Biology subjects

D'Ambrosio, S.

Publications and source records attributed to D'Ambrosio, S..

12 recordsLinked to original sources

bioRxiv2025

TMS-EEG reveals causal dynamics of the premotor cortex during musical improvisation

Musical improvisation illustrates the brains capacity for flexible, creative motor control, yet the causal mechanisms underlying this complex behaviour remain poorly understood. We employed transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) to probe state-dependent cortical dynamics in the left dorsal premotor cortex (PMd) of professional jazz pianists (n = 3) during improvisation, sight-reading, and rest. This proof-of-concept study demonstrates the feasibility of combining perturbational neuroscience with ecologically valid musical performance. Multiple convergent analyses revealed distinct cortical signatures during improvisation: reduced local mean field power, decreased phase-locking of evoked responses, and preserved but gain-modulated early components as revealed by Correlated Components Analysis. These findings suggest that improvisation is characterized by attenuated PMd excitability and more variable response timings, while preserving the fundamental architecture of cortical responses. This perturbational signature supports a neural efficiency model of expertise whereby expert musicians achieve creative flexibility through training-induced streamlined, optimized cortical processing. Our results establish TMS-EEG as a powerful approach for investigating the causal dynamics of creative cognition and demonstrate how the brain reconfigures its response properties to support internally driven motor performance.

neuroscience↗

bioRxiv2025

The specific spatiotemporal evolution of TMS-evoked potentials reflects the engagement of cortical circuits

Transcranial Magnetic Stimulation (TMS) evokes electroencephalographic (EEG) responses that can persist for hundreds of milliseconds. While the first 80 ms after the pulse are widely accepted to reflect genuine cortical responses to TMS, later components have mainly been attributed to the effects of sensory co-stimulations. Here we reappraise this view by investigating the target-specificity of the spatiotemporal evolution of TMS-evoked potentials (TEPs). To this end, we compared TEPs elicited by targeting the premotor and primary motor cortices in 16 healthy subjects, under conditions designed to optimize TMS effectiveness on the cortex while minimizing peripheral confounds. As a counterfactual, we conducted the same comparison on the EEG responses evoked by realistic sham TMS and high-intensity somatosensory scalp stimulation. We found that EEG responses to motor and premotor TMS can exhibit distinct spatiotemporal evolutions, lasting up to 300 ms, both at the group and single-subject levels. These differences were absent or marginally detectable in both realistic sham TMS and high-intensity somatosensory scalp stimulation. Our findings suggest that, when effectiveness is optimized and peripheral confounds are controlled, TMS elicits specific long-lasting genuine EEG responses that reflect the initial engagement of specific cortical targets. These results challenge previous assumptions and highlight how TMS-EEG can be reliably used to assess large-scale properties within corticothalamic networks.

physiology↗

bioRxiv2023

Impact and role of hypothalamic corticotropin releasing hormone neurons in withdrawal from chronic alcohol consumption in female and male mice.

Worldwide, alcohol use and abuse are a leading risk of mortality, causing 5.3% of all deaths (W.H.O., 2022). The endocrine stress system, initiated by the peripheral release of corticotropin releasing hormone (CRH) from primarily glutamatergic neurons in the paraventricular nucleus of the hypothalamus (PVN), is profoundly linked with alcohol use, abuse, and relapse (Blaine & Sinha, 2017). These PVN CRH-releasing (PVNCRH) neurons are essential for peripheral and central stress responses (Rasiah et al., 2023), but little is known about how alcohol affects these neurons. Here, we show that two- bottle choice alcohol consumption blunts the endocrine mediated corticosterone response to stress during acute withdrawal in female mice. Conversely, using slice electrophysiology, we demonstrate that acute withdrawal engenders a hyperexcitable phenotype of PVNCRH neurons in females that is accompanied by increased glutamatergic transmission in both male and female mice. Only male mice show a concurrent increase in GABAergic synaptic transmission. We then tested whether chemogenetic inhibition of PVNCRH neurons would restore stress response in female mice with a history of alcohol drinking in the looming disc test, which mimics an approaching predator threat. Accordingly, inhibition of PVNCRH neurons reduced active escape in hM4Di alcohol history mice only. This study indicates that stress responsive PVNCRH neurons in females are particularly affected by a history of alcohol consumption. Interestingly, women have indicated an increase in heavy alcohol use to cope with stress (Rodriguez et al., 2020), perhaps pointing to a potential underlying mechanism in alcohol mediated changes to PVNCRH neurons that alter stress response.

neuroscience↗

bioRxiv2023

Corticotropin Releasing Factor in the Bed Nucleus of the Stria Terminalis modulates the behavioral consequences of unpredictable threat

Fear responses to perceived danger are critical for survival, as they prompt the individual to respond to threats and avoid harm. However, excessive fear can impede normal biological processes and become harmful. This study investigates the neural mechanisms underlying two distinct forms of fear--phasic and sustained--in male and female mice, with a focus on the bed nucleus of the stria terminalis (BNST) and corticotropin-releasing factor (CRF) signaling. Phasic fear is characterized by immediate responses to clear threats, while sustained fear is driven by ambiguous or uncertain cues and persists longer. Using rodent models, we found that sustained fear, modeled by partial fear conditioning, induced greater arousal and BNST activity in males, especially during ambiguous threat cues. In contrast, females exhibited reduced BNST and BNSTCRF activity, highlighting significant sex differences in fear learning and expression. Additionally, CRF is crucial for appropriate fear response in females, as CRF knockdown led to increased fear responses, but had no effect in males. These sex-specific differences could help inform the development of targeted treatments for anxiety and trauma-related disorders, which disproportionately affect women.

neuroscience↗

bioRxiv2023

Disentangling the effects of Corticotrophin Releasing Factor and GABA release from the ventral bed nucleus of the stria terminalis on ethanol self-administration in mice

Excessive alcohol use causes a great deal of harm and negative health outcomes. Corticotrophin releasing factor (CRF), a stress-related neuropeptide, has been implicated in binge ethanol intake and ethanol dependence. CRF containing neurons in the bed nucleus of the stria terminalis (BNSTCRF) can control ethanol consumption. These BNSTCRF neurons also release GABA, raising the question, is it CRF or GABA release or both that is controlling alcohol consumption. Here, we used viral vectors to separate the effects of CRF and GABA release from BNSTCRF neurons on the escalation of ethanol intake in an operant self-administration paradigm in male and female mice. We found that CRF deletion in BNST neurons reduces ethanol intake in both sexes, with a stronger effect in males. For sucrose self-administration there was no effect of CRF deletion. Suppression of GABA release, via knockdown of vGAT, from BNSTCRF produced a transient increase in ethanol operant self-administration following in male mice, and reduced in motivation to work for sucrose on a progressive ratio schedule of reinforcement in a sex-dependent manner. Together, these results highlight how different signaling molecules from the same populations of neurons can bidirectionally control behavior. Moreover, they suggest that BNST CRF release is important for high intensity ethanol drinking that precedes dependence, whereas GABA release from these neurons may play a role in regulating motivation.

neuroscience↗

bioRxiv2022

Alcohol dependence modifies brain networks activated during abstinence and reaccess: a c-fos-based analysis in mice

High-level alcohol consumption causes neuroplastic changes in the brain that lead to negative affective and somatic symptoms when alcohol is withdrawn, promoting relapse drinking. We have some understanding of these plastic changes in defined brain circuits and cell types, but unbiased approaches are needed to explore broader patterns of adaptations. Here, we employed whole-brain c-fos mapping and network analysis to assess how brain-wide patterns of neuronal activity are altered during acute alcohol abstinence and reaccess in a well-characterized model of alcohol dependence. Mice underwent four cycles of chronic intermittent ethanol vapor exposure (CIE) with alternating weeks of voluntary alcohol drinking, and a subset of mice underwent forced swim stress (FSS) prior to drinking sessions to further escalate alcohol consumption. After four CIE cycles, brains were collected from mice in each group either 24 hours (abstinence) or immediately following a one-hour period of alcohol reaccess. Brains from CIE mice during acute abstinence displayed widespread neuronal activation relative to those from AIR mice, independent of FSS, and this increase in c-fos was reversed by reaccess drinking. For network analysis, mice were then classified as high or low drinkers (HD or LD). We computed Pearson correlations for all pairs of brain regions and used graph theoretical methods to identify changes in network properties associated with high-drinking behavior. Network modularity, a measure of network segregation into communities, was increased in HD mice after alcohol reaccess relative to abstinence. Within-community strength and diversity measures were computed for each region and condition, and highly coactive regions were identified. One high-diversity region, the cortical amygdala (COA), was further interrogated using a chemogenetic approach. COA silencing in CIE mice reduced voluntary drinking, validating our network analysis and indicating that this region may play an important but underappreciated role in alcohol dependence.

neuroscience↗

bioRxiv2022

Chronic Alcohol Consumption Alters Home-Cage Behaviors and Responses to Ethologically Relevant Predator Tasks in Mice

Alcohol use disorders (AUD) are the most prevalent substance use disorders worldwide. Considering recent reports indicating an increase in alcohol use particularly in females, it is vital to understand how alcohol history impacts behavior. Animal model research on withdrawal-associated affective states tends to focus on males, forced alcohol paradigms, and a few traditional anxiety/stress tests. While this has been essential, heavy alcohol use triggers adverse withdrawal-related affective states that can influence how people respond to a large variety of life events and stressors. To this end, we show that behaviors in the home-cage, open field, looming disc, and robogator predator threat task, which vary in task demand and intensity, are altered in mice with a history of voluntary alcohol consumption. In alcohol-exposed males, behaviors in the home cage, a low anxiety baseline environment, suggest increased vigilance/exploration. However, in the open field and robogator task, which induce heightened arousal and task demands, a more hesitant/avoidant phenotype is seen. Female alcohol mice show no behavioral alterations in the home cage and open field test, however, in the looming disc task, which mimics an overhead advancing predator and forces a behavioral choice, we see greater escape responses compared to water controls, indicative of active stress coping behaviors. This suggests females may begin to show alcohol-induced alterations as task demands increase. To date, few drugs have advanced past clinical trials for the treatment of AUD, and those that have are predominately used in life-threatening situations only. No treatments exist for ameliorating negative withdrawal related states, which could aid in harm reduction related to heavy alcohol use. Understanding how withdrawal alters a variety of behavioral responses that are linked to stress coping can widen our understanding of alcohol abuse and lead us closer to better therapeutics to help individuals with AUD.

neuroscience↗

bioRxiv2022

Sex-specific regulation of binge drinking and affective behaviors by subcortical serotonin 5HT2c receptors

Serotonin 5HT2c receptors have been implicated in the pathophysiology of both mood disorders and alcohol use disorder, but the circuits mediating the effects of systemic pharmacological manipulations of this receptor on behavior have not been identified. Binge alcohol consumption induces discrete social and arousal disturbances in human populations, which are thought to promote increased drinking. However, whether models of binge drinking in rodents can induce these same long-term negative behavioral symptoms is unknown. In this study, we employed multiple anatomical, physiological, and behavioral approaches to identify two populations of neurons expressing serotonin 5HT2c receptors, one in the lateral habenula (LHb5HT2c) and one in the bed nucleus of the stria terminalis (BNST5HT2c), that display coordinated in-vivo responses to social, arousal, and alcohol-related stimuli and are physiologically modulated by binge alcohol consumption in a sex-specific manner. Critically, these physiological changes were associated with sex-specific behavioral disturbances that closely mirror social and arousal symptoms observed in humans during abstinence from binge drinking. Specifically, we observed that one week of abstinence from three weeks of binge alcohol drinking induced social recognition deficits in females and potentiated acoustic startle responses in males. While both populations of neurons (BNST and LHb) and the 5HT2c receptor itself contribute to the sex-specific effects of alcohol on social and arousal behaviors to some degree, the primary causal mechanism underlying these phenomena appears to be excessive activation of LHb5HT2c neurons. These findings may have implications for the development of sex-specific treatments for mood and alcohol use disorders targeting the brains serotonin system.

neuroscience↗

bioRxiv2021

Delineation of dynorphin and kappa opioid receptor circuit elements in alcohol consumption

Alcohol use disorder is complex and multi-faceted, involving the coordination of multiple signaling systems across numerous brain regions. Previous work has indicated that both the insular cortex and dynorphin (DYN)/Kappa opioid receptor (KOR) systems contribute to excessive alcohol use. More recently, we identified a microcircuit in the medial aspect of the insular cortex that signals through DYN/KOR. Here, we explored the role of insula DYN/KOR circuit components on alcohol intake in a long-term intermittent access (IA) procedure. Using a combination of conditional knockout strategies and site-directed pharmacology, we discovered distinct and sex-specific roles for insula DYN and KOR in alcohol drinking and related behavior. Our findings show that insula DYN deletion blocked escalated consumption and decreased overall intake of and preference for alcohol in male and female mice. This effect was specific to alcohol in male mice, as DYN deletion did not impact sucrose intake. Further, insula KOR antagonism reduced alcohol intake and preference during the early phase of IA in male mice only. Alcohol consumption was not affected by insula KOR knockout in either sex. In addition, we found that long-term IA decreased the intrinsic excitability of DYN and deep layer pyramidal neurons (DLPN) in the insula of male mice. Excitatory synaptic transmission was also impacted by IA, as it drove an increase in excitatory synaptic drive in both DYN neurons and DLPN. Combined, our findings suggest there is a dynamic interplay between excessive alcohol consumption and insula DYN/KOR microcircuitry. Significance StatementThe insular cortex is a complex region that serves as an integratory hub for sensory inputs. In our previous work, we identified a microcircuit in the insula that signals through the kappa opioid receptor (KOR) and its endogenous ligand dynorphin (DYN). Both the insula and DYN/KOR systems have been implicated in excessive alcohol use and alcohol use disorder (AUD). Here, we utilize converging approaches to determine how insula DYN/KOR microcircuit components contribute to escalated alcohol consumption. Our findings show that insula DYN/KOR systems regulate distinct phases of alcohol consumption in a sex-specific manner, which may contribute to the progression to AUD.

neuroscience↗

bioRxiv2021

The rt-TEP tool: real-time visualization of TMS-evoked potentials to maximize cortical activation and minimize artifacts

BackgroundThe impact of transcranial magnetic stimulation (TMS) on cortical neurons is currently hard to predict based on a priori biophysical and anatomical knowledge alone. This problem can hamper the reliability and reproducibility of protocols aimed at measuring electroencephalographic (EEG) responses to TMS. New MethodWe introduce and release a novel software tool to facilitate and standardize the acquisition of TMS-evoked potentials (TEPs). The tool, rt-TEP (real-time TEP), interfaces with different EEG amplifiers and offers a series of informative visualization modes to assess in real time the immediate impact of TMS on the underlying neuronal circuits. ResultsWe show that rt-TEP can be used to abolish or minimize magnetic and muscle artifacts contaminating the post-stimulus period thus affording a clear visualization and quantification of the amplitude of the early (<50 ms) EEG response after averaging a limited number of trials. This real-time readout can then be used to adjust TMS parameters (e.g. site, orientation, intensity) and experimental settings (e.g. loudness and/or spectral features of the noise masking) to ultimately maximize direct cortical effects over the undesired sensory effects of the coils discharge. Comparison with Existing MethodsThe ensemble of real-time visualization modes of rt-TEP are not implemented in any current commercial software and provide a key readout to titrate TMS parameters beyond the a priori information provided by anatomical models. ConclusionsReal-time optimization of stimulation parameters with rt-TEP can facilitate the acquisition of reliable TEPs with a high signal-to-noise ratio and improve the standardization and reproducibility of data collection across laboratories. HighlightsO_LIrt-TEP provides an immediate EEG readout to assess the quality of TEPs in real time C_LIO_LIrt-TEP interfaces with most commercial EEG systems C_LIO_LIInformative, real time visualization allows maximising the cortical impact of TMS while minimizing artifacts C_LIO_LIrt-TEP facilitates the acquisition of reliable TEPs with a high signal-to-noise ratio C_LI

neuroscience↗

bioRxiv2021

TAAC - TMS Adaptable Auditory Control: a universal tool to mask TMS click

BackgroundCoupling transcranial magnetic stimulation with electroencephalography (TMS-EEG) allows recording the EEG response to a direct, non-invasive cortical perturbation. However, obtaining a genuine TMS-evoked EEG potential requires controlling for several confounds, among which a main source is represented by the auditory evoked potentials (AEPs) associated to the TMS discharge noise (TMS click). This contaminating factor can be in principle prevented by playing a masking noise through earphones. New methodHere we release TMS Adaptable Auditory Control (TAAC), a highly flexible, open-source, Matlab(R)-based interface that generates in real-time customized masking noises. TAAC creates noises starting from the stimulator-specific TMS click and tailors them to fit the individual, subject-specific click perception by mixing and manipulating the standard noises in both time and frequency domains. ResultsWe showed that TAAC allows us to provide standard as well as customized noises able to effectively and safely mask the TMS click. Comparison with existing methodsHere, we showcased two customized noises by comparing them to two standard noises previously used in the TMS literature (i.e., a white noise and a noise generated from the stimulator-specific TMS click only). For each, we quantified the Sound Pressure Level (SPL; measured by a Head and Torso Simulator - HATS) required to mask the TMS click in a population of 20 healthy subjects. Both customized noises were effective at safe (according to OSHA and NIOSH safety guidelines), lower SPLs with respect to standard noises. ConclusionsAt odds with previous methods, TAAC allows creating effective and safe masking noises specifically tailored on each TMS device and subject. The combination of TAAC with tools for the real-time visualization of TEPs can help control the influence of auditory confounds also in non-compliant patients. Finally, TAAC is a highly flexible and open-source tool, so it can be further extended to meet different experimental requirements.

neuroscience↗

bioRxiv2019

Local sleep-like cortical reactivity in the awake brain after focal injury

The functional consequences of brain injury are known to depend on neuronal alterations extending beyond the area of structural damage. Although a lateralized EEG slowing over the injured hemisphere was known since the early days of clinical neurophysiology, its electrophysiological mechanisms were not systematically investigated. In parallel, basic sleep research has thoroughly characterized the neuronal events underlying EEG slow waves in physiological conditions. These EEG events reflect brief interruptions of neuronal firing (OFF-periods) that can occur locally and have prominent consequences on network and behavioral functions. Notably, the EEG slow waves observed following focal brain injury have been never explicitly connected to local sleep-like neuronal events. In previous works, probing cortical circuits with transcranial magnetic stimulation coupled with EEG (TMS/EEG) proved as an effective way to reveal the tendency of cortical circuits to transiently plunge into silent OFF-periods. Here, using this approach, we show that the intact cortex surrounding focal brain injuries engages locally in pathological sleep-like dynamics. Specifically, we employed TMS/EEG in a cohort of thirty conscious awake patients with chronic focal and multifocal brain injuries of various etiologies. TMS systematically evoked prominent slow waves associated with sleep-like OFF-periods in the area surrounding focal cortico-subcortical lesions. These events were associated with a local disruption of signal complexity and were absent when stimulating the contralateral hemisphere. Perilesional sleep-like OFF-periods may represent a valid read-out of the electrophysiological state of discrete cortical circuits following brain injury as well as a potential target of interventions aimed at fostering functional recovery. One Sentence SummaryFocal cortical injuries are associated with local intrusion of sleep-like dynamics over the perilesional areas which disrupt local signal complexity and coexist with typical wakefulness cortical reactivity patterns within the same brain.

neuroscience↗