Basal forebrain integrity, cholinergic innervation and cognition in idiopathic Parkinson's disease.

Most individuals with Parkinson's disease experience cognitive decline. Mounting evidence suggests this is partially caused by cholinergic denervation due to α-synuclein pathology in the cholinergic basal forebrain. Alpha-synuclein deposition causes inflammation, which can be measured with free water fraction, a diffusion MRI-derived metric of extracellular water. Prior studies have shown an association between basal forebrain integrity and cognition, cholinergic levels and cognition, and basal forebrain volume and acetylcholine, but no study has directly investigated whether basal forebrain physiology mediates the relationship between acetylcholine and cognition in Parkinson's disease. We investigated the relationship between these variables in a cross-sectional analysis of 101 individuals with Parkinson's disease. Cholinergic levels were measured using fluorine-18 fluoroethoxybenzovesamicol (18F-FEOBV) PET imaging. Cholinergic innervation regions of interest included the medial, lateral capsular and lateral perisylvian regions and the hippocampus. Brain volume and free water fraction were quantified using T1 and diffusion MRI, respectively. Cognitive measures included composites of attention/working memory, executive function, immediate memory and delayed memory. Data were entered into parallel mediation analyses with the cholinergic projection areas as predictors, cholinergic basal forebrain volume and free water fraction as mediators and each cognitive domain as outcomes. All mediation analyses controlled for age, years of education, levodopa equivalency dose and systolic blood pressure. The basal forebrain integrity metrics fully mediated the relationship between lateral capsular and lateral perisylvian acetylcholine and attention/working memory, and partially mediated the relationship between medial acetylcholine and attention/working memory. Basal forebrain integrity metrics fully mediated the relationship between medial, lateral capsular and lateral perisylvian acetylcholine and free water fraction. For all mediations in attention/working memory and executive function, the free water mediation was significant, while the volume mediation was not. The basal forebrain integrity metrics fully mediated the relationship between hippocampal acetylcholine and delayed memory and partially mediated the relationship between lateral capsular and lateral perisylvian acetylcholine and delayed memory. The volume mediation was significant for the hippocampal and lateral perisylvian models, while free water fraction was not. Free water fraction in the cholinergic basal forebrain mediated the relationship between acetylcholine and attention/working memory and executive function, while cholinergic basal forebrain volume mediated the relationship between acetylcholine in temporal regions in memory. These findings suggest that these two metrics reflect different stages of neurodegenerative processes and add additional evidence for a relationship between pathology in the basal forebrain, acetylcholine denervation and cognitive decline in Parkinson's disease.

Evaluation of the Uniform Data Set version 3 teleneuropsychological measures.

OBJECTIVE: Few studies have evaluated in-home teleneuropsychological (teleNP) assessment and none, to our knowledge, has evaluated the National Alzheimer's Coordinating Center's (NACC) Uniform Data Set version 3 tele-adapted test battery (UDS v3.0 t-cog). The current study evaluates the reliability of the in-home UDS v3.0 t-cog with a prior in-person UDS v3.0 evaluation. METHOD: One hundred and eighty-one cognitively unimpaired or cognitively impaired participants from a longitudinal study of memory and aging completed an in-person UDS v3.0 and a subsequent UDS v3.0 t-cog evaluation (∼16 months apart) administered either via video conference (n = 122) or telephone (n = 59). RESULTS: We calculated intraclass correlation coefficients (ICCs) between each time point for the entire sample. ICCs ranged widely (0.01-0.79) but were generally indicative of "moderate" (i.e., ICCs ranging from 0.5-0.75) to "good" (i.e., ICCs ranging from 0.75-0.90) agreement. Comparable ICCs were evident when looking only at those with stable diagnoses. However, relatively stronger ICCs (Range: 0.35-0.87) were found between similarly timed in-person UDS v3.0 evaluations. CONCLUSIONS: Our findings suggest that most tests on the UDS v3.0 t-cog battery may serve as a viable alternative to its in-person counterpart, though reliability may be attenuated relative to the traditional in-person format. More tightly controlled studies are needed to better establish the reliability of these measures.

Identification of amnestic mild cognitive impairment among Black and White community-dwelling older adults using NIH Toolbox Cognition tablet battery.

OBJECTIVES: Identify which NIH Toolbox Cognition Battery (NIHTB-CB) subtest(s) best differentiate healthy controls (HC) from those with amnestic mild cognitive impairment (aMCI) and compare the discriminant accuracy between a model using a priori "Norm Adjusted" scores versus "Unadjusted" standard scores with age, sex, race/ethnicity, and education controlled for within the model. Racial differences were also examined. METHODS: Participants were Black/African American (B/AA) and White consensus-confirmed (HC = 96; aMCI = 62) adults 60-85 years old that completed the NIHTB-CB for tablet. Discriminant function analysis (DFA) was used in the Total Sample and separately for B/AA (n = 80) and White participants (n = 78). RESULTS: Picture Sequence Memory (an episodic memory task) was the highest loading coefficient across all DFA models. When stratified by race, differences were noted in the pattern of the highest loading coefficients within the DFAs. However, the overall discriminant accuracy of the DFA models in identifying HCs and those with aMCI did not differ significantly by race (B/AA, White) or model/score type (Norm Adjusted versus Unadjusted). CONCLUSIONS: Racial differences were noted despite the use of normalized scores or demographic covariates-highlighting the importance of including underrepresented groups in research. While the models were fairly accurate at identifying consensus-confirmed HCs, the models proved less accurate at identifying White participants with an aMCI diagnosis. In clinical settings, further work is needed to optimize computerized batteries and the use of NIHTB-CB norm adjusted scores is recommended. In research settings, demographically corrected scores or within model correction is suggested.

Comparing high definition transcranial direct current stimulation to left temporoparietal junction and left inferior frontal gyrus for logopenic primary progressive aphasia: A single-case study.

Logopenic variant primary progressive aphasia (lvPPA) is characterized by word-finding deficits and phonologic errors in fluent speech. Transcranial direct current stimulation (tDCS) targeting either left temporoparietal junction (TPJ) or left inferior frontal gyrus (IFG) show evidence of improving language function in lvPPA. The present case study evaluated the effects of two separate rounds of high definition tDCS (HD-tDCS) (4 mA; 30 sessions) on language and functional neuroimaging in a 57-year-old woman with lvPPA. Stimulation was centred on two different regions across rounds: (1) left TPJ, and (2) left (IFG). Results showed an improved proportion of content to floorholder words during a naturalistic speech task through both rounds as well as change in confrontation naming after TPJ (improvement) and IFG (worsened) stimulation. fMRI connectivity during task showed left lateralized positive correlations following round 1 and anti-correlations with components of the default mode network following round 2. Resting state segregation of a language-associated functional network increased following both rounds, and task-based segregation of the same network increased following IFG stimulation. These results suggest that stimulation to both regions using HD-tDCS may improve language function in lvPPA, while simultaneously eliciting widespread changes beyond the targeted area in neuronal activity and functional connectivity.

Salience network segregation mediates the effect of tau pathology on mild behavioral impairment.

INTRODUCTION: A recently developed mild behavioral impairment (MBI) diagnostic framework standardizes the early characterization of neuropsychiatric symptoms in older adults. However, the joint contributions of Alzheimer's disease (AD) pathology and brain function to MBI remain unclear. METHODS: We test a novel model assessing direct relationships between AD biomarker status and MBI symptoms, as well as mediated effects through segregation of the salience and default-mode networks, using data from 128 participants with diagnosis of amnestic mild cognitive impairment or mild dementia-AD type. RESULTS: We identified a mediated effect of tau positivity on MBI through functional segregation of the salience network from the other high-level, association networks. There were no direct effects of AD biomarkers status on MBI. DISCUSSION: Our findings suggest that tau pathology contributes to MBI primarily by disrupting salience network function and emphasize the role of the salience network in mediating relationships between neuropathological changes and behavioral manifestations. HIGHLIGHTS: Network segregation mediates Alzheimer's disease (AD) pathology impact on mild behavioral impairment (MBI). The salience network is pivotal in linking tau pathology and MBI. This study used path analysis with AD biomarkers and network integrity. The study evaluated the roles of salience, default mode, and frontoparietal networks. This is the first study to integrate MBI with AD biomarkers and network functionality.

A Systematic Review of tACS Effects on Cognitive Functioning in Older Adults Across the Healthy to Dementia Spectrum.

Transcranial alternating current stimulation (tACS) is a form of noninvasive brain stimulation that has experienced rapid growth within the aging population over the past decade due to its potential for modulating cognitive functioning across the "intact" to dementia spectrum. For this reason, we performed a systematic review of the literature to evaluate the efficacy of tACS on cognitive functioning in older adults, including those with cognitive impairment. Our review was completed in June 2023 using Psych INFO, Embase, PubMed, and Cochrane databases. Out of 479 screened articles, 21 met inclusion criteria and were organized according to clinical diagnoses. Seven out of nine studies targeted cognitively intact older adults and showed some type of cognitive improvement after stimulation, whereas nine out of twelve studies targeted clinical diagnoses and showed improved cognitive performance to varying degrees. Studies showed considerable heterogeneity in methodology, stimulation parameters, participant characteristics, choice of cognitive task, and analytic strategy, all of which reinforce the need for standardized reporting of tACS methods. Through this heterogeneity, multiple patterns are described, such as disease progression influencing tACS effects and the need for individualized tailoring. For clinical translation, it is imperative that the field (a) better understand the physiological effects of tACS in these populations, especially in respect to biomarkers, (b) document a causal relationship between tACS delivery and neurophysiological/cognitive effects, and (c) systematically establish dosing parameters (e.g., amplitude, stimulation frequency, number and duration of sessions, need for booster/maintenance sessions).

The association between cannabis use and subjective memory complaints in older adults in the United States.

OBJECTIVE: The U.S. population is aging and increasing numbers of older adults are using cannabis. Cognitive decline is common in older age and subjective memory complaints (SMC) have been associated with increased risk for dementia. While residual cognitive effects of cannabis use at younger ages are well understood, the links between cannabis use and cognition in older adults is less clear. The present study represents the first population-level analysis of cannabis use and SMC in older adults in the U.S. METHOD: We used the National Survey of Drug Use and Health (NSDUH) dataset to evaluate SMC in respondents over age 50 (N = 26,399) according to past-year cannabis use. RESULTS: Results revealed that 13.2% (95%CI: 11.5%-15.0%) of those who reported cannabis use also reported SMC, compared to 6.4% (95%CI: 6.1%-6.8%) among individuals with no cannabis use. Logistic regression revealed a two-fold increase (OR = 2.21, 95%CI: 1.88-2.60) of reporting SMC in respondents who had used cannabis in the past year, which was attenuated (OR = 1.38, 95%CI: 1.10-1.72) when controlling for additional factors. Other covariates, including physical health conditions, misuse of other substances, and mental illness also significantly contributed to SMC outcomes. CONCLUSIONS: Cannabis use represents a modifiable lifestyle factor that has potential for both risk and protective properties that may impact the trajectory of cognitive decline in older age. These hypothesis generating results are important for characterizing and contextualizing population-level trends related to cannabis use and SMC in older adults.

A Pilot Randomized Trial of a Purposeful and Stimulating Volunteer Opportunity: Program Satisfaction and Potential Impacts on Perceived Cognitive Change in a Neurologically Mixed Sample of Older Adults.

BACKGROUND: Purposeful social interactions are important for healthy aging. We conducted a pilot trial of SPEAK! (Seniors Promoting English Acquisition and Knowledge), an intervention providing older volunteers with a safe, accessible opportunity to converse via webcam with English-language learners. METHODS: A neurologically mixed sample of older adults was randomized to 8 weekly, webcam conversations with English-language learners or a waitlist control. Outcomes included the Cognitive Change Index (CCI) and surveys of program satisfaction. Here, we report on session completion, intervention satisfaction, and follow-up CCI scores. Exploratory analyses of CCI intervention effects controlled for baseline CCI scores and the interaction between group and baseline CCI. RESULTS: Participants (N=38) were on average 70.8 years of age, 28/38 were White, and 16/38 demonstrated possible cognitive impairment on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Pairs completed 115/136 sessions (85%) and all volunteers said they would recommend the program. Controlling for the interaction between baseline CCI and randomization group, SPEAK! volunteers had better follow-up CCI scores than controls (P=0.018). Improvements in CCI were greater among participants with fewer baseline memory problems. CONCLUSIONS: SPEAK! was feasible and appreciated by older adults with and without cognitive impairment. Larger studies should confirm benefits for memory and other determinants of quality of life.

Perspectives From Black and White Participants and Care Partners on Return of Amyloid and Tau PET Imaging and Other Research Results.

PURPOSE: Alzheimer disease (AD) biomarker testing is now common in research and approaching clinical translation. Disclosure protocols must be informed by diverse participants' perspectives on if/how the information would be useful. METHODS: This study utilized semistructured interviews assessing interest in receiving positron emission tomography (PET) amyloid and tau results, as well as perceived risks and benefits of hypothetical PET disclosure as a function of race and participant diagnosis. PARTICIPANTS: Participants [39% Black; 61% White; Mage =74.28 (5.98)] included 57 adults diagnosed as either cognitively healthy (58%) or with mild cognitive impairment (42%) and their respective care partners [33% Black; 67% White; Mage =66.93 (10.92)]. RESULTS: Most dyads endorsed strong interest in PET results (82.5% of both participants and partners) regardless of race or diagnosis. Black care partners were less interested in receiving the participant's results than White care partners ( χ2(4) =8.31, P =0.047). Reasons for disclosure were diverse and highly personalized, including access to treatments or clinical trials (23.2% participants; 29.8% partners), advance planning (14.3% participants; 17.5% partners), and improved health knowledge (12.5% participants; 15.8% partners). In contrast, over 80% of respondents denied any risks of disclosure. DISCUSSION: Results suggest that predisclosure education, decisional capacity assessment, and a flexible disclosure approach are needed.

Mild Cognitive Impairment Subtype Performance in Comparison to Healthy Older Controls on the NIH Toolbox and Cogstate.

BACKGROUND: Early detection is necessary for the treatment of dementia. Computerized testing has become more widely used in clinical trials; however, it is unclear how sensitive these measures are to early signs of neurodegeneration. We investigated the use of the NIH Toolbox-Cognition (NIHTB-CB) and Cogstate-Brief computerized neuropsychological batteries in the identification of mild cognitive impairment (MCI) versus healthy older adults [healthy control (HC)] and amnestic (aMCI) versus nonamnestic MCI (naMCI). Exploratory analyses include investigating potential racial differences. METHODS: Two hundred six older adults were diagnosed as aMCI (n = 58), naMCI (n = 15), or cognitively healthy (HC; n = 133). RESULTS: The NIH Toolbox-CB subtests of Flanker, Picture Sequence Memory, and Picture Vocabulary significantly differentiated MCI from HC. Further, subtests from both computerized batteries differentiated patients with aMCI from those with naMCI. Although the main effect of race differences was noted on tests and in diagnostic groups was significant, there were no significant race-by-test interactions. CONCLUSIONS: Computer-based subtests vary in their ability to help distinguish MCI subtypes, though these tests provide less expensive and easier-to-administer clinical screeners to help identify patients early who may qualify for more comprehensive evaluations. Further work is needed, however, to refine computerized tests to achieve better precision in distinguishing impairment subtypes.

High-definition transcranial direct current stimulation enhances network segregation during spatial navigation in mild cognitive impairment.

Spatial navigation is essential for everyday life and relies on complex network-level interactions. Recent evidence suggests that transcranial direct current stimulation (tDCS) can influence the activity of large-scale functional brain networks. We characterized brain-wide changes in functional network segregation (i.e. the balance of within vs. between-network connectivity strength) induced by high-definition (HD) tDCS in older adults with mild cognitive impairment (MCI) during virtual spatial navigation. Twenty patients with MCI and 22 cognitively intact older adults (healthy controls-HC) underwent functional magnetic resonance imaging following two counterbalanced HD-tDCS sessions (one active, one sham) that targeted the right parietal cortex (center anode at P2) and delivered 2 mA for 20 min. Compared to HC, MCI patients showed lower brain-wide network segregation following sham HD-tDCS. However, following active HD-tDCS, MCI patients' network segregation increased to levels similar to those in HC, suggesting functional normalization. Follow-up analyses indicated that the increase in network segregation for MCI patients was driven by HD-tDCS effects on the "high-level"/association brain networks, in particular the dorsal-attention and default-mode networks. HD-tDCS over the right parietal cortex may normalize the segregation/integration balance of association networks during spatial navigation in MCI patients, highlighting its potential to restore brain activity in Alzheimer's disease.

HD-tDCS as a neurorehabilitation technique for a case of post-anoxic leukoencephalopathy.

Post-anoxic leukoencephalopathy is a rare event that causes global demyelination secondary to anoxic injury. Given the nature and extent of the damage, cognitive and functional deficits are typically chronic even after standard therapies. Here, we describe a novel treatment approach that used high definition transcranial direct-current stimulation (HD-tDCS) with a 62-year-old male who was 5 years post-anoxic leukoencephalopathy secondary to an accidental drug overdose. HD-tDCS was administered over the left lateral prefrontal cortex across 29 daily sessions at 2 mA (20 min/session) in order to address dysexecutive behaviors. Results demonstrated improved delayed memory and trends for improved visuospatial and semantic fluency performance as well as improved insight and daily functioning, all of which returned to baseline by the end of a 10 week no-contact follow up period. Resting state fMRI connectivity results mirrored these changes by showing increased dorsal attention and cingulo-opercular but reduced ventral attention network connectivity after session 29, all of which returned to baseline at follow-up. These findings suggest HD-tDCS may benefit functioning even following serious and pervasive anoxic injury. Findings also suggest the need for continued HD-tDCS for maintenance purposes, though future work is needed to identify optimal dose-response information.

Toward rational use of cognitive training in those with mild cognitive impairment.

The term cognitive training includes a range of techniques that hold potential for treating cognitive impairment caused by neurologic injury and disease. Our central premise is that these techniques differ in their mechanisms of action and therefore engage distinct brain regions (or neural networks). We support this premise using data from a single-blind randomized-controlled trial in which patients with mild cognitive impairment were randomized to either mnemonic strategy training (MST) or spaced retrieval training (SRT) as they learned ecologically relevant object-location associations. Both training approaches were highly effective in the short term, but MST demonstrated a clear advantage after days to weeks. MST also increased activation in and functional connectivity between frontal, temporal, and parietal regions as well as the hippocampus. In contrast, patterns of reduced activation and functional connectivity were evident following SRT. These findings support the rational development of cognitive training techniques.

Comparison of Transcranial Focused Ultrasound and Transcranial Pulse Stimulation for Neuromodulation: A Computational Study.

OBJECTIVE: The objective of the study was to investigate transcranial wave propagation through two low-intensity focused ultrasound (LIFU)-based brain stimulation techniques-transcranial focused ultrasound stimulation (tFUS) and transcranial pulse stimulation (TPS). Although tFUS involves delivering long trains of acoustic pulses, the newly introduced TPS delivers ultrashort (∼3 µs) pulses repeated at 4 Hz. Accordingly, only a single simulation study with limited geometry currently exists for TPS. We considered a high-resolution three-dimensional (3D) whole human head model in addition to water bath simulations. We anticipate that the results of this study will help researchers investigating LIFU have a better understanding of the effects of the two different techniques. APPROACH: With an objective to first reproduce previous computational results, we considered two spherical tFUS transducers that were previously modeled. We assumed identical parameters (geometry, position, and imaging data set) to demonstrate differences, purely because of the waveform considered. For simulations with a 3D head data set, we also considered a parabolic transducer that has been used for TPS delivery. RESULTS: Our initial results successfully verified previous modeling workflow. The tFUS distribution was characterized by the typical elliptical profile, with its major axis perpendicular to the face of the transducer. The TPS distribution resembled two mirrored meniscus profiles, with its widest diameter oriented parallel to the face of the transducer. The observed intensity value differences were theoretical because the two waveforms differ in both intensity and time. The consideration of a realistic 3D human head model resulted in only a minor distortion of the two waveforms. SIGNIFICANCE: This study simulated TPS administration using a 3D realistic image-derived data set. Although our comparison results are strictly limited to the model parameters and assumptions made, we were able to elucidate some clear differences between the two approaches. We hope this initial study will pave the way for systematic comparison between the two approaches in the future.

Toward a theory-based specification of non-pharmacological treatments in aging and dementia: Focused reviews and methodological recommendations.

INTRODUCTION: Non-pharmacological treatments (NPTs) have the potential to improve meaningful outcomes for older people at risk of, or living with dementia, but research often lacks methodological rigor and continues to produce mixed results. METHODS: In the current position paper, experts in NPT research have specified treatment targets, aims, and ingredients using an umbrella framework, the Rehabilitation Treatment Specification System. RESULTS: Experts provided a snapshot and an authoritative summary of the evidence for different NPTs based on the best synthesis efforts, identified main gaps in knowledge and relevant barriers, and provided directions for future research. Experts in trial methodology provide best practice principles and recommendations for those working in this area, underscoring the importance of prespecified protocols. DISCUSSION: We conclude that the evidence strongly supports various NPTs in relation to their primary targets, and discuss opportunities and challenges associated with a unifying theoretical framework to guide future efforts in this area.

The effects of strategy training on spatial memory in diencephalic amnesia: a randomized controlled study.

Alcoholic Korsakoff's syndrome is characterized by severe amnesia, also affecting spatial memory. To date, research on cognitive rehabilitation in these patients is scarce. Aim of the present study is to examine the efficacy of a mnemonic strategy training in patients with Korsakoff's syndrome. A randomized controlled exploratory study was performed. A convenience sample of 14 patients with amnesia due to alcoholic Korsakoff's syndrome was included and randomized into a mnemonic strategy training group (n = 7) and a control group (n = 7). The training group completed a 3-day 45-60 min mnemonic strategy training that focused on specific strategies to encode and retrieve information about specific objects and their locations in virtual rooms, using labeling, verbal reasoning and mental imagery. The control group only received care as usual. Outcome measure was an object-location memory task consisting of novel, untrained object locations administered 1 day before the intervention, as well as 1 day and 1 week after completing the intervention. Patients in the intervention group were able to acquire and use the strategies, but no significant differences were found between the intervention group and the control group, and no significant change in performance was demonstrated compared to baseline 1 day and 1 week after the intervention. To conclude, the mnemonic strategy training in KS patients did not result in a better spatial memory performance 1 day or 1 week after training completion compared to participation in the regular non-cognitive treatment program that focused on occupational therapy, music therapy and exercise.

Impact of using a broad-based multi-institutional approach to build capacity for non-communicable disease research in Thailand.

Thailand's transition to high middle-income country status has been accompanied by demographic changes and associated shifts in the nation's public health challenges. These changes have necessitated a significant shift in public health focus from the treatment of infectious diseases to the more expensive and protracted management of non-communicable diseases (NCDs) in older adults.In 2010, in response to this shift in focus, the University of Michigan and colleagues at the Praboromarajchanok Institute for Health Workforce Development in Thailand began work on a broad-based multi-institutional programme for NCD research capacity-building in Thailand.To begin to build a base of intervention research we paired our programme's funded Thai postdoctoral fellows with United States mentors who have strong programmes of intervention research. One direct impact of the programme was the development of research 'hubs' focused upon similar areas of investigative focus such as self-management of cancer symptoms, self-management of HIV/AIDS and health technology information applications for use in community settings. Within these hubs, interventions with proven efficacy in the United States were used as a foundation for culturally relevant interventions in Thailand. The programme also aimed to develop the research support structures necessary within departments and colleges for grant writing and management, dissemination of new knowledge, and ethical conduct of human subject research.In an effort to capitalise on large national health datasets and big data now available in Thailand, several of the programme's postdoctoral fellows began projects that use data science methods to mine this asset. The investigators involved in these ground-breaking projects form the core of a network of research hubs that will be able to capitalise on the availability of lifespan health data from across Thailand and provide a robust working foundation for expansion of research using data science approaches.Going forward, it is vitally important to leverage this groundwork in order to continue fostering rapid growth in NCD research and training as well as to capitalise upon these early gains to create a sustaining influence for Thailand to lead in NCD research, improve the health of its citizens, and provide ongoing leadership in Southeast Asia.

Neurophysiologic and Cognitive Changes Arising from Cognitive Training Interventions in Persons with Mild Cognitive Impairment: A Systematic Review.

Background: Previous reviews have generally reported cognitive//behavioral improvements after cognitively oriented treatments (COTs) in persons with MCI. However, comparatively little is known about the neural mechanisms associated with such cognitive improvement. Objective: The primary aim of the current review was to examine neurophysiological changes measured by functional magnetic resonance imaging (fMRI) and possible cognitive changes following COTs in those with MCI. Methods. An extensive literature search was conducted up to August 2018. Inclusion criteria were (1) studies that evaluated the effects of the COTs in patients with amnestic single- or multiple-domain MCI using fMRI, (2) the MCI patient sample having met Petersen's or Jack/Bond's criteria, (3) randomized and/or controlled trials, (4) fMRI and cognitive assessments completed pre- and post-intervention, and (5) articles available in English. Results: Amongst the 26 articles found, 7 studies were included according to the above inclusion criteria. A total of 3 studies applied rehearsal-based strategies as the primary intervention, all of which used computerized cognitive training. Four studies used fMRI to investigate the neurophysiologic and cognitive changes associated with memory strategy training. The majority of the studies included in this review showed evidence of improved objective cognitive performance associated with COTs, even in tasks similar to everyday life activities. In addition, there were significant changes in brain activation associated with interventions, in both typical and atypical brain areas and networks related to memory. Conclusions: Although additional studies are needed given the small sample size, these initial findings suggest that cognitive improvement after COTs is generally associated with both compensatory (i.e., engaging alternative brain regions or networks not "typically" engaged) and restorative (i.e., reengaging the "typical" brain regions or networks) mechanisms.

Growth hormone deficiency after mild combat-related traumatic brain injury.

OBJECTIVE: Traumatic brain injury (TBI) has been recognized as a cause of growth hormone deficiency (GHD) in civilians. However, comparable data are sparse in veterans who incurred TBI during combat. Our objective was to determine the prevalence of GHD in veterans with a history of combat-related TBI, and its association with cognitive and psychosocial dysfunction. DESIGN: Single center prospective study. PATIENTS: Twenty male veterans with mild TBI incurred during combat 8-72 months prior to enrollment. MEASUREMENTS: GHD was defined by a GH peak <3 µg/L during glucagon stimulation test. Differences in neuropsychological, emotional, and quality of life of the GHD Veterans were described using Cohen's d. Large effect sizes were considered meaningful. RESULTS: Mean age was 33.7 years (SD 7.8) and all subjects had normal thyroid hormone and cortisol levels. Five (25%) exhibited a subnormal response to glucagon. Sixteen participants (80%) provided sufficient effort for valid neuropsychological assessment (12 GH-sufficient, 4 GHD). There were large effect size differences in self-monitoring during memory testing (d = 1.46) and inhibitory control (d = 0.92), with worse performances in the GHD group. While fatigue and post-traumatic stress disorder were comparable, the GHD group reported more depression (d = 0.80) and lower quality of life (d = 0.64). CONCLUSIONS: Our study found a 25% prevalence of GHD in veterans with mild TBI as shown by glucagon stimulation. The neuropsychological findings raise the possibility that GHD has adverse effects on executive abilities and mood. Further studies are needed to determine whether GH replacement is an effective treatment in these patients.

Cognitive rehabilitation of memory for mild cognitive impairment: a methodological review and model for future research.

Several recent reviews have suggested that cognitive rehabilitation may hold promise in the treatment of memory deficits experienced by patients with mild cognitive impairment. In contrast to the previous reviews that mainly focused on outcome, the current review examines key methodological challenges that are critical for designing and interpreting research studies and translating results into clinical practice. Using methodological details from 36 studies, we first examine diagnostic variability and how the use of cutoffs may bias samples toward more severely impaired patients. Second, the strengths and limitations of several common rehabilitative techniques are discussed. Half of the reviewed studies used a multi-technique approach that precludes the causal attribution between any specific technique and subsequent improvement. Third, there is a clear need to examine the dose-response relationship since this information was strikingly absent from most studies. Fourth, outcome measures varied widely and frequently depended on neuropsychological tests with little theoretical justification or ecological relevance. Fifth, we discuss how the variability in each of these other four areas complicates efforts to examine training generalization. Overall, future studies should place greater emphasis on ecologically relevant treatment approaches and outcome measures and we propose a hierarchical model that may aid in this pursuit.