Transcranial electrostimulation as part of combination therapy for mental disorders

From the December Issue of JAMDA

Cognitive training in MCI may stimulate pre-existing neural reserves or recruit neural circuitry as “compensatory scaffolding” prompting neuroplastic reorganization to meet task demands (Reuter-Lorenz & Park, 2014). However, existing systematic reviews and meta-analytic studies exploring the benefits of cognitive interventions in MCI have been mixed. An updated examination regarding the efficacy of cognitive intervention in MCI is needed given improvements in adherence to MCI diagnostic criteria in subject selection, better defined interventions and strategies applied, increased use of neuropsychological measures pre- and post-intervention, as well as identification of moderator variables which may influence treatment. As such, this meta-analytic review was conducted to examine the efficacy of cognitive intervention in individuals diagnosed with mild cognitive impairment (MCI) versus MCI controls based on performance of neuropsychological outcome measures in randomized controlled trials (RCT). RCT studies published from January 1995 to June 2017 were obtained through source databases of MEDLINE-R, PubMed, Healthstar, Global Health, PSYCH-INFO, and Health and Psychological Instruments using search parameters for MCI diagnostic category (mild cognitive impairment, MCI, pre-Alzheimer’s disease, early cognitive decline, early onset Alzheimer’s disease, and preclinical Alzheimer’s disease) and the intervention or training conducted (intervention, training, stimulation, rehabilitation, or treatment). Other inclusion and exclusion criteria included subject selection based on established MCI criteria, RCT design in an outpatient setting, MCI controls (active or passive), and outcomes based on objective neuropsychological measures. From the 1199 abstracts identified, 26 articles met inclusion criteria for the meta-analyses completed across eleven (11) countries; 92.31% of which have been published within the past 7 years. A series of meta-analyses were performed to examine the effects of cognitive intervention by cognitive domain, type of training, and intervention content (cognitive domain targeted). We found significant, moderate effects for multicomponent training (Hedges’ g observed = 0.398; CI [0.164, 0.631]; Z = 3.337; p = 0.001; Q = 55.511; df = 15; p = 0.000; I2 = 72.978%; τ2 = 0.146) as well as multidomain-focused strategies (Hedges’ g = 0.230; 95% CI [0.108, 0.352]; Z = 3.692; p < 0.001; Q = 12.713; df = 12; p = 0.390; I2 = 5.612; τ2 = 0.003). The effects for other interventions explored by cognitive domain, training type, or intervention content were indeterminate due to concerns for heterogeneity, bias, and small cell sizes. In addition, subgroup and meta-regression analyses were conducted with the moderators of MCI category, mode of intervention, training type, intervention content, program duration (total hours), type of control group (active or passive), post-intervention follow-up assessment period, and control for repeat administration. We found significant overall effects for intervention content with memory focused interventions appearing to be more effective than multidomain approaches. There was no evidence of an influence on outcomes for the other covariates examined. Overall, these findings suggest individuals with MCI who received multicomponent training or interventions targeting multiple domains (including lifestyle changes) were apt to display an improvement on outcome measures of cognition post-intervention. As such, multicomponent and multidomain forms of intervention may prompt recruitment of alternate neural processes as well as support primary networks to meet task demands simultaneously. In addition, interventions with memory and multidomain forms of content appear to be particularly helpful, with memory-based approaches possibly being more effective than multidomain methods. Other factors, such as program duration, appear to have less of an influence on intervention outcomes. Given this, although the creation of new primary network paths appears strained in MCI, interventions with memory-based or multidomain forms of content may facilitate partial activation of compensatory scaffolding and neuroplastic reorganization. The positive benefit of memory-based strategies may also reflect transfer effects indicative of compensatory network activation and the multiple-pathways involved in memory processes. Limitations of this review are similar to other meta-analysis in MCI, including a modest number studies, small sample sizes, multiple forms of interventions and types of training applied (some overlapping), and, while greatly improved in our view, a large diversity of instruments used to measure outcome. This is apt to have contributed to the presence of heterogeneity and publication bias precluding a more definitive determination of the outcomes observed.

BackgroundEffective non-pharmacological cognitive interventions to prevent Alzheimer's dementia or slow its progression are an urgent international priority. The aim of this review was to evaluate cognitive training trials in individuals with mild cognitive impairment (MCI), and evaluate the efficacy of training in memory strategies or cognitive exercises to determine if cognitive training could benefit individuals at risk of developing dementia.MethodsA systematic review of eligible trials was undertaken, followed by effect size analysis. Cognitive training was differentiated from other cognitive interventions not meeting generally accepted definitions, and included both cognitive exercises and memory strategies.ResultsTen studies enrolling a total of 305 subjects met criteria for cognitive training in MCI. Only five of the studies were randomized controlled trials. Meta-analysis was not considered appropriate due to the heterogeneity of interventions. Moderate effects on memory outcomes were identified in seven trials. Cognitive exercises (relative effect sizes ranged from .10 to 1.21) may lead to greater benefits than memory strategies (.88 to -1.18) on memory.ConclusionsPrevious conclusions of a lack of efficacy for cognitive training in MCI may have been influenced by not clearly defining the intervention. Our systematic review found that cognitive exercises can produce moderate-to-large beneficial effects on memory-related outcomes. However, the number of high quality RCTs remains low, and so further trials must be a priority. Several suggestions for the better design of cognitive training trials are provided.

Cognitive training for persons with mild cognitive impairment.

Background: Awareness of cognitive deficits is considered to be decisive for the effectiveness of cognitive training in mild cognitive impairment (MCI). However, it is unclear in what way awareness influences motivation to participate in cognitive training. Methods: Thirty-two elderly adults with MCI and 72 controls completed the 5-scale Memory Functioning Questionnaire (MFQ) and a motivation questionnaire. The predictive value of the MFQ scales on motivation was analyzed using regression analysis. Results: In the MCI group, but not in controls, higher perceived frequency of memory failures was associated with a lower motivation score. Conclusion: Our findings indicate that, in MCI, greater awareness of cognitive deficits does not necessarily increase motivation to participate in cognitive trainings, and suggest that success expectancy may be a moderating factor.

Introduction Nearly half of older adults with mild cognitive impairment (MCI) experience comorbid insomnia, which worsens cognitive symptoms. There are no pharmacological treatments for cognition and behavioral insomnia treatments require trained therapists, while sleep medications are associated with adverse side effects such as increased fall risk and cognitive disturbance. This study evaluated preliminary effects of computerized cognitive training for improving cognition and sleep in older adults with MCI and insomnia. Methods Older Adults (N=27, Mage=67.63±5.90, 21 women) with MCI (MoCA score of 18-26/30 or 1.5 SD below norms on 1+ cognitive task, intact activities of daily living) and insomnia [DSM-5 criteria plus sleep diaries showing &amp;gt;30 mins sleep onset latency or wake time after sleep onset (WASO) on 3+ nights/7] were randomized (2:1) to 8 weeks of cognitive training (n=19; Cognifit) or trivia control (n=8; answering questions online) for 45 mins, 3x per week. Cognition (Cambridge Brain Sciences battery), subjective sleep (Insomnia Severity Index, average 7-day diary-reported sleep onset latency, WASO, sleep efficiency, #awakenings, total sleep time) and objective sleep [WatchPAT; same metrics and %lighter, %deep, %Rapid Eye Movement (REM) sleep] were assessed at baseline and post-intervention. Planned baseline vs. post-intervention comparisons and effect size estimation across outcomes were conducted for cognitive training versus trivia control. Results Cognitive training significantly improved spatial planning (p=.028; hedges g=.54, moderate effect), and showed trends for improved visuospatial (p=.08; hedges g=.53) and verbal (p=.08; hedges g=.50) working memory, with no changes in controls (ps ranged from.27-.94). Cognitive training also significantly reduced diary-#awakenings (p=.007, hedges g=.46), improved objective sleep efficiency (p=.05, hedges g=.47), and trended towards reduced diary-WASO (p=.067, hedges g=.53), with no changes in controls (ps ranged from.29-.80). Objective REM% increased for trivia control (p=.02, hedges g=1.00), but not cognitive training (p=.23). Conclusion Preliminary findings suggest in older adults with MCI, at home computerized multimodal cognitive training leads to near transfer effects for non-trained cognition and far transfer effects for sleep maintenance and efficiency symptoms. Larger randomized controlled trials with longer follow-up and evaluation of mechanisms underlying cognitive training transfer effects are warranted. Support (if any) Triumph Initiative Award, University of Missouri School of Medicine (PI:Curtis).

Older adults with mild cognitive impairment (MCI) receive fewer guideline-concordant treatments for multiple health conditions than those with normal cognition. Reasons for this disparity are unclear. To better understand this disparity, we describe physician understanding and experience with patient MCI, particularly physician identification of MCI, ability to distinguish between MCI and dementia, and perspectives on education and training in MCI and dementia. As part of a mixed-methods study assessing the influence of patient MCI on physician recommendations for acute myocardial infraction and stroke treatments, we conducted a descriptive qualitative study using semi-structured interviews of physicians from three specialties. Key question topics included participants' identification of MCI, impressions of MCI and dementia awareness within their practice specialty, and perspectives on training and education in MCI. The study included 22 physicians (8 cardiologists, 7 neurologists, and 7 internists). We identified two primary themes: There is 1) a lack of adequate understanding of the distinction between MCI and dementia; and 2) variation in physician approaches to identifying whether an older adult has MCI. These findings suggest that physicians have a poor understanding of MCI. Our results suggest that interventions that improve physician knowledge of MCI are needed.

This preliminary study aimed to compare the outcomes of an occupational therapist-led and a nurse-led computerized cognitive training (CCT) for mild cognitive impairment (MCI) in older adults. A single-blind randomized controlled trial was performed. Participants 65 years of age and older with MCI were randomly assigned to a group led by an occupational therapist or by a nurse. Both groups received CCT for 4 weeks. Six participants in the occupational therapist-led group and nine in the nurse-led group completed CCT. The nurse-led group showed significant improvement in scores on the Seoul Verbal Learning Test-Elderly's version immediate recall scores (p = .030) and the Korean-Boston Naming Test (p = .012). Nurse-led CCT demonstrated improvement in some language and memory areas in older adults with MCI. This study supports the idea of educating nurses to use a CCT program for treating older adults with MCI to improve their cognitive function.

Cognitive Training (CT) has demonstrated some benefits to cognitive and psychosocial function in Mild Cognitive Impairment (MCI) and early dementia, but the certainty related to those findings remains unclear. Therefore, understanding the mechanisms by which CT improves cognitive functioning may help to understand the relationships between CT and cognitive function. The purpose of this review was to identify the evidence for neuroimaging outcomes in studies of CT in MCI and early Alzheimer's Disease (AD). Medline, Embase, Web of Science, PsycINFO, CINAHL, and The Cochrane Library were searched with a predefined search strategy, which yielded 1778 articles. Studies were suitable for inclusion where a CT program was used in patients with MCI or AD, with a structural or functional Magnetic Resonance Imaging (MRI) outcome. Studies were assessed for quality using the Downs and Black criteria. A total of 19 studies met the inclusion criteria. Quality of the included studies was variable and there was significant heterogeneity for studies included in this review. Task activation was generally increased post-training, but functional connectivity was both increased and decreased after training. Results varied by diagnosis, type of CT program, and brain networks examined. No effects were seen on hippocampal volumes post-training, but cortical thickening and increased grey matter volumes were demonstrated. CT resulted in variable functional and structural changes in dementia, and conclusions are limited by heterogeneity and study quality. Larger, more robust studies are required to correlate these findings with clinical benefits from CT.

Transcranial direct current stimulation as an adjunct to cognitive training for older adults with mild cognitive impairment: A randomized controlled trial.

Pointing the FINGER at multimodal dementia prevention – Authors' reply

BackgroundDeveloping non-pharmacological interventions with strong potential to prevent or delay the onset of Alzheimer’s disease (AD) in high-risk populations is critical. Aerobic exercise and cognitive training are two promising interventions. Aerobic exercise increases aerobic fitness, which in turn improves brain structure and function, while cognitive training improves selective brain function intensively. Hence, combined aerobic exercise and cognitive training may have a synergistic effect on cognition by complementary strengthening of different neural functions. Few studies have tested the effects of such a combined intervention, and the findings have been discrepant, largely due to varying doses and formats of the interventions.Methods/designThe purpose of this single-blinded, 2 × 2 factorial phase II randomized controlled trial is to test the efficacy and synergistic effects of a 6-month combined cycling and speed of processing training intervention on cognition and relevant mechanisms (aerobic fitness, cortical thickness, and functional connectivity in the default mode network) in older adults with amnestic mild cognitive impairment. This trial will randomize 128 participants equally to four arms: cycling and speed of processing, cycling only, speed of processing only, or attention control for 6 months, and then follow them for another 12 months. Cognition and aerobic fitness will be assessed at baseline and at 3, 6, 12, and 18 months; cortical thickness and functional connectivity at baseline and at 6, 12, and 18 months; Alzheimer’s disease (AD) conversion at 6, 12, and 18 months. The specific aims are to (1) determine the efficacy and synergistic effects of the combined intervention on cognition over 6 months, (2) examine the underlying mechanisms of the combined intervention, and (3) calculate the long-term effect sizes of the combined intervention on cognition and AD conversion. The analysis will use intention-to-treat and linear mixed-effects modeling.DiscussionThis trial will be among the first to test the synergistic effects on cognition and mechanisms (relevant to Alzheimer’s-associated neurodegeneration) of a uniquely conceptualized and rigorously designed aerobic exercise and cognitive training intervention in older adults with mild cognitive impairment. It will advance Alzheimer’s prevention research by providing precise effect-size estimates of the combined intervention.Trial registrationClinicalTrials.gov, NCT03313895. Registered on 18 October 2017.

A - 03 Emotion Domains and Response to Cognitive Training for Mild Cognitive Impairment.

Objective:Compensatory strategy training has been identified as a useful mechanism to improve everyday cognitive function among older adults with Mild Cognitive Impairment (MCI). Despite this, few studies have looked at cognitive factors that support adherence and engagement in these programs, which are key to maximizing benefit. The present study aimed to evaluate the relationship between cognition, adherence, and engagement during a group-based compensatory strategy training for people with MCI. We hypothesized individuals with better memory and executive function performance would show better adherence and higher engagement scores in cognitive training classes.Participants and Methods:Twenty-five participants enrolled in Emory University's Charles and Harriet Schaffer Cognitive Empowerment Program (CEP) completed an 11-week compensatory strategy training group (CEP-CT). CEP-CT is adapted from Ecologically Oriented Neurorehabilitation to be suitable for people with MCI. Participants enrolled were on average 74.3 years old (SD= 5.4), 52% Male, primarily Caucasian (80%; 16% African American), and college educated (M= 16.5 years; SD= 2.7). All participants received clinical diagnoses of MCI prior to enrollment in the program. Participants completed multiple cognitive measures, including Montreal Cognitive Assessment (MoCA), Hopkins Verbal Learning Test (HVLT), Trail Making Test A &amp; B (TMT), Number Span Forward (NSF) and verbal fluency (S-words and Animals). For all group sessions, class attendance (present vs. not present) was recorded for each participant and their care partner, and engagement ratings for participants were recorded by the facilitator on a 1 to 5 scale (higher scores indicate better engagement). Outcomes include adherence to cognitive training (percentage of sessions attended; M= 82% class attendance, SD= 18%) as well as the average engagement ratings across 11 weeks (M= 3.25, SD= .40).Results:Bivariate Pearson correlations revealed that individuals who attended more classes also demonstrated better engagement in class, r= .44, p= .03. Class attendance was significantly related to performance on measures of memory and executive function (HVLT: r= -.42, p= .04; TMT-B: r= .69, p= .04), such that participants who performed worse on these measures attended more CEP-CT classes. Average engagement ratings were unrelated to cognitive performance.Conclusions:Results did not support initial hypotheses, and instead indicate individuals with poorer performance on measures of memory and executive function had better adherence to CEP-CT classes, as measured by attendance. These results may indicate individuals experiencing cognitive difficulties are more likely to attend cognitive training classes. Subjective engagement ratings were unrelated to cognition; however, individuals who attended more sessions were more engaged in cognitive training classes. Future areas of research include objective measurement of class engagement as well as the incorporation of nuanced adherence metrics to further elucidate the relationship between these factors and cognition in MCI.

In mild cognitive impairment (MCI), small benefits from cognitive training were observed for memory functions but there appears to be great variability in the response to treatment. Our study aimed to improve the characterization and selection of those participants who will benefit from cognitive intervention. We evaluated the predictive value of disease-specific biological factors for the outcome after cognitive training in MCI (n = 25) and also considered motivation of the participants. We compared the results of the cognitive intervention group with two independent control groups of MCI patients (local memory clinic, n = 20; ADNI cohort, n = 302). The primary outcome measure was episodic memory as measured by verbal delayed recall of a 10-word list. Episodic memory remained stable after treatment and slightly increased 6 months after the intervention. In contrast, in MCI patients who did not receive an intervention, episodic memory significantly decreased during the same time interval. A larger left entorhinal cortex predicted more improvement in episodic memory after treatment and so did higher levels of motivation. Adding disease-specific biological factors significantly improved the prediction of training-related change compared to a model based simply on age and baseline performance. Bootstrapping with resampling (n = 1000) verified the stability of our finding. Cognitive training might be particularly helpful in individuals with a bigger left entorhinal cortex as individuals who did not benefit from intervention showed 17% less volume in this area. When extended to alternative treatment options, stratification based on disease-specific biological factors is a useful step towards individualized medicine.