Application of MRI Connectivity in Stereotactic Functional Neurosurgery

This thesis examines potential applications of advanced MRI-connectivity studies in stereotactic functional neurosurgery. Several new analysis methodologies are employed to: (1) build predictive models of DBS surgery outcome; (2) refine the surgical target and (3) help build a better understanding of the pathogenesis of the treated conditions and the mechanism of action of DBS therapy. The experimental component is divided into three main parts focusing on the following pathologies: (1) Parkinson’s disease (PD), (2) tremor and (3) trigeminal autonomic cephalalgias (TAC). Section I: In the first experiment (chapter 3), resting state fMRI was used to find radiological biomarkers predictive of response to L-DOPA in 19 patients undergoing subthalamic nucleus (STN) DBS for PD. A greater improvement in UPDRS-III scores following L-DOPA administration was characterized by higher resting state functional connectivity (fcMRI) between the prefrontal cortex and the striatum (p=0.001) and lower fcMRI between the pallidum (p=0.001), subthalamic nucleus (p=0.003) and the paracentral lobule. In the second experiment (chapter 4), structural (diffusion) connectivity was used to map out the influence of the hyperdirect pathways on outcome and identify the therapeutic ‘sweet spots’ in twenty PD patients undergoing STN-DBS. Clusters corresponding to maximum improvement in symptoms were in the posterior, superior and lateral portion of the STN. Greater connectivity to the primary motor area, supplementary motor area and prefrontal cortex was predictive of higher improvement in tremor, bradykinesia and rigidity, and rigidity respectively. The third experiment (chapter 5) examined pyramidal tract (PT) activation in 20 PD patients with STN-DBS. Volume of tissue activation (VTA) around DBS contacts were modelled in relation to the PT. VTA/ PT overlap predicted EMG activation thresholds. Sections II: Pilot data suggest that probabilistic tractography techniques can be used to segment the ventrolateral (VL) and ventroposterior (VP) thalamus based on cortical and cerebellar connectivity in nine patients who underwent thalamic DBS for tremor (chapter 6). The thalamic area, best representing the ventrointermedialis nucleus (VIM), was connected to the contralateral dentate cerebellar nucleus. Streamlines corresponding to the dentato-rubro-thalamic tract (DRT) connected M1 to the contralateral dentate nucleus via the dentato-thalamic area. Good response was seen when the active contact’s VTA was in the thalamic area with the highest connectivity to the contralateral dentate nucleus. Section III: The efficacy and safety of DBS in the ventral tegmental area (VTa) in the treatment of chronic cluster headache (CH) and short lasting unilateral neuralgiform headache attacks (SUNA) were examined (chapters 7 and 8). The optimum stimulation site within the VTa that best controls symptoms was explored (chapter 9). The average responders’ deep brain stimulation activation volume lay on the trigemino-hypothalamic tract, connecting the trigeminal system and other nociceptive brainstem nuclei, with the hypothalamus, and the prefrontal and mesial temporal areas

Spinal Cord Stimulation for Gait Disorders in Parkinson's Disease

BACKGROUND: Spinal cord stimulation (SCS) is a therapeutic procedure widely used in the management of refractory chronic pain. Evidence from case reports and small descriptive studies has emerged suggesting a role for SCS in patients with gait dysfunction, such as freezing of gait (FoG) and postural imbalance. These are severely debilitating symptoms of advanced Parkinson's disease (PD). OBJECTIVE: To establish the current evidence base for the potential application of SCS on gait and balance dysfunction in PD patients. METHODS: Three online databases were screened for relevant manuscripts. Two separate searches and four different search strategies were applied to yield relevant results. The main parameters of interest were postural and gait symptoms; secondary outcomes were Quality of Life (QoL) and adverse effects. RESULTS: Nineteen studies fulfilled the inclusion criteria. Motor improvements using section III of the Unified Parkinson's Disease Rating Score (UPDRS-III) were available in 13 studies. Measurements to assess FoG reported the following improvements: FoG questionnaires (in 1/19 studies); generalized freezing parameters (2); and walkway/wireless accelerometer measurements (2). Parameters of postural imbalance and falling improved as follows: BBS (1); posture sagittal vertical axis (1); and generalized data on postural instability (8). Two studies reported on adverse effects. QoL was shown to improve as follows: EQ-5D (2); ADL (1); SF-36 (1); BDI-II (1); PDQ-8 (1); HDRS (1); and VAS (5). CONCLUSION: SCS may have a therapeutic potential in advanced PD patients suffering from postural and gait-related symptoms. The existing evidence suggests that SCS positively affects patients' QoL with an acceptable safety profile in this patient population

Keep your Distance: Determining Sampling and Distance Thresholds in Machine Learning Monitoring

Machine Learning~(ML) has provided promising results in recent years across different applications and domains. However, in many cases, qualities such as reliability or even safety need to be ensured. To this end, one important aspect is to determine whether or not ML components are deployed in situations that are appropriate for their application scope. For components whose environments are open and variable, for instance those found in autonomous vehicles, it is therefore important to monitor their operational situation to determine its distance from the ML components' trained scope. If that distance is deemed too great, the application may choose to consider the ML component outcome unreliable and switch to alternatives, e.g. using human operator input instead. SafeML is a model-agnostic approach for performing such monitoring, using distance measures based on statistical testing of the training and operational datasets. Limitations in setting SafeML up properly include the lack of a systematic approach for determining, for a given application, how many operational samples are needed to yield reliable distance information as well as to determine an appropriate distance threshold. In this work, we address these limitations by providing a practical approach and demonstrate its use in a well known traffic sign recognition problem, and on an example using the CARLA open-source automotive simulator

Subthalamic nucleus deep brain stimulation for Parkinson's disease: current trends and future directions

Over the last three decades, extensive basic and clinical research has been performed on the use of subthalamic nucleus (STN) as the preferred deep brain stimulation (DBS) target for the treatment of Parkinson's disease (PD). The mechanism underlying the benefit for the motor symptoms in PD is related to the modulation of firing patterns within the hyperdirect projections from motor cortical areas, as well as within the afferent and efferent fibers to the motor STN. Advancements in neuroimaging techniques allow us to identify precisely the STN optimizing surgical targeting. In this review, we provide an update on the current uses of STN-DBS as a routine therapy as well as its experimental indications in PD, the critical aspects associated with its successful implementation and recent advances in DBS technology

Chronic Subthalamic Nucleus Stimulation in Parkinson's Disease: Optimal Frequency for Gait Depends on Stimulation Site and Axial Symptoms

Axial symptoms emerge in a significant proportion of patients with Parkinson's disease (PD) within 5 years of deep brain stimulation (STN-DBS). Lowering the stimulation frequency may reduce these symptoms. The objectives of the current study were to establish the relationship between gait performance and STN-DBS frequency in chronically stimulated patients with PD, and to identify factors underlying variability in this relationship. Twenty-four patients treated chronically with STN-DBS (>4 years) were studied off-medication. The effect of stimulation frequency (40–140 Hz, 20 Hz-steps, constant energy) on gait was assessed in 6 sessions spread over 1 day. Half of the trials/session involved walking through a narrow doorway. The influence of stimulation voltage was investigated separately in 10 patients. Gait was measured using 3D motion capture and axial symptoms severity was assessed clinically. A novel statistical method established the optimal frequency(ies) for each patient by operating on frequency-tuning curves for multiple gait parameters. Narrowly-tuned optimal frequencies (20 Hz bandwidth) were found in 79% of patients. Frequency change produced a larger effect on gait performance than voltage change. Optimal frequency varied between patients (between 60 and 140 Hz). Contact site in the right STN and severity of axial symptoms were independent predictors of optimal frequency (P = 0.009), with lower frequencies associated with more dorsal contacts and worse axial symptoms. We conclude that gait performance is sensitive to small changes in STN-DBS frequency. The optimal frequency varies considerably between patients and is associated with electrode contact site and severity of axial symptoms. Between-subject variability of optimal frequency may stem from variable pathology outside the basal ganglia

Entraining stepping movements of Parkinson's patients to alternating subthalamic nucleus deep brain stimulation

Patients with advanced Parkinson's can be treated by deep brain stimulation of the subthalamic nucleus (STN). This affords a unique opportunity to record from this nucleus and stimulate it in a controlled manner. Previous work has shown that activity in the STN is modulated in a rhythmic pattern when Parkinson's patients perform stepping movements, raising the question whether the STN is involved in the dynamic control of stepping. To answer this question, we tested whether an alternating stimulation pattern resembling the stepping-related modulation of activity in the STN could entrain patients' stepping movements as evidence of the STN's involvement in stepping control. Group analyses of ten Parkinson's patients (one female) showed that alternating stimulation significantly entrained stepping rhythms. We found a remarkably consistent alignment between the stepping and stimulation cycle when the stimulation speed was close to the stepping speed in the five patients that demonstrated significant individual entrainment to the stimulation cycle. Our study suggests that the STN is causally involved in dynamic control of step timing, and motivates further exploration of this biomimetic stimulation pattern as a potential basis for the development of deep brain stimulation strategies to ameliorate gait impairments.SIGNIFICANCE STATEMENTWe test if the subthalamic nucleus in humans is causally involved in controlling stepping movements. To this end we studied patients with Parkinson's disease who have undergone therapeutic deep brain stimulation, as in these individuals we can stimulate the subthalamic nuclei in a controlled manner. We developed an alternating pattern of stimulation that mimics the pattern of activity modulation recorded in this nucleus during stepping. The alternating DBS could entrain patients' stepping rhythm, suggesting a causal role of the STN in dynamic gait control. This type of stimulation may potentially form the basis for improved DBS strategies for gait

Clinical outcomes after MRI connectivity-guided radiofrequency thalamotomy for tremor

OBJECTIVE: Radiofrequency thalamotomy (RF-T) is an established treatment for refractory tremor. It is unclear whether connectivity-guided targeting strategies could further augment outcomes. The aim of this study was to evaluate the efficacy and safety of MRI connectivity-guided RF-T in severe tremor. METHODS: Twenty-one consecutive patients with severe tremor (14 with essential tremor [ET], 7 with Parkinson's disease [PD]) underwent unilateral RF-T at a single institution between 2017 and 2020. Connectivity-derived thalamic segmentation was used to guide targeting. Changes in the Fahn-Tolosa-Marin Rating Scale (FTMRS) were recorded in treated and nontreated hands as well as procedure-related side effects. RESULTS: Twenty-three thalamotomies were performed (with 2 patients receiving a repeated intervention). The mean postoperative assessment time point was 14.1 months. Treated-hand tremor scores improved by 63.8%, whereas nontreated-hand scores deteriorated by 10.1% (p < 0.01). Total FTMRS scores were significantly better at follow-up compared with baseline (mean 34.7 vs 51.7, p = 0.016). Baseline treated-hand tremor severity (rho = 0.786, p < 0.01) and total FTMRS score (rho = 0.64, p < 0.01) best correlated with tremor improvement. The most reported side effect was mild gait ataxia (n = 11 patients). CONCLUSIONS: RF-T guided by connectivity-derived segmentation is a safe and effective option for severe tremor in both PD and ET

Keep Your Distance: Determining Sampling and Distance Thresholds in Machine Learning Monitoring

Machine Learning (ML) has provided promising results in recent years across different applications and domains. However, in many cases, qualities such as reliability or even safety need to be ensured. To this end, one important aspect is to determine whether or not ML components are deployed in situations that are appropriate for their application scope. For components whose environments are open and variable, for instance those found in autonomous vehicles, it is therefore important to monitor their operational situation in order to determine its distance from the ML components’ trained scope. If that distance is deemed too great, the application may choose to consider the ML component outcome unreliable and switch to alternatives, e.g. using human operator input instead. SafeML is a model-agnostic approach for performing such monitoring, using distance measures based on statistical testing of the training and operational datasets. Limitations in setting SafeML up properly include the lack of a systematic approach for determining, for a given application, how many operational samples are needed to yield reliable distance information as well as to determine an appropriate distance threshold. In this work, we address these limitations by providing a practical approach and demonstrate its use in a well known traffic sign recognition problem, and on an example using the CARLA open-source automotive simulator

Directional deep brain stimulation electrodes in Parkinson’s disease: meta-analysis and systematic review of the literature

Background: Since their introduction in 2015, directional leads have practically replaced conventional leads for deep brain stimulation (DBS) in Parkinson’s disease (PD). Yet, the benefits of directional DBS (dDBS) over omnidirectional DBS (oDBS) remain unclear. This meta-analysis and systematic review compares the literature on dDBS and oDBS for PD. // Methods: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Database searches included Pubmed, Cochrane (CENTRAL) and EmBase, using relevant keywords such as ‘directional’, ‘segmented’, ‘brain stimulation’ and ‘neuromodulation’. The screening was based on the title and abstract. // Results: 23 papers reporting on 1273 participants (1542 leads) were included. The therapeutic window was 0.70 mA wider when using dDBS (95% CI 0.13 to 1.26 mA, p=0.02), with a lower therapeutic current (0.41 mA, 95% CI 0.27 to 0.54 mA, p=0.01) and a higher side-effect threshold (0.56 mA, 95% CI 0.38 to 0.73 mA, p<0.01). However, there was no relevant difference in mean Unified Parkinson’s Disease Rating Scale III change after dDBS (45.8%, 95% CI 30.7% to 60.9%) compared with oDBS (39.0%, 95% CI 36.9% to 41.2%, p=0.39), in the medication-OFF state. Median follow-up time for dDBS and oDBS studies was 6 months and 3 months, respectively (range 3–12 for both). The use of directionality often improves dyskinesia, dysarthria, dysesthesia and pyramidal side effects. Directionality was used in 55% of directional leads at 3–6 months, remaining stable over time (56% at a mean of 14.1 months). // Conclusions: These findings suggest that stimulation parameters favour dDBS. However, these do not appear to have a significant impact on motor scores, and the availability of long-term data is limited. dDBS is widely accepted, but clinical data justifying its increased complexity and cost are currently sparse. // PROSPERO registration number: CRD42023438056