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.

Dorsal subthalamic nucleus targeting in deep brain stimulation: microelectrode recording versus 7-Tesla connectivity.

Connectivity-derived 7-Tesla MRI segmentation and intraoperative microelectrode recording can both assist subthalamic nucleus targeting for deep brain stimulation in Parkinson's disease. It remains unclear whether deep brain stimulation electrodes placed in the 7-Tesla MRI segmented subdivision with predominant projections to cortical motor areas (hyperdirect pathway) achieve superior motor improvement and whether microelectrode recording can accurately distinguish the motor subdivision. In 25 patients with Parkinson's disease, deep brain stimulation electrodes were evaluated for being inside or outside the predominantly motor-connected subthalamic nucleus (motor-connected subthalamic nucleus or non-motor-connected subthalamic nucleus, respectively) based on 7-Tesla MRI connectivity segmentation. Hemi-body motor improvement (Movement Disorder Society Unified Parkinson's Disease Rating Scale, Part III) and microelectrode recording characteristics of multi- and single-unit activities were compared between groups. Deep brain stimulation electrodes placed in the motor-connected subthalamic nucleus resulted in higher hemi-body motor improvement, compared with electrodes placed in the non-motor-connected subthalamic nucleus (80% versus 52%, P < 0.0001). Multi-unit activity was found slightly higher in the motor-connected subthalamic nucleus versus the non-motor-connected subthalamic nucleus (P < 0.001, receiver operating characteristic 0.63); single-unit activity did not differ between groups. Deep brain stimulation in the connectivity-derived 7-Tesla MRI subthalamic nucleus motor segment produced a superior clinical outcome; however, microelectrode recording did not accurately distinguish this subdivision within the subthalamic nucleus.

Neuroimmune Modulation Through Vagus Nerve Stimulation Reduces Inflammatory Activity in Crohn's Disease Patients: A Prospective Open-label Study.

BACKGROUND AND AIMS: Crohn's disease [CD] is a debilitating, inflammatory condition affecting the gastrointestinal tract. There is no cure and sustained clinical and endoscopic remission is achieved by fewer than half of patients with current therapies. The immunoregulatory function of the vagus nerve, the 'inflammatory reflex', has been established in patients with rheumatoid arthritis and biologic-naive CD. The aim of this study was to explore the safety and efficacy of vagus nerve stimulation in patients with treatment-refractory CD, in a 16-week, open-label, multicentre, clinical trial. METHODS: A vagus nerve stimulator was implanted in 17 biologic drug-refractory patients with moderately to severely active CD. One patient exited the study pre-treatment, and 16 patients were treated with vagus nerve stimulation [4/16 receiving concomitant biologics] during 16 weeks of induction and 24 months of maintenance treatment. Endpoints included clinical improvement, patient-reported outcomes, objective measures of inflammation [endoscopic/molecular], and safety. RESULTS: There was a statistically significant and clinically meaningful decrease in CD Activity Index at Week 16 [mean ±â€…SD: -86.2 ±â€…92.8, p = 0.003], a significant decrease in faecal calprotectin [-2923 ±â€…4104, p = 0.015], a decrease in mucosal inflammation in 11/15 patients with paired endoscopies [-2.1 ±â€…1.7, p = 0.23], and a decrease in serum tumour necrosis factor and interferon-γ [46-52%]. Two quality-of-life indices improved in 7/11 patients treated without biologics. There was one study-related severe adverse event: a postoperative infection requiring device explantation. CONCLUSIONS: Neuroimmune modulation via vagus nerve stimulation was generally safe and well tolerated, with a clinically meaningful reduction in clinical disease activity associated with endoscopic improvement, reduced levels of faecal calprotectin and serum cytokines, and improved quality of life.

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.

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.

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.

Efficacy and quality of life after 6-9 years of deep brain stimulation for depression.

BACKGROUND: Given the invasiveness of deep brain stimulation (DBS), the effect should prove to be stable over the long-term and translate into an improvement of quality of life (QOL). OBJECTIVE: To study the effectiveness and QOL up to nine years after the DBS surgery. METHODS: We treated 25 adult patients with major depression with DBS of the ventral anterior limb of the internal capsule (vALIC). We followed them up naturalistically for 6-9 years after surgery (mean: 7.7 [SD:1.5] years), including a randomized crossover phase after the first year comparing sham with active DBS. Symptom severity was quantified using the Hamilton Depression Scale with response defined as a ≥50% decrease of the score compared to baseline. Quality of life was measured using the WHOQOL-BREF, assessing 5 domains (general, physical, psychological, social, environmental). RESULTS: Intention-to-treat response rates remained mostly stable from Year 3 to last follow-up (Year 3, 5 and 6: 40%; Year 4: 36%; Last observation: 44%). General, physical, psychological (all P < 0.001) and the environmental (P = 0.02) domain scores increased during DBS optimization and remained stable over the long term. No statistically significant changes were detected on the social domain. Patients scored significantly higher during active than sham DBS on the psychological, social and environmental domains, and trended towards a higher score on the general and physical domains. CONCLUSION: This study shows continued efficacy of vALIC DBS in depression, which translates into an improvement of QOL providing further support for DBS as a durable treatment for TRD.

Evaluating and Optimizing Dentato-Rubro-Thalamic-Tract Deterministic Tractography in Deep Brain Stimulation for Essential Tremor.

BACKGROUND: Dentato-rubro-thalamic tract (DRT) deep brain stimulation (DBS) suppresses tremor in essential tremor (ET) patients. However, DRT depiction through tractography can vary depending on the included brain regions. Moreover, it is unclear which section of the DRT is optimal for DBS. OBJECTIVE: To evaluate deterministic DRT tractography and tremor control in DBS for ET. METHODS: After DBS surgery, DRT tractography was conducted in 37 trajectories (20 ET patients). Per trajectory, 5 different DRT depictions with various regions of interest (ROI) were constructed. Comparison resulted in a DRT depiction with highest correspondence to intraoperative tremor control. This DRT depiction was subsequently used for evaluation of short-term postoperative adverse and beneficial effects. RESULTS: Postoperative optimized DRT tractography employing the ROI motor cortex, posterior subthalamic area (PSA), and ipsilateral superior cerebellar peduncle and dentate nucleus best corresponded with intraoperative trajectories (92%) and active DBS contacts (93%) showing optimal tremor control. DRT tractography employing a red nucleus or ventral intermediate nucleus of the thalamus (VIM) ROI often resulted in a more medial course. Optimal stimulation was located in the section between VIM and PSA. CONCLUSION: This optimized deterministic DRT tractography strongly correlates with optimal tremor control. This technique is readily implementable for prospective evaluation in DBS target planning for ET.

Deep brain stimulation response in obsessive-compulsive disorder is associated with preoperative nucleus accumbens volume.

BACKGROUND: Deep brain stimulation (DBS) is a new treatment option for patients with therapy-resistant obsessive-compulsive disorder (OCD). Approximately 60% of patients benefit from DBS, which might be improved if a biomarker could identify patients who are likely to respond. Therefore, we evaluated the use of preoperative structural magnetic resonance imaging (MRI) in predicting treatment outcome for OCD patients on the group- and individual-level. METHODS: In this retrospective study, we analyzed preoperative MRI data of a large cohort of patients who received DBS for OCD (n = 57). We used voxel-based morphometry to investigate whether grey matter (GM) or white matter (WM) volume surrounding the DBS electrode (nucleus accumbens (NAc), anterior thalamic radiation), and whole-brain GM/WM volume were associated with OCD severity and response status at 12-month follow-up. In addition, we performed machine learning analyses to predict treatment outcome at an individual-level and evaluated its performance using cross-validation. RESULTS: Larger preoperative left NAc volume was associated with lower OCD severity at 12-month follow-up (pFWE < 0.05). None of the individual-level regression/classification analyses exceeded chance-level performance. CONCLUSIONS: These results provide evidence that patients with larger NAc volumes show a better response to DBS, indicating that DBS success is partly determined by individual differences in brain anatomy. However, the results also indicate that structural MRI data alone does not provide sufficient information to guide clinical decision making at an individual level yet.

Targeting of the Subthalamic Nucleus in Patients with Parkinson's Disease Undergoing Deep Brain Stimulation Surgery.

Precise stereotactic targeting of the dorsolateral motor part of the subthalamic nucleus (STN) is paramount for maximizing clinical effectiveness and preventing side effects of deep brain stimulation (DBS) in patients with advanced Parkinson's disease. With recent developments in magnetic resonance imaging (MRI) techniques, direct targeting of the dorsolateral part of the STN is now feasible, together with visualization of the motor fibers in the nearby internal capsule. However, clinically relevant discrepancies were reported when comparing STN borders on MRI to electrophysiological STN borders during microelectrode recordings (MER). Also, one should take into account the possibility of a 3D inaccuracy of up to 2 mm of the applied stereotactic technique. Pneumocephalus and image fusion errors may further increase implantation inaccuracy. Even when implantation has been successful, suboptimal lead anchoring on the skull may cause lead migration during follow-up. Meticulous pre- and intraoperative imaging is therefore indispensable, and so is postoperative imaging when the effects of DBS deteriorate during follow-up. Thus far, most DBS centers employ MRI targeting, multichannel MER, and awake test stimulation in STN surgery, but randomized trials comparing surgery under local versus general anesthesia and additional studies comparing MER-STN borders to high-field MRI-STN may change this clinical practice. Further developments in imaging protocols and improvements in image fusion processes are needed to optimize placement of DBS leads in the dorsolateral motor part of the STN in Parkinson's disease.

Structural and functional correlates of subthalamic deep brain stimulation-induced apathy in Parkinson's disease.

BACKGROUND: Notwithstanding the large improvement in motor function in Parkinson's disease (PD) patients treated with deep brain stimulation (DBS), apathy may increase. Postoperative apathy cannot always be related to a dose reduction of dopaminergic medication and stimulation itself may play a role. OBJECTIVE: We studied whether apathy in DBS-treated PD patients could be a stimulation effect. METHODS: In 26 PD patients we acquired apathy scores before and >6 months after DBS of the subthalamic nucleus (STN). Magnetoencephalography recordings (ON and OFF stimulation) were performed ≥6 months after DBS placement. Change in apathy severity was correlated with (i) improvement in motor function and dose reduction of dopaminergic medication, (ii) stimulation location (merged MRI and CT-scans) and (iii) stimulation-related changes in functional connectivity of brain regions that have an alleged role in apathy. RESULTS: Average apathy severity significantly increased after DBS (p < 0.001) and the number of patients considered apathetic increased from two to nine. Change in apathy severity did not correlate with improvement in motor function or dose reduction of dopaminergic medication. For the left hemisphere, increase in apathy was associated with a more dorsolateral stimulation location (p = 0.010). The increase in apathy severity correlated with a decrease in alpha1 functional connectivity of the dorsolateral prefrontal cortex (p = 0.006), but not with changes of the medial orbitofrontal or the anterior cingulate cortex. CONCLUSIONS: The present observations suggest that apathy after STN-DBS is not necessarily related to dose reductions of dopaminergic medication, but may be an effect of the stimulation itself. This highlights the importance of determining optimal DBS settings based on both motor and non-motor symptoms.

Distance to white matter trajectories is associated with treatment response to internal capsule deep brain stimulation in treatment-refractory depression.

BACKGROUND: Deep brain stimulation (DBS) is an innovative treatment for treatment-refractory depression. DBS is usually targeted at specific anatomical landmarks, with patients responding to DBS in approximately 50% of cases. Attention has recently shifted to white matter tracts to explain DBS response, with initial open-label trials targeting white matter tracts yielding much higher response rates (>70%). OBJECTIVE/HYPOTHESIS: Our aim was to associate distance to individual white matter tracts around the stimulation target in the ventral anterior limb of the internal capsule to treatment response. METHODS: We performed diffusion magnetic resonance tractography of the superolateral branch of the medial forebrain bundle and the anterior thalamic radiation in fourteen patients that participated in our randomized clinical trial. We combined the tract reconstructions with the postoperative images to identify the DBS leads and estimated the distance between tracts and leads, which we subsequently associated with treatment response. RESULTS: Stimulation closer to both tracts was significantly correlated to a larger symptom decrease (r = 0.61, p = 0.02), suggesting that stimulation more proximal to the tracts was beneficial. Biophysical modelling indicated that 37.5% of tracts were even outside the volume of activated tissue. There was no difference in lead placement with respect to anatomical landmarks, which could mean that differences in treatment response were driven by individual differences in white matter anatomy. CONCLUSIONS: Our results suggest that deep brain stimulation of the ventral anterior limb of the internal capsule could benefit from targeting white matter bundles. We recommend acquiring diffusion magnetic resonance data for each individual patient.

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.

Implementation of Intraoperative Cone-Beam Computed Tomography (O-arm) for Stereotactic Imaging During Deep Brain Stimulation Procedures.

BACKGROUND: Intraoperative cone-beam computed tomography (iCBCT) allows for rapid 3-dimensional imaging. However, it is currently unknown whether this imaging technique offers sufficient accuracy for stereotactic registration during deep brain stimulation (DBS) procedures. OBJECTIVE: To determine the accuracy of iCBCT, with the O-arm O2 (Medtronic), for stereotactic registration by comparing this modality to stereotactic magnetic resonance imaging (MRI). METHODS: All DBS patients underwent a preoperative non-stereotactic 3 Tesla MRI, stereotactic 1.5 Tesla MRI, stereotactic O-arm iCBCT, postimplantation O-arm iCBCT, and postoperative conventional multidetector computed tomography (CT) scan. We compared stereotactic (X, Y, and Z) coordinates of the anterior commissure (AC), the posterior commissure (PC), and midline reference (MR) between stereotactic MRI and iCBCT. For localisation comparison of electrode contacts, stereotactic coordinates of electrode tips were compared between the postoperative multidetector CT and iCBCT. RESULTS: A total of 20 patients were evaluated. The average absolute difference in stereotactic coordinates of AC, PC, and MR was 0.4 ± 0.4 mm for X, 0.4 ± 0.4 mm for Y, and 0.7 ± 0.5 mm for Z. The average absolute difference in X-, Y-, and Z-coordinates for electrode localisation (N = 34) was 0.3 ± 0.3 mm, 0.6 ± 0.3 mm, and 0.6 ± 0.6 mm. These differences were small enough not to be considered clinically relevant. CONCLUSION: Stereotactic MRI and O-arm iCBCT yield comparable coordinates in pre- and postoperative imaging. Differences found are below the threshold of clinical relevance. Intraoperative O-arm CBCT offers rapid stereotactic registration and evaluation of electrode placement. This increases patient comfort and neurosurgical workflow efficiency.