Deep brain stimulation modifies the progression of early Parkinson's disease

Abstract

This disclosure relates to the treatment of patients with early-stage Parkinson's disease using subthalamic nucleus deep brain stimulation (STN-DBS) to target defined regions of the brain. In particular, improved therapeutic benefit is obtained by positioning and / or programming DBS electrodes to stimulate cortical input fibers from the supplementary motor area (but not from the pre-SMA).

Description

[Technical Field]

[0001] Priority claims This application claims the benefit of priority to U.S. Provisional Application No. 63 / 413,760, filed October 6, 2022. The entire contents of U.S. Provisional Application No. 63 / 413,760 are incorporated herein by reference.

[0002] background I. Field The present disclosure relates to the fields of medicine, central nervous system disorders, and neurobiology. More particularly, the present disclosure relates to improved methods of performing subthalamic nucleus deep brain stimulation (STN-DBS) in subjects suffering from early-stage Parkinson's disease. [Background technology]

[0003] II. Related Technologies Parkinson's disease (PD) is a long-term degenerative disorder of the central nervous system that primarily affects the motor system. Symptoms generally progress slowly over time. Tremor, rigidity, bradykinesia, and difficulty walking are most evident early in the disease. Thought and behavioral problems may also occur, and dementia, as well as depression and anxiety, are common in the advanced stages of the disease (seen in more than one-third of PD patients). Other symptoms include sensory, sleep, and emotional problems. PD is therefore a devastating disease with very limited treatment options. There is no known cure.

[0004] Subthalamic nucleus deep brain stimulation (STN-DBS) is an established adjunctive treatment for intermediate- and advanced-stage Parkinson's disease (PD), improving motor symptoms and quality of life and reducing medication burden and dyskinesias (Deuschl et al., 2006; Schuepbach et al., 2013). Although many PD patients experience significant clinical benefit, individual motor responses to DBS can vary widely (e.g., 3%–63% improvement (Weaver et al., 2012)), with approximately 25% of patients experiencing no significant improvement in quality of life (Deuschl et al., 2006). Numerous groups have investigated the causes of this heterogeneity, finding that patient factors such as young age, short disease duration, and a strong preoperative response to levodopa predict a favorable response to STN-DBS in advanced PD (Charles et al., 2002; Welter et al., 2002).

[0005] Besides patient characteristics, the precise delivery of the intervention (i.e., electrode placement and subsequent programming) is also strongly associated with clinical outcomes ( Caire et al., 2013 ; Frizon et al., 2018 ; Horn, Li, et al., 2019 ; Neudorfer et al., 2022 ). Although there is no consensus regarding the optimal location, or "sweet spot" (Blomstedt et al., 2018; Butson et al., 2006; Maks et al., 2008; Plaha et al., 2006), in recent years the field seems to agree on optimal outcomes using active contact within the dorsolateral (sensorimotor) STN (Akram et al., 2017; Bot et al., 2018; Caire et al., 2013; Horn, Li, et al., 2019) [for a review, see Horn, 2019]. Furthermore, the STN receives input from numerous functional areas in the frontal cortex, and therefore, the stimulation site also determines the precise network modulated by DBS. Although Parkinson's disease has been considered a network disease since its discovery, and neuromodulation has targeted networks since the first days of electrical brain stimulation (Hariz et al., 2010), the field has increasingly used advanced neuroimaging sequences to conceptualize DBS as a network procedure in individual patients and define networks as three-dimensional structures within stereotactic space (Akram et al., 2017; Horn, Reich, et al., 2017; Krauss et al., 2020; Lozano & Lipsman, 2013a; Sobesky et al., 2022). Furthermore, from a bioelectrical perspective that considers the tissue surrounding the electrode, benefits arise from stimulating axons rather than cell bodies. This underscores the field's increasing focus on determining white matter targets (Jakobs et al., 2019; Li et al., 2020).The association between Parkinson's motor improvement and hyperdirect, pallidofugal, and nigrofugal / striatofugal pathways suggests that precise positioning to stimulate specific neural tracts (i.e., white matter tracts) connecting relevant structures involved in motor control is crucial for optimal symptomatic benefit of STN-DBS in PD (Akram et al., 2017; Avecillas-Chasin & Honey, 2020; Horn, Reich, et al., 2017). These recent DBS reports support earlier evidence from lesion studies (Hassler et al., 1960) that cortical input from the supplementary motor cortex appears to be particularly important in modulating hypomotor symptoms (Akram et al., 2017; Horn, Li, et al., 2019; Horn, Reich, et al., 2017).

[0006] The robust improvements of STN-DBS in patients with intermediate and advanced PD have motivated research into whether STN-DBS can be extended or even enhance its benefits in very early PD. Numerous preclinical studies suggest that DBS interventions have the potential to modify disease, but only if applied early in the neurodegenerative process (Maesawa et al., 2004; Musacchio et al., 2017; AL Spieles-Engemann et al., 2010; Temel et al., 2006). With postmortem evidence demonstrating a 90% loss of dopaminergic innervation in the putamen by 4 years after diagnosis (Kordower et al., 2013), it is increasingly accepted that if DBS (or any potentially disease-modifying intervention) is to slow PD progression, it must be applied at the very earliest stages of the disease (DL Fischer & Sortwell, 2019).

[0007] In the first clinical trial to date evaluating DBS in early PD (diagnosis within 4 years, with no history or evidence of dyskinesia or motor fluctuations) with the potential to slow PD progression, 30 patients were randomized to bilateral STN-DBS plus optimal medical therapy (ODT) or ODT alone and followed for 2 years (David Charles et al., 2014). In this trial, a 7-day washout of all PD medications and DBS stimulation was completed at baseline, where applicable, and every 6 months for 2 years. Instead of biomarkers tracking disease progression, a 7-day cessation of PD therapy allowed for assessment of underlying motor symptom progression without the overt influence of symptomatic treatment (i.e., STN-DBS and PD medication). All subjects who completed the 2-year trial enrolled in a 5-year follow-up visit, which included on-therapy-only assessments at years 3, 4, and 5. Post-hoc analyses provided Class II evidence that DBS in early PD slows the progression of resting tremor (M. Hacker et al., 2018). Furthermore, 5-year outcomes provided Class II evidence that DBS in early PD reduces the risk of disease progression and polypharmacy (M. L. Hacker et al., 2020).

[0008] Thus, although we have previously reported that STN-DBS can slow or halt tremor progression in some early PD patients, a deeper understanding of these results is needed to increase the number of patients who receive such benefit. Summary of the Invention

[0009] overview According to the present disclosure, in one aspect, there is provided a method of placing deep brain stimulation (DBS) electrodes in a patient with early Parkinson's disease (PD), comprising: (a) mapping the patient's brain by identifying (i) nerve tracts from the patient's supplementary motor area and / or primary motor cortex to the subthalamic nucleus (STN) and (ii) nerve tracts from the patient's pre-supplementary motor area to the STN to determine locations for DBS electrode placement; and (b) implanting a DBS electrode to target (a)(i) and not target (a)(ii). A method is provided, comprising:

[0010] step (a) identifying patient-specific locations of the tracts defined in (a)(i) and (a)(ii) from a normative connectome by using inverse normalization to warp the tracts from template space to patient brain space; or Identifying patient-specific locations of the tracts defined in (a)(i) and (a)(ii) from the normative connectome by normalizing the patient brain to a template space containing the tracts. may include:

[0011] Step (a) includes, in order to identify (a)(i) and (a)(ii), (1) Regions of interest (ROIs) derived from the supplementary motor area projecting to the STN; (2) regions of interest derived from the primary motor cortex that project to the STN; and (3) Region of interest originating from the pre-SMA projecting to the STN The method may include utilizing patient-specific tractography data collected from diffusion-weighted brain imaging of the patient's brain using

[0012] The method may further include performing a post-operative scan of the patient's brain.

[0013] In one aspect, a method of placing and programming deep brain stimulation (DBS) electrodes in a patient with early Parkinson's disease (PD) comprises: (a) implanting a DBS electrode to target the subthalamic nucleus (STN) of a patient; (b) mapping the patient's brain by identifying (i) neural tracts from the patient's supplementary motor area and / or primary motor cortex to the subthalamic nucleus (STN) and (ii) neural tracts from the patient's pre-supplementary motor area to the STN to determine programming of the DBS electrodes, wherein the DBS electrodes are programmed to stimulate (i) and not stimulate (ii). A method is provided, comprising:

[0014] step (b) identifying patient-specific locations of the tracts defined in (b)(i) and (b)(ii) from the normative connectome by using inverse normalization to warp the tracts from the template space to the patient brain space; or Identifying patient-specific locations of the tracts defined in (b)(i) and (b)(ii) from the normative connectome by normalizing the patient brain to a template space containing the tracts. may include:

[0015] Step (b) includes, in order to identify (b)(i) and (b)(ii), (1) Regions of interest (ROIs) derived from the supplementary motor area projecting to the STN; (2) regions of interest derived from the primary motor cortex that project to the STN; and (3) Region of interest originating from the pre-SMA projecting to the STN The method may include utilizing patient-specific tractography data collected from diffusion-weighted brain imaging of the patient's brain using

[0016] The method may include determining whether the DBS electrode achieved the intended (b)(i) pre-operative targeting and (b)(ii) non-targeting.

[0017] The DBS electrode may comprise multiple contacts or segments, and the method further includes determining which contacts or segments provide maximal stimulation of (b)(i) and avoid (b)(ii).

[0018] The DBS electrode may comprise multiple contacts or segments, and the method further includes determining a field shape for the contacts or segments that results in maximal stimulation of (b)(i) and avoids (b)(ii).

[0019] Any of the above methods may further include the step of treating the patient by delivering current through the DBS electrodes, for example, by continuous delivery, patient-adjusted delivery, or adaptive delivery based on patient parameters.

[0020] The patient may be a male human patient, a female human patient, or a non-human mammalian subject.

[0021] DBS may be performed multiple times, for example chronically.

[0022] Any of the above methods may further comprise treating the patient with a second PD therapy. The second PD therapy may be administered before, simultaneously with, or after STN-DBS. The second PD therapy may be selected from levodopa, optionally in combination with a DOPA decarboxylase inhibitor (carbidopa, benserazide) or a COMT inhibitor (tolcapone, entacapone), a dopamine agonist (e.g., apomorphine, bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, lisuride), an MAO-B inhibitor (e.g., safinamide, selegiline, rasagiline), amantadine, an anticholinergic cholinesterase inhibitor, and lesion surgery, or a combination thereof.

[0023] STN-DBS may result in one or more of slowing, halting, and / or reversing motor symptom progression. STN-DBS may result in one or more of: reducing stimulation parameters, reducing the need for postoperative dopaminergic medications, and / or reducing the occurrence of levodopa-associated dyskinesias or other motor fluctuations.

[0024] In one embodiment, a PD therapeutic is provided for use in treating Parkinson's disease (PD) in a subject, wherein the subject receives subthalamic nucleus (STN) deep brain stimulation (DBS) separately, simultaneously, or sequentially by a method defined by any one of the present embodiments.

[0025] The PD therapeutic agent may be administered prior to, simultaneously with, or after STN-DBS.

[0026] PD therapeutics may be levodopa, optionally in combination with DOPA decarboxylase inhibitors (carbidopa, benserazide) or COMT inhibitors (tolcapone, entacapone), dopamine agonists (e.g., apomorphine, bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, lisuride), MAO-B inhibitors (e.g., safinamide, selegiline, rasagiline), amantadine, and anticholinergic cholinesterase inhibitors, or combinations thereof.

[0027] In one aspect, a computer-implemented method for identifying placement locations for deep brain stimulation (DBS) electrodes for DBS treatment of a patient with early Parkinson's disease (PD) is provided, the method comprising: (a) receiving brain imaging data of a patient; (b) processing the brain image data to identify (i) neural pathways from the patient's supplementary motor area and / or primary motor cortex to the subthalamic nucleus (STN), and (ii) neural pathways from the patient's pre-supplementary motor area to the STN; and (c) creating an electrode placement map for treating the patient with DBS such that the implanted electrodes target (a)(i) and not (a)(ii); A method is provided herein, comprising:

[0028] In one aspect, a computer-implemented method for identifying placement programming of deep brain stimulation (DBS) electrodes for DBS treatment of a patient with early Parkinson's disease (PD) is provided, the method comprising: (a) receiving brain imaging data of a patient; (b) processing the brain imaging data to identify (i) neural pathways from the patient's supplementary motor area and / or primary motor cortex to the subthalamic nucleus (STN), and (ii) neural pathways from the patient's pre-supplementary motor area to the STN; and (c) creating an electrode programming map for treating the patient with DBS such that the implanted electrodes target (a)(i) and not (a)(ii); A method is provided herein, comprising:

[0029] The computer-implemented method may further include identifying patient-specific locations of the tracts defined in (a)(i) and (a)(ii) from the normative connectome by using inverse normalization to warp the tracts from the template space to the patient brain space. To identify (a)(i) and (a)(ii), the computer-implemented method may: (1) Regions of interest (ROIs) derived from the supplementary motor area projecting to the STN; (2) regions of interest derived from the primary motor cortex that project to the STN; and (3) Region of interest originating from the pre-SMA projecting to the STN The method may further include utilizing patient-specific tractography data collected from diffusion-weighted brain imaging of the patient's brain using

[0030] The computer-implemented method is receiving postoperative brain image data of the patient; and processing the post-operative brain image data to determine whether the DBS electrodes achieved the intended (a)(i) pre-operative targeting and (a)(ii) non-targeting. It may further include:

[0031] As used herein, "a" or "an" may mean one or more. As used in the claims herein, when used in conjunction with the word "comprising," the words "a" or "an" may mean one or more.

[0032] Use of the term "or" in the claims is used to mean "and / or" unless expressly stated to refer to alternatives only or to refer to mutually exclusive alternatives, but this disclosure supports a definition that refers to alternatives only and "and / or." As used herein, "another" can mean at least a second, or more.

[0033] Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error of the device, the inherent variation of error of the method being used to determine the value, or the inherent variation of error that exists between study subjects. Such inherent variation may be ±10% variation of the stated value.

[0034] Other objects, features, and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of example only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. [Brief explanation of the drawings]

[0035] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure, which may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0036] [Figure 1]Motor progression and treatment requirements of "top" and "typical" responding DBS + ODT subjects compared with control subjects. Motor progression responder analysis using the UPDRS-III 7-day off score change from baseline to 24 months was used to separate early DBS + ODT subjects into two groups: "top responders" (yellow, n = 5; Δ ≤ 0) and "typical responders" (blue, n = 9; Δ > 0). Early ODT control subjects are shown in gray (n = 14). A subset of early DBS + ODT subjects (yellow line) demonstrated slower motor progression (Figure 1A) while requiring fewer PD medications (Figure 1B) and smaller stimulation amplitudes (Figure 1C). Mean ± SEM. Wilcoxon rank sum P < 0.05. *top vs. typical DBS + ODT responders; #top DBS + ODT responders vs. ODT subjects. [Figure 2] Anatomical distribution of DBS electrodes at the midbrain level. (Figure 2A) Reconstruction of the examined leads in the early PD pilot cohort (n = 14 subjects) characterized in the coronal plane. (Figure 2B) 3D visualization of the STN characterized electrode active contacts reflected in the right hemisphere in the sagittal plane. Top responders, n = 5 subjects (n = 10 electrodes), yellow. Typical responders, n = 9 subjects (n = 18 electrodes), blue. STN: purple. The STN from the DISTAL Minimal Atlas (Ewert et al. 2018) is superimposed on a slice of a 7T brain scan at 100 μm in MNI 152 space (Edlow et al. 2019). [Figure 3]The sweet spot correlates with slowing of motor progression in early Parkinson's disease. (Figures 3A-C) The magnitude of the electric field vector for all DBS subjects was rank-order correlated voxelwise with the motor progression score. The centers of the (Figure 3A) coronal, (Figure 3B) transverse, and (Figure 3C) sagittal views were placed at functional coordinates: 11.07 ± 0.82 mm lateral, 1.83 ± 0.61 mm posterior, and 3.53 ± 0.38 mm inferior to the midcommissural point (MNI peak coordinates: 11.4, -13.7, -7.6 mm). The STN is depicted in purple. The red nucleus is depicted in red. The optimal location is indicated by the Bejani line (Bejani et al., 2000), a dashed white line. (Figures 3D-F) N-images of the stimulation volume demonstrated broad coverage throughout the STN at the group level. [Figure 4A]White matter tracts associated with motor progression in early Parkinson's disease. (Figure 4A) The extent of E-field modulation of fibers was rank-order correlated with motor progression slowing scores (UPDRS-III 7-day off baseline to 24-month scores) across the DBS cohort. Orange fibers (darker, more posterior) correlated positively with motor progression slowing (R 0.06 to 0.58), whereas cyan fibers correlated negatively (R -0.53 to -0.01). Subthalamic nucleus (STN), purple. (Figure 4B) Density maps of cortical fiber projections (positive / orange and negative / cyan) were overlaid onto an MNI spatial template [Johns Hopkins University (JHU) atlas parcellation: M1 (JHU: 25 & 26, precentral gyrus), SMA & pre-SMA (JHU: 1 & 2, superior frontal gyrus, posterior segment)] using Surf Ice software (available on the World Wide Web at nitrc.org / projects / surfice). (Figure 4C) Stimulation sites for superior (green; #10) and poorly responding (red; #1) illustrative example subjects and their association with fibers (orange) associated with slowed motor progression. (Figure 4D) Top: Leave-one-patient-out cross-validation of the neural tract model shown in Figures 4A-C to estimate outcomes with previously unseen data. The analysis was repeated iteratively, each time excluding one patient and estimating outcomes by associating stimulation sites with positively and negatively weighted nerve tracts. Repeating the same analysis with 5-fold or 10-fold cross-validation also yielded significant correlations (R = 0.50, P = 0.033 and R = 0.53, P = 0.027, respectively). Data from the illustrative example subjects in Figure 4C were characterized. Bottom: Distribution of motor progression scores by randomization group from the "DBS in Early PD" pilot clinical trial. DBS, n = 14. ODT, n = 14. (Figure 4E) Null distribution of the leave-one-patient-out experiment from Figure 4D (calculated by repeating the analysis 1,000 times after permuting motor progression values ​​across subjects). [Figure 4B] See legend to Figure 4A. [Figure 4C] See legend to Figure 4A. [Figure 4D] See legend to Figure 4A. [Figure 4E] See legend to Figure 4A. [Figure 5A] Sweet Spots and White Matter Tracts of Symptomatic Motor Improvement. (Figures 5A-C) Electric field magnitude values ​​for all early PD subjects were rank-order correlated with percent symptomatic motor improvement (UPDRS-III MedON baseline to 24-month MedON / StimON scores). This corresponds to the same analysis performed using the motor progression scores shown in Figures 3A-C. The centers of the (Figure 5A) coronal and (Figure 5B) axial views were placed at peak functional coordinates: 11.08 ± 0.82 mm lateral, 1.93 ± 0.60 mm posterior, and 3.48 ± 0.38 mm inferior to the midcommissural point (MNI coordinates: 11.2, -13.7, -7.4 mm). The STN is depicted in purple. The red nucleus is depicted in red. Bejani line 32 = dashed white line. (Figure 5C) The degree of E-field modulation of fibers was rank-order correlated with symptomatic motor improvement (UPDRS-III on-baseline to 24-month scores) across cohorts. This corresponds to the same analysis performed using the motor progression scores shown in Figures 3A–C. Orange fibers were positively correlated with symptomatic motor improvement (R 0.00–0.59), whereas cyan fibers showed a negative correlation (R -0.53–0.00). (Figure 5D–F) The analyses in Figures 3A–C were repeated after regressing symptomatic improvement (MedON / StimON) scores from the motor progression scores (as analyzed in Figures 5A–C). [Figure 5B] See legend to Figure 5A. [Figure 5C] See legend to Figure 5A. [Figure 5D] See legend to Figure 5A. [Figure 5E] See legend to Figure 5A. [Figure 5F] See legend to Figure 5A. [Figure 6A]Spatial correlation between the early Parkinsonian sweet spot and established landmarks for DBS targeting in Parkinson's disease. (Figure 6A) Visualization of optimal early PD locations (green spheres) associated with motor progression and symptomatic motor improvement, and their correlation with mean coordinates (red spheres) derived from a meta-analysis of 342 standard-of-care PD electrodes (Caire et al. 2013). The mean Euclidean distance between the meta-analytic sweet spot and the sweet spot in the current study was 2.2 ± 0.01 mm. Transverse (Figure 6B) and sagittal (Figure 6C) sections characterize peak coordinates in MNI space. Béjani's lines are drawn in red. STN functional areas: associative (blue), limbic (white), and sensorimotor (orange). Red nucleus (red). [Figure 6B] See legend to Figure 6A. [Figure 6C] See legend to Figure 6A. [Figure 7] We distinguish between symptomatic and disease-modifying therapies. The red line indicates relentless disease progression. The green line indicates treatments that completely halted disease progression but were not curative. The gray line indicates therapies that are only symptomatic. Symptomatic means that symptoms may improve temporarily for a short period of time, but return as soon as the therapy (e.g., levodopa dose for PD bradykinesia) is gradually tapered. The black dotted line indicates a therapy that is disease-modifying when applied in very early Parkinson's disease, in this case, slowing disease progression. This therapy improves symptoms when applied in the short term (symptomatic benefit) and continues to provide benefit in slowing PD progression because this effect remains long after the therapy is discontinued (i.e., disease-modifying). [Figure 8]Timing of DBS intervention versus nigrostriatal degeneration (modified from Fischer & Sortwell, 2019). Nigrostriatal degeneration [putamen TH immunoreactivity (left y-axis) and nigral neuron count (right y-axis)] versus time since PD diagnosis (x-axis). Gray boxes indicate the time at which other DBS trials were performed (i.e., intermediate PD, B; advanced PD, C–E). The Vanderbilt DBS trial (A) is the only trial performed when nigrostriatal neurons were still present and connections were preserved. Therefore, this is the only trial in which DBS can modify PD progression. [Figure 9A] Correlation between motor progression and PD therapy. (Figure 9A) Slower motor progression correlates with smaller stimulation amplitude (24-month voltage) for DBS subjects; R=-0.52, P=0.02. Amplitude is shown as the average of left and right leads. V = voltage. (Figure 9B) Slower motor progression is also associated with larger LEDD declines after surgery for DBS subjects (black dots; R=-0.59, P=0.01). There is no correlation for ODT subjects (tan dots; R=0.16, P=0.54). (Figure 9C) Stimulation sites for superior (green) and poorly responding (red) example example subjects. Figures 9A-B characterize stimulation and PD medication data from an example example DBS subject. [Figure 9B] See legend to Figure 9A. [Figure 9C] See legend to Figure 9A. DETAILED DESCRIPTION OF THE INVENTION

[0037] Detailed Description As discussed above, subthalamic nucleus deep brain stimulation (STN-DBS) is an effective adjunctive therapy for intermediate- and advanced-stage Parkinson's disease (PD). However, individual motor improvement is variable, and electrode positioning is an important determinant of efficacy. The DBS in Early PD Pilot Clinical Trial randomized early PD patients 1:1 to optimal medical therapy (ODT) or bilateral STN DBS + ODT and included a 7-day treatment washout to assess progression of untreated motor symptoms over the 2-year trial. The objectives of the study described here were (1) to examine individual motor progression in DBS in Early PD trials and (2) to explore the relationship between electrode positioning and motor progression.

[0038] Post-hoc motor progression responder analyses were performed using the Unified Parkinson Disease Rating Scale Part III (UPDRS-III) 7-day off-therapy scores (DBS+ODT n = 14, ODT n = 14). Voxel-wise probabilistic mapping and tract connectivity (based on the normative connectome) were used to assess the association between electrode positioning and the clinical outcomes of motor progression (UPDRS-III 7-day off) and symptomatic motor improvement (UPDRS-III on) in 14 subjects who underwent DBS for early PD.

[0039] Untreated motor scores from baseline to 2 years worsened for all subjects (14 / 14) randomized to ODT, whereas scores remained unchanged (n=1) or improved (n=4) for one-third (5 / 14) of subjects randomized to early DBS + ODT. The odds of motor deterioration were more than three times higher in the ODT group compared with the DBS + ODT group. The stimulation location most strongly associated with slowing of motor progression was in the posterolateral STN (MNI coordinates: +11.25, -13.56, -7.44 mm). Tracts projecting to the STN from the supplementary motor area (SMA) and primary motor cortex (M1) were positively correlated with slowing of motor progression, whereas tracts originating from the anterior SMA and cerebellum were negatively associated with motor progression. The R-map model of stimulated fibers associated with changes in motor progression was validated by leave-one-patient-out (R = 0.56, P = 0.02), 5-fold (R = 0.50, P = 0.03), and 10-fold (R = 0.53, P = 0.03) cross-validation. Repeated sweet spot and tract analysis using symptomatic motor improvement scores showed strong similarity with the location and connectivity of motor progression.

[0040] These results suggest that stimulating the posterolateral STN, specifically the area that receives input from M1 and SMA, can slow motor progression in early PD. A larger study will be conducted to further validate this finding, which has already been approved by the FDA for a multicenter phase 3 clinical trial evaluating DBS in early PD.

[0041] These and other aspects of the disclosure are set forth below.

[0042] I. Parkinson's disease Parkinson's disease (PD) is a long-term degenerative disorder of the central nervous system that primarily affects the motor system. Symptoms generally progress slowly over time. Tremor, rigidity, bradykinesia, and difficulty walking are most evident early in the disease. Thought and behavioral problems may also occur. Dementia is common in the advanced stages of the disease. Depression and anxiety are also common and occur in more than one-third of people with PD. Other symptoms include sensory, sleep, and emotional problems. The main motor symptoms are collectively referred to as "parkinsonism" or "parkinsonism."

[0043] The causes of Parkinson's disease are generally unknown, but both genetic and environmental factors are thought to play a role. People with an affected family member are more likely to develop the disease. Risk is also increased among people exposed to certain pesticides and those with a history of head trauma. In contrast, risk is lower among smokers and coffee or tea drinkers. The disease's motor symptoms result from cell death in the substantia nigra, a region of the midbrain. This results in a lack of dopamine in these areas. The reasons for this cell death are not fully understood, but it involves the accumulation of proteins in neurons as Lewy bodies. Diagnosis of typical cases is primarily based on symptoms, with tests such as neuroimaging used to rule out other disorders.

[0044] Currently, there is no cure for Parkinson's disease. Initial treatment is typically with the antiparkinsonian drug L-DOPA (levodopa), followed by dopamine agonists when levodopa becomes ineffective. As the disease progresses and neuronal loss continues, these drugs become ineffective and complications characterized by writhing, involuntary movements (i.e., dyskinesias) develop. Diet and some types of rehabilitation have shown some effectiveness in improving symptoms. Surgery to place microelectrodes for deep brain stimulation has been used to alleviate motor symptoms in severe cases that are resistant to medication. Evidence for treatments for non-motor-related symptoms of PD, such as sleep disorders and emotional problems, is less strong.

[0045] In 2013, PD affected 53 million people and caused approximately 103,000 deaths worldwide. Parkinson's disease typically occurs in people over the age of 60, affecting approximately 1% of these people. Men are more likely to be affected than women. When present in people before age 40 or 50, Parkinson's disease is called early-onset PD. Life expectancy after diagnosis is 7-14 years.

[0046] The term parkinsonism is used for a movement syndrome whose main symptoms are resting tremor, rigidity, slowed movement, and postural instability. Parkinsonism can be divided into four subtypes according to its origin: (1) primary or idiopathic, (2) secondary or acquired, (3) hereditary parkinsonism, and (4) parkinsonism-plus syndrome or multisystem degeneration.

[0047] Parkinson's disease is the most common form of parkinsonism and is usually defined as "primary" parkinsonism, meaning parkinsonism without an identifiable external cause. In recent years, several genes have been discovered that are directly associated with some cases of Parkinson's disease. This contradicts the definition of Parkinson's disease as an idiopathic disease, but genetic parkinsonism disorders with a clinical course similar to PD are generally included under the Parkinson's disease label. The terms "familial Parkinson's disease" and "sporadic Parkinson's disease" are sometimes used to distinguish between hereditary and truly idiopathic forms of the disease.

[0048] Although PD is usually classified as a movement disorder, several non-motor symptoms, such as sensory deficits, cognitive difficulties, and sleep problems, also occur. Parkinson's plus diseases are primary parkinsonisms that exhibit additional features. These include multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and dementia with Lewy bodies.

[0049] From a pathophysiological perspective, in contrast to other diseases such as Alzheimer's disease, in which the brain accumulates tau protein in the form of neurofibrillary tangles, PD is considered a synucleinopathy caused by the abnormal accumulation of α-synuclein protein in the brain in the form of Lewy bodies. Nevertheless, there is clinical and pathological overlap between tauopathies and synucleinopathies. While dementia, the most typical symptom of Alzheimer's disease, occurs in the advanced stages of PD, neurofibrillary tangles are commonly found in the brains of patients with PD. Dementia with Lewy bodies (DLB) is another synucleinopathy that shares similarities with PD, particularly with some PD cases accompanied by dementia. However, the relationship between PD and DLB is complex and remains unclear. They may be part of a continuum or may be separate diseases.

[0050] A. Signs and Symptoms Parkinson's disease affects movement, resulting in motor symptoms. Non-motor symptoms, including autonomic dysfunction, neuropsychiatric problems (changes in mood, cognition, behavior, or thinking), and sensory and sleep difficulties, are also common. Some of these non-motor symptoms are often present at the time of diagnosis and may precede motor symptoms.

[0051] Four motor symptoms are considered cardinal symptoms of PD: tremor, rigidity, bradykinesia, and postural instability. Tremor is the most obvious and well-known symptom. Tremor is the most common. Approximately 30% of individuals with PD have no tremor at disease onset, but most develop tremor as the disease progresses. Tremor is usually a resting tremor that is greatest when the limb is at rest and disappears with voluntary movement and sleep. Tremor affects the most distal parts of the limb to a greater extent. At onset, it typically affects only one arm or leg, later becoming bilateral. PD tremors have a frequency of 4 to 6 hertz (cycles per second). A characteristic feature of tremor is pill-rolling, a tendency for the index finger of the hand to contact the thumb and perform a circular motion together. The term originates from the similarity of the movement of people with PD to the former pharmaceutical technique of manually forming pills.

[0052] Bradykinesia, another distinctive feature of PD, is a slowing of motor execution. Sequential and simultaneous motor execution is impaired. Early manifestations include problems performing everyday tasks requiring fine motor control, such as writing, sewing, or dressing. Clinical assessment is based on similar tasks, such as alternating between the hands or between the feet. Bradykinesia is not uniform across all movements or time periods. Bradykinesia can vary depending on the subject's activity or emotional state, to the point where some people can barely walk but still ride a bicycle. Generally, people with PD have less difficulty when certain external cues are provided.

[0053] Rigidity is stiffness and resistance to limb movement caused by increased muscle tone, which is excessive and continuous muscle contraction. In Parkinsonism, rigidity can be uniform (plumb-like) or ratchety (cogwheel-like). A combination of tremor and increased tone is thought to be at the origin of ratchety. Stiffness can be associated with joint pain, which is a frequent early manifestation of the disease. In early Parkinson's disease, stiffness is often asymmetric and tends to affect the muscles of the neck and shoulders before the muscles of the face and limbs. As the disease progresses, stiffness typically affects the entire body, reducing mobility.

[0054] Postural instability is common in the late stages of the disease, leading to balance problems and frequent falls, and secondarily to fractures. Instability is often absent early on, especially in younger people. Up to 40% of people may experience a fall, and approximately 10% may fall weekly, with the number of falls correlated with the severity of PD.

[0055] Other recognised motor signs and symptoms include gait and postural disturbances such as febrile gait (a quick, shuffling gait and a stooped posture when walking), speech and swallowing difficulties including dysphonia, mask-like facial expressions or small print, although the range of possible motor problems that may present is wide.

[0056] Parkinson's disease can cause neuropsychiatric disorders that can range from mild to severe. These include disorders of speech, cognition, mood, behavior, and thought. Cognitive impairments can occur early in the disease, sometimes before diagnosis, and their prevalence increases with disease duration. The most common cognitive impairment in affected individuals is executive dysfunction, which can include problems with planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting inappropriate actions, working memory, and selecting relevant sensory information. Other cognitive difficulties include fluctuations in attention, impaired perception and time estimation, and slowed cognitive processing speed. Memory, specifically, recall of learned information, is affected. Nevertheless, improvement occurs when recall is aided by cues. Visuospatial difficulties are also part of the disease and are noted when individuals are asked to perform tests of, for example, face recognition and recognizing the direction of drawn lines.

[0057] People with PD are at increased risk of dementia compared with the general population. The prevalence of dementia increases with the duration of the disease. Dementia is associated with decreased quality of life, increased mortality, and an increased likelihood of needing nursing home care in people with PD and their caregivers.

[0058] Behavioral and mood changes are more common in PD without cognitive impairment than in the general population and are usually present in PD with dementia. The most frequent mood disturbances are depression, apathy, and anxiety. Establishing a diagnosis of depression is complicated by symptoms often present in Parkinson's disease, including dementia, reduced facial expression, reduced movement, apathy, and hushed speech. Substance abuse and impulse control behaviors such as craving, overeating, hypersexual activity, or problem gambling can appear in PD and have been associated with medications used to manage the disease. Psychotic symptoms, such as hallucinations or delusions, occur in 4% of people with PD, and dopaminergic excess secondary to treatment is thought to be the primary factor driving psychotic phenomena in Parkinson's disease. Accordingly, this becomes more common with aging and levodopa intake.

[0059] In addition to cognitive and motor symptoms, PD can impair other physical functions. Sleep problems are a hallmark of the disease and can be exacerbated by medication. Symptoms can manifest as daytime sleepiness, disturbances during REM sleep, or insomnia. A systematic review showed that narcolepsy occurs in 13.0% of Parkinson's disease patients taking dopaminergic medications.

[0060] Changes in the autonomic nervous system can lead to orthostatic hypotension (low blood pressure when standing up), oily skin and excessive sweating, urinary incontinence, and changes in sexual function. Constipation and gastric motility disorders can cause discomfort and may be severe enough to even jeopardize health. PD is associated with several eye and vision abnormalities, such as a decreased blink rate, dry eyes, deficits in eye tracking (target-following) and saccadic eye movements (rapid, automatic movements of both eyes in the same direction), difficulty directing gaze upward, and blurred or double vision. Sensory changes can include loss of smell, sensations of pain, and paresthesia (skin tingling and numbness). All of these symptoms can appear years before disease diagnosis.

[0061] B. Cause In most people, Parkinson's disease is idiopathic (without a specific known cause). However, a small percentage of cases can be attributed to known genetic factors. Other factors have been associated with the risk of developing PD, but the causal relationship is unknown.

[0062] A number of environmental factors have been associated with an increased risk of Parkinson's disease, including pesticide exposure, head injury, and rural or agricultural living. Rural environments and drinking well water may be risks because they are indirect measures of pesticide exposure. Agents implicated include insecticides, primarily chlorpyrifos and organochlorines, as well as pesticides such as rotenone or paraquat, and herbicides such as Agent Orange and ziram. Exposure to heavy metals has been proposed as a risk factor due to their possible accumulation in the substantia nigra, but research on this issue is inconclusive.

[0063] PD has traditionally been considered a non-genetic disorder. However, approximately 15% of individuals with PD have a first-degree relative with the disease. At least 5% of people are now known to have a form of the disease that occurs due to a mutation in one of several specific genes.

[0064] Mutations in specific genes have been conclusively shown to cause PD. These genes encode α-synuclein (SNCA), parkin (PRKN), leucine-rich repeat kinase 2 (LRRK2 or dardarin), PTEN-induced putative kinase 1 (PINK1), DJ-1, and ATP13A2. In most cases, people with these mutations develop PD. However, with the exception of LRRK2, these mutations account for only a small number of PD cases. SNCA and LRRK2 are the most widely studied PD-associated genes. Mutations in genes including SNCA, LRRK2, and glucocerebrosidase (GBA) have been identified as risk factors for sporadic PD. GBA mutations are known to cause Gaucher disease. Genome-wide association studies have explored mutant alleles with low penetrance in sporadic cases, and many positive results have now been obtained.

[0065] The role of the SNCA gene is important in PD because the α-synuclein protein is the main component of Lewy bodies. Missense mutations (in which a single nucleotide in the gene is changed) of this gene, as well as duplications and triploidizations of the locus containing it, have been found in different groups with familial PD. Missense mutations are rare. On the other hand, duplications of the SNCA locus account for approximately 2% of familial cases. Duplications have been found in asymptomatic carriers. This suggests that penetrance is incomplete or age-dependent.

[0066] The LRRK2 gene (PARK8) encodes a protein called dardarin. The name dardarin comes from the Basque word for tremor because the gene was first identified in families from the UK and northern Spain. LRRK2 mutations are the most common known cause of familial and sporadic PD, accounting for approximately 5% of individuals with a family history of the disease and 3% of sporadic cases. Although many mutations in LRRK2 have been described, there is very little clear evidence of a causal relationship.

[0067] Several Parkinson's-related genes are involved in the function of lysosomes, organelles that digest cellular waste products, and it has been suggested that lysosomal dysfunction that reduces the cell's ability to degrade alpha-synuclein may cause some forms of Parkinson's.

[0068] C. Diagnosis Doctors diagnose Parkinson's disease from a medical history and neurological examination. There are no medical tests that clearly identify the disease, although brain scans are sometimes used to rule out disorders that can produce similar symptoms. Levodopa may be given, and the resulting alleviation of motor decline tends to confirm the diagnosis. The discovery of Lewy bodies in the midbrain at autopsy is usually considered evidence that a person had Parkinson's disease. Over time, as the disease progresses, the condition may turn out not to be Parkinson's disease, and some authorities recommend periodic reconsideration of the diagnosis.

[0069] Other possible secondary causes of parkinsonism include Alzheimer's disease, multiple cerebral infarction, and drug-induced parkinsonism. Parkinson-plus syndromes, such as progressive supranuclear palsy and multiple system atrophy, must be excluded. Antiparkinsonian medications are typically ineffective in managing symptoms in parkinsonian-plus syndromes. A rapid rate of progression, early cognitive dysfunction or postural instability, minimal tremor, or symmetry at onset may indicate parkinsonian-plus disease rather than PD itself. While inherited forms are usually classified as PD, the terms "familial Parkinson's disease" and "familial parkinsonism" are used to refer to disease entities with autosomal dominant or recessive patterns of inheritance.

[0070] To facilitate and standardize the diagnostic process, especially in the early stages of the disease, medical institutions have developed diagnostic criteria. The most widely recognized criteria are from the UK Parkinson's Disease Society Brain Bank and the US National Institute of Neurological Disorders and Stroke. The PD Society Brain Bank criteria require bradykinesia (slow movements) and either rigidity, resting tremor, or postural instability. Other possible causes of these symptoms must be excluded. Finally, three or more of the following features are required during onset or progression: unilateral onset, resting tremor, progression over time, asymmetry of motor symptoms, a response to levodopa for at least 5 years, a clinical course of at least 10 years, and the emergence of dyskinesias induced by excessive levodopa intake. Diagnostic criteria assessed at autopsy have an accuracy rate of 75–90%, with the highest rate achieved by specialists such as neurologists.

[0071] Computed tomography (CT) and conventional magnetic resonance imaging (MRI) brain scans of people with PD usually appear normal. Nevertheless, these techniques are useful for ruling out other diseases that may be secondary causes of parkinsonism, such as basal ganglia tumors, vascular lesions, and hydrocephalus. One specific technique of MRI, susceptibility-weighted imaging, has been found to distinguish patients from disease-free subjects, and another technique, diffusion MRI, has been reported to be useful in distinguishing between typical and atypical parkinsonism, although its exact diagnostic value is still under investigation. Dopaminergic function in the basal ganglia can be measured using various PET and SPECT radiotracers. Examples include isoflurane ( 123 I) (trade name DaTSCAN) and iometopan (Dopascan), or fluorodeoxyglucose ( 18F) and DTBZ. The pattern of decreased dopaminergic activity in the basal ganglia can aid in the diagnosis of PD.

[0072] D. Prevention, management, rehabilitation, and palliative care Exercising in midlife reduces the risk of Parkinson's disease later in life. Caffeine also appears to be protective, with large consumption of caffeinated beverages such as coffee associated with a significant reduction in risk. Tobacco smoke causes adverse health effects, reducing life expectancy and quality of life, but may reduce PD risk by one-third compared with nonsmokers. The basis for this effect is unknown, but possibilities include the effect of nicotine as a dopamine stimulant. Tobacco smoke contains compounds that act as MAO inhibitors, which may also contribute to this effect.

[0073] Antioxidants such as vitamins C and D have been proposed to prevent disease, but research results are conflicting and no positive effects have been demonstrated. Results regarding fats and fatty acids are conflicting, with various studies reporting protective, risk-increasing, or no effect. Furthermore, possible protective roles for estrogen and anti-inflammatory drugs have been preliminarily demonstrated.

[0074] Although there is no cure for Parkinson's disease, medication, surgery, and multidisciplinary management can alleviate symptoms. The main drug groups useful for treating motor symptoms are levodopa (usually combined with dopa decarboxylase inhibitors or COMT inhibitors, which do not cross the blood-brain barrier), dopamine agonists, and MAO-B inhibitors. The stage of the disease determines which group is most useful. Two phases are usually distinguished: an early phase, in which individuals with PD already develop some disability requiring pharmacological treatment, and a second phase, in which individuals develop motor complications related to levodopa use. Treatment in the early phase aims to achieve an optimal trade-off between good symptom control and side effects resulting from improved dopaminergic function. The initiation of levodopa treatment can be delayed by using other drugs, such as MAO-B inhibitors and dopamine agonists, in the hope of delaying the onset of dyskinesias. In the second phase, the goal is to alleviate symptoms while controlling fluctuations in response to the drugs. Abrupt discontinuation or abuse of medication must be managed. Surgery and deep brain stimulation may be useful when medications are not sufficient to control symptoms. In the final stages of the disease, palliative care is provided to improve quality of life.

[0075] Levodopa has been the most widely used treatment for 30 years. L-DOPA is converted to dopamine by dopa decarboxylase in dopaminergic neurons. Because motor symptoms result from a lack of dopamine in the substantia nigra, L-DOPA administration temporarily reduces motor symptoms.

[0076] Only 5–10% of L-DOPA crosses the blood-brain barrier. The remainder is often metabolized to dopamine elsewhere, causing various side effects, including nausea, dyskinesia, and joint stiffness. Carbidopa and benserazide are peripheral dopa decarboxylase inhibitors that block L-DOPA metabolism before it reaches dopaminergic neurons, thus helping to reduce side effects and increase bioavailability. They are commonly given in combination preparations with levodopa. Existing preparations are carbidopa / levodopa (co-careldopa) and benserazide / levodopa (co-beneldopa). Levodopa has been linked to dopamine dysregulation syndrome, a condition characterized by compulsive drug abuse and binge drinking. Sustained-release versions of levodopa are available as intravenous and enteral infusions, extending the drug's effects. These sustained-release levodopa preparations did not demonstrate increased control of motor symptoms or motor complications when compared with immediate-release preparations.

[0077] Tolcapone inhibits the COMT enzyme, which breaks down dopamine, thereby prolonging the effects of levodopa. Tolcapone has been used to complement levodopa; however, its usefulness is limited by potential side effects, such as liver damage. Entacapone, a similarly effective drug, has not been shown to cause significant changes in liver function. Licensed entacapone preparations contain either entacapone alone or in combination with carbidopa and levodopa.

[0078] Over the long term, levodopa preparations can lead to the development of motor complications characterized by involuntary movements called dyskinesias and fluctuating drug response. When this occurs, people with PD may go from a phase in which they respond well to the drug and have few symptoms (the "on" state) to a phase in which they do not respond to the drug and have significant motor symptoms (the "off" state). For this reason, levodopa doses are kept as low as possible while maintaining function. It is customary to delay the initiation of levodopa therapy by using alternatives (dopamine agonists and MAO-B inhibitors). A previous strategy to reduce motor complications was to discontinue L-DOPA medication for a period of time. This is no longer recommended because it can result in dangerous side effects, such as neuroleptic malignant syndrome. Most people with PD eventually require levodopa and subsequently develop motor side effects.

[0079] Several dopamine agonists, which bind to dopaminergic postsynaptic receptors in the brain, have effects similar to levodopa. They were initially used as complementary therapy to levodopa for individuals experiencing on-off fluctuations and dyskinesias. They are now used alone as initial treatment for motor symptoms, primarily to delay motor complications. When used in late-stage PD, they are useful in shortening off periods. Dopamine agonists include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, and lisuride.

[0080] Dopamine agonists cause significant but usually mild side effects, including drowsiness, hallucinations, insomnia, nausea, and constipation. Side effects sometimes occur even at the lowest clinically effective doses, prompting physicians to seek alternative medications. Compared with levodopa, dopamine agonists may delay the motor complications of drug use but are less effective at managing symptoms. Nevertheless, dopamine agonists are usually effective enough to manage symptoms in the first few years. Dopamine agonists tend to be more effective than levodopa. Dyskinesias due to dopamine agonists are rare in young people with PD but, along with other side effects, become more common with age at onset. Therefore, in contrast to levodopa in late-onset disease, dopamine agonists are the preferred initial treatment for early-onset disease. Agonists have been associated with impulse control disorders (e.g., compulsive sexual activity and eating, and pathological gambling and shopping) even more strongly than levodopa.

[0081] Apomorphine is a parenteral dopamine agonist that may be used to reduce off periods and dyskinesias in late-stage PD. Apomorphine is administered by intermittent injection or continuous subcutaneous infusion. Secondary effects, such as confusion and hallucinations, are common, so individuals receiving apomorphine treatment must be closely monitored. Two dopamine agonists administered through a skin patch (lisuride and rotigotine) are useful in people in the early stages of the disease and possibly for managing off states in people with more advanced disease.

[0082] MAO-B inhibitors (safinamide, selegiline, and rasagiline) increase dopamine levels in the basal ganglia by blocking its metabolism. MAO-B inhibitors inhibit monoamine oxidase B (MAO-B), which breaks down dopamine secreted by dopaminergic neurons. Decreased MAO-B activity increases L-DOPA in the striatum. Like dopamine agonists, MAO-B inhibitors used as monotherapy improve motor symptoms and delay the need for levodopa in early-stage disease, but they produce more side effects and are less effective than levodopa. There are few studies of the efficacy of MAO-B inhibitors in advanced disease, but results suggest they may be useful in reducing fluctuations between on and off periods. Early studies suggested that the combination of selegiline and levodopa increased the risk of death, but this was later proven incorrect.

[0083] Other medications, such as amantadine and anticholinergics, may be useful in treating motor symptoms. However, the evidence supporting these medications lacks quality, and therefore they are not first-line treatments. In addition to motor symptoms, PD is associated with a wide range of symptoms. Many medications have been used to treat some of these problems. Examples include quetiapine for psychosis, cholinesterase inhibitors for dementia, and modafinil for daytime sleepiness. A 2010 meta-analysis found that nonsteroidal anti-inflammatory drugs (excluding aspirin) are associated with at least a 15 percent reduction in the incidence of Parkinson's disease (even more so in long-term and regular users).

[0084] Surgery to treat motor symptoms was once common, but the number of procedures declined after the discovery of levodopa. Research over the past few decades has significantly improved surgical techniques, resulting in a resurgence in surgery for people with advanced PD for whom drug therapy is no longer sufficient. Surgical procedures for PD can be divided into two main groups: lesions and deep brain stimulation (DBS). Target areas, or lesions, for DBS include the thalamus, globus pallidus, or subthalamic nucleus. Deep brain stimulation, developed in the 1980s by Alim Louis Benabid and colleagues, is the most commonly used surgical procedure. It involves the implantation of a medical device called a neurostimulator, which delivers electrical impulses to specific parts of the brain. DBS is recommended for people with PD with motor fluctuations and tremors that are inadequately managed with medication, or for people who are intolerant to medication, unless they also have some neuropsychiatric issues. Other, less common surgical therapies involve the intentional creation of lesions to suppress hyperactivity in specific subcortical regions. For example, pallidotomy involves the surgical destruction of the globus pallidus to manage dyskinesias.

[0085] Exercise programs are recommended for people with Parkinson's disease. There is some evidence that rehabilitation can improve speech or mobility problems, but studies are scarce and of poor quality. Regular physical exercise, with or without physical therapy, may be beneficial in maintaining and improving mobility, mobility, strength, walking speed, and quality of life. When exercise programs are performed under the supervision of a physical therapist, motor symptoms, mental and emotional function, activities of daily living, and quality of life are significantly improved compared with self-administered home exercise programs. In terms of improving mobility and range of motion for people who experience stiffness, generalized relaxation techniques such as gentle rocking have been found to reduce excessive muscle tension. Other effective techniques for promoting relaxation include slow rotational movements of the limbs and trunk, rhythmic initiation, diaphragmatic breathing, and meditation. Regarding walking exercises, they address disease-related challenges such as slowed movement (bradykinesia), limping, and reduced arm swing. Physical therapists have various strategies for improving functional mobility and safety. Areas of interest regarding gait during rehabilitation programs focus on, but are not limited to, improving gait speed, base of support, stride length, trunk, and arm swing. Strategies include the use of assistive devices (pole walking and treadmill walking), verbal cueing (hand, visual, and auditory), exercise (marching and PNF patterns), and varying environments (surface, input, open vs. closed). Strengthening training has shown improvements in strength and motor function for people with primary muscle weakness and mild to moderate Parkinson's disease-related weakness associated with inactivity. However, reports have shown a significant interaction between strength and the time medications are taken. Therefore, it is recommended that people with PD exercise 45 minutes to 1 hour after medication administration, when they are at their best. Additionally, due to the stooped posture and respiratory insufficiency in advanced Parkinson's disease, deep diaphragmatic breathing exercises are beneficial for improving chest wall mobility and lung capacity. Exercise may improve constipation.

[0086] One of the most widely used treatments for speech disorders associated with Parkinson's disease is Lee Silverman voice treatment (LSVT). Speech therapy, specifically LSVT, can improve speech. Occupational therapy (OT) aims to promote health and quality of life by helping people with the disease participate in as many daily activities as possible. While studies on the effectiveness of OT are few and of limited quality, some have shown that it can improve motor skills and quality of life over the course of therapy.

[0087] Palliative care is specialized medical care for people with serious illnesses, including Parkinson's disease. The goal is to improve the quality of life for people with Parkinson's disease and their families by alleviating the symptoms, pain, and stress of the disease. Because Parkinson's disease is not a curable disease, all treatments are focused on slowing decline and improving quality of life and are therefore symptomatic in nature. Palliative care must be involved early in the disease process rather than later. Palliative care professionals can help with physical symptoms, emotional factors such as loss of function and work, depression, fears, and existential concerns.

[0088] Palliative care provides emotional support to both patients and families and plays an important role in addressing the goals of care. People with Parkinson's disease may have many difficult decisions to make as the disease progresses, such as whether to use a feeding tube, noninvasive ventilation, and tracheostomy; whether or not to use cardiopulmonary resuscitation; and when to use hospice care. Palliative care team members can answer questions and help guide people with Parkinson's disease through these complex and emotional topics to help them make the best decisions based on their own values.

[0089] The muscles and nerves that control the digestive process are affected in PD, which can lead to constipation and gastroparesis (food remains in the stomach for a longer period than normal). A balanced diet based on regular nutritional assessment is recommended and must be designed to avoid weight loss or weight gain and minimize the consequences of gastrointestinal dysfunction. As the disease progresses, difficulty swallowing (dysphagia) may develop. In such cases, the use of thickening agents for liquid intake and upright positioning at mealtimes may be helpful. Both procedures reduce the risk of choking. A gastrostomy to deliver food directly to the stomach may occur in severe cases.

[0090] Levodopa and protein use the same transport systems at the intestine and the blood-brain barrier, and therefore compete for access. When they are taken together, this leads to a decrease in the drug's effectiveness. Therefore, excessive protein intake is not recommended when levodopa is introduced, and a well-balanced Mediterranean diet is recommended. For similar reasons, in advanced stages, increased intake of low-protein products such as bread or pasta is recommended. Levodopa should be taken 30 minutes before meals to minimize interactions with protein. At the same time, PD regimens limit protein intake during breakfast and lunch, allowing protein intake in the evening.

[0091] Repetitive transcranial magnetic stimulation temporarily improves levodopa-induced dyskinesias. The usefulness of transcranial magnetic stimulation in PD is an open research topic, but recent studies have shown no benefit from rTMS. Several nutrients have been proposed as possible treatments. However, there is no evidence that vitamins or food additives improve symptoms. There is no evidence that acupuncture and qigong or tai chi (Tai Chi) practice have any effect on the course of the disease or symptoms. Further research is needed on the feasibility of tai chi (Tai Chi) for balance or motor skills. Fava beans and velvet beans are natural sources of levodopa and are eaten by many people with PD. Although they have shown some efficacy in clinical trials, their consumption is not without risk. Life-threatening adverse reactions, such as neuroleptic malignant syndrome, have been described.

[0092] PD progresses steadily over time. A severity rating known as the Unified Parkinson's Disease Rating Scale (UPDRS) is the most commonly used metric for clinical research. A modified version known as the MDS-UPDRS is sometimes used. An older rating known as the Hoehn and Yahr scale (first published in 1967) and a similar scale known as the Modified Hoehn and Yahr scale have also been commonly used. The Hoehn and Yahr scale defines five basic stages of progression.

[0093] If untreated, motor symptoms progress aggressively early in the disease and more slowly later. Untreated individuals can expect to lose independent walking after an average of 8 years and become bedridden after 10 years. However, it is now rare to find untreated individuals. While medication has improved the prognosis for motor symptoms, it also represents an emerging cause of disability because the undesirable effects of levodopa appear after years of use. In people taking levodopa, the time it takes for symptoms to progress to a stage of high caregiver dependency can exceed 15 years. However, predicting the course of the disease for a particular individual is difficult. Age is the best predictor of disease progression. People with less functional decline at diagnosis experience a faster rate of motor decline, whereas cognitive impairment frequently occurs in people over 70 years of age at symptom onset.

[0094] Because current therapies improve motor symptoms, disability at this time is primarily associated with non-motor features of the disease. Nevertheless, the relationship between disease progression and disability is not linear. Disability is initially associated with motor symptoms. As the disease progresses, disability becomes more associated with motor symptoms that do not respond well to medication, such as swallowing / speech difficulties and gait / balance problems, and is also associated with motor complications that appear in up to 50% of individuals after 5 years of levodopa use. Ultimately, after 10 years, most people with the disease have autonomic dysfunction, sleep problems, mood changes, and cognitive decline. All of these symptoms, especially cognitive decline, significantly increase disability.

[0095] People with PD have a reduced life expectancy. The mortality rate is approximately twice that of unaffected people. Cognitive decline and dementia, older age at onset, more advanced disease status, and the presence of swallowing problems are all risk factors for mortality. On the other hand, a disease pattern characterized primarily by tremor, as opposed to rigidity, predicts improved survival. Death from aspiration pneumonia is twice as common in individuals with PD as in the healthy population. In 2013, PD caused approximately 103,000 deaths worldwide, an increase from 44,000 deaths in 1990. Mortality rates increased from an average of 1.5 to 1.8 per 100,000 cases during that time.

[0096] II. Disease-Modifying Therapies An important advantage of the present disclosure is the provision of disease-modifying therapies (i.e., therapies that can modify the progression of one or more features of a disease). This differs from symptomatic therapies, which provide temporary relief from symptoms while the therapy is being administered but do nothing to alter the course of the underlying disease itself. In other words, with disease-modifying therapies, the condition being studied does not worsen even after the therapy is removed. In one example of symptomatic treatment for Parkinson's disease, when a patient takes levodopa, the tremor decreases for 2-3 hours and then returns to normal (see Figure 7, where the therapy is removed). Over the years, the tremor continues to worsen, and as the drug is gradually discontinued, the patient suffers from even worse tremors. Specifically, as Parkinson's disease progresses, patients receive less benefit from levodopa, and some patients develop complete tremor resistance to levodopa, never even experiencing the transient and temporary benefit observed immediately after taking the drug.

[0097] In the case of DBS therapy, when the therapy is administered, i.e., when the device is turned on, this treatment, such as levodopa, can symptomatically reduce tremor. However, when the device is turned off after a short period of time, tremor returns to its underlying untreated severity (see Temperli et al., 2003). Here, the disclosed method (a) is directed to people with only very early Parkinson's disease and (b) is delivered to stimulate specific neural pathways. This provides early PD patients with benefits regarding tremor progression (not just tremor symptoms) that persist even after the DBS device is turned off, i.e., after a full week of being turned off, so that the patient's tremor is measured without any symptomatic (short-term) benefits of DBS. These findings here enable the unique application of DBS to slow and potentially even halt disease progression in early Parkinson's disease.

[0098] Preclinical studies have demonstrated the importance of early DBS intervention ( Maesawa et al., 2004 ; Musacchio et al., 2017 ; AL Spieles-Engemann et al., 2010 ; Temel et al., 2006 ), and the rationale for early intervention is further emphasized by postmortem data showing that 50% of putaminal denervation occurs by the time PD is diagnosed, surging to 90% by 4 years of disease duration ( Kordower et al., 2013 ). Thus, although numerous studies have evaluated the association between electrode placement and motor improvement in PD (Akram et al., 2017; Blomstedt et al., 2012; Bot et al., 2018; Butson et al., 2006; Caire et al., 2013; Horn, Li, et al., 2019; Maks et al., 2008; Plaha et al., 2006), this is the first study to evaluate how stimulation location may affect disease progression. See Figure 8.

[0099] Importantly, an overwhelming body of evidence in the literature supports that tremors treated with VIM / DBS continue to progress relentlessly despite such treatment (Shih et al., 2013; Favilla et al., 2012; Peters and Tisch, 2021; Fasano and Fasano, 2019; Paschen et al., 2019). Furthermore, as the disease progresses, many tremor patients become VIM / DBS resistant (Favilla et al., 2012; Peters and Tisch, 2021; Fasano and Fasano, 2019). Thus, the disclosed method represents a major advancement in STN-DBS delivery by providing a unique way to define DBS lead placement and activation that can reproducibly and precisely deliver such long-term disease-modifying therapy.

[0100] III. Electrode Placement in Subthalamic Nucleus Deep Brain Stimulation (STN-DBS) A. Conventional Electrode Placement and Programming Identifying the location for electrode placement has traditionally been accomplished by: (1) preoperative evaluation to determine placement of bony alignment markers, patient brain imaging, and preoperative target planning and trajectory assignment; and (2) postoperative testing of contacts and field geometry for maximum effect.

[0101] The first procedure, involving outpatient imaging and placement of bony registration markers, identification of surgical targets, entry points, and landmarks, is performed by a neurosurgeon.

[0102] During the second procedure, in which the STN nucleus is mapped, a frame is attached to the patient, and a tungsten microelectrode (1 MΩ at 1 kHz) is placed in a guide tube and advanced using an electrode drive. Microelectrode recording (MER) is performed using a recording system. The microelectrode is advanced into the STN along a predefined trajectory. Recordings are periodically made, beginning above the target and ending below the target or at the dorsal border of the substantia nigra pars reticularis (SNr). Recordings are interpreted by a neurophysiologist in the operating room based on accepted criteria and used to define the boundaries of the STN and SNr. The optimal stimulation target is determined by consensus among the neurosurgeon, neurologist, and neurophysiologist.

[0103] The general procedure for identifying the STN nucleus is outlined in Starr (2002), who discloses that "essential steps in DBS implantation are magnetic resonance imaging (MRI)-guided stereotactic positioning, identification of the motor area of ​​the target nucleus using microelectrode mapping, and intraoperative test stimulation to determine the voltage threshold for stimulation-induced side effects." Details regarding methods for identifying the STN nucleus and target selection are disclosed in Hutchinson et al. (1998), who state that "The STN can be identified by the presence of neurons with a characteristic 25-45 Hz firing frequency and irregular firing patterns that may have movement-related or tremor-related activity."

[0104] Location selection is the subject of a review presented by Gross et al. (2006) and is the rationale for using physiological mapping in addition to standard imaging methods to map the STN most accurately. The ideal location for electrode placement is determined intraoperatively by microstimulation. Gross states that "microstimulation at the site of recording of tremor-related neurons can induce tremor cessation with short latencies..." and "this effect is limited to specific body parts according to a somatotopic arrangement. The use of longer pulse durations (>0.5 ms) usually extends the anti-tremor effect to other body regions after a longer delay (1-2 s)."

[0105] B. Tractography-based electrode placement and programming More recently, tractography-based surgical planning methods have been used to exploit knowledge of the association between brain connectivity and clinical outcomes. Under this "tractography-based" surgical planning paradigm, identification of sites for electrode placement is accomplished as follows: (1) Preoperative evaluation to determine patient brain imaging, including placement of bony registration markers, incorporation of tractography data, and preoperative target planning and trajectory assignment; and (2) Postoperative evaluation of patient brain imaging to confirm lead placement and identify DBS electrode contacts (conventional) or segments (directional) that are predicted to produce favorable clinical outcomes based on prior studies.

[0106] The conventional electrode placement approaches described above attempt to identify locations that provide symptomatic (i.e., transient, reversible, in the absence of therapy) benefit. We present here a completely novel, tractography-based, electrode placement and programming approach with the goal of modifying (i.e., slowing, halting, or reversing) the progression of Parkinson's disease. Additional information required for this novel approach is provided below: (1) Preoperative target planning and trajectory assignment in a tractography database, including placement of bone registration markers, patient brain imaging, and tractography database preoperative target planning and trajectory assignment, including identifying neural tracts that (i) target (i.e., maximally stimulate) the STN from the supplementary motor area (SMA) and / or primary motor cortex (M1) of the cortex and (ii) avoid the STN from the pre-SMA of the cortex; and (2) Postoperative evaluation of patient brain imaging to confirm lead placement and identify DBS electrode contacts (conventional) or segments (directional) that (i) target (i.e., maximally stimulate) the white matter tracts from the cortical supplementary motor area (SMA) and / or primary motor cortex (M1) to the STN and (ii) avoid stimulating the cortical pre-SMA to STN tract. Includes:

[0107] After step 1, bone alignment markers, is placed, preoperative evaluation begins with a preoperative MRI scan of the patient's brain. The next step, determining the location of lead placement to achieve the intended delivery and avoidance of electrical stimulation, can be performed using two different approaches: "patient-specific tractography" and "atlas-based tractography." The first approach involves an additional preoperative scan to acquire a diffusion-weighted MRI of the patient's brain and analyzing the patient's brain scan using deterministic fiber tractography software to determine the location of relevant white matter tracts. The second approach involves registering (i.e., warping or standardizing) the patient's preoperative MRI brain scan with a brain "atlas" with previously identified tracts (i.e., from a normative connectome in a previous study) visualized to predict the location of relevant white matter tracts. Once the target and avoided white matter tracts have been located in the patient's brain scan, "tractography-based surgical planning" is completed by providing the neurosurgeon with the tractography output (i.e., imaging files) imported into standard target planning software such as Brainlab Elements (Brainlab AG, Munich, Germany) or StealthStation FrameLink (Medtronic, USA) to place electrodes in positions that optimally stimulate positive nerve tracts and avoid negative nerve tracts.

[0108] The first aspect is sometimes called "patient-specific tractography," in which preoperative patient scans are analyzed using software to map relevant white matter tracts. Deterministic tractography ("fiber tracking") is performed based on diffusion-weighted (DWI) scans acquired before surgery. The patient's DWI brain scan is co-registered to the patient's structural (i.e., T1, T2) brain scan. Regions of interest (ROIs) are identified in the structural brain scan to define the beginning and end of the desired white matter tracts. Numerous publications, including Graat et al., 2022, Riva-Posse et al., 2017, and Noecker et al., 2018, describe this established methodology. For the method specified in this application, the following ROI pairs are required for surgical planning: white matter tracts from the target tracts (M1 to STN, SMA to STN) and the avoided tracts (pre-SMA to STN).

[0109] The second aspect is sometimes called "atlas-based tractography." Various software packages, including ANTs Rigid / Affine (Ashburner, 2007), BRAINSFIT (Johnson et al., 2007), SPM Co-register (Friston et al., 2004), FSL FLIRT (Jenkinson et al., 2002), Hybrid SPM / ANTs, Hybrid SPN / FSL, and Hybrid SPM / BRAINSFIT, allow users to visualize a reference "atlas" brain and then perform "warping" or standardization to the patient brain scan (or vice versa, known as "back transformation" or "back standardization"). Another example is the Lead-DBS toolbox reported by Ewert et al. (2019), which uses the "effective low variance + subcortical refinement" preset of the highly optimized ANTS SyN algorithm to nonlinearly register subcortical elements with submillimeter accuracy. The Lead-DBS toolbox was initially developed at Charite - University of Medicine (CCM) in Berlin, Germany (Horn & Kuhn, NeuroImage, 107:127-135, 2015). This "atlas-based tractography" methodology was described by Oxenford et al. (2022) using the Lead-DBS, Lead-Group, and Lead-OR software framework, which supports integration with planning software (Brainlab Elements, Brainlab AG, Munich, Germany) and the NeuroOmega system (Alpha Omega Engineering).For the inventions set forth herein, specific white matter tracts identified from a canonical connectome (described in Example 1 below) within ICBM 2009b NLIN asymmetric ("MNI") space (Fonov et al., 2011) template space are warped onto a patient's preoperative MRI scan to visualize these tracts in "patient space" (i.e., native space) required for surgical planning.

[0110] Postoperative evaluation includes the acquisition of additional scans (e.g., CT or MRI) of the patient's brain, which allow visualization of the implanted DBS electrodes. To facilitate DBS programming based on target and avoidance white matter tracts (e.g., "tractography-based DBS programming"), the patient's postoperative brain scan is co-registered to the patient's preoperative structural scan, which includes target and avoidance tracts identified by any of the methods described above. Probabilistic software, such as Lead-DBS or the CranialVault / CranialCloud™ suite, is used to reconstruct DBS electrodes and subsequently visualize white matter tract activation based on active electrode contacts or segments.

[0111] C. Stimulation Paradigm Once electrode placement and contact selection are completed as described above, the device is activated to deliver stimulation therapy to the patient. Conventional deep brain stimulation (cDBS) systems are typically "open-loop," meaning that high-frequency stimulation settings do not change between visits by the programming physician. Recently, a new type of DBS stimulation has been introduced that adapts to signals received from the patient. This type of stimulation, currently under investigation, is also known as "closed-loop" or adaptive DBS (aDBS). Adaptive DBS turns stimulation on or off in response to patient data, which may include physiological signals (i.e., beta-band signals detected from a "sensing" DBS system such as Medtronic Percept) or motion-based signals (i.e., patient movement detected from a wearable device). The efficacy of conventional DBS is well established (Deuschl et al., 2006; Schuepbach et al., 2013). In contrast, a clinical trial evaluating the efficacy of closed-loop / adaptive DBS is ongoing (NCT04547712).

[0112] IV. Combination Treatment In the treatment of PD, it may also prove advantageous to use combination therapy, adding other therapies to STN-DBS therapy. Such therapies, when combined, may produce better results than the individual therapies, and in some cases, may have a greater than additive effect. In other cases, such therapy may reduce the amount of one or the other therapy needed to achieve clinical benefit.

[0113] This process may involve administering both therapies simultaneously. Alternatively, the STN-DBS therapy may precede or follow the other treatment by intervals ranging from minutes to weeks. In embodiments in which the other therapy and STN-DBS are administered to a subject separately, one will generally ensure that no significant time period elapses between their respective deliveries, so that the other therapy and STN-DBS can still exert their beneficial combined effect on the subject. In such cases, it is contemplated that both modalities may be administered within about 12 to 24 hours of each other, more preferably within about 6 to 12 hours of each other. In some circumstances, it may be desirable to extend the duration of treatment significantly. However, in this case, one or several days (2, 3, 4, 5, 6, or 7 days) to several weeks (1, 2, 3, 4, 5, 6, 7, or 8 weeks) will lapse between the respective administrations.

[0114] Various combinations may be used, for example, STN-DBS therapy is "A" and a second PD therapy is "B". TIFF2025533844000002.tif22128

[0115] Administration of therapy to a patient will follow the general protocol for administering that particular second-line therapy, taking into account the toxicities / side effects, if any, of the treatment. It is expected that treatment cycles will be repeated as necessary.

[0116] As discussed above, there is no cure for Parkinson's disease, but medications, surgery, and multidisciplinary management can alleviate symptoms. These therapies include levodopa (usually combined with DOPA decarboxylase inhibitors such as carbidopa and benserazide, which do not cross the blood-brain barrier, or COMT inhibitors such as tolcapone or entacapone), dopamine agonists (e.g., apomorphine, bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, and lisuride), MAO-B inhibitors (e.g., safinamide, selegiline, and rasagiline), amantadine, anticholinergic cholinesterase inhibitors, and lesional surgery. [Example]

[0117] V. Working Examples The following examples are included to demonstrate preferred embodiments of the present disclosure. It will be understood by those of skill in the art that the techniques disclosed in the following examples represent techniques discovered by the inventors to function well in the practice of the present disclosure, and therefore can be considered to constitute preferred embodiments for the practice of the present disclosure. However, those of skill in the art, in light of the present disclosure, will appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the present disclosure.

[0118] Example 1 - Method Parkinson's disease cohort This retrospective study evaluated outcomes from DBS in an early PD pilot clinical trial (NCT00282152; IDEG050016; Vanderbilt IRB#040797). The trial design (D. Charles et al., 2012), intraoperative and surgical targeting experience (Camalier et al., 2014; E. Kahn et al., 2011), 2-year (David Charles et al., 2014) and 5-year (M. L. Hacker et al., 2020) outcomes, and post-hoc analyses (M. Hacker et al., 2018; M. L. Hacker et al., 2015) have been previously reported. Briefly, 30 patients with early PD were randomized 1:1 to receive bilateral STN-DBS plus ODT or ODT alone for 2 years. Key inclusion criteria included 6 months to 4 years of PD medication, modified Hohen-Yahr stage II off-medication status, and no history or evidence of dyskinesia or motor fluctuations. Fifteen subjects randomized to early STN-DBS + ODT were implanted bilaterally with quadripolar DBS electrodes (model 3389, Medtronic, Minneapolis, MN). One early DBS + ODT subject was excluded from this analysis due to missing data (baseline Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) 7-day off score and 24-month stimulation parameters for the right electrode explanted before the 24-month assessment).

[0119] Treatment washout and clinical evaluation During the 2-year trial, subjects were admitted to the Vanderbilt Clinical Research Center for a 7-day washout of all PD therapy at baseline, 6 months, 12 months, 18 months, and 24 months. At baseline, UPDRS-III motor testing was videotaped in on-therapy (Day 1; on-medication) and 7-day off-therapy (Day 8; off-medication). At subsequent study visits, UPDRS-III motor testing was again videotaped in on-therapy (Day 1; on-medication and on-stimulation, if applicable) and 7-day off-therapy (Day 8; off-medication and off-stimulation, if applicable). After study completion, videotapes were scored by an independent assessor blinded to treatment assignment, on- vs. off-therapy status, and the order of study visits. Baseline UPDRS 7-day OFF scores were used to calculate PD phenotype (i.e., tremor dominance (TD), postural instability / gait difficulty (PIGD)) according to previously reported methods ( M. Hacker et al., 2018 ; Stebbins et al., 2013 ).

[0120] treatment management The subject's treating neurologist administered medication and stimulation parameters. All DBS+ODT subjects were treated with monopolar stimulation with one case positive and one optimal contact negative electrode (David Charles et al., 2014). Optimal contact was programmed at 130 Hertz (Hz) and 60 μsec pulse width beginning 4 weeks after surgery. Levodopa equivalent daily doses (LEDD) were calculated as previously described (Tomlinson et al., 2010).

[0121] DBS electrode positioning Preoperative T1 and T2 MRI scans and postoperative CT scans were acquired (Camalier et al., 2014). Electrodes were positioned using the advanced processing pipeline at Lead-DBS (lead-dbs.org; Horn & Kuhn, 2015). Postoperative CT scans were linearly coregistrated to the preoperative MRI using the advanced normalization tool (ANTs; stnava.github.io / ANTs / ; Brian B. Avants et al., 2011). The subsequent coregistration was inspected and refined if necessary. A brain shift correction step from Lead-DBS was applied. All preoperative volumes were normalized to ICBM 2009b NLIN asymmetric ("MNI") space (Fonov et al., 2011) using ANTs SyN Diffeomorphic Mapping (Avants et al., 2008) with the preset "effective: low variance default + subcortical refinement." This method was the top performer for segmenting the STN with accuracy comparable to manual expert segmentation in a recent comparative study (Ewert et al., 2018). DBS electrodes were automatically pre-reconstructed using the phantom-validated and fully-automated PaCER method (Husch et al., 2018) and manually refined as needed. Atlas segmentation in this study was defined by the DISTAL atlas (Ewert et al., 2018). Group visualization was performed using the Lead Group toolbox (Treu et al., 2020).

[0122] E-field modeling The magnitude of the electric field vector (the term E-field is used as shorthand for the purposes of this manuscript) was used to estimate the volume of tissue adjusted around the electrode. E-fields were calculated based on 24-month DBS programming settings applied using a modified SimBio / FieldTrip pipeline (Vorwerk et al., 2013), as implemented in Lead-DBS (Horn, Li, et al., 2019). As asymmetric effects were not anticipated, E-fields were nonlinearly inverted to the contralateral side. This resulted in 2 × 14 = 28 E-fields across the cohort.

[0123] DBS Sweet Spot Mapping The sweet spot associated with clinical outcomes (motor symptom progression (UPDRS-III 7-day OFF change from baseline to 24 months); symptomatic motor improvement (UPDRS-III ON percent change from baseline to 24 months)) was assessed using Lead-Group (Treu et al., 2020). For each voxel covered by the E-field group across cohorts in MNI space, the magnitude of the E-field vector between subjects was Spearman rank-correlated with the two clinical outcome variables (motor progression and motor improvement). Regions of interest were conservatively restricted to voxels covered by at least 20% of the E-fields with a vector magnitude greater than 0.2 V / m (a typical value expected for DBS to activate axons (Astrom et al., 2015)). For visualization, the sweet spot was smoothed using a 2 mm full-width-half-maximum kernel. In contrast, the rank correlation coefficients in the color bars in Figures 3A–F and 5A–F were obtained from the unsmoothed file.

[0124] DBS Fiber Filtering To include additional connections from the cortex to the STN and from the STN to the substantia nigra pars compacta and pars reticulata, we assessed neural tract connectivity using a connectome adapted from the DBS Tractography Atlas (Middlebrooks et al., 2020) (Supplementary Methods). For the resulting finite set of 6,525,876 neural tracts represented in the Netstim Tractography Atlas and each subject's E-field, we calculated the probabilistic influence value on the tract as previously described (Horn et al., 2022). A tract was considered connected if the mean E-field magnitude across the tract was >1000 V / m and the tract was coupled to >5% of the E-field.

[0125] statistical analysis A motor progression responder analysis was performed. In this analysis, each subject was classified as improved (Δ<0), unchanged (Δ=0), or worsened (Δ>0) based on the change (Δ) from baseline to 2 years after washout in the UPDRS-III 7-day off motor score. Fisher's exact test was used to assess the difference between the ODT and DBS + ODT groups in the risk of motor score deterioration (worsening vs. improved or unchanged). The difference between the two groups in the trend toward worsening was assessed using exact logistic regression of ordered outcome scores (improved, unchanged, worsening). The logistic model included treatment group (1 = ODT, 0 = DBS + ODT) as the outcome and the change in motor score from baseline to 2 years as the ordered score (improved = 0, unchanged = 1, worsening = 2) as the only explanatory variable. The difference in the trend toward worsening was assessed using the estimated odds ratio of the ordered scores. Mean stimulation amplitude was compared between top and typical DBS + ODT responders at each follow-up visit using the Wilcoxon rank-sum test, and LEDD change from baseline was compared between top and typical DBS + ODT responders and between top DBS + ODT responders and ODT subjects. Clinical data were analyzed in SAS 9.3 (SAS Institute Inc, Cary, NC) and STATA 17.0 (StataCorp LP, College Station, TX).

[0126] Structural connectivity strength was correlated with changes in motor progression (baseline to 24 months) using Spearman rank correlations. This yielded connectivity maps (i.e., R-maps) showing the association of positive and negative tracts with motor progression or improvement. In other words, the Spearman rank correlation coefficient was positive for maximally associated tract populations with electrodes in highly responding subjects and negative for coordinated tract populations in poorly responding subjects. Significance (P = 0.05 level) was tested using out-of-sample data (leave-one-patient-out, 5-fold and 10-fold cross-validation).

[0127] Example 2 - Results The demographics and baseline characteristics of subjects randomized in the DBS pilot clinical trial in early PD are shown in Table 1. Clinical results are detailed elsewhere (David Charles et al., 2014; M.L. Hacker et al., 2020). Briefly, the DBS+ODT cohort included 14 patients (13 males, mean baseline age 60.9±6.9 years) operated on in early PD (mean baseline disease duration 2.6±1.9 years).

[0128] Exercise Progression Responder Analysis Responder analyses were performed to assess motor symptom progression from baseline to 24 months. As expected, UPDRS-III 7-day off-medication motor scores worsened over 2 years for all subjects (14 / 14) randomized to ODT. In contrast, UPDRS-III 7-day off-medication / off-stimulation motor scores remained stable or improved for five subjects (5 / 14, Figure 1A) randomized to early DBS + ODT. The odds of motor deterioration were more than three times higher in the ODT group compared with the DBS + ODT group (median unbiased estimated odds ratio of exact logistic regression, ODT vs. ODT + DBS = 3.68, P = 0.04). To examine DBS-related differences in terms of electrical stimulation, the DBS+ODT cohort was divided into two groups based on UPDRS-III OFF change scores: "top responders" (n=5; UPDRS-III OFF Δ≦0) and "typical responders" (n=9; UPDRS-III OFF Δ>0). Among top responders, the 2-year UPDRS-III 7-day OFF score improved from baseline for four of five subjects and remained unchanged for the fifth subject. Demographic and baseline characteristics of top and typical DBS+ODT responders are characterized in Table 1.

[0129] Drug and irritation reduction In the DBS + ODT cohort, top responders (n = 5; UPDRS-III off-Δ ≤ 0) required less medication, on average, at each follow-up visit compared with baseline (Figure 1B). The mean change in LEDD from baseline to 24 months for DBS + ODT top responders (-148 ± 227 mg) was significantly smaller than that for DBS + ODT typical responders (245 ± 357 mg) and ODT subjects (215 ± 360 mg; P = 0.04 and P = 0.03, respectively). The mean stimulation voltage for early DBS + ODT top responders was also smaller than that for typical responders, and this difference remained significant at 12, 18, and 24 months (P < 0.01, P = 0.04, and P = 0.03, respectively) (Figure 1C). At 24 months, the mean stimulation voltage for superior DBS + ODT responders was 1.6 ± 0.3 V, compared with 2.0 ± 0.2 V for typical DBS + ODT responders. In other words, this subgroup of early DBS + ODT subjects required less medication and smaller stimulation amplitudes while demonstrating slower motor progression. To determine whether differences in stimulation site between DBS + ODT cohorts could explain the observed differences in clinical outcomes and treatment requirements, we performed voxel-wise probabilistic stimulation mapping and structural connectivity analysis.

[0130] Association between movement progression and stimulation location DBS Sweet Spot Analysis As previously reported (Elyne Kahn et al., 2012), electrode positioning revealed active contact placement within the STN and surrounding eloquent area in all subjects (Figure 2A-B). E-fields were used to identify regions associated with changes in motor progression in all early DBS+ODT subjects (Figure 3A-C). Aggregate volume derived from voxel-wise probabilistic mapping revealed the strongest motor slowing in the posterolateral motor portion of the STN (Figure 3A-C). The peak location (i.e., the location most strongly associated with motor slowing) was located at the following MNI coordinates: +11.25, -13.56, -7.44 mm (Spearman rank correlation coefficient at peak: R = 0.67). When expressed in functional (AC / PC) coordinates (Horn, Kuhn, et al., 2017), this region is located 11.07 ± 0.82 mm lateral, 1.83 ± 0.61 mm posterior, and 3.53 ± 0.38 mm inferior to the midcommissural point. In contrast, impingement in more anterior and more dorsal regions, primarily including the zona incerta, was associated with a greater degree of motor progression.

[0131] The peak location (i.e., the location most strongly associated with the least amount of motor progression) was located at MNI coordinates: +11.25, -13.56, -7.44 mm (peak Spearman rank correlation coefficient: R = 0.67). When expressed in functional (AC / PC) coordinates (Horn, Kuhn, et al., 2017), this was located 11.07 ± 0.82 mm lateral, 1.83 ± 0.61 mm posterior, and 3.53 ± 0.38 mm inferior to the midcommissural point. In contrast, involvement of more anterior and more dorsal regions, primarily including the zona incerta, was associated with a greater degree of motor progression. N-maps of the stimulation volume covered an even larger region, including the entire motor STN (Figure 3D-F).

[0132] DBS fiber filtering analysis To investigate the structural networks involved in motor progression, we seeded the structural connectome (Netstim Tractography Atlas) using E-fields obtained from the DBS+ODT cohort. Rank-order correlations between E-field magnitude and motor progression scores revealed distinct neural tracts associated with contrasting clinical outcomes (Figure 4A). Specifically, positively correlated fibers projected from the supplementary motor area (SMA) and primary motor cortex (M1) to the posterior STN (Figure 4A-B). In contrast, negatively correlated fibers originated from the anterior SMA and cerebellum and reached the more anterior and posterior subthalamic area (PSA) of the STN, respectively, where the sensorimotor / associative transition zone is located (Figure 4A).

[0133] Tracts were weighted by the degree to which these adjustments correlated with motor progression across DBS cohorts. This model was validated using leave-one-patient-out (Figure 4D, R = 0.56, P = 0.02), 5-fold (R = 0.50, P = 0.03), and 10-fold (R = 0.53, P = 0.03) cross-validation. To examine the relative contributions of the positive and negative pathways, the analysis was repeated using only the positive pathways (Leave-one-patient-out CV: R = 0.48, P = 0.05), 5-fold CV: R = 0.41, P = 0.07, and 10-fold CV: R = 0.46, P = 0.05), and again using only the negative pathways (Leave-one-patient-out CV: R = 0.35, P = 0.12), 5-fold CV: R = 0.34, P = 0.12, and 10-fold CV: R = 0.42, P = 0.07). Repeating the leave-one-patient-out analysis 1,000 times after permuting the motor progression values ​​across subjects revealed the null distribution for this experiment (Figure 4E). This centered near R = 0 (unpermuted R = 0.56, ranked significantly at p = 0.039). The motor progression distribution for each randomized group from the "DBS in Early PD" pilot trial is shown in Figure 4D. Notably, one-third of early DBS subjects had the same or better motor progression scores 2 years after baseline (5 / 14; Figure 4D). Sensitivity analyses using the "full UPDRS-III" motor progression score (blinded scores + unblinded stiffness scores) yielded similar tractography profiles and cross-validation to the primary analysis (leave-one-patient-out CV: R = 0.49, P = 0.04), 5-fold CV: R = 0.38, P = 0.10), and 10-fold CV: R = 0.47, P = 0.04).

[0134] Association between motor improvement and stimulation site While a key focus of this study was to determine the association between stimulation site and slowing of motor progression (comparing the 7-day OFF score before surgery with the 7-day OFF score 2 years after surgery), it was important to compare these results with the optimal stimulation site associated with symptomatic motor improvement (comparing the ON-medication score before surgery with the score while treated with both medication and DBS 2 years after surgery). We felt it would be important to determine whether the optimal sites and networks for these two different measures coincide, or whether each requires stimulation of different spots / networks.

[0135] Therefore, we repeated the sweet spot analysis using the motor improvement score (UPDRS-III 7-day OFF percent change from baseline to 24 months; Figure 5A-B) instead of the motor progression score (UPDRS-III 7-day OFF change from baseline to 24 months; Figure 3A-F, Figure 4A-E). Overall, the locations associated with motor improvement and slowing of motor progression clearly overlapped at the subthalamic level (Euclidean distance: 0.12 mm). Indeed, the motor improvement sweet spot map peaked at +11.2, -13.7, and -7.4 mm (MNI coordinates; peak Spearman rank correlation coefficient of R = 0.92), in the immediate vicinity of the motor progression sweet spot (Figure 3A-F). When expressed in functional (AC / PC) coordinates (Horn, Kuhn, et al., 2017), this is located 11.08 ± 0.82 mm lateral, 1.93 ± 0.60 mm posterior, and 3.48 ± 0.38 mm inferior to the midcommissural point. Fiber filtering analysis was also repeated using motor improvement outcomes. Results converged on a network highly similar to motor progression outcomes (Figure 5C), again demonstrating strong and significant correlations (leave-one-patient-out CV: R = 0.68, P < 0.01), 5-fold CV: R = 0.62, P = 0.01, and 10-fold CV: R = 0.69, P = 0.04). Independent validation of the positive and negative tracts revealed significant correlations when using the positive tract (leave-one-patient-out CV: R = 0.70, P < 0.01), 5-fold CV: R = 0.67, P < 0.01), and 10-fold CV: R = 0.72, P < 0.01), but not when using the negative tract (leave-one-patient-out CV: R = 0.02, P = 0.468; 5-fold CV: R = 0.11, P = 0.36; and 10-fold CV: R = 0.10, P = 0.36). To further explore the (in)dependence of motor progression scores and symptomatic improvement outcomes (R = 0.46, P = 0.03) in relation to our primary outcome, we repeated the sweet spot and fiber filtering analyses on motor progression scores subtracted from the motor improvement outcome score (Figure 5D-F). This showed very similar results. This suggests that the two scores are not identical at the group level, but share additional differences.

[0136] Comparison with other sweet spots To further characterize the anatomical relevance of our identified early PD sweet spot relative to previously established anatomical boundaries and targets, we searched the literature for established landmarks in DBS targeting. The search yielded two established landmarks: the Bejjani line (Bejjani et al., 2000), identified on transverse slices and constituting a line connecting the anterior aspect of the red nucleus at the STN level with its greatest diameter, commonly used as an anatomical reference in STN-DBS planning, and the meta-analysis target by Caire et al. (Caire et al., 2013), derived from 171 patients and associated with optimal outcomes (Horn, Kuhn, et al., 2017). The spatial relationship between previously published PD sweet spots in the literature and the identified motor progression and motor improvement sweet spots in this early cohort is characterized in Figures 6A–C. Comparison of target locations revealed that both these targets and those identified by Caire et al. (2013) overlapped with Bejjani's lines (Bejjani et al., 2000). However, the sweet spots associated with motor improvement and slowing of motor progression in this study revealed variability in the mediolateral and ventrodorsal planes, indicating a more ventral and lateral location of these targets relative to the meta-analysis of advanced PD targets by Caire et al. (Bejjani et al., 2000) (mean Euclidean distance: 2.2–0.01 mm).

[0137] Association between motor progression and PD therapy To explore whether the slower motor progression among subjects receiving STN-DBS could be explained by higher stimulation voltages and / or more PD medication, we assessed the correlation between motor progression and symptomatic treatment discontinued during the 7-day washout period. Critically, smaller stimulation amplitudes at 24 months correlated with slower motor progression (R = -0.52, P = 0.02; Figure 9A). Among DBS subjects, there was also a significant correlation between larger LEDD reductions (change from baseline to 24 months) and slower motor progression (R = -0.59, P = 0.01; Figure 9B). There was no association between LEDD change and motor progression among subjects randomized to ODT (R = 0.16, P = 0.54; Figure 9B). These results, combined with our electrode positioning analysis, suggest that stimulation location, rather than the amount of PD therapy administered, is the determining factor in motor benefit.

[0138] Example 3 - Discussion Results from DBS in early PD pilot clinical trials provided Class II evidence that early DBS slows the progression of resting tremor and reduces the risk of disease progression and polypharmacy (M. Hacker et al., 2018; M. L. Hacker et al., 2020). To further understand these findings, this study assessed motor progression in each individual subject and explored the association between stimulation area and motor progression.

[0139] There are four main conclusions that can be drawn from this study. First, one-third of subjects randomized to DBS + ODT did not progress in untreated motor symptoms over 2 years, compared with progression in all subjects randomized to ODT. Second, slowing of motor progression was significantly correlated with stimulation of cortical input fibers from the M1 and supplementary motor area (but not with stimulation of cortical input fibers from the pre-SMA). Third, the optimal locations and tracts for slowing of motor progression in early PD were highly similar to those associated with symptomatic motor improvement in early PD. In other words, networks associated with optimal clinical response were also associated with slowing of motor progression. Finally, the locations and tracts identified for optimal benefit in early PD were similar to previously reported effective locations from studies of patients who received DBS in more advanced stages of PD (Akram et al., 2017; Horn, Li, et al., 2019; Horn, Reich, et al., 2017).

[0140] The untreated motor symptoms of one-third of subjects randomized to receive early DBS did not progress from baseline to two years. In fact, scores improved from baseline for four of the five top responders. In contrast, motor symptoms worsened for all subjects randomized to ODT. This striking finding raises an important new question: Why did motor progression slow so strongly in these early DBS subjects? And importantly, how can future early DBS trials increase the number of participants whose motor progression slows?

[0141] We created DBS subgroups using post hoc motor progression outcomes. Therefore, it is not surprising to see such a large difference between top and typical responders in Figure 1A. However, this subgrouping did not affect the statistical value of subsequent image analyses, and separating the DBS+ODT group based on this responder analysis revealed an independent and significant difference between the groups. That is, top responders required significantly lower levels of medication (Figure 1B) and stimulation (Figure 1C) than typical responders, yet still demonstrated slower motor progression. Because optimal electrode placement is not only associated with reduced therapy (drugs and stimulation) requirements but also represents an important source of variation among DBS patients (Caire et al., 2013; Frizon et al., 2018; Horn, Li, et al., 2019), this finding motivated us to further explore electrode placement in this unique cohort.

[0142] The optimal stimulation site identified here lies close to previously published sweet spots associated with symptom improvement in advanced PD (Akram et al., 2017; Bot et al., 2018; Horn, Li, et al., 2019) (for a review, see Horn, 2019). This location of the posterolateral STN is aligned anteriorly and posteriorly with the anterior border of the red nucleus, known as the Bejjani line. The Bejjani line is commonly used for surgical targeting of STN-DBS for PD (Bejjani et al., 2000). Because DBS is intended to be used throughout the PD progression, it is an important finding that the optimal targets for PD symptom improvement align with the optimal targets for motor progression, and that these targets also align between early and more advanced stages of PD. This suggests that precise surgical targeting of this established location in advanced PD would not only provide symptomatic benefit in early PD, but would also potentially slow motor progression, and importantly, this slowing of motor progression does not require stimulation of additional networks or sites.

[0143] While targeting the STN lesion location (defined by its local relationship to landmarks) is commonly used in surgical planning (Bejjani et al., 2000), there is an increasing paradigm shift in conceptualizing DBS benefits in relation to the global networks modulated by DBS (Horn, Reich, et al., 2017; Lozano & Lipsman, 2013b). Motor benefits in early PD correlated strongly with tracts from the hyperdirect pathway, specifically those connecting the M1 and SMA to the STN, but not those connecting the pre-SMA to the STN. Given previous associations between hyperdirect pathways and symptomatic motor improvement in STN-DBS patients with advanced disease (Akram et al., 2017; Avecillas-Chasin & Honey, 2020; Horn, Reich, et al., 2017), it is not surprising that these tracts also confer motor benefits in early PD patients. There is growing evidence that connections from the SMA improve motor symptoms, whereas connections from the M1 improve tremor (Akram et al., 2017; Sobesky et al., 2022). This supports knowledge established by early lesion studies (Hassler et al., 1960). The precise boundary between hyperdirect inputs from the SMA and pre-SMA in DBS for PD is less clear. These adjacent cortical regions are not directly connected to each other (Akkal et al., 2007) and also show significant differences in functional roles and connectivity profiles (Kim et al., 2010). Interestingly, here, modulating the hyperdirect pathway originating from the pre-SMA was negatively associated with slowed motor progression and clinical improvement. The same negative association held true for fibers in pathways corresponding to the uncrossed dentatothalamic tract.Although it is uncertain whether these negative pathways play a causal role or result from spurious correlations (i.e., patients with poor outcomes just happened to modulate these connections), the causal component was that these negative pathways did not modulate beneficial connections. Notably, excluding either the negative or positive pathways (repeated analyses) did not result in worse motor progression slowing. This suggests that modulating positive pathways, but not negative pathways, may play a role in mediating the effect. Critically, this was not the case for pathways associated with symptom improvement; only stimulus overlap with the positive pathways showed significant predictive value (in contrast, reanalysis of the data using only the negative pathways did not yield significant results).

[0144] Preclinical studies have demonstrated the importance of early DBS intervention ( Maesawa et al., 2004 ; Musacchio et al., 2017 ; AL Spieles-Engemann et al., 2010 ; Temel et al., 2006 ), and the rationale for early intervention is further emphasized by postmortem data showing that 50% of putaminal denervation occurs by the time PD is diagnosed, surging to 90% by 4 years of disease duration ( Kordower et al., 2013 ). Thus, although numerous studies have evaluated the association between electrode placement and motor improvement in PD (Akram et al., 2017; Blomstedt et al., 2012; Bot et al., 2018; Butson et al., 2006; Caire et al., 2013; Horn, Li, et al., 2019; Maks et al., 2008; Plaha et al., 2006), this is the first study to evaluate how stimulation location may affect disease progression.

[0145] Our results suggest that targeting the M1 and SMA hyperdirect pathway to the STN in early PD is associated with slowing of motor progression. It is important to clarify that these results are based on post-hoc analyses and small samples and do not constitute evidence of neuroprotection, which cannot be demonstrated without validated biomarkers. However, modifying the PD course by slowing motor progression corresponds to disease modification (Vijiaratnam et al., 2021). How such disease-modifying effects may occur is currently unclear, but research from others may shed light on potential mechanisms. Prolonged beta-band attenuation after DBS cessation in two longitudinal studies suggests long-term DBS-induced plasticity in the sensorimotor network (Chen et al., 2020; Trager et al., 2016). Because the hyperdirect pathway may be a major source of high beta activity in the STN (Oswal et al., 2021), the association of this pathway with slowing of early PD motor progression is intriguing. However, it is likely that indirect projections to the same subthalamic loop play a similar role but were not detected in our analysis. Anatomically, these correspond to comb fibers, which are not discernible in dMRI-based tractography datasets (Horn, Ewert, et al., 2019; Noecker et al., 2021). Now that long-term sensing-enabled DBS systems enable long-term electrophysiological recordings, future studies exploring how electrode location affects beta-band activity and motor progression will help elucidate potential mechanisms. Furthermore, preclinical studies point to brain-derived neurotrophic factor (BDNF) signaling as a potential mediator of these effects. Namely, STN stimulation increases BDNF in the striatum, substantia nigra, and M1 cortex ( A. L. Spieles-Engemann et al., 2011 ), and BDNF signaling via its high-affinity receptor, tropomyosin-related kinase type B (trkB), has been associated with the neuroprotective and symptomatic efficacy of STN-DBS ( D. Fischer et al., 2017 ).Increases in this prominent neurotrophic growth factor may promote neuronal survival, maintenance of cortico-basal ganglia circuitry, or even decrease α-synuclein ( DL Fischer & Sortwell, 2019 ).

[0146] The limitations of this retrospective analysis must also be discussed. The pilot trial did not collect patient-specific tractography data; instead, normative connectome data were used. While this approach lacks patient-specific anatomical features, test-retest studies have shown that a significant proportion of the discrepancies observed in personalized tractography data are attributable to noise (not true anatomical differences between patients) (Petersen et al., 2017). For example, in DBS, the influence of the MRI scanner can be greater than the influence of the patient (Jakab et al., 2016). Furthermore, normative connectome data have been shown to produce results similar to patient-specific data in PD (Wang et al., 2021). Future studies collecting patient-specific connectivity data may explain larger discrepancies. Similarly, the reconstruction of electrode placement and the aggregation of electrodes into a common space, which allows for comparison, leads to biases due to image resolution. Therefore, the reconstructed electrodes do not precisely match the actual ones. To this end, we used a modern pipeline purpose-built for this task, employing concepts such as brain shift correction, multispectral normalization (Horn, Li, et al., 2019), phantom-confirmed electrode localization (Husch et al., 2018), and a validated segmentation framework (Ewert et al., 2019). Furthermore, biases introduced by user-localized lead-DBS and postoperative imaging modalities were recently quantified and remained below the order of magnitude of image resolution (Lofredi et al., 2022). Because this is the only cohort in which DBS was implanted in early PD and the only study to evaluate motor progression outcomes, we were unable to independently validate our findings in a separate cohort. Therefore, these results are hypothesis-generating and must be prospectively tested in future studies.One of the key strengths of this study is the meticulous, longitudinal, blinded clinical evaluation of the UPDRS-III motor test (on therapy and 7 days off therapy). However, the blinded evaluation essentially relies on videotaped recordings for scoring, except for the assessment of rigidity. While the symptomatic effects of DBS wash out within hours (Temperli et al., 2003), prolonged symptomatic effects from PD medications can persist for longer than 7 days. For example, the symptomatic effects of levodopa can last for weeks or even months (Hauser & Holford, 2002; Nutt et al., 1997; Olanow et al., 1995). However, for clinical trials evaluating DBS in early PD, a 7-day treatment washout strikes an appropriate balance between scientific rigor (i.e., how long is required to wash out the symptomatic effects of the intervention being tested?) and reasonable burden to study participants (i.e., what is realistic and ethically feasible to ask early PD patients to tolerate?). Importantly, compared with DBS+ODT subjects, participants randomized to ODT received more medication throughout the trial (David Charles et al., 2014) and are therefore expected to have prolonged symptomatic effects. Relevantly, in this study, the five top DBS+ODT responders whose motor symptoms did not progress over 2 years were taking less medication than both the typical DBS+ODT responders and the ODT control group.

[0147] This study analyzed the association between electrode location from DBS and motor outcomes in an early PD pilot clinical trial. These results suggest that DBS electrodes stimulating the posterolateral STN, specifically the subdivision of the nucleus that receives input from M1 and SMA, can slow motor progression in early PD. This finding must be prospectively confirmed in larger studies. The FDA has approved a planned multicenter phase 3 clinical trial evaluating DBS in early PD.

[0148] Table 1. Demographic and baseline characteristics TIFF2025533844000003.tif105146LEDD, Levodopa Equivalent Daily Dose ODT, Optimal Drug Therapy PIGD, postural instability and gait disturbance UPDRS, Unified Parkinson's Disease Rating Scale ~ Eliminate stiffness # Off scores were used to calculate PD phenotypes using the method described by Stebbins et al. and previously used in Hacker et al.

[0149] All of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure.Although the compositions and methods of the present disclosure have been described in terms of preferred embodiments, it will be apparent to those skilled in the art that variations may be applied to the compositions and / or methods described herein, as well as to the steps or order of steps of the methods, without departing from the concept, spirit, and scope of the present disclosure.More specifically, it will be apparent that certain chemically and physiologically related agents may be substituted for the agents described herein, while still achieving the same or similar results.All such similar substitutions and modifications apparent to those skilled in the art are deemed to be within the spirit, scope, and concept of the present disclosure, as defined by the appended claims.

[0150] VI. References The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference. TIFF2025533844000004.tif184146TIFF2025533844000005.tif224146TIFF2025533844000006.tif218146TIFF2025533844000007.tif77146

Claims

1. A method of placing deep brain stimulation (DBS) electrodes in a patient with early Parkinson's disease (PD), comprising the steps of: (a) mapping the patient's brain by identifying (i) neural tracts from the patient's supplementary motor area and / or primary motor cortex to the subthalamic nucleus (STN) and (ii) neural tracts from the patient's pre-supplementary motor area to the STN to determine locations for DBS electrode placement; and (b) implanting a DBS electrode to target (a)(i) and not target (a)(ii).

2. 1. A method of placing and programming deep brain stimulation (DBS) electrodes in a patient with early Parkinson's disease (PD), comprising the steps of: (a) implanting a DBS electrode targeting the subthalamic nucleus (STN) in said patient; (b) mapping the patient's brain by identifying (i) neural tracts from the patient's supplementary motor area and / or primary motor cortex to the subthalamic nucleus (STN) and (ii) neural tracts from the patient's pre-supplementary motor area to the STN to determine programming of the DBS electrode, wherein the DBS electrode is programmed to stimulate (i) and not stimulate (ii).

3. 3. The method of claim 1 or 2, further comprising treating the patient by delivering current through the DBS electrodes, e.g., by continuous delivery, patient-adjusted delivery, or adaptive delivery based on patient parameters.

4. The method of any one of claims 1 to 3, wherein the patient is a male human patient.

5. The method of any one of claims 1 to 4, wherein the patient is a female human patient.

6. The method of any one of claims 1 to 5, wherein the patient is a non-human mammalian subject.

7. The method of any one of claims 1 to 6, wherein DBS is performed multiple times, for example chronically.

8. The method of any one of claims 1 to 7, further comprising treating the patient with a second PD therapy.

9. 10. The method of claim 8, wherein the second PD therapy is administered before STN-DBS.

10. 10. The method of claim 8, wherein the second PD therapy is administered simultaneously with STN-DBS.

11. 10. The method of claim 8, wherein the second PD therapy is administered after STN-DBS.

12. 9. The method of claim 8, wherein the second PD therapy is selected from levodopa, optionally in combination with a DOPA decarboxylase inhibitor (carbidopa, benserazide) or a COMT inhibitor (tolcapone, entacapone), a dopamine agonist (e.g., apomorphine, bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, lisuride), an MAO-B inhibitor (e.g., safinamide, selegiline, rasagiline), amantadine, an anticholinergic cholinesterase inhibitor, and lesion surgery, or a combination thereof.

13. 13. The method of any one of claims 1-12, wherein STN-DBS results in one or more of slowing motor symptom progression, stopping motor symptom progression, and / or reversing motor symptom progression.

14. 13. The method of any one of claims 1-12, wherein STN-DBS results in one or more of: a reduction in stimulation parameters, a reduction in the need for postoperative dopaminergic medication, and / or a reduction in the occurrence of levodopa-associated dyskinesias or other motor fluctuations.

15. step (a) comprises identifying patient-specific locations of the tracts defined in (a)(i) and (a)(ii) from a normative connectome by using inverse normalization to warp the tracts from template space to patient brain space; or step (a) comprising identifying patient-specific locations of the tracts defined in (a)(i) and (a)(ii) from the normative connectome by normalizing the patient brain to a template space containing the tracts; 15. The method of any one of claims 1 and 3 to 14.

16. Step (a) includes: (1) Regions of interest (ROIs) derived from the supplementary motor area projecting to the STN; (2) regions of interest derived from the primary motor cortex that project to the STN; and (3) Region of interest originating from the pre-SMA projecting to the STN 15. The method of any one of claims 1 and 3-14, comprising utilizing patient-specific tractography data collected from diffusion-weighted brain imaging of the patient's brain using:

17. 17. The method of any one of claims 1 and 3 to 16, further comprising the step of performing a post-operative scan of the patient's brain.

18. step (b) comprises identifying patient-specific locations of the tracts defined in (b)(i) and (b)(ii) from the normative connectome by using inverse normalization to warp the tracts from the template space to the patient brain space; or step (b) comprising identifying patient-specific locations of the tracts defined in (b)(i) and (b)(ii) from the normative connectome by normalizing the patient brain to a template space containing the tracts; 3. The method of claim 2.

19. Step (b) includes: (1) Regions of interest (ROIs) derived from the supplementary motor area projecting to the STN; (2) regions of interest derived from the primary motor cortex that project to the STN; and (3) Region of interest originating from the pre-SMA projecting to the STN 3. The method of claim 2, comprising utilizing patient-specific tractography data collected from diffusion-weighted brain imaging of the patient's brain using:

20. 20. The method of claim 18, further comprising determining whether the DBS electrode achieved the intended (b)(i) pre-operative targeting and (b)(ii) non-targeting.

21. 20. The method of claim 18 or 19, wherein the DBS electrode comprises multiple contacts or segments, and the method further comprises determining which contacts or segments provide maximal stimulation of (b)(i) and avoid (b)(ii).

22. 20. The method of claim 18 or 19, wherein the DBS electrode comprises multiple contacts or segments, and the method further comprises determining an electric field shape for the contacts or segments that results in maximal stimulation of (b)(i) and avoids (b)(ii).

23. 3. The method of claim 2, wherein the DBS electrode comprises multiple contacts or segments, and the method further comprises determining which contacts or segments provide maximal stimulation of (b)(i) and avoid (b)(ii).

24. 3. The method of claim 2, wherein the DBS electrode comprises multiple contacts or segments, and the method further comprises determining an electric field shape for the contacts or segments that results in maximal stimulation of (b)(i) and avoids (b)(ii).

25. 21. A PD therapeutic for use in treating Parkinson's disease (PD) in a subject, wherein the subject separately, simultaneously, or sequentially receives subthalamic nucleus (STN) deep brain stimulation (DBS) by a method defined by any one of claims 1-7 or 13-20.

26. 26. The PD therapeutic for use in treating PD in a subject of claim 25, wherein the PD therapeutic is administered before STN-DBS.

27. 26. The PD therapeutic for use in treating PD in a subject of claim 25, wherein the PD therapeutic is administered simultaneously with STN-DBS.

28. 26. The PD therapeutic for use in treating PD in a subject according to claim 25, wherein the PD therapeutic is after STN-DBS.

29. 29. The PD therapeutic for use in treating PD in a subject of any one of claims 25-28, wherein the PD therapeutic is levodopa, a dopamine agonist (e.g., apomorphine, bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, lisuride), an MAO-B inhibitor (e.g., safinamide, selegiline, rasagiline), amantadine, and an anticholinergic cholinesterase inhibitor, or a combination thereof, optionally in combination with a DOPA decarboxylase inhibitor (carbidopa, benserazide) or a COMT inhibitor (tolcapone, entacapone).

30. 1. A computer-implemented method for identifying placement locations of deep brain stimulation (DBS) electrodes for DBS treatment of a patient with early Parkinson's disease (PD), comprising the steps of: (a) receiving brain image data of the patient; (b) processing the brain imaging data to identify (i) neural pathways from the patient's supplementary motor area and / or primary motor cortex to the subthalamic nucleus (STN), and (ii) neural pathways from the patient's pre-supplementary motor area to the STN; and (c) creating an electrode placement map for treatment of said patient with DBS such that implanted electrodes target (a)(i) and not (a)(ii).

31. 1. A computer-implemented method for specifying placement programming of deep brain stimulation (DBS) electrodes for DBS treatment of a patient with early Parkinson's disease (PD), comprising the steps of: (a) receiving brain image data of the patient; (b) processing the brain imaging data to identify (i) neural pathways from the patient's supplementary motor area and / or primary motor cortex to the subthalamic nucleus (STN), and (ii) neural pathways from the patient's pre-supplementary motor area to the STN; and (c) creating an electrode programming map for treatment of said patient with DBS such that implanted electrodes target (a)(i) and not (a)(ii).

32. 32. The computer-implemented method of claim 30 or 31, further comprising identifying patient-specific locations of the tracts defined in (a)(i) and (a)(ii) from the normative connectome by using inverse normalization to warp the tracts from template space to patient brain space.

33. To identify (a)(i) and (a)(ii), Regions of interest (ROIs) derived from the supplementary motor area projecting to the STN; Regions of interest derived from the primary motor cortex that project to the STN; and Area of ​​interest derived from the pre-SMA projecting to the STN 32. The computer-implemented method of claim 30 or 31, further comprising utilizing patient-specific tractography data collected from diffusion-weighted brain imaging of the patient's brain using:

34. receiving post-operative brain image data of the patient; and processing the post-operative brain image data to determine whether the DBS electrodes achieved the intended (a)(i) pre-operative targeting and (a)(ii) non-targeting.

32. The computer-implemented method of claim 30 or 31, further comprising:

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