Complex analysis of neuronal spike trains of deep brain nuclei in patients with Parkinson's disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been used to alleviate symptoms of Parkinson's disease. During image-guided stereotactic surgery, signals from microelectrode recordings are used to distinguish the STN from adjacent areas, particularly from the substantia nigra pars reticulata (SNr). Neuronal firing patterns based on interspike intervals (ISI) are commonly used. In the present study, arrival time-based measures, including Lempel-Ziv complexity and deviation-from-Poisson index were employed. Our results revealed significant differences in the arrival time-based measures among non-motor STN, motor STN and SNr and better discrimination than the ISI-based measures. The larger deviations from the Poisson process in the SNr implied less complex dynamics of neuronal discharges. If spike classification was not used, the arrival time-based measures still produced statistical differences among STN subdivisions and SNr, but the ISI-based measures only showed significant differences between motor and non-motor STN. Arrival time-based measures are less affected by spike misclassifications, and may be used as an adjunct for the identification of the STN during microelectrode targeting.     

Basal ganglia neural responses during behaviorally effective deep brain stimulation of the subthalamic nucleus in rats performing a treadmill locomotion test

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for Parkinson's disease (PD). In spite of proven therapeutic success, the mechanism underlying the benefits of DBS has not been resolved. A multiple-channel single-unit recording technique was used in the present study to investigate basal ganglia (BG) neural responses during behaviorally effective DBS of the STN in a rat model of PD. Rats underwent unilateral dopamine (DA) depletion by injection of 6-hydroxyDA (6-OHDA) into one side of the medial forebrain bundle and subsequently developed a partial akinesia, which was assessed during the treadmill locomotion task. High frequency stimulation (HFS) of the STN restored normal treadmill locomotion behavior. Simultaneous recording of single unit activity in the striatum (STR), globus pallidus (GP), substantia nigra pars reticulata (SNr), and STN revealed a variety of neural responses during behaviorally effective HFS of the STN. Predominant inhibitory responses appeared in the STN stimulation site. Nearly equal numbers of excitatory and inhibitory responses were found in the GP and SNr, whereas more rebound excitatory responses were found in the STR. Mean firing rate did not change significantly in the STR, GP, and SNr, but significantly decreased in both sides of STN during DBS. A decrease in firing rate in the contralateral side of STN provides neural substrate for the clinical observation that unilateral DBS produces bilateral benefits in patients with PD. In addition to the firing rate changes, a decrease in burst firing was observed in the GP and STN. The present study indicates that DBS induces complex modulations of the BG circuit and further suggests that BG network reorganization, rather than a simple excitation or inhibition, may underlie the therapeutic effects of DBS in patients with PD.     

Correspondence of optimal stimulation and beta power varies regionally in STN DBS for Parkinson disease

IntroductionSubthalamic nucleus deep brain stimulation (STN DBS) for Parkinson disease (PD) normalizes neuronal hypersynchrony in the beta frequency range (13–30 Hz). The spatial correspondence of maximal beta power to the site of optimal stimulation along the DBS lead trajectory has been debated.MethodsWe determined the trajectory locations of the active contact, maximal beta power, and the dorsal border of the STN (DB-STN) in DBS patients. Beta power profiles were measured during intraoperative microelectrode recording (MER). Active contact locations were assigned during blinded, postoperative DBS programming. The DB-STN was identified both electrophysiologically during MER and anatomically on MRI. After grouping DBS trajectories into quadrants relative to the anatomic STN midpoint, we examined regional variations in the relative trajectory locations of the three entities.ResultsSTN DBS significantly improved motor performance for all 13 DBS patients, with active contacts at the DB-STN. Along trajectories passing posterior-medial to the STN midpoint, maximal beta power co-localized with active contacts at the DB-STN (difference Δ = 0.4 ± 1.6 mm, p = 0.57). By contrast, in posterior-lateral trajectories, maximal beta arose within the STN, ventral to active contacts (Δ = 1.9 ± 1.3 mm, p = 0.002). For trajectories anterior to the STN midpoint, maximal beta power co-localized with the DB-STN, while active contacts were ventral to peak beta power (p = 0.05).ConclusionOur findings indicate that co-localization of optimal stimulation and beta power varies by anatomical region in STN DBS for Parkinson disease.     

Electrophysiologic Evidence That Directional Deep Brain Stimulation Activates Distinct Neural Circuits in Patients With Parkinson Disease

ObjectivesDeep brain stimulation (DBS) delivered via multicontact leads implanted in the basal ganglia is an established therapy to treat Parkinson disease (PD). However, the different neural circuits that can be modulated through stimulation on different DBS contacts are poorly understood. Evidence shows that electrically stimulating the subthalamic nucleus (STN) causes a therapeutic effect through antidromic activation of the hyperdirect pathway—a monosynaptic connection from the cortex to the STN. Recent studies suggest that stimulating the substantia nigra pars reticulata (SNr) may improve gait. The advent of directional DBS leads now provides a spatially precise means to probe these neural circuits and better understand how DBS affects distinct neural networks.Materials and MethodsWe measured cortical evoked potentials (EPs) using electroencephalography (EEG) in response to low-frequency DBS using the different directional DBS contacts in eight patients with PD.ResultsA short-latency EP at 3 milliseconds originating from the primary motor cortex appeared largest in amplitude when stimulating DBS contacts closest to the dorsolateral STN (p < 0.001). A long-latency EP at 10 milliseconds originating from the premotor cortex appeared strongest for DBS contacts closest to the SNr (p < 0.0001).ConclusionsOur results show that at the individual patient level, electrical stimulation of different nuclei produces distinct EP signatures. Our approach could be used to identify the functional location of each DBS contact and thus help patient-specific DBS programming.Clinical Trial RegistrationThe ClinicalTrials.gov registration number for the study is NCT04658641.     

Functional neuronal activity and connectivity within the subthalamic nucleus in Parkinson’s disease

ObjectiveCharacterization of the functional neuronal activity and connectivity within the subthalamic nucleus (STN) in patients with Parkinson’s disease (PD).MethodsSingle units were extracted from micro-electrode recording (MER) of 18 PD patients who underwent STN deep brain stimulation (DBS) surgery. The firing rate and pattern of simultaneously recorded spike trains and their coherence were analyzed. To provide a precise functional assignment of position to the observed activities, for each patient we mapped its classified multichannel STN MERs to a generic atlas representation with a sensorimotor part and a remaining part.ResultsWithin the sensorimotor part we found significantly higher mean firing rate (P < 0.05) and significantly more burst-like activity (P < 0.05) than within the remaining part. The proportion of significant coherence in the beta band (13–30 Hz) is significantly higher in the sensorimotor part of the STN than elsewhere (P =  0.015).ConclusionsThe STN sensorimotor part distinguishes itself from the remaining part with respect to beta coherence, firing rate and burst-like activity and postoperatively was found as the preferred target area.SignificanceOur firing behavior analysis may help to discriminate the STN sensorimotor part for the placement of the DBS electrode.     

Selective deep brain stimulation in the substantia nigra reduces myoclonus in progressive myoclonic epilepsy: a novel observation and short review of the literature

We report the case of a patient suffering from pharmacotherapy‐resistant bilateral progressive myoclonic epilepsy (PME) showing a beneficial response upon selective deep brain stimulation (DBS) of the substantia nigra pars reticulata. As an individual experimental therapeutic approach, we implanted DBS electrodes in the transitional zone between the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr). Electrode placement allowed for a selective stimulation of either the STN, SNr, or both targets. Postoperatively, we observed a moderate subjective and objective improvement in positive and negative myoclonus by high‐frequency DBS of the STN/SNr transitional zone. However, a systematic exploration of different stimulation settings revealed that monopolar stimulation of the substantia nigra alone was more effective than high‐frequency monopolar DBS of either the motor STN (monopolar) or stimulation of both targets (STN/SNr). This observation confirms earlier findings showing that patients with PME benefit from high‐frequency DBS. However, in contrast to previous reports stimulating the STN/SNr transitional zone, our patient showed the most significant effect upon selective stimulation of the SNr. We propose that in patients undergoing DBS for myoclonus, at least one electrode contact should be placed in the SNr allowing for selective monopolar stimulation of this target.     

Elevated potassium provides an ionic mechanism for deep brain stimulation in the hemiparkinsonian rat

The mechanism of high‐frequency stimulation used in deep brain stimulation (DBS) for Parkinson's disease (PD) has not been completely elucidated. Previously, high‐frequency stimulation of the rat entopeduncular nucleus, a basal ganglia output nucleus, elicited an increase in [K⁺]_e to 18 mm , in vitro. In this study, we assessed whether elevated K⁺ can elicit DBS‐like therapeutic effects in hemiparkinsonian rats by employing the limb‐use asymmetry test and the self‐adjusting stepping test. We then identified how these effects were meditated with in‐vivo and in‐vitro electrophysiology. Forelimb akinesia improved in hemiparkinsonian rats undergoing both tests after 20 mm KCl injection into the substantia nigra pars reticulata (SNr) or the subthalamic nucleus. In the SNr, neuronal spiking activity decreased from 38.2 ± 1.2 to 14.6 ± 1.6 Hz and attenuated SNr beta‐frequency (12–30 Hz) oscillations after K⁺ treatment. These oscillations are commonly associated with akinesia/bradykinesia in patients with PD and animal models of PD. Pressure ejection of 20 mm KCl onto SNr neurons in vitro caused a depolarisation block and sustained quiescence of SNr activity. In conclusion, our data showed that elevated K⁺ injection into the hemiparkinsonian rat SNr improved forelimb akinesia, which coincided with a decrease in SNr neuronal spiking activity and desynchronised activity in SNr beta frequency, and subsequently an overall increase in ventral medial thalamic neuronal activity. Moreover, these findings also suggest that elevated K⁺ may provide an ionic mechanism that can contribute to the therapeutic effects of DBS for the motor treatment of advanced PD.     

Acute low frequency dorsal subthalamic nucleus stimulation improves verbal fluency in Parkinson's disease

BackgroundParkinson's disease (PD) is a common neurodegenerative disorder that results in movement-related dysfunction and has variable cognitive impairment. Deep brain stimulation (DBS) of the dorsal subthalamic nucleus (STN) has been shown to be effective in improving motor symptoms; however, cognitive impairment is often unchanged, and in some cases, worsened particularly on tasks of verbal fluency. Traditional DBS strategies use high frequency gamma stimulation for motor symptoms (∼130 Hz), but there is evidence that low frequency theta oscillations (5–12 Hz) are important in cognition.MethodsWe tested the effects of stimulation frequency and location on verbal fluency among patients who underwent STN DBS implantation with externalized leads. During baseline cognitive testing, STN field potentials were recorded and the individual patients’ peak theta frequency power was identified during each cognitive task. Patients repeated cognitive testing at five different stimulation settings: no stimulation, dorsal contact gamma (130 Hz), ventral contact gamma, dorsal theta (peak baseline theta) and ventral theta (peak baseline theta) frequency stimulation.ResultsAcute left dorsal peak theta frequency STN stimulation improves overall verbal fluency compared to no stimulation and to either dorsal or ventral gamma stimulation. Stratifying by type of verbal fluency probes, verbal fluency in episodic categories was improved with dorsal theta stimulation compared to all other conditions, while there were no differences between stimulation conditions in non-episodic probe conditions.ConclusionHere, we provide evidence that dorsal STN theta stimulation may improve verbal fluency, suggesting a potential possibility of integrating theta stimulation into current DBS paradigms to improve cognitive outcomes.     

Increased Subthalamic Nucleus Deep Brain Stimulation Amplitude Impairs Inhibitory Control of Eye Movements in Parkinson's Disease

Background and ObjectivesBilateral subthalamic nucleus deep brain stimulation (STN DBS) in Parkinson's disease (PD) can have detrimental effects on eye movement inhibitory control. To investigate this detrimental effect of bilateral STN DBS, we examined the effects of manipulating STN DBS amplitude on inhibitory control during the antisaccade task. The prosaccade error rate during the antisaccade task, that is, directional errors, was indicative of impaired inhibitory control. We hypothesized that as stimulation amplitude increased, the prosaccade error rate would increase.Materials and MethodsTen participants with bilateral STN DBS completed the antisaccade task on six different stimulation amplitudes (including zero amplitude) after a 12-hour overnight withdrawal from antiparkinsonian medication.ResultsWe found that the prosaccade error rate increased as stimulation amplitude increased (p < 0.01). Additionally, prosaccade error rate increased as the modeled volume of tissue activated (VTA) and STN overlap decreased, but this relationship depended on stimulation amplitude (p = 0.04).ConclusionsOur findings suggest that higher stimulation amplitude settings can be modulatory for inhibitory control. Some individual variability in the effect of stimulation amplitude can be explained by active contact location and VTA-STN overlap. Higher stimulation amplitudes are more deleterious if the active contacts fall outside of the STN resulting in a smaller VTA-STN overlap. This is clinically significant as it can inform clinical optimization of STN DBS parameters. Further studies are needed to determine stimulation amplitude effects on other aspects of cognition and whether inhibitory control deficits on the antisaccade task result in a meaningful impact on the quality of life.     

Evoked potentials reveal neural circuits engaged by human deep brain stimulation

BackgroundDeep brain stimulation (DBS) is an effective therapy for reducing the motor symptoms of Parkinson’s disease, but the mechanisms of action of DBS and neural correlates of symptoms remain unknown.ObjectiveTo use the neural response to DBS to reveal connectivity of neural circuits and interactions between groups of neurons as potential mechanisms for DBS.MethodsWe recorded activity evoked by DBS of the subthalamic nucleus (STN) in humans with Parkinson’s disease. In follow up experiments we also simultaneously recorded activity in the contralateral STN or the ipsilateral globus pallidus from both internal (GPi) and external (GPe) segments.ResultsDBS local evoked potentials (DLEPs) were stereotyped across subjects, and a biophysical model of reciprocal connections between the STN and the GPe recreated DLEPs. Simultaneous STN and GP recordings during STN DBS demonstrate that DBS evoked potentials were present throughout the basal ganglia and confirmed that DLEPs arose from the reciprocal connections between the STN and GPe. The shape and amplitude of the DLEPs were dependent on the frequency and duration of DBS and were correlated with resting beta band oscillations. In the frequency domain, DLEPs appeared as a 350 Hz high frequency oscillation (HFO) independent of the frequency of DBS.ConclusionsDBS evoked potentials suggest that the intrinsic dynamics of the STN and GP are highly interlinked and may provide a promising new biomarker for adaptive DBS.     

Subthalamic Nucleus Deep Brain Stimulation Induces Motor Network BOLD Activation: Use of a High Precision MRI Guided Stereotactic System for Nonhuman Primates

BackgroundFunctional magnetic resonance imaging (fMRI) is a powerful method for identifying in vivo network activation evoked by deep brain stimulation (DBS).ObjectiveIdentify the global neural circuitry effect of subthalamic nucleus (STN) DBS in nonhuman primates (NHP).MethodAn in-house developed MR image-guided stereotactic targeting system delivered a mini-DBS stimulating electrode, and blood oxygenation level-dependent (BOLD) activation during STN DBS in healthy NHP was measured by combining fMRI with a normalized functional activation map and general linear modeling.ResultsSTN DBS significantly increased BOLD activation in the sensorimotor cortex, supplementary motor area, caudate nucleus, pedunculopontine nucleus, cingulate, insular cortex, and cerebellum (FDR < 0.001).ConclusionOur results demonstrate that STN DBS evokes neural network grouping within the motor network and the basal ganglia. Taken together, these data highlight the importance and specificity of neural circuitry activation patterns and functional connectivity.     

Changes in Glucose Metabolism in Cerebral Cortex and Cerebellum Correlate With Tremor and Rigidity Control by Subthalamic Nucleus Stimulation in Parkinson's Disease: A Positron Emission Tomography Study

Objective. Employing [¹⁸F]fluorodeoxyglucose (FDG) positron emission tomography (PET) to assess the correlation between the effect of deep brain stimulation (DBS) on the subthalamic nucleus (STN) and the regional cerebral metabolic rate of glucose (rCMRGlc) in advanced Parkinson's disease patients (N = 8). Materials and Methods. On the basis of patients’ diary records, we performed FDG‐PET during the off‐period of motor activity with on‐ or off‐stimulation by STN‐DBS on separate days and analyzed the correlation between changes in motor symptoms and alterations in the rCMRGlc. Result. When FDG‐PET was performed, the motor score on the unified Parkinson's disease rating scale (UPDRS) was 64% lower with on‐stimulation than with off‐stimulation (p < 0.001, Wilcoxon single‐rank test). STN‐DBS increased the rCMRGlc in the posterior part of the right middle frontal gyrus, which corresponded to the premotor area, and the right anterior lobe of the cerebellum (p < 0.005, paired t‐test). No region exhibited a decrease in rCMRGlc. Among the items of the UPDRS motor score, the changes in resting tremor and rigidity of the left extremities showed a significant correlation with the changes in rCMRGlc observed in the right premotor area (p < 0.02 and p < 0.05, respectively, Spearman's rank correlation). Conclusions. STN‐DBS either activates the premotor area or normalizes the deactivation of the premotor area. These FDG‐PET findings obtained are consistent with the idea that STN‐DBS modifies the activities of neural circuits involved in motor control.     

Flexible vs. standard subthalamic stimulation in Parkinson disease: A double-blind proof-of-concept cross-over trial

BackgroundDeep brain stimulation (DBS) of the subthalamus (STN) is effective for the treatment of cardinal motor signs of Parkinson disease (PD). Structures around the STN can suppress dyskinesia and tremor (zona incerta) and improve gait and balance (substantia nigra pars reticulata).ObjectiveIs the newer 8-contact linear lead connected to a ‘flexible’ DBS system superior to standard 4-contact stimulation in PD patients receiving STN DBS?MethodsAfter 3 months of open label programming, 10 patients were randomized to standard or flexible stimulation before crossing over to the other arm (3 months each period). Patients and assessors were blinded.ResultsA trend to improvement in Patient Global Impression of Change scores was seen with standard to flexible stimulation and worsening from flexible to standard stimulation (mean ± SD: 0.7 ± 1.2 and −0.4 ± 1.5 respectively, p = 0.152). There was a significant reduction in the number of troublesome symptoms reported prior to DBS (2.6 ± 3.3 per patient), more so with flexible stimulation (0.4 ± 0.6 vs. 1.5 ± 1.6 with standard stimulation, p = 0.001 and p = 0.034). There was no significant difference between the flexible and standard stimulation groups.ConclusionFurther studies confirming that flexible stimulation is superior to standard DBS are warranted.     

Biochemical and electrophysiological changes of substantia nigra pars reticulata driven by subthalamic stimulation in patients with Parkinson's disease

To understand the events underlying the clinical efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN), electrophysiological recordings and microdialysis evaluations were carried out in the substantia nigra pars reticulata (SNr), one of the two basal ganglia (BG) nuclei targeted by STN output, in patients with Parkinson's disease (PD). Clinically effective STN-DBS caused a significant increase of the SNr firing rate. The poststimulus histogram (PSTH) showed an excitation peak at 1.92-3.85 ms after the STN stimulus. The spontaneous discharge of SNr neurons was driven at the frequency of the stimulation (130 Hz), as shown in the autocorrelograms (AutoCrl). The fast Fourier transform (FFT) analysis showed a peak at 130 Hz, and a less pronounced second one at 260 Hz. Accordingly, in the distribution of the interspike intervals (ISIs), the mode was earlier, and skewness more asymmetric. Biochemically, the increased excitatory driving from the STN was reflected by a clear-cut increase in cyclic guanosine 3',5'-monophosphate (cGMP) levels in the SNr. These results indicate that the beneficial effect of DBS in PD patients is paralleled with a stimulus-synchronized activation of the STN target, SNr. Our findings suggest that, during STN-DBS, a critical change towards a high-frequency oscillatory discharge occurs.     

The effect of dexmedetomidine on the firing properties of STN neurons in Parkinson's disease

Dexmedetomidine (an alpha‐2 adrenergic agonist) sedation is commonly used during subthalamic nucleus (STN) deep‐brain stimulation (DBS). Its effects on the electrophysiological characteristics of human STN neurons are largely unknown. We hypothesised that dexmedetomidine modulates the firing rates and bursting of human STN neurons. We analysed microelectrode recording (MER) data from patients with Parkinson's disease who underwent STN DBS. A ‘Dex bolus’ group (dexmedetomidine bolus prior to MER; 27 cells from seven patients) was compared with a ‘no sedation’ group (29 cells from 11 patients). We also performed within‐patient comparisons with varying dexmedetomidine states. Cells were classified as dorsal half or ventral half based on their relative location in the STN. Neuronal burst and oscillation characteristics were analysed using the Kaneoke–Vitek methodology and local field potential (LFP) oscillatory activity was also investigated. Dexmedetomidine was associated with a slight increase in firing rate (41.1 ± 9.9 vs. 34.5 ± 10.6 Hz, P = 0.02) but a significant decrease in burstiness (number of bursts, P = 0.02; burst index, P < 0.001; percentage of spikes in burst, P = 0.002) of dorsal but not ventral STN neurons. This was not associated with modulation of beta oscillations in the spike‐oscillations analysis(beta peak, P = 0.4; signal‐to‐noise ratio in the beta range for spikes and bursts, P = 0.3 and P = 0.5, respectively) and LFP analysis (Beta power, P = 0.17). As bursting pattern is often used to identify STN and guide electrode placement, we recommend that high‐dose dexmedetomidine should be avoided during DBS surgery.     

Neuronal oscillations predict deep brain stimulation outcome in Parkinson's disease

BackgroundNeuronal oscillations are linked to symptoms of Parkinson's disease. This relation can be exploited for optimizing deep brain stimulation (DBS), e.g. by informing a device or human about the optimal location, time and intensity of stimulation. Whether oscillations predict individual DBS outcome is not clear so far.ObjectiveTo predict motor symptom improvement from subthalamic power and subthalamo-cortical coherence.MethodsWe applied machine learning techniques to simultaneously recorded magnetoencephalography and local field potential data from 36 patients with Parkinson's disease. Gradient-boosted tree learning was applied in combination with feature importance analysis to generate and understand out-of-sample predictions.ResultsA few features sufficed for making accurate predictions. A model operating on five coherence features, for example, achieved correlations of r > 0.8 between actual and predicted outcomes. Coherence comprised more information in less features than subthalamic power, although in general their information content was comparable. Both signals predicted akinesia/rigidity reduction best. The most important local feature was subthalamic high-beta power (20–35 Hz). The most important connectivity features were subthalamo-parietal coherence in the very high frequency band (>200 Hz) and subthalamo-parietal coherence in low-gamma band (36–60 Hz). Successful prediction was not due to the model inferring distance to target or symptom severity from neuronal oscillations.ConclusionThis study demonstrates for the first time that neuronal oscillations are predictive of DBS outcome. Coherence between subthalamic and parietal oscillations are particularly informative. These results highlight the clinical relevance of inter-areal synchrony in basal ganglia-cortex loops and might facilitate further improvements of DBS in the future.     

Subthalamic nucleus deep brain stimulation changes speech respiratory and laryngeal control in Parkinson’s disease

Adequate respiratory and laryngeal motor control are essential for speech, but may be impaired in Parkinson’s disease (PD). Bilateral subthalamic nucleus deep brain stimulation (STN DBS) improves limb function in PD, but the effects on respiratory and laryngeal control remain unknown. We tested whether STN DBS would change aerodynamic measures of respiratory and laryngeal control, and whether these changes were correlated with limb function and stimulation parameters. Eighteen PD participants with bilateral STN DBS were tested within a morning session after a minimum of 12 h since their most recent dose of anti-PD medication. Testing occurred when DBS was on, and again 1 h after DBS was turned off, and included aerodynamic measures during syllable production, and standard clinical ratings of limb function. We found that PD participants exhibited changes with DBS, consistent with increased respiratory driving pressure (n = 9) and increased vocal fold closure (n = 9). However, most participants exceeded a typical operating range for these respiratory and laryngeal control variables with DBS. Changes were uncorrelated with limb function, but showed some correlation with stimulation frequency and pulse width, suggesting that speech may benefit more from low-frequency stimulation and shorter pulse width. Therefore, high-frequency STN DBS may be less beneficial for speech-related respiratory and laryngeal control than for limb motor control. It is important to consider these distinctions and their underlying mechanisms when assessing the impact of STN DBS on PD.     

Inhibitory control and error monitoring by human subthalamic neurons

The subthalamic nucleus (STN) has been shown to be implicated in the control of voluntary action, especially during tasks involving conflicting choice alternatives or rapid response suppression. However, the precise role of the STN during nonmotor functions remains controversial. First, we tested whether functionally distinct neuronal populations support different executive control functions (such as inhibitory control or error monitoring) even within a single subterritory of the STN. We used microelectrode recordings during deep brain stimulation surgery to study extracellular activity of the putative associative-limbic part of the STN while patients with severe obsessive-compulsive disorder performed a stop-signal task. Second, 2–4 days after the surgery, local field potential recordings of STN were used to test the hypothesis that STN oscillations may also reflect executive control signals. Extracellular recordings revealed three functionally distinct neuronal populations: the first one fired selectively before and during motor responses, the second one selectively increased their firing rate during successful inhibitory control, and the last one fired selectively during error monitoring. Furthermore, we found that beta band activity (15–35 Hz) rapidly increased during correct and incorrect behavioral stopping. Taken together, our results provide critical electrophysiological support for the hypothesized role of the STN in the integration of motor and cognitive-executive control functions.     

Caregiver burden worsens in the second year after subthalamic nucleus deep brain stimulation for Parkinson's disease

BackgroundCaregiver burden (CB) in Parkinson's disease (PD) does not improve in the short term after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS), despite motor improvement. This may be due to increased caregiver demands after surgery or the possibility that DBS unresponsive non-motor factors, such as executive dysfunction, contribute to CB.ObjectiveTo evaluate the trajectory of CB in year 2 following bilateral STN DBS surgery for PD, and to test whether post-operative CB changes correlate with changes in executive function in a subgroup with available neuropsychological testing.MethodsThis retrospective analysis included 35 patients with PD whose caregivers completed the Caregiver Burden Inventory (CBI) at baseline and between 9 and 24 months after bilateral STN DBS. 14 of these patients had neuropsychological testing both at baseline and within 6 months of their follow up CBI assessment.ResultsCBI scores showed worsened CB from baseline to follow-up (16.4–21.5, p = 0.006). There was no correlation between change in executive function and change in CBI in the smaller subsample.ConclusionCB worsens in the 2 years after bilateral STN DBS despite improvement in motor symptoms and is not associated with change in executive dysfunction in the setting of advancing PD. These findings have implications on pre-operative counselling for patients and caregivers considering DBS for PD.