornix microstructure nor hippocampal microstructure or volume changes were significantly associated with performance. Further, models including control task performance (auditory verbal learning) and control white matter tract microstructure (uncinate fasciculus and parahippocampal cingulum) did not yield significant associations. Our results confirm that hippocampal pathways respond to short-term cognitive training, and extend previous findings by demonstrating that the magnitude of training-induced structural changes is associated with behavioral success in older adults. This suggests that the amount of fornix plasticity may not only be behaviorally relevant, but also a potential sensitive biomarker for the success of training interventions aimed at improving memory formation in older adults, a hypothesis to be evaluated in future studies.

Boosting Slow Oscillatory Activity Using tDCS during Early Nocturnal Slow Wave Sleep Does Not Improve Memory Consolidation in Healthy Older Adults

BACKGROUND Previous studies have demonstrated an enhancement of hippocampal-dependent declarative memory consolidation, associated slow wave sleep (SWS) and slow wave activity (SWA) after weak slow oscillatory stimulation (so-tDCS) during early non-rapid eye movement sleep (NREM) in young adults. Recent studies in older individuals could not confirm these findings. However, it remained unclear if this difference was due to variations in study protocol or to the age group under study. OBJECTIVE/HYPOTHESIS Here, we asked if so-tDCS promotes neurophysiological events and associated sleep-dependent memory in the visuo-spatial domain in older adults, using a stimulation protocol that closely resembled the one employed in young adults. METHODS In a randomized, placebo-controlled single-blind (participant) crossover study so-tDCS (0.75 Hz; max. current density 0.522 mA/cm(2)) vs. sham stimulation was applied over the frontal cortex of 21 healthy older subjects. Impact of stimulation on frequency band activity (linear mixed models), two declarative and one procedural memory tasks (repeated measures ANOVA) and percentage of sleep stages (comparison of means) was assessed. RESULTS so-tDCS, as compared to sham, increased SWA and spindle activity immediately following stimulation, accompanied by significantly impaired visuo-spatial memory consolidation. Furthermore, verbal and procedural memory remained unchanged, while percentage of NREM sleep stage 4 was decreased over the entire night (uncorrected). CONCLUSION so-tDCS increased SWA and spindle activity in older adults, events previously associated with stimulation-induced improved consolidation of declarative memories in young subjects. However, consolidation of visuo-spatial (primary outcome) and verbal memories was not beneficially modulated, possibly due to decline in SWS over the entire night that may have prevented and even reversed immediate beneficial effects of so-tDCS on SWA.

FV1. Physiological sleep alterations in heathy aging and mild cognitive impairment

Old adults do not sleep as well as young adults. Mounting evidence demonstrates that sleep characteristics, such as sleep duration, structures and importantly the quantity and quality of specific sleep oscillations, decrease during aging and particularly strong in neurodegenerative disorders. These alterations might be related to functional consequences like memory impairment as observed in Alzheimer’s disease (AD). Some previous work indicated that sleep disruptions occur even before clinical onset of AD, therefore sleep disturbances were proposed to play a direct role in the progression of the pathology. However, early sleep changes and their functional consequences during the preliminary mild cognitive impairment (MCI) state, need to be investigated in greater depth. This study focused on physiological differences of sleep between healthy young, healthy old subjects and patients with mild cognitive impairment. Sleep architecture and more fine grained analyses on memory-relevant sleep parameter such as slow oscillations, sleep spindles and their functional interaction that is considered to be pivotal in memory consolidation, were examined during a 90-min nap. Furthermore, associations of nap-sleep characteristics with retention performance in a verbal and visuo-spatial memory task were evaluated. With regard to sleep physiology, significant differences between all three groups were observed for cross-frequency coupling measures that indicated higher fast spindle power during SO up-phases and stronger synchronization for young subjects relative to both older groups, and higher measures for healthy older subjects as compared to MCI patients. Makro-level sleep analyses revealed an age group difference for the duration of slow wave sleep only, with young subjects spending more time in slow wave sleep relative to both elderly groups. Similarly, analyses on sleep characteristics such as slow oscillation and fast spindle power indicated an age group difference: young subjects showed higher activity in these measures as compared to healthy old participants and MCI patients. Further, concerning pre to post sleep memory performance change, a group difference was only evident between young and both older groups in the verbal memory task. In conclusion, our evidence indicates that most differences in sleep physiology are observed in the course of (healthy) aging. Main decline with respect to sleep physiology that is observed in the early course of neurodegenerative pathology is only observed for the functional coupling between slow oscillations and sleep spindles, a mechanistic component considered crucial for the transfer of memories from hippocampus to cortical long-term storage networks.

Transcranial stimulation enhances memory-relevant sleep oscillations and their functional coupling in mild cognitive impairment

Alzheimer’s disease (AD) not only involves loss of memory functions but also prominent deterioration of sleep physiology, already evident in the stage of mild cognitive impairment (MCI). Cortical slow oscillations (SO, 0.5-1 Hz) and thalamo-cortical spindle activity (12-15 Hz) during sleep, and their temporal coordination, are considered critical for memory formation. We investigated the potential of slow oscillatory transcranial direct current stimulation (so-tDCS), applied during a daytime nap in a sleep state-dependent manner, to modulate these activity patterns and sleep-related memory consolidation in 16 patients with MCI. Stimulation significantly increased overall SO and spindle power, amplified spindle power during SO up-phases, and led to stronger synchronization between SO and spindle power fluctuations in electroencephalographic recordings. Moreover, visual declarative memory was improved by so-tDCS compared to sham stimulation, associated with stronger synchronization. These findings indicate a well-tolerated therapeutic approach for disordered sleep physiology and deficits in memory consolidation in MCI patients.