Highlights • We conducted the first meta-analysis and a systematic review on clinical effects of deep brain stimulation in Tourette syndrome. • A significant median reduction of 53% in the Yale ...Global Tic Severity Scale was observed. • Comorbid depressive and obsessive-compulsive symptoms significantly improved. • Different brain targets showed comparable improvement rates, indicating a modulation of a common network. • Overall, younger patients may profit more from deep brain stimulation but different targets also provide different predictive values.
Tourette syndrome is a neurodevelopmental disorder associated with hyperactivity in dopaminergic networks. Dopaminergic hyperactivity in the basal ganglia has previously been linked to increased ...sensitivity to positive reinforcement and increases in choice impulsivity. In this study, we examine whether this extends to changes in temporal discounting, where impulsivity is operationalized as an increased preference for smaller-but-sooner over larger-but-later rewards. We assessed intertemporal choice in two studies including nineteen adolescents (age: meansd = 14.21±2.37, 13 male subjects) and twenty-five adult patients (age: meansd = 29.88 ±9.03; 19 male subjects) with Tourette syndrome and healthy age- and education matched controls. Computational modeling using exponential and hyperbolic discounting models via hierarchical Bayesian parameter estimation revealed reduced temporal discounting in adolescent patients, and no evidence for differences in adult patients. Results are discussed with respect to neural models of temporal discounting, dopaminergic alterations in Tourette syndrome and the developmental trajectory of temporal discounting. Specifically, adolescents might show attenuated discounting due to improved inhibitory functions that also affect choice impulsivity and/or the developmental trajectory of executive control functions. Future studies would benefit from a longitudinal approach to further elucidate the developmental trajectory of these effects.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Closed-loop neuromodulation is presumed to be the logical evolution for improving the effectiveness of deep brain stimulation (DBS) treatment protocols (Widge et al., 2018). Identifying ...symptom-relevant biomarkers that provide meaningful feedback to stimulator devices is an important initial step in this direction. This report demonstrates a technique for assaying neural circuitry hypothesized to contribute to OCD and DBS treatment outcomes. We computed phase-lag connectivity between LFPs and EEGs in thirteen treatment-refractory OCD patients. Simultaneous recordings from scalp EEG and externalized DBS electrodes in the ventral capsule/ventral striatum (VC/VS) were collected at rest during the perioperative treatment stage. Connectivity strength between midfrontal EEG sensors and VC/VS electrodes correlated with baseline OCD symptoms and 12-month posttreatment OCD symptoms. Results are qualified by a relatively small sample size, and limitations regarding the conclusiveness of VS and mPFC as neural generators given some concerns about volume conduction. Nonetheless, findings are consistent with treatment-relevant tractography findings and theories that link frontostriatal hyperconnectivity to the etiopathogenesis of OCD. Findings support the continued investigation of connectivity-based assays for aiding in determination of optimal stimulation location, and are an initial step towards the identification of biomarkers that can guide closed-loop neuromodulation systems.
•Phase-lag connectivity may inform closed-loop neuromodulation.•Change in frontostriatal (hyper)connectivity may be a therapeutic mechanism of DBS.•Phase-lag connectivity between frontal and striatal regions predicts OCD severity.•Network-level metrics may be useful for guiding on-demand neuromodulation.•Findings support frontostriatal theories of OCD etiopathogenesis.
Extended research has pointed to the efficacy of deep brain stimulation (DBS) in treatment of patients with treatment-refractory Tourette syndrome (TS). The four most commonly used DBS targets for TS ...include the centromedian nucleus-nucleus ventrooralis internus (CM-Voi) and the centromedian nucleus-parafascicular (CM-Pf) complexes of the thalamus, and the posteroventrolateral (pvIGPi) and the anteromedial portion of the globus pallidus internus (amGPi). Differences and commonalities between those targets need to be compared systematically.
Therefore, we evaluated whether DBS is effective in reducing TS symptoms and target-specific differences.
A PubMed literature search was conducted according to the PRISMA guidelines. Eligible literature was used to conduct a systematic review and meta-analysis.
In total, 65 studies with 376 patients were included. Overall, Yale Global Tic Severity Scale (YGTSS) scores were reduced by more than 50 in 69% of the patients. DBS also resulted in significant reductions of secondary outcome measures, including the total YGTSS, modified Rush Video-Based Tic Rating Scale (mRVRS), Yale-Brown Obsessive Compulsive Scale (YBOCS), and Becks Depression Inventory (BDI). All targets resulted in significant reductions of YGTSS scores and, with the exception of the CM-Pf, also in reduced YBOCS scores. Interestingly, DBS of pallidal targets showed increased YGTSS and YBOCS reductions compared to thalamic targets. Also, the meta-analysis including six randomized controlled and double-blinded trials demonstrated clinical efficacy of DBS for TS, that remained significant for GPi but not thalamic stimulation in two separate meta-analyses.
We conclude that DBS is a clinically effective treatment option for patients with treatment-refractory TS, with all targets showing comparable improvement rates. Future research might focus on personalized and symptom-specific target selection.
There is still a lack of controlled studies to prove efficacy of thalamic deep brain stimulation for Tourette's Syndrome.
In this controlled trial, we investigated the course of tic severity, ...comorbidities and quality of life during thalamic stimulation and whether changes in tic severity can be assigned to ongoing compared to sham stimulation.
We included eight adult patients with medically refractory Tourette's syndrome. Bilateral electrodes were implanted in the centromedian-parafascicular-complex and the nucleus ventro-oralis internus. Tic severity, quality of life and comorbidities were assessed before surgery as well as six and twelve months after. Short randomized, double-blinded sham-controlled crossover sequences with either active or sham stimulation were implemented at both six- and twelve-months’ assessments. The primary outcome measurement was the difference in the Yale Global Tic Severity Scale tic score between active and sham stimulation. Adverse events were systematically surveyed for all patients to evaluate safety.
Active stimulation resulted in significantly higher tic reductions than sham stimulation (F = 79.5; p = 0.001). Overall quality of life and comorbidities improved significantly in the open-label-phase. Over the course of the trial two severe adverse events occurred that were resolved without sequelae.
Our results provide evidence that thalamic stimulation is effective in improving tic severity and overall quality of life. Crucially, the reduction of tic severity was primarily driven by active stimulation. Further research may focus on improving stimulation protocols and refining patient selection to improve efficacy and safety of deep brain stimulation for Tourette's Syndrome.
•There is insufficient data from controlled trials to determine efficacy of thalamic DBS for Tourette Syndrome.•In this trial of n = 8, tic severity, quality of life and comorbidities significantly improved with continuous DBS.•Double-blinded discontinuation of stimulation resulted in a significant relapse of tic severity.•Our study adds novel evidence that thalamic DBS is a safe and effective treatment for severe Tourette Syndrome.
Deep brain stimulation (DBS) of the thalamus can effectively reduce tics in severely affected patients with Tourette syndrome (TS). Its effect on cortical oscillatory activity is currently unknown.
...We assessed whether DBS modulates beta activity at fronto-central electrodes. We explored concurrent EEG sources and probabilistic stimulation maps.
Resting state EEG of TS patients treated with thalamic DBS was recorded in repeated DBS-on and DBS-off states. A mixed linear model was employed for statistical evaluation. EEG sources were estimated with eLORETA. Thalamic probabilistic stimulation maps were obtained by assigning beta power difference scores (DBS-on minus DBS-off) to stimulation sites.
We observed increased beta power in DBS-on compared to DBS-off states. Modulation of cortical beta activity was localized to the midcingulate cortex. Beta modulation was more pronounced when stimulating the thalamus posteriorly, peaking in the ventral posterior nucleus.
Thalamic DBS in TS patients modulates beta frequency oscillations presumably important for sensorimotor function and relevant to TS pathophysiology.
•Thalamic deep brain stimulation increased cortical beta oscillations.•Increased beta power was localized to midcingulate cortex.•Peak beta modulation was related to stimulation of the ventral posterior nucleus.
Not a single day goes by without Pope Francis making charity and mercy – central characteristic traits of any Christian – the pivot of his sermons, exhortations and proclamations, formal and informal ...alike. The last holy year, concluding in November 2016, which explicitly featured the motto of mercy, offers a welcome opportunity for the canonist to contemplate the relationship between mercy and justice. Certainly, there is no lack of warning speeches and auguries against the oversimplification of the canonical norms through invoking a false understanding of an imperative of indefinite mercy. To do so would be to neglect the crucial and central commandment of justice, which ensures both legal certainty and an equal treatment of similar cases. The papal address given to the Tribunal of the Roman Rota in 2009 may serve as an eloquent example. In his address Benedict XVI emphasised the interrelation of love (caritas) and justice (iustitia), but at the same time explicitly cautioned against over-pastorally motivated charity as far as the application of the law is concerned:
Charity without justice is not charity, but a counterfeit, because charity itself requires that objectivity which is typical of justice and which must not be confused with inhuman coldness. In this regard, as my Predecessor, Venerable Pope John Paul II, said in his Address on the relationship between pastoral care and the law: ‘The judge … must always guard against the risk of misplaced compassion, which could degenerate into sentimentality, itself pastoral only in appearance.’
There is sufficient reason, therefore, to consider once more how mercy and justice relate to one another.
•Theta phase coherence is increased following negative performance feedback.•Deep brain stimulation globally modulates theta phase coherence.•Fronto-striatal connectivity is related to OCD symptom ...severity.
Symptoms of obsessive–compulsive disorder (OCD) are partly related to impaired cognitive control processes and theta modulations constitute an important electrophysiological marker for cognitive control processes such as signaling negative performance feedback in a fronto-striatal network. Deep brain stimulation (DBS) targeting the anterior limb of the internal capsule (ALIC)/nucleus accumbens (NAc) shows clinical efficacy in OCD, while the exact influence on the performance monitoring system remains largely unknown.
Seventeen patients with treatment-refractory OCD performed a probabilistic reinforcement learning task. Analyses were focused on 4–8 Hz (theta) power, intertrial phase coherence (ITPC) and debiased weighted Phase-Lag Index (dwPLI) in response to negative performance feedback. Combined EEG and local field potential (LFP) recordings were obtained shortly after DBS electrode implantation to investigate fronto-striatal network modulations. To assess the impact of clinically effective DBS on negative performance feedback modulations, EEG recordings were obtained pre-surgery and at follow-up with DBS on and off.
Medial frontal cortex ITPC, striatal ITPC and striato-frontal dwPLI were increased following negative performance feedback. Decreased right-lateralized dwPLI was associated with pre-surgery symptom severity. ITPC was globally decreased during DBS-off.
We observed a theta phase coherence mediated fronto-striatal performance monitoring network. Within this network, decreased connectivity was related to increased OCD symptomatology, consistent with the idea of impaired cognitive control in OCD. While ALIC/NAc DBS decreased theta network activity globally, this effect was unrelated to clinical efficacy and performance monitoring.
Since 1999, several targets for deep brain stimulation (DBS) in Gilles de la Tourette syndrome (GTS) have emerged showing similar success rates. Studies using different tractography techniques have ...identified connectivity profiles associated with a better outcome for individual targets. However, GTS patients might need individualized therapy. The objective of this study is to analyze the connectivity profile of different DBS targets for GTS. We identified standard target coordinates for the centromedian nucleus/nucleus ventro-oralis internus (CM/Voi), the CM/parafascicular (CM-Pf) complex, the anteromedial globus pallidus internus (amGPi), the posteroventral GPi (pvGPi), the ventral anterior/ventrolateral thalamus (VA/VL), and the nucleus accumbens/anterior limb of the internal capsule (Nacc/ALIC). Probabilistic tractography was performed from the targets to different limbic and motor areas based on patient-specific imaging and a normative connectome (HCP). Our analysis showed significant differences between the connectivity profiles of standard DBS targets (
< 0.05). Among all targets, the pvGPi showed the strongest connection to the sensorimotor cortex, while the amGPi showed the strongest connection to the prefrontal cortex in patient-specific imaging. Differences were observed between the connectivity profiles when using probabilistic tractography based on patient data and HCP. Our findings showed that the connectivity profiles of different DBS targets to major motor and limbic areas differ significantly. In the future, these differences may be considered when planning DBS for GTS patients employing an individualized approach. There were compelling differences in connectivity profiles when using different tractography techniques.
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