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Abstract

Pathological gambling develops in up to 8% of patients with Parkinson's disease. Although the pathophysiology of gambling remains unclear, several findings argue for a dysfunction in the basal ganglia circuits. To clarify the role of the subthalamic nucleus in pathological gambling, we studied its activity during economics decisions. We analyzed local field potentials recorded from deep brain stimulation electrodes in the subthalamic nucleus while parkinsonian patients with (n = 8) and without (n = 9) pathological gambling engaged in an economics decision-making task comprising conflictual trials (involving possible risk-taking) and non conflictual trials. In all parkinsonian patients, subthalamic low frequencies (2-12 Hz) increased during economics decisions. Whereas, in patients without gambling, low-frequency oscillations exhibited a similar pattern during conflictual and non conflictual stimuli, in those with gambling, low-frequency activity increased significantly more during conflictual than during non conflictual stimuli. The specific low-frequency oscillatory pattern recorded in patients with Parkinson's disease who gamble could reflect a subthalamic dysfunction that makes their decisional threshold highly sensitive to risky options. When parkinsonian patients process stimuli related to an economics task, low-frequency subthalamic activity increases. This task-related change suggests that the cognitive-affective system that drives economics decisional processes includes the subthalamic nucleus. The specific subthalamic neuronal activity during conflictual decisions in patients with pathological gambling supports the idea that the subthalamic nucleus is involved in behavioral strategies and in the pathophysiology of gambling. © 2013 Movement Disorder Society.

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... LFP recordings obtained at rest from the thalamus in patients with TS during tic-free epochs are characterized by activity predominantly at low-frequencies (2-7 Hz) and in the alpha band (8-13 Hz), but not in the beta band (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) [20]. Increased low-frequency intra-thalamic coherence has been reported to not be time-locked with motor tics [18]. ...
... After a rest period to avoid fatigue, the patients were instructed to lift their upper limb after an external cue (right limb first). To determine the time course of single oscillatory bands during the movements, we used the squared module of the Hilbert transform applied to LFPs bandpassed in each band of interest (low-frequency (2-7 Hz) alpha (8)(9)(10)(11)(12)(13), and high beta (20-35 Hz)), as previously described [32]. ...
... After a rest period to avoid fatigue, the patients were instructed to lift their upper limb after an external cue (right limb first). To determine the time course of single oscillatory bands during the movements, we used the squared module of the Hilbert transform applied to LFPs band-passed in each band of interest (low-frequency (2-7 Hz) alpha (8)(9)(10)(11)(12)(13), and high beta (20-35 Hz)), as previously described [32]. ...
Article
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Deep brain stimulation (DBS) has emerged as a novel therapy for the treatment of several movement and neuropsychiatric disorders, and may also be suitable for the treatment of Tourette syndrome (TS). The main DBS targets used to date in patients with TS are located within the basal ganglia-thalamo-cortical circuit involved in the pathophysiology of this syndrome. They include the ventralis oralis/centromedian-parafascicular (Vo/CM-Pf) nucleus of the thalamus and the nucleus accumbens. Current DBS treatments deliver continuous electrical stimulation and are not designed to adapt to the patient's symptoms, thereby contributing to unwanted side effects. Moreover, continuous DBS can lead to rapid battery depletion, which necessitates frequent battery replacement surgeries. Adaptive deep brain stimulation (aDBS), which is controlled based on neurophysiological biomarkers, is considered one of the most promising approaches to optimize clinical benefits and to limit the side effects of DBS. aDBS consists of a closed-loop system designed to measure and analyse a control variable reflecting the patient's clinical condition and to modify on-line stimulation settings to improve treatment efficacy. Local field potentials (LFPs), which are sums of pre- and post-synaptic activity arising from large neuronal populations, directly recorded from electrodes implanted for DBS can theoretically represent a reliable correlate of clinical status in patients with TS. The well-established LFP-clinical correlations in patients with Parkinson's disease reported in the last few years provide the rationale for developing and implementing new aDBS devices whose efficacies are under evaluation in humans. Only a few studies have investigated LFP activity recorded from DBS target structures and the relationship of this activity to clinical symptoms in TS. Here, we review the available literature supporting the feasibility of an LFP-based aDBS approach in patients with TS. In addition, to increase such knowledge, we report explorative findings regarding LFP data recently acquired and analysed in patients with TS after DBS electrode implantation at rest, during voluntary and involuntary movements (tics), and during ongoing DBS. Data available up to now suggest that patients with TS have oscillatory patterns specifically associated with the part of the brain they are recorded from, and thereby with clinical manifestations. The Vo/CM-Pf nucleus of the thalamus is involved in movement execution and the pathophysiology of TS. Moreover, the oscillatory patterns in TS are specifically modulated by DBS treatment, as reflected by improvements in TS symptoms. These findings suggest that LFPs recorded from DBS targets may be used to control new aDBS devices capable of adaptive stimulation responsive to the symptoms of TS.
... A more in-depth knowledge of the STN and its connections also may help shed light on recent unexpected findings related to the electrophysiology of patients with impulse control disorders that predate surgery. Rosa et al. 79 recently showed that during a gambling task, Parkinsonian patients with pathological gambling adopted a riskier strategy than patients without pathological gambling. 79 Those that adopted a conservative strategy showed no difference in lowfrequency STN power (2-12 Hz) between low-and high-conflict trials (Fig. 3A). ...
... Rosa et al. 79 recently showed that during a gambling task, Parkinsonian patients with pathological gambling adopted a riskier strategy than patients without pathological gambling. 79 Those that adopted a conservative strategy showed no difference in lowfrequency STN power (2-12 Hz) between low-and high-conflict trials (Fig. 3A). Those that adopted the risky strategy, however, showed differences between the trial types because of lower-amplitude low-frequency power during the low-conflict trials. ...
... The results shown on the left and right panels are from the same patient on and off of dopaminergic medication. Reproduced with permission from (A) Rosa et al. 79 and (B) Rodriguez-Oroz et al. 77 PD, Parkinson's disease; STN, subthalamic nucleus. Z A V A L A E T A L relationship between theta and behavior or even a compensatory mechanism that ameliorates the deficits induced by chronic dopaminergic activation. ...
Article
The subthalamic nucleus (STN), which is currently the most common target for deep brain stimulation (DBS) for Parkinson's disease (PD), has received increased attention over the past few years for the roles it may play in functions beyond simple motor control. In this article, we highlight several of the theoretical, interventional, and electrophysiological studies that have implicated the STN in response inhibition. Most influential among this evidence has been the reported effect of STN DBS in increasing impulsive responses in the laboratory setting. Yet, how this relates to pathological impulsivity in patients' everyday lives remains uncertain. © 2015 International Parkinson and Movement Disorder Society. © 2015 International Parkinson and Movement Disorder Society.
... To date, only one study has directly related STN activity during decision-making to presence of ICDs in PD. Rosa et al. (2013) used an economic decision-making task with conflictual and nonconflictual trials and recorded LFPs from the STN in PD patients, 8 of whom had pathological gambling. Based on an index of risk, 3 types of behavioral strategy-risky, random and nonrisky-were distinguished, that were, respectively, employed by 6 patients with pathological gambling, 5 patients (3 with pathological gambling and 2 without), and 6 patients without pathological gambling. ...
... These results directly relate low frequency STN activity to adoption of risky strategies in patients with PD and pathological gambling. Similar to these findings from Rosa et al. (2013), Rodriguez-Oroz et al. (2011) of research on impulsivity in PD, respectively, focused on ICDs and STN DBS induced inhibitory deficits. They recorded LFPs from the STN and reported that on medication, 10 PD patients who had ICDs before surgery had theta-alpha (4-10 Hz) activity generated 2-8 mm below the intercommissural line from the ventral contacts and cortico-subthalamic coherence in the 4-7.5 Hz range in scalp electrodes over the prefrontal cortex. ...
... Support is also provided based on the evidence reviewed above for speed-accuracy trade-off models which attributed a role to the STN in modulating response thresholds and influencing speed-accuracy trade-offs (Bogacz et al., 2010;Mansfield et al., 2011). As recently noted (Jahanshahi, 2013), what remains unclear is whether it is conflict per se (Cavanagh et al., 2011;Fumagalli et al., 2011;Zaghloul et al., 2012;Zavala et al., 2013), choice difficulty (Zaghloul et al., 2012;Green et al., 2013), choice accuracy (Zaghloul et al., 2012), the appetitive/aversive valence of the choices , information integration (Coulthard et al., 2012), adoption of a risk-taking strategy (Rosa et al., 2013) or simply time pressure (Pote et al., in preparation) that influences STN activity and engages it to dynamically modulate response thresholds. These possibilities need to be directly investigated and disentangled in future studies. ...
Article
Full-text available
Inhibition of inappropriate, habitual or prepotent responses is an essential component of executive control and a cornerstone of self-control. Via the hyperdirect pathway, the subthalamic nucleus (STN) receives inputs from frontal areas involved in inhibition and executive control. Evidence is reviewed from our own work and the literature suggesting that in Parkinson's disease (PD), deep brain stimulation (DBS) of the STN has an impact on executive control during attention-demanding tasks or in situations of conflict when habitual or prepotent responses have to be inhibited. These results support a role for the STN in an inter-related set of processes: switching from automatic to controlled processing, inhibitory and executive control, adjusting response thresholds and influencing speed-accuracy trade-offs. Such STN DBS-induced deficits in inhibitory and executive control may contribute to some of the psychiatric problems experienced by a proportion of operated cases after STN DBS surgery in PD. However, as no direct evidence for such a link is currently available, there is a need to provide direct evidence for such a link between STN DBS-induced deficits in inhibitory and executive control and post-surgical psychiatric complications experienced by operated patients.
... We enrolled 12 patients with PD 4 days after STN DBS macroelectrode positioning surgery as described elsewhere 3 (for clinical details, see table 1 from Ref. 3, patients number 1 -4, 8-12, 14, 15, 17). Of the 12 patients, 6 met the criteria for PG according to the Diagnostic and Statistical Manual of Mental Disorders (DSM IV-TR). ...
... Then, to obtain the mean frequency band power in conflictual and non-conflictual task conditions during the two task phases (black screen, feedback) for each type of feedback (risky positive, risky negative, non-risky positive, non-risky negative), we applied the Hilbert transform. 3 For behavioural analyses, the economics strategy each patient used during task performance was evaluated by calculating the sum of risky choices in conflictual trials. Differences between economics strategies in patients with and without PG were tested in a one-way analysis of variance (ANOVA) using PG (presence, absence) as between factor. ...
... 5 Our previous findings on the preparation of economics decision in parkinsonian patients with PG showed a subthalamic dysfunction that makes their decisional threshold highly sensitive to risky options. 3 In this study, we extend these results, suggesting that STN activity is also affected by reward and that PG could be related to a reward circuit disorder. Contributors MF and MR contributed equally to this study. ...
Article
Full-text available
Pathological gambling (PG) is an impulse control disorder that manifests in 2.2-7% of patients with Parkinson's disease (PD). Although the underlying neural mechanisms remain controversial, parkinsonian patients with PG show enhanced risk propensity, especially when assuming dopamine agonist drugs. The dopaminergic reward circuit, a neural network that participates in developing and monitoring motivated behaviours,1 includes the subthalamic nucleus (STN). Local field potentials (LFPs) recorded from macroelectrodes implanted in the STN for deep brain stimulation (DBS) show specific low-frequency oscillations in patients with PD with impulsive control disorders at rest and in patients with PG during the preparation of conflictual economics decisions.2 ,3 No study has yet investigated STN involvement in monetary reward processing, namely the phase that follows economics decisions, when participants face the outcome of their choice in patients with PD. Besides helping to understand the mechanisms underlying PG, this knowledge could promote the optimisation of therapies for impulse control disorders. We investigated the STN's role in risk-related monetary reward in parkinsonian patients. To do so, we studied the reward-related STN LFPs changes in patients with PD with and without PG engaged in an economics decision task.
... In PD patients with preoperative ICDs, theta activity in the STN was maximal in ventral electrodes, in agreement with impulsivity-related oscillatory changes 80 and behavioral effects of DBS. 81,82 The results of Rosa et al. 83 directly related low-frequency STN activity to adoption of risky strategies in patients with PD and pathological gambling. Thus, the current neurophysiological evidence strongly suggests that the STN is involved in inhibition, but does not conclusively demonstrate that it leads the cortex in inhibition. ...
... What remains unclear from the behavioral STN-DBS on versus off studies, imaging, and electrophysiological evidence is whether it is conflict per se, 122 choice difficulty, 79,95 the appetitive/aversive valence of the choices, 27 adoption of a risk-taking strategy, 83 information integration, 88 or acting under time pressure 96 that influence STN activity and adjustment of response thresholds. Future studies are required to refine which contacts or stimulation frequencies alter inhibition and thus will contribute to a better understanding of the current inconsistent results with improvement versus worsening of executive and inhibitory control on different tasks after STN-DBS. ...
... 101,123,124 Certainly, this is an imbalance that needs to be addressed in the future. Similarly, despite ample evidence for psychiatric problems suggestive of disinhibition following STN surgery in PD, with the exception of the two studies showing an association between STN LFP activity and ICDs in PD, 80,83 no efforts have been made to directly link the psychiatric sequelae of STN surgery to deficits in inhibitory control. Provision of such direct evidence is important from both clinical and theoretical perspectives. ...
Article
Although Parkinson's disease (PD) is primarily considered a disorder of initiation of actions, patients also have deficits in inhibitory control, both in the motor and cognitive domains. Impulse control disorders, which can develop in association with dopaminergic medication in a small proportion of patients with PD, are the symptoms most commonly considered as representing inhibitory deficits. However, there is now also a body of evidence suggesting a role for the subthalamic nucleus (STN), which is ordinarily hyperactive in PD, in inhibitory control. Here, we review evidence from animal studies, imaging studies, and investigations recording STN activity intra- or perioperatively in patients with PD having surgery for DBS of the STN (STN-DBS). We also highlight relevant hypotheses about the role of the STN and consider evidence from studies that have examined the effect of STN-DBS in patients with PD on performance of experimental tasks requiring inhibition of prepotent or habitual responses or decision making under conflict, as well as the psychiatric side effects of STN-DBS. Though the results are not always consistent, nevertheless, this body of evidence supports the role of the STN in inhibitory and executive control. © 2014 International Parkinson and Movement Disorder Society
... The authors showed that STN low-frequency oscillatory power (< 10 Hz) was modulated by the size of a promised monetary reward, with increased power when the reward was high. In another study focusing on gambling in PD patients, the authors proposed a task in which patients, with or without pathological gambling, had to choose a stimuli that could represent either a monetary loss or a gain with different probabilities (Rosa et al., 2013). In that study, modulation of STN oscillatory power in response to a potential reward was also described in the low frequencies (< 12 Hz). ...
... As a result, the STN activity might reflect integration of both cognitive processes. This proposition has received support from recordings of STN activity in animals (Isoda & Hikosaka, 2008;Espinosa-Parilla et al., 2015) and in humans (Zaghloul et al., 2012;Rosa et al., 2013;Fumagalli et al., 2015). Conflict has been associated with increase in theta band power in STN LFPs in numerous studies (see Zavala et al., 2015 for a review). ...
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Cognitive action control depends on cortical-subcortical circuits, involving notably the subthalamic nucleus (STN), as evidenced by local field potentials recordings (LFPs) studies. The STN consistently shows an increase in theta oscillations power during conflict resolution. Some studies have shown that cognitive action control in Parkinson's disease (PD) could be influenced by the occurrence of monetary reward. In this study, we investigated whether incentive motivation could modulate STN activity, and notably STN theta activity, during response conflict resolution. To achieve this objective, we recorded STN LFPs during a motivated Simon task in PD patients who had undergone deep brain stimulation surgery. Behavioral results revealed that promised rewards increased the difficulty in resolving conflict situations, thus replicating previous findings. Signal analyses locked on the imperative stimulus onset revealed the typical pattern of increased theta power in a conflict situation. However, this conflict-related modulation of theta power was not influenced by the size of the reward cued. We nonetheless identified a significant effect of the reward size on local functional organization (indexed by inter-trial phase clustering) of theta oscillations, with higher organization associated with high rewards while resolving conflict. When focusing on the period following the onset of the reward cue, we unveiled a stronger beta power decrease in higher reward conditions. However, these LFPs results were not correlated to behavioral results. Our study suggests that the STN is involved in how reward information can influence computations during conflict resolution. However, considering recent studies as well as the present results, we suspect that these effects are subtle.
... 85 Patients with Parkinson's disease with gambling disorders also have more low frequency activity in the subthalamic nucleus during risk-taking or confl ictual choices than do patients with Parkinson's disease without impulse control disorders. 86 Rodent models of Parkinson's disease reveal an eff ect of both parkinsonian lesions and individual impulsivity traits on motor impulsivity. In rats, α-synuclein-induced nigrostriatal neurodegeneration increases waiting impulsivity (a tendency to respond too early) and impulsive action compared with sham controls. ...
... Other potential mechanisms include shifting stimulation towards a continuous rather than pulsatile dopaminergic stimulation, or possibly normalising abnormal low frequency oscillations that have been shown to be enhanced in gambling disorders with confl ictual risky choices. 86 However, not all impulse control disorder subtypes respond equally; in particular, pathological eating behaviours might be more likely to not improve, worsen, or have de-novo onset. 111 Cognitive mechanisms underlying impulse control disorders and the eff ect of subthalamic nucleus DBS could explain the diff erential eff ect of DBS on reward subtypes. ...
Article
Full-text available
Dopaminergic medications used in the treatment of patients with Parkinson's disease are associated with motor and non-motor behavioural side-effects, such as dyskinesias and impulse control disorders also known as behavioural addictions. Levodopa-induced dyskinesias occur in up to 80% of patients with Parkinson's after a few years of chronic treatment. Impulse control disorders, including gambling disorder, binge eating disorder, compulsive sexual behaviour, and compulsive shopping occur in about 17% of patients with Parkinson's disease on dopamine agonists. These behaviours reflect the interactions of the dopaminergic medications with the individual's susceptibility, and the underlying neurobiology of Parkinson's disease. Parkinsonian rodent models show enhanced reinforcing effects of chronic dopaminergic medication, and a potential role for individual susceptibility. In patients with Parkinson's disease and impulse control disorders, impairments are observed across subtypes of decisional impulsivity, possibly reflecting uncertainty and the relative balance of rewards and losses. Impairments appear to be more specific to decisional than motor impulsivity, which might reflect differences in ventral and dorsal striatal engagement. Emerging evidence suggests impulse control disorder subtypes have dissociable correlates, which indicate that individual susceptibility predisposes towards the expression of different behavioural subtypes and neurobiological substrates. Therapeutic interventions to treat patients with Parkinson's disease and impulse control disorders have shown efficacy in randomised controlled trials. Large-scale studies are warranted to identify individual risk factors and novel therapeutic targets for these diseases. Mechanisms underlying impulse control disorders and dyskinesias could provide crucial insights into other behavioural symptoms in Parkinson's disease and addictions in the general population.
... Similarly, a recent structural MRI study observed a linear relationship between structural connectivity of a "reward evaluation" circuit and risky gambling in the ICD-group, but not in the ICD+ group, in the absence of differences in gambling behaviour between the groups. 52,53,5 Previous electrophysiological studies found risky strategies in gambling to manifest differently in STN in ICD+ patients. 52,53 Our finding suggests that STN activity relates to how soon ICD-patients stop their risky engagement, but that this relationship is disturbed in ICD+ patients. ...
... 52,53,5 Previous electrophysiological studies found risky strategies in gambling to manifest differently in STN in ICD+ patients. 52,53 Our finding suggests that STN activity relates to how soon ICD-patients stop their risky engagement, but that this relationship is disturbed in ICD+ patients. ...
Article
Full-text available
Dopaminergic treatment may impair the ability to suppress impulsive behaviours in patients with Parkinson's disease, triggering impulse control disorders. It is unclear how dopaminergic medication affects the neural networks that contribute to withholding inappropriate actions. To address this question, we mapped brain activity with whole-brain functional magnetic resonance imaging at 3 Tesla, while 26 patients with Parkinson’s disease performed a sequential gambling task while being ON and OFF their regular dopaminergic treatment. During a gambling round, patients repeatedly decided between the option to continue with gambling and accumulate more monetary reward under increasing risk or the option to bank the current balance and start a new round. 13 patients had an impulse control disorder (ICD+ group). These patients did not differ in risk-taking attitude during sequential gambling from 13 patients without impulse control disorder (ICD group–), but they displayed differences in gambling-related activity in cortico-subcortical brain areas supporting inhibitory control. First, the ICD+ group showed reduced “continue-to-gamble” activity in right inferior frontal gyrus and subthalamic nucleus. Second, the individual risk-attitude scaled positively with “continue-to-gamble” activity in right subthalamic nucleus and striatum in the ICD- group only. Third, ICD+ patients differed in their functional neural responses to dopaminergic treatment from ICD- patients: dopaminergic therapy reduced functional connectivity between inferior frontal gyrus and subthalamic nucleus during “continue-to-gamble” decisions and attenuated striatal responses towards accumulating reward and risk. Together, the medication-independent (trait) and medication-related (state) differences in neural activity may set a permissive stage for the emergence of impulse control disorders during dopamine replacement therapy in Parkinsońs disease.
... The authors showed that STN low-frequency oscillatory power (<10 Hz) was modulated by the size of a promised monetary reward, with increased power when the reward was high. In another study focusing on gambling in PD patients, the authors proposed a task in which patients, with or without pathological gambling, had to choose a stimuli that could represent either a monetary loss or a gain with different probabilities (Rosa et al., 2013). In that study, modulation of STN oscillatory power in response to a potential reward was also described in the low frequencies (<12 Hz). ...
... As a result, the STN activity might reflect integration of both cognitive processes. This proposition has received support from recordings of STN activity in animals (Isoda and Hikosaka, 2008;Espinosa-Parrilla et al., 2015) and in humans (Zaghloul et al., 2012;Rosa et al., 2013;Fumagalli et al., 2015). ...
Article
Full-text available
Cognitive action control depends on cortical-subcortical circuits, involving notably the subthalamic nucleus (STN), as evidenced by local field potentials recordings (LFPs) studies. The STN consistently shows an increase in theta oscillations power during conflict resolution. Some studies have shown that cognitive action control in Parkinson's disease (PD) could be influenced by the occurrence of monetary reward. In this study, we investigated whether incentive motivation could modulate STN activity, and notably STN theta activity, during response conflict resolution. To achieve this objective, we recorded STN LFPs during a motivated Simon task in PD patients who had undergone deep brain stimulation surgery. Behavioral results revealed that promised rewards increased the difficulty in resolving conflict situations, thus replicating previous findings. Signal analyses locked on the imperative stimulus onset revealed the typical pattern of increased theta power in a conflict situation. However, this conflict-related modulation of theta power was not influenced by the size of the reward cued. We nonetheless identified a significant effect of the reward size on local functional organization (indexed by inter-trial phase clustering) of theta oscillations, with higher organization associated with high rewards while resolving conflict. When focusing on the period following the onset of the reward cue, we unveiled a stronger beta power decrease in higher reward conditions. However, these LFPs results were not correlated to behavioral results. Our study suggests that the STN is involved in how reward information can influence computations during conflict resolution. However, considering recent studies as well as the present results, we suspect that these effects are subtle.
... While the alpha frequency band appears to be important for emotional processing in the STN (Brücke et al., 2007;Huebl et al., 2011;Kühn et al., 2005), motivational processing in the STN has been related to the theta band (Pearson et al., 2017;Rosa et al., 2013;Zénon et al., 2016). STN LFP recordings from PD patients while they had to decide whether to engage in a task based on the level of effort required and the value of the reward promised in return revealed a robust low frequency response (1-10 Hz) to both reward and effort cues (Zénon et al., 2016). ...
... Interestingly, the response was informative of the subjective value of the reward and level of effort rather than their actual quantities, such that they were predictive of the participant's decision (Zénon et al., 2016). A similar increase in STN LFP low frequency power (2-12 Hz) was also observed in PD patients with and without pathological gambling during an economic decision-making task (Rosa et al., 2013). In an attempt to dissociate the role of theta oscillations during economic decisions, microelectrode recordings in PD patients off dopaminergic medications were made during the performance of a self-paced risk-reward decision making task (Pearson et al., 2017). ...
Article
Full-text available
Recent progress in targeted interrogation of basal ganglia structures and networks with deep brain stimulation in humans has provided insights into the complex functions the subthalamic nucleus (STN). Beyond the traditional role of the STN in modulating motor function, recognition of its role in cognition was initially fueled by side effects seen with STN DBS and later revealed with behavioural and electrophysiological studies. Anatomical, clinical, and electrophysiological data converge on the view that the STN is a pivotal node linking cognitive and motor processes. The goal of this review is to synthesize the literature to date that used DBS to examine the contributions of the STN to motor and non-motor cognitive functions and control. Multiple modalities of research have provided us with an enhanced understanding of the STN and reveal that it is critically involved in motor and non-motor inhibition, decision-making, motivation and emotion. Understanding the role of the STN in cognition can enhance the therapeutic efficacy and selectivity not only for existing applications of DBS, but also in the development of therapeutic strategies to stimulate aberrant circuits to treat non-motor symptoms of Parkinson's disease and other disorders.
... Another interesting point is the correlation between theta power and OCB comorbidities, which is consistent over time: larger theta power before DBS is turned ON (as in the acute setting) is associated with larger improvement in YBOCS, thus suggesting to be a predictor of better thalamic DBS outcome on psychiatric comorbidities. Theta power in the basal-gangliathalamo-cortical loop has been shown to be related to nonmotor functions, such as decision processes (37), reward, and moral and ethical behaviors (38). For instance, larger responses in the theta power have been associated with compulsive behaviors in gamblers with Parkinson's disease (37). ...
... Theta power in the basal-gangliathalamo-cortical loop has been shown to be related to nonmotor functions, such as decision processes (37), reward, and moral and ethical behaviors (38). For instance, larger responses in the theta power have been associated with compulsive behaviors in gamblers with Parkinson's disease (37). We can therefore hypothesize that DBS delivered in the Cm-Pf/VO target is able to interfere also with OCB comorbidities, especially in those patients with larger theta band before DBS is turned ON, possibly related to a positioning of the target electrodes in areas encoding also non-motor information. ...
Article
Full-text available
Background: Local field potential (LFP) recordings helped to clarify the pathophysiology of Tourette syndrome (TS) and to define new strategies for deep brain stimulation (DBS) treatment for refractory TS, based on the delivery of stimulation in accordance with changes in the electrical activity of the DBS target area. However, there is little evidence on the relationship between LFP pattern and DBS outcomes in TS. Objective: To investigate the relationship between LFP oscillations and DBS effects on tics and on obsessive compulsive behavior (OCB) comorbidities. Methods: We retrospectively analyzed clinical data and LFP recordings from 17 patients treated with DBS of the centromedian-parafascicular/ventralis oralis (CM-Pf/VO) complex, and followed for more several years after DBS in the treating center. In these patients, LFPs were recorded either in the acute setting (3–5 days after DBS electrode implant) or in the chronic setting (during impulse generator replacement surgery). LFP oscillations were correlated with the Yale Global Tic Severity Scale (YGTSS) and the Yale–Brown Obsessive–Compulsive Scale (Y-BOCS) collected at baseline (before DBS surgery), 1 year after DBS, and at the last follow-up available. Results: We found that, at baseline, in the acute setting, the power of the oscillations included in the 5–15-Hz band, previously identified as TS biomarker, is correlated with the pathophysiology of tics, being significantly correlated with total YGTSS before DBS (Spearman's ρ = 0.701, p = 0.011). The power in the 5–15-Hz band was also correlated with the improvement in Y-BOCS after 1 year of DBS (Spearman's ρ = −0.587, p = 0.045), thus suggesting a relationship with the DBS effects on OCB comorbidities. Conclusions: Our observations confirm that the low-frequency (5–15-Hz) band is a significant biomarker of TS, being related to the severity of tics and, also to the long-term response on OCBs. This represents a step toward both the understanding of the mechanisms underlying DBS effects in TS and the development of adaptive DBS strategies.
... 85 Patients with Parkinson's disease with gambling disorders also have more low frequency activity in the subthalamic nucleus during risk-taking or confl ictual choices than do patients with Parkinson's disease without impulse control disorders. 86 Rodent models of Parkinson's disease reveal an eff ect of both parkinsonian lesions and individual impulsivity traits on motor impulsivity. In rats, α-synuclein-induced nigrostriatal neurodegeneration increases waiting impulsivity (a tendency to respond too early) and impulsive action compared with sham controls. ...
... Other potential mechanisms include shifting stimulation towards a continuous rather than pulsatile dopaminergic stimulation, or possibly normalising abnormal low frequency oscillations that have been shown to be enhanced in gambling disorders with confl ictual risky choices. 86 However, not all impulse control disorder subtypes respond equally; in particular, pathological eating behaviours might be more likely to not improve, worsen, or have de-novo onset. 111 Cognitive mechanisms underlying impulse control disorders and the eff ect of subthalamic nucleus DBS could explain the diff erential eff ect of DBS on reward subtypes. ...
Article
Dopaminergic medications used in the treatment of patients with Parkinson's disease are associated with motor and non-motor behavioural side-effects, such as dyskinesias and impulse control disorders also known as behavioural addictions. Levodopa-induced dyskinesias occur in up to 80% of patients with Parkinson's after a few years of chronic treatment. Impulse control disorders, including gambling disorder, binge eating disorder, compulsive sexual behaviour, and compulsive shopping occur in about 17% of patients with Parkinson's disease on dopamine agonists. These behaviours reflect the interactions of the dopaminergic medications with the individual's susceptibility, and the underlying neurobiology of Parkinson's disease. Parkinsonian rodent models show enhanced reinforcing effects of chronic dopaminergic medication, and a potential role for individual susceptibility. In patients with Parkinson's disease and impulse control disorders, impairments are observed across subtypes of decisional impulsivity, possibly reflecting uncertainty and the relative balance of rewards and losses. Impairments appear to be more specific to decisional than motor impulsivity, which might reflect differences in ventral and dorsal striatal engagement. Emerging evidence suggests impulse control disorder subtypes have dissociable correlates, which indicate that individual susceptibility predisposes towards the expression of different behavioural subtypes and neurobiological substrates. Therapeutic interventions to treat patients with Parkinson's disease and impulse control disorders have shown efficacy in randomised controlled trials. Large-scale studies are warranted to identify individual risk factors and novel therapeutic targets for these diseases. Mechanisms underlying impulse control disorders and dyskinesias could provide crucial insights into other behavioural symptoms in Parkinson's disease and addictions in the general population.
... Though theta oscillations in the basal ganglia have traditionally been associated with pathologic tremors (Deuschl et al. 1996;Magariños-Ascone et al. 2000), a growing body of evidence suggests that both mPFC and STN theta oscillations may play a physiologic role in encoding conflict. Both sites demonstrate conflict-related increases in theta-band activity (Cavanagh et al. , 2012Cohen and Cavanagh 2011;Fumagalli et al. 2011;Zavala et al. 2013Zavala et al. , 2014Cohen and van Gaal 2014), altered theta-band activity has been associated with impulse control disorders Rodriguez-Oroz et al. 2011;Rosa et al. 2013), and mPFC theta oscillations drive those of the STN during conflict (Zavala et al. 2014). Furthermore, previous studies suggest that STN DBS both alters activity in the mPFC (Ballanger et al. 2009) and reverses the relation between mPFC theta oscillations and conflict-induced slowing . ...
Article
Recent evidence has suggested that prefrontal cortical structures may inhibit impulsive actions during conflict through activation of the subthalamic nucleus (STN). Consistent with this hypothesis, deep brain stimulation to the STN has been associated with altered prefrontal cortical activity and impaired response inhibition. The interactions between oscillatory activity in the STN and its presumably antikinetic neuronal spiking, however, remain poorly understood. Here, we simultaneously recorded intraoperative local field potential and spiking activity from the human STN as participants performed a sensorimotor action selection task involving conflict. We identified several STN neuronal response types that exhibited different temporal dynamics during the task. Some neurons showed early, cue-related firing rate increases that remained elevated longer during high conflict trials, whereas other neurons showed late, movement-related firing rate increases. Notably, the high conflict trials were associated with an entrainment of individual neurons by theta- and beta-band oscillations, both of which have been observed in cortical structures involved in response inhibition. Our data suggest that frequency-specific activity in the beta and theta bands influence STN firing to inhibit impulsivity during conflict.
... Indeed, stimulating risk-taking and instrumental risk-taking have different impacts on risk processing and management of related information. This datum has been shown in certain categories of patients, such as cocaine users and Parkinson's disease sufferers (Gorini et al., 2014;Rosa et al., 2013). Subjects for whom the stimulating orientation prevails are characterised by high levels of impulsivity and quick decision-making. ...
Article
Optimistic bias defines the tendency for human beings to underrate risk when it pertains to themselves compared with their view of risk pertaining to other people in the same conditions. The aim of this work is to investigate the optimistic bias in risk perception and health-related behaviours for three specific conditions in a young adult sample: cancer, respiratory disorders and cardiovascular diseases. Young adults showed an optimistic bias related to cancer, and to cardiovascular diseases. Our findings suggest that optimistic bias is linked to specific behavioural patterns, largely widespread in young adults, such as tobacco cigarette smoking and alcohol consumption.
... It is thought that the dopamine mediated reward system underpins substance abuse and it is possible that the same neural substrate mediates gambling. In line with this is the finding that dopaminergic medication (e.g. for Parkinson's disease) may increase urges to gamble (Rosa et al., 2013). One of the most interesting findings in the study by Goldstein and Volkow (2011) was the strong involvement of the putamen. ...
Article
Research has found gambling to be related to a variety of other addictive behaviours. The study objective was to evaluate the association of Internet gambling with Internet addiction, online sexual engagement, suicidality and substance use, in a sample of Greek adults. The study sample consisted of 789 military personnel. During their annual medical examination the study participants anonymously completed a series of self-reported questionnaires in relation to socio-demographic data, Internet gambling practices, online sexual engagement, Internet addiction, suicidality and psychoactive substance use. We found that Internet addiction significantly predicted engagement with online gambling, followed by substance use in general, and, in particular, the use of cocaine or heroin. Finally, two other predictive indicators were self-reported suicide attempts and engagement with online sex. Online gambling is associated with various behaviours related to impulsivity such as Internet addiction, online sexual engagement, suicidality and substance use. Future research will increase our knowledge on the contribution of new technologies and the Internet in Internet gambling dimensions, as well as on the associations with other high-risk behaviours such as substance use, pornography and suicidality.
... Furthermore, on the stop-signal task, patients with PD without ICDs show an inhibition-related decrease in gamma-band activity (interpreted as cancellation of the intention to act) that was absent in the patients with PD with ICDs 67 , suggesting that the latter group have problems with inhibition. Compared with patients with PD and no ICDs, patients with PD and pathological gambling adopted more risky strategies during an economic decision-making task and showed larger changes in low-frequency power in the STN on trials with conflicting stimuli than on those with non-conflicting stimuli 109 . ...
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Classically, the basal ganglia have been considered to have a role in producing habitual and goal-directed behaviours. In this article, we review recent evidence that expands this role, indicating that the basal ganglia are also involved in neural and behavioural inhibition in the motor and non-motor domains. We then distinguish between goal-directed and habitual (also known as automatic) inhibition mediated by fronto-striato-subthalamic-pallido-thalamo-cortical networks. We also suggest that imbalance between goal-directed and habitual action and inhibition contributes to some manifestations of Parkinson's disease, Tourette syndrome and obsessive-compulsive disorder. Finally, we propose that basal ganglia surgery improves these disorders by restoring a functional balance between facilitation and inhibition.
... They have observed a generally increased blood flow in the OFC, hippocampus, parahippocampal gyrus, amygdala, ventral striatum and cuneus on the right hemisphere and in the insulae on both sides in Parkinson's patients with pathological gambling compared to both other groups. Rosa et al. (2013) studied the function of the subthalamic nucleus by capturing local field potentials (LFP) in Parkinson's patients with and without pathological gambling on medication during an economic task. The LFPs were recorded with the aid of STN DBS electrodes that were implanted 4 days prior to the experiment. ...
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The incidence of pathological gambling in Parkinson's patients is significantly greater than in the general population. A correlation has been observed between dopamine agonist medication and the development of pathological gambling. However, scientists conjecture that the affected patients have underlying risk factors. Studies analysing Parkinson's patients have detected that patients who developed pathological gambling are younger, score higher on novelty-seeking tests, are more impulsive and are more likely to have a personal or family history of alcohol addiction. In addition, some genetic variations have been associated with the susceptibility of developing pathological gambling, which include mutations of DRD3, 5-HTTLPR and GRIN2B. Studies focusing on neurofunctional discrepancies between Parkinson's patients with and without pathological gambling have found increased functional activation and dopamine release in regions associated with the mesolimbic reward system. Further, there is also evidence showing increased processing of reward and decreased activation elicited by punishment, suggesting altered learning processes. Further, the role of deep brain stimulation of the nucleus subthalamicus (STN DBS) is controversial. In most Parkinson's patients, pathological gambling resolved after the initiation of the STN DBS, which might be explained by discontinuation or decrease of dopamine agonist medication. However, it has been also shown that some patients are more impulsive while the STN DBS is activated. These differences may depend on the DBS localisation in the more limbic or motor part of the STN and their regulative effects on impulsivity. Further research is needed to clarify susceptibility factors for the development of pathological gambling in Parkinson's patients. This article is protected by copyright. All rights reserved.
... Electrophysiological studies in parkinsonian patients have also shown that enhanced control over decisions and actions is associated with changes in oscillatory activity in local field potentials (LFPs) recorded in the STN (Cavanagh et al., 2011;Brittain et al., 2012;Zavala et al., 2014). Recent electrophysiological studies have emphasized the contribution of STN to motivational and emotional processes (Huebl et al., 2014;Sieger et al., 2015) and a few studies have pointed out specific changes in STN LFP oscillations in parkinsonian patients during reward-based decisions (Rosa et al., 2013;Fumagalli et al., 2014). It has further been shown that STN stimulation in these patients may lead to mood disturbances, such as depression and hypomania (Appleby et al., 2007;Péron et al., 2013), possibly reflecting impaired reward processing. ...
Article
The subthalamic nucleus (STN) has been argued to be an important component of reward-sensitive basal ganglia circuitry. This view is especially supported by the behavioral changes observed after STN inactivation which could reflect impairments in the motivational control of action. However, it is still unclear how the STN integrates reward information and to what extent such integration correlates with behavior. In this study, we investigated the response properties of STN neurons in monkeys performing reaching movements with a cue predicting the identity of an upcoming liquid reward (juice or water). Although the timing of movements reliably indicated that monkeys had greater motivation for juice than water, rarely did task-related changes in neuronal activity depend on the nature of the expected reward. Conversely, when presented with a choice of selecting a response that leads to juice or water delivery, animals showed a clear preference for juice and more than half of the neurons were differentially modulated dependent on the reward obtained, mostly after the monkeys's overt choice of action. Under such circumstances, an increase in activity specifically followed the action outcomes across the population of neurons when monkeys failed to choose the juice reward. These results indicate that STN neurons encode whether or not a preferred reward had been received when a choice between response alternatives is required. This differential neuronal activity might reflect the participation of the STN in evaluating the reward value of chosen actions thus highlighting its contribution to decision-making processes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
... While many behavioral tasks are more suited to study in humans (Rosa et al 2013), studies with relatively simple behavioral contexts (e.g. voluntary or cued reaching, passive joint manipulations, or gait dynamics) are well suited to preclinical studies in animal models. ...
Article
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Objective: Using the Medtronic Activa® PC + S system, this study investigated how passive joint manipulation, reaching behavior, and deep brain stimulation (DBS) modulate local field potential (LFP) activity in the subthalamic nucleus (STN) and globus pallidus (GP). Approach: Five non-human primates were implanted unilaterally with one or more DBS leads. LFPs were collected in montage recordings during resting state conditions and during motor tasks that facilitate the expression of parkinsonian motor signs. These recordings were made in the naïve state in one subject, in the parkinsonian state in two subjects, and in both naïve and parkinsonian states in two subjects. Main results: LFPs measured at rest were consistent over time for a given recording location and parkinsonian state in a given subject; however, LFPs were highly variable between subjects, between and within recording locations, and across parkinsonian states. LFPs in both naïve and parkinsonian states across all recorded nuclei contained a spectral peak in the beta band (10-30 Hz). Moreover, the spectral content of recorded LFPs was modulated by passive and active movement of the subjects' limbs. LFPs recorded during a cued-reaching task displayed task-related beta desynchronization in STN and GP. The bidirectional capabilities of the Activa® PC + S also allowed for recording LFPs while delivering DBS. The therapeutic effect of STN DBS on parkinsonian rigidity outlasted stimulation for 30-60 s, but there was no correlation with beta band power. Significance: This study emphasizes (1) the variability in spontaneous LFPs amongst subjects and (2) the value of using the Activa® PC + S system to record neural data in the context of behavioral tasks that allow one to evaluate a subject's symptomatology.
... We also wish to recall the study in the field of invasive BCI, thanks to which the new BCI devices have been developed. Neurosurgery have done important progresses in using deep brain stimulation through electrodes implants, in many psychiatric and movement disorders (Kern & Kumar, 2007;Mayberg et al. 2003;Abosch & Lozano, 2003;Vidailhet et al., 2005) and especially for Parkinson disease (Komotar et al., 2010;Lucchiari et al., 2009;Fumagalli et al., 2011;Rosa et al. 2013). ...
Chapter
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Starting from the considerations that new generations communicate and manage social relationships in a different way, thanks to the use of new media, especially Internet, we wanted to study the effects of this communication mode on a neuro-cognitive level. Many studies, especially in sociological and psychological research fields, state that traditional communication among young people is decreasing and that the excessive use of social networking and mobile devices represents a limitation to the development of communication abilities. In this chapter, we present our concept of “sympateia” and show the results of our early-stage experiments addressing our research. Progresses in Neuroscience and current Brain-Computer Interface (BCI) devices enable NeuroInformatics to deeper experiment new Human-machine communication methods and technology. Our aim is to address research efforts in finding new technologies and new IT paradigms to explore the possibility of a direct Human-Human communication mediated by technology. The chapter consists of six sections: in section one, a theoretical background of the cognitive approach to communication and empathy will be defined. In section two, it will be traced the state-of-the-art in Information Technology and Neuroscience studies in human-computer interaction. In section three IT paradigms will be presented to individuate the well-suited ones, with particular attention to AI and learning machine methods. Section four will trace the scenario and the direction of the research, while section five will present some preliminary experiments performed. Finally, in section six will discuss some final considerations and future works.
... Synchronized lowfrequency oscillations (5-13 Hz) in Parkinson's disease increase after dopaminergic medication both in the STN and the GPi and are related to PD dyskinesias as well as to dystonic movements (Silberstein et al. 2003;Priori et al. 2004;Foffani et al. 2005;Marceglia et al. 2007;Barow et al. 2014). Their possible role in non-motor functions has been also documented Rosa et al. 2013). ...
Article
Purpose Cognitive adverse effects may accompany deep brain stimulation (DBS) treatment, as the basal ganglia have influence on widespread neocortical networks. The aim of this study was to investigate how complex motor-cognitive activities are processed in the subthalamic nucleus (STN) and internal globus pallidum (GPi). Methods Dystonia patients implanted with GPi-DBS electrodes (n = 5), and individuals with Parkinson’s disease (PD) (n = 4) or essential tremor (n = 1) with STN-DBS electrodes performed two tasks involving the writing of single letters: 1. copying letters from a monitor; and 2. writing of any letter other than that appearing on the monitor. The cognitive load of the second task was increased relative to the first. Intracranial recordings of task-related oscillatory changes were assessed and compared. Results Local event-related alpha and beta desynchronization (ERD) were more expressed during the second task while the lower gamma synchronization (ERS) decreased regardless of the basal ganglia structure from which recordings were obtained or the clinical diagnosis. Task-related ERD differences recorded from the language-dominant left hemisphere correlated with a behavioural (RT) measure of cognitive effort. ERD changes declined after levodopa intake in PD patients. Conclusions The STN and Gpi participate in cognitive networks. Alpha and beta ERD seems to be essential during processing complex motor-cognitive tasks and increase with enhanced cognitive effort.
... B. Erfassung inkongruenter Stimuli (sog. Konfl iktwahrnehmung) [ 25 ] , pathologisches Spielen [ 26 ] , impulsives Verhalten [ 27 ] , aber auch depressive Symptome [ 9 ] . Dem STN kommt durch seine Verschaltung eine zentrale Bedeutung bei der Informationsverarbeitung in den BG zu. ...
... The understanding that striatal DA is involved not only in motor control, but also in action-selection, learning and memory, and affective states is critical to explain and treat the non-motor symptoms of BG diseases such as PD (Conte et al., 2010 ), drug addiction (Wanat et al., 2009), bipolar disorder (Cousins et al., 2009), schizophrenia (Carlsson et al., 2004), attention deficit/hyperactive disorder (Del Campo et al., 2011), OCD, and TS. Deficits in aversive-driven learning related to the inability of striatal DA to encode negative-prediction errors may also explain why depression and gambling is much more prevalent in PD (Rosa et al., 2013). ...
... Top-down modulation of STN alpha-ERD has been related to the processing of stimulus valence (Brü cke et al., 2007) that is influenced by the affective state of the patient (Huebl et al., 2011). Moreover, modulation in STN low frequency activity (<12 Hz) is involved in non-motor processes such as conflict monitoring , pathological gambling (Rosa et al., 2013) and impulsive behavior (Rodriguez-Oroz et al., 2011) in PD. The STN can be viewed as an integrating node for emotional processing due to its central position in the cortex-BG circuit via the 'hyperdirect' pathway, direct and indirect pathways (Nambu et al., 2000). ...
... 18 Only rare recordings of basal ganglia oscillations in pathological, repetitive behaviors exist. 34 The use of depth electrodes in the course of epilepsy presurgical evaluation offers a potentially useful model with which to explore the cortical component of frontal-striatal pathways. ...
Article
The definition of stereotypies traditionally does not include "epileptic automatisms." However repetitive, sometimes rhythmic behaviors can occur during frontal lobe seizures in a reproducible pattern for a given patient. Thus, the concept of a frontostriatal "motor loop" could be relevant to repetitive ictal behaviors. We describe 17 patients with frontal lobe epilepsy who presented with motor and/or verbal stereotypies and who were explored using depth electrodes (stereoelectroencephalography [SEEG]) in the context of epilepsy presurgical evaluation. Motor patterns were typically reproducible between seizures for a given patient. Distal motor stereotypies were associated with anterior prefrontal localization, and proximal stereotypies were associated with posterior prefrontal localization. "Stereotypy" is a useful term to describe ictal repetitive behaviors produced by prefrontal seizure discharge. The expression of distal and proximal stereotypies follows a rostrocaudal gradient within the frontal lobes. Exploration of the cortical compartment of frontostriatal networks in epileptic patients offers a unique opportunity to study the mechanisms of stereotypies in vivo. © 2013 International Parkinson and Movement Disorder Society.
... Synchronized lowfrequency oscillations (5-13 Hz) in Parkinson's disease increase after dopaminergic medication both in the STN and the GPi and are related to PD dyskinesias as well as to dystonic movements (Silberstein et al. 2003;Priori et al. 2004;Foffani et al. 2005;Marceglia et al. 2007; Barow et al. 2014). Their possible role in non-motor functions has been also documented Rosa et al. 2013). ...
Article
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This study investigates how complex motor-cognitive activities are processed in the subthalamic nucleus (STN) and internal globus pallidum (GPi), as adverse neuropsychiatric effects may accompany deep brain stimulation (DBS), mainly in Parkinson's disease (PD) and STN-DBS. Dystonia patients with GPi-DBS electrodes (n = 5) and PD subjects (n = 5) with STN-DBS electrodes performed two tasks: (1) copying letters; and (2) writing any letter other than that appearing on the monitor. The cognitive load of the second task was greater than that of the first. Intracranial local field potentials (LFPs) were analysed. A beta power decrease was the main correlate of the enhanced cognitive load during the second task in both structures, with a lateralization to the left side, mainly in the GPi. A gamma power increase linked with the increased cognitive activity was observed only in the STN. Differences were also observed in the theta and alpha bandpasses. Beta ERD reactivity seems to be essential during the processing of complex motor-cognitive tasks, increases with enhanced cognitive effort, and was observed in both the STN and GPi. Oscillatory reactivity to effortful cognitive processing in other frequency bands was less consistent, with differences between the studied nuclei. Lateralization of activity related to cognitive factors was observed mainly in the GPi.
... Theta band activity was found to be more synchronized in patients with impulsive compulsive behaviors (ICB) both at rest (Rodriguez-Oroz et al., 2011) and during decision making tasks . In particular, theta power was stronger in the presence of highly conflicting decisions (Rosa et al., 2013). Theta band was found to increase further when the conflict was an ethical one (Fumagalli et al., 2011) rather than a perceptive or cognitive one. ...
Article
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In the last decades, clinical neuroscience found a novel ally in neurotechnologies, devices able to record and stimulate electrical activity in the nervous system. These technologies improved the ability to diagnose and treat neural disorders. Neurotechnologies are concurrently enabling a deeper understanding of healthy and pathological dynamics of the nervous system through stimulation and recordings during brain implants. On the other hand, clinical neurosciences are not only driving neuroengineering toward the most relevant clinical issues, but are also shaping the neurotechnologies thanks to clinical advancements. For instance, understanding the etiology of a disease informs the location of a therapeutical stimulation, but also the way stimulation patterns should be designed to be more effective/naturalistic. Here we describe cases of fruitful integration like Deep Brain Stimulation and cortical interfaces, to highlight how this symbiosis between clinical neuroscience and neurotechnology is closer to a novel integrated framework than to a simple interdisciplinary interaction.
... In this issue of Movement Disorders, the study by Rosa and colleagues, 21 Full financial disclosures and author roles may be found in the online version of this article. ...
... Recent experimental studies demonstrated that both STN and GPi have a role in reward and punishment processing in rodents [107,108], in nonhuman primates [109][110][111] and in humans [112]. In addition, two electrophysiological studies reported specific neuronal subthalamic activity in PD patients with ICDs surgically implanted with STN electrodes [113,114]. More recently, an electrophysiological study showed an association of ICD with increased reward responsive neurons and reduced loss responsive neurons in the STN, but not in the GPi in PD patients [115]. ...
Article
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Introduction: Impulse control disorders (ICDs) in Parkinson’s disease (PD) are a group of impulsive behaviors most often associated, but not limited to, dopamine replacement therapy (DRT), particularly the use of dopamine agonists (DA). ICDs can impair activities of daily living and have a strong negative impact on quality of life of patients and their families. Areas covered: This review mainly focusses on the most common ICDs in the context of currently accepted management strategies for PD and emphasizes areas of controversy in need of further research. The authors further describe the concept of dopamine agonist withdrawal (DAWS) syndrome and its implication for the treatment of ICDs, the role of recently available antiparkinsonian drugs and routes of delivery, and non-pharmacological treatments. Expert opinion: When ICDs develop, proper management mainly consists of reducing, discontinuing or switching dopaminergic agents, especially of DA. In these scenarios, patients should be closely followed up as their motor condition may deteriorate along with occurrence of DAWS. Assessment of the presence and intensity of ICDs should be carried throughout the course of the disease and not only when a particular treatment is started or when the dosage is increased, since their occurrence is not linearly related to DRT alone.
... Third, electrophysiological recordings acquired in PD patients while performing cognitive tasks revealed strong relationships between the oscillatory activity of the local field potentials (LFPs) of the STN and the mechanisms of response inhibition and the regulation of decision processes (Cavanagh et al., 2011;Brittain et al., 2012;Zavala et al., 2014). Studying the STN LFP oscillations also revealed that the subjective cost of an action, the subjective value of a reward (Zénon et al., 2016), and the specific motor effort to assign to a motor response are represented at the STN level (Tan et al., 2015) and that this structure is involved in monetary reward processing (Fumagalli et al., 2015) and economic decisions (Rosa et al., 2013). Moreover, electrophysiological data from behaving rodents and nonhuman primates indicate that STN neurons are modulated by cues predicting reward and reward occurrence (Matsumura et al., 1992;Darbaky et al., 2005;Teagarden and Rebec, 2007;Lardeux et al., 2009Lardeux et al., , 2013Espinosa-Parrilla et al., 2013Breysse et al., 2015), and that they could link reward information to the motor output (Espinosa-Parrilla et al., 2013) and differentiate reward types and relative values of reward (Lardeux et al., 2009(Lardeux et al., , 2013Breysse et al., 2015;Espinosa-Parrilla et al., 2015). ...
Article
The understanding of the electrophysiological properties of the subthalamic nucleus (STN) neurons is crucial since it represents the main target of deep brain stimulation for the treatment of Parkinson's Disease and obsessive compulsive disorders. The study of its non-motor properties could shed light on the cognitive and motivational alterations possibly encountered after stimulation. In this study, we recorded the activity of STN neurons in two male behaving monkeys (Macaca mulatta) while they performed a visuomotor motivational task in which visual cues indicated which amount of force was required to obtain which amount of reward. Our results evidenced force- and reward-modulated neurons. After the occurrence of the visual stimuli, the force-modulated neurons mainly fired when a high effort was required. Differently, the activity of the population of reward-modulated neurons encoded the motivational value of the stimuli. This population consisted of neurons increasing or decreasing their activity according to the motivational ranking of the task conditions. Both populations could play complementary roles, one in the implementation of the difficulty of the action and the other in enhancing or slowing its execution based on the subjective value of each conditions.SIGNIFICANT STATEMENT:An increasing number of studies confers a role to the subthalamic nucleus (STN) in motivational and reward-related processes. However, the electrophysiological bases of such properties at the neuronal level remains unclear. The present study investigated the modulation of STN neuronal activity in monkeys performing a motivational task in which the force to produce and the reward obtained were manipulated. We found two main populations of neurons, one modulated by the effort required and the other integrating the motivational subjective value of the stimuli. This last population could help at improving decision-making to act or not, depending on the subjective value set by the motivational context. This highlights the pivotal role of STN in valuation of cost/benefit for decision-making processes.
... The non-motor functions are related to the reactivity in the theta-alpha band, for example conflictual decision-making is related to an increase in the 5-13 Hz frequency range (Fumagalli et al. 2011) or a local decrease in alpha power is related to processing emotional stimuli and depression (Huebl et al. 2014). Increased theta-alpha activity is also associated with impulse control disorders (ICD) and pathological gambling in PD (Rodriguez-Oroz et al. 2011;Rosa et al. 2013). ...
Article
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Although deep brain stimulation of the subthalamic nucleus (STN-DBS) in Parkinson's disease (PD) is generally a successful therapy, adverse events and insufficient clinical effect can complicate the treatment in some patients. We studied clinical parameters and cortical oscillations related to STN-DBS to identify patients with suboptimal responses. High-density EEG was recorded during a visual oddball three-stimuli paradigm in DBS "off" and "on" conditions in 32 PD patients with STN-DBS. Pre-processed data were reconstructed into the source space and the time-frequency analysis was evaluated. We identified a subgroup of six patients with longer reaction times (RT) during the DBS "on" state than in the DBS "off" state after target stimuli. These subjects had lower motor responsiveness to DBS and decreased memory test results compared to the other subjects. Moreover, the alpha and beta power decrease (event-related desynchronizations, ERD), known as an activation correlate linked to motor and cognitive processing, was also reduced in the DBS "on" condition in these patients. A subgroup of PD patients with a suboptimal response to STN-DBS was identified. Evaluation of RT could potentially serve as a biomarker for responsiveness to STN-DBS.
... 18 Only rare recordings of basal ganglia oscillations in pathological, repetitive behaviors exist. 34 The use of depth electrodes in the course of epilepsy presurgical evaluation offers a potentially useful model with which to explore the cortical component of frontal-striatal pathways. ...
Article
Background: The definition of stereotypies traditionally does not include "epileptic automatisms." However repetitive, sometimes rhythmic behaviors can occur during frontal lobe seizures in a reproducible pattern for a given patient. Thus, the concept of a frontostriatal "motor loop" could be relevant to repetitive ictal behaviors. Methods: We describe 17 patients with frontal lobe epilepsy who presented with motor and/or verbal ster-eotypies and who were explored using depth electrodes (stereoelectroencephalography [SEEG]) in the context of epilepsy presurgical evaluation. Results: Motor patterns were typically reproducible between seizures for a given patient. Distal motor ster-eotypies were associated with anterior prefrontal local-ization, and proximal stereotypies were associated with posterior prefrontal localization. Conclusions: "Stereotypy" is a useful term to describe ictal repetitive behaviors produced by prefrontal seizure discharge. The expression of distal and proximal stereotypies follows a rostrocaudal gradient within the frontal lobes. Exploration of the cortical compartment of frontostriatal networks in epileptic patients offers a unique opportunity to study the mechanisms of stereo-typies in vivo. V C 2013 International Parkinson and Movement Disorder Society
... A suppression of alpha band activity during presentation of affective pictures has been found to correlate with the perceived valence (Brü cke et al., 2007) but has also been observed during movement (Oswal, Brown, & Litvak, 2013). Furthermore, an increase in theta power has been linked to processing of conflict during decision-making in economic, perceptual, and motor tasks (Rosa et al., 2013;B. A. Zavala et al., 2014;B. ...
Article
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The subthalamic nucleus (STN) is a core basal ganglia structure involved in the control of motor, cognitive, motivational and affective functions. The (challenged) tripartite subdivision hypothesis places these functions into distinct sensorimotor, cognitive/associate, and limbic subregions based on the topography of cortical projections. To a large extent, this hypothesis is used to motivate the choice of target coordinates for implantation of deep brain stimulation electrodes for treatment of neurological and psychiatric disorders. Yet, the parallel organization of basal ganglia circuits has been known to allow considerable cross-talk, which might contribute to the occurrence of neuropsychiatric side effects when stimulating the dorsolateral, putative sensorimotor, part of the STN for treatment of Parkinson’s disease. Any functional segregation within the STN is expected to be reflected both at micro-level microscopy and meso-level neural population activity. As such, we review the current empirical evidence from anterograde tracing and immunocytochemistry studies and from local field potential recordings for delineating the STN into distinct subregions. The spatial distribution of immunoreactivity presents as a combination of gradients, and although spectral power in distinct frequency bands appears spatially clustered, there is substantial overlap in peak locations. We argue that regional specialization without sharply defined borders is likely most representative of the STN’s functional organization.
... Recording of STN activity in PD patients also support these findings, in that very lowfrequency local field potentials (2-8 Hz) are increased during conflicting decision in PD patients with Gambling Disorder (Rosa et al., 2013). Recording of STN during performance of a financial decision-making task under uncertainty confirms its involvement in these processes and further shows that STN intermittent stimulation reduces risky choices, increasing risk-aversion (Patel et al., 2018). ...
Article
The subthalamic nucleus (STN) is known to play a role in the control of impulsivity of action and in impulsivity of choice under certain conditions. In order to assess its influence on decision‐making under uncertainty, we have tested here the effects of bilateral STN lesions in rats performing a probability discounting task (PDT) and a “loss‐chasing” task, both tasks assessing risky decision under uncertainty, but one in a positive context (probability to obtain a larger reward), the other in a negative context (risk for a larger loss). The PDT measures the choice between a small certain and a large uncertain reward. Conversely, in the “loss‐chasing” task, animals choose between accepting a small certain loss versus risking a larger but uncertain penalty. The results show that STN lesions reduce risk‐taking in both the PDT and the loss‐chasing task, suggesting that STN inactivation could decrease risky decision‐making whatever the nature of the outcome in an ambiguous context. Interestingly, opposite results were found in a small number of animals for which the lesions extended to the area dorsal to the STN (in the zona incerta), such that these animals increased choice of the uncertain option in the PDT. These results confirm the specificity of STN involvement in these processes and may provide explanations for some side‐effects reported in patients when STN manipulations extend to the Zona Incerta. They also support the choice of the STN as a target for the treatment of impulse control disorders in Parkinson’s Disease and in obsessive compulsive disorders.
... Many studies support a role for theta-alpha STN activity in emotional and cognitive functions such as response inhibition and impulse control. 24 Theta-alpha power increases in high-conflict trials in various tasks, including stroop task, 25 flanker task, 26 conflicting dot movement discrimination task, 27 economic decision-making task, 28 and a moral conflict task. 29 In most of these studies, spatial localization of theta-alpha activity was hard to achieve. ...
Article
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Background: Therapeutic outcomes of STN-DBS for movement and psychiatric disorders depend on electrode location within the STN. Electrophysiological and functional mapping of the STN has progressed considerably in the past years, identifying beta-band oscillatory activity in the dorsal STN as a motor biomarker. It also has been suggested that STN theta-alpha oscillations, involved in impulse control and action inhibition, have a ventral source. However, STN local field potential mapping of motor, associative, and limbic areas is often limited by poor spatial resolution. Objectives: Providing a high-resolution electrophysiological map of the motor, associative and limbic anatomical sub-areas of the subthalamic nucleus. Methods: We have analyzed high-spatial-resolution STN microelectrode electrophysiology recordings of PD patients (n = 303) that underwent DBS surgery. The patients' STN intraoperative recordings of spiking activity (933 electrode trajectories) were combined with their imaging data (n = 83 patients, 151 trajectories). Results: We found a high theta-alpha (7-10 Hz) oscillatory area, located near the STN ventromedial border in 29% of the PD patients. Theta-alpha activity in this area has higher power and lower central frequency in comparison to theta-alpha activity in more dorsal subthalamic areas. When projected on the DISTAL functional atlas, the theta-alpha oscillatory area overlaps with the STN limbic subarea. Conclusions: We suggest that theta-alpha oscillations can serve as an electrophysiological marker for the ventral subthalamic nucleus limbic subarea. Therefore, theta-alpha oscillations can guide optimal electrode placement in neuropsychiatric STN-DBS procedures and provide a reliable biomarker input for future closed-loop DBS device. © 2019 International Parkinson and Movement Disorder Society.
... Altered neural activity and abnormally synchronized oscillatory activity at multiple levels of the cortico-basal ganglia (BG) loop have been linked to motor dysfunction in PD patients with or without LID ( Alonso-Frech et al., 2006;Fogelson et al., 2006;Kühn et al., 2006; Lozano et al., 2000; Obeso et al., 2000). Indeed, it has been suggested that the reversion of these alterations may be the target for therapeutic strategies in PD ( Hammond et al., 2007 frequency ranges, including low frequency oscillations that have been associated with parkinsonian tremor ( Smirnov et al., 2008;Tass et al., 2010), essential tremor ( Tan et al., 2019), the expression of dyskinesia (Alonso-Frech et al., 2006), clinical improvement after L-DOPA intake ( Giannicola et al., 2013) and pathological gambling in PD ( Rosa et al., 2013). ...
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The pathophysiology of Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID) is associated with aberrant neuronal activity and abnormal high levels of oscillatory activity and synchronization in several basal ganglia nuclei and the cortex. Previously, we have shown that the firing activity of neurons in the substantia nigra pars reticulata (SNr) is relevant in dyskinesia and may be driven by subthalamic nucleus (STN) hyperactivity. Conversely, low frequency oscillatory activity and synchronization in these structures seem to be more important in PD because they are not influenced by prolonged L-DOPA administration. The aim of the present study was to assess (through single-unit extracellular recording techniques under urethane anaesthesia) the neuronal activity of the entopeduncular nucleus (EPN) and its relationship with LID and STN hyperactivity, together with the oscillatory activity and synchronization between these nuclei and the cerebral cortex in 6-OHDA-lesioned rats that received long term L-DOPA treatment (or not). Twenty-four hours after the last L-DOPA injection the firing activity of EPN neurons in long term L-DOPA treated 6-OHDA-lesioned rats was more irregular and bursting compared to sham rats, being those alterations partially reversed by the acute challenge of L-DOPA. No correlation between EPN neurons firing activity and abnormal involuntary movements score was found. However, there was a significant correlation between the firing activity parameters of EPN and STN neurons recorded from long term L-DOPA treated 6-OHDA-lesioned rats. Low frequency oscillatory activity and synchronization both within the EPN and with the cerebral cortex were enhanced in 6-OHDA-lesioned animals. These changes were reversed by the acute L-DOPA challenge only in long term L-DOPA treated 6-OHDA-lesioned rats. Altogether, these results obtained from long term L-DOPA treated 6-OHDA-lesioned rats suggest (1) a likely relationship between STN and EPN firing patterns and spiking phases induced by changes after prolonged L-DOPA administration and (2) that the effect of L-DOPA on the firing pattern, low frequency oscillatory activity and synchronization in the EPN may have a relevant role in LID.
... It is unclear what the physiological meaning of this high frequency activity is, but it demonstrates the possibility of measuring meaningful electrophysiological pathology in the basal ganglia. In a separate study, relative to PD patients without ICD, PD patients with ICDs exhibited stronger differences in low frequency (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) power between risky and non-risky gambling decisions (161). Lastly, a study of nine PD patients with ICDs and without dopamine-induced dyskinesias found more STN theta (4-7.5 Hz) activity that was associated with similar theta activity in the premotor and frontal cortex (162). ...
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Impulse control disorders (ICDs) in Parkinson's disease (PD) have a high cumulative incidence and negatively impact quality of life. ICDs are influenced by a complex interaction of multiple factors. Although it is now well-recognized that dopaminergic treatments and especially dopamine agonists underpin many ICDs, medications alone are not the sole cause. Susceptibility to ICD is increased in the setting of PD. While causality can be challenging to ascertain, a wide range of modifiable and non-modifiable risk factors have been linked to ICDs. Common characteristics of PD patients with ICDs have been consistently identified across many studies; for example, males with an early age of PD onset and dopamine agonist use have a higher risk of ICD. However, not all cases of ICDs in PD can be directly attributable to dopamine, and studies have concluded that additional factors such as genetics, smoking, and/or depression may be more predictive. Beyond dopamine, other ICD associations have been described but remain difficult to explain, including deep brain stimulation surgery, especially in the setting of a reduction in dopaminergic medication use. In this review, we will summarize the demographic, genetic, behavioral, and clinical contributions potentially influencing ICD onset in PD. These associations may inspire future preventative or therapeutic strategies.
... This probably reflects the depressive mood disturbances in PD patients with STN-DBS. Increased theta-alpha activity is associated with impulse control disorders (ICD) and pathological gambling in PD (Rodriguez-Oroz et al., 2011;Rosa et al., 2013); see Table 2. Oscillations in one frequency range can be accompanied and influenced by changes in another frequency range. Moreover, it has been shown that the phase of low frequency activity can drive the amplitude of gamma oscillations. ...
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Clinical symptoms of Parkinson's disease (PD) are accompanied by pathological phenomena detected locally in the basal ganglia (BG) as changes in local field potentials (LFPs) and also in cortical regions by electroencephalography (EEG). The literature published mainly between 2000 and 2017 was reviewed with an emphasis on approaches emerging after 2000, in particular on oscillatory dynamics, connectivity studies, and deep brain stimulation. Eighty-five articles were reviewed. The main observations were a general slowing of background activity, excessive synchronization of beta activity, and disturbed movement-related gamma oscillations in the BG and in the cortico-subcortical and cortico-cortical motor loops, suppressible by dopaminergic medication as well as by high-frequency deep brain stimulation (DBS). Non-motor symptoms are related mainly to changes in the alpha frequency range. EEG parameters can be useful in defining the risk of dementia in PD. Further progress was reported recently using advanced analytical technologies and high-performance computing (graph theory). Detailed knowledge of LFPs in PD enabled progress particularly in DBS therapy, which requires optimizing the clinical effect and minimizing adverse side effects. The neurocognitive networks and their dysfunction in PD and DBS therapy are promising targets for future research.
... ICDs are also closely related to impaired reward processing in PD patients, and ICDs can result from high levels of dopamine intake in PD, or occasionally after DBS (Rossi et al., 2015). In one study, PD patients with pathological gambling who used a risky strategy during a gambling task showed that while all PD patients exhibited STN low frequency power (2-12 Hz) increases during economics decisions, these increases were seen more during high-risk than low-risk decisions (Rosa et al., 2013). A recent study of one patient with OCD demonstrated increases in delta LFP power in the nucleus accumbens during reward anticipation (Wu et al., 2017). ...
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Although the basal ganglia have been implicated in a growing list of human behaviors, they include some of the least understood nuclei in the brain. For several decades studies have employed numerous methodologies to uncover evidence pointing to the basal ganglia as a hub of both motor and non-motor function. Recently, new electrophysiological characterization of the basal ganglia in humans has become possible through direct access to these deep structures as part of routine neurosurgery. Electrophysiological approaches for identifying non-motor function have the potential to unlock a deeper understanding of pathways that may inform clinical interventions and particularly neuromodulation. Various electrophysiological modalities can also be combined to reveal functional connections between the basal ganglia and traditional structures throughout the neocortex that have been linked to non-motor behavior. Several reviews have previously summarized evidence for non-motor function in the basal ganglia stemming from behavioral, clinical, computational, imaging, and non-primate animal studies; in this review, instead we turn to electrophysiological studies of non-human primates and humans. We begin by introducing common electrophysiological methodologies for basal ganglia investigation, and then we discuss studies across numerous non-motor domains–emotion, response inhibition, conflict, decision-making, error-detection and surprise, reward processing, language, and time processing. We discuss the limitations of current approaches and highlight the current state of the information.
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Recent evidence suggests that beta bursts in subthalamic nucleus (STN) play an important role in Parkinsonian pathophysiology. We studied the spatio-temporal relationship between STN beta bursts and cortical activity in 26 Parkinson's disease (PD) patients undergoing deep brain stimulation (DBS) surgery. Postoperatively, we simultaneously recorded STN local field potentials (LFP) from externalized DBS leads and cortical activity using whole-brain magnetoencephalography. Event-related magnetic fields (ERF) were averaged time-locked to STN beta bursts and subjected to source localization. Our results demonstrate that ERF exhibiting activity significantly different from baseline activity were localized within areas functionally related to associative, limbic, and motor systems as well as regions pertinent for visual and language processing. Our data suggest that STN beta bursts are involved in network formation between STN and cortex. This interaction is in line with the idea of parallel processing within the basal ganglia-cortex loop, specifically within the functional subsystems of the STN (i.e., associative, limbic, motor, and the related cortical areas). ERFs within visual and language-related cortical areas indicate involvement of beta bursts in STN-cortex networks beyond the associative, limbic, and motor loops. In sum, our results highlight the involvement of STN beta bursts in the formation of multiple STN - cortex loops in patients with PD.
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Introduction: Previous studies have reported improvement of impulse control disorders (ICDs) after subthalamic nucleus (STN) deep brain stimulation (DBS) as well as some de novo ICDs. However, it is not clear how STN DBS changes ICDs in the long-term. Methods materials: Eighty-nine patients with Parkinson's disease (PD) who had received a bilateral STN DBS from 2005 to 2009 and were included in our previous study were followed for 7 years with the modified Minnesota Impulsive Disorders Interview (mMIDI). Their mMIDI scores, medication, and frontal function tests measured preoperatively and at 1 and 7 years postoperatively were compared. Results: A total of 61 patients were analyzed after excluding 10 and 18 patients due to death and lost to follow-up, respectively. The numbers of the patients with an ICD at each point were 8, 10, and 7, respectively. All preoperative ICDs disappeared after DBS. De novo ICDs within 1 year after DBS disappeared except for 1 patient. Six of the seven patients, who reported ICDs 7 years after the DBS developed that ICD between 1 and 7 years. Their total levodopa equivalent daily dose (LEDD) and dopamine agonist dose were not higher compared to the other 54 patients without ICDs. There was no correlation with the frontal lobe dysfunction and the electrode position in the subthalamus. Conclusion: STN DBS improves baseline ICDs and results in the development of "transient" de novo ICDs in the short-term. In addition, there is a unique group of the patients who develop ICDs a long time after DBS.
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How do we decide what we do? This is the essence of action control, the process of selecting the most appropriate response among multiple possible choices. Suboptimal action control can involve a failure to initiate or adapt actions, or conversely it can involve making actions impulsively. There has been an increasing focus on the specific role of the subthalamic nucleus (STN) in action control. This has been fueled by the clinical relevance of this basal ganglia nucleus as a target for deep brain stimulation (DBS), primarily in Parkinson’s disease but also in obsessive-compulsive disorder. The context of DBS has opened windows to study STN function in ways that link neuroscientific and clinical fields closely together, contributing to an exceptionally high level of two-way translation. In this review, we first outline the role of the STN in both motor and nonmotor action control, and then discuss how these functions might be implemented by neuronal activity in the STN. Gaining a better understanding of these topics will not only provide important insights into the neurophysiology of action control but also the pathophysiological mechanisms relevant for several brain disorders and their therapies.
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Objective: The adaptive deep brain stimulation (aDBS) controlled by local field potentials (LFPs) is considered a promising treatment for advanced Parkinson's disease (PD). The clinical research investigating aDBS functioning is currently performed using external DBS systems that require LFP recording through the temporary externalisation of DBS leads. Although research examining LFP was first undertaken more than twenty years ago, only a small number of studies concern leads' externalisation and LFP recording safety. In the present retrospective study, we assessed the risk of infection related to these procedures. Methods: A total of 105 patients with PD who underwent DBS surgery and leads' externalisation at our hospital from 2002 to 2014 were included in the present study. The medical records were used to collect clinical data and information concerning surgical site infections. We assessed the infection incidence in our cohort and the infection's risk related to the LFP recording procedure. Results: The incidence of infections in patients who underwent leads' externalisation was 2.8%, which was consistent with the postoperative infectious risk reported in the literature (Wilcoxon Signed Rank Test, p>0.05). Moreover, the LFP recording procedure did not significantly increase the infection risk (LFP recordings vs no LFP recordings: 2.5% vs 4.2%; Fisher exact test, p>0.05). Conclusions: DBS leads' externalisation and LFP recording are safe and do not increase the post-operative infection risk in patients with PD who undergo DBS surgery. Our retrospective study supported further clinical research in the field of LFP-based aDBS.
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Deep brain stimulation (DBS) surgery offers a unique opportunity to record local field potentials (LFPs), the electrophysiological population activity of neurons surrounding the depth electrode in the target area. With direct access to the subcortical activity, LFP research has provided valuable insight into disease mechanisms and cognitive processes and inspired the advent of adaptive DBS for Parkinson’s disease (PD). A frequency-based framework is usually employed to interpret the implications of LFP signatures in LFP studies on PD. This approach standardizes the methodology, simplifies the interpretation of LFP patterns, and makes the results comparable across studies. Importantly, previous works have found that activity patterns do not represent disease-specific activity but rather symptom-specific or task-specific neuronal signatures that relate to the current motor, cognitive or emotional state of the patient and the underlying disease. In the present review, we aim to highlight distinguishing features of frequency-specific activities, mainly within the motor domain, recorded from DBS electrodes in patients with PD. Associations of the commonly reported frequency bands (delta, theta, alpha, beta, gamma, and high-frequency oscillations) to motor signs are discussed with respect to band-related phenomena such as individual tremor and high/low beta frequency activity, as well as dynamic transients of beta bursts. We provide an overview on how electrophysiology research in DBS patients has revealed and will continuously reveal new information about pathophysiology, symptoms, and behavior, e.g., when combining deep LFP and surface electrocorticography recordings.
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Background: Impulsivity is common in people with Parkinson's disease (PD), with many developing impulsive compulsive behavior disorders (ICB). Its pathophysiological basis remains unclear. Objectives: We aimed to investigate local field potential (LFP) markers of trait impulsivity in PD and their relationship to ICB. Methods: We recorded subthalamic nucleus (STN) LFPs in 23 PD patients undergoing deep brain stimulation implantation. Presence and severity of ICB were assessed by clinical interview and the Questionnaire for Impulsive-Compulsive Disorders in PD-Rating Scale (QUIP-RS), whereas trait impulsivity was estimated with the Barratt Impulsivity Scale (BIS-11). Recordings were obtained during the off dopaminergic states and the power spectrum of the subthalamic activity was analyzed using Fourier transform-based techniques. Assessment of each electrode contact localization was done to determine the topography of the oscillatory activity recorded. Results: Patients with (n = 6) and without (n = 17) ICB had similar LFP spectra. A multiple regression model including QUIP-RS, BIS-11, and Unified PD Rating Scale-III scores as regressors showed a significant positive correlation between 8-13 Hz power and BIS-11 score. The correlation was mainly driven by the motor factor of the BIS-11, and was irrespective of the presence or absence of active ICB. Electrode contact pairs with the highest α power, which also correlated most strongly with BIS-11, tended to be more ventral than contact pairs with the highest beta power, which localize to the dorsolateral motor STN. Conclusions: Our data suggest a link between α power and trait impulsivity in PD, irrespective of the presence and severity of ICB. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Chapter
Brain oscillations have been associated with Parkinson's disease (PD) for a long time mainly due to the fundamental oscillatory nature of parkinsonian rest tremor. Over the years, this association has been extended to frequencies well above that of tremor, largely owing to the opportunities offered by deep brain stimulation (DBS) to record electrical activity directly from the patients’ basal ganglia. This chapter reviews the results of research on brain oscillations in PD focusing on theta (4–7 Hz), beta (13–35 Hz), gamma (70–80 Hz) and high-frequency oscillations (200–400 Hz). For each of these oscillations, we describe localization and interaction with brain structures and between frequencies, changes due to dopamine intake, task-related modulation, and clinical relevance. The study of brain oscillations will also help to dissect the mechanisms of action of DBS. Overall, the chapter tentatively depicts PD in terms of “oscillopathy.”
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Economic decision-making is disrupted in individuals with gambling disorder, an addictive behavior observed in Parkinson’s disease (PD) patients receiving dopaminergic therapy. The subthalamic nucleus (STN) is involved in the inhibition of impulsive behaviors; however, its role in impulse control disorders and addiction is still unclear. Here, we recorded STN local field potentials (LFPs) in PD patients with and without gambling disorder during an economic decision-making task. Reaction times analysis showed that for all patients, the decision whether to risk preceded task onset. We compared then for both groups the STN LFP preceding high- and low-risk economic decisions. We found that risk avoidance in gamblers correlated with larger STN LFP low-frequency (<12-Hz) fluctuations preceding task onset. In particular, the amplitude of low-frequency LFP fluctuations carried significant information about future decisions. Decisions of patients not affected by gambling disorder were instead not correlated with pretask STN LFP. Our results suggest that STN activity preceding task onset affects risk decisions by preemptively inhibiting attraction to high but unlikely rewards in favor of a long-term payoff.
Chapter
Impulse control disorders (ICDs), such as compulsive gambling, buying, sexual, and eating behaviors, are a serious and increasingly recognized complication in Parkinson's disease (PD), occurring in up to 20% of PD patients over the course of their illness. Related behaviors include punding (stereotyped, repetitive, purposeless behaviors), dopamine dysregulation syndrome (DDS) (compulsive medication overuse), and hobbyism (e.g., compulsive internet use, artistic endeavors, and writing). These disorders have a significant impact on quality of life and function, strain interpersonal relationships, and worsen caregiver burden, and are associated with significant psychiatric comorbidity. ICDs have been most closely related to the use of dopamine agonists (DAs), while DDS is primarily associated with shorter acting, higher potency dopamine replacement therapy (DRT), such as levodopa. However, in preliminary research ICDs have also been reported to occur with monoamine oxidase inhibitor-B and amantadine treatment, and after deep brain stimulation (DBS) surgery. Other risk factors for ICDs may include sex (e.g., male sex for compulsive sexual behavior, and female sex for compulsive buying behavior); younger age overall at PD onset; a pre-PD history of an ICD; personal or family history of substance abuse, bipolar disorder, or gambling problems; and impulsive personality traits. Dysregulation of the mesocorticolimbic dopamine system is thought to be the major neurobiological substrate for ICDs in PD, but there is preliminary evidence for alterations in opiate and serotonin systems too. The primary treatment of ICDs in PD is discontinuation of the offending treatment, but not all patients can tolerate this due to worsening motor symptoms or DA withdrawal syndrome. While psychiatric medications and psychosocial treatments are frequently used to treat ICDs in the general population, there is limited empirical evidence for their use in PD, so it is critical for patients to be monitored closely for ICDs from disease onset and routine throughout its course. In the future, it may be possible to use a precision medicine approach to decrease the incidence of ICDs in PD by avoiding DA use in patients determined to be at highest risk based on their clinical and neurobiological (e.g., motor presentation, behavioral measures of medication response, genetics, dopamine transporter neuroimaging) profile. Additionally, as empirically validated treatments for ICDs and similar disorders (e.g., substance use disorders) emerge, it will also be important to examine their efficacy and tolerability in individuals with comorbid PD.
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We review the data concerning the neurophysiology of deep brain stimulation (DBS) in humans, especially in reference to Parkinson's disease. The electric field generated by DBS interacts with the brain in complex ways, and several variables could influence the DBS-induced biophysical and clinical effects. The neurophysiology of DBS comprises the DBS-induced effects per se as well as neurophysiological studies designed to record electrical activity directly from the basal ganglia (single-unit or local field potential) through the electrodes implanted for DBS. In the subthalamic nucleus, DBS locally excites and concurrently inhibits at single-unit level, synchronizes low-frequency activity, and desynchronizes beta activity and also induces neurochemical changes in cyclic guanosine monophosphate (cGMP) and GABA concentrations. DBS-induced effects at system level can be studied through evoked potentials, autonomic tests, spinal cord segmental system, motor cortical and brainstem excitability, gait, and decision-making tasks. All these variables are influenced by DBS, suggesting also distant effects on nonmotor structures of the brain. Last, advances in understanding the neurophysiological mechanisms underlying DBS led researchers to develop a new adaptive DBS technology designed to adapt stimulation settings to the individual patient's clinical condition through a closed-loop system controlled by signals from the basal ganglia.
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New adaptive systems for deep brain stimulation (DBS) could in the near future optimize stimulation settings online so as to achieve better control over the clinical fluctuations in Parkinson's disease (PD). Local field potentials (LFPs) recorded from the subthalamic nucleus (STN) in PD patients show that levodopa and DBS modulate STN oscillations. Because previous research has shown that levodopa and DBS variably influence beta LFP activity (8-20 Hz), we designed this study to find out how they affect low-frequency (LF) oscillations (2-7 Hz). STN LFPs were recorded in 19 patients with PD during DBS, after levodopa medication, and during DBS and levodopa intake combined. We investigated the relationship between LF modulations, DBS duration and levodopa intake. We also studied whether LF power depended on disease severity, the patient's clinical condition and whether LF modulations were related to electrode impedances. LF power increased during DBS, after levodopa intake and under both experimental conditions combined. The LF power increase correlated with the levodopa-induced clinical improvement and the higher the electrode impedance, the greater was the LF power change. These data suggest that the LF band could be useful as a control neurosignal for developing novel adaptive DBS systems for patients with PD.
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It takes effort and time to tame one's impulses. Although medial prefrontal cortex (mPFC) is broadly implicated in effortful control over behavior, the subthalamic nucleus (STN) is specifically thought to contribute by acting as a brake on cortico-striatal function during decision conflict, buying time until the right decision can be made. Using the drift diffusion model of decision making, we found that trial-to-trial increases in mPFC activity (EEG theta power, 4-8 Hz) were related to an increased threshold for evidence accumulation (decision threshold) as a function of conflict. Deep brain stimulation of the STN in individuals with Parkinson's disease reversed this relationship, resulting in impulsive choice. In addition, intracranial recordings of the STN area revealed increased activity (2.5-5 Hz) during these same high-conflict decisions. Activity in these slow frequency bands may reflect a neural substrate for cortico-basal ganglia communication regulating decision processes.
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In the past years, local field potential (LFP) signals recorded from the subthalamic nucleus (STN) in patients undergoing deep brain stimulation (DBS) for Parkinson's disease (PD) disclosed that DBS has a controversial effect on STN beta oscillations recorded 2-7 days after surgery for macroelectrode implantation. Nothing is known about these DBS-induced oscillatory changes 30 days after surgery. We recorded STN LFPs during ongoing DBS in 7 patients with PD, immediately (hyperacute phase) and 30 days (chronic phase) after surgery. STN LFP recordings showed stationary intranuclear STN beta LFP activity in hyperacute and chronic phases, confirming that beta peaks were also present in chronic recordings. Power spectra of nuclei with significant beta activity (54% of the sample) showed that it decreased significantly during DBS (p=0.021) under both recording conditions. The time course of beta activity showed more evident DBS-induced changes in the chronic than in the hyperacute phase (p=0.014). DBS-induced changes in STN beta LFPs in patients undergoing DBS in chronic phase provide useful information for developing a new neurosignal-controlled adaptive DBS system.
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Recently, the subthalamic nucleus (STN) has been shown to be critically involved in decision-making, action selection, and motor control. Here we investigate the effect of deep brain stimulation (DBS) of the STN on reward-based decision-learning in patients diagnosed with Parkinson's disease (PD). We determined computational measures of outcome evaluation and reward prediction from PD patients who performed a probabilistic reward-based decision-learning task. In previous work, these measures covaried with activation in the nucleus caudatus (outcome evaluation during the early phases of learning) and the putamen (reward prediction during later phases of learning). We observed that stimulation of the STN motor regions in PD patients served to improve reward-based decision-learning, probably through its effect on activity in frontostriatal motor loops (prominently involving the putamen and, hence, reward prediction). In a subset of relatively younger patients with relatively shorter disease duration, the effects of DBS appeared to spread to more cognitive regions of the STN, benefiting loops that connect the caudate to various prefrontal areas importantfor outcome evaluation. These results highlight positive effects of STN stimulation on cognitive functions that may benefit PD patients in daily-life association-learning situations.
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Misestimating risk could lead to disadvantaged choices such as initiation of drug use (or gambling) and transition to regular drug use (or gambling). Although the normative theory in decision-making under risks assumes that people typically take the probability-weighted expectation over possible utilities, experimental studies of choices among risks suggest that outcome probabilities are transformed nonlinearly into subjective decision weights by a nonlinear weighting function that overweights low probabilities and underweights high probabilities. Recent studies have revealed the neurocognitive mechanism of decision-making under risk. However, the role of modulatory neurotransmission in this process remains unclear. Using positron emission tomography, we directly investigated whether dopamine D₁ and D₂ receptors in the brain are associated with transformation of probabilities into decision weights in healthy volunteers. The binding of striatal D₁ receptors is negatively correlated with the degree of nonlinearity of weighting function. Individuals with lower striatal D₁ receptor density showed more pronounced overestimation of low probabilities and underestimation of high probabilities. This finding should contribute to a better understanding of the molecular mechanism of risky choice, and extreme or impaired decision-making observed in drug and gambling addiction.
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Although lesional, neuroimaging, and brain stimulation studies have provided an insight into the neural mechanisms of judgement and decision-making, all these works focused on the cerebral cortex, without investigating the role of subcortical structures such as the basal ganglia. Besides being an effective therapeutic tool, deep brain stimulation (DBS) allows local field potential (LFP) recordings through the stimulation electrodes thus providing a physiological "window" on human subcortical structures. In this study we assessed whether subthalamic nucleus LFP oscillations are modulated by processing of moral conflictual, moral nonconflictual, and neutral statements. To do so, in 16 patients with Parkinson's disease (8 men) bilaterally implanted with subthalamic nucleus (STN) electrodes for DBS, we recorded STN LFPs 4 days after surgery during a moral decision task. During the task, recordings from the STN showed changes in LFP oscillations. Whereas the 14--30 Hz band (beta) changed during the movement executed to perform the task, the 5--13 Hz band (low-frequency) changed when subjects evaluated the content of statements. Low-frequency band power increased significantly more during conflictual than during nonconflictual or neutral sentences. We conclude that STN responds specifically to conflictual moral stimuli, and could be involved in conflictual decisions of all kinds, not only those for moral judgment. LFP oscillations provide novel direct evidence that the neural processing of conflictual decision-making spreads beyond the cortex to the basal ganglia and encompasses a specific subcortical conflict-dependent component.
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Behavioural abnormalities such as impulse control disorders may develop when patients with Parkinson's disease receive dopaminergic therapy, although they can be controlled by deep brain stimulation of the subthalamic nucleus. We have recorded local field potentials in the subthalamic nucleus of 28 patients with surgically implanted subthalamic electrodes. According to the predominant clinical features of each patient, their Parkinson's disease was associated with impulse control disorders (n = 10), dyskinesias (n = 9) or no dopaminergic mediated motor or behavioural complications (n = 9). Recordings were obtained during the OFF and ON dopaminergic states and the power spectrum of the subthalamic activity as well as the subthalamocortical coherence were analysed using Fourier transform-based techniques. The position of each electrode contact was determined in the postoperative magnetic resonance image to define the topography of the oscillatory activity recorded in each patient. In the OFF state, the three groups of patients had similar oscillatory activity. By contrast, in the ON state, the patients with impulse control disorders displayed theta-alpha (4-10 Hz) activity (mean peak: 6.71 Hz) that was generated 2-8 mm below the intercommissural line. Similarly, the patients with dyskinesia showed theta-alpha activity that peaked at a higher frequency (mean: 8.38 Hz) and was generated 0-2 mm below the intercommissural line. No such activity was detected in patients that displayed no dopaminergic side effects. Cortico-subthalamic coherence was more frequent in the impulsive patients in the 4-7.5 Hz range in scalp electrodes placed on the frontal regions anterior to the primary motor cortex, while in patients with dyskinesia it was in the 7.5-10 Hz range in the leads overlying the primary motor and supplementary motor area. Thus, dopaminergic side effects in Parkinson's disease are associated with oscillatory activity in the theta-alpha band, but at different frequencies and with different topography for the motor (dyskinesias) and behavioural (abnormal impulsivity) manifestations. These findings suggest that the activity recorded in parkinsonian patients with impulse control disorders stems from the associative-limbic area (ventral subthalamic area), which is coherent with premotor frontal cortical activity. Conversely, in patients with l-dopa-induced dyskinesias such activity is recorded in the motor area (dorsal subthalamic area) and it is coherent with cortical motor activity. Consequently, the subthalamic nucleus appears to be implicated in the motor and behavioural complications associated with dopaminergic drugs in Parkinson's disease, specifically engaging different anatomo-functional territories.
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Local field potentials (LFPs) recorded through electrodes implanted in the subthalamic nucleus (STN) for deep brain stimulation (DBS) in patients with Parkinson's disease (PD) show that oscillations in the beta frequency range (8-20 Hz) decrease after levodopa intake. Whether and how DBS influences the beta oscillations and whether levodopa- and DBS-induced changes interact remains unclear. We examined the combined effect of levodopa and DBS on subthalamic beta LFP oscillations, recorded in nine patients with PD under four experimental conditions: without levodopa with DBS turned off; without levodopa with DBS turned on; with levodopa with DBS turned on; and with levodopa with DBS turned off. The analysis of STN-LFP oscillations showed that whereas levodopa abolished beta STN oscillations in all the patients (p=0.026), DBS significantly decreased the beta oscillation only in five of the nine patients studied (p=0.043). Another difference was that whereas levodopa completely suppressed beta oscillations, DBS merely decreased them. When we combined levodopa and DBS, the levodopa-induced beta disruption prevailed and combining levodopa and DBS induced no significant additive effect (p=0.500). Our observations suggest that levodopa and DBS both modulate LFP beta oscillations.
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Pathological gambling is an impulse control disorder reported in association with dopamine agonists used to treat Parkinson's disease. Although impulse control disorders are conceptualized as lying within the spectrum of addictions, little neurobiological evidence exists to support this belief. Functional imaging studies have consistently demonstrated abnormalities of dopaminergic function in patients with drug addictions, but to date no study has specifically evaluated dopaminergic function in Parkinson's disease patients with impulse control disorders. We describe results of a [(11)C] raclopride positron emission tomography (PET) study comparing dopaminergic function during gambling in Parkinson's disease patients, with and without pathological gambling, following dopamine agonists. Patients with pathological gambling demonstrated greater decreases in binding potential in the ventral striatum during gambling (13.9%) than control patients (8.1%), likely reflecting greater dopaminergic release. Ventral striatal bindings at baseline during control task were also lower in patients with pathological gambling. Although prior imaging studies suggest that abnormality in dopaminergic binding and dopamine release may be markers of vulnerability to addiction, this study presents the first evidence of these phenomena in pathological gambling. The emergence of pathological gambling in a number of Parkinson's disease patients may provide a model into the pathophysiology of this disorder.
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