BACKGROUND: Pain thresholds and primary headaches, including cluster headache attacks, have circadian rhythmicity. Thus, they might share a common neuronal mechanism.
OBJECTIVE: This study aimed to elucidate how the modulation of nociceptive input in the brainstem changes from noon to midnight. Insights into the mechanism of these fluctuations could allow for new hypotheses about the pathophysiology of cluster headache.
METHODS: This repeated measure observational study was conducted at the University Hospital Zurich from December 2019 to November 2022. Healthy adults between 18 and 85 years of age were eligible. All participants were examined at noon and midnight. We tested the pain threshold on both sides of the foreheads with quantitative sensory testing, assessed tiredness levels, and obtained high-field (7 Tesla) and high-resolution functional magnetic resonance imaging (MRI) at each visit. Functional connectivity was assessed at the two visits by performing a region-of-interest analysis. We defined nuclei in the brainstem implicated in processing nociceptive input as well as the thalamus and suprachiasmatic nucleus as the region-of-interest.
RESULTS: Ten people were enrolled, and seven participants were included. First, we did not find statistically significant differences between noon and midnight of A-delta-mediated pain thresholds (median mechanical pain threshold at noon: left 9.2, right 9.2; at night: left 6.5, right 6.1). Second, after correction for a false discovery rate, we found changes in the mechanical pain sensitivity to have a statistically significant effect on changes in the functional connectivity between the left parabrachial nucleus and the suprachiasmatic nucleus (T = -40.79).
CONCLUSIONS: The MRI data analysis suggested that brain stem nuclei and the hypothalamus modulate A-delta-mediated pain perception; however, these changes in pain perception did not lead to statistically significantly differing pain thresholds between noon and midnight. Hence, our findings shed doubt on our hypothesis that the physiologic circadian rhythmicity of pain thresholds could drive the circadian rhythmicity of cluster headache attacks.

Anticipatory postural adjustments (APAs) give feedforward postural control of the trunk, but they are delayed with ageing, affecting balance and mobility in older individuals. The reticulospinal tract contributes to postural control of the trunk; however, the extent to which age-related changes affect the reticulospinal contributions to APAs of the trunk remains unknown in humans. Here, we tested the hypothesis that a startling acoustic sound, which activates the reticulospinal tract, improves delayed APAs in older individuals. Twenty-two old (75 ± 6 years) and 20 healthy young adults (21 ± 4 years) performed a self-initiated fast bilateral shoulder flexion or shoulder extension task in response to visual, visual and auditory (80 dB), or visual and startling (115 dB) cues. Electromyography (EMG) was recorded from bilateral anterior deltoid (AD) and erector spinae (ES) during shoulder flexion and from bilateral posterior deltoid (PD) and rectus abdominis (RA) during shoulder extension. EMG onset of all muscles shortened during the startling cue in both age groups, suggesting a non-specific modulation of the reticulospinal tract on prime movers (AD or PD) and non-prime movers (ES or RA). Interestingly, APAs of the ES were accelerated in older participants to a similar degree as in younger participants during the startling cue. Conversely, APAs of the RA were not influenced by the startling cue in older participants. Our results suggest differential effects of ageing on functional contributions of the reticulospinal tract to APAs between back extensors and abdominal muscles.

The auditory cortex is the source of descending connections providing contextual feedback for auditory signal processing at almost all levels of the lemniscal auditory pathway. Such feedback is essential for cognitive processing. It is likely that corticofugal pathways are degraded with aging, becoming important players in age-related hearing loss and, by extension, in cognitive decline. We are testing the hypothesis that surface, epidural stimulation of the auditory cortex during aging may regulate the activity of corticofugal pathways, resulting in modulation of central and peripheral traits of auditory aging. Increased auditory thresholds during ongoing age-related hearing loss in the rat are attenuated after two weeks of epidural stimulation with direct current applied to the surface of the auditory cortex for two weeks in alternate days (Fernández del Campo et al., 2024). Here we report that the same cortical electrical stimulation protocol induces structural and cytochemical changes in the aging cochlea and auditory brainstem, which may underlie recovery of age-degraded auditory sensitivity. Specifically, we found that in 18 month-old rats after two weeks of cortical electrical stimulation there is, relative to age-matched non-stimulated rats: a) a larger number of choline acetyltransferase immunoreactive neuronal cell body profiles in the ventral nucleus of the trapezoid body, originating the medial olivocochlear system.; b) a reduction of age-related dystrophic changes in the stria vascularis; c) diminished immunoreactivity for the pro-inflammatory cytokine TNFα in the stria vascularis and spiral ligament. d) diminished immunoreactivity for Iba1 and changes in the morphology of Iba1 immunoreactive cells in the lateral wall, suggesting reduced activation of macrophage/microglia; d) Increased immunoreactivity levels for calretinin in spiral ganglion neurons, suggesting excitability modulation by corticofugal stimulation. Altogether, these findings support that non-invasive neuromodulation of the auditory cortex during aging preserves the cochlear efferent system and ameliorates cochlear aging traits, including stria vascularis dystrophy, dysregulated inflammation and altered excitability in primary auditory neurons.

Estimating the state of tract-specific inputs to spinal motoneurons is critical to understanding movement deficits induced by neurological injury and potential pathways to recovery but remains challenging in humans. In this study, we explored the capability of trans-spinal magnetic stimulation (TSMS) to modulate distal reflex circuits in young adults. TSMS was applied over the thoracic spine to condition soleus H-reflexes involving sacral-level motoneurons. Three TSMS intensities below the motor threshold were applied at interstimulus intervals (ISIs) between 2 and 20 ms relative to peripheral nerve stimulation (PNS). Although low-intensity TSMS yielded no changes in H-reflexes across ISIs, the two higher stimulus intensities yielded two phases of H-reflex inhibition: a relatively long-lasting period at 2- to 9-ms ISIs, and a short phase at 11- to 12-ms ISIs. H-reflex inhibition at 2-ms ISI was uniquely dependent on TSMS intensity. To identify the candidate neural pathways contributing to H-reflex suppression, we constructed a tract-specific conduction time estimation model. Based upon our model, H-reflex inhibition at 11- to 12-ms ISIs is likely a manifestation of orthodromic transmission along the lateral reticulospinal tract. In contrast, the inhibition at 2-ms ISI likely reflects orthodromic transmission along sensory fibers with activation reaching the brain, before descending along motor tracts. Multiple pathways may contribute to H-reflex modulation between 4- and 9-ms ISIs, orthodromic transmission along sensorimotor tracts, and antidromic transmission of multiple motor tracts. Our findings suggest that noninvasive TSMS can influence motoneuron excitability at distal segments and that the contribution of specific tracts to motoneuron excitability may be distinguishable based on conduction velocities.NEW & NOTEWORTHY This study explored the capability of trans-spinal magnetic stimulation (TSMS) over the thoracic spine to modulate distal reflex circuits, H-reflexes involving sacral-level motoneurons, in young adults. TSMS induced two inhibition phases of H-reflex across interstimulus intervals (ISIs): a relatively long-lasting period at 2- to 9-ms ISIs, and a short phase at 11- to 12-ms ISIs. An estimated probability model constructed from tract-specific conduction velocities allowed the identification of potential spinal tracts contributing to the changes in motoneuron excitability.

The anterior lateral motor cortex (ALM) is critical to subsequent correct movements and plays a vital role in predicting specific future movements. Different descending pathways of the ALM are preferentially involved in different roles in movements. However, the circuit function mechanisms of these different pathways may be concealed in the anatomy circuit. Clarifying the anatomy inputs of these pathways should provide some helpful information for elucidating these function mechanisms. Here, we used a retrograde trans-synaptic rabies virus to systematically generate, analyze, and compare whole brain maps of inputs to the thalamus (TH)-, medulla oblongata (Med)-, superior colliculus (SC)-, and pontine nucleus (Pons)-projecting ALM neurons in C57BL/6J mice. Fifty-nine separate regions from nine major brain areas projecting to the descending pathways of the ALM were identified. Brain-wide quantitative analyses revealed identical whole brain input patterns between these descending pathways. Most inputs to the pathways originated from the ipsilateral side of the brain, with most innervations provided by the cortex and TH. The contralateral side of the brain also sent sparse projections, but these were rare, emanating only from the cortex and cerebellum. Nevertheless, the inputs received by TH-, Med-, SC-, and Pons-projecting ALM neurons had different weights, potentially laying an anatomical foundation for understanding the diverse functions of well-defined descending pathways of the ALM. Our findings provide anatomical information to help elucidate the precise connections and diverse functions of the ALM.NEW & NOTEWORTHY Distinct descending pathways of anterior lateral motor cortex (ALM) share common inputs. These inputs are with varied weights. Most inputs were from the ipsilateral side of brain. Preferential inputs were provided by cortex and thalamus (TH).

Corticofugal projections to evolutionarily ancient, subcortical structures are ubiquitous across mammalian sensory systems. These \'descending\' pathways enable the neocortex to control ascending sensory representations in a predictive or feedback manner, but the underlying cellular mechanisms are poorly understood. Here, we combine optogenetic approaches with in vivo and in vitro patch-clamp electrophysiology to study the projection from mouse auditory cortex to the inferior colliculus (IC), a major descending auditory pathway that controls IC neuron feature selectivity, plasticity, and auditory perceptual learning. Although individual auditory cortico-collicular synapses were generally weak, IC neurons often integrated inputs from multiple corticofugal axons that generated reliable, tonic depolarizations even during prolonged presynaptic activity. Latency measurements in vivo showed that descending signals reach the IC within 30 ms of sound onset, which in IC neurons corresponded to the peak of synaptic depolarizations evoked by short sounds. Activating ascending and descending pathways at latencies expected in vivo caused a NMDA receptor-dependent, supralinear excitatory postsynaptic potential summation, indicating that descending signals can nonlinearly amplify IC neurons\' moment-to-moment acoustic responses. Our results shed light upon the synaptic bases of descending sensory control and imply that heterosynaptic cooperativity contributes to the auditory cortico-collicular pathway\'s role in plasticity and perceptual learning.

To understand the neural basis of behavior, it is important to reveal how movements are planned, executed, and refined by networks of neurons distributed throughout the nervous system. Here, we report the neuroanatomical organization and behavioral roles of cerebellospinal (CeS) neurons. Using intersectional genetic techniques, we find that CeS neurons constitute a small minority of excitatory neurons in the fastigial and interpositus deep cerebellar nuclei, target pre-motor circuits in the ventral spinal cord and the brain, and control distinct aspects of movement. CeS neurons that project to the ipsilateral cervical cord are required for skilled forelimb performance, while CeS neurons that project to the contralateral cervical cord are involved in skilled locomotor learning. Together, this work establishes CeS neurons as a critical component of the neural circuitry for skilled movements and provides insights into the organizational logic of motor networks.

Environmental signals act as input and are processed across successive stages in the brain to generate a meaningful behavioral output. However, a ubiquitous observation is that descending feedback projections from more central to more peripheral brain areas vastly outnumber ascending feedforward projections. Such projections generally act to modify how sensory neurons respond to afferent signals. Recent studies in the electrosensory system of weakly electric fish have revealed novel functions for feedback pathways in that their transformation of the afferent input generates neural firing rate responses to sensory signals mediating perception and behavior. In this review, we focus on summarizing these novel and recently uncovered functions and put them into context by describing the more \"classical\" functions of feedback in the electrosensory system. We further highlight the parallels between the electrosensory system and other systems as well as outline interesting future directions.

The emergence of new and increasingly sophisticated behaviors after birth is accompanied by dramatic increase of newly established synaptic connections in the nervous system. Little is known, however, of how nascent connections are organized to support such new behaviors alongside existing ones. To understand this, in the larval zebrafish we examined the development of spinal pathways from hindbrain V2a neurons and the role of these pathways in the development of locomotion. We found that new projections are continually layered laterally to existing neuropil, and give rise to distinct pathways that function in parallel to existing pathways. Across these chronologically layered pathways, the connectivity patterns and biophysical properties vary systematically to support a behavioral repertoire with a wide range of kinematics and dynamics. Such layering of new parallel circuits equipped with systematically changing properties may be central to the postnatal diversification and increasing sophistication of an animal\'s behavioral repertoire.

Although movement is controlled by different descending pathways, it remains unknown whether the integration of visual feedback and motor learning differs for movements controlled by different descending pathways. Here, we compare motor control and learning of the ankle joint and tongue because they are primarily controlled by the corticospinal and corticobulbar pathways, respectively. Twelve young adults (19.63 ± 2.11 years, 6 females) practiced a tracking task (combination of 0.02, 0.37, 0.5, and 1 Hz) with ankle dorsiflexion and with tongue elevation for 100 trials. The participants practiced each effector (ankle and tongue) in different days and the order of the effector was counterbalanced. Following practice, participants performed the same tracking task with concurrent contractions of the tongue and ankle (dual tracking task; transfer) with three different visual feedback conditions (no visual feedback, visual feedback only for ankle, visual feedback only for tongue). We quantified the force accuracy (RMSE) from each effector during the practice and transfer periods. During practice, the force accuracy and performance improvement to the visuomotor task was greater for the ankle dorsiflexion than tongue elevation. During the transfer task, the ankle dorsiflexion was more accurate than tongue elevation, independent of whether visual feedback was given for the ankle or tongue. The greater performance improvement for the ankle dorsiflexion during practice was related to superior transfer performance. These findings suggest that the corticospinal pathway integrates visual feedback more efficiently than the corticobulbar pathway, which enhances performance and learning of visuomotor tasks.