Bidirectional Interplay between Deep Brain Stimulation and Cognition in Parkinson's Disease: A Systematic Review.

BACKGROUND: Deep brain stimulation (DBS) is efficacious for treating motor symptoms in Parkinson's disease (PD). OBJECTIVES: The aim is to evaluate the evidence regarding DBS effectiveness after postoperative cognitive deterioration, the impact of preoperative cognition on DBS effectiveness, and the impact of DBS on cognition. METHODS: Literature searches were performed on MEDLINE, EMBASE, and CENTRAL (Cochrane library). Primary outcomes were OFF-drug Unified Parkinson Disease Rating Scale Part III score and cognitive test scores. RESULTS: DBS effectiveness did not differ in patients with postoperative declining compared to stable cognition (n = 5 studies). Preoperative cognition did not influence DBS effectiveness (n = 1 study). DBS moderately decreased verbal fluency compared to the best medical treatment (n = 24 studies), which may be transient. CONCLUSION: DBS motor effectiveness in PD does not appear to be influenced by cognition. DBS in PD seems cognitively safe, except for a moderate decline in verbal fluency. Further research is warranted. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Utilizing 7-Tesla Subthalamic Nucleus Connectivity in Deep Brain Stimulation for Parkinson Disease.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective surgical treatment for patients with advanced Parkinson disease (PD). Combining 7.0-Tesla (7T) T2- and diffusion-weighted imaging (DWI) sequences allows for selective segmenting of the motor part of the STN and, thus, for possible optimization of DBS. MATERIALS AND METHODS: 7T T2 and DWI sequences were obtained, and probabilistic segmentation of motor, associative, and limbic STN segments was performed. Left- and right-sided motor outcome (Movement Disorders Society Unified Parkinson's Disease Rating Scale) scores were used for evaluating the correspondence between the active electrode contacts in selectively segmented STN and the clinical DBS effect. The Bejjani line was reviewed for crossing of segments. RESULTS: A total of 50 STNs were segmented in 25 patients and proved highly feasible. Although the highest density of motor connections was situated in the dorsolateral STN for all patients, the exact partitioning of segments differed considerably. For all the active electrode contacts situated within the predominantly motor-connected segment of the STN, the average hemi-body Unified Parkinson's Disease Rating Scale motor improvement was 80%; outside this segment, it was 52% (p < 0.01). The Bejjani line was situated in the motor segment for 32 STNs. CONCLUSION: The implementation of 7T T2 and DWI segmentation of the STN in DBS for PD is feasible and offers insight into the location of the motor segment. Segmentation-guided electrode placement is likely to further improve motor response in DBS for PD. However, commercially available DBS software for postprocessing imaging would greatly facilitate widespread implementation.

The Fast Gray Matter Acquisition T1 Inversion Recovery Sequence in Deep Brain Stimulation: Introducing the Rubral Wing for Dentato-Rubro-Thalamic Tract Depiction and Tremor Control.

BACKGROUND: The dentato-rubro-thalamic tract (DRT) is currently considered as a potential target in deep brain stimulation (DBS) for various types of tremor. However, tractography depiction can vary depending on the included brain regions. The fast gray matter acquisition T1 inversion recovery (FGATIR) sequence, with excellent delineation of gray and white matter, possibly provides anatomical identification of rubro-thalamic DRT fibers. OBJECTIVE: This study aimed to evaluate the FGATIR sequence by comparison with DRT depiction, electrode localization, and effectiveness of DBS therapy. MATERIALS AND METHODS: In patients with DBS therapy because of medication-refractory tremor, the FGATIR sequence was evaluated for depiction of the thalamus, red nucleus (RN), and rubro-thalamic connections. Deterministic tractography of the DRT, electrode localization, and tremor control were compared. The essential tremor rating scale was used to assess (hand) tremor. Tremor control was considered successful when complete tremor suppression (grade 0) or almost complete suppression (grade 1) was observed. RESULTS: In the postoperative phase, we evaluated 14 patients who underwent DRT-guided DBS: 12 patients with essential tremor, one with tremor-dominant Parkinson disease, and one with multiple sclerosis, representing 24 trajectories. Mean follow-up was 11.3 months (range 6-19 months). The FGATIR sequence provided a clear delineation of a hypointense white matter tract within the hyperintense thalamus. In coronal plane, this tract was most readily recognizable as a "rubral wing," with the round RN as base and lateral triangular convergence. The deterministic DRT depiction was consistently situated within the rubral wing. The number of active contacts located within the DRT (and rubral wing) was 22 (92%), of which 16 (73%) showed successful tremor control. CONCLUSIONS: The FGATIR sequence offers visualization of the rubro-thalamic connections that form the DRT, most readily recognizable as a "rubral wing" in coronal plane. This sequence contributes to tractographic depiction of DRT and provides a direct anatomical DBS target area for tremor control.

Deep brain stimulation modulates directional limbic connectivity in obsessive-compulsive disorder.

Deep brain stimulation is effective for patients with treatment-refractory obsessive-compulsive disorder. Deep brain stimulation of the ventral anterior limb of the internal capsule rapidly improves mood and anxiety with optimal stimulation parameters. To understand these rapid effects, we studied functional interactions within the affective amygdala circuit. We compared resting state functional MRI data during chronic stimulation versus 1 week of stimulation discontinuation in patients, and obtained two resting state scans from matched healthy volunteers to account for test-retest effects. Imaging data were analysed using functional connectivity analysis and dynamic causal modelling. Improvement in mood and anxiety following deep brain stimulation was associated with reduced amygdala-insula functional connectivity. Directional connectivity analysis revealed that deep brain stimulation increased the impact of the ventromedial prefrontal cortex on the amygdala, and decreased the impact of the amygdala on the insula. These results highlight the importance of the amygdala circuit in the pathophysiology of obsessive-compulsive disorder, and suggest a neural systems model through which negative mood and anxiety are modulated by stimulation of the ventral anterior limb of the internal capsule for obsessive-compulsive disorder and possibly other psychiatric disorders.

Defining the Dorsal STN Border Using 7.0-T MRI: A Comparison to Microelectrode Recordings and Lower Field Strength MRI.

BACKGROUND: 7.0-T T2-weighted MRI offers excellent visibility of the subthalamic nucleus (STN), which is used as a target for deep brain stimulation (DBS) in Parkinson's disease (PD). A comparison of 7.0-T MRI to microelectrode recordings (MER) for STN border identification has not been performed. OBJECTIVE: To compare representation of STN borders on 7.0-T T2 MRI with the borders identified during MER in patients undergoing DBS for PD and to evaluate whether STN identification on 7.0-T T2 MRI leads to alterations in stereotactic target planning. DESIGN/METHODS: STN border identification was done using volumetric 7.0-T T2 MRI acquisitions. This was compared to the STN borders identified by MER. STN target planning was independently performed by 3 DBS surgeons on T2 imaging using 1.5-, 3.0-, and 7.0-T MRI. RESULTS: A total of 102 microelectrode tracks were evaluated in 19 patients. Identification of the dorsal STN border was well feasible on 7-T T2, whereas the ventral STN was un-distinguishable from the substantia nigra. The dorsal STN border on MRI was located more dorsal than MER in 73% of trajectories. The average distance from MRI to MER border was 0.9 mm (range -4.4 to +3.5 mm). STN target planning showed high correspondence between the 3 field strengths. CONCLUSION: 7.0-T T2 MRI offers the possibility of easy identification of the dorsal border of the STN. However, higher field strength MRI does not change the planning of the target. Compared to MER, the dorsal border on MRI was located more dorsal in the majority of cases, situating MER activity within STN representation.

Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a heterogeneous, prevalent, chronic autoimmune disease characterized by painful swollen joints and significant disabilities. Symptomatic relief can be achieved in up to 50% of patients using biological agents that inhibit tumor necrosis factor (TNF) or other mechanisms of action, but there are no universally effective therapies. Recent advances in basic and preclinical science reveal that reflex neural circuits inhibit the production of cytokines and inflammation in animal models. One well-characterized cytokine-inhibiting mechanism, termed the "inflammatory reflex," is dependent upon vagus nerve signals that inhibit cytokine production and attenuate experimental arthritis severity in mice and rats. It previously was unknown whether directly stimulating the inflammatory reflex in humans inhibits TNF production. Here we show that an implantable vagus nerve-stimulating device in epilepsy patients inhibits peripheral blood production of TNF, IL-1ß, and IL-6. Vagus nerve stimulation (up to four times daily) in RA patients significantly inhibited TNF production for up to 84 d. Moreover, RA disease severity, as measured by standardized clinical composite scores, improved significantly. Together, these results establish that vagus nerve stimulation targeting the inflammatory reflex modulates TNF production and reduces inflammation in humans. These findings suggest that it is possible to use mechanism-based neuromodulating devices in the experimental therapy of RA and possibly other autoimmune and autoinflammatory diseases.

Contributions of the Ventral Striatum to Conscious Perception: An Intracranial EEG Study of the Attentional Blink.

The brain is limited in its capacity to consciously process information, necessitating gating of information. While conscious perception is robustly associated with sustained, recurrent interactions between widespread cortical regions, subcortical regions, including the striatum, influence cortical activity. Here, we examined whether the ventral striatum, given its ability to modulate cortical information flow, contributes to conscious perception. Using intracranial EEG, we recorded ventral striatum activity while 7 patients performed an attentional blink task in which they had to detect two targets (T1 and T2) in a stream of distractors. Typically, when T2 follows T1 within 100-500 ms, it is often not perceived (i.e., the attentional blink). We found that conscious T2 perception was influenced and signaled by ventral striatal activity. Specifically, the failure to perceive T2 was foreshadowed by a T1-induced increase in α and low ß oscillatory activity as early as 80 ms after T1, indicating that the attentional blink to T2 may be due to very early T1-driven attentional capture. Moreover, only consciously perceived targets were associated with an increase in θ activity between 200 and 400 ms. These unique findings shed new light on the mechanisms that give rise to the attentional blink by revealing that conscious target perception may be determined by T1 processing at a much earlier processing stage than traditionally believed. More generally, they indicate that ventral striatum activity may contribute to conscious perception, presumably by gating cortical information flow. SIGNIFICANCE STATEMENT: What determines whether we become aware of a piece of information or not? Conscious access has been robustly associated with activity within a distributed network of cortical regions. Using intracranial electrophysiological recordings during an attentional blink task, we tested the idea that the ventral striatum, because of its ability to modulate cortical information flow, may contribute to conscious perception. We find that conscious perception is influenced and signaled by ventral striatal activity. Short-latency (80-140 ms) striatal responses to a first target determined conscious perception of a second target. Moreover, conscious perception of the second target was signaled by longer-latency (200-400 ms) striatal activity. These results suggest that the ventral striatum may be part of a subcortical network that influences conscious experience.

Deep brain stimulation for Parkinson's disease: defining the optimal location within the subthalamic nucleus.

BACKGROUND: Individual motor improvement after deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson's disease (PD) varies considerably. Stereotactic targeting of the dorsolateral sensorimotor part of the STN is considered paramount for maximising effectiveness, but studies employing the midcommissural point (MCP) as anatomical reference failed to show correlation between DBS location and motor improvement. The medial border of the STN as reference may provide better insight in the relationship between DBS location and clinical outcome. METHODS: Motor improvement after 12 months of 65 STN DBS electrodes was categorised into non-responding, responding and optimally responding body-sides. Stereotactic coordinates of optimal electrode contacts relative to both medial STN border and MCP served to define theoretic DBS 'hotspots'. RESULTS: Using the medial STN border as reference, significant negative correlation (Pearson's correlation -0.52, P<0.01) was found between the Euclidean distance from the centre of stimulation to this DBS hotspot and motor improvement. This hotspot was located at 2.8 mm lateral, 1.7 mm anterior and 2.5 mm superior relative to the medial STN border. Using MCP as reference, no correlation was found. CONCLUSION: The medial STN border proved superior compared with MCP as anatomical reference for correlation of DBS location and motor improvement, and enabled defining an optimal DBS location within the nucleus. We therefore propose the medial STN border as a better individual reference point than the currently used MCP on preoperative stereotactic imaging, in order to obtain optimal and thus less variable motor improvement for individual patients with PD following STN DBS.

Does deep brain stimulation improve lower urinary tract symptoms in Parkinson's disease?

AIMS: To investigate whether deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) or the subthalamic nucleus (STN) improve lower urinary tract symptoms (LUTS) in advanced Parkinson's disease (PD). METHODS: An exploratory post-hoc analysis was performed of specific LUTS items of questionnaires used in a randomized clinical trial with 128 patients (NSTAPS study). First, we compared scores on LUTS items at baseline and 12 months for the GPi DBS and STN DBS group separately. Second, we divided the group by sex, instead of DBS location; to assess a possible gender associated influence of anatomical and pathophysiological differences, again comparing scores at baseline and 12 months. Third, we reported on Foley-catheter use at baseline and after 12 months. RESULTS: Urinary incontinence and frequency improved after both GPi DBS and STN DBS at 12 months, postoperatively, but this was only statistically significant for the STN DBS group (P = 0.004). The improvements after DBS were present in both men (P = 0.01) and women (P = 0.05). Nocturia and urinary incontinence did not improve significantly after any type of DBS, irrespective of sex. At 12 months, none of the patients had a Foley-catheter. CONCLUSIONS: Urinary incontinence and frequency significantly improved after STN DBS treatment in male and female patients with PD. Nocturia and nighttime incontinence due to parkinsonism did not improve after DBS, irrespective of gender.

Electrode Penetration of the Caudate Nucleus in Deep Brain Stimulation Surgery for Parkinson's Disease.

OBJECTIVE: To evaluate the possible influence of electrode trajectories penetrating the caudate nucleus (CN) on cognitive outcomes in deep brain stimulation (DBS) surgery for Parkinson's disease (PD). BACKGROUND: It is currently unclear how mandatory CN avoidance during trajectory planning is. DESIGN/METHODS: Electrode trajectories were determined to be inside, outside, or in border region of the CN. Pre- and postoperative neuropsychological tests of each trajectory group were compared in order to evaluate possible differences in cognitive outcomes 12 months after bilateral STN DBS. RESULTS: One hundred six electrode tracks in 53 patients were evaluated. Bilateral penetration of the CN occurred in 15 (28%) patients, while unilateral penetration occurred in 28 (53%). In 19 (36%) patients tracks were located in the border region of the CN. There was no electrode penetration of the CN in 10 (19%) patients. No difference in cognitive outcomes was found between the different groups. CONCLUSION: Cognitive outcome was not influenced by DBS electrode tracks penetrating the CN. It is both feasible and sensible to avoid electrode tracks through the CN when possible, considering its function and anatomical position. However, penetration of the CN can be considered without major concerns regarding cognitive decline when this facilitates optimal trajectory planning due to specific individual anatomical variations.

Body Weight Changes after Deep Brain Stimulation for Obsessive-Compulsive Disorder or Depression.

BACKGROUND: In 2010, we published an often-cited case report describing smoking cessation and substantial weight loss after deep brain stimulation (DBS) for obsessive-compulsive disorder (OCD) in an obese patient. To test whether this single observation was also observed in the treated population at large, the weight changes of a larger cohort of patients who underwent DBS for OCD or major depressive disorder (MDD) were studied. RESULTS: Data were available for 46 patients (30 OCD and 16 MDD patients; mean age 46.2 years, SD 10.9) with an average baseline body mass index (BMI) of 28.0 (SD 7.3), 26 of whom (57%) were overweight (n = 11), obese (n = 12), or morbidly obese (n = 3). Mean follow-up was 3.8 years (range 10 months to 8.7 years, SD 2.3), after which the average BMI was 28.1 (SD 7.0), not significantly different from baseline. The average BMI of the 15 patients with (morbid) obesity at baseline decreased from 36.8 to 34.6 (ns), while the average BMI of the 31 normal or "only" overweight patients at baseline increased from 23.8 to 25.0 (ns). CONCLUSION: There was no significant change in body weight on group level after DBS for either OCD or MDD.

Psychiatric and social outcome after deep brain stimulation for advanced Parkinson's disease.

BACKGROUND: The aim of this study was to assess psychiatric and social outcome 12 months after bilateral deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) and subthalamic nucleus (STN) for advanced Parkinson's disease (PD). METHODS: We randomly assigned patients to receive GPi DBS (n = 65) or STN DBS (n = 63). Standardized psychiatric and social questionnaires were assessed at baseline and after 12 months. RESULTS: No differences were found between GPi DBS and STN DBS on psychiatric evaluation. Within-group comparisons showed small but statistically significant changes on several measures in both groups. Descriptive statistics indicated slight changes in social functioning. Marital satisfaction of patients and partners remained relatively stable after GPi and STN DBS. CONCLUSIONS: We found neither differences in psychiatric and social outcome between GPi DBS and STN DBS nor any relevant within-group differences. The decision for GPi DBS or STN DBS cannot be based on expected psychiatric or social effects.

Deep brain stimulation for obsessive-compulsive disorders: long-term analysis of quality of life.

OBJECTIVE: To evaluate the long-term effects of deep brain stimulation (DBS) on quality of life (QOL) in therapy-refractory obsessive-compulsive disorder (OCD) patients. DESIGN: 16 patients who met Diagnostic and Statistical Manual of Mental Disorders (4th ed) (DSM-IV) criteria for OCD and were considered therapy-refractory were treated with DBS. Patients were assessed 1 month before device implantation (T0), at 8 months of active stimulation (T1) and at 3-5 years of active stimulation (T2). QOL was measured with the WHO Quality of Life Scale-Brief Version (WHOQOL-BREF) that covers physical, psychological, social and environmental domains. The study was conducted between April 2005 and January 2011 at the Academic Medical Center, Amsterdam, The Netherlands. RESULTS: At T1 and T2, we found significant improvement (p<0.05) in the general score and in the physical, psychological and environmental domains of WHOQOL-BREF. Between T1 and T2, the physical and psychological domains improved further (p<0.05). At T2, the general score improved by a total of 90%, the physical and psychological domains both improved by 39.5% and the environmental domain improved by 16%. The social domain did not change between baseline and follow-up assessments. CONCLUSIONS: In line with symptom improvement, patient's QOL improved in the general score and in three of the four WHOQOL-BREF domains. This suggests that the improvement caused by DBS is not limited to symptom reduction alone, but also has a positive influence on patients' perception of their physical, psychological, environmental and global QOL. CLINICAL TRIAL REGISTRATION: http://isrctn.org identifier: ISRCTN23255677.

Active stimulation site of nucleus accumbens deep brain stimulation in obsessive-compulsive disorder is localized in the ventral internal capsule.

Obsessive-compulsive disorder (OCD) is a chronic psychiatric disorder characterized by persistent thoughts and repetitive ritualistic behaviours. Despite optimal cognitive-behavioral and pharmacological therapy, approximately 10 % of patients remain treatment-resistant. Deep brain stimulation (DBS) is being investigated as experimental therapy for treatment-refractory OCD. In the current study, we determined the relationship between anatomical location of active electrode contacts and clinical outcome in 16 OCD patients undergoing bilateral nucleus accumbens (NAc) DBS. We found that most patients actually do not receive active stimulation in the NAc but in the more laterally, anteriorly and dorsally located ventral part of the anterior limb of the internal capsule, ventral ALIC (vALIC). Our nine patients receiving bilateral vALIC DBS improved on average 73 % on their Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores, whereas the six patients with their centers of stimulation located otherwise improved on average only 42 %. We therefore propose bilateral vALIC as a promising new DBS target for patients with treatment-refractory OCD. Future studies employing a direct vALIC targeting approach in larger patient numbers are needed to test whether this proposal holds true.

Acute effects of deep brain stimulation on brain function in obsessive-compulsive disorder.

OBJECTIVE: Deep brain stimulation (DBS) is an effective treatment for refractory obsessive-compulsive disorder (OCD) yet neural markers of optimized stimulation parameters are largely unknown. We aimed to describe (sub-)cortical electrophysiological responses to acute DBS at various voltages in OCD. METHODS: We explored how DBS doses between 3-5 V delivered to the ventral anterior limb of the internal capsule of five OCD patients affected electroencephalograms and intracranial local field potentials (LFPs). We focused on theta power/ phase-stability, given their previously established role in DBS for OCD. RESULTS: Cortical theta power and theta phase-stability did not increase significantly with DBS voltage. DBS-induced theta power peaks were seen at the previously defined individualized therapeutic voltage. Although LFP power generally increased with DBS voltages, this occurred mostly in frequency peaks that overlapped with stimulation artifacts limiting its interpretability. Though highly idiosyncratic, three subjects showed significant acute DBS effects on electroencephalogram theta power and four subjects showed significant carry-over effects (pre-vs post DBS, unstimulated) on LFP and electroencephalogram theta power. CONCLUSIONS: Our findings challenge the presence of a consistent dose-response relationship between stimulation voltage and brain activity. SIGNIFICANCE: Theta power may be investigated further as a neurophysiological marker to aid personalized DBS voltage optimization in OCD.

Patient specific intracranial neural signatures of obsessions and compulsions in the ventral striatum.

Objective. Deep brain stimulation is a treatment option for patients with refractory obsessive-compulsive disorder. A new generation of stimulators hold promise for closed loop stimulation, with adaptive stimulation in response to biologic signals. Here we aimed to discover a suitable biomarker in the ventral striatum in patients with obsessive compulsive disorder using local field potentials.Approach.We induced obsessions and compulsions in 11 patients undergoing deep brain stimulation treatment using a symptom provocation task. Then we trained machine learning models to predict symptoms using the recorded intracranial signal from the deep brain stimulation electrodes.Main results.Average areas under the receiver operating characteristics curve were 62.1% for obsessions and 78.2% for compulsions for patient specific models. For obsessions it reached over 85% in one patient, whereas performance was near chance level when the model was trained across patients. Optimal performances for obsessions and compulsions was obtained at different recording sites.Significance. The results from this study suggest that closed loop stimulation may be a viable option for obsessive-compulsive disorder, but that intracranial biomarkers are patient and not disorder specific.Clinical Trial:Netherlands trial registry NL7486.