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We assessed the structure–function relationship of the human cholinergic system and hypothesized that structural measures are associated with short-latency sensory afferent inhibition (SAI), an electrophysiological measure of central cholinergic signal transmission. Healthy volunteers (n = 36) and patients with mild cognitive impairment (MCI, n = 20) underwent median nerve SAI and 3T structural MRI to determine the volume of the basal forebrain and the thalamus. Patients with MCI had smaller basal forebrain ( p  < 0.001) or thalamus volumes ( p  < 0.001) than healthy volunteers. Healthy SAI responders (> 10% SAI) had more basal forebrain volume than non-responders ( p  = 0.004) or patients with MCI ( p  < 0.001). More basal forebrain volume was associated with stronger SAI in healthy volunteers ( r  = 0.33, p  < 0.05) but not patients with MCI. There was no significant relationship between thalamus volumes and SAI. Basal forebrain volume is associated with cholinergic function (SAI) in healthy volunteers but not in MCI patients. The in-vivo investigation of the structure–function relationship could further our understanding of the human cholinergic system in patients with suspected or known cholinergic system degeneration.

Background Alzheimer’s disease (AD) is a major public health issue. Cognitive interventions such as computerized cognitive trainings (CCT) are effective in attenuating cognitive decline in AD. However, in those at risk of dementia related to AD, results are heterogeneous. Efficacy and feasibility of CCT needs to be explored in depth. Moreover, underlying mechanisms of CCT effects on the three cognitive domains typically affected by AD (episodic memory, semantic memory and spatial abilities) remain poorly understood. Methods In this bi-centric, randomized controlled trial (RCT) with parallel groups, participants (planned N  = 162, aged 60–85 years) at risk for AD and with at least subjective cognitive decline will be randomized to one of three groups. We will compare serious game-based CCT against a passive wait list control condition and an active control condition (watching documentaries). Training will consist of daily at-home sessions for 10 weeks (50 sessions) and weekly on-site group meetings. Subsequently, the CCT group will continue at-home training for an additional twenty-weeks including monthly on-site booster sessions. Investigators conducting the cognitive assessments will be blinded. Group leaders will be aware of participants’ group allocations. Primarily, we will evaluate change using a compound value derived from the comprehensive cognitive assessment for each of three cognitive domains. Secondary, longitudinal functional and structural magnetic resonance imaging (MRI) and evaluation of blood-based biomarkers will serve to investigate neuronal underpinnings of expected training benefits. Discussion The present study will address several shortcomings of previous CCT studies. This entails a comparison of serious game-based CCT with both a passive and an active control condition while including social elements crucial for training success and adherence, the combination of at-home and on-site training, inclusion of booster sessions and assessment of physiological markers. Study outcomes will provide information on feasibility and efficacy of serious game-based CCT in older adults at risk for AD and will potentially generalize to treatment guidelines. Moreover, we set out to investigate physiological underpinnings of CCT induced neuronal changes to form the grounds for future individually tailored interventions and neuro-biologically informed trainings. Trial registration This RCT was registered 1st of July 2020 at clinicaltrials.gov (Identifier NCT04452864).

Transcranial magnetic stimulation (TMS) is a well-established tool in probing cortical plasticity . 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.

BackgroundCompensation accounts for the dissociation between pathology and absence of behavioural change during premanifest stages of Huntington’s disease (HD). Despite neuronal loss, individuals with premanifest HD function at a level similar to that of a healthy population. Neural mechanisms underlying compensation, however, are generally poorly understood due to the lack of an operational definition of compensation. Here, we describe the first example of the modelling and empirical testing of compensation in HD.AimsWe hypothesise that compensation occurs where increased brain activation is required to maintain normal levels of behaviour until pathology becomes too severe. A compensatory relationship is thus characterised by non-linear longitudinal trajectories of brain activity and behaviour as disease load increases linearly across sequential phases of disease progression.MethodsWe tested our model in a large cohort of premanifest and early HD gene-carriers from the TrackOn-HD study. Focusing on both cognitive and motor networks, brain activity was measured using task and resting-state fMRI, volumetric loss by structural MRI and behaviour by task performance. Compensation was tested for across three sequential phases of disease progression.ResultsMaintained global cognition was associated with increased effective connectivity between the left and right dorsolateral prefrontal cortex, an important region for cognitive processing, while maintained motor performance was associated with increased connectivity between bilateral premotor cortex.ConclusionsOur empirical findings demonstrate theoretically-defined compensation in HD in networks central to the HD phenotype and can now be used to test both cross-sectional and longitudinal compensation in other neurodegenerative disease with similar patterns to HD.

LTP-like plasticity measured by visual evoked potentials (VEP) can be induced in the intact human brain by presenting checkerboard reversals. Also associated with LTP-like plasticity, around two third of participants respond to transcranial magnetic stimulation (TMS) with a paired-associate stimulation (PAS) protocol with a potentiation of their motor evoked potentials. LTP-like processes are also required for verbal and motor learning tasks. We compared effect sizes, responder rates and intercorrelations as well as the potential influence of attention between these four assessments in a group of 37 young and healthy volunteers. We observed a potentiation effect of the N75 and P100 VEP component which positively correlated with plasticity induced by PAS. Subjects with a better subjective alertness were more likely to show PAS and VEP potentiation. No correlation was found between the other assessments. Effect sizes and responder rates of VEP potentiation were higher compared to PAS. Our results indicate a high variability of LTP-like effects and no evidence for a system-specific nature. As a consequence, studies wishing to assess individual levels of LTP-like plasticity should employ a combination of multiple assessments.

Compensation is a concept that has been introduced in neurodegeneration to account for the common observation that macroscopic neurodegeneration is frequently evident in brain imaging many years prior to symptom onset with little or no deterioration in behaviour. It is proposed that this dissociation between brain pathology and normal behaviour early in neurodegenerative disease reflects some kind of neuronal compensation. However, models of compensation are often conceptual and not operationalised in a form that readily permits them to be tested.Recent reviews have proposed that to characterise compensation fully three different components and their relationship should be considered: brain activity, behaviour and pathology. We have previously devised an operational model of compensation that focusses on the relationship between brain activity and behaviour as a function of structural measures of disease load and successfully applied this to cross-sectional functional and structural imaging data obtained from the preclinical TrackOn-HD cohort.1However, we postulate that compensatory behaviours in response to brain disease will change differentially over time, dependent on changes in neuronal pathology and existing motor and cognitive deficits. In such a situation, investigation of compensation at a single time point will not provide an adequate characterisation of compensation. We now extend our cross-sectional models to account for the longitudinal change characteristic of neurodegeneration and examine the theoretical and conceptual underpinnings. We consider two approaches to measuring longitudinal compensation. First, estimation of average compensation over time accounting for dependence due to repeated measures and second, estimation of change in compensation over time.ReferenceKloppel S, Gregory S. Compensation in preclinical Huntington’s disease: evidence from the Track-On HD study. E Bio Medicine 2015

BackgroundIn premanifest Huntington’s disease (preHD), disease-related neuronal degeneration is dissociated from the capacity to maintain normal levels of performance during cognitive tasks, which could be explained by compensatory processes. Recently, we devised a novel model of compensation which examined the relationship between disease progression, brain activity and task performance and identified a pattern consistent with asymmetrical compensation in preHD. We now examine the hypotheses that due to changes in neuronal pathology, such compensatory processes will change over time.AimsTo examine possible changes in compensatory processes over time, we extended our cross-sectional model to cover repeated measurements. MethodsOver three annual time points we modelled a) average compensation and b) change in compensation in each case examining the relationships between disease progression using volumetric measures, brain activity using task-based and resting-state fMRI and cognitive task performance. ResultsFor the average model, we showed weak disease effects centred in the left hemisphere. We also identified a non-significant pattern of asymmetrical compensation consistent with our previous cross-sectional analyses: disease effect in the left hemisphere and compensatory effect in the right. There was, however, very limited evidence of longitudinal change in compensation. ConclusionWhile we interpret these findings with considerable caution, they suggest a consistent asymmetrical pattern of compensatory effects. However, the apparent absence of longitudinal change in compensation was more likely due to the fact that interaction models are generally less sensitive to small changes and moreover, the problems that can arise in trying to model compensation per se.

BackgroundCognitive and motor task performance in premanifest Huntington’s disease (HD) gene-carriers is often within normal ranges prior to clinical diagnosis, despite loss of brain volume in regions involved in these tasks. This indicates ongoing compensation, with the brain maintaining function in the presence of neuronal loss. However, thus far, compensatory processes in HD have not been explicitly addressed in statistical models. AimsUsing a new statistical model, which incorporates individual variability related to structural burden (i.e., loss of brain volume) and behaviour, we sought to identify functional correlates of compensation in premanifest-HD gene-carriers.MethodsWe investigated the modulatory effects of regional brain atrophy, indexed by structural measures of disease load, on the relationship between performance and brain activity (or connectivity) using task-based and resting-state functional MRI.ResultsConsistent with compensation, higher atrophy was associated with increased performance-related activity of the right parietal cortex during a working memory task. Similarly, higher functional coupling between the right dorsolateral prefrontal cortex and a left hemisphere network in the resting-state predicted better cognitive performance in individuals with higher disease burden. Such patterns were not detectable for the left hemisphere or for motor tasks.ConclusionOur findings provide evidence for active compensatory processes in premanifest-HD for cognitive demands and suggest a higher vulnerability of the left hemisphere to the effects of regional atrophy.

Deficits in motor functioning are one of the hallmarks of Huntington's disease (HD), a genetically caused neurodegenerative disorder. We applied functional magnetic resonance imaging (fMRI) and dynamic causal modeling (DCM) to assess changes that occur with disease progression in the neural circuitry of key areas associated with executive and cognitive aspects of motor control. Seventy-seven healthy controls, 62 pre-symptomatic HD gene carriers (preHD), and 16 patients with manifest HD symptoms (earlyHD) performed a motor finger-tapping fMRI task with systematically varying speed and complexity. DCM was used to assess the causal interactions among seven pre-defined regions of interest, comprising primary motor cortex, supplementary motor area (SMA), dorsal premotor cortex, and superior parietal cortex. To capture heterogeneity among HD gene carriers, DCM parameters were entered into a hierarchical cluster analysis using Ward's method and squared Euclidian distance as a measure of similarity. After applying Bonferroni correction for the number of tests, DCM analysis revealed a group difference that was not present in the conventional fMRI analysis. We found an inhibitory effect of complexity on the connection from parietal to premotor areas in preHD, which became excitatory in earlyHD and correlated with putamen atrophy. While speed of finger movements did not modulate the connection from caudal to pre-SMA in controls and preHD, this connection became strongly negative in earlyHD. This second effect did not survive correction for multiple comparisons. Hierarchical clustering separated the gene mutation carriers into three clusters that also differed significantly between these two connections and thereby confirmed their relevance. DCM proved useful in identifying group differences that would have remained undetected by standard analyses and may aid in the investigation of between-subject heterogeneity.