Subthalamic Nucleus Activity Research Articles

Machine learning explains response variability of deep brain stimulation on Parkinson’s disease quality of life

Improving health-related quality of life (QoL) is crucial for managing Parkinson’s disease. However, QoL outcomes after deep brain stimulation (DBS) of the subthalamic nucleus (STN) vary considerably. Current approaches lack integration of demographic, patient-reported, neuroimaging, and neurophysiological data to understand this variability. This study used explainable machine learning to analyze multimodal factors affecting QoL changes, measured by the Parkinson’s Disease Questionnaire (PDQ-39) in 63 patients, and quantified each variable’s contribution. Results showed that preoperative PDQ-39 scores and upper beta band activity (>20 Hz) in the left STN were key predictors of QoL changes. Lower initial QoL burden predicted worsening, while improvement was associated with higher beta activity. Additionally, electrode positions along the superior-inferior axis, especially relative to the z = −7 coordinate in standard space, influenced outcomes, with improved and worsened QoL above and below this marker. This study emphasizes a tailored, data-informed approach to optimize DBS treatment and improve patient QoL.

STN-PFC circuit related to attentional fluctuations during non-movement decision-making

Decision-making is a cognitive process, in which participants need to attend to relevant information and ignore the irrelevant information. Previous studies have described a set of cortical areas important for attention. It is unclear whether subcortical areas also serve a role. The subthalamic nucleus (STN), a part of basal ganglia, is traditionally considered a critical node in the cortico-basal ganglia-thalamus-cortico network. Given the location of the STN and its widespread connections with cortical and subcortical brain regions, the STN plays an important role in motor and non-motor cognitive processing. We would like to know if STN is also related to fluctuations in attentional task performance, and how the STN interacts with prefrontal cortical regions during the process. We examined neural activities within STN covaried with lapses of attention (defined as behavior error). We found that decreased neural activities in STN were associated with sustained attention. By examining connectivity across STN and various sub-regions of the prefrontal cortex (PFC), we found that decreased connectivity across areas was associated with sustained attention. Our results indicated that decreased STN activities were associated with sustained attention, and the STN-PFC circuit supported this process.

Social context and drug cues modulate inhibitory control in cocaine addiction: involvement of the STN evidenced through functional MRI.

Addictions often develop in a social context, although the influence of social factors did not receive much attention in the neuroscience of addiction. Recent animal studies suggest that peer presence can reduce cocaine intake, an influence potentially mediated, among others, by the subthalamic nucleus (STN). However, there is to date no neurobiological study investigating this mediation in humans. This study investigated the impact of social context and drug cues on brain correlates of inhibitory control in individuals with and without cocaine use disorder (CUD) using functional Magnetic Resonance Imaging (fMRI). Seventeen CUD participants and 17 healthy controls (HC) performed a novel fMRI "Social" Stop-Signal Task (SSST) in the presence or absence of an observer while being exposed to cocaine-related (vs. neutral) cues eliciting craving in drug users. The results showed that CUD participants, while slower at stopping with neutral cues, recovered control level stopping abilities with cocaine cues, while HC did not show any difference. During inhibition (Stop Correct vs Stop Incorrect), activity in the right STN, right inferior frontal gyrus (IFG), and bilateral orbitofrontal cortex (OFC) varied according to the type of cue. Notably, the presence of an observer reversed this effect in most areas for CUD participants. These findings highlight the impact of social context and drug cues on inhibitory control in CUD and the mediation of these effects by the right STN and bilateral OFC, emphasizing the importance of considering the social context in addiction research. They also comfort the STN as a potential addiction treatment target.

Auditory cues modulate the short timescale dynamics of STN activity during stepping in Parkinson's disease

BackgroundGait impairment has a major impact on quality of life in patients with Parkinson's disease (PD). It is believed that basal ganglia oscillatory activity at β frequencies (15–30 Hz) may contribute to gait impairment, but the precise dynamics of this oscillatory activity during gait remain unclear. Additionally, auditory cues are known to lead to improvements in gait kinematics in PD. If the neurophysiological mechanisms of this cueing effect were better understood they could be leveraged to treat gait impairments using adaptive Deep Brain Stimulation (aDBS) technologies. ObjectiveWe aimed to characterize the dynamics of subthalamic nucleus (STN) oscillatory activity during stepping movements in PD and to establish the neurophysiological mechanisms by which auditory cues modulate gait. MethodsWe studied STN local field potentials (LFPs) in eight PD patients while they performed stepping movements. Hidden Markov Models (HMMs) were used to discover transient states of spectral activity that occurred during stepping with and without auditory cues. ResultsThe occurrence of low and high β bursts was suppressed during and after auditory cues. This manifested as a decrease in their fractional occupancy and state lifetimes. Interestingly, α transients showed the opposite effect, with fractional occupancy and state lifetimes increasing during and after auditory cues. ConclusionsWe show that STN oscillatory activity in the α and β frequency bands are differentially modulated by gait-promoting oscillatory cues. These findings suggest that the enhancement of α rhythms may be an approach for ameliorating gait impairments in PD.

Physiological effects of dual target DBS in an individual with Parkinson's disease and a sensing-enabled pulse generator

IntroductionDeep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus (GP) is an established therapy for Parkinson's disease (PD). Novel DBS devices can record local field potential (LFP) physiomarkers from the STN or GP. While beta (13–30 Hz) and gamma (40–90 Hz) STN and GP LFP oscillations correlate with PD motor severity and with therapeutic effects of treatments, STN-GP interactions in electrophysiology in patients with PD are not well characterized. MethodsSimultaneous bilateral STN and GP LFPs were recorded in a patient with PD who received bilateral STN-DBS and GP-DBS. Power spectra in each target and STN-GP coherence were assessed in various ON- and OFF-levodopa and DBS states, both at rest and with voluntary movement. ResultsOFF-levodopa and OFF-DBS, beta peaks were present at bilateral STN and GP, coincident with prominent STN-GP beta coherence. Levodopa and dual-target-DBS (simultaneous STN-DBS and GP-DBS) completely suppressed STN-GP coherence. Finely-tuned gamma (FTG) activity at half the stimulation frequency (62.5 Hz) was seen in the STN during GP-DBS at rest. To assess the effects of movement on FTG activity, we recorded LFPs during instructed movement. We observed FTG activity in bilateral GP and bilateral STN during contralateral body movements while on GP-DBS and ON-levodopa. No FTG was seen with STN-DBS or dual-target-DBS. ConclusionDual-target-DBS and levodopa suppressed STN-GP coherence. FTG throughout the basal ganglia was induced by GP-DBS in the presence of levodopa and movement. This bilateral STN-FTG and GP-FTG corresponded with the least severe bradykinesia state, suggesting a pro-kinetic role for FTG.

The human subthalamic nucleus transiently inhibits active attentional processes.

The subthalamic nucleus (STN) of the basal ganglia is key to the inhibitory control of movement. Consequently, it is a primary target for the neurosurgical treatment of movement disorders like Parkinson's disease, where modulating the STN via deep brain stimulation (DBS) can release excess inhibition of thalamocortical motor circuits. However, the STN is also anatomically connected to other thalamocortical circuits, including those underlying cognitive processes like attention. Notably, STN-DBS can also affect these processes. This suggests that the STN may also contribute to the inhibition of non-motor activity and that STN-DBS may cause changes to this inhibition. Here we tested this hypothesis in humans. We used a novel, wireless outpatient method to record intracranial local field potentials (LFP) from STN DBS implants during a visual attention task (Experiment 1, n = 12). These outpatient measurements allowed the simultaneous recording of high-density EEG, which we used to derive the steady state visual evoked potential (SSVEP), a well established neural index of visual attentional engagement. By relating STN activity to this neural marker of attention (instead of overt behaviour), we avoided possible confounds resulting from STN's motor role. We aimed to test whether the STN contributes to the momentary inhibition of the SSVEP caused by unexpected, distracting sounds. Furthermore, we causally tested this association in a second experiment, where we modulated STN via DBS across two sessions of the task, spaced at least 1 week apart (n = 21, no sample overlap with Experiment 1). The LFP recordings in Experiment 1 showed that reductions of the SSVEP after distracting sounds were preceded by sound-related γ-frequency (>60 Hz) activity in the STN. Trial-to-trial modelling further showed that this STN activity statistically mediated the sounds' suppressive effect on the SSVEP. In Experiment 2, modulating STN activity via DBS significantly reduced these sound-related SSVEP reductions. This provides causal evidence for the role of the STN in the surprise-related inhibition of attention. These findings suggest that the human STN contributes to the inhibition of attention, a non-motor process. This supports a domain-general view of the inhibitory role of the STN. Furthermore, these findings also suggest a potential mechanism underlying some of the known cognitive side effects of STN-DBS treatment, especially on attentional processes. Finally, our newly established outpatient LFP recording technique facilitates the testing of the role of subcortical nuclei in complex cognitive tasks, alongside recordings from the rest of the brain, and in much shorter time than peri-surgical recordings.

7-Tesla Magnetic Resonance Imaging Scanning in Deep Brain Stimulation for Parkinson's Disease: Improving Visualization of the Dorsolateral Subthalamic Nucleus.

Identifying the dorsolateral subthalamic nucleus (STN) for deep brain stimulation (DBS) in Parkinson's disease (PD) can be challenging due to the size and double-oblique orientation. Since 2015 we implemented 7-Tesla T2 weighted magnetic resonance imaging (7 T T2) for improving visualization and targeting of the dorsolateral STN. We describe the changes in surgical planning and outcome since implementation of 7 T T2 for DBS in PD. By comparing two cohorts of STN DBS patients in different time periods we evaluated the influence of 7 T T2 on STN target planning, the number of microelectrode recording (MER) trajectories, length of STN activity and the postoperative motor (UPDRS) improvement. From February 2007 to January 2014, 1.5 and 3-Tesla T2 guided STN DBS with 3 MER channels was performed in 76 PD patients. Average length of recorded STN activity in the definite electrode trajectory was 3.9 ± 1.5 mm. From January 2015 to January 2022 7 T T2 and MER-guided STN DBS was performed in 182 PD patients. Average length of recorded STN activity in the definite electrode trajectory was 5.1 ± 1.3 mm and used MER channels decreased from 3 to 1. Average UPDRS improvement was comparable. Implementation of 7 T T2 for STN DBS enabled a refinement in targeting. Combining classical DBS targeting with dorsolateral STN alignment may be used to determine the optimal trajectory. The improvement in dorsolateral STN visualization can be used for further target refinements, for example adding probabilistic subthalamic connectivity, to enhance clinical outcome of STN DBS.

Subthalamic Activity for Motor Execution and Cancelation in Monkeys.

The subthalamic nucleus (STN) receives cortical inputs via the hyperdirect and indirect pathways, projects to the output nuclei of the basal ganglia, and plays a critical role in the control of voluntary movements and movement disorders. STN neurons change their activity during execution of movements, while recent studies emphasize STN activity specific to cancelation of movements. To address the relationship between execution and cancelation functions, we examined STN activity in two Japanese monkeys (Macaca fuscata, both sexes) who performed a goal-directed reaching task with a delay that included Go, Cancel, and NoGo trials. We first examined responses to the stimulation of the forelimb regions in the primary motor cortex and/or supplementary motor area. STN neurons with motor cortical inputs were found in the dorsal somatomotor region of the STN. All these STN neurons showed activity changes in Go trials, suggesting their involvement in execution of movements. Part of them exhibited activity changes in Cancel trials and sustained activity during delay periods, suggesting their involvement in cancelation of planed movements and preparation of movements, respectively. The STN neurons rarely showed activity changes in NoGo trials. Go- and Cancel-related activity was selective to the direction of movements, and the selectivity was higher in Cancel trials than in Go trials. Changes in Go- and Cancel-related activity occurred early enough to initiate and cancel movements, respectively. These results suggest that the dorsal somatomotor region of the STN, which receives motor cortical inputs, is involved in preparation and execution of movements and cancelation of planned movements.

Dynamic activity model of movement disorders: a unified view to understand their pathophysiology

Malfunction of the basal ganglia leads to movement disorders such as Parkinson's disease, dystonia, Huntington's disease, dyskinesia, and hemiballism, but their underlying pathophysiology is still subject to debate. To understand their pathophysiology in a unified manner, we propose the "dynamic activity model", on the basis of alterations of cortically induced responses in individual nuclei of the basal ganglia. In the normal state, electric stimulation in the motor cortex, mimicking cortical activity during initiation of voluntary movements, evokes a triphasic response consisting of early excitation, inhibition, and late excitation in the output stations of the basal ganglia of monkeys, rodents, and humans. Among three components, cortically induced inhibition, which is mediated by the direct pathway, releases an appropriate movement at an appropriate time by disinhibiting thalamic and cortical activity, whereas early and late excitation, which is mediated by the hyperdirect and indirect pathways, resets on-going cortical activity and stops movements, respectively. Cortically induced triphasic response patterns are systematically altered in various movement disorder models and could well explain the pathophysiology of their motor symptoms. In monkey and mouse models of Parkinson's disease, cortically induced inhibition is reduced and prevents the release of movements, resulting in akinesia/bradykinesia. On the other hand, in a mouse model of dystonia, cortically induced inhibition is enhanced and releases unintended movements, inducing involuntary muscle contractions. Moreover, after blocking the subthalamic nucleus activity in a monkey model of Parkinson's disease, cortically induced inhibition is recovered and enables voluntary movements, explaining the underlying mechanism of stereotactic surgery to ameliorate parkinsonian motor signs. The "dynamic activity model" gives us a more comprehensive view of the pathophysiology underlying motor symptoms of movement disorders and clues for their novel therapies.

Differences in neuronal activity of subthalamic nuclei in asymmetric manifestation of Parkinson’s disease

Parkinson’s disease (PD) is a widely prevalent condition that has spurred extensive research into identifying its biological markers. Different models posit that various patterns of subthalamic nucleus (STN) activity may constitute such markers, but as yet, none have been established definitively. One major limitation of human studies in this area is the lack of a reliable control group. Therefore, patients with asymmetric motor symptoms in Parkinson’s disease are of great interest. I.I. Koloman and A.Sh. Chimagomedova [1] demonstrated that motor malfunctions’ asymmetry is indicative of asymmetry in the degenerative process within the substantia nigra. Additionally, while the disease normally manifests unilaterally, only a limited number of patients maintain notable distinctions in motor symptom severity as the condition advances. In our study, we analyzed the single-unit activity (SUA) and local field potentials (LFP) recordings obtained duringdeep brain stimulation (DBS) surgeries in 12 patients. Neurologists assessed the severity of bradykinesia, rigidity, and tremor using the UPDRS 3 scale to meet the inclusion criteria, and the difference between hemibodies for each symptom had to be at least 25%. The median disease duration at the time of surgery ranged from 6 to 22 years. The subthalamic nucleus that exhibits more pronounced disturbances on the contralateral side of the body is labeled as “affected”, while the opposite STN, acting as the conditional control, is labeled as “nonaffected”. For analysis, we used a hierarchical clustering method following Ward’s algorithm [2] to classify the recorded neurons into three groups based on their activity type: tonic, burst, and pause cells. We observed no significant differences in neuron activity between hemispheres, as well as the predicted hyperactivity of affected STN neurons outlined by the classical model [3] of basal ganglia functioning. However, the research demonstrates a significant increase in pause neurons and decrease in burst neurons within the affected nucleus. Furthermore, both of these types were found to be situated in the upper half of the STN, which is recognized as the motor region of the nucleus. Our hypothesis is that as the disease advances, some STN neurons (specifically burst neurons in our sample) modify their activity patterns towards a more rhythmic activity (pause neurons in our sample). This supports the notion that rhythmic STN neuron activity is linked to Parkinson’s disease [4]. LFPs were analyzed by estimating oscillation synchrony (o-scores) in multiple spectral bands following 1/f correction. Parkinson’s disease is typically associated with boosted oscillation power in the beta range (13–30 Hz). Our findings established that the power of oscillations in the low-frequency beta range (13–20 Hz) were indeed increased in the affected nucleus, but, in contrast to expectations, the power in the high-frequency part (20–30 Hz) of the band was significantly lower. This is in line with the modern theory of distinct physiological functions of oscillations in these subbands [5]. Additionally, we noticed a rise in frequency spectrum in the alpha range (8–12 Hz) and a decrease in the gamma range (30–60 Hz) in the impacted nucleus. Our findings indicate that a more rhythmic burst neuron activity mode and an increased number of pause neurons in the motor zone of the STN can serve as a marker for PD. Increased power oscillation in alpha and low-frequency beta bands, along with reduced synchronization in high-beta and gamma bands, may also be linked to this disorder. However, further investigation is necessary to determine their association with disease symptoms.

Neural activity of the subthalamic nucleus during voluntary movements in patients with Parkinson’s disease

Microelectrode recording (MER) during electrode implantation for deep brain stimulation (DBS) can determine the boundaries of the subthalamic nucleus (STN), and track neural activity during rest and voluntary movement in Parkinson’s disease (PD) patients. However, the functional role of STN in motor control remains unclear, despite its effectiveness in stimulation. Single unit activity of STN was recorded in 16 patients with PD during implantation of deep brain stimulation electrodes. Electromyograms of forearm muscles and a phonogram featuring verbal commands were simultaneously recorded with MER. The patients were instructed to perform motor tests involving clenching their hand into a fist. Out of the 560 neurons studied, 93 (16.6%) responded to motor tasks. The registered neurons were classified into three patterns using the hierarchical clustering method of histograms of interspike interval density — namely, tonic, burst, and pause patterns. Sensitive neurons were classified according to their responses, with activation (76.9%) and inhibition (23.1%) being the two identified types. In 90% of cases, neuron activation preceded movement. Of the responses, 53.8% were classified as tonic and 46.2% as phasic. Two thirds of inhibitory responses were advanced, occurring 0.2–0.3 seconds before movement onset. One third of neurons were activated after movement initiation with a delay of 0.05–0.2 seconds. 83.3% of the inhibitory neurons responded tonically, while the remaining 16.7% responded phasically. Notably, all phasic reactions occurred before the onset of movement. A comparison of the parameters of sensitive and non-sensitive neurons revealed several differences. The findings suggest a potential physiological distinction between the two neuron types. All three patterns of activity were present in both types of neurons, but sensitive neurons exhibited a wider representation of pause neurons (57.9% vs. 49.5%). Additionally, burst and pause neurons responded to movements that featured significantly lower variance of multiple activity parameters, such as firing rate, burst index, mean burst length, and oscillation scores in the 8–12 and 12–20 Hz range. The distribution of sensitive neurons along the electrode trajectory through the subthalamic nucleus was analyzed. Sensitive neurons were located significantly more dorsally compared to non-sensitive neurons, and no sensitive pause cells were observed in the ventral half of the STN. Based on our findings, it is presumed that the pause pattern plays a critical role in both motor control and its related disorders in Parkinson’s disease. A diverse range of neuronal responses suggests a high degree of heterogeneity among STN neurons implicated in motor control. The presence of both delayed and advanced neural responses suggests that STN involvement in motor control encompasses both the preparation and initiation of movement, as well as the regulation of ongoing movements via afferent feedback. The range of neural responses aligns with the dynamic model of basal ganglia, which suggests that STN can perform distinct functional roles during different stages of movement, including initiation, control, and completion.

Average power and burst analysis revealed complementary information on drug-related changes of motor performance in Parkinson’s disease

In patients with Parkinson’s disease (PD), suppression of beta and increase in gamma oscillations in the subthalamic nucleus (STN) have been associated with both levodopa treatment and motor functions. Recent results suggest that modulation of the temporal dynamics of theses oscillations (bursting activity) might contain more information about pathological states and behaviour than their average power. Here we directly compared the information provided by power and burst analyses about the drug-related changes in STN activities and their impact on motor performance within PD patients. STN local field potential (LFP) signals were recorded from externalized patients performing self-paced movements ON and OFF levodopa. When normalised across medication states, both power and burst analyses showed an increase in low-beta oscillations in the dopamine-depleted state during rest. When normalised within-medication state, both analyses revealed that levodopa increased movement-related modulation in the alpha and low-gamma bands, with higher gamma activity around movement predicting faster reaches. Finally, burst analyses helped to reveal opposite drug-related changes in low- and high-beta frequency bands, and identified additional within-patient relationships between high-beta bursting and movement performance. Our findings suggest that although power and burst analyses share a lot in common they also provide complementary information on how STN-LFP activity is associated with motor performance, and how levodopa treatment may modify these relationships in a way that helps explain drug-related changes in motor performance. Different ways of normalisation in the power analysis can reveal different information. Similarly, the burst analysis is sensitive to how the threshold is defined – either for separate medication conditions separately, or across pooled conditions. In addition, the burst interpretation has far-reaching implications about the nature of neural oscillations – whether the oscillations happen as isolated burst-events or are they sustained phenomena with dynamic amplitude variations? This can be different for different frequency bands, and different for different medication states even for the same frequency band.

Dynamic modulation of subthalamic nucleus activity facilitates adaptive behavior.

Adapting actions to changing goals and environments is central to intelligent behavior. There is evidence that the basal ganglia play a crucial role in reinforcing or adapting actions depending on their outcome. However, the corresponding electrophysiological correlates in the basal ganglia and the extent to which these causally contribute to action adaptation in humans is unclear. Here, we recorded electrophysiological activity and applied bursts of electrical stimulation to the subthalamic nucleus, a core area of the basal ganglia, in 16 patients with Parkinson's disease (PD) on medication using temporarily externalized deep brain stimulation (DBS) electrodes. Patients as well as 16 age- and gender-matched healthy participants attempted to produce forces as close as possible to a target force to collect a maximum number of points. The target force changed over trials without being explicitly shown on the screen so that participants had to infer target force based on the feedback they received after each movement. Patients and healthy participants were able to adapt their force according to the feedback they received (P < 0.001). At the neural level, decreases in subthalamic beta (13 to 30 Hz) activity reflected poorer outcomes and stronger action adaptation in 2 distinct time windows (Pcluster-corrected < 0.05). Stimulation of the subthalamic nucleus reduced beta activity and led to stronger action adaptation if applied within the time windows when subthalamic activity reflected action outcomes and adaptation (Pcluster-corrected < 0.05). The more the stimulation volume was connected to motor cortex, the stronger was this behavioral effect (Pcorrected = 0.037). These results suggest that dynamic modulation of the subthalamic nucleus and interconnected cortical areas facilitates adaptive behavior.

Subthalamic Nucleus Activity during Cognitive Load and Gait Dysfunction in Parkinson's Disease.

Gait freezing is a common, disabling symptom of Parkinson's disease characterized by sudden motor arrest during walking. Adaptive deep brain stimulation devices that detect freezing and deliver real-time, symptom-specific stimulation are a potential treatment strategy. Real-time alterations in subthalamic nucleus firing patterns have been demonstrated with lower limb freezing, however, whether similar abnormal signatures occur with freezing provoked by cognitive load, is unknown. We obtained subthalamic nucleus microelectrode recordings from eight Parkinson's disease patients performing a validated virtual reality gait task, requiring responses to on-screen cognitive cues while maintaining motor output. Signal analysis during 15 trials containing freezing or significant motor output slowing precipitated by dual-tasking demonstrated reduced θ frequency (3-8 Hz) firing compared to 18 unaffected trials. These preliminary results reveal a potential neurobiological basis for the interplay between cognitive factors and gait disturbances including freezing in Parkinson's disease, informing development of adaptive deep brain stimulation protocols. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dopamine depletion leads to pathological synchronization of distinct basal ganglia loops in the beta band.

Motor symptoms of Parkinson's Disease (PD) are associated with dopamine deficits and pathological oscillation of basal ganglia (BG) neurons in the β range ([12-30] Hz). However, how dopamine depletion affects the oscillation dynamics of BG nuclei is still unclear. With a spiking neurons model, we here capture the features of BG nuclei interactions leading to oscillations in dopamine-depleted condition. We highlight that both the loop between subthalamic nucleus (STN) and Globus Pallidus pars externa (GPe) and the loop between striatal fast spiking and medium spiny neurons and GPe display resonances in the β range, and synchronize to a common β frequency through interaction. Crucially, the synchronization depends on dopamine depletion: the two loops are largely independent for high levels of dopamine, but progressively synchronize as dopamine is depleted due to the increased strength of the striatal loop. The model is validated against recent experimental reports on the role of cortical inputs, STN and GPe activity in the generation of β oscillations. Our results highlight the role of the interplay between the GPe-STN and the GPe-striatum loop in generating sustained β oscillations in PD subjects, and explain how this interplay depends on the level of dopamine. This paves the way to the design of therapies specifically addressing the onset of pathological β oscillations.

Patterns of neural activity and clinical outcomes in a juvenile Huntington's Disease patient undergoing Deep Brain Stimulation of the subthalamic nucleus

BackgroundHuntington's disease (HD) is a hereditary neurodegenerative disease leading to cognitive and motor impairment. HD depends on basal ganglia dysfunctions, but the role of subthalamic nucleus (STN) neurons is not completely known. Drug-resistant motor symptoms of HD can be alleviated by neuromodulation of the basal ganglia through Deep Brain Stimulation (DBS) of STN. DBS target selection is supported by intra-operative microelectrode recordings (MER). MER have been previously used to characterize neural dynamics of STN in several movement disorders and can provide information on firing patterns underlying HD. MethodsWe analyzed MER data acquired during bilateral DBS of STN in a juvenile HD female patient with hypokinetic motor symptoms (generalized dystonia, stiffness, and severe gait impairment). Firing patterns of STN in HD were characterized by isolating single neuron activities (n = 23) and measuring their regularity, bursting, and oscillatory behavior. Multi-unit activity recordings spectrum was used to estimate the presence of network oscillations. ResultsSTN neurons displayed irregular dynamics and intense and sparse bursting. Only 3/23 neurons presented oscillatory activity. However, network oscillations were detected, in particular in the beta (12–30 Hz) band. After bilateral STN-DBS surgery, the Unified Huntington's Disease Rating Scale decreased from 60 to 54. ConclusionsThe most salient difference between HD and other movement disorders in STN activity is the presence of a weakly synchronized oscillatory mode, in which oscillations are evident at the network level but not at the single neuron level.

Correlated activity in globus pallidus and thalamus during voluntary reaching movement in three children with primary dystonia

Classical models of the physiology of dystonia suggest that involuntary muscle contractions are caused by inappropriately low activity in Globus Pallidus internus (GPi) that fails to adequately inhibit thalamic inputs to cortex. We test this prediction in three children with primary dystonia undergoing depth electrode recording in basal ganglia and thalamus during selection of targets for deep brain stimulation (DBS) implantation. We compare muscle activity to the power in the spectrogram of the local field potential, as well as to counts of identified spikes in GPi, subthalamic nucleus (STN), and the Ventral oralis (VoaVop) and Ventral Anterior (VA) subnuclei of the thalamus, while subjects are at rest or attempting to make active voluntary arm or leg reaching movements. In all three subjects, both spectrogram power and spike activity in GPi, STN, VoaVop, and VA are significantly positively correlated with movement. In particular, GPi and STN both increase activity during attempted movement. These results contradict the classical rate model of the physiology of dystonia, and support more recent models that propose abnormalities in the detailed pattern of activity rather than the overall lumped activity of pallidum and thalamus.

Bilateral deep brain stimulation of the subthalamic nucleus: Targeting differences between the first and second side

Introduction and objectivesDeep brain stimulation (DBS) of the subthalamic nucleus (STN) is a recognized treatment for drug-refractory Parkinson's disease (PD). However, the therapeutic success depends on the accuracy of targeting. This study aimed to evaluate potential accuracy differences in the placement of the first and second electrodes implanted, by comparing chosen electrode trajectories, STN activity detected during microelectrode recording (MER), and the mismatch between the initially planned and final electrode positions on each side. Materials and methodsIn this retrospective cohort study, we analyzed data from 30 patients who underwent one-stage bilateral DBS. For most patients, three arrays of microelectrodes were used to determine the physiological location of the STN. Final target location depended also on the results of intraoperative stimulation. The choice of central versus non-central channels was compared. The Euclidean vector deviation was calculated using the initially planned coordinates and the final position of the tip of the electrode according to a CT scan taken at least a month after the surgery. ResultsThe central channel was chosen in 70% of cases on the first side and 40% of cases on the second side. The mean length of high-quality STN activity recorded in the central channel was longer on the first side than the second (3.07±1.85mm vs. 2.75±1.94mm), while in the anterior channel there were better MER recordings on the second side (1.59±2.07mm on the first side vs. 2.78±2.14mm on the second). Regarding the mismatch between planned versus final electrode position, electrodes on the first side were placed on average 0.178±0.917mm lateral, 0.126±1.10mm posterior and 1.48±1.64mm inferior to the planned target, while the electrodes placed on the second side were 0.251±1.08mm medial, 0.355±1.29mm anterior and 2.26±1.47mm inferior to the planned target. ConclusionThere was a tendency for the anterior trajectory to be chosen more frequently than the central on the second side. There was also a statistically significant deviation of the second electrodes in the anterior and inferior directions, when compared to the electrodes on the first side, suggesting that another cause other than brain shift may be responsible. We should therefore factor this during planning for the second implanted side. It might be useful to plan the second side more anteriorly, possibly reducing the number of MER trajectories tested and the duration of surgery.

Bilateral deep brain stimulation of the subthalamic nucleus: Targeting differences between the first and second side

Introduction and objectivesDeep brain stimulation (DBS) of the subthalamic nucleus (STN) is a recognized treatment for drug-refractory Parkinson's disease (PD). However, the therapeutic success depends on the accuracy of targeting. This study aimed to evaluate potential accuracy differences in the placement of the first and second electrodes implanted, by comparing chosen electrode trajectories, STN activity detected during microelectrode recording (MER), and the mismatch between the initially planned and final electrode positions on each side. Materials and methodsIn this retrospective cohort study, we analyzed data from 30 patients who underwent one-stage bilateral DBS. For most patients, three arrays of microelectrodes were used to determine the physiological location of the STN. Final target location depended also on the results of intraoperative stimulation. The choice of central versus non-central channels was compared. The Euclidean vector deviation was calculated using the initially planned coordinates and the final position of the tip of the electrode according to a CT scan taken at least a month after the surgery. ResultsThe central channel was chosen in 70% of cases on the first side and 40% of cases on the second side. The mean length of high-quality STN activity recorded in the central channel was longer on the first side than the second (3.07±1.85mm vs. 2.75±1.94mm), while in the anterior channel there were better MER recordings on the second side (1.59±2.07mm on the first side vs. 2.78±2.14mm on the second). Regarding the mismatch between planned versus final electrode position, electrodes on the first side were placed on average 0.178±0.917mm lateral, 0.126±1.10mm posterior and 1.48±1.64mm inferior to the planned target, while the electrodes placed on the second side were 0.251±1.08mm medial, 0.355±1.29mm anterior and 2.26±1.47mm inferior to the planned target. ConclusionThere was a tendency for the anterior trajectory to be chosen more frequently than the central on the second side. There was also a statistically significant deviation of the second electrodes in the anterior and inferior directions, when compared to the electrodes on the first side, suggesting that another cause other than brain shift may be responsible. We should therefore factor this during planning for the second implanted side. It might be useful to plan the second side more anteriorly, possibly reducing the number of MER trajectories tested and the duration of surgery.

Therapeutic deep brain stimulation disrupts movement-related subthalamic nucleus activity in parkinsonian mice.

Subthalamic nucleus deep brain stimulation (STN DBS) relieves many motor symptoms of Parkinson's disease (PD), but its underlying therapeutic mechanisms remain unclear. Since its advent, three major theories have been proposed: (1) DBS inhibits the STN and basal ganglia output; (2) DBS antidromically activates motor cortex; and (3) DBS disrupts firing dynamics within the STN. Previously, stimulation-related electrical artifacts limited mechanistic investigations using electrophysiology. We used electrical artifact-free GCaMP fiber photometry to investigate activity in basal ganglia nuclei during STN DBS in parkinsonian mice. To test whether the observed changes in activity were sufficient to relieve motor symptoms, we then combined electrophysiological recording with targeted optical DBS protocols. Our findings suggest that STN DBS exerts its therapeutic effect through the disruption of movement-related STN activity, rather than inhibition or antidromic activation. These results provide insight into optimizing PD treatments and establish an approach for investigating DBS in other neuropsychiatric conditions.