A growing body of evidence indicates a pivotal role of cognition and in particular executive function in gait control and fall prevention. In a recent gait study using electroencephalographic (EEG) imaging, we provided direct proof for cortical top-down inhibitory control in step adaptation. A crucial part of motor inhibition is recognizing stimuli that signal the need to inhibit or adjust motor actions such as steps during walking. One of the EEG signatures of performance monitoring in response to events signaling the need to adjust motor responses, are error-related potential (error-ERP) features. To examine whether error-ERP features may index executive control during gait adaptation, we analyzed high-density (108-channel) EEG data from an auditory gait pacing study. Participants (N = 18) walking on a steadily moving treadmill were asked to step in time to an auditory cue tone sequence, and then to quickly adapt their step length and rate, to regain step-cue synchrony following occasional unexpected shifts in the pacing cue train to a faster or slower cue tempo. Decomposition of the continuous EEG data by independent component analysis revealed a negative deflection in the source-resolved event-related potential (ERP) time locked to 'late' cue tones marking a shift to a slower cue tempo. This vertex-negative ERP feature, localized primarily to posterior medial frontal cortex (pMFC) and peaking 250 ms after the onset of the tempo-shift cue, we here refer to as the step-cue delay negativity (SDN). SDN source, timing, and polarity resemble other error-related ERP features, e.g., the Error-Related Negativity (ERN) and Feedback-Related Negativity (FRN) in (seated) button press response tasks. In single trials, SDN amplitude varied with the magnitude of the cue latency deviation (the time interval between the expected and actual cue onsets). Regression analysis also identified linear coupling between SDN amplitude and the subsequent speed of gait tempo adaptation (as measured by the increase in length of the ensuing adaptation step). The SDN in this paradigm thus seems both to index the perceived need for and the subsequent magnitude of the immediate gait adjustment, consistent with performance-monitoring models. Future research might investigate relationships of these control processes to the impairment of gait adjustment in motor disorders and cognitive decline, for example to develop a biomarker for fall risk prediction in early-stage Parkinson's.

Background. Gait impairments are common in Parkinson's disease (PD) and increase falls risk. Visual cues can improve gait in PD, particularly freezing of gait (FOG), but mechanisms involved in visual cue response are unknown. This study aimed to examine brain activity in response to visual cues in people with PD who do (PD+FOG) and do not report FOG (PD-FOG) and explore relationships between attention, brain activity and gait. Methods. Mobile EEG measured brain activity during gait in 20 healthy older adults and 43 PD participants (n=22 PD+FOG, n=21 PD-FOG). Participants walked for 2-minutes with and without visual cues (transverse lines to step over). We report power spectral density (PSD) in Delta (1-4 Hz), Theta (4-7 Hz), Alpha (8-12 Hz), Beta (14-24 Hz) and Gamma (30-50 Hz) bands within clusters of similarly brain localized independent component sources. Results. PSDs within the parietal and occipital lobes were altered when walking with visual cues in PD, particularly in PD+FOG. Between group, differences suggested that parietal sources in PD, particularly with PD+FOG, had larger activity compared to healthy older adults when walking. Within group, visual cues altered brain activity in PD, particularly in PD+FOG, within visual processing brain regions. In PD participants, brain activity differences with cues correlated with gait improvements, and in PD+FOG those with worse attention required more visual attentional processing (reduced alpha PSD) in the occipital lobe. Conclusions. Visual cues improve gait and influence brain activity during walking in PD, particularly in PD+FOG. Findings may allow development of more effective therapeutics.

Recent applications of simultaneous scalp electroencephalography (EEG) and transcranial magnetic stimulation (TMS) suggest that adapting stimulation to underlying brain states may enhance neuroplastic effects of TMS. It is often assumed that longer-lasting effects of TMS on brain function may be mediated by phasic interactions between TMS pulses and endogenous cortical oscillatory dynamics. The mechanisms by which TMS exerts its neuromodulatory effects, however, remain unknown. Here, we discuss evidence concerning the functional effects on synaptic plasticity of oscillatory cross-frequency coupling in cortical networks as a potential framework for understanding the neuromodulatory effects of TMS. We first discuss evidence for interactions between endogenous oscillatory brain dynamics and externally induced electromagnetic field activity. Alpha band (8-12 Hz) activities are of special interest here because of the wide application and therapeutic effectiveness of rhythmic TMS (rTMS) using a stimulus repetition frequency at or near 10 Hz. We discuss the large body of literature on alpha oscillations suggesting that alpha oscillatory cycles produce periodic inhibition or excitation of neuronal processing through phase-amplitude coupling (PAC) of low-frequency oscillations with high-frequency broadband (or gamma) bursting. Such alpha-gamma coupling may reflect excitability of neuronal ensembles underlying neuroplasticity effects of TMS. We propose that TMS delivery with simultaneous EEG recording and near real-time estimation of source-resolved alpha-gamma PAC might be used to select the precise timing of TMS pulse deliveries so as to enhance the neuroplastic effects of TMS therapies.

Modulation of the amplitude of high-frequency cortical field activity locked to changes in the phase of a slower brain rhythm is known as phase-amplitude coupling (PAC). The study of this phenomenon has been gaining traction in neuroscience because of several reports on its appearance in normal and pathological brain processes in humans as well as across different mammalian species. This has led to the suggestion that PAC may be an intrinsic brain process that facilitates brain inter-area communication across different spatiotemporal scales. Several methods have been proposed to measure the PAC process, but few of these enable detailed study of its time course. It appears that no studies have reported details of PAC dynamics including its possible directional delay characteristic. Here, we study and characterize the use of a novel information theoretic measure that may address this limitation: local transfer entropy. We use both simulated and actual intracranial electroencephalographic data. In both cases, we observe initial indications that local transfer entropy can be used to detect the onset and offset of modulation process periods revealed by mutual information estimated phase-amplitude coupling (MIPAC). We review our results in the context of current theories about PAC in brain electrical activity, and discuss technical issues that must be addressed to see local transfer entropy more widely applied to PAC analysis. The current work sets the foundations for further use of local transfer entropy for estimating PAC process dynamics, and extends and complements our previous work on using local mutual information to compute PAC (MIPAC).

In this report we present a mobile brain/body imaging (MoBI) dataset that allows study of source-resolved cortical dynamics supporting coordinated gait movements in a rhythmic auditory cueing paradigm. Use of an auditory pacing stimulus stream has been recommended to identify deficits and treat gait impairments in neurologic populations. Here, the rhythmic cueing paradigm required healthy young participants to walk on a treadmill (constant speed) while attempting to maintain step synchrony with an auditory pacing stream and to adapt their step length and rate to unanticipated shifts in tempo of the pacing stimuli (e.g., sudden shifts to a faster or slower tempo). High-density electroencephalography (EEG, 108 channels), surface electromyography (EMG, bilateral tibialis anterior), pressure sensors on the heel (to register timing of heel strikes), and goniometers (knee, hip, and ankle joint angles) were concurrently recorded in 20 participants. The data is provided in the Brain Imaging Data Structure (BIDS) format to promote data sharing and reuse, and allow the inclusion of the data into fully automated data analysis workflows.

Inflammation and dysfunction of the extrahepatic biliary tree are common causes of human pathology, including gallstones and cholangiocarcinoma. Despite this, we know little about the local regulation of biliary inflammation. Tuft cells, rare sensory epithelial cells, are particularly prevalent in the mucosa of the gallbladder and extrahepatic bile ducts. Here, we show that biliary tuft cells express a core genetic tuft cell program in addition to a tissue-specific gene signature and, in contrast to small intestinal tuft cells, decreased postnatally, coincident with maturation of bile acid production. Manipulation of enterohepatic bile acid recirculation revealed that tuft cell abundance is negatively regulated by bile acids, including in a model of obstructive cholestasis in which inflammatory infiltration of the biliary tree correlated with loss of tuft cells. Unexpectedly, tuft cell-deficient mice spontaneously displayed an increased gallbladder epithelial inflammatory gene signature accompanied by neutrophil infiltration that was modulated by the microbiome. We propose that biliary tuft cells function as bile acid-sensitive negative regulators of inflammation in biliary tissues and serve to limit inflammation under homeostatic conditions.

BRAT1 biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases allowing us to study a large cohort of 97 individuals and draw phenotype-genotype correlations. Fifty-nine individuals presented with BRAT1-related RMFSL phenotype. Most of them had no psychomotor acquisition (100%), epilepsy (100%), microcephaly (91%), limb rigidity (93%), and died prematurely (93%). Thirty-eight individuals presented a non-lethal phenotype of BRAT1-related NEDCAS phenotype. Seventy-six percent of the patients in this group were able to walk and 68% were able to say at least a few words. Most of them had cerebellar ataxia (82%), axial hypotonia (79%) and cerebellar atrophy (100%). Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46; 100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS (28/34; 82%). The phenotype of patients carrying splice variants was variable: 41% presented with RMFSL (7/17) and 59% with NEDCAS (10/17).