Demographic changes are increasing the pressure to improve therapeutic strategies against cognitive decline in Alzheimer disease (AD) and mild cognitive impairment (MCI). Besides drug treatment, ...physical activity seems to be a promising intervention target as epidemiological and clinical studies suggest beneficial effects of exercise training on cognition. Using comparable inclusion and exclusion criteria, we analyzed the efficacy of drug therapy (cholinesterase inhibitors, memantine, and Ginkgo biloba) and exercise interventions for improving cognition in AD and MCI populations.
We searched The Cochrane Library, EBSCO, OVID, Web of Science, and U.S Food and Drug Administration data from inception through October 30, 2013. Randomized controlled trials in which at least one treatment arm consisted of an exercise or a pharmacological intervention for AD or MCI patients, and which had either a non-exposed control condition or a control condition that received another intervention. Treatment discontinuation rates and Standardized Mean Change score using Raw score standardization (SMCR) of cognitive performance were calculated.
Discontinuation rates varied substantially and ranged between 0% and 49% with a median of 18%. Significantly increased discontinuation rates were found for galantamine and rivastigmine as compared to placebo in AD studies. Drug treatments resulted in a small pooled effect on cognition (SMCR: 0.23, 95% CI: 0.20 to 0.25) in AD studies (N = 45, 18,434 patients) and no effect in any of the MCI studies (N = 5, 3,693 patients; SMCR: 0.03, 95% CI: 0.00 to 0.005). Exercise interventions had a moderate to strong pooled effect size (SMCR: 0.83, 95% CI: 0.59 to 1.07) in AD studies (N = 4, 119 patients), and a small effect size (SMCR: 0.20, 95% CI: 0.11 to 0.28) in MCI (N = 6, 443 patients).
Drug treatments have a small but significant impact on cognitive functioning in AD and exercise has the potential to improve cognition in AD and MCI. Head-to-head trials with sufficient statistical power are necessary to directly compare efficacy, safety, and acceptability. Combining these two approaches might further increase the efficacy of each individual intervention.
PROSPERO (2013:CRD42013003910).
Subjects with schizophrenia are impaired at reinforcement-driven reversal learning from as early as their first episode. The neurobiological basis of this deficit is unknown. We obtained behavioral ...and fMRI data in 24 unmedicated, primarily first episode, schizophrenia patients and 24 age-, IQ- and gender-matched healthy controls during a reversal learning task. We supplemented our fMRI analysis, focusing on learning from prediction errors, with detailed computational modeling to probe task solving strategy including an ability to deploy an internal goal directed model of the task. Patients displayed reduced functional activation in the ventral striatum (VS) elicited by prediction errors. However, modeling task performance revealed that a subgroup did not adjust their behavior according to an accurate internal model of the task structure, and these were also the more severely psychotic patients. In patients who could adapt their behavior, as well as in controls, task solving was best described by cognitive strategies according to a Hidden Markov Model. When we compared patients and controls who acted according to this strategy, patients still displayed a significant reduction in VS activation elicited by informative errors that precede salient changes of behavior (reversals). Thus, our study shows that VS dysfunction in schizophrenia patients during reward-related reversal learning remains a core deficit even when controlling for task solving strategies. This result highlights VS dysfunction is tightly linked to a reward-related reversal learning deficit in early, unmedicated schizophrenia patients.
•Probabilistic reversal learning was examined in unmedicated schizophrenia patients.•Computational modeling assessed subjects ability to use the latent task structure.•SZ patients showed lower reinforcement sensitivity and higher switch tendency.•Blunted striatal prediction error signal in unmedicated schizophrenia patients.•PFC activation during reversal errors intact in SZ patients able to do the task.
The mechanisms underlying increased dual-task costs in the comparison of modality compatible stimulus-response mappings (e.g., visual-manual, auditory-vocal) and modality incompatible mappings (e.g., ...visual-vocal, auditory-manual) remain elusive. To investigate whether additional control mechanisms are at work in simultaneously processing two modality incompatible mappings, we applied a transfer logic between both types of dual-task mappings in the context of a mental fatigue induction. We expected an increase in dual-task costs for both modality mappings after a fatigue induction with modality compatible tasks. In contrast, we expected an additional, selective increase in modality incompatible dual-task costs after a fatigue induction with modality incompatible tasks. We tested a group of 45young individuals (19–30 years) in an online pre-post design, in which participants were assigned to one of three groups. The two fatigue groups completed a 90-min time-on-task intervention with a dual task comprising either compatible or incompatible modality mappings. The third group paused for 90 min as a passive control group. Pre and post-session contained single and dual tasks in both modality mappings for all participants. In addition to behavioral performance measurements, seven subjective items (effort, focus, subjective fatigue, motivation, frustration, mental and physical capacity) were analyzed. Mean dual-task performance during and after the intervention indicated a practice effect instead of the presumed fatigue effect for all three groups. The modality incompatible intervention group showed a selective performance improvement for the modality incompatible mapping but no transfer to the modality compatible dual task. In contrast, the compatible intervention group showed moderately improved performance in both modality mappings. Still, participants reported increased subjective fatigue and reduced motivation after the fatigue intervention. This dynamic interplay of training and fatigue effects suggests that high control demands were involved in the prolonged performance of a modality incompatible dual task, which are separable from modality compatible dual-task demands.
As indicated by previous research, aging is associated with a decline in working memory (WM) functioning, related to alterations in fronto-parietal neural activations. At the same time, previous ...studies showed that WM training in older adults may improve the performance in the trained task (training effect), and more importantly, also in untrained WM tasks (transfer effects). However, neural correlates of these transfer effects that would improve understanding of its underlying mechanisms, have not been shown in older participants as yet. In this study, we investigated blood-oxygen-level-dependent (BOLD) signal changes during n-back performance and an untrained delayed recognition (Sternberg) task following 12sessions (45min each) of adaptive n-back training in older adults. The Sternberg task used in this study allowed to test for neural training effects independent of specific task affordances of the trained task and to separate maintenance from updating processes. Thirty-two healthy older participants (60–75years) were assigned either to an n-back training or a no-contact control group. Before (t1) and after (t2) training/waiting period, both the n-back task and the Sternberg task were conducted while BOLD signal was measured using functional Magnetic Resonance Imaging (fMRI) in all participants. In addition, neuropsychological tests were performed outside the scanner. WM performance improved with training and behavioral transfer to tests measuring executive functions, processing speed, and fluid intelligence was found. In the training group, BOLD signal in the right lateral middle frontal gyrus/caudal superior frontal sulcus (Brodmann area, BA 6/8) decreased in both the trained n-back and the updating condition of the untrained Sternberg task at t2, compared to the control group. fMRI findings indicate a training-related increase in processing efficiency of WM networks, potentially related to the process of WM updating. Performance gains in untrained tasks suggest that transfer to other cognitive tasks remains possible in aging.
•Working memory training leads to neural activation decrease in the right MFG in aging.•Neural changes in transfer task are related to updating (compared to maintenance).•Neural correlates of training and transfer effects overlap in the right MFG.•Behavioral transfer to executive functions, processing speed, fluid intelligence•Results advance understanding of neural mechanisms of training and transfer.
Addiction is supposedly characterized by a shift from goal-directed to habitual decision making, thus facilitating automatic drug intake. The two-step task allows distinguishing between these ...mechanisms by computationally modeling goal-directed and habitual behavior as model-based and model-free control. In addicted patients, decision making may also strongly depend upon drug-associated expectations. Therefore, we investigated model-based versus model-free decision making and its neural correlates as well as alcohol expectancies in alcohol-dependent patients and healthy controls and assessed treatment outcome in patients.
Ninety detoxified, medication-free, alcohol-dependent patients and 96 age- and gender-matched control subjects underwent functional magnetic resonance imaging during the two-step task. Alcohol expectancies were measured with the Alcohol Expectancy Questionnaire. Over a follow-up period of 48 weeks, 37 patients remained abstinent and 53 patients relapsed as indicated by the Alcohol Timeline Followback method.
Patients who relapsed displayed reduced medial prefrontal cortex activation during model-based decision making. Furthermore, high alcohol expectancies were associated with low model-based control in relapsers, while the opposite was observed in abstainers and healthy control subjects. However, reduced model-based control per se was not associated with subsequent relapse.
These findings suggest that poor treatment outcome in alcohol dependence does not simply result from a shift from model-based to model-free control but is instead dependent on the interaction between high drug expectancies and low model-based decision making. Reduced model-based medial prefrontal cortex signatures in those who relapse point to a neural correlate of relapse risk. These observations suggest that therapeutic interventions should target subjective alcohol expectancies.
To investigate the efficacy of animal-assisted therapy (AAT) on symptoms of agitation/aggression and depression in nursing home residents with dementia in a randomized controlled trial. Previous ...studies have indicated that AAT has beneficial effects on neuropsychiatric symptoms in various psychiatric disorders but few studies have investigated the efficacy of AAT in patients suffering from dementia.
Of 65 nursing home residents with dementia (mean standard deviation age: 81.8 9.2 years; mean Mini-Mental State Examination score: 7.1 0.7), 27 matched pairs (N = 54) were randomly assigned to either treatment as usual or treatment as usual combined with AAT, administered over 10 weekly sessions. Blinded raters assessed cognitive impairment with the Mini-Mental State Examination, presence of agitation/aggression with the Cohen-Mansfield Agitation Inventory, and depression with the Dementia Mood Assessment Scale at baseline and during a period of 4 weeks after AAT intervention.
In the control group, symptoms of agitation/aggression and depression significantly increased over 10 weeks; in the intervention group, patients receiving combined treatment displayed constant frequency and severity of symptoms of agitation/aggression (F1,48 = 6.43; p <0.05) and depression (F1,48 = 26.54; p <0.001). Symptom amelioration did not occur in either group.
AAT is a promising option for the treatment of agitation/aggression and depression in patients with dementia. Our results suggest that AAT may delay progression of neuropsychiatric symptoms in demented nursing home residents. Further research is needed to determine its long-time effects.
Depression is a leading cause of disability worldwide and a significant contributor to the global burden of disease. Altered leptin levels are known to be associated with depressive symptoms, however ...discrepancies in the results of increased or decreased levels exist. Due to various limitations associated with commonly used antidepressant drugs, alternatives such as exercise therapy are gaining more importance. Therefore, the current study investigates whether depressed patients have higher leptin levels compared to healthy controls and if exercise is efficient to reduce these levels.
Leptin levels of 105 participants with major depressive disorder (MDD; 45.7% female, age mean ± SEM: 39.1 ± 1.0) and 34 healthy controls (HC; 61.8% female, age mean ± SEM: 36.0 ± 2.0) were measured before and after a bicycle ergometer test. Additionally, the MDD group was separated into three groups: two endurance exercise intervention groups (EX) differing in their intensities, and a waiting list control group (WL). Leptin levels were measured pre and post a 12-week exercise intervention or the waiting period.
Baseline data showed no significant differences in leptin levels between the MDD and HC groups. As expected, correlation analyses displayed significant relations between leptin levels and body weight (HC: r = 0.474, p = 0.005; MDD: r = 0.198, p = 0.043) and even more with body fat content (HC: r = 0.755, p < 0.001; MDD: r = 0.675, p < 0.001). The acute effect of the bicycle ergometer test and the 12-week training intervention showed no significant changes in circulating leptin levels.
Leptin levels were not altered in patients with major depression compared to healthy controls and exercise, both the acute response and after 12 weeks of endurance training, had no effect on the change in leptin levels.
The study was registered at the German register for clinical studies (DRKS) and the International Clinical Trials Registry Platform of the World Health Organization https://trialsearch.who.int/Trial2.aspx?TrialID=DRKS00008869 on 28/07/2015.
In the domain of working memory (WM), a sigmoid-shaped relationship between WM load and brain activation patterns has been demonstrated in younger adults. It has been suggested that age-related ...alterations of this pattern are associated with changes in neural efficiency and capacity. At the same time, WM training studies have shown that some older adults are able to increase their WM performance through training. In this study, functional magnetic resonance imaging during an n-back WM task at different WM load levels was applied to compare blood oxygen level-dependent (BOLD) responses between younger and older participants and to predict gains in WM performance after a subsequent 12-session WM training procedure in older adults. We show that increased neural efficiency and capacity, as reflected by more "youth-like" brain response patterns in regions of interest of the frontoparietal WM network, were associated with better behavioral training outcome beyond the effects of age, sex, education, gray matter volume, and baseline WM performance. Furthermore, at low difficulty levels, decreases in BOLD response were found after WM training. Results indicate that both neural efficiency (i.e., decreased activation at comparable performance levels) and capacity (i.e., increasing activation with increasing WM load) of a WM-related network predict plasticity of the WM system, whereas WM training may specifically increase neural efficiency in older adults.
Episodic memory arises as a function of dynamic interactions between the hippocampus and the neocortex, yet the mechanisms have remained elusive. Here, using human intracranial recordings during a ...mnemonic discrimination task, we report that 4-5 Hz (theta) power is differentially recruited during discrimination vs. overgeneralization, and its phase supports hippocampal-neocortical when memories are being formed and correctly retrieved. Interactions were largely bidirectional, with small but significant net directional biases; a hippocampus-to-neocortex bias during acquisition of new information that was subsequently correctly discriminated, and a neocortex-to-hippocampus bias during accurate discrimination of new stimuli from similar previously learned stimuli. The 4-5 Hz rhythm may facilitate the initial stages of information acquisition by neocortex during learning and the recall of stored information from cortex during retrieval. Future work should further probe these dynamics across different types of tasks and stimuli and computational models may need to be expanded accordingly to accommodate these findings.
Elective surgeries are among the most common health stressors in later life and put a significant risk at functional and mental health, making them an important target of research into healthy aging ...and physical resilience. Large-scale longitudinal research mostly conducted in non-clinical samples provided support of the predictive value of self-rated health (SRH) for both functional and mental health. Thus, SRH may have the potential to predict favorable adaptation processes after significant health stressors, that is, physical resilience. So far, a study examining the interplay between SRH, functional and mental health and their relative importance for health changes in the context of health stressors was missing. The present study aimed at addressing this gap.
We used prospective data of 1,580 inpatients (794 complete cases) aged 70 years or older of the PAWEL study, collected between October 2017 and May 2019 in Germany. Our analyses were based on SRH, functional health (Barthel Index) and self-reported mental health problems (PHQ-4) before and 12 months after major elective surgery. To examine changes and interrelationships in these health indicators, bivariate latent change score (BLCS) models were applied.
Our analyses provided evidence for improvements of SRH, functional and mental health from pre-to-post surgery. BLCS models based on complete cases and the total sample pointed to a complex interplay of SRH, functional health and mental health with bidirectional coupling effects. Better pre-surgery SRH was associated with improvements in functional and mental health, and better pre-surgery functional health and mental health were associated with improvements in SRH from pre-to-post surgery. Effects of pre-surgery SRH on changes in functional health were smaller than those of functional health on changes in SRH.
Meaningful changes of SRH, functional and mental health and their interplay could be depicted for the first time in a clinical setting. Our findings provide preliminary support for SRH as a physical resilience factor being associated with improvements in other health indicators after health stressors. Longitudinal studies with more timepoints are needed to fully understand the predictive value of SRH for multidimensional health.
PAWEL study, German Clinical Trials Register, number DRKS00013311. Registered 10 November 2017 - Retrospectively registered, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013311 .
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