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Huntington’s disease (HD) is a genetically caused neurodegenerative disorder characterized by heterogeneous motor, psychiatric, and cognitive symptoms. Although motor symptoms may be the most prominent presentation, cognitive symptoms such as memory deficits and executive dysfunction typically co-occur. We used functional magnetic resonance imaging (fMRI) and task fMRI-based dynamic causal modeling (DCM) to evaluate HD-related changes in the neural network underlying working memory (WM). Sixty-four pre-symptomatic HD mutation carriers (preHD), 20 patients with early manifest HD symptoms (earlyHD), and 83 healthy control subjects performed an n-back fMRI task with two levels of WM load. Effective connectivity was assessed in five predefined regions of interest, comprising bilateral inferior parietal cortex, left anterior cingulate cortex, and bilateral dorsolateral prefrontal cortex. HD mutation carriers performed less accurately and more slowly at high WM load compared with the control group. While between-group comparisons of brain activation did not reveal differential recruitment of the cortical WM network in mutation carriers, comparisons of brain connectivity as identified with DCM revealed a number of group differences across the whole WM network. Most strikingly, we observed decreasing connectivity from several regions toward right dorsolateral prefrontal cortex (rDLPFC) in preHD and even more so in earlyHD. The deterioration in rDLPFC connectivity complements results from previous studies and might mirror beginning cortical neural decline at premanifest and early manifest stages of HD. We were able to characterize effective connectivity in a WM network of HD mutation carriers yielding further insight into patterns of cognitive decline and accompanying neural deterioration.

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.

Background: Cognitive 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 modeled explicitly. Using a new model, which incorporates individual variability related to structural change and behavior, we sought to identify functional correlates of compensation in premanifest-HD gene-carriers. Methods: We 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. Findings: Consistent with compensation, as atrophy increased performance-related activity increased in the right parietal cortex during a working memory task. Similarly, increased functional coupling between the right dorsolateral prefrontal cortex and a left hemisphere network in the resting-state predicted better cognitive performance as atrophy increased. Such patterns were not detectable for the left hemisphere or for motor tasks. Interpretation: Our 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.

The left dorsolateral prefrontal cortex (DLPFC) is involved in encoding and retrieval of episodic memories, and thus, is frequently targeted in non-invasive brain stimulation paradigms, aiming for its functional modulation. Anodal transcranial direct current stimulation (tDCS), that boosts neuronal excitability in stimulated cortical areas, has been found to increase cognitive skills differentially, depending on the initial performance. We hypothesize that the benefit of tDCS on verbal episodic memory can be extrapolated from the participants’ baseline performance. In the present randomized, double-blind, parallel group study, healthy young adults (n = 43) received either real anodal or sham tDCS over their left DLPFC during the encoding phase of a verbal episodic memory task. Forty words were presented visually thrice with immediate vocal retrieval after each block and an additional delayed recall. We conducted a moderation analysis to test the modulating effect of initial episodic memory retrieval, adjusted for primacy and recency effects, on delayed recall under real or sham stimulation. Despite the absence of a significantly beneficial tDCS effect at the group level, we found that the number of remembered midlist words in the first retrieval significantly moderated the stimulation effect in such a way that initially low performers experienced the highest gain from real stimulation. These results suggest that anodal tDCS to the left DLPFC improves memory functions only so far. While only marginal stimulation-induced gains occur in cognitively unimpaired populations, greater stimulation benefits might be expected in individuals with clinically relevant deficiencies in the verbal episodic memory domain.

Diagnostic features of emotional expressions are differentially distributed across the face. The current study examined whether these diagnostic features are preferentially attended to even when they are irrelevant for the task at hand or when faces appear at different locations in the visual field. To this aim, fearful, happy and neutral faces were presented to healthy individuals in two experiments while measuring eye movements. In Experiment 1, participants had to accomplish an emotion classification, a gender discrimination or a passive viewing task. To differentiate fast, potentially reflexive, eye movements from a more elaborate scanning of faces, stimuli were either presented for 150 or 2000 ms. In Experiment 2, similar faces were presented at different spatial positions to rule out the possibility that eye movements only reflect a general bias for certain visual field locations. In both experiments, participants fixated the eye region much longer than any other region in the face. Furthermore, the eye region was attended to more pronouncedly when fearful or neutral faces were shown whereas more attention was directed toward the mouth of happy facial expressions. Since these results were similar across the other experimental manipulations, they indicate that diagnostic features of emotional expressions are preferentially processed irrespective of task demands and spatial locations. Saliency analyses revealed that a computational model of bottom-up visual attention could not explain these results. Furthermore, as these gaze preferences were evident very early after stimulus onset and occurred even when saccades did not allow for extracting further information from these stimuli, they may reflect a preattentive mechanism that automatically detects relevant facial features in the visual field and facilitates the orientation of attention towards them. This mechanism might crucially depend on amygdala functioning and it is potentially impaired in a number of clinical conditions such as autism or social anxiety disorders.