Parallel and identical test-retest reliability of the Tower of London test - Freiburg version.

OBJECTIVES: The Tower of London - Freiburg version (TOL-F) was developed in three parallel-test versions (A, B, and C) that only differ in their physical appearance by interchanged ball colors, but not in their cognitive demands. We addressed the question whether the test-retest reliability of an identical problem set differs from the parallel test-retest reliability of a structurally identical problem set with a marginally different physical appearance. METHODS: Reliabilities were assessed in two samples of young adults over a 1-week interval: In the parallel test-retest sample (n = 93; 49 female), half of the participants accomplished version A at the first session and version B at the second session, while the other half started with version B in the first session and continued with A in the second session. In the identical test-retest sample (n = 86; 48 female), half of the participants performed on version A in both the first and the second session, while the other half went through the same procedure with version B. RESULTS: For overall planning accuracy, intraclass correlation coefficients for absolute agreement were r = .501 for the parallel test-retest and r = .605 for the identical test-retest sample, with Pearson correlations of r = .559 and r = .708 respectively. Greatest lower bound estimates of reliability were adequate to high in the two samples (ranging between .765 and .854) confirming previous studies. CONCLUSIONS: Although the TOL-F revealed only moderate intraclass correlations for absolute agreement, it showed some of the highest psychometric indices compared to repeated assessments with other TOL tests.

Interaction between cognitive reserve and age moderates effect of lesion load on stroke outcome.

The concepts of brain reserve and cognitive reserve were recently suggested as valuable predictors of stroke outcome. To test this hypothesis, we used age, years of education and lesion size as clinically feasible coarse proxies of brain reserve, cognitive reserve, and the extent of stroke pathology correspondingly. Linear and logistic regression models were used to predict cognitive outcome (Montreal Cognitive Assessment) and stroke-induced impairment and disability (NIH Stroke Scale; modified Rankin Score) in a sample of 104 chronic stroke patients carefully controlled for potential confounds. Results revealed 46% of explained variance for cognitive outcome (p < 0.001) and yielded a significant three-way interaction: Larger lesions did not lead to cognitive impairment in younger patients with higher education, but did so in younger patients with lower education. Conversely, even small lesions led to poor cognitive outcome in older patients with lower education, but didn't in older patients with higher education. We observed comparable three-way interactions for clinical scores of stroke-induced impairment and disability both in the acute and chronic stroke phase. In line with the hypothesis, years of education conjointly with age moderated effects of lesion on stroke outcome. This non-additive effect of cognitive reserve suggests its post-stroke protective impact on stroke outcome.

The rostro-caudal gradient in the prefrontal cortex and its modulation by subthalamic deep brain stimulation in Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) alleviates motor symptoms in Parkinson's disease (PD) but also affects the prefrontal cortex (PFC), potentially leading to cognitive side effects. The present study tested alterations within the rostro-caudal hierarchy of neural processing in the PFC induced by STN-DBS in PD. Granger-causality analyses of fast functional near-infrared spectroscopy (fNIRS) measurements were used to infer directed functional connectivity from intrinsic PFC activity in 24 PD patients treated with STN-DBS. Functional connectivity was assessed ON stimulation, in steady-state OFF stimulation and immediately after the stimulator was switched ON again. Results revealed that STN-DBS significantly enhanced the rostro-caudal hierarchical organization of the PFC in patients who had undergone implantation early in the course of the disease, whereas it attenuated the rostro-caudal hierarchy in late-implanted patients. Most crucially, this systematic network effect of STN-DBS was reproducible in the second ON stimulation measurement. Supplemental analyses demonstrated the significance of prefrontal networks for cognitive functions in patients and matched healthy controls. These findings show that the modulation of prefrontal functional networks by STN-DBS is dependent on the disease duration before DBS implantation and suggest a neurophysiological mechanism underlying the side effects on prefrontally-guided cognitive functions observed under STN-DBS.

Psychometric analyses of the Tower of London planning task reveal high reliability and feasibility in typically developing children and child patients with ASD and ADHD.

The Tower of London (TOL) is probably the most often used assessment tool for planning ability in healthy and clinical samples. Various versions, including our proposed standard problem set, have proven to be feasible and reliable in adults. In contrast, reliability information for typically developing (TD) children and neurodevelopmental disorders during childhood are largely missing. Also, it would be highly desirable to attain a problem set that can be used across the whole lifespan. Therefore, here we examine reliability of our proposed standard problem set using a computerized TOL version in 178 TD children (two different samples), 49 children with high-functioning autism spectrum disorder (ASD) and 56 children with attention-deficit/hyperactivity disorder (ADHD) (age ranges of each group 6 to 13 years), and 130 young adults (age range 18 to 32 years). Greatest lower bound estimates of reliability were adequate to high in the two samples of TD children (.76 and .80) and high to very high in patients (ASD: .90; ADHD: .83). In young adults, all reliability indices were adequate to high. Moreover, a subset of four- and five-move problems exhibited sufficient performance variability and high part-whole correlations with the complete problem set in all samples. These findings demonstrate the reliability of the presented TOL problem set in both clinical and non-clinical child samples. A clinically feasible subset of four- and five-move problems is reflective of overall planning performance at all ages, hence enabling comparisons of planning ability within and between developmental samples across almost the whole lifespan.

Determinants of Inter-Individual Variability in Corticomotor Excitability Induced by Paired Associative Stimulation.

Transcranial magnetic stimulation (TMS) is a well-established tool in probing cortical plasticity in vivo. Changes in corticomotor excitability can be induced using paired associative stimulation (PAS) protocol, in which TMS over the primary motor cortex is conditioned with an electrical peripheral nerve stimulation of the contralateral hand. PAS with an inter-stimulus interval of 25 ms induces long-term potentiation (LTP)-like effects in cortical excitability. However, the response to a PAS protocol tends to vary substantially across individuals. In this study, we used univariate and multivariate data-driven methods to investigate various previously proposed determinants of inter-individual variability in PAS efficacy, such as demographic, cognitive, clinical, neurophysiological, and neuroimaging measures. Forty-one right-handed participants, comprising 22 patients with amnestic mild cognitive impairment (MCI) and 19 healthy controls (HC), underwent the PAS protocol. Prior to stimulation, demographic, genetic, clinical, as well as structural and resting-state functional MRI data were acquired. The two groups did not differ in any of the variables, except by global cognitive status. Univariate analysis showed that only 61% of all participants were classified as PAS responders, irrespective of group membership. Higher PAS response was associated with lower TMS intensity and with higher resting-state connectivity within the sensorimotor network, but only in responders, as opposed to non-responders. We also found an overall positive correlation between PAS response and structural connectivity within the corticospinal tract, which did not differ between groups. A multivariate random forest (RF) model identified age, gender, education, IQ, global cognitive status, sleep quality, alertness, TMS intensity, genetic factors, and neuroimaging measures (functional and structural connectivity, gray matter (GM) volume, and cortical thickness as poor predictors of PAS response. The model resulted in low accuracy of the RF classifier (58%; 95% CI: 42 - 74%), with a higher relative importance of brain connectivity measures compared to the other variables. We conclude that PAS variability in our sample was not well explained by factors known to influence PAS efficacy, emphasizing the need for future replication studies.

Dissociation among preserved resistance to proactive interference and impaired behavioral inhibition in a patient with bilateral lesions in the inferior frontal gyrus: A single-case study.

Inhibition is not a unitary construct, as different inhibition-related functions have been disentangled. The present single-case study compares performance of a patient with bilateral lesions in the inferior frontal gyrus (IFG) and anterior insula to healthy age-matched controls in different inhibition-related tasks. Particular focus was on the resolution of proactive interference that is supposed to rely on bilateral IFG and anterior insula. Two working memory tasks previously proven sensitive to deficits in proactive interference (recent-probes, n-back) and two tasks measuring behavioral inhibition (verb generation task, Stroop task) were administered. Against expectations, the patient did not show any deficits in measures of proactive interference. However, compared to controls, she demonstrated considerably reduced performance in both measures of behavioral inhibition, thus resulting in a classical dissociation between proactive interference and behavioral inhibition. Although performance improved during the chronic phase post stroke, the overall pattern of a classical dissociation between proactive interference and behavioral inhibition remained stable across time. Taken together, the present data support the role of the IFG in inhibition-related functions, but a direct relationship between lesions in the IFG and difficulties in resolution of proactive interference could not be corroborated.

Data on the test-retest reproducibility of streamline counts as a measure of structural connectivity.

These data provide estimations of test-retest reproducibility of streamline counts based on diffusion weighted imaging (DWI) data using a global tractography algorithm in a sample of young healthy adults. Data on descriptive statistics and factorial analyses of within-session and between-session reproducibility in terms of intra-class correlation coefficients for the absolute agreement between measurements are provided. The effect of several exemplary methodological parameters pertaining to different steps along the tractography processing pipeline on reproducibility are considered. These data are related to the research article entitled 'Probing the reproducibility of quantitative estimates of structural connectivity derived from global tractography' (Schumacher et al., Neuroimage, 175 (2018) 215-229).

Brain Aging and APOE ε4 Interact to Reveal Potential Neuronal Compensation in Healthy Older Adults.

Compensation implies the recruitment of additional neuronal resources to prevent the detrimental effect of age-related neuronal decline on cognition. Recently suggested statistical models comprise behavioral performance, brain activation, and measures related to aging- or disease-specific pathological burden to characterize compensation. Higher chronological age as well as the APOE ε4 allele are risk factors for Alzheimer's disease. A more biological approach to characterize aging compared with chronological age is the brain age gap estimation (BrainAGE), taking into account structural brain characteristics. We utilized this estimate in an fMRI experiment together with APOE variant as measures related to pathological burden and aimed at identifying compensatory regions during working memory (WM) processing in a group of 34 healthy older adults. According to published compensation criteria, better performance along with increased brain activation would indicate successful compensation. We examined the moderating effects of BrainAGE on the relationship between task performance and brain activation in prefrontal cortex, as previous studies suggest predominantly frontal compensatory activation. Then we statistically compared them to the effects of chronological age (CA) tested in a previous study. Moreover, we examined the effects of adding APOE variant as a further moderator. Herewith, we strived to uncover neuronal compensation in healthy older adults at risk for neurodegenerative disease. Higher BrainAGE alone was not associated with an increased recruitment in prefrontal cortex. When adding APOE variant as a second moderator, we found an interaction of BrainAGE and APOE variant, such that ε4 carriers recruited right inferior frontal gyrus with higher BrainAGE to maintain WM performance, thus showing a pattern compatible with successful neuronal compensation. Exploratory analyses yielded similar patterns in left inferior and bilateral middle frontal gyrus. These results contrast those from a previous study, where we found no indication of compensation in prefrontal cortex in ε4 carriers with increasing CA. We conclude that BrainAGE together with APOE variant can help to reveal potential neuronal compensation in healthy older adults. Previous results on neuronal compensation in frontal areas corroborate our findings. Compensatory brain regions could be targeted in affected individuals by training or stimulation protocols to maintain cognitive functioning as long as possible.

Probing the reproducibility of quantitative estimates of structural connectivity derived from global tractography.

As quantitative measures derived from fiber tractography are increasingly being used to characterize the structural connectivity of the brain, it is important to establish their reproducibility. However, no such information is as yet available for global tractography. Here we provide the first comprehensive analysis of the reproducibility of streamline counts derived from global tractography as quantitative estimates of structural connectivity. In a sample of healthy young adults scanned twice within one week, within-session and between-session test-retest reproducibility was estimated for streamline counts of connections based on regions of the AAL atlas using the intraclass correlation coefficient (ICC) for absolute agreement. We further evaluated the influence of the type of head-coil (12 versus 32 channels) and the number of reconstruction repetitions (reconstructing streamlines once or aggregated over ten repetitions). Factorial analyses demonstrated that reproducibility was significantly greater for within- than between-session reproducibility and significantly increased by aggregating streamline counts over ten reconstruction repetitions. Using a high-resolution head-coil incurred only small beneficial effects. Overall, ICC values were positively correlated with the streamline count of a connection. Additional analyses assessed the influence of different selection variants (defining fuzzy versus no fuzzy borders of the seed mask; selecting streamlines that end in versus pass through a seed) showing that an endpoint-based variant using fuzzy selection provides the best compromise between reproducibility and anatomical specificity. In sum, aggregating quantitative indices over repeated estimations and higher numbers of streamlines are important determinants of test-retest reproducibility. If these factors are taken into account, streamline counts derived from global tractography provide an adequately reproducible quantitative measure that can be used to gauge the structural connectivity of the brain in health and disease.

Biological Factors Contributing to the Response to Cognitive Training in Mild Cognitive Impairment.

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.

Real-world navigation in amnestic mild cognitive impairment: The relation to visuospatial memory and volume of hippocampal subregions.

Spatial disorientation is a frequent symptom in Alzheimer's disease and in mild cognitive impairment (MCI). In the clinical routine, spatial orientation is less often tested with real-world navigation but rather with 2D visuoconstructive tasks. However, reports about the association between the two types of tasks are sparse. Additionally, spatial disorientation has been linked to volume of the right hippocampus but it remains unclear whether right hippocampal subregions have differential involvement in real-world navigation. Yet, this would help uncover different functional roles of the subregions, which would have important implications for understanding the neuronal underpinnings of navigation skills. We compared patients with amnestic MCI (aMCI; n = 25) and healthy elderly controls (HC; n = 25) in a real-world navigation task that engaged different spatial processes. The association between real-world navigation and different visuoconstructive tasks was tested (i.e., figures from the Consortium to Establish a Registry for Alzheimer's Disease; CERAD, the Rey-Osterrieth Complex Figure task; and clock drawing). Furthermore, the relation between spatial navigation and volume of right hippocampal subregions was examined. Linear regression and relative weight analysis were applied for statistical analyses. Patients with aMCI were significantly less able to correctly navigate through a route compared to HC but had comparable map drawing and landmark recognition skills. The association between visuoconstructive tasks and real-world navigation was only significant when using the visuospatial memory component of the Rey figure. In aMCI, more volume of the right hippocampal tail was significantly associated with better navigation skills, while volume of the right CA2/3 region was a significant predictor in HC. Standard visuoconstructive tasks (e.g., the CERAD figures or clock drawing) are not sufficient to detect real-world spatial disabilities in aMCI. Consequently, more complex visuoconstructive tasks (i.e., the Rey figure) should be routinely included in the assessment of cognitive functions in the context of AD. Moreover, in those elderly individuals with impaired complex visuospatial memory, route finding behaviour should be evaluated in detail. Regarding the contribution of hippocampal subregions to spatial navigation, the right hippocampal tail seems to be particularly important for patients with aMCI, while the CA2/3 region appears to be more relevant in HC.

APOE moderates compensatory recruitment of neuronal resources during working memory processing in healthy older adults.

The APOE ε4 allele increases the risk for sporadic Alzheimer's disease and modifies brain activation patterns of numerous cognitive domains. We assessed cognitively intact older adults with a letter n-back task to determine if previously observed increases in ε4 carriers' working-memory-related brain activation are compensatory such that they serve to maintain working memory function. Using multiple regression models, we identified interactions of APOE variant and age in bilateral hippocampus independently from task performance: ε4 carriers only showed a decrease in activation with increasing age, suggesting high sensitivity of fMRI data for detecting changes in Alzheimer's disease-relevant brain areas before cognitive decline. Moreover, we identified ε4 carriers to show higher activations in task-negative medial and task-positive inferior frontal areas along with better performance under high working memory load relative to non-ε4 carriers. The increased frontal recruitment is compatible with models of neuronal compensation, extends on existing evidence, and suggests that ε4 carriers require additional neuronal resources to successfully perform a demanding working memory task.

Are semantic and phonological fluency based on the same or distinct sets of cognitive processes? Insights from factor analyses in healthy adults and stroke patients.

Verbal fluency for semantic categories and phonological letters is frequently applied to studies of language and executive functions. Despite its popularity, it is still debated whether measures of semantic and phonological fluency reflect the same or distinct sets of cognitive processes. Word generation in the two task variants is believed to involve different types of search processes. Findings from the lesion and neuroimaging literature further suggest a stronger reliance of phonological and semantic fluency on frontal and temporal brain areas, respectively. This evidence for differential cognitive and neural contributions is, however, strongly challenged by findings from factor analyses, which have consistently yielded only one explanatory factor. As all previous factor-analytical approaches were based on very small item sets, this apparent discrepancy may be due to methodological limitations. In this study, we therefore applied a German version of the verbal fluency task with 8 semantic (i.e. categories) and 8 phonological items (i.e. letters). An exploratory factor analysis with oblique rotation in N=69 healthy young adults indeed revealed a two-factor solution with markedly different loadings for semantic and phonological items. This pattern was corroborated by a confirmatory factor analysis in a sample of N=174 stroke patients. As results from both samples also revealed a substantial portion of common variance between the semantic and phonological factor, the present data further demonstrate that semantic and phonological verbal fluency are based on clearly distinct but also on shared sets of cognitive processes.