Neurofilaments and progranulin are related to atrophy in frontotemporal lobar degeneration - A transdiagnostic study cross-validating atrophy and fluid biomarkers.

INTRODUCTION: Frontotemporal lobar degeneration (FTLD) encompasses behavioral variant frontotemporal dementia (bvFTD), progressive supranuclear palsy, corticobasal syndrome/degeneration, and primary progressive aphasias (PPAs). We cross-validated fluid biomarkers and neuroimaging. METHODS: Seven fluid biomarkers from cerebrospinal fluid and serum were related to atrophy in 428 participants including these FTLD subtypes, logopenic variant PPA (lvPPA), Alzheimer's disease (AD), and healthy subjects. Atrophy was assessed by structural magnetic resonance imaging and atlas-based volumetry. RESULTS: FTLD subtypes, lvPPA, and AD showed specific profiles for neurofilament light chain, phosphorylated heavy chain, tau, phospho-tau, amyloid beta1-42 from serum/cerebrospinal fluid, and brain atrophy. Neurofilaments related to regional atrophy in bvFTD, whereas progranulin was associated with atrophy in semantic variant PPA. Ubiquitin showed no effects. DISCUSSION: Results specify biomarker and atrophy patterns in FTLD and AD supporting differential diagnosis. They identify neurofilaments and progranulin in interaction with structural imaging as promising candidates for monitoring disease progression and therapy. HIGHLIGHTS: Study cross-validated neuroimaging and fluid biomarkers in dementia. Five kinds of frontotemporal lobar degeneration and two variants of Alzheimer's disease. Study identifies disease-specific fluid biomarker and atrophy profiles. Fluid biomarkers and atrophy interact in a disease-specific way. Neurofilaments and progranulin are proposed as biomarkers for diagnosis and therapy.

Inter-individual differences in audio-motor learning of piano melodies and white matter fiber tract architecture.

Humans vary substantially in their ability to learn new motor skills. Here, we examined inter-individual differences in learning to play the piano, with the goal of identifying relations to structural properties of white matter fiber tracts relevant to audio-motor learning. Non-musicians (n = 18) learned to perform three short melodies on a piano keyboard in a pure audio-motor training condition (vision of their own fingers was occluded). Initial learning times ranged from 17 to 120 min (mean ± SD: 62 ± 29 min). Diffusion-weighted magnetic resonance imaging was used to derive the fractional anisotropy (FA), an index of white matter microstructural arrangement. A correlation analysis revealed that higher FA values were associated with faster learning of piano melodies. These effects were observed in the bilateral corticospinal tracts, bundles of axons relevant for the execution of voluntary movements, and the right superior longitudinal fasciculus, a tract important for audio-motor transformations. These results suggest that the speed with which novel complex audio-motor skills can be acquired may be determined by variability in structural properties of white matter fiber tracts connecting brain areas functionally relevant for audio-motor learning.

Functional dissociation of ventral frontal and dorsomedial default mode network components during resting state and emotional autobiographical recall.

Humans spend a substantial share of their lives mind-wandering. This spontaneous thinking activity usually comprises autobiographical recall, emotional, and self-referential components. While neuroimaging studies have demonstrated that a specific brain "default mode network" (DMN) is consistently engaged by the "resting state" of the mind, the relative contribution of key cognitive components to DMN activity is still poorly understood. Here we used fMRI to investigate whether activity in neural components of the DMN can be differentially explained by active recall of relevant emotional autobiographical memories as compared with the resting state. Our study design combined emotional autobiographical memory, neutral memory and resting state conditions, separated by a serial subtraction control task. Shared patterns of activation in the DMN were observed in both emotional autobiographical and resting conditions, when compared with serial subtraction. Directly contrasting autobiographical and resting conditions demonstrated a striking dissociation within the DMN in that emotional autobiographical retrieval led to stronger activation of the dorsomedial core regions (medial prefrontal cortex, posterior cingulate cortex), whereas the resting state condition engaged a ventral frontal network (ventral striatum, subgenual and ventral anterior cingulate cortices) in addition to the IPL. Our results reveal an as yet unreported dissociation within the DMN. Whereas the dorsomedial component can be explained by emotional autobiographical memory, the ventral frontal one is predominantly associated with the resting state proper, possibly underlying fundamental motivational mechanisms engaged during spontaneous unconstrained ideation.

Inhibitory control and working memory predict rhythm production abilities in patients with neurocognitive deficits.

Deficits in rhythm perception and production have been reported in a variety of psychiatric, neurodevelopmental and neurologic disorders. Since correlations between rhythmic abilities and cognitive functions have been demonstrated in neurotypical individuals, we here investigate whether and how rhythmic abilities are associated with cognitive functions in 35 participants with neurocognitive deficits due to acquired brain lesions. We systematically assessed a diverse set of rhythm perception and production abilities including time and beat perception and finger-tapping tasks. Neuropsychological tests were applied to assess separable cognitive functions. Using multiple regression analyses we show that lower variability in aligning movements to a pacing sequence was predicted by better inhibitory control and better working memory performance. Working memory performance also predicted lower variability of rhythmic movements in the absence of an external pacing sequence and better anticipatory timing to sequences with gradual tempo changes. Importantly, these predictors remained significant for all regression models when controlling for other cognitive variables (i.e., cognitive flexibility, information processing speed, and verbal learning ability) and potential confounders (i.e., age, symptom strength of depression, manual dexterity, duration of illness, severity of cognitive impairment, and musical experience). Thus, all rhythm production abilities were significantly predicted by measures of executive functions. In contrast, rhythm perception abilities (time perception/beat perception) were not predicted by executive functions in this study. Our results, enhancing the understanding of cognitive underpinnings of rhythmic abilities in individuals with neurocognitive deficits, may be a first mandatory step to further potential therapeutic implications of rhythm-based interventions in neuropsychological rehabilitation.

Dissecting neural correlates of theory of mind and executive functions in behavioral variant frontotemporal dementia.

Behavioral variant frontotemporal dementia (bvFTD) is characterized by profound and early deficits in social cognition (SC) and executive functions (EF). To date it remains unclear whether deficits of the respective cognitive domains are based on the degeneration of distinct brain regions. In 103 patients with a diagnosis of bvFTD (possible/probable/definite: N = 40/58/5) from the frontotemporal lobar degeneration (FTLD) consortium Germany cohort (age 62.5±9.4 years, gender 38 female/65 male) we applied multimodal structural imaging, i.e. voxel-based morphometry, cortical thickness (CTH) and networks of structural covariance via source based morphometry. We cross-sectionally investigated associations with performance in a modified Reading the Mind in the Eyes Test (RMET; reflective of theory of mind - ToM) and five different tests reflective of EF (i.e. Hamasch-Five-Point Test, semantic and phonemic Fluency, Trail Making Test, Stroop interference). Finally, we investigated the conjunction of RMET correlates with functional networks commonly associated with SC respectively ToM and EF as extracted meta-analytically within the Neurosynth database. RMET performance was mainly associated with gray matter volume (GMV) and CTH within temporal and insular cortical regions and less within the prefrontal cortex (PFC), whereas EF performance was mainly associated with prefrontal regions (GMV and CTH). Overlap of RMET and EF associations was primarily located within the insula, adjacent subcortical structures (i.e. putamen) and the dorsolateral PFC (dlPFC). These patterns were more pronounced after adjustment for the respective other cognitive domain. Corroborative results were obtained in analyses of structural covariance networks. Overlap of RMET with meta-analytically extracted functional networks commonly associated with SC, ToM and EF was again primarily located within the temporal and insular region and the dlPFC. In addition, on a meta-analytical level, strong associations were found for temporal cortical RMET correlates with SC and ToM in particular. These data indicate a temporo-frontal dissociation of bvFTD related disturbances of ToM and EF, with atrophy of the anterior temporal lobe being critically involved in ToM deficits. The consistent overlap within the insular cortex may be attributable to the multimodal and integrative role of this region in socioemotional and cognitive processing.

Learning piano melodies in visuo-motor or audio-motor training conditions and the neural correlates of their cross-modal transfer.

To investigate the cross-modal transfer of movement patterns necessary to perform melodies on the piano, 22 non-musicians learned to play short sequences on a piano keyboard by (1) merely listening and replaying (vision of own fingers occluded) or (2) merely observing silent finger movements and replaying (on a silent keyboard). After training, participants recognized with above chance accuracy (1) audio-motor learned sequences upon visual presentation (89±17%), and (2) visuo-motor learned sequences upon auditory presentation (77±22%). The recognition rates for visual presentation significantly exceeded those for auditory presentation (p<.05). fMRI revealed that observing finger movements corresponding to audio-motor trained melodies is associated with stronger activation in the left rolandic operculum than observing untrained sequences. This region was also involved in silent execution of sequences, suggesting that a link to motor representations may play a role in cross-modal transfer from audio-motor training condition to visual recognition. No significant differences in brain activity were found during listening to visuo-motor trained compared to untrained melodies. Cross-modal transfer was stronger from the audio-motor training condition to visual recognition and this is discussed in relation to the fact that non-musicians are familiar with how their finger movements look (motor-to-vision transformation), but not with how they sound on a piano (motor-to-sound transformation).

Neural Correlates of Listening to Varying Synchrony Between Beats in Samba Percussion and Relations to Feeling the Groove.

Listening to samba percussion often elicits feelings of pleasure and the desire to move with the beat-an experience sometimes referred to as "feeling the groove"- as well as social connectedness. Here we investigated the effects of performance timing in a Brazilian samba percussion ensemble on listeners' experienced pleasantness and the desire to move/dance in a behavioral experiment, as well as on neural processing as assessed via functional magnetic resonance imaging (fMRI). Participants listened to different excerpts of samba percussion produced by multiple instruments that either were "in sync", with no additional asynchrony between instrumental parts other than what is usual in naturalistic recordings, or were presented "out of sync" by delaying the snare drums (by 28, 55, or 83 ms). Results of the behavioral experiment showed increasing pleasantness and desire to move/dance with increasing synchrony between instruments. Analysis of hemodynamic responses revealed stronger bilateral brain activity in the supplementary motor area, the left premotor area, and the left middle frontal gyrus with increasing synchrony between instruments. Listening to "in sync" percussion thus strengthens audio-motor interactions by recruiting motor-related brain areas involved in rhythm processing and beat perception to a higher degree. Such motor related activity may form the basis for "feeling the groove" and the associated desire to move to music. Furthermore, in an exploratory analysis we found that participants who reported stronger emotional responses to samba percussion in everyday life showed higher activity in the subgenual cingulate cortex, an area involved in prosocial emotions, social group identification and social bonding.

From correlational approaches to meta-analytical symptom reading in individual patients: Bilateral lesions in the inferior frontal junction specifically cause dysexecutive syndrome.

BACKGROUND: Executive functions describe a wide variety of higher order cognitive processes allowing the modification of thought and behavior in response to changing contexts. Recent comprehensive quantitative and systematic meta-analyses on functional imaging studies in healthy subjects identified the inferior frontal junction (IFJ), located at the junction of the inferior frontal sulcus and the inferior precentral sulcus, as essential for executive functions. Lesion studies in patients are necessary for confirmation of this finding. CASE PRESENTATION: We present, as a proof of concept, a 56 year old woman with bilateral ischemic lesions in the IFJ caused by multiple stroke-related brain infarcts in the bilateral territory of the middle cerebral artery. Comprehensive neuropsychological testing revealed specific deficits in executive functions, namely working memory, task switching, inhibitory control, interference resolution, fluency, and complex executive function tests focusing on action planning and problem solving abilities. Memory functions were within the normal range. Furthermore, we applied comprehensive meta-analyses to validate the importance of the IFJ for executive functions. (i) Lesions in the patient's brain in the IFJ coincide with regional activation in functional imaging studies for working memory, task switching, and the Stroop task. (ii) Lesions in the patient's IFJ should affect a frontoparietal network as shown with connectivity analyses. (iii) We introduce a new analysis tool - Meta-Analytical Reading of Symptoms (MARS) - that enables prediction of clinical symptoms from imaging data in individual patients. CONCLUSIONS: Our study confirms the importance of the IFJ as the causal agent, in a frontoparietal network, for dysexecutive syndrome. As a lesion study, it goes beyond correlational imaging approaches. The new meta-analytical symptom reading approach can be applied in other patients and diseases. It has a high potential to foster individualized diagnosis and therapy in clinical settings in the framework of personalized medicine.

Kinesthetic working memory and action control within the dorsal stream.

There is wide agreement that the "dorsal (action) stream" processes visual information for movement control. However, movements depend not only on vision but also on tactile and kinesthetic information (=haptics). Using functional magnetic resonance imaging, the present study investigates to what extent networks within the dorsal stream are also utilized for kinesthetic action control and whether they are also involved in kinesthetic working memory. Fourteen blindfolded participants performed a delayed-recognition task in which right-handed movements had to be encoded, maintained, and later recognized without any visual feedback. Encoding of hand movements activated somatosensory areas, superior parietal lobe (dorsodorsal stream), anterior intraparietal sulcus (aIPS) and adjoining areas (ventrodorsal stream), premotor cortex, and occipitotemporal cortex (ventral stream). Short-term maintenance of kinesthetic information elicited load-dependent activity in the aIPS and adjacent anterior portion of the superior parietal lobe (ventrodorsal stream) of the left hemisphere. We propose that the action representation system of the dorsodorsal and ventrodorsal stream is utilized not only for visual but also for kinesthetic action control. Moreover, the present findings demonstrate that networks within the ventrodorsal stream, in particular the left aIPS and closely adjacent areas, are also engaged in working memory maintenance of kinesthetic information.

Motor learning affects visual movement perception.

In the present study we investigated whether imitation of artificial movement trajectories of meaningless objects has an effect on how these trajectories are later perceptually processed within the human brain. During observation of a sequence of artificial object movements 10 participants (experimental group) actively imitated the trajectories during motor training and 10 participants (control group) solved a working memory task without motor training. The haemodynamic responses were recorded before and after the intervention while participants observed the movements and either had to detect colour changes of one of the objects (colour task, motor-irrelevant) or had to judge whether the movement pattern could be imitated with the hands (simulation judgement task, motor-relevant). The between-group comparison of the post-intervention haemodynamic responses revealed stronger activity for the motor training than for the control group during the simulation judgement task. This activity appeared in motor-related areas (supplementary motor area and inferior parietal lobe) and in the occipito-temporal area. During the colour task, the motor training group showed stronger activity in the occipital lobe. The control group did not reveal any stronger activity than the motor training group for either task. The results suggest that motor training has task-specific effects on neural processes that are involved in perception of movements. Furthermore, they indicate that motor-related areas are triggered by observed artificial object movements, but only if a motor-relevant task is pursued.

What activates the human mirror neuron system during observation of artificial movements: bottom-up visual features or top-down intentions?

In a recent study we could show that during observation of artificial object movements a similar cortical network, including the areas of the so-called human mirror neuron system (hMNS), was activated as during the observation of hand movements. The present study investigated whether activation of the hMNS during the observation of artificial object movements depends more on the visual features of the movements (buttom-up), or, by manipulating the task instructions, on the intentional goal of an observer (top-down). Using a factorial design we recorded the hemodynamic responses in 20 healthy participants while they watched arbitrary artificial object movements following two types of movement trajectories (smooth vs. discontinuous). In one part of the experiment participants had to detect color changes of two objects (color task) and in another part they had to judge whether the movement pattern of two objects could be performed with human hands (simulation task). We found stronger activation in the hMNS during the simulation than during the color task for both types of movement trajectories. In contrast, the color task activated the left ventral-occipital area (human V4). A direct comparison of smooth vs. discontinuous movement trajectories revealed significant effects neither in the structures of the hMNS nor in human V4. The present findings suggest that it is not a specific visual feature, such as a smooth biological movement trajectory, that activates the hMNS. Rather, the hMNS seems to respond when an observed movement is matched to a motor representation triggered by the intentional goal of the observer.

Identifying musical pieces from fMRI data using encoding and decoding models.

Encoding models can reveal and decode neural representations in the visual and semantic domains. However, a thorough understanding of how distributed information in auditory cortices and temporal evolution of music contribute to model performance is still lacking in the musical domain. We measured fMRI responses during naturalistic music listening and constructed a two-stage approach that first mapped musical features in auditory cortices and then decoded novel musical pieces. We then probed the influence of stimuli duration (number of time points) and spatial extent (number of voxels) on decoding accuracy. Our approach revealed a linear increase in accuracy with duration and a point of optimal model performance for the spatial extent. We further showed that Shannon entropy is a driving factor, boosting accuracy up to 95% for music with highest information content. These findings provide key insights for future decoding and reconstruction algorithms and open new venues for possible clinical applications.

Neural bases of ingroup altruistic motivation in soccer fans.

Humans have a strong need to belong to social groups and a natural inclination to benefit ingroup members. Although the psychological mechanisms behind human prosociality have extensively been studied, the specific neural systems bridging group belongingness and altruistic motivation remain to be identified. Here, we used soccer fandom as an ecological framing of group membership to investigate the neural mechanisms underlying ingroup altruistic behaviour in male fans using event-related functional magnetic resonance. We designed an effort measure based on handgrip strength to assess the motivation to earn money (i) for oneself, (ii) for anonymous ingroup fans, or (iii) for a neutral group of anonymous non-fans. While overlapping valuation signals in the medial orbitofrontal cortex (mOFC) were observed for the three conditions, the subgenual cingulate cortex (SCC) exhibited increased functional connectivity with the mOFC as well as stronger hemodynamic responses for ingroup versus outgroup decisions. These findings indicate a key role for the SCC, a region previously implicated in altruistic decisions and group affiliation, in dovetailing altruistic motivations with neural valuation systems in real-life ingroup behaviour.

Enhancing Motor Network Activity Using Real-Time Functional MRI Neurofeedback of Left Premotor Cortex.

Neurofeedback by functional magnetic resonance imaging (fMRI) is a technique of potential therapeutic relevance that allows individuals to be aware of their own neurophysiological responses and to voluntarily modulate the activity of specific brain regions, such as the premotor cortex (PMC), important for motor recovery after brain injury. We investigated (i) whether healthy human volunteers are able to up-regulate the activity of the left PMC during a right hand finger tapping motor imagery (MI) task while receiving continuous fMRI-neurofeedback, and (ii) whether successful modulation of brain activity influenced non-targeted motor control regions. During the MI task, participants of the neurofeedback group (NFB) received ongoing visual feedback representing the level of fMRI responses within their left PMC. Control (CTL) group participants were shown similar visual stimuli, but these were non-contingent on brain activity. Both groups showed equivalent levels of behavioral ratings on arousal and MI, before and during the fMRI protocol. In the NFB, but not in CLT group, brain activation during the last run compared to the first run revealed increased activation in the left PMC. In addition, the NFB group showed increased activation in motor control regions extending beyond the left PMC target area, including the supplementary motor area, basal ganglia and cerebellum. Moreover, in the last run, the NFB group showed stronger activation in the left PMC/inferior frontal gyrus when compared to the CTL group. Our results indicate that modulation of PMC and associated motor control areas can be achieved during a single neurofeedback-fMRI session. These results contribute to a better understanding of the underlying mechanisms of MI-based neurofeedback training, with direct implications for rehabilitation strategies in severe brain disorders, such as stroke.

Neural correlates of auditory temporal predictions during sensorimotor synchronization.

Musical ensemble performance requires temporally precise interpersonal action coordination. To play in synchrony, ensemble musicians presumably rely on anticipatory mechanisms that enable them to predict the timing of sounds produced by co-performers. Previous studies have shown that individuals differ in their ability to predict upcoming tempo changes in paced finger-tapping tasks (indexed by cross-correlations between tap timing and pacing events) and that the degree of such prediction influences the accuracy of sensorimotor synchronization (SMS) and interpersonal coordination in dyadic tapping tasks. The current functional magnetic resonance imaging study investigated the neural correlates of auditory temporal predictions during SMS in a within-subject design. Hemodynamic responses were recorded from 18 musicians while they tapped in synchrony with auditory sequences containing gradual tempo changes under conditions of varying cognitive load (achieved by a simultaneous visual n-back working-memory task comprising three levels of difficulty: observation only, 1-back, and 2-back object comparisons). Prediction ability during SMS decreased with increasing cognitive load. Results of a parametric analysis revealed that the generation of auditory temporal predictions during SMS recruits (1) a distributed network of cortico-cerebellar motor-related brain areas (left dorsal premotor and motor cortex, right lateral cerebellum, SMA proper and bilateral inferior parietal cortex) and (2) medial cortical areas (medial prefrontal cortex, posterior cingulate cortex). While the first network is presumably involved in basic sensory prediction, sensorimotor integration, motor timing, and temporal adaptation, activation in the second set of areas may be related to higher-level social-cognitive processes elicited during action coordination with auditory signals that resemble music performed by human agents.

The perception of musical spontaneity in improvised and imitated jazz performances.

The ability to evaluate spontaneity in human behavior is called upon in the esthetic appreciation of dramatic arts and music. The current study addresses the behavioral and brain mechanisms that mediate the perception of spontaneity in music performance. In a functional magnetic resonance imaging experiment, 22 jazz musicians listened to piano melodies and judged whether they were improvised or imitated. Judgment accuracy (mean 55%; range 44-65%), which was low but above chance, was positively correlated with musical experience and empathy. Analysis of listeners' hemodynamic responses revealed that amygdala activation was stronger for improvisations than imitations. This activation correlated with the variability of performance timing and intensity (loudness) in the melodies, suggesting that the amygdala is involved in the detection of behavioral uncertainty. An analysis based on the subjective classification of melodies according to listeners' judgments revealed that a network including the pre-supplementary motor area, frontal operculum, and anterior insula was most strongly activated for melodies judged to be improvised. This may reflect the increased engagement of an action simulation network when melodic predictions are rendered challenging due to perceived instability in the performer's actions. Taken together, our results suggest that, while certain brain regions in skilled individuals may be generally sensitive to objective cues to spontaneity in human behavior, the ability to evaluate spontaneity accurately depends upon whether an individual's action-related experience and perspective taking skills enable faithful internal simulation of the given behavior.

Synchronized drumming enhances activity in the caudate and facilitates prosocial commitment--if the rhythm comes easily.

Why does chanting, drumming or dancing together make people feel united? Here we investigate the neural mechanisms underlying interpersonal synchrony and its subsequent effects on prosocial behavior among synchronized individuals. We hypothesized that areas of the brain associated with the processing of reward would be active when individuals experience synchrony during drumming, and that these reward signals would increase prosocial behavior toward this synchronous drum partner. 18 female non-musicians were scanned with functional magnetic resonance imaging while they drummed a rhythm, in alternating blocks, with two different experimenters: one drumming in-synchrony and the other out-of-synchrony relative to the participant. In the last scanning part, which served as the experimental manipulation for the following prosocial behavioral test, one of the experimenters drummed with one half of the participants in-synchrony and with the other out-of-synchrony. After scanning, this experimenter "accidentally" dropped eight pencils, and the number of pencils collected by the participants was used as a measure of prosocial commitment. Results revealed that participants who mastered the novel rhythm easily before scanning showed increased activity in the caudate during synchronous drumming. The same area also responded to monetary reward in a localizer task with the same participants. The activity in the caudate during experiencing synchronous drumming also predicted the number of pencils the participants later collected to help the synchronous experimenter of the manipulation run. In addition, participants collected more pencils to help the experimenter when she had drummed in-synchrony than out-of-synchrony during the manipulation run. By showing an overlap in activated areas during synchronized drumming and monetary reward, our findings suggest that interpersonal synchrony is related to the brain's reward system.

How moving objects become animated: the human mirror neuron system assimilates non-biological movement patterns.

The so-called mirror neuron system (MNS) responds when humans observe actions performed by a member of their own species. This activity is understood as an internal motor representation of the observed movement pattern. By contrasting meaningless human hand movements with meaningless artificial movements of objects in space, we tested the claim that exclusively movements belonging to the human motor repertoire have direct access to the MNS. Eighteen participants observed video clips of moving hands and objects while the hemodynamic response was recorded with functional magnetic resonance imaging. Second-level analysis of the hemodynamic response revealed substantially overlapping activation patterns for both types of movements including relevant structures of the MNS (bilateral premotor and parietal areas, occipito-temporal junction, postcentral gyrus and the right superior temporal sulcus). This suggests that perceptual processing of moving hands and objects recruits similar and overlapping cortical networks. Direct comparison of the two movement types revealed stronger activations for hand movements mainly in structures of the MNS suggesting an "expertise effect". Overall, our results provide evidence that observing movements not explicitly belonging to the human motor repertoire can activate the human MNS, most likely because an association with a biological movement is evoked.