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Despite its uniform appearance, the cerebellar cortex is highly heterogeneous in terms of structure, genetics and physiology. Purkinje cells (PCs), the principal and sole output neurons of the cerebellar cortex, can be categorized into multiple populations that differentially express molecular markers and display distinctive physiological features. Such features include action potential rate, but also their propensity for synaptic and intrinsic plasticity. However, the precise molecular and genetic factors that correlate with the differential physiological properties of PCs remain elusive. In this article, we provide a detailed overview of the cellular mechanisms that regulate PC activity and plasticity. We further perform a pathway analysis to highlight how molecular characteristics of specific PC populations may influence their physiology and plasticity mechanisms.

The delicate balance between discrimination and generalization of responses is crucial for survival in our ever-changing environment. In particular, it is important to understand how stimulus discrimination affects the level of stimulus generalization. For example, when we use non-differential training for Pavlovian eyeblink conditioning to investigate generalization of cerebellar-related eyelid motor responses, we find generalization effects on amount, amplitude and timing of the conditioned responses. However, it is unknown what the generalization effects are following differential training. We trained mice to close their eyelids to a 10 kHz tone with an air-puff as the reinforcing stimulus (CS+), while alternatingly exposing them to a tone frequency of either 4 kHz, 9 kHz or 9.5 kHz without the air-puff (CS-) during the training blocks. We tested the generalization effects during the expression of the responses after the training period with tones ranging from 2 kHz to 20 kHz. Our results show that the level of generalization tended to positively correlate with the difference between the CS+ and the CS- training stimuli. These effects of generalization were found for the probability, amplitude but not for the timing of the conditioned eyelid responses. These data indicate the specificity of the generalization effects following differential versus non-differential training, highlighting the relevance of discrimination learning for stimulus generalization.

The investigation of the dynamics of Purkinje cell (PC) activity is crucial to unravel the role of the cerebellum in motor control, learning and cognitive processes. Within the cerebellar cortex (CC), these neurons receive all the incoming sensory and motor information, transform it and generate the entire cerebellar output. The relatively homogenous and repetitive structure of the CC, common to all vertebrate species, suggests a single computation mechanism shared across all PCs. While PC models have been developed since the 70's, a comprehensive review of contemporary models is currently lacking. Here, we provide an overview of PC models, ranging from the ones focused on single cell intracellular PC dynamics, through complex models which include synaptic and extrasynaptic inputs. We review how PC models can reproduce physiological activity of the neuron, including firing patterns, current and multistable dynamics, plateau potentials, calcium signaling, intrinsic and synaptic plasticity and input/output computations. We consider models focusing both on somatic and on dendritic computations. Our review provides a critical performance analysis of PC models with respect to known physiological data. We expect our synthesis to be useful in guiding future development of computational models that capture real-life PC dynamics in the context of cerebellar computations.

Precisely tracking time over second-long timescales is important for accurate anticipation and consequential actions, yet the neurobiological underpinnings remain unknown. In this issue of Neuron, Garcia-Garcia and colleagues1 show that computations in the cerebellum resulting from interactions between the mossy fiber and climbing fiber pathways contribute to long-interval learning during operant conditioning.

Four-dimensional ultrasound imaging of complex biological systems such as the brain is technically challenging because of the spatiotemporal sampling requirements. We present computational ultrasound imaging (cUSi), an imaging method that uses complex ultrasound fields that can be generated with simple hardware and a physical wave prediction model to alleviate the sampling constraints. cUSi allows for high-resolution four-dimensional imaging of brain hemodynamics in awake and anesthetized mice., Computer Engineering, Signal Processing Systems

Four-dimensional ultrasound imaging of complex biological systems such as the brain is technically challenging because of the spatiotemporal sampling requirements. We present computational ultrasound imaging (cUSi), an imaging method that uses complex ultrasound fields that can be generated with simple hardware and a physical wave prediction model to alleviate the sampling constraints. cUSi allows for high-resolution four-dimensional imaging of brain hemodynamics in awake and anesthetized mice.

The olivocerebellar system, which is critical for sensorimotor performance and learning, functions through modules with feedback loops. The main feedback to the inferior olive comes from the cerebellar nuclei (CN), which are predominantly GABAergic and contralateral. However, for the d subnucleus of the caudomedial accessory olive (cdMAO), a crucial region for oculomotor and upper-body movements, the source of GABAergic input has yet to be identified. Here, we demonstrate the existence of a disynaptic inhibitory projection from the medial CN (MCN) to the cdMAO via the superior colliculus (SC) by exploiting retrograde, anterograde and transsynaptic viral tracing at the light microscopic level as well as anterograde classical and viral tracing combined with immunocytochemistry at the electron microscopic level. Retrograde tracing in Gad2-Cre mice reveals that the cdMAO receives GABAergic input from the contralateral SC. Anterograde transsynaptic tracing uncovered that the SC neurons receiving input from the contralateral MCN provide predominantly inhibitory projections to contralateral cdMAO, ipsilateral to the MCN. Following ultrastructural analysis of the monosynaptic projection about half of the SC terminals within the contralateral cdMAO are GABAergic. The disynaptic GABAergic projection from the MCN to the ipsilateral cdMAO mirrors that of the monosynaptic excitatory projection from the MCN to the contralateral cdMAO. Thus, while completing the map of inhibitory inputs to the olivary subnuclei, we established that the MCN inhibits the cdMAO via the contralateral SC, highlighting a potential push-pull mechanism in directional gaze control that appears unique in terms of laterality and polarity among olivocerebellar modules.Significance Statement All dendritic spines of the inferior olive receive a combined inhibitory and excitatory input, which is critical for regulation of temporal control during sensorimotor coordination. Yet, some sources of GABAergic input

Four-dimensional ultrasound imaging of complex biological systems such as the brain is technically challenging because of the spatiotemporal sampling requirements. We present computational ultrasound imaging (cUSi), an imaging method that uses complex ultrasound fields that can be generated with simple hardware and a physical wave prediction model to alleviate the sampling constraints. cUSi allows for high-resolution four-dimensional imaging of brain hemodynamics in awake and anesthetized mice.

Gait ataxia is one of the most common and impactful consequences of cerebellar dysfunction. Purkinje cells, the sole output neurons of the cerebellar cortex, are often involved in the underlying pathology, but their specific functions during locomotor control in health and disease remain obfuscated. We aimed to describe the effect of gradual adult-onset Purkinje cell degeneration on gaiting patterns in mice, and to determine whether two different mechanisms that both lead to Purkinje cell degeneration cause different patterns in the development of gait ataxia. Using the ErasmusLadder together with a newly developed limb detection algorithm and machine learning-based classification, we subjected mice to a challenging locomotor task with detailed analysis of single limb parameters, intralimb coordination and whole-body movement. We tested two Purkinje cell-specific mouse models, one involving stochastic cell death due to impaired DNA repair mechanisms (Pcp2-Ercc1-/-), the other carrying the mutation that causes spinocerebellar ataxia type 1 (Pcp2-ATXN1[82Q]). Both mouse models showed progressive gaiting deficits, but the sequence with which gaiting parameters deteriorated was different between mouse lines. Our longitudinal approach revealed that gradual loss of Purkinje cell function can lead to a complex pattern of loss of function over time, and that this pattern depends on the specifics of the pathological mechanisms involved. We hypothesize that this variability will also be present in disease progression in patients, and that our findings will facilitate the study of therapeutic interventions in mice, as subtle changes in locomotor abilities can be quantified by our methods.

Gait ataxia is one of the most common and impactful consequences of cerebellar dysfunction. Purkinje cells, the sole output neurons of the cerebellar cortex, are often involved in the underlying pathology, but their specific functions during locomotor control in health and disease remain obfuscated. We aimed to describe the effect of gradual adult-onset Purkinje cell degeneration on gaiting patterns in mice, and to determine whether two different mechanisms that both lead to Purkinje cell degeneration cause different patterns in the development of gait ataxia. Using the ErasmusLadder together with a newly developed limb detection algorithm and machine learning-based classification, we subjected mice to a challenging locomotor task with detailed analysis of single limb parameters, intralimb coordination and whole-body movement. We tested two Purkinje cell-specific mouse models, one involving stochastic cell death due to impaired DNA repair mechanisms (Pcp2-Ercc1-/-), the other carrying the mutation that causes spinocerebellar ataxia type 1 (Pcp2-ATXN1[82Q]). Both mouse models showed progressive gaiting deficits, but the sequence with which gaiting parameters deteriorated was different between mouse lines. Our longitudinal approach revealed that gradual loss of Purkinje cell function can lead to a complex pattern of loss of function over time, and that this pattern depends on the specifics of the pathological mechanisms involved. We hypothesize that this variability will also be present in disease progression in patients, and that our findings will facilitate the study of therapeutic interventions in mice, as subtle changes in locomotor abilities can be quantified by our methods.

Unhealthy ageing poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the ageing process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, promoting healthy longevity in the old population. In response to the challenge of the ageing population and with a view to the future, Norway and the UK are fostering collaborations, supported by a "Money Follows Cooperation agreement" between the two nations. The inaugural Norway-UK joint meeting on ageing and dementia gathered leading experts on ageing and dementia from the two nations to share their latest discoveries in related fields. Since ageing is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular ageing mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (e.g., using NAD+ precursors). The meeting facilitated dialogue among policy makers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy ageing.

The whisker system is widely used as a model system for understanding sensorimotor integration. Purkinje cells in the crus regions of the cerebellum have been reported to linearly encode whisker midpoint, but it is unknown whether the paramedian and simplex lobules as well as their target neurons in the cerebellar nuclei also encode whisker kinematics and if so which ones. Elucidating how these kinematics are represented throughout the cerebellar hemisphere is essential for understanding how the cerebellum coordinates multiple sensorimotor modalities. Exploring the cerebellar hemisphere of mice using optogenetic stimulation, we found that whisker movements can be elicited by stimulation of Purkinje cells in not only crus1 and crus2, but also in the paramedian lobule and lobule simplex; activation of cells in the medial paramedian lobule had on average the shortest latency, whereas that of cells in lobule simplex elicited similar kinematics as those in crus1 and crus2. During spontaneous whisking behaviour, simple spike activity correlated in general better with velocity than position of the whiskers, but it varied between protraction and retraction as well as per lobule. The cerebellar nuclei neurons targeted by the Purkinje cells showed similar activity patterns characterized by a wide variety of kinematic signals, yet with a dominance for velocity. Taken together, our data indicate that whisker movements are much more prominently and diversely represented in the cerebellar cortex and nuclei than assumed, highlighting the rich repertoire of cerebellar control in the kinematics of movements that can be engaged during coordination. KEY POINTS: Excitation of Purkinje cells throughout the cerebellar hemispheres induces whisker movement, with the shortest latency and longest duration within the paramedian lobe. Purkinje cells have differential encoding for the fast and slow components of whisking. Purkinje cells encode not only the position but also the velocity of w

The whisker system is widely used as a model system for understanding sensorimotor integration. Purkinje cells in the crus regions of the cerebellum have been reported to linearly encode whisker midpoint, but it is unknown whether the paramedian and simplex lobules as well as their target neurons in the cerebellar nuclei also encode whisker kinematics and if so which ones. Elucidating how these kinematics are represented throughout the cerebellar hemisphere is essential for understanding how the cerebellum coordinates multiple sensorimotor modalities. Exploring the cerebellar hemisphere of mice using optogenetic stimulation, we found that whisker movements can be elicited by stimulation of Purkinje cells in not only crus1 and crus2, but also in the paramedian lobule and lobule simplex; activation of cells in the medial paramedian lobule had on average the shortest latency, whereas that of cells in lobule simplex elicited similar kinematics as those in crus1 and crus2. During spontaneous whisking behaviour, simple spike activity correlated in general better with velocity than position of the whiskers, but it varied between protraction and retraction as well as per lobule. The cerebellar nuclei neurons targeted by the Purkinje cells showed similar activity patterns characterized by a wide variety of kinematic signals, yet with a dominance for velocity. Taken together, our data indicate that whisker movements are much more prominently and diversely represented in the cerebellar cortex and nuclei than assumed, highlighting the rich repertoire of cerebellar control in the kinematics of movements that can be engaged during coordination. (Figure presented.). Key points: Excitation of Purkinje cells throughout the cerebellar hemispheres induces whisker movement, with the shortest latency and longest duration within the paramedian lobe. Purkinje cells have differential encoding for the fast and slow components of whisking. Purkinje cells encode not only the position but a

The cerebellum is involved in many motor, autonomic and cognitive functions, and new tasks that have a cerebellar contribution are discovered on a regular basis. Simultaneously, our insight into the functional compartmentalization of the cerebellum has markedly improved. Additionally, studies on cerebellar output pathways have seen a renaissance due to the development of viral tracing techniques. To create an overview of the current state of our understanding of cerebellar efferents, we undertook a systematic review of all studies on monosynaptic projections from the cerebellum to the brainstem and the diencephalon in mammals. This revealed that important projections from the cerebellum, to the motor nuclei, cerebral cortex, and basal ganglia, are predominantly di- or polysynaptic, rather than monosynaptic. Strikingly, most target areas receive cerebellar input from all three cerebellar nuclei, showing a convergence of cerebellar information at the output level. Overall, there appeared to be a large level of agreement between studies on different species as well as on the use of different types of neural tracers, making the emerging picture of the cerebellar output areas a solid one. Finally, we discuss how this cerebellar output network is affected by a range of diseases and syndromes, with also non-cerebellar diseases having impact on cerebellar output areas.

The cerebellum is involved in many motor, autonomic and cognitive functions, and new tasks that have a cerebellar contribution are discovered on a regular basis. Simultaneously, our insight into the functional compartmentalization of the cerebellum has markedly improved. Additionally, studies on cerebellar output pathways have seen a renaissance due to the development of viral tracing techniques. To create an overview of the current state of our understanding of cerebellar efferents, we undertook a systematic review of all studies on monosynaptic projections from the cerebellum to the brainstem and the diencephalon in mammals. This revealed that important projections from the cerebellum, to the motor nuclei, cerebral cortex, and basal ganglia, are predominantly di- or polysynaptic, rather than monosynaptic. Strikingly, most target areas receive cerebellar input from all three cerebellar nuclei, showing a convergence of cerebellar information at the output level. Overall, there appeared to be a large level of agreement between studies on different species as well as on the use of different types of neural tracers, making the emerging picture of the cerebellar output areas a solid one. Finally, we discuss how this cerebellar output network is affected by a range of diseases and syndromes, with also non-cerebellar diseases having impact on cerebellar output areas.

According to the motor learning theory by Albus and Ito, synaptic depression at the parallel fibre to Purkinje cells synapse (pf-PC) is the main substrate responsible for learning sensorimotor contingencies under climbing fibre control. However, recent experimental evidence challenges this relatively monopolistic view of cerebellar learning. Bidirectional plasticity appears crucial for learning, in which different microzones can undergo opposite changes of synaptic strength (e.g. downbound microzones-more likely depression, upbound microzones-more likely potentiation), and multiple forms of plasticity have been identified, distributed over different cerebellar circuit synapses. Here, we have simulated classical eyeblink conditioning (CEBC) using an advanced spiking cerebellar model embedding downbound and upbound modules that are subject to multiple plasticity rules. Simulations indicate that synaptic plasticity regulates the cascade of precise spiking patterns spreading throughout the cerebellar cortex and cerebellar nuclei. CEBC was supported by plasticity at the pf-PC synapses as well as at the synapses of the molecular layer interneurons (MLIs), but only the combined switch-off of both sites of plasticity compromised learning significantly. By differentially engaging climbing fibre information and related forms of synaptic plasticity, both microzones contributed to generate a well-timed conditioned response, but it was the downbound module that played the major role in this process. The outcomes of our simulations closely align with the behavioural and electrophysiological phenotypes of mutant mice suffering from cell-specific mutations that affect processing of their PC and/or MLI synapses. Our data highlight that a synergy of bidirectional plasticity rules distributed across the cerebellum can facilitate finetuning of adaptive associative behaviours at a high spatiotemporal resolution.

Despite its uniform appearance, the cerebellar cortex is highly heterogeneous in terms of structure, genetics and physiology. Purkinje cells (PCs), the principal and sole output neurons of the cerebellar cortex, can be categorized into multiple populations that differentially express molecular markers and display distinctive physiological features. Such features include action potential rate, but also their propensity for synaptic and intrinsic plasticity. However, the precise molecular and genetic factors that correlate with the differential physiological properties of PCs remain elusive. In this article, we provide a detailed overview of the cellular mechanisms that regulate PC activity and plasticity. We further perform a pathway analysis to highlight how molecular characteristics of specific PC populations may influence their physiology and plasticity mechanisms.

Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a “Money Follows Cooperation agreement” between the 2 nations. The inaugural Norway–UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging., Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a "Money Follows Cooperation agreement" between the 2 nations. The inaugural Norway-UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging.

According to the motor learning theory by Albus and Ito, synaptic depression at the parallel fibre to Purkinje cells synapse (pf-PC) is the main substrate responsible for learning sensorimotor contingencies under climbing fibre control. However, recent experimental evidence challenges this relatively monopolistic view of cerebellar learning. Bidirectional plasticity appears crucial for learning, in which different microzones can undergo opposite changes of synaptic strength (e.g. downbound microzones-more likely depression, upbound microzones- more likely potentiation), and multiple forms of plasticity have been identified, distributed over different cerebellar circuit synapses. Here, we have simulated classical eyeblink conditioning (CEBC) using an advanced spiking cerebellar model embedding downbound and upbound modules that are subject to multiple plasticity rules. Simulations indicate that synaptic plasticity regulates the cascade of precise spiking patterns spreading throughout the cerebellar cortex and cerebellar nuclei. CEBC was supported by plasticity at the pf-PC synapses as well as at the synapses of the molecular layer interneurons (MLIs), but only the combined switch-off of both sites of plasticity compromised learning significantly. By differentially engaging climbing fibre information and related forms of synaptic plasticity, both microzones contributed to generate a well-timed conditioned response, but it was the downbound module that played the major role in this process. The outcomes of our simulations closely align with the behavioural and electrophysiological phenotypes of mutant mice suffering from cell-specific mutations that affect processing of their PC and/or MLI synapses. Our data highlight that a synergy of bidirectional plasticity rules distributed across the cerebellum can facilitate finetuning of adaptive associative behaviours at a high spatiotemporal resolution.

Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a "Money Follows Cooperation agreement" between the 2 nations. The inaugural Norway-UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging.

The olivocerebellar system, which is critical for sensorimotor performance and learning, functions through modules with feedback loops. The main feedback to the inferior olive comes from the cer-ebellar nuclei (CN), which are predominantly GABAergic and contralateral. However, for the subnu-cleus d of the caudomedial accessory olive (cdMAO), a crucial region for oculomotor and upper body movements, the source of GABAergic input has yet to be identified. Here, we demonstrate the ex-istence of a disynaptic inhibitory projection from the medial CN (MCN) to the cdMAO via the superior colliculus (SC) by exploiting retrograde, anterograde, and transsynaptic viral tracing at the light microscopic level as well as anterograde classical and viral tracing combined with immunocytochem-istry at the electron microscopic level. Retrograde tracing in Gad2-Cre mice reveals that the cdMAO receives GABAergic input from the contralateral SC. Anterograde transsynaptic tracing uncovered that the SC neurons receiving input from the contralateral MCN provide predominantly inhibitory projections to contralateral cdMAO, ipsilateral to the MCN. Following ultrastructural analysis of the monosynaptic projection about half of the SC terminals within the contralateral cdMAO are GABAergic. The disynaptic GABAergic projection from the MCN to the ipsilateral cdMAO mirrors that of the monosynaptic excitatory projection from the MCN to the contralateral cdMAO. Thus, while completing the map of inhibitory inputs to the olivary subnuclei, we established that the MCN inhibits the cdMAO via the contralateral SC, highlighting a potential push–pull mechanism in directional gaze control that appears unique in terms of laterality and polarity among olivocere-bellar modules.

Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a “Money Follows Cooperation agreement” between the 2 nations. The inaugural Norway–UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging., Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a "Money Follows Cooperation agreement" between the 2 nations. The inaugural Norway-UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging.

Functional ultrasound (fUS) using a 1-D-array transducer normally is insufficient to capture volumetric functional activity due to being restricted to imaging a single brain slice at a time. Typically, for volumetric fUS, functional recordings are repeated many times as the transducer is moved to a new location after each recording, resulting in a nonunique average mapping of the brain response and long scan times. Our objective was to perform volumetric 3-D fUS in an efficient and cost-effective manner. This was achieved by mounting a 1-D-array transducer to a high-precision motorized linear stage and continuously translating over the mouse brain in a sweeping manner. We show how the speed at which the 1-D-array is translated over the brain affects the sampling of the hemodynamic response (HR) during visual stimulation as well as the quality of the resulting power Doppler image (PDI). Functional activation maps were compared between stationary recordings, where only one functional slice is obtained for every recording, and our swept-3-D method, where volumetric fUS was achieved in a single functional recording. The results show that the activation maps obtained with our method closely resemble those obtained during a stationary recording for that same location, while our method is not restricted to functional imaging of a single slice. Lastly, a mouse brain subvolume of 6 mm is scanned at a volume rate of 1.5 s per volume, with a functional PDI reconstructed every 200\mu \text{m} , highlighting swept-3-D's potential for volumetric fUS. Our method provides an affordable alternative to volumetric fUS using 2-D-matrix transducers, with a high SNR due to using a fully sampled 1-D-array transducer, and without the need to repeat functional measurements for every 2-D slice, as is most often the case when using a 1-D-array. This places our swept-3-D method as a potentially valuable addition to conventional 2-D fUS, especially when investigating whole-brain functional c, Signal Processing Systems

Volumetric 3-D Doppler ultrasound imaging can be used to investigate large scale blood dynamics outside of the limited view that conventional 2-D power Doppler images (PDIs) provide. To create 3-D PDIs, 2-D-matrix array transducers can be used to insonify a large volume for every transmission; however, these matrices suffer from low sensitivity, high complexity, and high cost. More typically, a 1-D-Array transducer is used to scan a series of stationary 2-D PDIs, after which a 3-D volume is created by concatenating the 2-D PDIs in postprocessing, which results in long scan times due to repeated measurements. Our objective was to achieve volumetric 3-D Doppler ultrasound imaging with a high Doppler sensitivity, similar to that of a typical stationary recording using a 1-D-Array transducer, while being more affordable than using 2-D-matrix arrays. We achieved this by mounting a 1-D-Array transducer to a high-precision motorized linear stage and continuously translating over the mouse brain in a sweeping manner. For Part I of this article, we focused on creating the best vascular images by investigating how to best combine filtered beamformed ultrasound frames, which were not acquired at the same spatial locations, into PDIs. Part II focuses on the implications of sampling transient brain hemodynamics through functional ultrasound (fUS) while continuously translating over the mouse brain. In Part I, we show how the speed at which we sweep our 1-D-Array transducer affects the Doppler spectrum in a flow phantom. In vivo recordings were performed on the mouse brain while varying the sweeping speed, showing how higher sweeping speeds negatively affect the PDI quality. A weighting vector is found to combine frames while continuously moving over the mouse brain, allowing us to create swept PDIs of similar sensitivity when compared with those obtained using a stationary 1-D-Array while allowing a significantly higher 3-D Doppler volume rate and maintaining the benefits of, Signal Processing Systems

In Nyxnob mice, a model for congenital nystagmus associated with congenital stationary night blindness (CSNB), synchronous oscillating retinal ganglion cells (RGCs) lead to oscillatory eye movements, i.e. nystagmus. Given the specific expression of mGluR6 and Cav1.4 in the photoreceptor to bipolar cell synapses, as well as their clinical association with CSNB, we hypothesize that Grm6nob3 and Cav1.4-KO mutants show, like the Nyxnob mouse, oscillations in both their RGC activity and eye movements. Using multi-electrode array recordings of RGCs and measurements of the eye movements, we demonstrate that Grm6nob3 and Cav1.4-KO mice also show oscillations of their RGCs as well as a nystagmus. Interestingly, the preferred frequencies of RGC activity as well as the eye movement oscillations of the Grm6nob3, Cav1.4-KO and Nyxnob mice differ among mutants, but the neuronal activity and eye movement behaviour within a strain remain aligned in the same frequency domain. Model simulations indicate that mutations affecting the photoreceptor–bipolar cell synapse can form a common cause of the nystagmus of CSNB by driving oscillations in RGCs via AII amacrine cells. (Figure presented.). Key points: In Nyxnob mice, a model for congenital nystagmus associated with congenital stationary night blindness (CSNB), their oscillatory eye movements (i.e. nystagmus) are caused by synchronous oscillating retinal ganglion cells. Here we show that the same mechanism applies for two other CSNB mouse models – Grm6nob3 and Cav1.4-KO mice. We propose that the retinal ganglion cell oscillations originate in the AII amacrine cells. Model simulations show that by only changing the input to ON-bipolar cells, all phenotypical differences between the various genetic mouse models can be reproduced.

Recently, a Y727C variant in the dual-specific 3',5'-cyclic nucleotide phosphodiesterase 11A (PDE11A-Y727C) was linked to increased sleep quality and reduced myopia risk in humans. Given the well-established role that the PDE11 substrates cAMP and cGMP play in eye physiology and sleep, we determined if (1) PDE11A protein is expressed in the retina or other eye segments in mice, (2) PDE11A-Y7272C affects catalytic activity and/or subcellular compartmentalization more so than the nearby suicide-associated PDE11A-M878V variant, and (3) Pde11a deletion alters eye growth or sleep quality in male and female mice. Western blots show distinct protein expression of PDE11A4, but not PDE11A1-3, in eyes of Pde11a WT, but not KO mice, that vary by eye segment and age. In HT22 and COS-1 cells, PDE11A4-Y727C reduces PDE11A4 catalytic activity far more than PDE11A4-M878V, with both variants reducing PDE11A4-cAMP more so than PDE11A4-cGMP activity. Despite this, Pde11a deletion does not alter age-related changes in retinal or lens thickness or axial length, nor vitreous or anterior chamber depth. Further, Pde11a deletion only minimally changes refractive error and sleep quality. That said, both variants also dramatically alter the subcellular compartmentalization of human and mouse PDE11A4, an effect occurring independently of dephosphorylating PDE11A4-S117/S124 or phosphorylating PDE11A4-S162. Rather, re-compartmentalization of PDE11A4-Y727C is due to the loss of the tyrosine changing how PDE11A4 is packaged/repackaged via the trans-Golgi network. Therefore, the protective impact of the Y727C variant may reflect a gain-of-function (e.g., PDE11A4 displacing another PDE) that warrants further investigation in the context of reversing/preventing sleep disturbances or myopia.

Recently, a Y727C variant in the dual-specific 3′,5′-cyclic nucleotide phosphodiesterase 11A (PDE11A-Y727C) was linked to increased sleep quality and reduced myopia risk in humans. Given the well-established role that the PDE11 substrates cAMP and cGMP play in eye physiology and sleep, we determined if (1) PDE11A protein is expressed in the retina or other eye segments in mice, (2) PDE11A-Y7272C affects catalytic activity and/or subcellular compartmentalization more so than the nearby suicide-associated PDE11A-M878V variant, and (3) Pde11a deletion alters eye growth or sleep quality in male and female mice. Western blots show distinct protein expression of PDE11A4, but not PDE11A1-3, in eyes of Pde11a WT, but not KO mice, that vary by eye segment and age. In HT22 and COS-1 cells, PDE11A4-Y727C reduces PDE11A4 catalytic activity far more than PDE11A4-M878V, with both variants reducing PDE11A4-cAMP more so than PDE11A4-cGMP activity. Despite this, Pde11a deletion does not alter age-related changes in retinal or lens thickness or axial length, nor vitreous or anterior chamber depth. Further, Pde11a deletion only minimally changes refractive error and sleep quality. That said, both variants also dramatically alter the subcellular compartmentalization of human and mouse PDE11A4, an effect occurring independently of dephosphorylating PDE11A4-S117/S124 or phosphorylating PDE11A4-S162. Rather, re-compartmentalization of PDE11A4-Y727C is due to the loss of the tyrosine changing how PDE11A4 is packaged/repackaged via the trans-Golgi network. Therefore, the protective impact of the Y727C variant may reflect a gain-of-function (e.g., PDE11A4 displacing another PDE) that warrants further investigation in the context of reversing/preventing sleep disturbances or myopia.

Volumetric 3-D Doppler ultrasound imaging can be used to investigate large scale blood dynamics outside of the limited view that conventional 2-D power Doppler images (PDIs) provide. To create 3-D PDIs, 2-D-matrix array transducers can be used to insonify a large volume for every transmission; however, these matrices suffer from low sensitivity, high complexity, and high cost. More typically, a 1-D-Array transducer is used to scan a series of stationary 2-D PDIs, after which a 3-D volume is created by concatenating the 2-D PDIs in postprocessing, which results in long scan times due to repeated measurements. Our objective was to achieve volumetric 3-D Doppler ultrasound imaging with a high Doppler sensitivity, similar to that of a typical stationary recording using a 1-D-Array transducer, while being more affordable than using 2-D-matrix arrays. We achieved this by mounting a 1-D-Array transducer to a high-precision motorized linear stage and continuously translating over the mouse brain in a sweeping manner. For Part I of this article, we focused on creating the best vascular images by investigating how to best combine filtered beamformed ultrasound frames, which were not acquired at the same spatial locations, into PDIs. Part II focuses on the implications of sampling transient brain hemodynamics through functional ultrasound (fUS) while continuously translating over the mouse brain. In Part I, we show how the speed at which we sweep our 1-D-Array transducer affects the Doppler spectrum in a flow phantom. In vivo recordings were performed on the mouse brain while varying the sweeping speed, showing how higher sweeping speeds negatively affect the PDI quality. A weighting vector is found to combine frames while continuously moving over the mouse brain, allowing us to create swept PDIs of similar sensitivity when compared with those obtained using a stationary 1-D-Array while allowing a significantly higher 3-D Doppler volume rate and maintaining the benefits of

Functional ultrasound (fUS) using a 1-D-array transducer normally is insufficient to capture volumetric functional activity due to being restricted to imaging a single brain slice at a time. Typically, for volumetric fUS, functional recordings are repeated many times as the transducer is moved to a new location after each recording, resulting in a nonunique average mapping of the brain response and long scan times. Our objective was to perform volumetric 3-D fUS in an efficient and cost-effective manner. This was achieved by mounting a 1-D-array transducer to a high-precision motorized linear stage and continuously translating over the mouse brain in a sweeping manner. We show how the speed at which the 1-D-array is translated over the brain affects the sampling of the hemodynamic response (HR) during visual stimulation as well as the quality of the resulting power Doppler image (PDI). Functional activation maps were compared between stationary recordings, where only one functional slice is obtained for every recording, and our swept-3-D method, where volumetric fUS was achieved in a single functional recording. The results show that the activation maps obtained with our method closely resemble those obtained during a stationary recording for that same location, while our method is not restricted to functional imaging of a single slice. Lastly, a mouse brain subvolume of 6 mm is scanned at a volume rate of 1.5 s per volume, with a functional PDI reconstructed every 200\mu \text{m} , highlighting swept-3-D's potential for volumetric fUS. Our method provides an affordable alternative to volumetric fUS using 2-D-matrix transducers, with a high SNR due to using a fully sampled 1-D-array transducer, and without the need to repeat functional measurements for every 2-D slice, as is most often the case when using a 1-D-array. This places our swept-3-D method as a potentially valuable addition to conventional 2-D fUS, especially when investigating whole-brain functional c

Local feedforward and recurrent connectivity are rife in the frontal areas of the cerebral cortex, which gives rise to rich heterogeneous dynamics observed in such areas. Recently, similar local connectivity motifs have been discovered among Purkinje and molecular layer interneurons of the cerebellar cortex, however, task-related activity in these neurons has often been associated with relatively simple facilitation and suppression dynamics. Here, we show that the rodent cerebellar cortex supports heterogeneity in task-related neuronal activity at a scale similar to the cerebral cortex. We provide a computational model that inculcates recent anatomical insights into local microcircuit motifs to show the putative basis for such heterogeneity. We also use cell-type specific chronic viral lesions to establish the involvement of cerebellar lobules in associative learning behaviors. Functional heterogeneity in neuronal profiles may not merely be the remit of the associative cerebral cortex, similar principles may be at play in subcortical areas, even those with seemingly crystalline and homogenous cytoarchitectures like the cerebellum.

In all species, unipolar brush cells (UBCs) are most abundant in the vestibulocerebellum. Yet, the role of these excitatory interneurons in the cerebellar input stage during visual and vestibular stimulation remains elusive. Here, we review the main morphological and electrophysiological properties of UBCs in the vestibulocerebellum, and we highlight their potential role in the flocculus during the coordination of compensatory eye movements. We advocate that they are well designed to contribute to expansion coding in the temporal domain, while preserving the identity of sensory and/or oculomotor encoding, so as to facilitate the optimal acquisition of all possible components of movement kinematics.

Associative learning during delay eyeblink conditioning (EBC) depends on an intact cerebellum. However, the relative contribution of changes in the cerebellar nuclei to learning remains a subject of ongoing debate. In particular, little is known about the changes in synaptic inputs to cerebellar nuclei neurons that take place during EBC and how they shape the membrane potential of these neurons. Here, we probed the ability of these inputs to support associative learning in mice, and investigated structural and cell-physiological changes within the cerebellar nuclei during learning. We find that optogenetic stimulation of mossy fiber afferents to the anterior interposed nucleus (AIP) can substitute for a conditioned stimulus and is sufficient to elicit conditioned responses (CRs) that are adaptively well-timed. Further, EBC induces structural changes in mossy fiber and inhibitory inputs, but not in climbing fiber inputs, and it leads to changes in subthreshold processing of AIP neurons that correlate with conditioned eyelid movements. The changes in synaptic and spiking activity that precede the CRs allow for a decoder to distinguish trials with a CR. Our data reveal how structural and physiological modifications of synaptic inputs to cerebellar nuclei neurons can facilitate learning.

Local feedforward and recurrent connectivity are rife in the frontal areas of the cerebral cortex, which gives rise to rich heterogeneous dynamics observed in such areas. Recently, similar local connectivity motifs have been discovered among Purkinje and molecular layer interneurons of the cerebellar cortex, however, task-related activity in these neurons has often been associated with relatively simple facilitation and suppression dynamics. Here, we show that the rodent cerebellar cortex supports heterogeneity in task-related neuronal activity at a scale similar to the cerebral cortex. We provide a computational model that inculcates recent anatomical insights into local microcircuit motifs to show the putative basis for such heterogeneity. We also use cell-type specific chronic viral lesions to establish the involvement of cerebellar lobules in associative learning behaviors. Functional heterogeneity in neuronal profiles may not merely be the remit of the associative cerebral cortex, similar principles may be at play in subcortical areas, even those with seemingly crystalline and homogenous cytoarchitectures like the cerebellum.

The inferior olive provides the climbing fibers to Purkinje cells in the cerebellar cortex, where they elicit all-or-none complex spikes and control major forms of plasticity. Given their important role in both short-term and long-term coordination of cerebellum-dependent behaviors, it is paramount to understand the factors that determine the output of olivary neurons. Here, we use mouse models to investigate how the inhibitory and excitatory inputs to the olivary neurons interact with each other, generating spiking patterns of olivary neurons that align with their intrinsic oscillations. Using dual color optogenetic stimulation and whole-cell recordings, we demonstrate how intervals between the inhibitory input from the cerebellar nuclei and excitatory input from the mesodiencephalic junction affect phase and gain of the olivary output at both the sub- and suprathreshold level. When the excitatory input is activated shortly (~50 ms) after the inhibitory input, the phase of the intrinsic oscillations becomes remarkably unstable and the excitatory input can hardly generate any olivary spike. Instead, when the excitatory input is activated one cycle (~150 ms) after the inhibitory input, the excitatory input can optimally drive olivary spiking, riding on top of the first cycle of the subthreshold oscillations that have been powerfully reset by the preceding inhibitory input. Simulations of a large-scale network model of the inferior olive highlight to what extent the synaptic interactions penetrate in the neuropil, generating quasi-oscillatory spiking patterns in large parts of the olivary subnuclei, the size of which also depends on the relative timing of the inhibitory and excitatory inputs.

The classification of neuronal subpopulations has significantly advanced, yet its relevance for behavior remains unclear. The highly organized flocculus of the cerebellum, known to fine-tune multi-axial eye movements, is an ideal substrate for the study of potential functions of neuronal subpopulations. Here, we demonstrate that its recently identified subpopulations of 9+ and 9- Purkinje cells exhibit an intermediate Aldolase C expression and electrophysiological profile, providing evidence for a graded continuum of intrinsic properties among PC subpopulations. By identifying and utilizing two Cre-lines that genetically target these floccular domains, we show with high spatial specificity that these subpopulations of Purkinje cells participate in separate micromodules with topographically organized connections. Finally, optogenetic excitation of the respective subpopulations results in movements around the same axis in space, yet with distinct kinematic profiles. These results indicate that Purkinje cell subpopulations integrate in discrete circuits and mediate particular parameters of single movements.

Cerebellar output neurons integrate strong inhibitory input and weaker excitatory input during the control of spontaneous and learned movements. A new study sheds light on how those inputs are integrated during associative swimming in zebrafish larvae.

The inferior olive provides the climbing fibers to Purkinje cells in the cerebellar cortex, where they elicit all-or-none complex spikes and control major forms of plasticity. Given their important role in both short-term and long-term coordination of cerebellum-dependent behaviors, it is paramount to understand the factors that determine the output of olivary neurons. Here, we use mouse models to investigate how the inhibitory and excitatory inputs to the olivary neurons interact with each other, generating spiking patterns of olivary neurons that align with their intrinsic oscillations. Using dual color optogenetic stimulation and whole-cell recordings, we demonstrate how intervals between the inhibitory input from the cerebellar nuclei and excitatory input from the mesodiencephalic junction affect phase and gain of the olivary output at both the sub- and suprathreshold level. When the excitatory input is activated shortly (~50 ms) after the inhibitory input, the phase of the intrinsic oscillations becomes remarkably unstable and the excitatory input can hardly generate any olivary spike. Instead, when the excitatory input is activated one cycle (~150 ms) after the inhibitory input, the excitatory input can optimally drive olivary spiking, riding on top of the first cycle of the subthreshold oscillations that have been powerfully reset by the preceding inhibitory input. Simulations of a large-scale network model of the inferior olive highlight to what extent the synaptic interactions penetrate in the neuropil, generating quasi-oscillatory spiking patterns in large parts of the olivary subnuclei, the size of which also depends on the relative timing of the inhibitory and excitatory inputs.

Volumetric 3D Doppler ultrasound imaging can be used to investigate large scale blood dynamics outside of the limited view that conventional 2D power Doppler images (PDIs) provide. To create 3D PDIs, 2D-matrix array transducers can be used to insonify a large volume for every transmission, however these matrices suffer from low sensitivity, high complexity, and high cost. More typically, a 1D-array transducer is used to scan a series of stationary 2D PDIs, after which a 3D volume is created by concatenating the 2D PDIs in post-processing, which results in long scan times due to the repeated measurements. Our objective was to achieve volumetric 3D Doppler ultrasound imaging with a high Doppler sensitivity, similar to that of a typical stationary recording using a 1D-array transducer, while being more affordable than using 2D-matrix arrays. We achieved this by mounting a 1D-array transducer to a high precision motorized linear stage and continuously translating over the mouse brain in a sweeping manner. For Part I of this paper we focused on creating the best vascular images by investigating how to best combine filtered beamformed ultrasound frames, that were not acquired at the same spatial locations, into PDIs. Part II focuses on the implications of sampling transient brain hemodynamics through functional ultrasound while continuously translating over the mouse brain. In Part I we show how the speed at which we sweep our 1D-array transducer effects the Doppler spectrum in a flow phantom. In-vivo recordings were performed on the mouse brain while varying the sweeping speed, showing how higher sweeping speeds negatively effect the PDI quality. A weighting vector is found to combine frames while continuously moving over the mouse brain, allowing us to create swept PDIs of similar sensitivity when compared to those obtained using a stationary 1D-array while allowing a significantly higher 3D Doppler volume rate and maintaining the benefits of having a low computation

In Nyxnob mice, a model for congenital nystagmus associated with congenital stationary night blindness (CSNB), synchronous oscillating retinal ganglion cells (RGCs) lead to oscillatory eye movements, i.e. nystagmus. Given the specific expression of mGluR6 and Cav 1.4 in the photoreceptor to bipolar cell synapses, as well as their clinical association with CSNB, we hypothesize that Grm6nob3 and Cav 1.4-KO mutants show, like the Nyxnob mouse, oscillations in both their RGC activity and eye movements. Using multi-electrode array recordings of RGCs and measurements of the eye movements, we demonstrate that Grm6nob3 and Cav 1.4-KO mice also show oscillations of their RGCs as well as a nystagmus. Interestingly, the preferred frequencies of RGC activity as well as the eye movement oscillations of the Grm6nob3 , Cav 1.4-KO and Nyxnob mice differ among mutants, but the neuronal activity and eye movement behaviour within a strain remain aligned in the same frequency domain. Model simulations indicate that mutations affecting the photoreceptor-bipolar cell synapse can form a common cause of the nystagmus of CSNB by driving oscillations in RGCs via AII amacrine cells. KEY POINTS: In Nyxnob mice, a model for congenital nystagmus associated with congenital stationary night blindness (CSNB), their oscillatory eye movements (i.e. nystagmus) are caused by synchronous oscillating retinal ganglion cells. Here we show that the same mechanism applies for two other CSNB mouse models - Grm6nob3 and Cav 1.4-KO mice. We propose that the retinal ganglion cell oscillations originate in the AII amacrine cells. Model simulations show that by only changing the input to ON-bipolar cells, all phenotypical differences between the various genetic mouse models can be reproduced.

The classification of neuronal subpopulations has significantly advanced, yet its relevance for behavior remains unclear. The highly organized flocculus of the cerebellum, known to fine-tune multi-axial eye movements, is an ideal substrate for the study of potential functions of neuronal subpopulations. Here, we demonstrate that its recently identified subpopulations of 9+ and 9- Purkinje cells exhibit an intermediate Aldolase C expression and electrophysiological profile, providing evidence for a graded continuum of intrinsic properties among PC subpopulations. By identifying and utilizing two Cre-lines that genetically target these floccular domains, we show with high spatial specificity that these subpopulations of Purkinje cells participate in separate micromodules with topographically organized connections. Finally, optogenetic excitation of the respective subpopulations results in movements around the same axis in space, yet with distinct kinematic profiles. These results indicate that Purkinje cell subpopulations integrate in discrete circuits and mediate particular parameters of single movements.

Surgical resection of spinal cord hemangioblastomas remains a challenging endeavor: the neurosurgeon's aim to reach total tumor resections directly endangers their aim to minimize post-operative neurological deficits. The currently available tools to guide the neurosurgeon's intra-operative decision-making consist mostly of pre-operative imaging techniques such as MRI or MRA, which cannot cater to intra-operative changes in field of view. For a while now, spinal cord surgeons have adopted ultrasound and its submodalities such as Doppler and CEUS as intra-operative techniques, given their many benefits such as real-time feedback, mobility and ease of use. However, for highly vascularized lesions such as hemangioblastomas, which contain up to capillary-level microvasculature, having access to higher-resolution intra-operative vascular imaging could potentially be highly beneficial. µDoppler-imaging is a new imaging modality especially fit for high-resolution hemodynamic imaging. Over the last decade, µDoppler-imaging has emerged as a high-resolution, contrast-free sonography-based technique which relies on High-Frame-Rate (HFR)-ultrasound and subsequent Doppler processing. In contrast to conventional millimeter-scale (Doppler) ultrasound, the µDoppler technique has a higher sensitivity to detect slow flow in the entire field-of-view which allows for unprecedented visualization of blood flow down to sub-millimeter resolution. In contrast to CEUS, µDoppler is able to image high-resolution details continuously, without being contrast bolus-dependent. Previously, our team has demonstrated the use of this technique in the context of functional brain mapping during awake brain tumor resections and surgical resections of cerebral arteriovenous malformations (AVM). However, the application of µDoppler-imaging in the context of the spinal cord has remained restricted to a handful of mostly pre-clinical animal studies. Here we describe the first application of µDoppler-imagi

Surgical resection of spinal cord hemangioblastomas remains a challenging endeavor: the neurosurgeon’s aim to reach total tumor resections directly endangers their aim to minimize post-operative neurological deficits. The currently available tools to guide the neurosurgeon’s intra-operative decision-making consist mostly of pre-operative imaging techniques such as MRI or MRA, which cannot cater to intra-operative changes in field of view. For a while now, spinal cord surgeons have adopted ultrasound and its submodalities such as Doppler and CEUS as intra-operative techniques, given their many benefits such as real-time feedback, mobility and ease of use. However, for highly vascularized lesions such as hemangioblastomas, which contain up to capillary-level microvasculature, having access to higher-resolution intra-operative vascular imaging could potentially be highly beneficial. µDoppler-imaging is a new imaging modality especially fit for high-resolution hemodynamic imaging. Over the last decade, µDoppler-imaging has emerged as a high-resolution, contrast-free sonography-based technique which relies on High-Frame-Rate (HFR)-ultrasound and subsequent Doppler processing. In contrast to conventional millimeter-scale (Doppler) ultrasound, the µDoppler technique has a higher sensitivity to detect slow flow in the entire field-of-view which allows for unprecedented visualization of blood flow down to sub-millimeter resolution. In contrast to CEUS, µDoppler is able to image high-resolution details continuously, without being contrast bolus-dependent. Previously, our team has demonstrated the use of this technique in the context of functional brain mapping during awake brain tumor resections and surgical resections of cerebral arteriovenous malformations (AVM). However, the application of µDoppler-imaging in the context of the spinal cord has remained restricted to a handful of mostly pre-clinical animal studies. Here we describe the first application of µDoppler-imagi

Respiration is a brain function on which our lives essentially depend. Control of respiration ensures that the frequency and depth of breathing adapt continuously to metabolic needs. In addition, the respiratory control network of the brain has to organize muscular synergies that integrate ventilation with posture and body movement. Finally, respiration is coupled to cardiovascular function and emotion. Here, we argue that the brain can handle this all by integrating a brainstem central pattern generator circuit in a larger network that also comprises the cerebellum. Although currently not generally recognized as a respiratory control center, the cerebellum is well known for its coordinating and modulating role in motor behavior, as well as for its role in the autonomic nervous system. In this review, we discuss the role of brain regions involved in the control of respiration, and their anatomical and functional interactions. We discuss how sensory feedback can result in adaptation of respiration, and how these mechanisms can be compromised by various neurological and psychological disorders. Finally, we demonstrate how the respiratory pattern generators are part of a larger and integrated network of respiratory brain regions.

When the brain is exposed, such as after a craniotomy in neurosurgical procedures, we are provided with the unique opportunity for real-time imaging of brain functionality. Real-time functional maps of the exposed brain are vital to ensuring safe and effective navigation during these neurosurgical procedures. However, current neurosurgical practice has yet to fully harness this potential as it pre-dominantly relies on inherently limited techniques such as electrical stimulation to provide functional feedback to guide surgical decision-making. A wealth of especially experimental imaging techniques show unique potential to improve intra-operative decision-making and neurosurgical safety, and as an added bonus, improve our fundamental neuroscientific understanding of human brain function. In this review we compare and contrast close to twenty candidate imaging techniques based on their underlying biological substrate, technical characteristics and ability to meet clinical constraints such as compatibility with surgical workflow. Our review gives insight into the interplay between technical parameters such sampling method, data rate and a technique’s real-time imaging potential in the operating room. By the end of the review, the reader will understand why new, real-time volumetric imaging techniques such as functional Ultrasound (fUS) and functional Photoacoustic Computed Tomography (fPACT) hold great clinical potential for procedures in especially highly eloquent areas, despite the higher data rates involved. Finally, we will highlight the neuroscientific perspective on the exposed brain. While different neurosurgical procedures ask for different functional maps to navigate surgical territories, neuroscience potentially benefits from all these maps. In the surgical context we can uniquely combine healthy volunteer studies, lesion studies and even reversible lesion studies in in the same individual. Ultimately, individual cases will build a greater understanding of

When the brain is exposed, such as after a craniotomy in neurosurgical procedures, we are provided with the unique opportunity for real-time imaging of brain functionality. Real-time functional maps of the exposed brain are vital to ensuring safe and effective navigation during these neurosurgical procedures. However, current neurosurgical practice has yet to fully harness this potential as it pre-dominantly relies on inherently limited techniques such as electrical stimulation to provide functional feedback to guide surgical decision-making. A wealth of especially experimental imaging techniques show unique potential to improve intra-operative decision-making and neurosurgical safety, and as an added bonus, improve our fundamental neuroscientific understanding of human brain function. In this review we compare and contrast close to twenty candidate imaging techniques based on their underlying biological substrate, technical characteristics and ability to meet clinical constraints such as compatibility with surgical workflow. Our review gives insight into the interplay between technical parameters such sampling method, data rate and a technique's real-time imaging potential in the operating room. By the end of the review, the reader will understand why new, real-time volumetric imaging techniques such as functional Ultrasound (fUS) and functional Photoacoustic Computed Tomography (fPACT) hold great clinical potential for procedures in especially highly eloquent areas, despite the higher data rates involved. Finally, we will highlight the neuroscientific perspective on the exposed brain. While different neurosurgical procedures ask for different functional maps to navigate surgical territories, neuroscience potentially benefits from all these maps. In the surgical context we can uniquely combine healthy volunteer studies, lesion studies and even reversible lesion studies in in the same individual. Ultimately, individual cases will build a greater understanding of

Respiration is a brain function on which our lives essentially depend. Control of respiration ensures that the frequency and depth of breathing adapt continuously to metabolic needs. In addition, the respiratory control network of the brain has to organize muscular synergies that integrate ventilation with posture and body movement. Finally, respiration is coupled to cardiovascular function and emotion. Here, we argue that the brain can handle this all by integrating a brainstem central pattern generator circuit in a larger network that also comprises the cerebellum. Although currently not generally recognized as a respiratory control center, the cerebellum is well known for its coordinating and modulating role in motor behavior, as well as for its role in the autonomic nervous system. In this review, we discuss the role of brain regions involved in the control of respiration, and their anatomical and functional interactions. We discuss how sensory feedback can result in adaptation of respiration, and how these mechanisms can be compromised by various neurological and psychological disorders. Finally, we demonstrate how the respiratory pattern generators are part of a larger and integrated network of respiratory brain regions.

Volitional suppression of responses to distracting external stimuli enables us to achieve our goals. This volitional inhibition of a specific behavior is supposed to be mainly mediated by the cerebral cortex. However, recent evidence supports the involvement of the cerebellum in this process. It is currently not known whether different parts of the cerebellar cortex play differential or synergistic roles in the planning and execution of this behavior. Here, we measured Purkinje cell (PC) responses in the medial and lateral cerebellum in two rhesus macaques during pro- and anti-saccade tasks. During an antisaccade trial, non-human primates (NHPs) were instructed to make a saccadic eye movement away from a target, rather than toward it, as in prosaccade trials. Our data show that the cerebellum plays an important role not only during the execution of the saccades but also during the volitional inhibition of eye movements toward the target. Simple spike (SS) modulation during the instruction and execution periods of pro- and anti-saccades was prominent in PCs of both the medial and lateral cerebellum. However, only the SS activity in the lateral cerebellar cortex contained information about stimulus identity and showed a strong reciprocal interaction with complex spikes (CSs). Moreover, the SS activity of different PC groups modulated bidirectionally in both of regions, but the PCs that showed facilitating and suppressive activity were predominantly associated with instruction and execution, respectively. These findings show that different cerebellar regions and PC groups contribute to goal-directed behavior and volitional inhibition, but with different propensities, highlighting the rich repertoire of the cerebellar control in executive functions.