Intrinsic auricular muscle zone stimulation for Parkinson disease: The EARSTIM-PD Phase II multi-center pilot study results.

BACKGROUND: Studies have suggested that intrinsic auricular muscle zones (IAMZ) stimulation alleviates motor features of Parkinson disease (PD). METHODS: A randomized, blinded, active sham-controlled pilot trial was conducted to evaluate the safety and dose-response-time curve of Earstim using a 3-treatment, 3-period crossover design in PD patients experiencing OFF time on levodopa. Treatments were: short (20-min) IAMZ stimulation; long (60-min) IAMZ stimulation; and 20-min active sham stimulation of non-muscular areas. Assessment time points were: prior to treatment, and 20, 40, 60, 90, and 120 min after treatment onset. Primary safety endpoints were adverse events frequency and severity. Primary efficacy endpoint was the change in MDS-UPDRS motor score at 20 min after treatment onset in the IAMZ treatment groups versus sham. RESULTS: Forty-six individuals consented; 38 were randomized (average age 64 years, 65 % male, mean 8.2 years from diagnosis). No serious adverse events or significant device-related events occurred. At 20 min after treatment onset, motor improvements did not differ between IAMZ treatments versus sham. However, at 60 min after treatment onset, motor improvement peaked on IAMZ treatments compared to sham (difference: 3.1 [-5.9 to 0.3], p = 0.03). While the difference in 120-min AUC change between IAMZ treatments versus sham was not significant, the short-stimulation IAMZ treatment showed the largest aggregate motor score improvement (AUC = -456 points, 95 % CI -691 to -221) compared to sham. CONCLUSION: Earstim was well-tolerated. The greatest motor improvement occurred at 60 min after stimulation onset in the short-stimulation IAMZ treatment, and supports its further study to alleviate OFF periods.

Effect of anisotropic brain conductivity on patient-specific volume of tissue activation in deep brain stimulation for Parkinson disease.

OBJECTIVE: Deep brain stimulation (DBS) modeling can improve surgical targeting by quantifying the spatial extent of stimulation relative to subcortical structures of interest. A certain degree of model complexity is required to obtain accurate predictions, particularly complexity regarding electrical properties of the tissue around DBS electrodes. In this study, the effect of anisotropy on the volume of tissue activation (VTA) was evaluated in an individualized manner. METHODS: Tissue activation models incorporating patient-specific tissue conductivity were built for 40 Parkinson disease patients who had received bilateral subthalamic nucleus (STN) DBS. To assess the impact of local changes in tissue anisotropy, one VTA was computed at each electrode contact using identical stimulation parameters. For comparison, VTAs were also computed assuming isotropic tissue conductivity. Stimulation location was considered by classifying the anisotropic VTAs relative to the STN. VTAs were characterized based on volume, spread in three directions, sphericity, and Dice coefficient. RESULTS: Incorporating anisotropy generated significantly larger and less spherical VTAs overall. However, its effect on VTA size and shape was variable and more nuanced at the individual patient and implantation levels. Dorsal VTAs had significantly higher sphericity than ventral VTAs, suggesting more isotropic behavior. Contrastingly, lateral and posterior VTAs had significantly larger and smaller lateral-medial spreads, respectively. Volume and spread correlated negatively with sphericity. CONCLUSION: The influence of anisotropy on VTA predictions is important to consider, and varies across patients and stimulation location. SIGNIFICANCE: This study highlights the importance of considering individualized factors in DBS modeling to accurately characterize the VTA.

Impact of subthalamic nucleus stimulation on urinary dysfunction and constipation in Parkinson's disease.

OBJECTIVE: The effect of subthalamic nucleus (STN) deep brain stimulation (DBS) on urinary dysfunction and constipation in Parkinson's disease (PD) is variable. This study aimed to identify potential surgical and nonsurgical variables predictive of these outcomes. METHODS: The authors used the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I to assess urinary dysfunction (item 10) and constipation (item 11) preoperatively and at 6-12 months postoperatively. A multiple linear regression model was used to investigate the impact of global cerebral atrophy (GCA) and active electrode contact location on the urinary dysfunction and constipation follow-up scores, controlling for age, disease duration, baseline score, motor improvement, and levodopa-equivalent dose changes. An electric field model was applied to localize the maximal-effect sites for constipation and urinary dysfunction compared with those for motor improvement. RESULTS: Among 74 patients, 23 improved, 28 deteriorated, and 23 remained unchanged for urinary dysfunction; 25 improved, 15 deteriorated, and 34 remained unchanged for constipation. GCA score and age significantly predicted urinary dysfunction follow-up score (R2 = 0.36, p < 0.001). Increased GCA and age were independently associated with worsening urinary symptoms. Disease duration, baseline constipation score, and anterior active electrode contacts in both hemispheres were significant predictors of constipation follow-up score (R2 = 0.31, p < 0.001). Higher baseline constipation score and disease duration were associated with worsening constipation; anterior active contact location was associated with improvement in constipation. CONCLUSIONS: Anterior active contact location was associated with improvement in constipation in PD patients after STN DBS. PD patients with greater GCA scores before surgery were more likely to experience urinary deterioration after DBS.

Dorsal subthalamic deep brain stimulation improves pain in Parkinson's disease.

Introduction: Inconsistent effects of subthalamic deep brain stimulation (STN DBS) on pain, a common non-motor symptom of Parkinson's disease (PD), may be due to variations in active contact location relative to some pain-reducing locus of stimulation. This study models and compares the loci of maximal effect for pain reduction and motor improvement in STN DBS. Methods: We measured Movement Disorder Society Unified PD Rating Scale (MDS-UPDRS) Part I pain score (item-9), and MDS-UPDRS Part III motor score, preoperatively and 6-12 months after STN DBS. An ordinary least-squares regression model was used to examine active contact location as a predictor of follow-up pain score while controlling for baseline pain, age, dopaminergic medication, and motor improvement. An atlas-independent isotropic electric field model was applied to distinguish sites of maximally effective stimulation for pain and motor improvement. Results: In 74 PD patients, mean pain score significantly improved after STN DBS (p = 0.01). In a regression model, more dorsal active contact location was the only significant predictor of pain improvement (R2 = 0.17, p = 0.03). The stimulation locus for maximal pain improvement was lateral, anterior, and dorsal to that for maximal motor improvement. Conclusion: STN stimulation, dorsal to the site of optimal motor improvement, improves pain. This region contains the zona incerta, which is known to modulate pain in humans, and may explain this observation.

Predictors of Cognitive Change in Parkinson Disease: A 2-year Follow-up Study.

BACKGROUND: Mild cognitive impairment is common in Parkinson disease (PD-MCI). However, instability in this clinical diagnosis and variability in rates of progression to dementia raises questions regarding its utility for longitudinal tracking and prediction of cognitive change in PD. We examined baseline neuropsychological test and cognitive diagnosis predictors of cognitive change in PD. METHODS: Persons with PD, without dementia PD (N=138) underwent comprehensive neuropsychological assessment at baseline and were followed up to 2 years. Level II Movement Disorder Society criteria for PD-MCI and PD dementia (PDD) were applied annually. Composite global and domain cognitive z -scores were calculated based on a 10-test neuropsychological battery. RESULTS: Baseline diagnosis of PD-MCI was not associated with a change in global cognitive z -scores. Lower baseline attention and higher executive domain z -scores were associated with greater global cognitive z -score worsening regardless of cognitive diagnosis. Worse baseline domain z -scores in the attention and language domains were associated with progression to MCI or PDD, whereas higher baseline scores in all cognitive domains except executive function were associated with clinical and psychometric reversion to "normal" cognition. CONCLUSIONS: Lower scores on cognitive tests of attention were predictive of worse global cognition over 2 years of follow-up in PD, and lower baseline attention and language scores were associated with progression to MCI or PDD. However, PD-MCI diagnosis per se was not predictive of cognitive decline over 2 years. The association between higher executive domain z -scores and greater global cognitive worsening is probably a spurious result.

Localization of deep brain stimulation trajectories via automatic mapping of microelectrode recordings to MRI.

Objective. Suboptimal electrode placement during subthalamic nucleus deep brain stimulation (STN DBS) surgery may arise from several sources, including frame-based targeting errors and intraoperative brain shift. We present a computer algorithm that can accurately localize intraoperative microelectrode recording (MER) tracks on preoperative magnetic resonance imaging (MRI) in real-time, thereby predicting deviation between the surgical plan and the MER trajectories.Approach. Random forest (RF) modeling was used to derive a statistical relationship between electrophysiological features on intraoperative MER and voxel intensity on preoperative T2-weighted MR imaging. This model was integrated into a larger algorithm that can automatically localize intraoperative MER recording tracks on preoperative MRI in real-time. To verify accuracy, targeting error of both the planned intraoperative trajectory ('planned') and the algorithm-derived trajectory ('calculated') was estimated by measuring deviation from the final DBS lead location on postoperative high-resolution computed tomography ('actual').Main results. MR imaging and MERs were obtained from 24 STN DBS implant trajectories. The cross-validated RF model could accurately distinguish between gray and white matter regions along MER trajectories (AUC 0.84). When applying this model within the localization algorithm, thecalculatedMER trajectory estimate was found to be significantly closer to theactualDBS lead when compared to theplannedtrajectory recorded during surgery (1.04 mm vs 1.52 mm deviation,p< 0.002), with improvement shown in 19/24 cases (79%). When applying the algorithm to simulated DBS trajectory plans with randomized targeting error, up to 4 mm of error could be resolved to <2 mm on average (p< 0.0001).Significance. This work presents an automated system for intraoperative localization of electrodes during STN DBS surgery. This neuroengineering solution may enhance the accuracy of electrode position estimation, particularly in cases where high-resolution intraoperative imaging is not available.

Thalamic Segmentation and Neural Activation Modeling Based on Individual Tissue Microstructure in Deep Brain Stimulation for Essential Tremor.

OBJECTIVE: Thalamic deep brain stimulation (DBS) is the primary surgical therapy for essential tremor (ET). Thalamic DBS traditionally uses an atlas-based targeting approach, which, although nominally accurate, may obscure individual anatomic differences from population norms. The objective of this study was to compare this traditional atlas-based approach with a novel quantitative modeling methodology grounded in individual tissue microstructure (N-of-1 approach). MATERIALS AND METHODS: The N-of-1 approach uses individual patient diffusion tensor imaging (DTI) data to perform thalamic segmentation and volume of tissue activation (VTA) modeling. For each patient, the thalamus was individually segmented into 13 nuclei using DTI-based k-means clustering. DBS-induced VTAs associated with tremor suppression and side effects were then computed for each patient with finite-element electric-field models incorporating DTI microstructural data. Results from N-of-1 and traditional atlas-based modeling were compared for a large cohort of patients with ET treated with thalamic DBS. RESULTS: The size and shape of individual N-of-1 thalamic nuclei and VTAs varied considerably across patients (N = 22). For both methods, tremor-improving therapeutic VTAs showed similar overlap with motor thalamic nuclei and greater motor than sensory nucleus overlap. For VTAs producing undesirable sustained paresthesia, 94% of VTAs overlapped with N-of-1 sensory thalamus estimates, whereas 74% of atlas-based segmentations overlapped. For VTAs producing dysarthria/motor contraction, the N-of-1 approach predicted greater spread beyond the thalamus into the internal capsule and adjacent structures than the atlas-based method. CONCLUSIONS: Thalamic segmentation and VTA modeling based on individual tissue microstructure explain therapeutic stimulation equally well and side effects better than a traditional atlas-based method in DBS for ET. The N-of-1 approach may be useful in DBS targeting and programming, particularly when patient neuroanatomy deviates from population norms.

Perceived social support declines after deep brain stimulation surgery in patients with Parkinson's disease.

INTRODUCTION: The Social Provisions Scale (SPS) measures a person's perceived social support. We evaluated the perceived social support in Parkinson's disease (PD) patients before and after subthalamic nucleus (STN) deep brain stimulation (DBS) and its impact on clinical outcomes following DBS. METHODS: We analyzed 55 PD patients who underwent STN DBS surgery and completed the SPS, PDQ-39, and MDS-UPDRS Parts I-IV before and 6-12 months after surgery. Some patients also completed global cognitive, mood and apathy scales. Caregivers completed the CBI at each visit. Linear regression models and linear mixed models evaluated the association between the SPS baseline score, MDS-UPDRS and PDQ-39 scores, the association between MDS-UPDRS, CBI and the SPS follow-up score, and the association between SPS, global cognition and other psychological variables. RESULTS: DBS implantation improved MDS-UPDRS I-IV and PDQ-39 scores. Perceived social support declined after DBS (baseline SPS total 82.55 ± 7.52 vs. follow-up SPS total 78.83 ± 9.02, p = 0.0001). Baseline SPS total score was not significantly associated with the MDS-UPDRS or PDQ-39 scores at follow-up. MDS-UPDRS scores and the CBI at follow-up had no significant association with SPS total score at follow-up. Measures of global cognition, mood and apathy were associated with the SPS before and after DBS, and the association was independent of STN DBS. CONCLUSION: After STN DBS, PD patients experienced a decrease in perceived social support, but baseline perceived social support did not impact clinical outcomes. It is important to further identify factors that may contribute to this perception of worsened social support.

Serotonin Transporter Imaging in Multiple System Atrophy and Parkinson's Disease.

BACKGROUND: Both Parkinson's disease (PD) and multiple system atrophy (MSA) exhibit degeneration of brainstem serotoninergic nuclei, affecting multiple subcortical and cortical serotoninergic projections. In MSA, medullary serotoninergic neuron pathology is well documented, but serotonin system changes throughout the rest of the brain are less well characterized. OBJECTIVES: To use serotonin transporter [11 C]3-amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile positron emission tomography (PET) to compare serotoninergic innervation in patients with MSA and PD. METHODS: We performed serotonin transporter PET imaging in 18 patients with MSA, 23 patients with PD, and 16 healthy controls to explore differences in brainstem, subcortical, and cortical regions of interest. RESULTS: Patients with MSA showed lower serotonin transporter distribution volume ratios compared with patients with PD in the medulla, raphe pontis, ventral striatum, limbic cortex, and thalamic regions, but no differences in the dorsal striatal, ventral anterior cingulate, or total cortical regions. Controls showed greater cortical serotonin transporter binding compared with PD or MSA groups but lower serotonin transporter binding in the striatum and other relevant basal ganglia regions. There were no regional differences in binding between patients with MSA-parkinsonian subtype (n = 8) and patients with MSA-cerebellar subtype (n = 10). Serotonin transporter distribution volume ratios in multiple different regions of interest showed an inverse correlation with the severity of Movement Disorders Society Unified Parkinson's Disease Rating Scale motor score in patients with MSA but not patients with PD. CONCLUSIONS: Brainstem and some forebrain subcortical region serotoninergic deficits are more severe in MSA compared with PD and show an MSA-specific correlation with the severity of motor impairments. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Neural correlates of risky decision making in Parkinson's disease patients with impulse control disorders.

Some patients with Parkinson's disease (PD) experience impulse control disorders (ICDs), characterized by deficient voluntary control over impulses, drives, or temptations regarding excessive hedonic behavior. The present study aimed to better understand the neural basis of impulsive, risky decision making in PD patients with ICDs by disentangling potential dysfunctions in decision and outcome mechanisms. We collected fMRI data from 20 patients with ICDs and 28 without ICDs performing an information gathering task. Patients viewed sequences of bead colors drawn from hidden urns and were instructed to infer the majority bead color in each urn. With each new bead, they could choose to either seek more evidence by drawing another bead (draw choice) or make an urn-inference (urn choice followed by feedback). We manipulated risk via the probability of bead color splits (80/20 vs. 60/40) and potential loss following an incorrect inference ($10 vs. $0). Patients also completed the Barratt Impulsiveness Scale (BIS) to assess impulsivity. Patients with ICDs showed greater urn choice-specific activation in the right middle frontal gyrus, overlapping the dorsal premotor cortex. Across all patients, fewer draw choices (i.e., more impulsivity) were associated with greater activation during both decision making and outcome processing in a variety of frontal and parietal areas, cerebellum, and bilateral striatum. Our findings demonstrate that ICDs in PD are associated with differences in neural processing of risk-related information and outcomes, implicating both reward and sensorimotor dopaminergic pathways.

Clinically-derived oscillatory biomarker predicts optimal subthalamic stimulation for Parkinson's disease.

Objective. Choosing the optimal electrode trajectory, stimulation location, and stimulation amplitude in subthalamic nucleus deep brain stimulation (STN DBS) for Parkinson's disease remains a time-consuming empirical effort. In this retrospective study, we derive a data-driven electrophysiological biomarker that predicts clinical DBS location and parameters, and we consolidate this information into a quantitative score that may facilitate an objective approach to STN DBS surgery and programming.Approach. Random-forest feature selection was applied to a dataset of 1046 microelectrode recordings (MERs) sites across 20 DBS implant trajectories to identify features of oscillatory activity that predict clinically programmed volumes of tissue activation (VTAs). A cross-validated classifier was used to retrospectively predict VTA regions from these features. Spatial convolution of probabilistic classifier outputs along MER trajectories produced a biomarker score that reflects the probability of localization within a clinically optimized VTA.Main results. Biomarker scores peaked within the VTA region and were significantly correlated with percent improvement in postoperative motor symptoms (Part III of the Movement Disorders Society revision of the Unified Parkinson Disease Rating Scale,R= 0.61,p= 0.004). Notably, the length of STN, a common criterion for trajectory selection, did not show similar correlation (R= -0.31,p= 0.18). These findings suggest that biomarker-based trajectory selection and programming may improve motor outcomes by 9 ± 3 percentage points (p= 0.047) in this dataset.Significance. A clinically defined electrophysiological biomarker not only predicts VTA size and location but also correlates well with motor outcomes. Use of this biomarker for trajectory selection and initial stimulation may potentially simplify STN DBS surgery and programming.

Motor speech effects in subthalamic deep brain stimulation for Parkinson's disease.

OBJECTIVE: A motor speech disorder or dysarthria commonly arises in patients with Parkinson's disease (PD). The impact of subthalamic nucleus (STN) deep brain stimulation (DBS) on motor speech and the potential of intraoperative motor speech testing to predict outcomes are unknown. This study examined 1) the types and prevalence of motor speech changes observed with STN DBS and their relation to the preoperative condition, 2) the ability of intraoperative testing to predict postoperative changes in motor speech, and 3) the spatial relationship between stimulation sites producing maximal motor improvement, as measured by the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), and maximal motor speech deterioration. METHODS: Comprehensive preoperative, intraoperative, and postoperative motor speech/dysarthria evaluations were performed in consecutive patients with advanced idiopathic PD who underwent STN DBS surgery in the period from 2011 to 2016. Preoperative type of dysarthria and overall dysarthria severity rating along with intraoperative motor speech testing results were evaluated as predictors of postoperative change. Atlas-independent, fully individualized field modeling was used to identify stimulation sites associated with maximal MDS-UPDRS motor improvement and motor speech deterioration. RESULTS: Forty-three patients with PD treated with STN DBS were prospectively studied. Improved MDS-UPDRS motor scores and worsened dysarthria were demonstrated by a subset of patients (16/43). Preoperative dysarthria characteristics did not predict postoperative deterioration. Intraoperative assessment of motor speech strongly predicted postoperative outcomes (OR 4.4, p = 0.02). Sites of maximal MDS-UPDRS motor improvement and worsened dysarthria were distinct. Worsened dysarthria was associated with capsular stimulation, anterior and ventral to the site of maximal MDS-UPDRS motor improvement. CONCLUSIONS: The predictive reliability of intraoperative motor speech testing, together with the identification of distinct stimulation sites for motor speech impairment and improved MDS-UPDRS motor function, raise the possibility that DBS lead repositioning or reprogramming could reduce adverse effects on motor speech without impacting MDS-UPDRS motor outcomes in patients undergoing STN DBS.

Characterization and localization of upper and lower extremity motor improvements in STN DBS for Parkinson's disease.

INTRODUCTION: Subthalamic deep brain stimulation (STN DBS) may have differential effects on cardinal motor signs of Parkinson's disease (PD) in the upper and lower extremities. In addition, sites of maximally effective DBS for each sign and extremity may be distinct. Our study seeks to elucidate these structure-function relationships. METHODS: We applied an ordinary least squares linear regression model to measure motor effects of STN DBS on upper (UE) and lower (LE) extremity tremor, rigidity, and bradykinesia. We then applied an atlas-independent electrical-field model to identify sites of maximally effective stimulation for each sign and each extremity. Distances between sites and statistical power to resolve differences were calculated. RESULTS: In our study population (n = 78 patients), STN DBS improved all cardinal motor signs (ß = 0.64, p < .05). Improvement magnitudes were tremor > rigidity > bradykinesia. Effects of STN DBS on UE versus LE signs were statistically equal for tremor and bradykinesia, but greater for UE rigidity than LE rigidity (ß = 0.19, p < .05). UE maximal-effect loci were lateral, anterior, and dorsal to LE loci, but were not statistically resolved, despite sufficient statistical power to resolve differences of ≤0.48 mm (p < .05) between maximally effective loci of stimulation. CONCLUSION: STN DBS produces differential effects on UE and LE rigidity, but not for tremor or bradykinesia. This finding is not explained by distinct UE and LE loci of maximally effective stimulation. Instead, we hypothesize that downstream effects of STN DBS on motor networks and limb biomechanics are responsible for observed differences in UE and LE responses.

Longitudinal Change in Quality of Life in Neurological Disorders Measures Over 3 Years in Patients with Early Parkinson's Disease.

BACKGROUND: The Quality of Life in Neurological Disorders (Neuro-QoL) is a publicly available health-related quality-of-life measurement system. OBJECTIVE: The aim of this study was to evaluate the utility of Neuro-QoL item banks as outcome measures for clinical trials in Parkinson's disease. METHODS: An analysis of Neuro-QoL responsiveness to change and construct validity was performed in a multicenter clinical trial cohort. RESULTS: Among 310 participants over 3 years, changes in five of eight Neuro-QoL domains were significant (P < 0.05) but very modest. The largest effect sizes were seen in the cognition and mobility domains (0.35-0.39). The largest effect size for change over the year in which levodopa was initiated was -0.19 for lower extremity function-mobility. For a similarly designed clinical trial, estimated sample size required to demonstrate a 50% reduction in worsening ranged from 420 to more than 1000 participants per group. CONCLUSIONS: More sensitive tools will be required to serve as an outcome measure in early Parkinson's disease. © 2021 International Parkinson and Movement Disorder Society.

Non-Motor Fluctuations in Parkinson's Disease: Validation of the Non-Motor Fluctuation Assessment Questionnaire.

BACKGROUND: In patients with Parkinson's disease (PD), sleep, mood, cognitive, autonomic, and other non-motor symptoms may fluctuate in a manner similar to motor symptoms. OBJECTIVES: To validate a final version of a patient-rated questionnaire that captures the presence and severity of non-motor fluctuations in levodopa-treated PD patients (NoMoFA). METHODS: We recruited PD subjects from five movement disorders centers across the US and Canada. We assessed the internal consistency, floor and ceiling effects, test-retest reliability, and concurrent validity of NoMoFA. Classical test theory and item response theory methods informed item reduction and Delphi process yielded a final questionnaire. RESULTS: Two hundred subjects and their care-partners participated in the study (age: 66.4 ± 9.6 years; disease duration: 9 ± 5.5 years; median Hoehn and Yahr [H&Y] OFF: 3 [range 1-5]; mean Unified Parkinson's Disease Rating Scale (UPDRS) III ON score: 27.4 ± 14.9). Acceptability of the scale was adequate. There were floor effects in 8/28 items. Cronbach's alpha was 0.894. While eight items had "item-to-total" correlations below the cutoff of 0.4, removing these items did not improve Cronbach's alpha. Test-retest reliability was acceptable (intraclass correlation coefficient [ICC] 0.73; 95% confidence interval, 0.64-0.80). Concurrent validity was adequate with all Spearman's rho values comparing NoMoFA score to other measures of parkinsonian severity showing significance and in the expected direction. A final Delphi panel eliminated one item to avoid redundancy. CONCLUSIONS: The final 27-item self-administered NoMoFA is a valid and reliable questionnaire, capturing both static and fluctuating non-motor symptoms in PD. © 2021 International Parkinson and Movement Disorder Society.

Atlas-independent, N-of-1 tissue activation modeling to map optimal regions of subthalamic deep brain stimulation for Parkinson disease.

BACKGROUND: Motor outcomes after subthalamic deep brain stimulation (STN DBS) for Parkinson disease (PD) vary considerably among patients and strongly depend on stimulation location. The objective of this retrospective study was to map the regions of optimal STN DBS for PD using an atlas-independent, fully individualized (N-of-1) tissue activation modeling approach and to assess the relationship between patient-level therapeutic volumes of tissue activation (VTAs) and motor improvement. METHODS: The stimulation-induced electric field for 40 PD patients treated with bilateral STN DBS was modeled using finite element analysis. Neurostimulation models were generated for each patient, incorporating their individual STN anatomy, DBS lead position and orientation, anisotropic tissue conductivity, and clinical stimulation settings. A voxel-based analysis of the VTAs was then used to map the optimal location of stimulation. The amount of stimulation in specific regions relative to the STN was measured and compared between STNs with more and less optimal stimulation, as determined by their motor improvement scores and VTA. The relationship between VTA location and motor outcome was then assessed using correlation analysis. Patient variability in terms of STN anatomy, active contact position, and VTA location were also evaluated. Results from the N-of-1 model were compared to those from a simplified VTA model. RESULTS: Tissue activation modeling mapped the optimal location of stimulation to regions medial, posterior, and dorsal to the STN centroid. These regions extended beyond the STN boundary towards the caudal zona incerta (cZI). The location of the VTA and active contact position differed significantly between STNs with more and less optimal stimulation in the dorsal-ventral and anterior-posterior directions. Therapeutic stimulation spread noticeably more in the dorsal and posterior directions, providing additional evidence for cZI as an important DBS target. There were significant linear relationships between the amount of dorsal and posterior stimulation, as measured by the VTA, and motor improvement. These relationships were more robust than those between active contact position and motor improvement. There was high variability in STN anatomy, active contact position, and VTA location among patients. Spherical VTA modeling was unable to reproduce these results and tended to overestimate the size of the VTA. CONCLUSION: Accurate characterization of the spread of stimulation is needed to optimize STN DBS for PD. High variability in neuroanatomy, stimulation location, and motor improvement among patients highlights the need for individualized modeling techniques. The atlas-independent, N-of-1 tissue activation modeling approach presented in this study can be used to develop and evaluate stimulation strategies to improve clinical outcomes on an individual basis.

Psychedelic-assisted therapy for functional neurological disorders: A theoretical framework and review of prior reports.

Functional neurological disorders (FNDs), which are sometimes also referred to as psychogenic neurological disorders or conversion disorder, are common disabling neuropsychiatric disorders with limited treatment options. FNDs can present with sensory and/or motor symptoms, and, though they may mimic other neurological conditions, they are thought to occur via mechanisms other than those related to identifiable structural neuropathology and, in many cases, appear to be triggered and sustained by recognizable psychological factors. There is intriguing preliminary evidence to support the use of psychedelic-assisted therapy in a growing number of psychiatric illnesses, including FNDs. We review the theoretical arguments for and against exploring psychedelic-assisted therapy as a treatment for FNDs. We also provide an in-depth discussion of prior published cases detailing the use of psychedelics for psychosomatic conditions, analyzing therapeutic outcomes from a contemporary neuroscientific vantage as informed by several recent neuroimaging studies on psychedelics and FNDs.