Specificity in Generalization Effects of Transcranial Direct Current Stimulation Over the Left Inferior Frontal Gyrus in Primary Progressive Aphasia.

OBJECTIVES: Generalization (or near-transfer) effects of an intervention to tasks not explicitly trained are the most desirable intervention outcomes. However, they are rarely reported and even more rarely explained. One hypothesis for generalization effects is that the tasks improved share the same brain function/computation with the intervention task. We tested this hypothesis in this study of transcranial direct current stimulation (tDCS) over the left inferior frontal gyrus (IFG) that is claimed to be involved in selective semantic retrieval of information from the temporal lobes. MATERIALS AND METHODS: In this study, we examined whether tDCS over the left IFG in a group of patients with primary progressive aphasia (PPA), paired with a lexical/semantic retrieval intervention (oral and written naming), may specifically improve semantic fluency, a nontrained near-transfer task that relies on selective semantic retrieval, in patients with PPA. RESULTS: Semantic fluency improved significantly more in the active tDCS than in the sham tDCS condition immediately after and two weeks after treatment. This improvement was marginally significant two months after treatment. We also found that the active tDCS effect was specific to tasks that require this IFG computation (selective semantic retrieval) but not to other tasks that may require different computations of the frontal lobes. CONCLUSIONS: We provided interventional evidence that the left IFG is critical for selective semantic retrieval, and tDCS over the left IFG may have a near-transfer effect on tasks that depend on the same computation, even if they are not specifically trained. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT02606422.

Long-Term Changes in Axon Calibers after Injury: Observations on the Mouse Corticospinal Tract.

White matter pathology is common across a wide spectrum of neurological diseases. Characterizing this pathology is important for both a mechanistic understanding of neurological diseases as well as for the development of neuroimaging biomarkers. Although axonal calibers can vary by orders of magnitude, they are tightly regulated and related to neuronal function, and changes in axon calibers have been reported in several diseases and their models. In this study, we utilize the impact acceleration model of traumatic brain injury (IA-TBI) to assess early and late changes in the axon diameter distribution (ADD) of the mouse corticospinal tract using Airyscan and electron microscopy. We find that axon calibers follow a lognormal distribution whose parameters significantly change after injury. While IA-TBI leads to 30% loss of corticospinal axons by day 7 with a bias for larger axons, at 21 days after injury we find a significant redistribution of axon frequencies that is driven by a reduction in large-caliber axons in the absence of detectable degeneration. We postulate that changes in ADD features may reflect a functional adaptation of injured neural systems. Moreover, we find that ADD features offer an accurate way to discriminate between injured and non-injured mice. Exploring injury-related ADD signatures by histology or new emerging neuroimaging modalities may offer a more nuanced and comprehensive way to characterize white matter pathology and may also have the potential to generate novel biomarkers of injury.

Deductive derivation and turing-computerization of semiparametric efficient estimation.

Researchers often seek robust inference for a parameter through semiparametric estimation. Efficient semiparametric estimation currently requires theoretical derivation of the efficient influence function (EIF), which can be a challenging and time-consuming task. If this task can be computerized, it can save dramatic human effort, which can be transferred, for example, to the design of new studies. Although the EIF is, in principle, a derivative, simple numerical differentiation to calculate the EIF by a computer masks the EIF's functional dependence on the parameter of interest. For this reason, the standard approach to obtaining the EIF relies on the theoretical construction of the space of scores under all possible parametric submodels. This process currently depends on the correctness of conjectures about these spaces, and the correct verification of such conjectures. The correct guessing of such conjectures, though successful in some problems, is a nondeductive process, i.e., is not guaranteed to succeed (e.g., is not computerizable), and the verification of conjectures is generally susceptible to mistakes. We propose a method that can deductively produce semiparametric locally efficient estimators. The proposed method is computerizable, meaning that it does not need either conjecturing, or otherwise theoretically deriving the functional form of the EIF, and is guaranteed to produce the desired estimates even for complex parameters. The method is demonstrated through an example.

Estimation of treatment effects in matched-pair cluster randomized trials by calibrating covariate imbalance between clusters.

We address estimation of intervention effects in experimental designs in which (a) interventions are assigned at the cluster level; (b) clusters are selected to form pairs, matched on observed characteristics; and (c) intervention is assigned to one cluster at random within each pair. One goal of policy interest is to estimate the average outcome if all clusters in all pairs are assigned control versus if all clusters in all pairs are assigned to intervention. In such designs, inference that ignores individual level covariates can be imprecise because cluster-level assignment can leave substantial imbalance in the covariate distribution between experimental arms within each pair. However, most existing methods that adjust for covariates have estimands that are not of policy interest. We propose a methodology that explicitly balances the observed covariates among clusters in a pair, and retains the original estimand of interest. We demonstrate our approach through the evaluation of the Guided Care program.

Is sertraline treatment or depression remission in depressed Alzheimer patients associated with improved caregiver well being? Depression in Alzheimer's Disease Study 2.

OBJECTIVE: We wanted to assess if sertraline treatment (versus placebo) or remission of depression at 12 weeks (versus nonremission) in Alzheimer patients is associated with improved caregiver well being. METHODS: We conducted a randomized, double-blind, placebo-controlled clinical trial of the efficacy and safety of sertraline for the treatment of depression in individuals with Alzheimer disease in five clinical research sites across the United States. Participants were caregivers of patients enrolled in the Depression in Alzheimer's Disease Study 2 (N = 131). All caregivers received standardized psychosocial support throughout the study. Caregiver outcome measures included depression (Beck Depression Inventory), distress (Neuropsychiatric Inventory), burden (Zarit Burden Interview), and quality of life (Medical Outcomes Study Short Form Health Survey). RESULTS: Fifty-nine percent of caregivers were spouses, 63.4% were women, and 64.1% were white. Caregivers of patients in both treatment groups had significant reductions in distress scores over the 24-week study period, but there was not a greater benefit for caregivers of patients taking sertraline. However, caregivers of patients whose depression was in remission at week 12 had greater declines in distress scores over the 24 weeks than caregivers of patients whose depression did not remit by week 12. CONCLUSION: Patient treatment with sertraline was not associated with significantly greater reductions in caregiver distress than placebo treatment. Distress but not level of depression or burden lessened for all caregivers regardless of remission status and even more so for those who cared for patients whose depression remitted. Results imply an interrelationship between caregiver distress and patient psychiatric outcomes.

Choosing profile double-sampling designs for survival estimation with application to President's Emergency Plan for AIDS Relief evaluation.

Most studies that follow subjects over time are challenged by having some subjects who dropout. Double sampling is a design that selects and devotes resources to intensively pursue and find a subset of these dropouts, then uses data obtained from these to adjust naïve estimates, which are potentially biased by the dropout. Existing methods to estimate survival from double sampling assume a random sample. In limited-resource settings, however, generating accurate estimates using a minimum of resources is important. We propose using double-sampling designs that oversample certain profiles of dropouts as more efficient alternatives to random designs. First, we develop a framework to estimate the survival function under these profile double-sampling designs. We then derive the precision of these designs as a function of the rule for selecting different profiles, in order to identify more efficient designs. We illustrate using data from the United States President's Emergency Plan for AIDS Relief-funded HIV care and treatment program in western Kenya. Our results show why and how more efficient designs should oversample patients with shorter dropout times. Further, our work suggests generalizable practice for more efficient double-sampling designs, which can help maximize efficiency in resource-limited settings.

Baseline functional connectivity predicts who will benefit from neuromodulation: evidence from primary progressive aphasia.

Background: Identifying the characteristics of individuals who demonstrate response to an intervention allows us to predict who is most likely to benefit from certain interventions. Prediction is challenging in rare and heterogeneous diseases, such as primary progressive aphasia (PPA), that have varying clinical manifestations. We aimed to determine the characteristics of those who will benefit most from transcranial direct current stimulation (tDCS) of the left inferior frontal gyrus (IFG) using a novel heterogeneity and group identification analysis. Methods: We compared the predictive ability of demographic and clinical patient characteristics (e.g., PPA variant and disease progression, baseline language performance) vs. functional connectivity alone (from resting-state fMRI) in the same cohort. Results: Functional connectivity alone had the highest predictive value for outcomes, explaining 62% and 75% of tDCS effect of variance in generalization (semantic fluency) and in the trained outcome of the clinical trial (written naming), contrasted with <15% predicted by clinical characteristics, including baseline language performance. Patients with higher baseline functional connectivity between the left IFG (opercularis and triangularis), and between the middle temporal pole and posterior superior temporal gyrus, were most likely to benefit from tDCS. Conclusions: We show the importance of a baseline 7-minute functional connectivity scan in predicting tDCS outcomes, and point towards a precision medicine approach in neuromodulation studies. The study has important implications for clinical trials and practice, providing a statistical method that addresses heterogeneity in patient populations and allowing accurate prediction and enrollment of those who will most likely benefit from specific interventions.

Estimating parsimonious models of longitudinal causal effects using regressions on propensity scores.

Parsimony is important for the interpretation of causal effect estimates of longitudinal treatments on subsequent outcomes. One method for parsimonious estimates fits marginal structural models by using inverse propensity scores as weights. This method leads to generally large variability that is uncommon in more likelihood-based approaches. A more recent method fits these models by using simulations from a fitted g-computation, but requires the modeling of high-dimensional longitudinal relations that are highly susceptible to misspecification. We propose a new method that, first, uses longitudinal propensity scores as regressors to reduce the dimension of the problem and then uses the approximate likelihood for the first estimates to fit parsimonious models. We demonstrate the methods by estimating the effect of anticoagulant therapy on survival for cancer and non-cancer patients who have inferior vena cava filters.

A broad symmetry criterion for nonparametric validity of parametrically based tests in randomized trials.

Pilot phases of a randomized clinical trial often suggest that a parametric model may be an accurate description of the trial's longitudinal trajectories. However, parametric models are often not used for fear that they may invalidate tests of null hypotheses of equality between the experimental groups. Existing work has shown that when, for some types of data, certain parametric models are used, the validity for testing the null is preserved even if the parametric models are incorrect. Here, we provide a broader and easier to check characterization of parametric models that can be used to (i) preserve nonparametric validity of testing the null hypothesis, i.e., even when the models are incorrect, and (ii) increase power compared to the non- or semiparametric bounds when the models are close to correct. We demonstrate our results in a clinical trial of depression in Alzheimer's patients.

Cognitive outcomes after sertaline treatment in patients with depression of Alzheimer disease.

OBJECTIVES: Although many depressed patients with Alzheimer disease (AD) are treated with antidepressants, the effect of such treatment on cognitive performance in these patients is not known. The authors report cognitive outcomes in patients with depression of AD (dAD) after a 24-week trial of sertraline or placebo. DESIGN: Placebo-controlled, randomized, double-blind trial. SETTING: Outpatient memory clinics at five academic medical centers in the United States. PARTICIPANTS: A total of 131 patients with dAD (60 men) and Mini-Mental State Examination scores of 10-26. INTERVENTION: Sertraline (n = 67), target dose of 100 mg daily or matching placebo (n = 64). Caregivers received standardized psychosocial intervention throughout the trial. MEASUREMENTS: Mini-Mental State Examination, cognitive subscale of the Alzheimer's Disease Assessment Scale, letter fluency, backward digit span, Symbol Digit Modalities Test, and Finger Tapping Test, administered at baseline, and 8, 16, and 24 weeks following baseline. RESULTS: A series of linear models indicated no effect of treatment or of depression remission on cognitive test performance at 24 weeks. Regardless of treatment condition, very little change in cognitive test performance was noted in general. CONCLUSIONS: Treatment with sertraline in patients with dAD is not associated with greater improvement in cognition at week 24 than treatment with placebo.

The function of the left anterior temporal pole: evidence from acute stroke and infarct volume.

The role of the anterior temporal lobes in cognition and language has been much debated in the literature over the last few years. Most prevailing theories argue for an important role of the anterior temporal lobe as a semantic hub or a place for the representation of unique entities such as proper names of peoples and places. Lately, a few studies have investigated the role of the most anterior part of the left anterior temporal lobe, the left temporal pole in particular, and argued that the left anterior temporal pole is the area responsible for mapping meaning on to sound through evidence from tasks such as object naming. However, another recent study indicates that bilateral anterior temporal damage is required to cause a clinically significant semantic impairment. In the present study, we tested these hypotheses by evaluating patients with acute stroke before reorganization of structure-function relationships. We compared a group of 20 patients with acute stroke with anterior temporal pole damage to a group of 28 without anterior temporal pole damage matched for infarct volume. We calculated the average percent error in auditory comprehension and naming tasks as a function of infarct volume using a non-parametric regression method. We found that infarct volume was the only predictive variable in the production of semantic errors in both auditory comprehension and object naming tasks. This finding favours the hypothesis that left unilateral anterior temporal pole lesions, even acutely, are unlikely to cause significant deficits in mapping meaning to sound by themselves, although they contribute to networks underlying both naming and comprehension of objects. Therefore, the anterior temporal lobe may be a semantic hub for object meaning, but its role must be represented bilaterally and perhaps redundantly.

Sertraline for the treatment of depression in Alzheimer disease: genetic influences.

OBJECTIVE: To assess the potential for genetic influences on sertraline treatment efficacy for depression of Alzheimer disease (dAD). Four functional genetic variants were studied: 2 serotonin receptors (HTR2A-T102C and HTR2C-Cys23Ser), the serotonin transporter (5HTT-LPR), and brain-derived neurotrophic factor (BDNF-Val66Met). Treatment response by genotype was measured by (1) the modified Alzheimer's Disease Cooperative Study Clinical Global Impression of Change, (2) the Cornell scale for Depression in Dementia, and (3) remission of depression. METHODS: We utilized data from the Depression in Alzheimer's Disease Study 2 (DIADS-2), a 24-week, randomized, multicenter trial showing no significant treatment effect of sertraline on dAD. Proportional odds logistic regression and mixed effects models were used to examine the above mentioned outcome measures. RESULTS: No significant interactions were seen between any of the genetic polymorphisms and the selected outcomes above at 12 or 24 weeks. DISCUSSION: Treatment outcomes in the DIADS-2 trial were not significantly influenced by genetic variation at the loci that were assessed. Future studies should continue to examine the interaction of depression-related genetic variants with antidepressant treatment in Alzheimer disease patients with depression.

Do treatment effects vary among differing baseline depression criteria in depression in Alzheimer's disease study ± 2 (DIADS-2)?

OBJECTIVE: To determine if the effect of sertraline in the depression in Alzheimer's disease study - 2 (DIADS-2) differed in subgroups of patients defined by baseline depression criteria. METHODS: DIADS-2 was a randomized, parallel, placebo-controlled, multicenter trial designed to evaluate the efficacy and safety of sertraline (target dose of 100 mg/day) for the treatment of depression in patients with Alzheimer's disease. DIADS-2 enrolled 131 patients who met criteria for the depression of Alzheimer's disease (dAD). Analyses reported here examined if the effect of sertraline differed in various subgroups, including those meeting criteria for major depressive episode (MaD), minor depressive episode (MiD), and Alzheimer's-associated affective disorder (AAAD) at baseline. RESULTS: At baseline, 52 of 131 participants (39.7%) met criteria for MaD, 54 (41.2%) for MiD, and 90 (68.7%) for AAAD. For the primary outcome of modified Alzheimer's Disease Cooperative Study Clinical Global Impression of Change (mADCS-CGIC) scores at 12 weeks of follow-up, the odds of being at or better than a given mADCS-CGIC category did not significantly differ between the two treatment groups for those patients with MaD at baseline (OR(sertraline) = 0.66 [95% CI: 0.24, 1.82], p = 0.42); tests for interactions between treatment group and baseline depression diagnostic subgroup were not significant for MaD versus MiD versus neither (χ(2) = 1.05 (2df), p = 0.59) or AAAD versus no AAAD (χ(2) = 0.06 (1df), p = 0.81). CONCLUSIONS: There was no evidence that sertraline treatment was more efficacious in those patients meeting baseline criteria for MaD compared to MiD or to neither.

Neural Correlates of Letter and Semantic Fluency in Primary Progressive Aphasia.

Verbal fluency (VF) is an informative cognitive task. Lesion and functional imaging studies implicate distinct cerebral areas that support letter versus semantic fluency and the understanding of neural and cognitive mechanisms underlying task performance. Most lesion studies include chronic stroke patients. People with primary progressive aphasia (PPA) provide complementary evidence for lesion-deficit associations, as different brain areas are affected in stroke versus PPA. In the present study we sought to determine imaging, clinical and demographic correlates of VF in PPA. Thirty-five patients with PPA underwent an assessment with letter and category VF tasks, evaluation of clinical features and an MRI scan for volumetric analysis. We used stepwise regression models to determine which brain areas are associated with VF performance while acknowledging the independent contribution of clinical and demographic factors. Letter fluency was predominantly associated with language severity (R2 = 38%), and correlated with the volume of the left superior temporal regions (R2 = 12%) and the right dorsolateral prefrontal area (R2 = 5%). Semantic fluency was predominantly associated with dementia severity (R2 = 47%) and correlated with the volume of the left inferior temporal gyrus (R2 = 7%). No other variables were significantly associated with performance in the two VF tasks. We concluded that, independently of disease severity, letter fluency is significantly associated with the volume of frontal and temporal areas whereas semantic fluency is associated mainly with the volume of temporal areas. Furthermore, our findings indicated that clinical severity plays a critical role in explaining VF performance in PPA, compared to the other clinical and demographic factors.

Estimating treatment effects of longitudinal designs using regression models on propensity scores.

We derive regression estimators that can compare longitudinal treatments using only the longitudinal propensity scores as regressors. These estimators, which assume knowledge of the variables used in the treatment assignment, are important for reducing the large dimension of covariates for two reasons. First, if the regression models on the longitudinal propensity scores are correct, then our estimators share advantages of correctly specified model-based estimators, a benefit not shared by estimators based on weights alone. Second, if the models are incorrect, the misspecification can be more easily limited through model checking than with models based on the full covariates. Thus, our estimators can also be better when used in place of the regression on the full covariates. We use our methods to compare longitudinal treatments for type II diabetes mellitus.

The method of envelopes to concisely calculate semiparametric efficient scores under parametric restrictions.

When addressing semiparametric problems with parametric restrictions (assumptions on the distribution), the efficient score (ES) of a parameter is often important for generating useful estimates. However, usual derivation of ES, although conceptually simple, is often lengthy and with many steps that do not help in understanding why its final form arises. This drawback often casts onto semiparametric estimation a mantle that can turn away otherwise able doctoral students or researchers. Here we show that many ESs can be obtained as a one-step derivation after we characterize those features (envelopes) of the unrestricted problem that are constrained in the restricted problem. We demonstrate our arguments in three problems with known ES but whose usual derivations are lengthy. We show that the envelope-based derivation is dramatically explanatory and compact, needing essentially two lines where the standard approach needs 10 or more pages. This suggests that the envelope method can add useful intuition and exegesis to both teaching and research of semiparametric estimation.

The need for double-sampling designs in survival studies: an application to monitor PEPFAR.

In 2007, there were 33.2 million people around the world living with HIV/AIDS (UNAIDS/WHO, 2007). In May 2003, the U.S. President announced a global program, known as the President's Emergency Plan for AIDS Relief (PEPFAR), to address this epidemic. We seek to estimate patient mortality in PEPFAR in an effort to monitor and evaluate this program. This effort, however, is hampered by loss to follow-up that occurs at very high rates. As a consequence, standard survival data and analysis on observed nondropout data are generally biased, and provide no objective evidence to correct the potential bias. In this article, we apply double-sampling designs and methodology to PEPFAR data, and we obtain substantially different and more plausible estimates compared with standard methods (1-year mortality estimate of 9.6% compared to 1.7%). The results indicate that a double-sampling design is critical in providing objective evidence of possible nonignorable dropout and, thus, in obtaining accurate data in PEPFAR. Moreover, we show the need for appropriate analysis methods coupled with double-sampling designs.

Written Verb Naming Improves After tDCS Over the Left IFG in Primary Progressive Aphasia.

Transcranial direct current stimulation (tDCS), a non-invasive neuromodulation technique, is an effective adjunct to naming treatments in post-stroke aphasia and primary progressive aphasia (PPA). Enhanced performance in oral and written naming and spelling of nouns with tDCS has been quantified in detail, but it is not known whether it is effective for verb treatment in PPA. We addressed the question of whether performance in naming and spelling of verbs can be augmented with anodal tDCS over the left inferior frontal gyrus (IFG). We compared tDCS coupled with oral and written verb naming/spelling treatment with oral and written verb naming/spelling treatment alone. In a double-blind, sham-controlled, crossover design, 11 participants with logopenic or non-fluent variant PPA received approximately 15 consecutive sessions of anodal tDCS and sham over the left IFG coupled with oral and written verb-naming + spelling treatment. Written verb-naming performance improved significantly more for trained verbs in the tDCS than the sham condition. Importantly, tDCS effects generalized to untrained items for written verb naming and were significant even at 2 months post-treatment. We conclude that tDCS over the left IFG can improve written verb naming and spelling in PPA.

Electrical brain stimulation in different variants of primary progressive aphasia: A randomized clinical trial.

INTRODUCTION: Transcranial direct current stimulation (tDCS) has been recently shown to improve language outcomes in primary progressive aphasia (PPA) but most studies are small and the influence of PPA variant is unknown. METHODS: Thirty-six patients with PPA participated in a randomized, sham-controlled, double-blind, within-subject crossover design for 15 daily sessions of stimulation coupled with written naming/spelling therapy. Outcome measures were letter accuracy of treated and untreated words immediately after and at 2 weeks and 2 months posttreatment. RESULTS: tDCS treatment was more effective than sham: gains for treated words were maintained 2 months posttreatment; gains from tDCS also generalized to untreated words and were sustained 2 months posttreatment. Different effects were obtained for each PPA variant, with no tDCS advantage for semantic variant PPA. DISCUSSION: The study supports using tDCS as an adjunct to written language interventions in individuals with logopenic or nonfluent/agrammatic PPA seeking compensatory treatments in clinical settings.