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Consciousness, defined as being aware of and responsive to one's surroundings, is characteristic of normal waking life and typically is lost during sleep and general anaesthesia. The traditional view of consciousness as a global brain state has evolved toward a more sophisticated interplay between global and local states, with the presence of local sleep in the awake brain and local wakefulness in the sleeping brain. However, this interplay is not clear for general anaesthesia, where loss of consciousness was recently suggested to be associated with a global state of brain‐wide synchrony that selectively involves layer 5 cortical pyramidal neurons across sensory, motor and associative areas. According to this global view, local wakefulness of layer 5 cortex should be incompatible with deep anaesthesia, a hypothesis that deserves to be scrutinised with causal manipulations. Here, we show that unilateral chemogenetic activation of layer 5 pyramidal neurons in the sensorimotor cortex of isoflurane‐anaesthetised mice induces a local state transition from slow‐wave activity to tonic firing in the transfected hemisphere. This wakefulness‐like activity dramatically disrupts layer 5 interhemispheric synchrony with mirror‐image locations in the contralateral hemisphere, but does not reduce the level of unconsciousness under deep anaesthesia, nor in the transitions to/from anaesthesia. Global layer 5 synchrony may thus be a sufficient condition for anaesthesia‐induced unconsciousness, but is not a necessary one, at least under isoflurane anaesthesia. Local wakefulness‐like activity of layer 5 cortex can be induced and maintained under deep anaesthesia, encouraging further investigation into the local vs. global aspects of anaesthesia‐induced unconsciousness. Key points: The neural correlates of consciousness have evolved from global brain states to a nuanced interplay between global and local states, evident in terms of local sleep in awake brains and local wakefulness in sleeping brains.The concept of local wakefulness remains unclear for general anaesthesia, where the loss of consciousness has been recently suggested to involve brain‐wide synchrony of layer 5 cortical neurons.We found that local wakefulness‐like activity of layer 5 cortical can be chemogenetically induced in anaesthetised mice without affecting the depth of anaesthesia or the transitions to and from unconsciousness.Global layer 5 synchrony may thus be a sufficient but not necessary feature for the unconsciousness induced by general anaesthesia.Local wakefulness‐like activity of layer 5 neurons is compatible with general anaesthesia, thus promoting further investigation into the local vs. global aspects of anaesthesia‐induced unconsciousness. [ABSTRACT FROM AUTHOR]

Social cognition (SC) encompasses a set of cognitive functions that enable individuals to understand and respond appropriately to social interactions. Although focused ultrasound subthalamotomy (FUS‐STN) effectively treats Parkinson's disease (PD) clinical motor features, its impact and safety on cognitive‐behavioral interactions/interpersonal awareness are unknown. This study investigated the effects of unilateral FUS‐STN on facial emotion recognition (FER) and affective and cognitive theory of mind (ToM) in PD patients from a randomized sham‐controlled trial (NCT03454425). Subjects performed SC evaluation before and 4 months after the procedure while still under blind assessment conditions. The SC assessment included the Karolinska Directed Emotional Faces task for FER, the Reading the Mind in the Eyes (RME) test for affective ToM, and The Theory of Mind Picture Stories Task (ToM PST) (order, questions, and total score) for cognitive ToM. The active treatment group showed anecdotal‐to‐moderate evidence of no worsening in SC after FUS‐STN. Anecdotal evidence for an improvement was recognized in the SC score changes, from baseline to post‐treatment, for the active treatment group compared with sham for the RME, ToM PST order, ToM PST total, FER total, and recognition of fear, disgust, and anger. This study provides the first evidence that unilateral FUS‐STN does not impair social cognitive abilities, indicating that it can be considered a safe treatment approach for this domain in PD patients. Furthermore, the results suggest FUS‐STN may even lead to some improvement in social cognitive outcomes, which should be considered as a preliminary finding requiring further investigation with larger samples sizes. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Parkinson's disease is characterized by exaggerated beta activity (13–35 Hz) in cortico‐basal ganglia motor loops. Beta activity includes both periodic fluctuations (i.e. oscillatory activity) and aperiodic fluctuations reflecting spiking activity and excitation/inhibition balance (i.e. non‐oscillatory activity). However, the relative contribution, dopamine dependency and clinical correlations of oscillatory vs. non‐oscillatory beta activity remain unclear. We recorded, modelled and analysed subthalamic local field potentials in parkinsonian patients at rest while off or on medication. Autoregressive modelling with additive 1/f noise clarified the relationships between measures of beta activity in the time domain (i.e. amplitude and duration of beta bursts) or in the frequency domain (i.e. power and sharpness of the spectral peak) and oscillatory vs. non‐oscillatory activity: burst duration and spectral sharpness are specifically sensitive to oscillatory activity, whereas burst amplitude and spectral power are ambiguously sensitive to both oscillatory and non‐oscillatory activity. Our experimental data confirmed the model predictions and assumptions. We subsequently analysed the effect of levodopa, obtaining strong‐to‐extreme Bayesian evidence that oscillatory beta activity is reduced in patients on vs. off medication, with moderate evidence for absence of modulation of the non‐oscillatory component. Finally, specifically the oscillatory component of beta activity correlated with the rate of motor progression of the disease. Methodologically, these results provide an integrative understanding of beta‐based biomarkers relevant for adaptive deep brain stimulation. Biologically, they suggest that primarily the oscillatory component of subthalamic beta activity is dopamine dependent and may play a role not only in the pathophysiology but also in the progression of Parkinson's disease. Key points: Beta activity in Parkinson's disease includes both true periodic fluctuations (i.e. oscillatory activity) and aperiodic fluctuations reflecting spiking activity and synaptic balance (i.e. non‐oscillatory activity).The relative contribution, dopamine dependency and clinical correlations of oscillatory vs. non‐oscillatory beta activity remain unclear.Burst duration and spectral sharpness are specifically sensitive to oscillatory activity, while burst amplitude and spectral power are ambiguously sensitive to both oscillatory and non‐oscillatory activity.Only the oscillatory component of subthalamic beta activity is dopamine‐dependent.Stronger beta oscillatory activity correlates with faster motor progression of the disease. [ABSTRACT FROM AUTHOR]

We describe a novel application of methodology for high‐density surface electromyography (HDsEMG) decomposition to identify motor unit (MU) firings in response to transcranial magnetic stimulation (TMS). The method is based on the MU filter estimation from HDsEMG decomposition with convolution kernel compensation during voluntary isometric contractions and its application to contractions elicited by TMS. First, we simulated synthetic HDsEMG signals during voluntary contractions followed by simulated motor evoked potentials (MEPs) recruiting an increasing proportion of the motor pool. The estimation of MU filters from voluntary contractions and their application to elicited contractions resulted in high (>90%) precision and sensitivity of MU firings during MEPs. Subsequently, we conducted three experiments in humans. From HDsEMG recordings in first dorsal interosseous and tibialis anterior muscles, we demonstrated an increase in the number of identified MUs during MEPs evoked with increasing stimulation intensity, low variability in the MU firing latency and a proportion of MEP energy accounted for by decomposition similar to voluntary contractions. A negative relationship between the MU recruitment threshold and the number of identified MU firings was exhibited during the MEP recruitment curve, suggesting orderly MU recruitment. During isometric dorsiflexion we also showed a negative association between voluntary MU firing rate and the number of firings of the identified MUs during MEPs, suggesting a decrease in the probability of MU firing during MEPs with increased background MU firing rate. We demonstrate accurate identification of a large population of MU firings in a broad recruitment range in response to TMS via non‐invasive HDsEMG recordings. Key points: Transcranial magnetic stimulation (TMS) of the scalp produces multiple descending volleys, exciting motor pools in a diffuse manner.The characteristics of a motor pool response to TMS have been previously investigated with intramuscular electromyography (EMG), but this is limited in its capacity to detect many motor units (MUs) that constitute a motor evoked potential (MEP) in response to TMS.By simulating synthetic signals with known MU firing patterns, and recording high‐density EMG signals from two human muscles, we show the feasibility of identifying firings of many MUs that comprise a MEP.We demonstrate the identification of firings of a large population of MUs in the broad recruitment range, up to maximal MEP amplitude, with fewer required stimuli compared to intramuscular EMG recordings.The methodology demonstrates an emerging possibility to study responses to TMS on a level of individual MUs in a non‐invasive manner. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) exhibits a high prevalence of dementia as disease severity and duration progress. Focused ultrasound (FUS) has been applied for transient blood-brain barrier (BBB) opening of cortical regions in neurodegenerative disorders. The striatum is a primary target for delivery of putative therapeutic agents in PD.Objective: Here, we report a prospective, single-arm, nonrandomized, proof-of-concept, phase I clinical trial (NCT03608553 amended) in PD with dementia to test the safety and feasibility of striatal BBB opening in PD patients.Methods: Seven PD patients with cognitive impairment were treated for BBB opening in the posterior putamen. This was performed in two sessions separated by 2 to 4 weeks, where the second session included bilateral putamina opening in 3 patients. Primary outcome measures included safety and feasibility of focal striatal BBB opening. Changes in motor and cognitive functions, magnetic resonance imaging (MRI), 18 F-fluorodopa (FDOPA), and β-amyloid PET (positron emission tomography) images were determined.Results: The procedure was feasible and well tolerated, with no serious adverse events. No neurologically relevant change in motor and cognitive (battery of neuropsychological tests) functions was recognized at follow-up. MRI revealed putamen BBB closing shortly after treatment (24 hours to 14 days) and ruled out hemorrhagic and ischemic lesions. There was a discrete but significant reduction in β-amyloid uptake in the targeted region and no change in FDOPA PET.Conclusions: These initial results indicate that FUS-mediated striatal BBB opening is feasible and safe and therefore could become an effective tool to facilitate the delivery of putative neurorestorative molecules in PD. © 2022 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

A major unmet need in Parkinson's disease (PD) is to slow the inexorable progression of neurodegeneration. Clinical trials that evaluated promising pharmacological strategies have repeatedly failed. Nonetheless, the advent of focused ultrasound provides new opportunities toward the goal of developing a safe and effective disease-modifying therapy for PD. Here we discuss the rationale, possible avenues, and challenges along this path, exploiting the potential of focused ultrasound for (1) performing focal thermal lesions to restore the basic basal ganglia abnormalities associated with dopamine depletion, and (2) transiently opening the blood-brain barrier for targeted delivery of therapeutic agents. First, the classic idea of excitotoxicity mediated by hyperactivity of the subthalamic nucleus suggests that focused ultrasound subthalamotomy may offer a clinically viable disease-modifying therapy in very-early PD. Second, the concept of retrograde nigrostriatal neurodegeneration, supported by our recent cortical pathogenic theory of PD, points toward the putamen as a principal site for focused ultrasound blood-brain barrier opening and targeted drug delivery. In principle, both therapeutic strategies-subthalamotomy and putaminal blood-brain barrier opening-could eventually be applied in the same patient. Clinical application is still a long road ahead; nevertheless, focused ultrasound may open a twofold path toward disease modification in PD. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Essential tremor is the most common movement disorder in adults. In patients who are not responsive to medical treatment, functional neurosurgery and, more recently, transcranial MR‐guided focused ultrasound thalamotomy are considered effective therapeutic approaches. However, the structural brain changes following a thalamotomy that mediates the clinical improvement are still unclear. In here diffusion weighted images were acquired in a cohort of 24 essential tremor patients before and 3 months after unilateral transcranial MR‐guided focused ultrasound thalamotomy targeting at the posteroventral part of the VIM. Microstructural changes along the DRTT were quantified by means of probabilistic tractography, and later related to the clinical improvement of the patients at 3‐months and at 1‐year after the intervention. In addition the changes along two neighboring tracts, that is, the corticospinal tract and the medial lemniscus, were assessed, as well as the relation between these changes and the presence of side effects. Thalamic lesions produced local and distant alterations along the trajectory of the DRTT, and each correlated with clinical improvement. Regarding side effects, gait imbalance after thalamotomy was associated with greater impact on the DRTT, whereas the presence of paresthesias was significantly related to a higher overlap between the lesion and the medial lemniscus. This work represents the largest series describing the microstructural changes following transcranial MR‐guided focused ultrasound thalamotomy in essential tremor. These results suggest that clinical benefits are specific for the impact on the cerebello‐thalamo‐cortical pathway, thus reaffirming the potential of tractography to aid thalamotomy targeting. [ABSTRACT FROM AUTHOR]

Key points We investigate the elementary responses of the hippocampus to somatosensory stimulation (peripheral and lemniscal) in rats given its relevance for episodic memory function., We integrate local field potential and multi-unit data from multisite silicon probes, single-unit data from tetrode recordings and membrane potential data from intracellular recordings., Somatosensory signals reach the hippocampus mainly from layer II entorhinal cortex to directly discharge dentate gyrus granule cells, while a different predominantly inhibitory process takes place in CA1, further controlling the hippocampal output., Hippocampal responses to somatosensory stimuli were dependent on fluctuations in the strength and composition of synaptic inputs due to changes of the ongoing local (hippocampal) and distant (cortical) state., Our data reveal a distinct organization of somatosensory-related extra-hippocampal inputs converging onto dentate gyrus and CA1., Abstract The hippocampus is a pivotal structure for episodic memory function. This ability relies on the possibility of integrating different features of sensory stimuli with the spatio-temporal context in which they occur. While recent studies now suggest that somatosensory information is already processed by the hippocampus, the basic mechanisms still remain unexplored. Here, we used electrical stimulation of the paws, the whisker pad or the medial lemniscus to probe the somatosensory pathway to the hippocampus in the anaesthetized rat, and multisite electrodes, in combination with tetrode and intracellular recordings, to look at the properties of somatosensory hippocampal responses. We found that peripheral and lemniscal stimulation elicited small local field potential responses in the dorsal hippocampus about 35-40 ms post-stimulus. Current source density analysis established the local nature of these responses, revealing associated synaptic sinks that were consistently confined to the molecular layer (ML) of the dentate gyrus (DG), with less regular activation of the CA1 stratum lacunosum moleculare (SLM). A delayed (40-45 ms), potentially active, current source that outlasted the SLM sink was present in about 50% cases around the CA1 pyramidal cell layer. Somatosensory stimulation resulted in multi-unit firing increases in the majority of DG responses (79%), whereas multi-unit firing suppression was observed in the majority of CA1 responses (62%). Tetrode and intracellular recordings of individual cells confirmed different firing modulation in the DG and the CA1 region, and verified the active nature of both the early ML sink and delayed somatic CA1 source. Hippocampal responses to somatosensory stimuli were dependent on fluctuations in the strength and composition of synaptic inputs due to changes of the ongoing local (hippocampal) and distant (cortical) state. We conclude that somatosensory signals reach the hippocampus mainly from layer II entorhinal cortex to directly discharge DG granule cells, while a different predominantly inhibitory process takes place in CA1, further controlling the hippocampal output. Therefore, our data reveal a distinct organization of somatosensory-related extra-hippocampal inputs converging onto DG and CA1. [ABSTRACT FROM AUTHOR]

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Deep brain stimulation (DBS) of the ventralis oralis (VO) complex of the thalamus improves tics in patients with Tourette syndrome (TS). To neurophysiologically describe the VO complex we recorded, in seven patients with TS undergoing DBS electrode implantation, single-unit activity during surgery and local field potentials (LFPs) a few days after surgery. Single unit recordings showed that the VO complex is characterized by a localized pattern of bursting neuronal activity. LFP spectra demonstrated that VO of TS patients has a prominent oscillatory activity at low frequencies (2-7 Hz) and in the α-band (8-13 Hz), and a virtually absent beta activity. In each patient, the main LFP frequency significantly correlated with single-unit interburst frequency. In conclusion, we observed an oscillatory bursting activity in the VO as target region in patients with severe TS undergoing DBS surgery. © 2010 Movement Disorder Society [ABSTRACT FROM AUTHOR]