Biology subjects

Gulberti, A.

Publications and source records attributed to Gulberti, A..

7 recordsLinked to original sources

bioRxiv2026

Cortical E-fields of deep brain stimulation in Parkinson's disease patients exceed typical E-field magnitudes of transcranial electrical stimulation

BackgroundDeep brain stimulation (DBS) is an established and effective intervention for Parkinsons disease. Although the exact mechanisms of action are still unclear, both therapeutic benefits and side effects are solely attributed to neuromodulation via strong electric fields (E-fields) in the surgical target. Nevertheless, DBS generates E-fields that extend beyond the stimulation site and can be detected throughout the brain. Recent evidence from transcranial electrical stimulation studies shows that weak cortical E-fields even below 1 V/m can have a neuromodulatory effect, raising the question of a physiological relevance of weak cortical fields of DBS. However, the strength of cortical E-fields of DBS is currently unknown. ObjectiveUsing a novel framework, we aimed to quantify the whole-brain E-field distribution in patients with Parkinsons disease receiving therapeutic DBS of the subthalamic nucleus (STN-DBS). MethodsIn this work, we developed a pipeline to simulate DBS E-field distributions throughout the brain, based on the existing open-source toolboxes Lead-DBS and SimNIBS. We constructed patient-specific whole-head models including electrode leads for 25 patients with Parkinsons disease receiving subthalamic DBS, and simulated E-fields using the patients clinical stimulation settings for 49 hemispheres. ResultsWe found that median peak E-field magnitudes exceeded 0.3 V/m in all cortical regions and were greater than 1 V/m in the orbital gyrus, superior temporal gyrus, fusiform gyrus, parahippocampal gyrus, insular gyrus, cingulate gyrus. Most prominently, the orbital and insular gyri showed peak magnitudes ranging from 0.81 to 8.61 V/m and 0.90 to 8.01 V/m. ConclusionsOur results indicate that the E-fields of STN-DBS reach cortical peak magnitudes that exceed typically reported values of transcranial electrical stimulation. This opens the possibility that weak E-fields of DBS could have a direct neuromodulatory effect in wider regions of the brain, for example in cortical regions.

neuroscience↗

bioRxiv2025

Modulation of temporal prediction by STN-DBS in Parkinson's disease: Links between behavior and cortical oscillations

BACKGROUNDAccurate temporal prediction is essential for adaptive behavior and relies on coordinated neural activity within cortico-basal ganglia circuits. Parkinsons disease (PD), with the main hallmark of dopaminergic depletion and abnormal neural synchrony, impairs this ability. Deep brain stimulation deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a widely used treatment for reducing motor symptoms in PD, but its effects on temporal prediction remain not fully understood. OBJECTIVESThis study aimed to investigate how STN-DBS influences temporal prediction performance and its underlying oscillatory dynamics in PD patients, with a particular focus on beta-band power and delta-band inter-trial phase consistency (ITPC). METHODS13 PD patients (5 female, age: 64 {+/-} 5.7 years; disease duration: 11.8 {+/-} 1.8 years) with STN-DBS performed a temporal prediction task with (DBS ON) and without (DBS OFF) stimulation, while 64-channel-electroencephalography (EEG) was recorded. 20 age-matched healthy controls completed the same task. Behavioral performance was assessed using psychometric function slopes. Time-frequency analyses and source-level EEG measures examined beta power and delta ITPC. RESULTSPD patients showed impaired temporal prediction performance compared to controls, reflected in shallower psychometric slopes. DBS significantly improved performance to a level comparable to those of controls. EEG revealed reduced beta suppression in PD patients during DBS OFF, while beta suppression in DBS ON was comparable to controls. Both DBS OFF and ON exhibited reduced delta ITPC compared to controls. In DBS ON, source-level delta ITPC was positively correlated with temporal prediction accuracy. CONCLUSIONSTN-DBS improves temporal prediction performance in PD, likely through modulation of beta and delta oscillatory activity. While beta power suppression is partially restored, deficits in delta phase alignment persist, suggesting frequency-specific DBS effects on temporal prediction processes.

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bioRxiv2023

The effect of deep brain stimulation on cortico-subcortical networks in Parkinson's disease patients with freezing of gait: Exhaustive exploration of a basic model

Current treatments of Parkinsons disease (PD) have limited efficacy in alleviating freezing of gait (FoG). In this context, concomitant deep brain stimulation (DBS) of the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr) has been suggested as a potential therapeutic approach. However, the mechanisms underlying this approach are unknown. While the current rationale relies on network-based hypotheses of intensified disinhibition of brainstem locomotor areas to facilitate the release of gait motor programs, it is still unclear how simultaneous high-frequency DBS in two interconnected basal ganglia nuclei affects large-scale cortico-subcortical network activity. Here, we use a basic model of neural excitation, the susceptible-excited-refractory (SER) model, to compare effects of different stimulation modes of the network underlying FoG. We develop a network-based computational framework to compare subcortical DBS targets through exhaustive analysis of the brain attractor dynamics in the healthy, PD and DBS states. We demonstrate the validity of the approach and the superior performance of combined STN+SNr DBS in the normalization of spike propagation flow in the FoG network. The framework aims to move towards a mechanistic understanding of the network effects of DBS and may be applicable to further perturbation-based therapies of brain disorders. AUTHOR SUMMARYParkinsons disease patients with Freezing of Gait (FoG) may be treated by deep brain stimulation, which produces effects mediated by brain networks. Currently, the approach of combined DBS of the subthalamic nucleus and the substantia nigra pars reticulata is investigated for being particularly beneficial for patients with axial symptoms, but the exact mechanisms of this effect are unknown. Here, we present a network-based computational framework using a basic excitable model that enables us to simulate the complete activity patterns of the brain network involved in FoG. These simulations reveal network mechanisms underlying STN+SNr DBS and its efficacy in alleviating FoG. The proposed framework can capture the influence of the DBS target sites on cortico-subcortical networks and help to identify suitable stimulation targets.

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bioRxiv2019

Parkinsons disease uncovers an underlying sensitivity of subthalamic nucleus neurons to beta-frequency cortical input

Abnormally sustained beta-frequency synchronisation between the motor cortex and subthalamic nucleus (STN) is associated with motor symptoms in Parkinsons disease (PD). It is currently unclear whether STN neurons have a preference for beta-frequency input (12-35Hz), rather than cortical input at other frequencies, and how such a preference would arise following dopamine depletion. To address this question, we combined analysis of cortical and STN recordings from awake PD patients undergoing deep brain stimulation surgery with recordings of identified STN neurons in anaesthetised rats. In PD patients, we demonstrate that a subset of STN neurons are strongly and selectively sensitive to fluctuations of cortical beta oscillations over time, linearly increasing their phase-locking strength with respect to full range of instantaneous amplitude. In rats, we probed the frequency response of STN neurons more precisely, by recording spikes evoked by short bursts of cortical stimulation with variable frequency (4-40Hz) and constant amplitude. In both healthy and dopamine-depleted animals, only beta-frequency stimulation selectively led to a progressive reduction in the variability of spike timing through the stimulation train. We hypothesize, that abnormal activation of the indirect pathway, via dopamine depletion and/or cortical stimulation, could trigger an underlying sensitivity of the STN microcircuit to beta-frequency input.

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bioRxiv2018

Temporal evolution of beta bursts in the parkinsonian cortico-basal ganglia network

Prevalence and temporal dynamics of transient oscillations in the beta frequency band (15-35 Hz), referred to as beta bursts, are correlated with motor performance and tactile perception. Disturbance of these activities is a candidate mechanism for motor impairment in Parkinsons disease (PD), where the excessively long bursts correlate with symptom severity and are reduced by pharmacological and surgical treatments. To date, characterization of beta bursts in PD has been limited to the local field potentials in the subthalamic nucleus (STN) and cortical EEG. Here, we describe the changes that take place in spiking activity across the cortico-basal ganglia circuit, providing a unique insight into the network dynamics of these transient oscillations. Firstly, we demonstrate that rhythmic subthalamic spiking activity emerges at a fixed phase relationship with respect to cortical beta bursts in PD patients. Using multichannel recordings of ensembles of neurons in the 6-OHDA rat model of PD, we then dissect the beta burst dynamics across the sensorimotor cortex and several basal ganglia structures: striatum (Str), globus pallidus externus (GPe) and STN. Each subcortical structure exhibits enhanced rhythmic activity in the beta band locked to the onset of cortical beta bursts and longer cortical bursts lead to stronger subcortical rhythmicity. Crucially, enhanced subcortical rhythmic activity emerges at a fixed phase relationship with respect to the motor cortex, comparable to the relationship observed in PD patients. Striatal beta bursts terminate prior to the recruitment of those in the STN and GPe, suggesting that while they could play an important role in establishing synchrony in the beta band, they do not extensively contribute to its maintenance in other basal ganglia structures. Critically, changes in cortico-subcortical phase coupling precede the onset of a cortical beta burst, supporting the hypothesis that phase alignment across the cortico-basal ganglia network could recruit these structures into synchronous network oscillations. We provide a powerful approach that not only examines pathophysiology of PD across the motor circuit, but also offer insights that could aid in the design of novel neuromodulation strategies to manipulate the state of the motor system before pathological activities emerge.

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bioRxiv2018

Synchronised spiking activity underlies phase amplitude coupling in the subthalamic nucleus of Parkinson’s disease patients

Both phase-amplitude coupling (PAC) and beta-bursts in the subthalamic nucleus have been significantly linked to symptom severity in Parkinsons disease (PD) in humans and emerged independently as competing biomarkers for closed-loop deep brain stimulation (DBS). However, the underlying nature of subthalamic PAC is poorly understood and its relationship with transient beta burst-events has not been investigated. To address this, we studied macro- and micro electrode recordings of local field potentials (LFPs) and single unit activity from 15 hemispheres in 10 PD patients undergoing DBS surgery. PAC between beta phase and high frequency oscillation (HFO) amplitude was compared to single unit firing rates, spike triggered averages, power spectral densities and phase-spike locking, and was studied in periods of beta-bursting. We found a significant synchronisation of spiking to HFOs and correlation of mean firing rates with HFO-amplitude when the latter was coupled to beta phase (i.e. in the presence of PAC). In the presence of PAC, single unit power spectra displayed peaks in the beta and HFO frequency range and the HFO frequency was correlated with that in the LFP. Finally, PAC significantly increased with beta burst-duration. Our findings offer new insight in the pathology of Parkinsons disease by providing evidence that subthalamic PAC reflects the locking of spiking activity to network beta oscillations and that this coupling progressively increases with beta-burst duration. These findings suggest that beta-bursts capture periods of increased subthalamic input/output synchronisation in the beta frequency range and have important implications for therapeutic closed-loop DBS.\n\nSignificance statementIdentifying biomarkers for closed-loop deep brain stimulation (DBS) has become an increasingly important issue in Parkinsons Disease (PD) research. Two such biomarkers, phase-amplitude coupling (PAC) and beta-bursts, recorded from the implanted electrodes in subthalamic nucleus in PD patients, correlate with motor impairment. However, the physiological basis of PAC, and it relationship to beta bursts, is unclear. We provide multiple lines of evidence that PAC in the human STN reflects the locking of spiking activity to network beta oscillations and that this coupling progressively increases with the duration of beta-bursts. This suggests that beta-bursts capture increased subthalamic input/output synchronisation and provides new insights in PD pathology with direct implications for closed-loop DBS therapy strategies.

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bioRxiv2018

Phase-dependent suppression of beta oscillations in Parkinson’s disease patients

Synchronized oscillations within and between brain areas facilitate normal processing, but are often amplified in disease. A prominent example is the abnormally sustained beta-frequency (~20Hz) oscillations recorded from the cortex and subthalamic nucleus of Parkinson's Disease patients. Computational modelling suggests that the amplitude of such oscillations could be modulated by applying stimulation at a specific phase. Such a strategy would allow selective targeting of the oscillation, with relatively little effect on other activity parameters. Here we demonstrate in awake, parkinsonian patients undergoing functional neurosurgery, that electrical stimulation arriving on consecutive cycles of a specific phase of the subthalamic oscillation can suppress its amplitude and coupling to cortex. Stimulus-evoked changes in spiking did not have a consistent time course, suggesting that the oscillation was modulated independently of net output. Phase-dependent stimulation could thus be a valuable strategy for treating brain diseases and probing the function of oscillations in the healthy brain.

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