Periodic Reporting for period 1 - RAB-PPS (Reactive adaptive behaviour elicited by events in close proximity of the body)
Periodo di rendicontazione: 2023-05-01 al 2025-04-30
Sintesi del contesto e degli obiettivi generali del progetto
The main research goal was to systematically explore how the brain copes with sudden transient events (perceived as threats) in close proximity of our body, within the Peripersonal Space (PPS). Here we could carry out research on healthy human subjects, on a clinical population (patients affected by Parkinson’s disease (PD), a severe movement disorder (Poewe et al., 2017), and on non-human primates. Several, challenging, research techniques (e.g. behavioural methods, electroencephalography (EEG), electromyography (EMG), intracranial electrophysiology (iEEG) on non-human primate and neuromodulation, such as transcranial electrical stimulation (tES) (Paulus, 2011) were involved to address the research questions.
The project systematically investigated how the human cortex modulates subcortical defensive reflexes, focusing on the Hand Blink Reflex (HBR) as a model for rapid, adaptive defensive behaviour within peripersonal space (PPS). The HBR, a brainstem-mediated blink response to somatosensory stimulation of the hand, was chosen because its magnitude is strongly influenced by the hand’s proximity to the face, reflecting the nervous system’s estimation of threat value.
This multidisciplinary project had ambitious goals to achieve in a short time. However, data collection was completed within the two-year timeframe. We are now at the stage of drafting the first two papers that will be ready for submission in the next few months. We are currently finalising data analysis on both patients affected by Parkinson’s Disease and non-human primates. The final phase of the project experienced delays due to reliance on external institutions for patient recruitment and access to non-human primate data, which proved challenging within the project's timeframe.
Problems and Needs Addressed
* Scientific gap: The precise mechanisms and cortical areas responsible for modulating subcortical defensive reflexes in humans are still unclear, limiting our understanding of how the brain integrates sensory, motor, and contextual information to generate adaptive responses.
* Clinical need: Early and accurate differentiation between PD and atypical parkinsonism remains a major challenge in neurology, often leading to delayed diagnosis and suboptimal care45. There is a pressing need for objective, neurophysiological markers and innovative diagnostic tools.
* Societal relevance: As Europe’s population ages, the prevalence of neurodegenerative diseases is increasing, with significant societal and economic costs. Improving early diagnosis and rehabilitation strategies for PD and related disorders aligns with EU policy priorities, including “Economy that works for people” and “Europe for the digital age”.
Overall Objectives and Pathway to Impact This project set out to:
* Systematically characterize the neural mechanisms underlying defensive behaviours (with a primary focus on the HBR) in both healthy individuals and clinical populations, using a multidisciplinary approach that combines behavioural testing, electrophysiology, and non-invasive brain stimulation.
* Identify the cortical substrates and oscillatory dynamics (especially in Brodmann area 7, BA7) that modulate subcortical defensive reflexes, providing direct causal evidence of top-down control in humans.
* Develop and validate neuromodulation-based protocols (e.g. tDCS, tACS) as potential diagnostic and rehabilitative tools for movement disorders, with a special focus on differentiating PD from atypical parkinsonism.
* Bridge basic neuroscience with clinical and social sciences by integrating psychological assessments (e.g. anxiety questionnaires), collaborating with clinicians and psychologists, and engaging in public outreach and education.
Scale and Significance of Expected Impact
* Scientific impact: The project advances the state of the art by providing new insights into the cortical control of defensive reflexes, revealing the frequency-specific role of beta oscillations in modulating the HBR, and establishing BA7 as a key hub in these processes.
* Clinical impact: Preliminary results suggest that neuromodulation protocols can distinguish PD from atypical parkinsonism, supporting earlier and more accurate diagnoses, and paving the way for novel rehabilitation strategies.
* Societal and policy impact: By improving diagnostic tools and rehabilitation approaches, the project addresses urgent healthcare needs, supports healthy aging, and contributes to EU priorities on innovation and societal well-being.
* Interdisciplinary integration: The project brings together neuroscience, clinical neurology, psychology, and social sciences, fostering a holistic understanding of defensive behaviour and its modulation in health and disease.
Setting the Scene This research responds to the urgent need for a deeper understanding of how the human brain generates and controls defensive behaviours, and how these mechanisms break down in disease. By combining cutting-edge neuroscience with clinical translation and public engagement, the project aims to deliver tangible benefits for science, medicine, and society.
The project systematically investigated how the human cortex modulates subcortical defensive reflexes, focusing on the Hand Blink Reflex (HBR) as a model for rapid, adaptive defensive behaviour within peripersonal space (PPS). The HBR, a brainstem-mediated blink response to somatosensory stimulation of the hand, was chosen because its magnitude is strongly influenced by the hand’s proximity to the face, reflecting the nervous system’s estimation of threat value.
This multidisciplinary project had ambitious goals to achieve in a short time. However, data collection was completed within the two-year timeframe. We are now at the stage of drafting the first two papers that will be ready for submission in the next few months. We are currently finalising data analysis on both patients affected by Parkinson’s Disease and non-human primates. The final phase of the project experienced delays due to reliance on external institutions for patient recruitment and access to non-human primate data, which proved challenging within the project's timeframe.
Problems and Needs Addressed
* Scientific gap: The precise mechanisms and cortical areas responsible for modulating subcortical defensive reflexes in humans are still unclear, limiting our understanding of how the brain integrates sensory, motor, and contextual information to generate adaptive responses.
* Clinical need: Early and accurate differentiation between PD and atypical parkinsonism remains a major challenge in neurology, often leading to delayed diagnosis and suboptimal care45. There is a pressing need for objective, neurophysiological markers and innovative diagnostic tools.
* Societal relevance: As Europe’s population ages, the prevalence of neurodegenerative diseases is increasing, with significant societal and economic costs. Improving early diagnosis and rehabilitation strategies for PD and related disorders aligns with EU policy priorities, including “Economy that works for people” and “Europe for the digital age”.
Overall Objectives and Pathway to Impact This project set out to:
* Systematically characterize the neural mechanisms underlying defensive behaviours (with a primary focus on the HBR) in both healthy individuals and clinical populations, using a multidisciplinary approach that combines behavioural testing, electrophysiology, and non-invasive brain stimulation.
* Identify the cortical substrates and oscillatory dynamics (especially in Brodmann area 7, BA7) that modulate subcortical defensive reflexes, providing direct causal evidence of top-down control in humans.
* Develop and validate neuromodulation-based protocols (e.g. tDCS, tACS) as potential diagnostic and rehabilitative tools for movement disorders, with a special focus on differentiating PD from atypical parkinsonism.
* Bridge basic neuroscience with clinical and social sciences by integrating psychological assessments (e.g. anxiety questionnaires), collaborating with clinicians and psychologists, and engaging in public outreach and education.
Scale and Significance of Expected Impact
* Scientific impact: The project advances the state of the art by providing new insights into the cortical control of defensive reflexes, revealing the frequency-specific role of beta oscillations in modulating the HBR, and establishing BA7 as a key hub in these processes.
* Clinical impact: Preliminary results suggest that neuromodulation protocols can distinguish PD from atypical parkinsonism, supporting earlier and more accurate diagnoses, and paving the way for novel rehabilitation strategies.
* Societal and policy impact: By improving diagnostic tools and rehabilitation approaches, the project addresses urgent healthcare needs, supports healthy aging, and contributes to EU priorities on innovation and societal well-being.
* Interdisciplinary integration: The project brings together neuroscience, clinical neurology, psychology, and social sciences, fostering a holistic understanding of defensive behaviour and its modulation in health and disease.
Setting the Scene This research responds to the urgent need for a deeper understanding of how the human brain generates and controls defensive behaviours, and how these mechanisms break down in disease. By combining cutting-edge neuroscience with clinical translation and public engagement, the project aims to deliver tangible benefits for science, medicine, and society.
Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti
Activities Performed
The project systematically investigated the neural mechanisms underlying defensive behaviours in humans and clinical populations, with a primary focus on the Hand Blink Reflex (HBR) as a model of rapid, subcortical defensive response. The HBR was selected because, despite being a well-characterized brainstem reflex, it remains unclear how and where this response is modulated by the cortex in humans.
Key technical and scientific activities included:
* Behavioural and Electrophysiological Paradigms: Developed and implemented experimental protocols to elicit and record the HBR in healthy individuals and patients with Parkinson’s disease (PD) and atypical parkinsonism. The paradigm involved electrical stimulation of the median nerve while participants held their hand at varying distances from the face, allowing precise mapping of peripersonal space (PPS) modulation.
* Non-invasive Brain Stimulation: Applied high-definition transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS) over Brodmann area 7 (BA7) to test its causal role in modulating the HBR. Both anodal and cathodal tDCS, as well as beta (20 Hz) and gamma (80 Hz) tACS, were systematically tested.
* Clinical Translation: Extended the HBR and neuromodulation protocols to clinical cohorts. Posturography experiments were designed to assess whether neuromodulation could reveal diagnostic differences between PD and atypical parkinsonism.
* Cross-Species Analysis: Analysed intracranial recordings from non-human primates exposed to multimodal (visuo-tactile) stimuli to investigate the evolutionary conservation of PPS mechanisms.
Main Scientific Achievements and Outcomes
* Cortical Modulation of Defensive Reflexes: Demonstrated for the first time that BA7 is a key cortical hub for modulating both the magnitude and proximity-dependent enhancement of the HBR. Anodal tDCS over BA7 significantly increased HBR amplitude, while beta-frequency (20 Hz) tACS robustly inhibited the reflex. Gamma-frequency tACS and cathodal tDCS had no significant effect, revealing a frequency-specific mechanism for cortical-subcortical communication.
* Clinical Insights: Preliminary results showed that PD patients exhibited increased postural oscillations during 1 Hz tACS (but not at baseline) compared to healthy controls, while atypical parkinsonism patients showed elevated baseline oscillations. These findings suggest neuromodulation protocols may support early differential diagnosis between PD and atypical parkinsonism.
* Cross-Species Validation: Initial analysis of non-human primate data revealed robust, multimodal responses in premotor cortex PPS neurons, supporting the evolutionary conservation of defensive space coding.
* Milestones:
* Completion of all planned experiments on healthy participants.
* Substantial progress in clinical and non-human primate studies.
* Two manuscripts in advanced preparation for high-impact journals.
* Results presented at major international conferences (Society for Neuroscience 2024, FENS 2025).
Summary: The project advanced the understanding of how the human cortex modulates subcortical defensive reflexes, identified BA7 and beta-frequency oscillations as key modulators, and developed protocols with potential clinical diagnostic value. All major scientific objectives were addressed, with ongoing analyses expected to further strengthen the translational impact.
The project systematically investigated the neural mechanisms underlying defensive behaviours in humans and clinical populations, with a primary focus on the Hand Blink Reflex (HBR) as a model of rapid, subcortical defensive response. The HBR was selected because, despite being a well-characterized brainstem reflex, it remains unclear how and where this response is modulated by the cortex in humans.
Key technical and scientific activities included:
* Behavioural and Electrophysiological Paradigms: Developed and implemented experimental protocols to elicit and record the HBR in healthy individuals and patients with Parkinson’s disease (PD) and atypical parkinsonism. The paradigm involved electrical stimulation of the median nerve while participants held their hand at varying distances from the face, allowing precise mapping of peripersonal space (PPS) modulation.
* Non-invasive Brain Stimulation: Applied high-definition transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS) over Brodmann area 7 (BA7) to test its causal role in modulating the HBR. Both anodal and cathodal tDCS, as well as beta (20 Hz) and gamma (80 Hz) tACS, were systematically tested.
* Clinical Translation: Extended the HBR and neuromodulation protocols to clinical cohorts. Posturography experiments were designed to assess whether neuromodulation could reveal diagnostic differences between PD and atypical parkinsonism.
* Cross-Species Analysis: Analysed intracranial recordings from non-human primates exposed to multimodal (visuo-tactile) stimuli to investigate the evolutionary conservation of PPS mechanisms.
Main Scientific Achievements and Outcomes
* Cortical Modulation of Defensive Reflexes: Demonstrated for the first time that BA7 is a key cortical hub for modulating both the magnitude and proximity-dependent enhancement of the HBR. Anodal tDCS over BA7 significantly increased HBR amplitude, while beta-frequency (20 Hz) tACS robustly inhibited the reflex. Gamma-frequency tACS and cathodal tDCS had no significant effect, revealing a frequency-specific mechanism for cortical-subcortical communication.
* Clinical Insights: Preliminary results showed that PD patients exhibited increased postural oscillations during 1 Hz tACS (but not at baseline) compared to healthy controls, while atypical parkinsonism patients showed elevated baseline oscillations. These findings suggest neuromodulation protocols may support early differential diagnosis between PD and atypical parkinsonism.
* Cross-Species Validation: Initial analysis of non-human primate data revealed robust, multimodal responses in premotor cortex PPS neurons, supporting the evolutionary conservation of defensive space coding.
* Milestones:
* Completion of all planned experiments on healthy participants.
* Substantial progress in clinical and non-human primate studies.
* Two manuscripts in advanced preparation for high-impact journals.
* Results presented at major international conferences (Society for Neuroscience 2024, FENS 2025).
Summary: The project advanced the understanding of how the human cortex modulates subcortical defensive reflexes, identified BA7 and beta-frequency oscillations as key modulators, and developed protocols with potential clinical diagnostic value. All major scientific objectives were addressed, with ongoing analyses expected to further strengthen the translational impact.
Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)
Results and Potential Impacts
Overview of Results
The project delivered several key scientific advances in understanding how the human cortex modulates subcortical defensive reflexes, using the Hand Blink Reflex (HBR) as a model system:
Cortical Modulation of Defensive Reflexes:
For the first time, the project demonstrated that Brodmann area 7 (BA7) in the parietal cortex causally modulates both the magnitude and proximity-dependent enhancement of the HBR in humans. Anodal tDCS over BA7 significantly increased HBR amplitude, while beta-frequency (20 Hz) tACS robustly inhibited the reflex. Gamma-frequency tACS and cathodal tDCS had no significant effect, revealing a frequency-specific mechanism for cortical-subcortical communication.
Clinical Translation:
The HBR and neuromodulation protocols were extended to clinical cohorts. Preliminary results showed that Parkinson’s disease (PD) patients exhibited increased postural oscillations during 1 Hz tACS compared to healthy controls (with no baseline difference), while atypical parkinsonism patients showed elevated baseline oscillations even before stimulation. This suggests that neuromodulation protocols may serve as early, objective diagnostic tools for differentiating PD from atypical parkinsonism—a major clinical challenge.
Cross-Species Validation:
Analysis of intracranial recordings from non-human primates revealed robust, multimodal responses in premotor cortex PPS neurons, supporting the evolutionary conservation of defensive space coding and strengthening the translational value of the human findings.
Multidisciplinary Integration:
The project combined behavioural neuroscience, clinical neurology, electrophysiology, and non-invasive brain stimulation, and incorporated psychological assessments (e.g. anxiety questionnaires) to link defensive reflexes with anxiety traits, paving the way for future research on neuropsychiatric conditions.
Potential Impacts
Scientific Impact:
The project advances the state of the art in neuroscience by providing causal evidence for frequency-specific cortical control of subcortical defensive reflexes. The identification of BA7 and beta oscillations as key modulators opens new avenues for basic and translational research.
Clinical Impact:
The development of neuromodulation-based protocols for early differential diagnosis and rehabilitation in movement disorders could lead to improved patient outcomes, reduced diagnostic delays, and more targeted therapies for PD and atypical parkinsonism.
Societal and Policy Impact:
By addressing urgent healthcare needs related to neurodegenerative and anxiety disorders, the project aligns with EU priorities such as "Economy that works for people" and "Europe for the digital age." Early diagnosis and intervention can yield substantial societal and economic benefits.
Researcher Career Impact:
The fellow acquired advanced skills in neuromodulation, clinical research, and cross-disciplinary collaboration, enhancing future career prospects in both academic and clinical settings.
Key Needs for Further Uptake and Success
Further Research and Validation:
Additional large-scale clinical studies are needed to validate the diagnostic and therapeutic potential of the neuromodulation protocols developed here, particularly for distinguishing PD from atypical parkinsonism and for application in neuropsychiatric disorders.
Demonstration and Clinical Trials:
Demonstration projects and clinical trials will be essential to translate these findings into routine clinical practice and to assess long-term efficacy and safety.
Access to Markets and Finance:
Partnerships with clinical centers, industry, and technology transfer offices will support the development of market-ready diagnostic and rehabilitation tools based on project results.
Commercialisation and IPR Support:
Intellectual property protection (with support from the host institution’s Technology Transfer Office) will be important for commercial exploitation of neuromodulation protocols and related software/hardware. Open-access datasets and tools will also be made available to maximize research impact.
Regulatory and Standardisation Frameworks:
Engagement with regulatory bodies and standardisation initiatives will facilitate the adoption of neuromodulation technologies in clinical settings.
Internationalisation:
Continued collaboration with international partners, including non-EU clinical and research centers, will further enhance the scientific and societal impact of the project.
Overview of Results
The project delivered several key scientific advances in understanding how the human cortex modulates subcortical defensive reflexes, using the Hand Blink Reflex (HBR) as a model system:
Cortical Modulation of Defensive Reflexes:
For the first time, the project demonstrated that Brodmann area 7 (BA7) in the parietal cortex causally modulates both the magnitude and proximity-dependent enhancement of the HBR in humans. Anodal tDCS over BA7 significantly increased HBR amplitude, while beta-frequency (20 Hz) tACS robustly inhibited the reflex. Gamma-frequency tACS and cathodal tDCS had no significant effect, revealing a frequency-specific mechanism for cortical-subcortical communication.
Clinical Translation:
The HBR and neuromodulation protocols were extended to clinical cohorts. Preliminary results showed that Parkinson’s disease (PD) patients exhibited increased postural oscillations during 1 Hz tACS compared to healthy controls (with no baseline difference), while atypical parkinsonism patients showed elevated baseline oscillations even before stimulation. This suggests that neuromodulation protocols may serve as early, objective diagnostic tools for differentiating PD from atypical parkinsonism—a major clinical challenge.
Cross-Species Validation:
Analysis of intracranial recordings from non-human primates revealed robust, multimodal responses in premotor cortex PPS neurons, supporting the evolutionary conservation of defensive space coding and strengthening the translational value of the human findings.
Multidisciplinary Integration:
The project combined behavioural neuroscience, clinical neurology, electrophysiology, and non-invasive brain stimulation, and incorporated psychological assessments (e.g. anxiety questionnaires) to link defensive reflexes with anxiety traits, paving the way for future research on neuropsychiatric conditions.
Potential Impacts
Scientific Impact:
The project advances the state of the art in neuroscience by providing causal evidence for frequency-specific cortical control of subcortical defensive reflexes. The identification of BA7 and beta oscillations as key modulators opens new avenues for basic and translational research.
Clinical Impact:
The development of neuromodulation-based protocols for early differential diagnosis and rehabilitation in movement disorders could lead to improved patient outcomes, reduced diagnostic delays, and more targeted therapies for PD and atypical parkinsonism.
Societal and Policy Impact:
By addressing urgent healthcare needs related to neurodegenerative and anxiety disorders, the project aligns with EU priorities such as "Economy that works for people" and "Europe for the digital age." Early diagnosis and intervention can yield substantial societal and economic benefits.
Researcher Career Impact:
The fellow acquired advanced skills in neuromodulation, clinical research, and cross-disciplinary collaboration, enhancing future career prospects in both academic and clinical settings.
Key Needs for Further Uptake and Success
Further Research and Validation:
Additional large-scale clinical studies are needed to validate the diagnostic and therapeutic potential of the neuromodulation protocols developed here, particularly for distinguishing PD from atypical parkinsonism and for application in neuropsychiatric disorders.
Demonstration and Clinical Trials:
Demonstration projects and clinical trials will be essential to translate these findings into routine clinical practice and to assess long-term efficacy and safety.
Access to Markets and Finance:
Partnerships with clinical centers, industry, and technology transfer offices will support the development of market-ready diagnostic and rehabilitation tools based on project results.
Commercialisation and IPR Support:
Intellectual property protection (with support from the host institution’s Technology Transfer Office) will be important for commercial exploitation of neuromodulation protocols and related software/hardware. Open-access datasets and tools will also be made available to maximize research impact.
Regulatory and Standardisation Frameworks:
Engagement with regulatory bodies and standardisation initiatives will facilitate the adoption of neuromodulation technologies in clinical settings.
Internationalisation:
Continued collaboration with international partners, including non-EU clinical and research centers, will further enhance the scientific and societal impact of the project.