Generalizable brain network markers of major depressive disorder across multiple imaging sites.

Many studies have highlighted the difficulty inherent to the clinical application of fundamental neuroscience knowledge based on machine learning techniques. It is difficult to generalize machine learning brain markers to the data acquired from independent imaging sites, mainly due to large site differences in functional magnetic resonance imaging. We address the difficulty of finding a generalizable marker of major depressive disorder (MDD) that would distinguish patients from healthy controls based on resting-state functional connectivity patterns. For the discovery dataset with 713 participants from 4 imaging sites, we removed site differences using our recently developed harmonization method and developed a machine learning MDD classifier. The classifier achieved an approximately 70% generalization accuracy for an independent validation dataset with 521 participants from 5 different imaging sites. The successful generalization to a perfectly independent dataset acquired from multiple imaging sites is novel and ensures scientific reproducibility and clinical applicability.

Distinctive alterations in the mesocorticolimbic circuits in various psychiatric disorders.

AIM: Increasing evidence suggests that psychiatric disorders are linked to alterations in the mesocorticolimbic dopamine-related circuits. However, the common and disease-specific alterations remain to be examined in schizophrenia (SCZ), major depressive disorder (MDD), and autism spectrum disorder (ASD). Thus, this study aimed to examine common and disease-specific features related to mesocorticolimbic circuits. METHODS: This study included 555 participants from four institutes with five scanners: 140 individuals with SCZ (45.0% female), 127 individuals with MDD (44.9%), 119 individuals with ASD (15.1%), and 169 healthy controls (HC) (34.9%). All participants underwent resting-state functional magnetic resonance imaging. A parametric empirical Bayes approach was adopted to compare estimated effective connectivity among groups. Intrinsic effective connectivity focusing on the mesocorticolimbic dopamine-related circuits including the ventral tegmental area (VTA), shell and core parts of the nucleus accumbens (NAc), and medial prefrontal cortex (mPFC) were examined using a dynamic causal modeling analysis across these psychiatric disorders. RESULTS: The excitatory shell-to-core connectivity was greater in all patients than in the HC group. The inhibitory shell-to-VTA and shell-to-mPFC connectivities were greater in the ASD group than in the HC, MDD, and SCZ groups. Furthermore, the VTA-to-core and VTA-to-shell connectivities were excitatory in the ASD group, while those connections were inhibitory in the HC, MDD, and SCZ groups. CONCLUSION: Impaired signaling in the mesocorticolimbic dopamine-related circuits could be an underlying neuropathogenesis of various psychiatric disorders. These findings will improve the understanding of unique neural alternations of each disorder and will facilitate identification of effective therapeutic targets.

I Hear My Voice; Therefore I Spoke: The Sense of Agency Over Speech Is Enhanced by Hearing One's Own Voice.

The subjective experience of causing an action is known as the sense of agency. Dysfunctional sense of agency over speech has been suggested as a cause of auditory hallucinations. However, agency over speech has not been extensively characterized in previous empirical studies. Here, we manipulated self-voice identity, an indicator of self, embedded in the acoustic quality of voice and examined implicit and explicit measures of the sense of agency. Experiment 1 (N = 29 adults) demonstrated more compression of a perceived interval between action and outcome when participants heard their undistorted voices than their pitch-distorted voices. Experiment 2 (N = 28 adults) revealed a strong top-down effect of self-voice identity: Specifically, the judgment of agency over speech was more resistant than the judgment of agency over hand/limb movement to low-level sensorimotor inconsistency. Our findings provide new insight into the sense of agency over speech and an informative perspective for understanding aberrant experience in auditory hallucinations.

Harmonization of resting-state functional MRI data across multiple imaging sites via the separation of site differences into sampling bias and measurement bias.

When collecting large amounts of neuroimaging data associated with psychiatric disorders, images must be acquired from multiple sites because of the limited capacity of a single site. However, site differences represent a barrier when acquiring multisite neuroimaging data. We utilized a traveling-subject dataset in conjunction with a multisite, multidisorder dataset to demonstrate that site differences are composed of biological sampling bias and engineering measurement bias. The effects on resting-state functional MRI connectivity based on pairwise correlations because of both bias types were greater than or equal to psychiatric disorder differences. Furthermore, our findings indicated that each site can sample only from a subpopulation of participants. This result suggests that it is essential to collect large amounts of neuroimaging data from as many sites as possible to appropriately estimate the distribution of the grand population. Finally, we developed a novel harmonization method that removed only the measurement bias by using a traveling-subject dataset and achieved the reduction of the measurement bias by 29% and improvement of the signal-to-noise ratios by 40%. Our results provide fundamental knowledge regarding site effects, which is important for future research using multisite, multidisorder resting-state functional MRI data.

Sense of Agency Beyond Sensorimotor Process: Decoding Self-Other Action Attribution in the Human Brain.

The sense of agency is defined as the subjective experience that "I" am the one who is causing the action. Theoretical studies postulate that this subjective experience is developed through multistep processes extending from the sensorimotor to the cognitive level. However, it remains unclear how the brain processes such different levels of information and constitutes the neural substrates for the sense of agency. To answer this question, we combined two strategies: an experimental paradigm, in which self-agency gradually evolves according to sensorimotor experience, and a multivoxel pattern analysis. The combined strategies revealed that the sensorimotor, posterior parietal, anterior insula, and higher visual cortices contained information on self-other attribution during movement. In addition, we investigated whether the found regions showed a preference for self-other attribution or for sensorimotor information. As a result, the right supramarginal gyrus, a portion of the inferior parietal lobe (IPL), was found to be the most sensitive to self-other attribution among the found regions, while the bilateral precentral gyri and left IPL dominantly reflected sensorimotor information. Our results demonstrate that multiple brain regions are involved in the development of the sense of agency and that these show specific preferences for different levels of information.

Compress global, dilate local: Intentional binding in action-outcome alternations.

Intentional binding refers to subjective temporal attraction between an action and its outcome. However, the nature of intentional binding in multiple actions remains unclear. We examined intentional binding in alternated action-outcome dyads. Participants actively or passively pressed a key, followed by a tone, and they again pressed the key; resulting in four keypress-tone dyads in a trial. Participants reproduced the duration of alternated keypress-tone dyads or the temporal interval between a dyad embedded in the alternations. The reproduced duration was shorter in the active than in the passive condition, suggesting the intentional binding in action-outcome alternations. In contrast, the reproduced interval between a dyad was longer in the active condition and did not correlate with the reproduced duration. These results suggest that subjective time during actions relies not only on an internal clock but also on postdictive biases that are switched based on what we recall.

Temporal recalibration of motor and visual potentials in lag adaptation in voluntary movement.

Adaptively recalibrating motor-sensory asynchrony is critical for animals to perceive self-produced action consequences. It is controversial whether motor- or sensory-related neural circuits recalibrate this asynchrony. By combining magnetoencephalography (MEG) and functional MRI (fMRI), we investigate the temporal changes in brain activities caused by repeated exposure to a 150-ms delay inserted between a button-press action and a subsequent flash. We found that readiness potentials significantly shift later in the motor system, especially in parietal regions (average: 219.9 ms), while visually evoked potentials significantly shift earlier in occipital regions (average: 49.7 ms) in the delay condition compared to the no-delay condition. Moreover, the shift in readiness potentials, but not in visually evoked potentials, was significantly correlated with the psychophysical measure of motor-sensory adaptation. These results suggest that although both motor and sensory processes contribute to the recalibration, the motor process plays the major role, given the magnitudes of shift and the correlation with the psychophysical measure.

Neural Substrates Related to Motor Memory with Multiple Timescales in Sensorimotor Adaptation.

Recent computational and behavioral studies suggest that motor adaptation results from the update of multiple memories with different timescales. Here, we designed a model-based functional magnetic resonance imaging (fMRI) experiment in which subjects adapted to two opposing visuomotor rotations. A computational model of motor adaptation with multiple memories was fitted to the behavioral data to generate time-varying regressors of brain activity. We identified regional specificity to timescales: in particular, the activity in the inferior parietal region and in the anterior-medial cerebellum was associated with memories for intermediate and long timescales, respectively. A sparse singular value decomposition analysis of variability in specificities to timescales over the brain identified four components, two fast, one middle, and one slow, each associated with different brain networks. Finally, a multivariate decoding analysis showed that activity patterns in the anterior-medial cerebellum progressively represented the two rotations. Our results support the existence of brain regions associated with multiple timescales in adaptation and a role of the cerebellum in storing multiple internal models.

Connectivity Neurofeedback Training Can Differentially Change Functional Connectivity and Cognitive Performance.

Advances in functional magnetic resonance imaging have made it possible to provide real-time feedback on brain activity. Neurofeedback has been applied to therapeutic interventions for psychiatric disorders. Since many studies have shown that most psychiatric disorders exhibit abnormal brain networks, a novel experimental paradigm named connectivity neurofeedback, which can directly modulate a brain network, has emerged as a promising approach to treat psychiatric disorders. Here, we investigated the hypothesis that connectivity neurofeedback can induce the aimed direction of change in functional connectivity, and the differential change in cognitive performance according to the direction of change in connectivity. We selected the connectivity between the left primary motor cortex and the left lateral parietal cortex as the target. Subjects were divided into 2 groups, in which only the direction of change (an increase or a decrease in correlation) in the experimentally manipulated connectivity differed between the groups. As a result, subjects successfully induced the expected connectivity changes in either of the 2 directions. Furthermore, cognitive performance significantly and differentially changed from preneurofeedback to postneurofeedback training between the 2 groups. These findings indicate that connectivity neurofeedback can induce the aimed direction of change in connectivity and also a differential change in cognitive performance.

Human sensorimotor cortex represents conflicting visuomotor mappings.

Behavioral studies have shown that humans can adapt to conflicting sensorimotor mappings that cause interference after intensive training. While previous research works indicate the involvement of distinct brain regions for different types of motor learning (e.g., kinematics vs dynamics), the neural mechanisms underlying joint adaptation to conflicting mappings within the same type of perturbation (e.g., different angles of visuomotor rotation) remain unclear. To reveal the neural substrates that represent multiple sensorimotor mappings, we examined whether different mappings could be classified with multivoxel activity patterns of functional magnetic resonance imaging data. Participants simultaneously adapted to opposite rotational perturbations (+90° and - 90°) during visuomotor tracking. To dissociate differences in movement kinematics with rotation types, we used two distinct patterns of target motion and tested generalization of the classifier between different combinations of rotation and motion types. Results showed that the rotation types were classified significantly above chance using activities in the primary sensorimotor cortex and the supplementary motor area, despite no significant difference in averaged signal amplitudes within the region. In contrast, low-level sensorimotor components, including tracking error and movement speed, were best classified using activities of the early visual cortex. Our results reveal that the sensorimotor cortex represents different visuomotor mappings, which permits joint learning and switching between conflicting sensorimotor skills.

Consensus paper: the cerebellum's role in movement and cognition.

While the cerebellum's role in motor function is well recognized, the nature of its concurrent role in cognitive function remains considerably less clear. The current consensus paper gathers diverse views on a variety of important roles played by the cerebellum across a range of cognitive and emotional functions. This paper considers the cerebellum in relation to neurocognitive development, language function, working memory, executive function, and the development of cerebellar internal control models and reflects upon some of the ways in which better understanding the cerebellum's status as a "supervised learning machine" can enrich our ability to understand human function and adaptation. As all contributors agree that the cerebellum plays a role in cognition, there is also an agreement that this conclusion remains highly inferential. Many conclusions about the role of the cerebellum in cognition originate from applying known information about cerebellar contributions to the coordination and quality of movement. These inferences are based on the uniformity of the cerebellum's compositional infrastructure and its apparent modular organization. There is considerable support for this view, based upon observations of patients with pathology within the cerebellum.

The sensitivity and criterion of sense of agency.

The sense of agency, which refers to the subjective feeling of control, is an essential aspect of self-consciousness. We argue that distinguishing between the sensitivity and criterion of this feeling is important for discussing individual differences in the sense of agency and its connections with other cognitive functions.

Fear in action: Fear conditioning and alleviation through body movements.

Fear memories enhance survival especially when the memories guide defensive movements to minimize harm. Accordingly, fear memories and body movements have tight relationships in animals: Fear memory acquisition results in adapting reactive defense movements, while training active defense movements reduces fear memory. However, evidence in humans is scarce because their movements are typically suppressed in experiments. Here, we tracked adult participants' body motions while they underwent ecologically valid fear conditioning in a 3D virtual space. First, with body motion tracking, we revealed that distinct spatiotemporal body movement patterns emerge through fear conditioning. Second, subsequent training to actively avoid threats with naturalistic defensive actions led to a long-term (24 h) reduction of physiological and embodied conditioned responses, while extinction or vicarious training only transiently reduced the responses. Together, our results highlight the role of body movements in human fear memory and its intervention.

Proprioceptive short-term memory in passive motor learning.

A physical trainer often physically guides a learner's limbs to teach an ideal movement, giving the learner proprioceptive information about the movement to be reproduced later. This instruction requires the learner to perceive kinesthetic information and store the instructed information temporarily. Therefore, (1) proprioceptive acuity to accurately perceive the taught kinesthetics and (2) short-term memory to store the perceived information are two critical functions for reproducing the taught movement. While the importance of proprioceptive acuity and short-term memory has been suggested for active motor learning, little is known about passive motor learning. Twenty-one healthy adults (mean age 25.6 years, range 19-38 years) participated in this study to investigate whether individual learning efficiency in passively guided learning is related to these two functions. Consequently, learning efficiency was significantly associated with short-term memory capacity. In particular, individuals who could recall older sensory stimuli showed better learning efficiency. However, no significant relationship was observed between learning efficiency and proprioceptive acuity. A causal graph model found a direct influence of memory on learning and an indirect effect of proprioceptive acuity on learning via memory. Our findings suggest the importance of a learner's short-term memory for effective passive motor learning.

Generalizable neuromarker for autism spectrum disorder across imaging sites and developmental stages: A multi-site study.

Autism spectrum disorder (ASD) is a lifelong condition, and its underlying biological mechanisms remain elusive. The complexity of various factors, including inter-site and development-related differences, makes it challenging to develop generalizable neuroimaging-based biomarkers for ASD. This study used a large-scale, multi-site dataset of 730 Japanese adults to develop a generalizable neuromarker for ASD across independent sites (U.S., Belgium, and Japan) and different developmental stages (children and adolescents). Our adult ASD neuromarker achieved successful generalization for the US and Belgium adults (area under the curve [AUC] = 0.70) and Japanese adults (AUC = 0.81). The neuromarker demonstrated significant generalization for children (AUC = 0.66) and adolescents (AUC = 0.71; all P<0.05, family-wise-error corrected). We identified 141 functional connections (FCs) important for discriminating individuals with ASD from TDCs. These FCs largely centered on social brain regions such as the amygdala, hippocampus, dorsomedial and ventromedial prefrontal cortices, and temporal cortices. Finally, we mapped schizophrenia (SCZ) and major depressive disorder (MDD) onto the biological axis defined by the neuromarker and explored the biological continuity of ASD with SCZ and MDD. We observed that SCZ, but not MDD, was located proximate to ASD on the biological dimension defined by the ASD neuromarker. The successful generalization in multifarious datasets and the observed relations of ASD with SCZ on the biological dimensions provide new insights for a deeper understanding of ASD.

Aberrant Large-Scale Network Interactions Across Psychiatric Disorders Revealed by Large-Sample Multi-Site Resting-State Functional Magnetic Resonance Imaging Datasets.

BACKGROUND AND HYPOTHESIS: Dynamics of the distributed sets of functionally synchronized brain regions, known as large-scale networks, are essential for the emotional state and cognitive processes. However, few studies were performed to elucidate the aberrant dynamics across the large-scale networks across multiple psychiatric disorders. In this paper, we aimed to investigate dynamic aspects of the aberrancy of the causal connections among the large-scale networks of the multiple psychiatric disorders. STUDY DESIGN: We applied dynamic causal modeling (DCM) to the large-sample multi-site dataset with 739 participants from 4 imaging sites including 4 different groups, healthy controls, schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BD), to compare the causal relationships among the large-scale networks, including visual network, somatomotor network (SMN), dorsal attention network (DAN), salience network (SAN), limbic network (LIN), frontoparietal network, and default mode network. STUDY RESULTS: DCM showed that the decreased self-inhibitory connection of LIN was the common aberrant connection pattern across psychiatry disorders. Furthermore, increased causal connections from LIN to multiple networks, aberrant self-inhibitory connections of DAN and SMN, and increased self-inhibitory connection of SAN were disorder-specific patterns for SCZ, MDD, and BD, respectively. CONCLUSIONS: DCM revealed that LIN was the core abnormal network common to psychiatric disorders. Furthermore, DCM showed disorder-specific abnormal patterns of causal connections across the 7 networks. Our findings suggested that aberrant dynamics among the large-scale networks could be a key biomarker for these transdiagnostic psychiatric disorders.

Generalizable neuromarker for autism spectrum disorder across imaging sites and developmental stages: A multi-site study.

Autism spectrum disorder (ASD) is a lifelong condition, and its underlying biological mechanisms remain elusive. The complexity of various factors, including inter-site and development-related differences, makes it challenging to develop generalizable neuroimaging-based biomarkers for ASD. This study used a large-scale, multi-site dataset of 730 Japanese adults to develop a generalizable neuromarker for ASD across independent sites and different developmental stages. Our adult ASD neuromarker achieved successful generalization for the US and Belgium adults and Japanese adults. The neuromarker demonstrated significant generalization for children and adolescents. We identified 141 functional connections (FCs) important for discriminating individuals with ASD from TDCs. Finally, we mapped schizophrenia (SCZ) and major depressive disorder (MDD) onto the biological axis defined by the neuromarker and explored the biological continuity of ASD with SCZ and MDD. We observed that SCZ, but not MDD, was located proximate to ASD on the biological dimension defined by the ASD neuromarker. The successful generalization in multifarious datasets and the observed relations of ASD with SCZ on the biological dimensions provide new insights for a deeper understanding of ASD.

Cerebellar internal models: implications for the dexterous use of tools.

Humans have remarkable abilities in the dexterous use of tools to extend their physical capabilities. Although previous neuropsychological and functional neuroimaging studies have mainly focused on the contribution of frontal-parietal cerebral networks to skills for tool use, dense anatomical and functional connections are known to exist between the frontal-parietal regions and the lateral cerebellum, suggesting that the cerebellum also supports the information processing necessary for the dexterous use of tools. In this article, we review functional and structural imaging studies reporting that the cerebellum is related to the learning acquisition of neural mechanisms representing input-output properties of controlled objects, including tools. These studies also suggest that such mechanisms are modularly organized in the cerebellum corresponding to the different properties of objects, such as kinematic or dynamic properties and types of tools, and that they enable humans to flexibly cope with discrete changes in objects and environments by reducing interference and combining acquired modules. Based on these studies, we propose a hypothesis that the cerebellum contributes to the skillful use of tools by representing the input-output properties of tools and providing information on the prediction of the sensory consequences of manipulation with the parietal regions, which are related to multisensory processing, and information on the necessary control of tools with the premotor regions, which contribute to the control of hand movements.

Neuroimaging Examination of Driving Mode Switching Corresponding to Changes in the Driving Environment.

Car driving is supported by perceptual, cognitive, and motor skills trained through continuous daily practice. One of the skills that characterize experienced drivers is to detect changes in the driving environment and then flexibly switch their driving modes in response to the changes. Previous functional neuroimaging studies on motor control investigated the mechanisms underlying behaviors adaptive to changes in control properties or parameters of experimental devices such as a computer mouse or a joystick. The switching of multiple internal models mainly engages adaptive behaviors and underlies the interplay between the cerebellum and frontoparietal network (FPN) regions as the neural process. However, it remains unclear whether the neural mechanisms identified in previous motor control studies also underlie practical driving behaviors. In the current study, we measure functional magnetic resonance imaging (fMRI) activities while participants control a realistic driving simulator inside the MRI scanner. Here, the accelerator sensitivity of a virtual car is abruptly changed, requiring participants to respond to this change flexibly to maintain stable driving. We first compare brain activities before and after the sensitivity change. As a result, sensorimotor areas, including the left cerebellum, increase their activities after the sensitivity change. Moreover, after the change, activity significantly increases in the inferior parietal lobe (IPL) and dorsolateral prefrontal cortex (DLPFC), parts of the FPN regions. By contrast, the posterior cingulate cortex, a part of the default mode network, deactivates after the sensitivity change. Our results suggest that the neural bases found in previous experimental studies can serve as the foundation of adaptive driving behaviors. At the same time, this study also highlights the unique contribution of non-motor regions to addressing the high cognitive demands of driving.

Real-Time Detection and Feedback of Canonical Electroencephalogram Microstates: Validating a Neurofeedback System as a Function of Delay.

Recent neurotechnology has developed various methods for neurofeedback (NF), in which participants observe their own neural activity to be regulated in an ideal direction. EEG-microstates (EEGms) are spatially featured states that can be regulated through NF training, given that they have recently been indicated as biomarkers for some disorders. The current study was conducted to develop an EEG-NF system for detecting "canonical 4 EEGms" in real time. There are four representative EEG states, regardless of the number of channels, preprocessing procedures, or participants. Accordingly, our 10 Hz NF system was implemented to detect them (msA, B, C, and D) and audio-visually inform participants of its detection. To validate the real-time effect of this system on participants' performance, the NF was intentionally delayed for participants to prevent their cognitive control in learning. Our results suggest that the feedback effect was observed only under the no-delay condition. The number of Hits increased significantly from the baseline period and increased from the 1- or 20-s delay conditions. In addition, when the Hits were compared among the msABCD, each cognitive or perceptual function could be characterized, though the correspondence between each microstate and psychological ability might not be that simple. For example, msD should be generally task-positive and less affected by the inserted delay, whereas msC is more delay-sensitive. In this study, we developed and validated a new EEGms-NF system as a function of delay. Although the participants were naive to the inserted delay, the real-time NF successfully increased their Hit performance, even within a single-day experiment, although target specificity remains unclear. Future research should examine long-term training effects using this NF system.