Alessandro Gulberti

Activity parameters of subthalamic nucleus neurons selectively predict motor symptom severity in Parkinson's disease.

Parkinsons disease (PD) is a heterogeneous disorder that leads to variable expression of several different motor symptoms. While changes in firing rate, pattern, and oscillation of basal ganglia neurons have been observed in PD patients and experimental animals, there is limited evidence linking them to specific motor symptoms. Here we examined this relationship using extracellular recordings of subthalamic nucleus neurons from 19 PD patients undergoing surgery for deep brain stimulation. For each patient, ≥10 single units and/or multi-units were recorded in the OFF medication state. We correlated the proportion of neurons displaying different activities with preoperative Unified Parkinsons Disease Rating Scale subscores (OFF medication). The mean spectral power at sub-beta frequencies and percentage of units oscillating at beta frequencies were positively correlated with the axial and limb rigidity scores, respectively. The percentage of units oscillating at gamma frequency was negatively correlated with the bradykinesia scores. The mean intraburst rate was positively correlated with both bradykinesia and axial scores, while the related ratio of interspike intervals below/above 10 ms was positively correlated with these symptoms and limb rigidity. None of the activity parameters correlated with tremor. The grand average of all the significantly correlated subthalamic nucleus activities accounted for >60% of the variance of the combined bradykinetic-rigid and axial scores. Our results demonstrate that the occurrence of alterations in the rate and pattern of basal ganglia neurons could partly underlie the variability in parkinsonian phenotype.

Asymmetric pallidal neuronal activity in patients with cervical dystonia

The origin of asymmetric clinical manifestation of symptoms in patients suffering from cervical dystonia (CD) is hitherto poorly understood. Dysregulated neuronal activity in the basal ganglia has been suggested to have a role in the pathophysiology of CD. Here, we re-assessed the question to what extent relative changes occur in the direct vs. indirect basal ganglia pathway in CD, whether these circuit changes are lateralized, and how these alterations relate to CD symptoms. To this end, we recorded ongoing single cell and local field potential (LFP) activity from the external (GPe) and internal pallidal segment (GPi) of 13 CD patients undergoing microelectrode-guided stereotactic surgery for deep brain stimulation in the GPi. We compared pallidal recordings from CD patients operated under local anaesthesia (LA) with those obtained in CD patients operated under general anaesthesia (GA). In awake patients, mean GPe discharge rate (52 Hz) was lower than that of GPi (72 Hz). Mean GPi discharge ipsilateral to the side of head turning was higher than contralateral and correlated with torticollis symptom severity. Lateralized differences were absent at the level of the GPe and in recordings from patients operated under GA. Furthermore, in the GPi of CD patients there was a subpopulation of theta-oscillatory cells with unique bursting characteristics. Power and coherence of GPe– and GPi–LFPs were dominated by a theta peak and also exhibited band-specific interhemispheric differences. Strong cross-frequency coupling of low-gamma amplitude to theta phase was a feature of pallidal LFPs recorded under LA, but not GA. These results indicate that CD is associated with an asymmetric pallidal outflow. Based on the finding of symmetric neuronal discharges in the GPe, we propose that an imbalanced interhemispheric direct pathway gain may be involved in CD pathophysiology.

STN Stimulation in General Anaesthesia: Evidence Beyond ‘Evidence-Based Medicine’

Awake surgery is regarded mandatory for optimal electrode implantation into the subthalamic nucleus (STN) for deep brain stimulation (DBS) in Parkinsons disease (PD). However, this is questionable since general anaesthesia (GA) does not preclude intraoperative microrecordings and clinical evaluation of, for example, current spread to the corticospinal tract. In addition, even in the awake state, clinical testing is not without limitations. We report on intra- and postoperative findings in 11 patients suffering from advanced PD who were operated under GA (propofol/remifentanil). The activity of STN neurons under GA was characterized by excessive burst discharges that differed fundamentally from the irregular tonic patterns observed in the STN of awake patients. In all patients, we obtained improved motor symptoms and reduced levodopa-induced dyskinesias and motor fluctuations, which was associated with a reduction in the levodopa equivalent daily dose. Therapeutic DBS was not limited by current spread to the corticospinal tract in any of the patients. The trajectories chosen for electrode implantation in GA compared well to awake surgery. Our results indicate that STN surgery in GA can be performed in a safe manner. It can be offered to anxious patients, and represents a viable option when awake surgery bears a risk for the patient.

Predictive timing functions of cortical beta oscillations are impaired in Parkinson's disease and influenced by L-DOPA and deep brain stimulation of the subthalamic nucleus

Cortex-basal ganglia circuits participate in motor timing and temporal perception, and are important for the dynamic configuration of sensorimotor networks in response to exogenous demands. In Parkinsons disease (PD) patients, rhythmic auditory stimulation (RAS) induces motor performance benefits. Hitherto, little is known concerning contributions of the basal ganglia to sensory facilitation and cortical responses to RAS in PD. Therefore, we conducted an EEG study in 12 PD patients before and after surgery for subthalamic nucleus deep brain stimulation (STN-DBS) and in 12 age-matched controls. Here we investigated the effects of levodopa and STN-DBS on resting-state EEG and on the cortical-response profile to slow and fast RAS in a passive-listening paradigm focusing on beta-band oscillations, which are important for auditory–motor coupling. The beta-modulation profile to RAS in healthy participants was characterized by local peaks preceding and following auditory stimuli. In PD patients RAS failed to induce pre-stimulus beta increases. The absence of pre-stimulus beta-band modulation may contribute to impaired rhythm perception in PD. Moreover, post-stimulus beta-band responses were highly abnormal during fast RAS in PD patients. Treatment with levodopa and STN-DBS reinstated a post-stimulus beta-modulation profile similar to controls, while STN-DBS reduced beta-band power in the resting-state. The treatment-sensitivity of beta oscillations suggests that STN-DBS may specifically improve timekeeping functions of cortical beta oscillations during fast auditory pacing.

Stopping eyes and hands: evidence for non-independence of stop and go processes and for a separation of central and peripheral inhibition

In the stop-signal paradigm, participants perform a primary reaction task, for example a visual or auditory discrimination task, and have to react to a go stimulus as quickly as possible with a specified motor response. In a certain percentage of trials, after presentation of the stimulus (go signal), another stimulus (stop signal) is presented with a variable stop-signal delay. Whenever a stop signal occurs, the participant is asked to inhibit the execution of the response. Here, an extended test of the popular horse race model for this task (Logan and Cowan, 1984) is presented. Responses for eye and hand movements in both single-task and dual-task conditions were collected. Saccadic reaction times revealed some significant violations of the models basic assumption of independent go and inhibition processes for all six participants. Saccades that escaped an early stop signal were systematically slower and had smaller amplitudes compared to saccades without a stop signal. Moreover, the analysis of concomitant electromyographic responses recorded from the upper arm suggests the existence of two separate inhibitory mechanisms: a slow, selective, central inhibitory mechanism and a faster, highly efficient, peripheral one, which is probably ineffective for saccades.

Walking in Virtual Reality: Effects of Manipulated Visual Self-Motion on Walking Biomechanics

Walking constitutes the predominant form of self-propelled movement from one geographic location to another in our real world. Likewise, walking in virtual environments (VEs) is an essential part of a users experience in many application domains requiring a high degree of interactivity. However, researchers and practitioners often observe that basic implementations of virtual walking, in which head-tracked movements are mapped isometrically to a VE are not estimated as entirely natural. Instead, users estimate a virtual walking velocity as more natural when it is slightly increased compared to the users physical body movement. In this article, we investigate the effects of such nonisometric mappings between physical movements and virtual motions in the VE on walking velocity and biomechanics of the gait cycle. Therefore, we performed an experiment in which we measured and analyzed parameters of the biomechanics of walking under conditions with isometric as well as nonisometric mappings. Our results show significant differences in most gait parameters when walking in the VE in the isometric mapping condition compared to the corresponding parameters in the real world. For nonisometric mappings we found an increased divergence of gait parameters depending on the velocity of visual self-motion feedback. The results revealed a symmetrical effect of gait detriments for up- or down-scaled virtual velocities, which we discuss in the scope of the previous findings.

Adverse events in deep brain stimulation: A retrospective long-term analysis of neurological, psychiatric and other occurrences

Background and objective The extent to which deep brain stimulation (DBS) can improve quality of life may be perceived as a permanent trade-off between neurological improvements and complications of therapy, comorbidities, and disease progression. Patients and methods We retrospectively investigated 123 consecutive and non-preselected patients. Indications for DBS surgery were Parkinsons disease (82), dystonia (18), tremor of different etiology (21), Huntingtons disease (1) and Gilles de la Tourette syndrome (1). AEs were defined as any untoward clinical occurrence, sign or patient complaint or unintended disease if related or unrelated to the surgical procedures, implanted devices or ongoing DBS therapy. Results Over a mean/median follow-up period of 4.7 years (578 patient-years) 433 AEs were recorded in 106 of 123 patients (86.2%). There was no mortality or persistent morbidity from the surgical procedure. All serious adverse events (SAEs) that occurred within 4 weeks of surgery were reversible. Neurological AEs (193 in 85 patients) and psychiatric AEs (78 in 48 patients) were documented most frequently. AEs in 4 patients (suicide under GPI stimulation, weight gain >20 kg, impairment of gait and speech, cognitive decline >2 years following surgery) were severe or worse, at least possibly related to DBS and non reversible. In PD 23.1% of the STN-stimulated patients experienced non-reversible (or unknown reversibility) AEs that were at least possibly related to DBS in the form of impaired speech or gait, depression, weight gain, cognitive disturbances or urinary incontinence (severity was mild or moderate in 15 of 18 patients). Age and Hoehn&Yahr stage of STN-simulated PD patients, but not preoperative motor impairment or response to levodopa, showed a weak correlation (r = 0.24 and 0.22, respectively) with the number of AEs. Conclusions DBS-related AEs that were severe or worse and non-reversible were only observed in PD (4 of 82 patients; 4.9%), but not in other diseases. PD patients exhibited a significant risk for non-severe AEs most of which also represented preexisting and progressive axial and non-motor symptoms of PD. Mild gait and/or speech disturbances were rather frequent complaints under VIM stimulation. GPI stimulation for dystonia could be applied with negligible DBS-related side effects.

Subthalamic deep brain stimulation improves auditory sensory gating deficit in Parkinson's disease

OBJECTIVE While motor effects of dopaminergic medication and subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinsons disease (PD) patients are well explored, their effects on sensory processing are less well understood. Here, we studied the impact of levodopa and STN-DBS on auditory processing. METHODS Rhythmic auditory stimulation (RAS) was presented at frequencies between 1 and 6Hz in a passive listening paradigm. High-density EEG-recordings were obtained before (levodopa ON/OFF) and 5months following STN-surgery (ON/OFF STN-DBS). We compared auditory evoked potentials (AEPs) elicited by RAS in 12 PD patients to those in age-matched controls. Tempo-dependent amplitude suppression of the auditory P1/N1-complex was used as an indicator of auditory gating. RESULTS Parkinsonian patients showed significantly larger AEP-amplitudes (P1, N1) and longer AEP-latencies (N1) compared to controls. Neither interruption of dopaminergic medication nor of STN-DBS had an immediate effect on these AEPs. However, chronic STN-DBS had a significant effect on abnormal auditory gating characteristics of parkinsonian patients and restored a physiological P1/N1-amplitude attenuation profile in response to RAS with increasing stimulus rates. CONCLUSIONS This differential treatment effect suggests a divergent mode of action of levodopa and STN-DBS on auditory processing. SIGNIFICANCE STN-DBS may improve early attentive filtering processes of redundant auditory stimuli, possibly at the level of the frontal cortex.

The Sense of Agency Is More Sensitive to Manipulations of Outcome than Movement-Related Feedback Irrespective of Sensory Modality

The sense of agency describes the ability to experience oneself as the agent of ones own actions. Previous studies of the sense of agency manipulated the predicted sensory feedback related either to movement execution or to the movement’s outcome, for example by delaying the movement of a virtual hand or the onset of a tone that resulted from a button press. Such temporal sensorimotor discrepancies reduce the sense of agency. It remains unclear whether movement-related feedback is processed differently than outcome-related feedback in terms of agency experience, especially if these types of feedback differ with respect to sensory modality. We employed a mixed-reality setup, in which participants tracked their finger movements by means of a virtual hand. They performed a single tap, which elicited a sound. The temporal contingency between the participants’ finger movements and (i) the movement of the virtual hand or (ii) the expected auditory outcome was systematically varied. In a visual control experiment, the tap elicited a visual outcome. For each feedback type and participant, changes in the sense of agency were quantified using a forced-choice paradigm and the Method of Constant Stimuli. Participants were more sensitive to delays of outcome than to delays of movement execution. This effect was very similar for visual or auditory outcome delays. Our results indicate different contributions of movement- versus outcome-related sensory feedback to the sense of agency, irrespective of the modality of the outcome. We propose that this differential sensitivity reflects the behavioral importance of assessing authorship of the outcome of an action.

STN-DBS Reduces Saccadic Hypometria but Not Visuospatial Bias in Parkinson's Disease Patients.

In contrast to its well-established role in alleviating skeleto-motor symptoms in Parkinsons disease, little is known about the impact of deep brain stimulation (DBS) of the subthalamic nucleus (STN) on oculomotor control and attention. Eye-tracking data of 17 patients with left-hemibody symptom onset was compared with 17 age-matched control subjects. Free-viewing of natural images was assessed without stimulation as baseline and during bilateral DBS. To examine the involvement of ventral STN territories in oculomotion and spatial attention, we employed unilateral stimulation via the left and right ventralmost contacts respectively. When DBS was off, patients showed shorter saccades and a rightward viewing bias compared with controls. Bilateral stimulation in therapeutic settings improved saccadic hypometria but not the visuospatial bias. At a group level, unilateral ventral stimulation yielded no consistent effects. However, the evaluation of electrode position within normalized MNI coordinate space revealed that the extent of early exploration bias correlated with the precise stimulation site within the left subthalamic area. These results suggest that oculomotor impairments “but not higher-level exploration patterns” are effectively ameliorable by DBS in therapeutic settings. Our findings highlight the relevance of the STN topography in selecting contacts for chronic stimulation especially upon appearance of visuospatial attention deficits.