Improving symptoms in mid- to late-stage parkinson's disease patients using with deep brain stimulation

Abstract

The present disclosure relates to the treatment of patients with mid- to late-stage Parkinson's Disease using subthalamic nucleus deep brain stimulation (STN-DBS) to a target a defined region of the brain. In particular, by positioning and / or programming the DBS electrode to stimulate cortical input fibers from the primary motor and supplementary motor areas (but not the pre-SMA), improved therapeutic benefits are obtained.

Description

[0001] DESCRIPTION

[0002] IMPROVING SYMPTOMS IN MID- TO LATE-STAGE PARKINSON’S DISEASE PATIENTS USING WITH DEEP BRAIN STIMULATION

[0003] PRIORITY CLAIM

[0004] The present application claims benefit of priority to U.S. Provisional Application Serial No. 63 / 720,303, filed November 14, 2024, the entire contents of which are hereby incorporated by reference.

[0005] FEDERAL FUNDING SUPPORT CLAUSE

[0006] This invention was made with government support under TR000445, AG066971, EB006136, TR002243, and TR000011 awarded by the National Institutes of Health. The government has certain rights in the invention

[0007] BACKGROUND

[0008] I. Field

[0009] The present disclosure relates to the fields of medicine, central nervous system disorders and neurobiology. More particularly, the disclosure relates to an improved method of performing subthalamic nucleus deep brain stimulation (STN-DBS) on a subject afflicted with mid- to late-stage Parkinson’s Disease.

[0010] IL Related Art

[0011] Parkinson's disease (PD) is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms generally come on slowly over time. Early in the disease, the most obvious are shaking, rigidity, slowness of movement, and difficulty with walking. Thinking and behavioral problems may also occur, and dementia becomes common in the advanced stages of the disease, as well as depression and anxiety (see in more than a third of PD patients). Other symptoms include sensory, sleep, and emotional problems. Thus, PD is a devastating disease with very limited treatment options; no cure is known.

[0012] Subthalamic nucleus deep brain stimulation (STN-DBS) is an established adjunctive therapy for mid- and advanced-stage Parkinson’s disease (PD) that improves motor symptoms and quality of life as well as reduces medication burden and dyskinesia (Deuschi et al., 2006;

[0013] 1

[0014] 4932-4302-8600, V. 1 Schuepbach et al., 2013). While many PD patients receive notable clinical benefit, individual motor response to DBS can be highly variable (ex: 3% to 63% improvement (Weaver et al., 2012)), and -25% of patients do not achieve a significant improvement in quality of life (Deuschi et al., 2006). Numerous groups have studied the source of this heterogenity, and patient factors such as younger age, shorter disease duration, and strong pre-operative response to levodopa predict good response to STN-DBS in advanced-stage PD (P.D. Charles et al., 2002; Welter et al., 2002).

[0015] Outside of patient characteristics, precise delivery of the intervention (i.e., electrode placement and subsequent programming) is also strongly associated with clinical outcome (Caire et al., 2013: Frizon et al., 2018; Hom et al.. 2019; Neudorfer et al., 2022). Although there is not consensus on 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 with active contacts within the dorsolateral (sensorimotor) STN (Akram et al., 2017; Bot etal., 2018; Caire etal., 2013; Hornet al., 2019). For a review see (Hom, 2019). Furthermore, the STN receives input from numerous functional areas in the frontal cortex, and therefore, the site of stimulation will also determine the exact network modulated by DBS. While Parkinson’s Disease has been considered a network disease since its discovery and neuromodulation has been targeting networks since the first days of electric brain stimulation (Hariz et al., 2010), the field is increasingly using advanced neuroimaging sequences to conceptualize DBS as a network treatment in individual patients, defining the networks as three-dimensional structures within stereotactic space (Akram et al., 2017; Horn, Reich, et al., 2017; Krauss et al., 2020; Lozano & Lipsman, 2013; Sobesky et al., 2022). Moreover, from a bioelectrical perspective considering the tissue surrounding the electrode, effects arise from stimulating axons, not cell bodies, which may underline the increasing focus of the field on detemining white matter targets (Jakobs et al., 2019; Li et al., 2020). Associations between Parkinson’s motor improvement and the hyperdirect, pallidofugal, and nigrofugal / striatofugal pathways suggest that precise localization stimulating specific fiber tracts (i.e., white matter tracts) connecting to relevant structures associated with motor control is extermely important for optimal symptomatic benefit of STN-DBS in PD (Akram et al., 2017; Avecillas-Chasin & Honey, 2020; Hom, Reich, et al., 2017). These recent DBS reports confirm early evidence from leisonal studies (Hassler et al., 1960) that cortical input from the supplementary motor cortex seems crucial, espeically when modulating hypokinetic symptoms (Akram et al., 2017; Horn et al., 2019; Hom, Reich, et al., 2017).

[0016] 2

[0017] 4932-4302-8600, v. 1 The robust improvements of STN-DBS in patients with mid- and advanced-stage PD motivate investigations into whether STN-DBS in very early-stage PD would extended or even enhance those benefits. Numerous preclinical studies suggest DBS intervention could be disease-modifying but only if applied early in the neurodegenerative process (Maesawa et al. , 2004; Musacchio et al., 2017; A. L. Spieles-Engemann et al., 2010; Temel et al., 2006). With post-mortem evidence showing that 90% of dopaminergic innervation of the putamen is lost by 4 years after diagnosis (Kordower et al., 2013), there is growing acceptance that if DBS (or any potentially disease-modifying intervention) could slow PD progression, it would have to be applied at the very earliest stage of the disease (D. L. Fischer & Sortwell, 2019). Indeed, at present, the existing literature does not support the notion that DBS can slow motor progression in advanced stage PD. “The rates of progression in patients with STN DBS were within the range of previously reported data from longitudinal imaging studies in PD. Therefore this study could not confirm the neuroprotective properties of DBS in the STN target” (Hilker, 2005).

[0018] The first and, to date, only clinical trial to evaluate DBS at a stage with the potential to slow PD progression (early-stage PD: within four years of diagnosis, without history or evidence of dyskinesia or motor fluctuations) randomized 30 patients to bilateral STN-DBS plus optimal drug therapy (ODT) or ODT alone and followed them for two years (David Charles et al., 2014). In this trial, a 7-day washout of all PD medications and DBS stimulation, if applicable, was completed at baseline and every 6 months for 2 years. In lieu of a biomarker to track disease progression, the 7-day withdrawal of PD therapy allowed evaluation of underlying motor symptom progression without the overt influence of symptomatic therapies (i.e., STN-DBS and PD medications). All subjects who completed the 2-year trial enrolled in a 5-year follow-up visit which included ON therapy only evaluations at years 3, 4 and 5. A post-hoc analysis resulted in class II evidence that DBS in early-stage PD slows rest tremor progression (M. Hacker et al., 2018). Moreover, five-year outcomes provided class II evidence that DBS in early-stage PD decreases the risk of disese progression and polypharmacy (M. L. Hacker et al. , 2020). With respect to mid and advanced-stage disease, (Mahlknecht et al. , 2022) reported that “In summary, there is currently no evidence from clinical studies that DBS would exert modifying effects on the underlying neurobiological progression of PD.” They also stated that “[O]verall on motor function, particularly axial features, and ADL-scores deteriorate below pre-surgical levels within 5 years following DBS surgery, consistent with continued disease progression.”

[0019] Recently, the inventors demonstrated that deep brain stimulation (DBS) of a specific site within the dorsolateral region of the subthalamic nucleus (STN) is associated with slower 3

[0020] 4932-4302-8600, v. 1 motor progression for early-stage Parkinson' s disease (PD) patients (Hacker et al., 2023). This site receives cortical (hyperdirect) input from the primary motor (Ml) and supplementary motor area (SMA) but not from the pre-SMA. These results built upon a post hoc analysis of the DBS for early-stage PD trial (Hacker et al., 2018). The specific site that the inventors identified is similar to, yet slightly more ventral than, a previously reported metanalytic location associated with optimal symptomatic motor benefit in advanced-stage PD (Claire et al., 2013). Moreover, a similar connectivity profile (i.e., stimulating Ml / SMA) has also been associated with symptomatic motor improvement in advanced-stage PD (Akram et al., 2017; Avecillas-Chasin & Honey, 2020; Hom et al., 2017). Therefore, it could be that these sites, i.e., the one associated with slower motor progression and the one associated with optimal motor symptom improvements, are the same. An important distinction in the early-stage study by the present inventors, mentioned above, was the identification of specific fiber tracts from pre-SMA that need to be avoided, while also actively stimulating Ml / SMA, in order to provide optimal motor benefit.

[0021] Thus, while it remains unclear whether mid- to late-stage PD patients would in fact benefit from similar approaches, there are a number of reports indicating that mid / advanced PD patients treated with STN-DBS do not stay the same or improve long-term with regards to their ON therapy motor function. Krack et al., 2003, showed that in advanced-stage patients, progression at 3 years and 5 years was observed. See Table 3. Castrioto et al., 2011, similarly showed that advanced-stage patients worsened at 5 years and 10 years post-treatment. See Table 3. Piboolnurak et al., 2007, measuring total UPDRS II and III scores before and after surgery, also showed progression at 3 years and 5 years after surgery. See Tables 2 and 3. Liang et al., 2006, showed (Table 3) comparison of medication-on scores at baseline with medication-on / stimulati on-on scores at 1-year and long-term evaluations. Long-term evaluations occurred at a median of 33.7 months after surgery and showed progression.

[0022] Moreover, Fox et al., 2018 (“A total of 143 new studies qualified. There are no clinically useful interventions to prevent / delay [Parkinson’s] disease progression.”), King et al., 2022 (suppl 2). (“Only a minority of interventions showing promise in phase 2 trials have undergone phase 3 evaluation. Phase 2 trial success is not translated into positive phase 3 outcomes.”), and Zahoor et al., 2018 (“At the present time, there are no established treatments able to slow, stop, or modify the disease course.”) all indicate that no treatment to slow Parkinson’s is known.

[0023] 4

[0024] 4932-4302-8600, v. 1 SUMMARY

[0025] In accordance with the present disclosure, in one embodiment, there is provided a method of placing a deep brain stimulation (DBS) electrode into a patient having mid- to latestage Parkinson’s Disease (PD) comprising:

[0026] (a) mapping the patient’s brain to determine a location for DBS electrode placement by identifying (i) fiber tracts from the supplementary motor area and / or primary motor area to the subthalamic nucleus (STN) of the patient; and (ii) fiber tracts from the pre-supplementary motor area to the STN of the patient; and

[0027] (b) implanting a DBS electode to target (a)(i) and avoid targeting (a)(ii).

[0028] In addition, there is provided a method of placing and programming a deep brain stimulation (DBS) electrode into a patient having mid to late-stage Parkinson’s Disease (PD) comprising:

[0029] (a) implanting a DBS electode target the subthalamic nucleus (STN) of the patient;

[0030] (b) mapping the patient’s brain to determine programming of said DBS electrode by identifying (i) fiber tracts from the supplementary motor area and / or primary motor area to the subthalamic nucleus (STN) of the patient; and (ii) fiber tracts from the pre-supplementary motor area to the STN of the patient, wherein the DBS electrode is programmed to stimulate (i) and avoid stimulating (ii).

[0031] Further provided is a method of programming a deep brain stimulation (DBS) electrode in a patient having mid to late-stage Parkinson’s Disease (PD) comprising mapping the patient’s brain to determine programming of said DBS electrode by identifying (i) fiber tracts from the supplementary motor area and / or primary motor area to the subthalamic nucleus (STN) of the patient; and (ii) fiber tracts from the pre-supplementary motor area to the STN of the patient, wherein the DBS electrode is programmed to stimulate (i) and avoid stimulating (ii), optionally wherein said subject has an implanted DBS electrode at the time of mapping.

[0032] The methods may further comprise treating said patient by delivering an electrical current through said DBS electrode, such as by continous delivery, patient modulated delivery, or by adaptive delivery based on patient parameters. The patient may be a male human patient or a female human patient. The patient may be a non-human mammalian subject.

[0033] The DBS may be performed more than once, such as on a chronic basis. The methods may further comprise treating said patient with a second PD therapy. The second PD therapy 5

[0034] 4932-4302-8600, v. 1 may be administered prior to STN-DBS, at the same time as STN-DBS, 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 anticholinergics cholinesterase inhibitor, and lesional surgery, or combinations thereof.

[0035] The STN-DBS may result in one or more of post-operative motor symptom improvements compared to pre-surgical motor symptoms, lack of post-operative motor symptom changes compared to pre-surgical motor symptoms, and / or lack of post-operative motor symptom worsening compared to motor symptoms severity prior to surgery. The STN-DBS may result in one or more of lower stimulation parameters, less need for post-operative dopaminergic medication, and / or less development of levodopa associated dyskinesia or other motor fluctuations. The method may further comprise performing a post-operative scan of the patient’s brain.

[0036] Mapping may comprise:

[0037] identifying the patient-specific location of the fiber tracts from the supplementary motor area and / or primary motor area to the subthalamic nucleus (STN) of the patient; and the fiber tracts from the pre-supplementary motor area to the STN of the patient from a normative connectome by using inverse normalization to warp the tracts from the template space into the patient’s brain space; or

[0038] identifying the patient-specific location of the fiber tracts from the supplementary motor area and / or primary motor area to the subthalamic nucleus (STN) of the patient; and the fiber tracts from the pre-supplementary motor area to the STN of the patient from a normative connectome by normalizing the patient’s brain to the template space which includes the tracts.

[0039] Mapping may also comprise utilizing patient-specific tractography data collected from diffusion-weighted brain imaging of the patient’s brain to identify the fiber tracts from the supplementary motor area and / or primary motor area to the subthalamic nucleus (STN) of the patient; and the fiber tracts from the pre-supplementary motor area to the STN of the patient using the following regions of interest (ROI):

[0040] 1) from the supplementary motor area projecting to the STN;

[0041] 2) from the primary motor area projecting to the STN; and

[0042] 6

[0043] 4932-4302-8600, v. 1 3) from the pre-SMA projecting to the STN.

[0044] The DBS electrode may achieve intended preoperative targeting and non-targeting of.

[0045] The DBS electrode may comprise a plurality of contacts or segments and said method further comprises determining which contact(s) or segment(s) provide(s) the maximal stimulation of (i) and avoids (ii). The DBS electrode may comprise a plurality of contacts or segments, and said method further comprises determining a field shape for said contact(s) or segment(s) that provide(s) maximal stimulation of (i) and that avoids (ii). The DBS electrode may comprise a plurality of contacts or segments and said method further comprises determining which contact(s) or segment(s) provide(s) the maximal stimulation of (i) and avoids (ii). The DBS electrode may comprise a plurality of contacts or segments, and said method further comprises determining a field shape for said contact(s) or segment(s) that provide(s) maximal stimulation of (i) and that avoids (ii).

[0046] Also provided is a Parkinson’ s Disease (PD) therapeutic agent for use in treating mid-to late-stage PD in a subject, wherein the subject separately, simultaneously or sequentially receives subthalamic nucleus (STN) deep brain stimulation (DBS) by a method as defined herein. The PD therapeutic agent may be administered prior to STN-DBS, at the same time as STN-DBS, or after STN-DBS. The PD therapeutic agent may be 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, and an anticholinergics cholinesterase inhibitor, or combinations thereof.

[0047] In another embodiment, there is provided a computer implemented method for identifying deep brain stimulation (DBS) electrode placement locations for DBS treatment of a patient having mid- to late-stage Parkinson’s Disease (PD) comprising the steps of:

[0048] (a) receiving brain image data for the patient;

[0049] (b) processing the brain image data to identify fiber tracts (i) from the supplementary motor area and / or primary motor area to the subthalamic nucleus (STN) of the patient, and (ii) from the pre-supplementary motor area to the STN of the patient; and

[0050] (c) generating an electrode placement map for the treatment of the patient using DBS, such that the implanted electrodes will target (b)(i) and avoid targeting (b)(ii).

[0051] 7

[0052] 4932-4302-8600, v. 1 Further, there is provided a computer implemented method for identifying deep brain stimulation (DBS) electrode placement programming for DBS treatment of a patient having mid- to late-stage Parkinson’s Disease (PD) comprising the steps of:

[0053] (a) receiving brain image data for the patient;

[0054] (b) processing the brain image data to identify fiber tracts (i) from the supplementary motor area and / or primary motor area to the subthalamic nucleus (STN) of the patient, and (ii) from the pre-supplementary motor area to the STN of the patient; and

[0055] (c) generating an electrode programming map for the treatment of the patient using DBS, such that the implanted electrodes will target (b)(i) and avoid targeting (b)(ii).

[0056] The computer-implemented methods may further comprise identifying the patient-specific location of the tracts defined in (a)(i) and (a)(ii) from a normative connectome by using inverse normalization to warp the tracts from the template space into the patient’s brain space. The computer-implemented methods may further comprise utilizing patient-specific tractography data collected from diffusion-weighted brain imaging of the patient’s brain to identify (a)(i) and (a)(ii) using the following regions of interest (ROI): from the supplementary motor area projecting to the STN; from the primary motor area projecting to the STN; and from the pre-SMA projecting to the STN. The computer-implemented methods may further comprise the steps of receiving postoperative brain image data for the patient; and processing the postoperative brain image data to determine whether said DBS electrode has achieved the intended preoperative targeting of (b)(i) and non-targeting of (b)(ii).

[0057] As used herein the specification, “a” or “an” may mean one or more. As used herein in the claim(s), when used in conjunction with the word “comprising”, the words “a” or “an” may mean one or more than one.

[0058] The use of the term “or” in the claims is used to mean “and / or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and / or.” As used herein “another” may mean at least a second or more.

[0059] Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, for the method being employed to determine the value, or that exists among the study subjects. Such an inherent variation may be a variation of ± 10% of the stated value.

[0060] 8

[0061] 4932-4302-8600, v. 1 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 the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration 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.

[0062] 9

[0063] 4932-4302-8600, v. 1 BRIEF DESCRIPTION OF THE DRAWINGS

[0064] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure. The disclosure may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0065] FIGS. 1A-G. Active Contacts vs Motor Progression in the DBS in Early- Stage PD Pilot Clinical Trial Cohort. (FIGS. 1 A-D) Mirrored active contacts for the early DBS cohort are shown when dividing the cohort into two groups (yellow spheres = top responders; blue spheres = remaining subjects) at several motor progression thresholds (reported below each respective panel). (FIGS. 1E-G) Clinical features of DBS subjects without motor progression whose active contacts are shown in panel B (yellow lines) vs the other DBS subjects (blue lines) and subjects randomized to the optimal drug therapy (ODT) control group (gray lines). Early DBS subjects without motor progression (FIG. 1 A, yellow lines) required fewer PD medications (FIG. B) and lower stimulation amplitudes (FIG. 1C) Mean ± SEM.

[0066] FIGS.2A-D. Validation of the Early PD Motor Progression Sweet Spot and Connectivity Model in Patients with Mid- and Advanced-Stage Parkinson’s Disease. The motor progression sweet spot (FIGS. 2A-B) and connectivity model (FIGS. 2C-D) identified in 14eaiiy-stage PDpatientsl were each used to estimate longterm motor outcomes in an independent cohort of 29 standard of care PD patients. (FIG. 2A) The degree of overlap with the motor progression sweet spot identified from the early DBS cohort (i.e., “Sweetspot Score”) significantly correlated with long-term UPDRS-III improvements (DBS duration at follow-up = 5.4 ± 2.0 years; Spearman’s R=0.37, P=0.046). (FIG. 2B) The motor progression sweet spot froml. STN is outlined in purple. Red nucleus is outlined in red. Bejanni line = white dashed line15. (FIG. 2C) The degree of stimulating positive tracts and not stimulating negative tracts identified from the early DBS cohort (i.e., the “Weighted Mean of Fiber R-Scores” of the Motor Progression Connectivity Model) significantly correlated with long-term UPDRS-III improvements (Spearman’s R=0.60, P<0.001). Two illustrative example patients are marked with colored circles in FIG. 2C and their stimulation volumes are shown in FIG. 2D (top responder example = green; poor responder example = red). (FIG. 2D) The motor progression connectivity model 1 consists of positive (orange) tracts

[0067] 10

[0068] 4932-4302-8600, v. 1 originating from Ml and SMA and negative (cyan) tracts originating from pre-SMA and cerebellum.

[0069] FIG. 3. Comparison of MDS-UPDRS scale with the original UPDRS scale.

[0070] Table 1 from Goetz et al., 2008.

[0071] 11

[0072] 4932-4302-8600, v. 1 DETAILED DESCRIPTION

[0073] As discussed above, subthalamic nucleus deep brain stimulation (STN-DBS) is an effective adjunctive therapy for mid- and advanced-stage Parkinson’s disease (PD); however, individual motor improvement is variable, with electrode localization being a key determinant of efficacy. The inventors recently reported that stimulation of a specific site in the dorsolateral subthalamic nucleus (STN) was recently associated with slower motor progression in Parkinson’s Disease (PD), based on the deep brain stimulation (DBS) in early-stage PD pilot trial.

[0074] It is important recognize that the PD literature states clearly that DBS does not slow motor progression in advanced stage PD. Hiker (2005) noted that “The rates of progression in patients with STN DBS were within the range of previously reported data from longitudinal imaging studies in PD. Therefore, this study could not confirm the neuroprotective properties of DBS in the STN target.” Similarly, Mahlknecht et al. (2020) stated that “There was no evidence for DBS effects on underlying disease progression.” Visser-Vandewalle et al. (2005) commented that “It has been hypothesised through animal studies that ‘silencing’ the STN by HFS could lead to slowing of or even halting the disease progression .... To date, however, no clear clinical evidence has become available to support this hypothesis.”

[0075] Regarding long-term changes in UPDRS-III after DBS, DBS applied in standard of care PD patients who are measured on therapy (ON medication as well as ON DBS) does not improve motor scores long-term. See Krack et al. (2003; see Table 3) and Castrioto et al. (2011; see Table 3), which show that scores worsen following the 1 year “honeymoon period” post-surgery. Also, it is important to compare patients that are fully treated, i.e., on medication and on DBS. Comparing patients taken off of medication before surgery with off medications but on DBS after surgery would be expected to show improvement.

[0076] Here, the inventors analyzed contacts of their same early DBS cohort (N=14). Sweet spot and connectivity models derived from this cohort were then used to estimate long-term motor outcomes in an independent DBS cohort of advanced-stage PD patients (N=29). In early-stage PD, proximity of stimulation to the dorsolateral STN is associated with slower motor progression; however, in advanced-stage (mid to late) PD, stimulation proximity to the same site was associated with better long-term motor outcomes (R=0.60, P<0.001). These results suggest stimulation of a specific site in the dorsolateral STN, specifically areas receiving input from Ml and SMA but specifically not pre-SMA, results in both slower motor progression and long-term motor improvements in PD.

[0077] 12

[0078] 4932-4302-8600, v. 1 These and other aspects of the disclosure are set forth below.

[0079] I. Parkinson’s Disease

[0080] Parkinson's disease (PD) is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms generally come on slowly over time. Early in the disease, the most obvious are shaking, rigidity, slowness of movement, and difficulty with walking. Thinking and behavioral problems may also occur. Dementia becomes common in the advanced stages of the disease. Depression and anxiety are also common occurring in more than a third of people with PD. Other symptoms include sensory, sleep, and emotional problems. The main motor symptoms are collectively called "parkinsonism", or a "parkinsonian syndrome. "

[0081] The cause of Parkinson's disease is generally unknown but believed to involve both genetic and environmental factors. Those with a family member affected are more likely to get the disease themselves. There is also an increased risk in people exposed to certain pesticides and among those who have had prior head injuries while there is a reduced risk in tobacco smokers and those who drink coffee or tea. The motor symptoms of the disease result from the death of cells in the substantia nigra, a region of the midbrain. This results in not enough dopamine in these areas. The reason for this cell death is poorly understood but involves the build-up of proteins into Lewy bodies in the neurons. Diagnosis of typical cases is mainly based on symptoms, with tests such as neuroimaging being used to rule out other diseases.

[0082] There is currently no cure for Parkinson's disease. Initial treatment is typically with the anti-parkinsonian medication L-DOPA (levodopa), with dopamine agonists being used once levodopa becomes less effective. As the disease progresses and neurons continue to be lost, these medications become less effective while at the same time they produce a complication marked by involuntary writhing movements (i.e., dyskinesia). Diet and some forms of rehabilitation have shown some effectiveness at improving symptoms. Surgery to place microelectrodes for deep brain stimulation has been used to reduce motor symptoms in severe cases where drugs are ineffective. Evidence for treatments for the non-movement-related symptoms of PD, such as sleep disturbances and emotional problems, is less strong.

[0083] In 2013, PD was present in 53 million people and resulted in about 103,000 deaths globally. Parkinson's disease typically occurs in people over the age of 60, of which about one percent are affected. Males are more often affected than females. When it is seen in people before the age of 40 or 50, it is called young onset PD. The average life expectancy following diagnosis is between 7 and 14 years.

[0084] 13

[0085] 4932-4302-8600, v. 1 The term parkinsonism is used for a motor syndrome whose main symptoms are tremor at rest, stiffness, slowing of movement and postural instability. Parkinsonian syndromes can be divided into four subtypes, according to their origin (1) primary or idiopathic, (2) secondary or acquired, (3) hereditary parkinsonism, and (4) Parkinson plus syndromes or multiple system degeneration.

[0086] Parkinson's disease is the most common form of parkinsonism and is usually defined as "primary" parkinsonism, meaning parkinsonism with no external identifiable cause. In recent years several genes that are directly related to some cases of Parkinson's disease have been discovered. As much as this conflicts with the definition of Parkinson's disease as an idiopathic illness, genetic parkinsonism disorders with a similar clinical course to PD are generally included under the Parkinson's disease label. The terms "familial Parkinson's disease" and "sporadic Parkinson's disease" can be used to differentiate genetic from truly idiopathic forms of the disease.

[0087] Usually classified as a movement disorder, PD also gives rise to several non-motor types of symptoms such as sensory deficits, cognitive difficulties, and sleep problems. Parkinson plus diseases are primary parkinsonisms which present additional features. They include multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and dementia with Lewy bodies.

[0088] In terms of pathophysiology, PD is considered a synucleinopathy due to an abnormal accumulation of alpha-synuclein protein in the brain in the form of Lewy bodies, as opposed to other diseases such as Alzheimer's disease where the brain accumulates tau protein in the form of neurofibrillary tangles. Nevertheless, there is clinical and pathological overlap between tauopathies and synucleinopathies. The most typical symptom of Alzheimer's disease, dementia, occurs in advanced stages of PD, while it is common to find neurofibrillary tangles in brains affected by PD. Dementia with Lewy bodies (DLB) is another synucleinopathy that has similarities with PD, and especially with the subset of PD cases with dementia. However, the relationship between PD and DLB is complex and still has to be clarified. They may represent parts of a continuum, or they may be separate diseases.

[0089] A. Signs and Symptoms

[0090] Parkinson's disease affects movement, producing motor symptoms. Non-motor symptoms, which include autonomic dysfunction, neuropsychiatric problems (mood, cognition, behavior or thought alterations), and sensory and sleep difficulties, are also

[0091] 14

[0092] 4932-4302-8600, v. 1 common. Some of these non-motor symptoms are often present at the time of diagnosis and can precede motor symptoms.

[0093] Four motor symptoms are considered cardinal in PD: tremor, rigidity, slowness of movement, and postural instability. Tremor is the most apparent and well-known symptom. It is the most common; though around 30% of individuals with PD do not have tremor at disease onset, most develop it as the disease progresses. It is usually a rest tremor - maximal when the limb is at rest and disappearing with voluntary movement and sleep. It affects to a greater extent the most distal part of the limb and at onset typically appears in only a single arm or leg, becoming bilateral later. Frequency of PD tremor is between 4 and 6 hertz (cycles per second). A feature of tremor is pill-rolling, the tendency of the index finger of the hand to get into contact with the thumb and perform together a circular movement. The term derives from the similarity between the movement of people with PD and the earlier pharmaceutical technique of manually making pills.

[0094] Bradykinesia is another characteristic feature of PD and is a slowness in the execution of movement. Performance of sequential and simultaneous movement is hindered. Initial manifestations are problems when performing daily tasks which require fine motor control such as writing, sewing or getting dressed. Clinical evaluation is based on similar tasks such as alternating movements between both hands or between both feet. Bradykinesia is not equal for all movements or times. It is modified by the activity or emotional state of the subject, to the point that some people are barely able to walk yet can still ride a bicycle. Generally, people with PD have less difficulty when some sort of external cue is provided.

[0095] Rigidity is stiffness and resistance to limb movement caused by increased muscle tone, an excessive and continuous contraction of muscles. In parkinsonism, the rigidity can be uniform (lead-pipe rigidity) or ratchety (cogwheel rigidity). The combination of tremor and increased tone is considered to be at the origin of cogwheel rigidity. Rigidity may be associated with joint pain; such pain being a frequent initial manifestation of the disease. In early stages of Parkinson's disease, rigidity is often asymmetrical and it tends to affect the neck and shoulder muscles prior to the muscles of the face and extremities. With the progression of the disease, rigidity typically affects the whole body and reduces the ability to move.

[0096] Postural instability is typical in the late stages of the disease, leading to impaired balance and frequent falls, and secondarily to bone fractures. Instability is often absent in the initial stages, especially in younger people. Up to 40% may experience falls and around 10% may have falls weekly, with the number of falls being related to the severity of PD.

[0097] 15

[0098] 4932-4302-8600, v. 1 Other recognized motor signs and symptoms include gait and posture disturbances such as festination (rapid shuffling steps and a forward-flexed posture when walking), speech and swallowing disturbances including voice disorders, “mask-like” face expression or small handwriting, although the range of possible motor problems that can appear is large.

[0099] Parkinson's disease can cause neuropsychiatric disturbances, which can range from mild to severe. This includes disorders of speech, cognition, mood, behavior, and thought. Cognitive disturbances can occur in the early stages of the disease and sometimes prior to diagnosis and increase in prevalence with duration of the disease. The most common cognitive deficit 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. Fluctuations in attention, impaired perception and estimation of time, slowed cognitive processing speed are among other cognitive difficulties. Memory is affected, specifically in recalling learned information. Nevertheless, improvement appears when recall is aided by cues. Visuospatial difficulties are also part of the disease, seen for example when the individual is asked to perform tests of facial recognition and perception of the orientation of drawn lines.

[0100] A person with PD has an increased risk of dementia compared to the general population. The prevalence of dementia increases with duration of the disease. Dementia is associated with a reduced quality of life in people with PD and their caregivers, increased mortality, and a higher probability of needing home care by a nurse.

[0101] Behavior and mood alterations 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 difficulties are depression, apathy and anxiety. Establishing the diagnosis of depression is complicated by symptoms that often occur in Parkinson's including dementia, decreased facial expression, decreased movement, a state of indifference, and quiet speech. Impulse control behaviors such as medication overuse and craving, binge eating, hypersexuality, or problem gambling can appear in PD and have been related to the medications used to manage the disease. Psychotic symptoms - hallucinations or delusions - occur in 4% of people with PD, and it is assumed that the main precipitant of psychotic phenomena in Parkinson's disease is dopaminergic excess secondary to treatment; it therefore becomes more common with increasing age and levodopa intake.

[0102] In addition to cognitive and motor symptoms, PD can impair other body functions. Sleep problems are a feature of the disease and can be worsened by medications. Symptoms 16

[0103] 4932-4302-8600, v. 1 can manifest as daytime drowsiness, disturbances in REM sleep, or insomnia. A systematic review shows that sleep attacks occur in 13.0% of patients with Parkinson's disease on dopaminergic medications.

[0104] Alterations in the autonomic nervous system can lead to orthostatic hypotension (low blood pressure upon standing), oily skin and excessive sweating, urinary incontinence and altered sexual function. Constipation and gastric dysmotility can be severe enough to cause discomfort and even endanger health. PD is related to several eye and vision abnormalities such as decreased blink rate, dry eyes, deficient ocular pursuit (eye tracking) and saccadic movements (fast automatic movements of both eyes in the same direction), difficulties in directing gaze upward, and blurred or double vision. Changes in perception may include an impaired sense of smell, sensation of pain and paresthesia (skin tingling and numbness). All of these symptoms can occur years before diagnosis of the disease.

[0105] B. Causes

[0106] Parkinson's disease in most people is idiopathic (having no specific known cause). However, a small proportion of cases can be attributed to known genetic factors. Other factors have been associated with the risk of developing PD, but no causal relationships have been proven.

[0107] A number of environmental factors have been associated with an increased risk of Parkinson's, including pesticide exposure, head injuries, and living in the country or farming. Rural environments and the drinking of well water may be risks, as they are indirect measures of exposure to pesticides. Implicated agents include insecticides, primarily chlorpyrifos and org anochlorines and pesticides, such as rotenone or paraquat, and herbicides, such as Agent Orange and ziram. Exposure to heavy metals has been proposed to be a risk factor, through possible accumulation in the substantia nigra, but studies on the issue have been inconclusive.

[0108] PD traditionally has been considered a non-genetic disorder; however, around 15% of individuals with PD have a first-degree relative who has the disease. At least 5% of people are now known to have forms of the disease that occur because of a mutation of one of several specific genes.

[0109] Mutations in specific genes have been conclusively shown to cause PD. These genes code for alpha-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 will develop PD. With the exception of LRRK2, however, they account for only a small minority of cases of PD. The most extensively studied PD-related

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[0111] 4932-4302-8600, v. 1 genes are SNCA and LRRK2. Mutations in genes including SNCA, LRRK2 and glucocerebrosidase (GBA) have been found to be risk factors for sporadic PD. Mutations in GBA are known to cause Gaucher's disease. Genome-wide association studies, which search for mutated alleles with low penetrance in sporadic cases, have now yielded many positive results.

[0112] The role of the SNCA gene is important in PD, because the alpha-synuclein protein is the main component of Lewy bodies. Missense mutations of the gene (in which a single nucleotide is changed), and duplications and triplications of the locus containing it have been found in different groups with familial PD. Missense mutations are rare. On the other hand, multiplications of the SNCA locus account for around 2% of familial cases. Multiplications have been found in asymptomatic carriers, which indicate that penetrance is incomplete or age dependent.

[0113] The LRRK2 gene (PARK8) encodes a protein called dardarin. The name dardarin was taken from a Basque word for tremor, because this gene was first identified in families from England and the north of Spain. Mutations in LRRK2 are the most commonly 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. There are many mutations described in LRRK2, however unequivocal proof of causation only exists for a few.

[0114] Several Parkinson-related genes are involved in the function of lysosomes, organelles that digest cellular waste products. It has been suggested that some forms of Parkinson may be caused by lysosome dysfunctions that reduce the ability of cells to break down alpha-synuclein.

[0115] C. Diagnosis

[0116] A physician will diagnose Parkinson's disease from the medical history and a neurological examination. There is no medical test that will clearly identify the disease, but brain scans are sometimes used to rule out disorders that could give rise to similar symptoms. People may be given levodopa and resulting relief of motor impairment tends to confirm the diagnosis. The finding of Lewy bodies in the midbrain on autopsy is usually considered proof that the person had Parkinson’s disease. The progress of the illness over time may reveal it is not Parkinson's disease, and some authorities recommend that the diagnosis should be periodically reviewed.

[0117] Other causes that can secondarily produce a parkinsonian syndrome are Alzheimer's disease, multiple cerebral infarction and drug-induced parkinsonism. Parkinson-plus syndromes such as progressive supranuclear palsy and multiple system atrophy must be ruled

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[0119] 4932-4302-8600, v. 1 out. Anti-Parkinson's medications are typically less effective at controlling symptoms in Parkinson-plus syndromes. Faster progression rates, early cognitive dysfunction or postural instability, minimal tremor or symmetry at onset may indicate a Parkinson-plus disease rather than PD itself. Genetic forms are usually classified as PD, although the terms “familial Parkinson's disease” and “familial parkinsonism” are used for disease entities with an autosomal dominant or recessive pattern of inheritance.

[0120] Medical organizations have created diagnostic criteria to ease and standardize the diagnostic process, especially in the early stages of the disease. The most widely known criteria come from the UK Parkinson's Disease Society Brain Bank and the U.S. National Institute of Neurological Disorders and Stroke. The PD Society Brain Bank criteria require slowness of movement (bradykinesia) plus either rigidity, resting tremor, or postural instability. Other possible causes of these symptoms need to be ruled out. Finally, three or more of the following features are required during onset or evolution: unilateral onset, tremor at rest, progression in time, asymmetry of motor symptoms, response to levodopa for at least five years, clinical course of at least ten years and appearance of dyskinesias induced by the intake of excessive levodopa. Accuracy of diagnostic criteria evaluated at autopsy is 75-90%, with specialists such as neurologists having the highest rates.

[0121] Computed tomography (CT) and conventional magnetic resonance imaging (MRI) brain scans of people with PD usually appear normal. These techniques are nevertheless useful to rule out other diseases that can be secondary causes of parkinsonism, such as basal ganglia tumors, vascular pathology and hydrocephalus. A specific technique of MRI, susceptibility weighted imaging has been found to differentiate between patients and subjects without the disease and another technique, diffusion MRI, has been reported to be useful at discriminating between typical and atypical parkinsonism, although its exact diagnostic value is still under investigation. Dopaminergic function in the basal ganglia can be measured with different PET and SPECT radioactive tracers. Examples are ioflupane (123I) (trade name DaTSCAN) and iometopane (Dopascar) for SPECT or fluorodeoxyglucose (18F) and DTBZ for PET. A pattern of reduced dopaminergic activity in the basal ganglia can aid in diagnosing PD.

[0122] D. Prevention, Management, Rehabilitation and Palliative Care Exercise in middle age reduces the risk of Parkinson's disease later in life. Caffeine also appears protective with a greater decrease in risk occurring with a larger intake of caffeinated beverages such as coffee. Although tobacco smoke causes adverse health effects, decreases life expectancy and quality of life, it may reduce the risk of PD by a third when compared to

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[0124] 4932-4302-8600, v. 1 non-smokers. The basis for this effect is not known, but possibilities include an effect of nicotine as a dopamine stimulant. Tobacco smoke contains compounds that act as MAO inhibitors that also might contribute to this effect.

[0125] Antioxidants, such as vitamins C and D, have been proposed to protect against the disease, but results of studies have been contradictory and no positive effect has been proven. The results regarding fat and fatty acids have been contradictory, with various studies reporting protective effects, risk-increasing effects or no effects. Also, there have been preliminary indications of a possible protective role of estrogens and anti-inflammatory drugs.

[0126] There is no cure for Parkinson's disease, but medications, surgery, and multidisciplinary management can provide relief from the symptoms. The main families of drugs useful for treating motor symptoms are levodopa (usually combined with a dopa decarboxylase inhibitor or COMT inhibitor that does not cross the blood-brain barrier), dopamine agonists and MAO-B inhibitors. The stage of the disease determines which group is most useful. Two stages are usually distinguished: an initial stage in which the individual with PD has already developed some disability for which he needs pharmacological treatment, then a second stage in which an individual develops motor complications related to levodopa usage. Treatment in the initial stage aims for an optimal tradeoff between good symptom control and side -effects resulting from improvement of dopaminergic function. The start of levodopa treatment may be delayed by using other medications such as MAO-B inhibitors and dopamine agonists, in the hope of delaying the onset of dyskinesias. In the second stage the aim is to reduce symptoms while controlling fluctuations of the response to medication. Sudden withdrawals from medication or overuse have to be managed. When medications are insufficient to control symptoms, surgery and deep brain stimulation can be of use. In the final stages of the disease, palliative care is provided to improve quality of life.

[0127] Levodopa has been the most widely used treatment for over 30 years. L-DOPA is converted into dopamine in the dopaminergic neurons by dopa decarboxylase. Since motor symptoms are produced by a lack of dopamine in the substantia nigra, the administration of L-DOPA temporarily diminishes the motor symptoms.

[0128] Only 5-10% of L-DOPA crosses the blood-brain barrier. The remainder is often metabolized to dopamine elsewhere, causing a variety of side effects including nausea, dyskinesias and joint stiffness. Carbidopa and benserazide are peripheral dopa decarboxylase inhibitors, which help to prevent the metabolism of L-DOPA before it reaches the dopaminergic neurons, therefore reducing side effects and increasing bioavailability. They are generally given as combination preparations with levodopa. Existing preparations are 20

[0129] 4932-4302-8600, v. 1 carbidopa / levodopa (co-careldopa) and benserazide / levodopa (co-beneldopa). Levodopa has been related to dopamine dysregulation syndrome, a compulsive overuse of the medication, as well as punding, a behavioral condition characterized by intense, repetitive, and non-goal-oriented activities, such as endlessly handling, examining, sorting, or taking apart common or technical objects. There are slow-release versions of levodopa in the form intravenous and intestinal infusions that spread out the effect of the medication. These slow-release levodopa preparations have not shown an increased control of motor symptoms or motor complications when compared to immediate release preparations.

[0130] Tolcapone inhibits the COMT enzyme, which degrades dopamine, thereby prolonging the effects of levodopa. It has been used to complement levodopa; however, its usefulness is limited by possible side effects such as liver damage. A similarly effective drug, entacapone, has not been shown to cause significant alterations of liver function. Licensed preparations of entacapone contain entacapone alone or in combination with carbidopa and levodopa.

[0131] Levodopa preparations lead in the long term to the development of motor complications characterized by involuntary movements called dyskinesias and fluctuations in the response to medication. When this occurs a person with PD can change from phases with good response to medication and few symptoms ("on" state), to phases with no response to medication and significant motor symptoms ("off" state). For this reason, levodopa doses are kept as low as possible while maintaining functionality. Delaying the initiation of therapy with levodopa by using alternatives (dopamine agonists and MAO-B inhibitors) is common practice. A former strategy to reduce motor complications was to withdraw L-DOPA medication for some time. This is discouraged now since it can bring dangerous side effects such as neuroleptic malignant syndrome. Most people with PD will eventually need levodopa and later develop motor side effects.

[0132] Several dopamine agonists that bind to dopaminergic post-synaptic receptors in the brain have similar effects to levodopa. These were initially used for individuals experiencing on-off fluctuations and dyskinesias as a complementary therapy to levodopa; they are now mainly used on their own as an initial therapy for motor symptoms with the aim of delaying motor complications. When used in late PD they are useful at reducing the off periods. Dopamine agonists include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine and lisuride.

[0133] Dopamine agonists produce significant, although usually mild, side effects including drowsiness, hallucinations, insomnia, nausea, and constipation. Sometimes side effects appear even at a minimal clinically effective dose, leading the physician to search for a different drug.

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[0135] 4932-4302-8600, v. 1 Compared with levodopa, dopamine agonists may delay motor complications of medication use, but are less effective at controlling symptoms. Nevertheless, they are usually effective enough to manage symptoms in the initial years. They tend to be more expensive than levodopa. Dyskinesias due to dopamine agonists are rare in younger people who have PD, but along with other side effects, become more common with age at onset. Thus, dopamine agonists are the preferred initial treatment for earlier onset, as opposed to levodopa in later onset. Agonists have been related to impulse control disorders (such as compulsive sexual activity and eating, and pathological gambling and shopping) even more strongly than levodopa.

[0136] Apomorphine, a non-orally administered dopamine agonist, may be used to reduce off periods and dyskinesia in late PD. It is administered by intermittent injections or continuous subcutaneous infusions. Since secondary effects such as confusion and hallucinations are common, individuals receiving apomorphine treatment should be closely monitored. Two dopamine agonists that are administered through skin patches (lisuride and rotigotine) and are useful for people in the initial stages and possibly to control off states in those in the advanced state.

[0137] MAO-B inhibitors (safinamide, selegiline and rasagiline) increase the level of dopamine in the basal ganglia by blocking its metabolism. They inhibit monoamine oxidase B (MAO-B) which breaks down dopamine secreted by the dopaminergic neurons. The reduction in MAO-B activity results in increased 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 disease but produce more adverse effects and are less effective than levodopa. There are few studies of their effectiveness in the advanced stage, although results suggest that they are useful to reduce fluctuations between on and off periods. An initial study indicated that selegiline in combination with levodopa increased the risk of death, but this was later disproven.

[0138] Other drugs such as amantadine and anticholinergics may be useful as treatment of motor symptoms. However, the evidence supporting them lacks quality, so they are not first choice treatments. In addition to motor symptoms, PD is accompanied by a diverse range of symptoms. A number of drugs have been used to treat some of these problems. Examples are the use of quetiapine for psychosis, cholinesterase inhibitors for dementia, and modafinil for daytime sleepiness. A 2010 meta-analysis found that nonsteroidal anti-inflammatory drugs (apart from aspirin), have been associated with at least a 15 percent (higher in long-term and regular users) reduction of incidence of the development of Parkinson's disease.

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[0140] 4932-4302-8600, v. 1 Treating motor symptoms with surgery was once a common practice, but since the discovery of levodopa, the number of operations declined. Studies in the past few decades have led to great improvements in surgical techniques, so that surgery is again being used in people with advanced PD for whom drug therapy is no longer sufficient. Surgery for PD can be divided in two main groups: lesional and deep brain stimulation (DBS). Target areas for DBS or lesions include the thalamus, the globus pallidus or the subthalamic nucleus. Deep brain stimulation is the most commonly used surgical treatment, developed in the 1980s by Alim Louis Benabid and others. It involves the implantation of a medical device called a neurostimulator, which sends electrical impulses to specific parts of the brain. DBS is recommended for people who have PD with motor fluctuations and tremor inadequately controlled by medication, or to those who are intolerant to medication, as long as they do not have severe neuropsychiatric problems. Other, less common, surgical therapies involve intentional formation of lesions to suppress overactivity of specific subcortical areas. For example, pallidotomy involves surgical destruction of the globus pallidus to control dyskinesia.

[0141] Exercise programs are recommended in people with Parkinson's disease. There is some evidence that speech or mobility problems can improve with rehabilitation, although studies are scarce and of low quality. Regular physical exercise with or without physical therapy can be beneficial to maintain and improve mobility, flexibility, strength, gait speed, and quality of life. When an exercise program is performed under the supervision of a physiotherapist, there are more improvements in motor symptoms, mental and emotional functions, daily living activities, and quality of life compared to a self-supervised exercise program at home. In terms of improving flexibility and range of motion for people experiencing rigidity, generalized relaxation techniques such as gentle rocking have been found to decrease excessive muscle tension. Other effective techniques to promote relaxation include slow rotational movements of the extremities and trunk, rhythmic initiation, diaphragmatic breathing, and meditation techniques. As for gait and addressing the challenges associated with the disease such as hypokinesia (slowness of movement), shuffling and decreased arm swing; physiotherapists have a variety of strategies to improve functional mobility and safety. Areas of interest with respect to gait during rehabilitation programs focus on, but are not limited to improving gait speed, the base of support, stride length, trunk and arm swing movement. Strategies include utilizing assistive equipment (pole walking and treadmill walking), verbal cueing (manual, visual and auditory), exercises (marching and PNF patterns) and altering environments (surfaces, inputs, open vs. closed). Strengthening exercises have shown improvements in 23

[0142] 4932-4302-8600, v. 1 strength and motor function for people with primary muscular weakness and weakness related to inactivity with mild to moderate Parkinson's disease. However, reports show a significant interaction between strength and the time the medications was taken. Therefore, it is recommended that people with PD should perform exercises 45 minutes to one hour after medications when they are at their best. Also, due to the forward flexed posture, and respiratory dysfunctions in advanced Parkinson's disease, deep diaphragmatic breathing exercises are beneficial in improving chest wall mobility and vital capacity. Exercise may improve constipation.

[0143] One of the most widely practiced treatments for speech disorders associated with Parkinson's disease is the Lee Silverman voice treatment (LSVT). Speech therapy and specifically LSVT may improve speech. Occupational therapy (OT) aims to promote health and quality of life by helping people with the disease to participate in as many of their daily living activities as possible. There have been few studies on the effectiveness of OT and their quality is poor, although there is some indication that it may improve motor skills and quality of life for the duration of the therapy.

[0144] Palliative care is specialized medical care for people with serious illnesses, including Parkinson's. The goal is to improve quality of life for both the person suffering from Parkinson's and the family by providing relief from the symptoms, pain, and stress of illnesses. As Parkinson's is not a curable disease, all treatments are focused on slowing decline and improving quality of life and are therefore palliative in nature. Palliative care should be involved earlier, rather than later in the disease course. Palliative care specialists can help with physical symptoms, emotional factors such as loss of function and jobs, depression, fear, and existential concerns.

[0145] Along with offering emotional support to both the patient and family, palliative care serves an important role in addressing goals of care. People with Parkinson's may have many difficult decisions to make as the disease progresses such as wishes for feeding tube, non-invasive ventilator, and tracheostomy; wishes for or against cardiopulmonary resuscitation; and when to use hospice care. Palliative care team members can help answer questions and guide people with Parkinson's on these complex and emotional topics to help them make the best decision based on their own values.

[0146] Muscles and nerves that control the digestive process may be affected by PD, resulting in constipation and gastroparesis (food remaining in the stomach for a longer period than normal). A balanced diet, based on periodical nutritional assessments, is recommended and should be designed to avoid weight loss or gain and minimize consequences of gastrointestinal 24

[0147] 4932-4302-8600, v. 1 dysfunction. As the disease advances, swallowing difficulties (dysphagia) may appear. In such cases it may be helpful to use thickening agents for liquid intake and an upright posture when eating, both measures reducing the risk of choking. Gastrostomy to deliver food directly into the stomach is possible in severe cases.

[0148] Levodopa and proteins use the same transportation system in the intestine and the blood-brain barrier, thereby competing for access. When they are taken together, this results in a reduced effectiveness of the drug. Therefore, when levodopa is introduced, excessive protein consumption is discouraged and well-balanced Mediterranean diet is recommended. In advanced stages, additional intake of low-protein products such as bread or pasta is recommended for similar reasons. To minimize interaction with proteins, levodopa should be taken 30 minutes before meals. At the same time, regimens for PD restrict proteins during breakfast and lunch, allowing protein intake in the evening.

[0149] Repetitive transcranial magnetic stimulation temporarily improves levodopa-induced dyskinesias. Its usefulness in PD is an open research topic, although recent studies have shown no effect by 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 to substantiate that acupuncture and practice of Qigong, or T’ai chi, have any effect on the course of the disease or symptoms. Further research on the viability of Tai chi for balance or motor skills are necessary. Fava beans and velvet beans are natural sources of levodopa and are eaten by many people with PD. While they have shown some effectiveness in clinical trials, their intake is not free of risks. Life-threatening adverse reactions have been described, such as the neuroleptic malignant syndrome.

[0150] PD invariably progresses with time. A severity rating method known as the Unified Parkinson's disease rating scale (UPDRS) is the most commonly used metric for clinical study. A modified version known as the MDS-UPDRS is also sometimes used. An older scaling method known as the Hoehn and Yahr scale (originally 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.

[0151] Motor symptoms, if not treated, advance aggressively in the early stages of the disease, and more slowly later. Untreated, individuals are expected to lose independent ambulation after an average of eight years and be bedridden after ten years. However, it is uncommon to find untreated people nowadays. Medication has improved the prognosis of motor symptoms, while at the same time it is a new source of disability, because of the undesired effects of levodopa after years of use. In people taking levodopa, the progression time of symptoms to a stage of 25

[0152] 4932-4302-8600, v. 1 high dependency from caregivers may be over 15 years. However, it is hard to predict what course the disease will take for a given individual. Age is the best predictor of disease progression. The rate of motor decline is greater in those with less impairment at the time of diagnosis, while cognitive impairment is more frequent in those who are over 70 years of age at symptom onset.

[0153] Since current therapies improve motor symptoms, disability at present is mainly related to non-motor features of the disease. Nevertheless, the relationship between disease progression and disability is not linear. Disability is initially related to motor symptoms. As the disease advances, disability is more related to motor symptoms that do not respond adequately to medication, such as swallowing / speech difficulties, and gait / balance problems; and also to motor complications, which appear in up to 50% of individuals after 5 years of levodopa usage. Finally, after ten years most people with the disease have autonomic disturbances, sleep problems, mood alterations and cognitive decline. All of these symptoms, especially cognitive decline, greatly increase disability.

[0154] The life expectancy of people with PD is reduced. Mortality rates are around twice those of unaffected people. Cognitive decline and dementia, old age at onset, a more advanced disease state and presence of swallowing problems are all mortality risk factors. On the other hand, a disease pattern mainly characterized 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 resulted in about 103,000 deaths globally, up from 44,000 deaths in 1990. The death rate increased from an average of 1.5 to 1.8 per 100,000 during that time.

[0155] IL Improving Symptoms in Mid- to Late-Stage Parkinson’s Disease Patient A. PD Stages

[0156] The Parkinson’s Foundation provides staging based on the Hoehn and Yahr scale. On this scale, stages 1 and 2 represent early-stage, 2 and 3 mid-stage, and 4 and 5 advanced-stage PD. Stage One is the initial stage, where the person has mild symptoms that generally do not interfere with daily activities. Tremor and other movement symptoms occur on one side of the body only. Changes in posture, walking and facial expressions occur. Stage Two is when symptoms start getting worse. Tremor, rigidity and other movement symptoms affect both sides of the body or the midline (such as the neck and the trunk). Walking problems and poor posture may be apparent. The person is able to live alone, but daily tasks are more difficult and lengthier. Stage Three is considered mid-stage, loss of balance (such as unsteadiness as the 26

[0157] 4932-4302-8600, v. 1 person turns or when he / she is pushed from standing) is the hallmark. Falls are more common. Motor symptoms continue to worsen. Functionally the person is somewhat restricted in his / her daily activities now, but is still physically capable of leading an independent life. Disability is mild to moderate at this stage. At Stage Four, symptoms are fully developed and severely disabling. The person is still able to walk and stand without assistance, but may need to ambulate with a cane / walker for safety. The person needs significant help with activities of daily living and is unable to live alone. Stage Five is the most advanced and debilitating stage. Stiffness in the legs may make it impossible to stand or walk. The person is bedridden or confined to a wheelchair unless aided. Around-the-clock care is required for all activities.

[0158] The Unified Parkinson's Disease Rating Scale (UPDRS) measures the impact of Parkinson’s disease on motor function. Part III (i.e., UPDRS-III) specifically evaluates motor symptoms. UPDRS-III total score is comprised of 14 items, with some items measuring more than one body segment. Each question is scored on a scale from 0 to 4, where 0 is normal function and 4 is severe impairment). The total score ranges from 0-108 is the sum of the scores of each individual question. Higher scores denote more significant motor impairment. The following patient parameters are included in the assessment:

[0159] 1. Speech: This item assesses the clarity and volume of the patient’s speech. The score ranges from 0 (normal) to 4 (severe impairment), with intermediate scores reflecting increasing levels of slurring or volume reduction.

[0160] 2. Facial Expression: This item evaluates the expressiveness of the patient’s face.

[0161] Scores range from 0 (normal) to 4 (severe), where a higher score indicates more significant facial masking or reduction in expressiveness.

[0162] 3. Tremor at Rest: This item assesses tremor when the patient is at rest, in five regions: head, right upper extremity, left upper extremity, right lower extremity, and left lower extremity. Each region is scored from 0 (absent) to 4 (severe), giving a total possible score range of 0 to 20.

[0163] 4. Action or Postural Tremor: This item evaluates tremor during action or while maintaining a posture, specifically in both hands. Each hand is scored from 0 (absent) to 4 (severe), resulting in a total score range of 0 to 8.

[0164] 5. Rigidity: This item assesses resistance to passive movement in the neck and four limbs (right upper extremity, left upper extremity, right lower extremity, and left lower extremity). Each region is scored from 0 (absent) to 4 (severe), allowing a total score range of 0 to 20.

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[0166] 4932-4302-8600, v. 1 6. Finger Taps: This item evaluates the patient’s ability to perform rapid, repetitive finger tapping movements, assessed in both hands. Each hand is scored from 0 (normal) to 4 (severe impairment), giving a total score range of O to 8.

[0167] 7. Hand Movements: This item assesses rapid, alternating hand movements in both hands. Each hand is scored from 0 (normal) to 4 (severe impairment), with a total score range of 0 to 8.

[0168] 8. Hand Pronation-Supination: This item evaluates rapid, alternating pronation and supination movements of the hands. Each hand is scored from 0 (normal) to 4 (severe impairment), resulting in a total score range of 0 to 8.

[0169] 9. Leg Agility: This item assesses the ability to perform rapid, repetitive leg movements, evaluated in both legs. Each leg is scored from 0 (normal) to 4 (severe impairment), giving a total score range of 0 to 8.

[0170] 10. Arising from Chair: This item evaluates the patient's ability to rise from a seated position. The score ranges from 0 (normal) to 4 (severe impairment), reflecting increasing difficulty in performing this task.

[0171] 11. Posture: This item assesses the patient’s posture, with scores ranging from 0 (normal) to 4 (severe), indicating more significant issues with stooping or alignment.

[0172] 12. Gait: This item evaluates walking ability, including the smoothness of steps, arm swing, and turning. The score ranges from 0 (normal) to 4 (severe impairment), indicating increasing difficulty with walking.

[0173] 13. Postural Stability: This item assesses balance and the ability to recover from a perturbation. The score ranges from 0 (normal) to 4 (severe impairment), indicating increasing issues with balance.

[0174] 14. Body Bradykinesia and Hypokinesia: This item evaluates the general slowness of movement (bradykinesia) and decreased amplitude of movement (hypokinesia). The score ranges from 0 (normal) to 4 (severe impairment), with higher scores indicating more pronounced slowness and reduced movement amplitude.

[0175] 15. The Movement Disorders Society updated this scale to improve clarity of the definitions of each level of rating and to add other measures, such as additional questions to break down the evaluation of tremor (Goetz et al. , 2008; FIG. 3 herein). Since it was introduced, this revised scale has become the predominant validated 28

[0176] 4932-4302-8600, v. 1 clinical rating for PD motor symptoms. Accepted cut-offs between mild / moderate PD (MDS-UPDRS-III 32 / 33) and moderate / severe PD (MDS-UPDRS-III 58 / 59) are reported in Martinez-Martin et al., 2015.

[0177] B. Symptomatic Improvement

[0178] As discussed above, any sustained symptomatic improvement in mid- to late-stage PD would be unprecedented. Here, there is evidence indicating that, applying the methods described herein, improvements in one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen or all of the UPDRS-III symptomatic measures may be stabilized / improved. For example, this improvement or lack of worsening may be measured is patient’s post-surgical, long-term status (2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 years), such as in any motor symptoms as compared to pre-surgical status (measured by UPDRS-III, MDS-UPDRS-III, or kinematic measures (Kinesia One, Kinesia 360, PKG, Apple Watch, etc.). One can also quantify motor symptom severity using software that automates video-based analysis of MDS-UPDRS-III motor tasks, such as VisionMD (open-source), KELVIN, PARK, FastEval, etc. “Reduced Therapeutic Burden” is defined as patients requiring less stimulation (due to close proximity to the target site) as well as a reduction in medication required to achieve a given clinical endpoint.

[0179] III. Positioning of Electrodes in Subthalamic Nucleus Deep Brain Stimulation (STN- DBS)

[0180] A. Traditional Electrode Placement and Programming

[0181] Identification of the location for electrode placement is traditionally achieved as follows: 1) placement of bone fiducial markers, preoperative assessment to determine the patient’s brain imaging, and preoperative target planning and trajectory assignment; and 2) post-operative testing of contacts and field shape for maximal effect.

[0182] The first procedure involving outpatient imaging and placement of bone fiducial markers, identifying operative targets, entry points, and landmarks is performed by a neurosurgeon.

[0183] During the second procedure by which the STN nucleus is mapped, a frame is affixed to the patient and tungsten microelectrodes (1MQ @ 1 kHz) are placed in guide tubes and advanced with electrode drives. Microelectrode recording (MER) is performed using a recording system. The microelectrodes are advanced toward the STN along the predefined trajectory. Recordings are made at regular intervals, beginning above the target and ending

[0184] 29

[0185] 4932-4302-8600, v. 1 below the target or at the dorsal border of the substantia nigra pars reticularis (SNr). The recordings are interpreted based on accepted criteria by a neurophysiologist in the operating room and are used to define the borders of the STN and SNr. Determination of the optimal stimulation target was determined by consensus opinion of the neurosurgeon, neurologist, and neurophysiologist.

[0186] A general procedure for the identification of the STN nucleus is outlined in Starr (2002), which discloses “[t]he essential steps in DBS implantation are magnetic-resonance imaging (MRl)-guided stereotactic localization, confirmation of the motor territory of the target nucleus with microelectrode mapping, and intra-operative test stimulation to determine voltage thresholds for stimulation-induced adverse effects.” Details regarding methods for the identification of the STN nucleus as well as target selection is taught in Hutchinson et al. (1998), stating “[t]he STN can be identified by the presence of neurons with characteristic 25-to 45-Hz firing rates and irregular firing patterns, which may have movement- or tremor-related activity.”

[0187] Location selection is the topic of the review presented in Gross et al. (2006), as well as the rationale for employing physiological mapping in addition to standard imaging techniques in order to most accurately map the STN. The ideal locations for electrode placement are determined intraoperatively through microstimulation. Gross recites, “[m]icrostimulation at the site of site where tremor-related neurons were recorded can induce tremor arrest with a short latency ... [and t]his effect is limited to specific body segments in accordance with the somatotopic arrangement. The use of a wider pulse duration (>0.5 ms) usually spreads the antitremor effect to other body regions after a longer delay (1-2 s).”

[0188] B. Tractography-Based Electrode Placement and Programming

[0189] More recently, tractography-based surgical planning approaches are being used to leverage knowledge about associations between brain connectivity and clinical outcomes. Under this paradigm of “tractography-based” surgical planning; identification of the location for electrode placement is achieved as follows:

[0190] 1) placement of bone fiducial markers, preoperative assessment to determine the patient’s brain imaging, including incorporation of tractography data, and preoperative target planning and trajectory assignment; and

[0191] 2) post-operative assessment of the patient’s brain imaging to confirm lead placement and to identify contacts (conventional) or segments (directional) of the DBS electrode expected to provide good clinical outcome based on prior studies.

[0192] 30

[0193] 4932-4302-8600, v. 1 The aforementioned Traditional Electrode Placement approach seeks to identify a location that provides symptomatic (i.e., transient, reversible in the absence of the therapy) benefit. The inventors introduce here an entirely novel tractography-based electrode placement and programming approach that aims to modify the progression of Parkinson’s disease (i.e., slow, stop or reverse progression). Additional infomation needed for this novel approach includes:

[0194] 1) placement of bone fiducial markers, preoperative assessment to determine the patient’s brain imaging, including collecting tractography data, and preoperative target planning and trajectory assignment based on the tractography data, which includes identifying fiber tracts to (i) target

[0195] (i.e., maximally stimulate) from the supplementary motor area (SMA) and / or primary motor area (Ml) of the cortex to the STN and (ii) avoid from pre-SMA of the cortex to the STN; and

[0196] 2) post-operative assessment of the patient’s brain imaging to confirm lead placement and to identify contacts (traditional) or segments (directional) of the DBS electrode that (i) target (i.e., maximally stimulate) white matter fiber tracts from the supplementary motor area (SMA) and / or primary motor area (Ml) of the cortex to the STN and (ii) avoid stimulating tracts from pre-SMA of the cortex to the STN.

[0197] Step 1 , after bone fiducial markers are placed, preoperative assessment begins with performing a pre-operative MRI scan of the patient’s brain. The next step - determining the location of lead placement to achieve the intended delivery and avoidance of delivery of electrical stimulation - can be performed using two different approaches: “patient-specific tractography” and “atlas-based tractography”. The first approach includes an additional pre-operative scan to collect a diffusion- weighted MRI of the patient’s brain and using deterministic fiber tractography software to analyze the patient’s brain scan to locate the relevant white matter fiber tracts. The second approach is to register (i.e., warp or normalize) the patient’s preoperative MRI brain scan with a brain “atlas” that has the fiber tracts previously identified (i. e. , from a normative connectome in a prior study) visualized to predict the location of the relevant white matter fiber tracts. Once the target and avoidance white matter tracts are localized in a scan of the patient’s brain, the “tractography-based surgical planning” is completed by providing the neurosurgeon with the tractography output (i.e., imaging file) that is incorporated into standard target planning software such as Brainlab Elements (Brainlab AG, Munich, Germany) or StealthStation FrameLink (Medtronic, USA) to place the electrode in a position that will optimally stimulate positive fiber tracts and avoid negative fiber tracts.

[0198] 31

[0199] 4932-4302-8600, v. 1 The first embodiment may be referred to as “patient-specific tractography” where preoperative patient scans are analyzed by software to map the relevant white matter fiber tracts. Deterministic tractography (“fiber tracking”) is performed based on the diffusion-weighted (DWI) scans collected preoperatively. The patient’s DWI brain scans are co-registered to the patient’s structural (i.e., Tl, T2) brain scans. Regions of interest (ROIs) are identified on the structural brain scans and to establish the start and finish of the desired white matter tract. Numerous publications describe this established methodology, including Graat et al., 2022, Riva-Posse etal., 2017, and Noecker et al., 2018. For the methods specified in this application, white matter tracts from the following ROI pairs are needed for surgical planning: tracts to target (Ml to STN, SMA to STN), tracts to avoid (pre-SMA to STN).

[0200] The second embodiment may be referred to as “atlas-based tractography.” A variety of software packages allow the user to visualize the reference “atlas” brain and then perform the “warping” or normalization into a patient’s brain scan (and vice versa, known as an “inverse transformation” or “reverse normalization”), including ANTs Rigid / Affine (Ashbumer, 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 / BRA1NSFIT. Another example is the Lead-DBS toolbox reported by Ewert et al. (2019) which uses an “effective low variance + subcortical refinement” preset of the ANTS SyN algorithm that are highly optimized for nonlinearly registering subcortical elements with submillimeter precision. The Lead-DBS toolbox was originally developed at Charite - University of Medicine (CCM), Berlin, Germany (Hom & Kuhn, 2015). This “atlas-based tractography” methodology is described by Oxenford et al., 2022 using the Lead-DBS, Lead-Group, 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 invention specified in this application, specific white matter fiber tracts identified from a normative connectome (described below, Example 1), which are in ICBM 2009b NLIN asymmetric (“MNI”) space (Fonov et al., 2011) template space, are warped into the patient’s pre-operative MRI scan to allow for the visualization of these fiber tracts in “patient space” (i.e., native space) needed for surgical planning.

[0201] Postoperative assessment includes collecting an additional scan of the patient’s brain (e.g., CT or MRI) that permits visualization of the implanted DBS electrodes. To facilitate DBS programming based on the target and avoidance white matter fiber tracts (e.g., “tractography-based DBS programming”), the patient’s post-operative brain scans are coregistered to the patient’s pre-operative structural scans which contain the target and avoidance 32

[0202] 4932-4302-8600, v. 1 tracts, which can be identified through either method described above). Probabilistic software, such as the Lead-DBS or CranialVault / CranialCloud™ suites, is used to reconstruct the DBS electrode and subsequently visualize the white matter tract activation based on the contact or segments of the electrode that are active.

[0203] C. Stimulation Paradigms

[0204] Once the electrode placement and contact selection is complete, as described above, the device is then activated so that stimulation therapy is given to the patient. Conventional deep brain stimulation (eDBS) systems are “open-loop" such that high-frequency stimulation settings are typically unchanged between clinic visits with the programming physician. Recently, a new type of DBS stimulation has been introduced which adapts to signals received from the patient. This type of stimulation is currently investigational and also known as “closed-loop" or adaptive DBS (aDBS). Adaptive DBS turns stimulation on or off by responding to patient data, which can include physiological signals (z'.e., beta band signals detected from “sensing” DBS systems, such as Medtronic Percept) or movement-based signals (i.e., patient motion detected from a wearable device). Efficacy for conventional DBS is well-established (Deuschi et al., 2006; Schuepbach et al., 2013), while clinical trials evaluating efficacy for closed-loop / adaptive DBS are ongoing (NCT04547712).

[0205] IV. Combination Treatments

[0206] It also may prove advantageous to use combination therapies in the treatment of PD, where a therapy is added to the STN-DBS therapy. Such therapies may, in combination, provide better results than the individual component therapies, and in some cases, may provide more than additive effects. In other cases, they may reduce the amount of one or the other therapies required to achieve clinical benefit.

[0207] This process may involve administering both therapies at the same time. Alternatively, the STN-DBS therapy may precede or follow the other treatment by intervals ranging from minutes to weeks. In embodiments where the other therapy and STN-DBS are applied separately to the subject, one would generally ensure that a significant period of time did not expire between each delivery, such that the other therapy and STN-DBS would still be able to exert an advantageously combined effect on the subject. In such instances, it is contemplated that one may administer both modalities within about 12-24 h of each other and, more preferably, within about 6-12 h of each other. In some situations, it may be desirable to extend

[0208] 33

[0209] 4932-4302-8600, v. 1 the time period for treatment significantly, however, where one or several days (2, 3, 4, 5, 6 or 7) to several weeks (1, 2, 3, 4, 5, 6, 7 or 8) lapse between the respective administrations.

[0210] Various combinations may be employed; for example, the STN-DBS therapy is “A” and the second PD therapy is “B”:

[0211] A / B / A B / A / B B / B / A A / A / B A / B / B B / A / A A / B / B / B B / A / B / B B / B / B / A B / B / A / B A / A / B / B A / B / A / B A / B / B / A B / B / A / A B / A / B / A B / A / A / B A / A / A / B B / A / A / A A / B / A / A A / A / B / A Administration of the therapies to a patient will follow general protocols for the administration of that particular secondary therapy, taking into account the toxicity / side effects, if any, of the treatments. It is expected that the treatment cycles would be repeated as necessary.

[0212] As discussed above, while there is no cure for Parkinson's disease, medications, surgery, and multidisciplinary management can provide relief from the symptoms. These therapies include levodopa (usually combined with a DOPA decarboxylase inhibitor like carbidopa and benserazide or a COMT inhibitor, such as tolcapone or entacapone, that does not cross the blood-brain barrier), dopamine agonists (e.g., apomorphine, bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine and lisuride), MAO-B inhibitors (e.g., safinamide, selegiline and rasagiline), amantadine, anticholinergics cholinesterase inhibitors, and lesional surgery.

[0213] V. Examples

[0214] The following examples are included to demonstrate preferred embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.

[0215] Example 1 - Methods

[0216] Cohorts. This study revisits data from Vanderbilt “DBS in early-stage PD” pilot clinical trial (NCT00282152; IDEG050016; IRB#040797), which was a prospective, randomized, single-blind clinical trial evaluating bilateral STN in patients with early-stage PD 34

[0217] 4932-4302-8600, v. 1 (aged 50-75 years; PD medication duration 1-4 years; no history or evidence of dyskinesia or motor fluctuations)9. All 14 subjects with complete data for the prior electrode localization study1are included in this analysis, alongside clinical outcomes for subjects randomized to optimal drug therapy (ODT) in the pilot trial9. The present study also includes an independent cohort of 29 advanced-stage PD patients who received STN-DBS as standard care and participated in a long-term outcomes study at Vanderbilt University Medical Center (IRB#181198). The standard of care DBS subjects were recruited at least two years postsurgery. All subjects provided written informed consent for participation.

[0218] Clinical Outcomes. In the early-stage PD cohort, motor progression was defined as the change in the Unified Parkinson’s Disease Rating Scale Part III score (UPDRS-III) from pre-operative baseline to 24 months measured after a seven-day washout (baseline: OFF Medications; 24 months: OFF Medications and OFF Stimulation), which was blindly rated from video-recorded motor examinations at the conclusion of the trial (Charles et al., 2014). In the advanced-stage PD cohort, pre-operative (ON Medications) and longitudinal postoperative (ON Medications, ON Stimulation) UPDRS-III motor examinations were videorecorded and blindly rated. Long-term motor symptom changes were defined as the percent change from the pre-operative UPDRS-III to the longitudinal post-operative UPDRS-III. UPDRS-III scores for both cohorts do not include rigidity which cannot be evaluated via video. Levodopa equivalent daily doses (LEDD) were calculated for both cohorts as previously described (Tomlinson et al., 2010).

[0219] Electrode Localizations. Electrodes for both cohorts were localized with Lead-DBS (Hom et al., 2019; Neudorfer et al., 2022) using pre-operative Tl-weighted and T2-weighted magnetic resonance (MRI) scans and post-operative computed tomography (CT) scans. The same processing pipeline for localizations previously reported for the early DBS cohort (Hacker et al., 2023) was applied to the standard of care DBS cohort. Group visualizations were performed using Lead-Group (Treu et al., 2020).

[0220] Therapeutic Washout and Clinical Assessments. During the 2 -year trial, subjects were admitted to the Vanderbilt Clinical Research Center for a 7-day washout of all PD therapies at baseline, 6-, 12-, 18- and 24-months. At baseline, the UPDRS-III motor examination was videotaped in the ON and OFF therapy states: ON therapy (day 1; ON medication) and 7 days OFF therapy (day 8; OFF medication). At subsequent study visits, the UPDRS-III motor examination was again videotaped in the ON and OFF therapy states: ON therapy (day 1; ON medication and ON stimulation, if applicable) and 7 days OFF therapy (day 8; OFF medication and OFF stimulation, if applicable). After the trial completed,

[0221] 35

[0222] 4932-4302-8600, v. 1 videotapes were scored by an independent rater blinded to treatment assignment, ON versus OFF therapy status, and study visit sequence. Baseline UPDRS 7-day OFF scores were used to calculate PD phenotype (z.e., tremor-dominant (TD), postural instability / gait difficulty (PIGD)), following previously reported methods (M. Hacker et al., 2018; Stebbins et al., 2013).

[0223] Therapeutic Management. Subjects’ treating neurologists managed medication and stimulation parameters. All DBS+ODT subjects were treated using monopolar stimulation with case positive and a single optimal contact negative (Charles et al., 2014). Beginning four weeks postoperatively, the optimal contact was programmed at 130 Hertz (Hz) and 60 psec pulse width. Levodopa equivalent daily doses (LEDD) were calculated as previously described (Tomlinson et al., 2010).

[0224] E-field Modeling. Electric field vector magnitudes (the term E-fields will be used as shorthand for the purpose of this manuscript) were used to estimate the volume of tissue modulated around the electrodes. E-fields were calculated based on the 24-month DBS programming settings applied using an adaptation of the SimBio / FieldTrip pipeline (Vorwerk et al., 2013) as implemented in Lead-DBS (Horn et al., 2019). E-fields were nonlinearly flipped to the contralateral side since no asymmetric effects were assumed, resulting in 2 x 14 = 28 E-fields across the cohort.

[0225] DBS Sweet Spot Mapping. Sweet spots 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)) were assessed using Lead-Group (Treu et al., 2020). For each voxel covered by the group of E-fields across the cohort in MNI space, E-field vector magnitudes across subjects were Spearman rank-correlated with the two clinical outcome variables (motor progression and motor improvement). The area of interest was conservatively restricted to voxels that were covered by at least 20% of E-fields with a vector magnitude above 0.2 V / m (a typical value assumed for DBS to activate axons (Astrom et al., 2015)). For visualization, sweet spots were smoothed using a full-width-half-maximum kernel of 2 mm, while rank-correlation coefficients in color bars of FIGS. 3A-F and 5A-F were derived from unsmoothed files.

[0226] DBS Fiber Filtering. Fiber tract connectivity was assessed using a connectome modified from the DBS Tractography Atlas (Middlebrooks et al., 2020) to include additional connections from cortex to STN and from STN to substantia nigra pars compacta and pars reticulata (Supplemental Methods). For the finite set of 6,525,876 fiber tracts represented in the resulting Netstim Tractography Atlas and each subject’s E-field, a value of probabilistic 36

[0227] 4932-4302-8600, v. 1 impact on the tract was calculated as previously described (Horn et al., 2022). Tracts were considered connected if the mean E-field magnitude they traverse was >1000 V / m and if they were connected to >5% of E-fields.

[0228] Estimation of Stimulation Volumes and Validation of the Sweet Spot and Motor Progression Models. The motor progression sweet spot and connectivity models were defined using the early-stage PD cohort as previously published1. Using the early-stage PD sweet spot (defined by voxels covering by at least 3 Electric fields (i.e.. E-fields) with a vector magnitude >0.2V / mm1), E-field magnitudes for the standard of care, advanced-stage PD cohort were Spearman rank-correlated with their long-term motor improvement. For the connectivity model, for each subject’s E-field, field magnitude values along each streamline that was defined within a normative structural connectome were denoted. These values were then Spearman rank correlated with motor progression scores to assign each streamline with a positive or negative correlation value (‘Fiber R-scores’). Together, streamlines defined the connectivity model. Critically, the model was used exactly as priorly published with all model parameters unchanged1. This model was used to estimate long-term motor improvement of subjects in the advanced-stage PD cohort. For each E-field in this independent cohort, overlaps with the connectivity model were calculated and average weighted by the E-field magnitudes (‘Weighted Means of Fiber R-scores’).

[0229] Statistical Analysis. A motor progression responder analysis was conducted whereby each subject was categorized based on their post- washout change (A) in UPDRS-III 7-day OFF motor score from baseline to two years as improved (A<0), no change (A=0), or worsened (A>0). Fisher’s exact test was used to assess the difference between the ODT and DBS+ODT groups in the risk of motor score worsening (worsened vs. improved or no change). The difference between the two groups in the trend toward worsening was assessed using exact logistic regression of the ordered outcome scores (improved, no change, worsened); the logistic model included the treatment group as the outcome (1=ODT, 0=DBS+ODT) and the change in motor score from baseline to two years as an ordered score (improved=0, no change=l, worsened=2) as the only explanatory variable. The difference in trend towards worsening was assessed using the estimated odds ratio for the ordered score. Wilcoxon rank-sum tests were used to compare mean stimulation amplitude between top and typical DBS+ODT responders at each follow-up visit and LEDD change from baseline between top and typical DBS+ODT responders and between top DBS+ODT responders and ODT subjects. Analyses of clinical data were conducted in SAS 9.3 (SAS Institute Inc, Cary, NC) and STATA 17.0 (StataCorp LP, College Static, TX).

[0230] 37

[0231] 4932-4302-8600, v. 1 Strength of structural connectivity was Spearman rank-correlated with change in motor progression (baseline to 24 months) which yielded a connectivity map showing positive and negative tract associations with motor progression or with motor improvement (z.e., R-maps). In other words, Spearman’s rank correlation coefficients showing positive values for tract populations maximally associated with electrodes in top responding subjects and negative values for the ones modulated in poor responding subjects. Significance (at a P=0.05 level) was tested using out-of-sample data (leave-one-patient out, 5-fold and 10-fold cross-validations).

[0232] Data Availability. The de -identified data from the standard of care DBS cohort will be made available upon reasonable request. The de-identified data and related study documents from the ‘DBS in early-stage PD’ trial are not being publicly shared at this time as they are currently being used for the development of a proprietary, multicenter, phase III, pivotal clinical trial (IDE G050016).

[0233] Example 2 - Results

[0234] Early DBS Active Contacts Grouped by Motor Progression Thresholds. The early-stage PD cohort (13 / 14 male; mean disease duration 2.6 ± 1.9 years; 60.9 ± 6.9 years old) was randomized to surgery as part of the ‘DBS in early-stage PD’ pilot clinical trial9. Based on two-year motor progression scores, active contacts for the 14 early DBS patients were divided into two groups (top responding and remaining patients) and visualized. Since no objective rationale could define the threshold used for grouping, this was repeated at various thresholds. The active contact for the top responding subject localized to the dorsolateral STN (Fig. 1 A). This patient’s UPDRS-III score in the DBS OFF and medication OFF state did not deteriorate two years after surgery. In fact, it became 2 points better. When lowering the threshold to include all subjects with improved two-year UPDRS-III OFF scores (n=4) into the group of ‘top responders’, their stimulation sites showed proximity around the same coordinate within the dorsolateral STN (Fig. IB). Eowering the threshold further included subjects with increasingly more motor progression and showed increasing distance of active contacts to this stimulation site (Figs. 1C-1D). Figs. 1E-G shows motor progression, change in EEDD, and stimulation amplitude for the four top responding early DBS subjects featured in Fig. IB compared to the remaining early DBS subjects and the subjects randomized to ODT. Early DBS subjects with active contacts outside of the dorsolateral STN (i.e., ‘typical responders’) had motor progression similar to the ODT control group (Fig. IE). Early DBS subjects with active contacts close to the dorsolateral STN site required less medication on average at each 38

[0235] 4932-4302-8600, v. 1 follow-up visit as compared to baseline (Fig. IF) and their mean stimulation voltages were lower than the typical DBS responders (Fig. 1G).

[0236] External Validation of the Motor Progression Sweet Spot and Connectivity Model. An independent cohort of 29 advanced-stage PD patients who received DBS as standard care (25 / 29 male; aged 60.1 + 9.1 years at the time of surgery) was used to test the ability of the early -stage PD motor progression sweet spot and connectivity models (Hacker et al. , 2023) to predict long-term motor improvements. Mean disease duration at the time of DBS surgery for this cohort was 9.9 ± 5.0 years, and mean time from surgery to post-operative follow-up was 5.4 + 2.0 years (min: 2.2 years; max: 11.3 years). Long-term motor improvement was associated with optimal stimulation of the motor progression sweet spot in this independent cohort of advanced-stage PD patients (R=0.37, P=0.046; Figs. 2A-B). Optimal stimulation of the fiber tracts identified in the motor progression connectivity model also significantly associated with long-term motor improvement (P=0.60, P<0.001; Figs. 2C-D).

[0237] Motor symptom effects. To explore whether specific motor symptoms are influenced by activation of the motor progression connectivity model, the inventors evaluated Spearman correlations between subdomains of the UPDRS-III and the motor progression connectivity model. There was no correlation between the tremor subdomain (UPDRS-III item 20 rest tremor + UPDRS-III item 21 action tremor) and the motor progression connectivity model (p = 0.05, p=0.794).

[0238] In contrast, the speech / hypomimia subdomain (UPDRS-III item 18 speech + UPDRS-III item 19 facial expression) correlated with the motor progression connectivity model (p = 0.50, p=0.007). The limb bradykinesia subdomain (UPDRS-III items 23 finger tapping + item 24 hand movements + item 25 pronation-supination + item 26 leg agility) correlated with the motor progression connectivity model (p = 0.64, p<0.001). The global bradykinesia subdomain (UPDRS-III items 23 finger tapping + item 24 hand movements + item 25 pronation-supination + item 26 leg agility + item 31 body bradykinesia) correlated with the motor progression connectivity model (p = 0.64, p<0.001). The axial / postural instability and gait disorder (PIGD) subdomain (UPDRS-III items 27 arising from chair + item 28 posture + item 29 gait + item 30 postural stability) correlated with the motor progression connectivity model (p = 0.66, p<0.001.

[0239] These trends hold time for raw change scores (before surgery - after surgery; stats inline above) as well as percent change: (before surgery - after surgery) / (before surgery x 100%). The results are summarized in Table 4 below:

[0240] 39

[0241] 4932-4302-8600, v. 1

[0242] <

[0243] <

[0244]

[0245] Example 3 - Discussion

[0246] There are three main findings in this study. First, the inventors revisited the DBS in early-stage PD pilot clinical trial dataset to evaluate active contact locations at various thresholds to associate optimal stimulation location with the degree of motor progression on a single subject level. This confirmed that proximity to a specific site within the dorsolateral STN is associated with slower motor progression (Hacker et al., 2023). Second, motor progression in the patients from the early DBS trial that were stimulated outside of the dorsolateral STN was similar to motor progression in control subjects that received standard medical therapy in the trial. Finally, the motor progression sweet spot and connectivity models explained significant amounts of variance in long-term changes in motor symptoms in an independent group of advanced-stage PD patients (Hacker et al., 2024).

[0247] Numerous studies have shown that stimulating a specific site within the dorsolateral STN associates with optimal motor improvement in advanced-stage PD (Claire et al., 2013; Akram et al., 2017; Horn et al., 2019). The sites identified in these studies are remarkably similar to one another (Horn, 2019) and seem to correspond to the same site associated with slower motor progression in the inventors’ prior work (Hacker et al., 2023). Regarding brain connectivity, their previous study suggests that optimal site receives cortical input from Ml and SMA (Hacker et al., 2023). Critically, input from pre-SMA was instead negatively associated with slower motor progression. Here, the inventors demonstrated that the same site

[0248] 40

[0249] 4932-4302-8600, v. 1 - as identified based on slower motor progression - also accounted for long-term motor improvements in an independent typical advanced-stage (standard of care) PD cohort. This suggests that the site associated with slower motor progression is equally suited to maximize long-term motor improvements following STN-DBS for PD.

[0250] The identified optimal stimulation site is based on a low sample size, which is a key limitation. Unfortunately, additional cohorts that measure motor progression following DBS in humans do not yet exist, so the site may not be readily validated using additional data. However, very similar optimal stimulation sites have been described by others. Confirming utility of the stimulation site to estimate long-term motor improvements in an independent larger cohort may add further credibility.

[0251] While the association of this dorsolateral STN stimulation site with slower motor progression needs to be further validated by additional prospective studies, these results explore the current data at hand and conclude that the same site is associated with both slower motor progression and long-term motor benefit with STN-DBS in Parkinson's disease.

[0252] All of the compositions and / or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this disclosure have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and / or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the disclosure. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the disclosure as defined by the appended claims.

[0253] 41

[0254] 4932-4302-8600, v. 1 VI. References

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[0325] 4932-4302-8600, v. 1

Claims

WHAT IS CLAIMED:

1. A method of placing a deep brain stimulation (DBS) electrode into a patient having mid to late-stage Parkinson's Disease (PD) comprising:(a) mapping the patient’ s brain to determine a location for DB S electrode placement by identifying (i) fiber tracts from the supplementary motor area and / or primary motor area to the subthalamic nucleus (STN) of the patient; and (ii) fiber tracts from the pre-supplementary motor area to the STN of the patient; and(b) implanting a DBS electode to target (a)(i) and avoid targeting (a)(ii).

2. A method of placing and programming a deep brain stimulation (DBS) electrode into a patient having mid to late-stage Parkinson’s Disease (PD) comprising:(a) implanting a DBS electode target the subthalamic nucleus (STN) of the patient; (b) mapping the patient’s brain to determine programming of said DBS electrode by identifying (i) fiber tracts from the supplementary motor area and / or primary motor area to the subthalamic nucleus (STN) of the patient; and (ii) fiber tracts from the pre-supplementary motor area to the STN of the patient, wherein the DBS electrode is programmed to stimulate (i) and avoid stimulating (ii).

3. A method of programming a deep brain stimulation (DBS) electrode in a patient having mid to late-stage Parkinson’s Disease (PD) comprising mapping the patient’s brain to determine programming of said DBS electrode by identifying (i) fiber tracts from the supplementary motor area and / or primary motor area to the subthalamic nucleus (STN) of the patient; and (ii) fiber tracts from the pre-supplementary motor area to the STN of the patient, wherein the DBS electrode is programmed to stimulate (i) and avoid stimulating (ii), optionally wherein said subject has an implanted DBS electrode at the time of mapping.

4. The method of claim any one of claims 1-3, further comprising treating said patient by delivering an electrical cunent through said DBS electrode, such as by continous delivery, patient modulated delivery, or by adaptive delivery based on patient parameters.

5. The method of any one of claims 1-3, wherein said patient is a male human patient or a female patient.454932-4302-8600, v.

16. The method of any one of claims 1-5, wherein said patient is a non-human mammalian subject.

7. The method of any one of claims 1-6, wherein DBS is performed more than once, such as on a chronic basis.

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

9. The method of claim 8, wherein said second PD therapy is administered prior to STN- DBS.

10. The method of claim 8, wherein said second PD therapy is administered at the same time as STN-DBS.

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

12. The method of claim 8, wherein said 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 anticholinergics cholinesterase inhibitor, and lesional surgery, or combinations thereof.

13. The method of any one of claims 1-12, wherein STN-DBS results in one or more of post-operative motor symptom improvements compared to pre-surgical motor symptoms, lack of post-operative motor symptom changes compared to pre-surgical motor symptoms, and / or lack of post-operative motor symptom worsening compared to motor symptoms severity prior to surgery, such as wherein said motor symptom includes one or more of speech / hypomimia, limb bradykinesia, global bradykinesia, axial / postural instability and gait disorder.

14. The method of any one of claims 1-12, wherein STN-DBS results in one or more of lower stimulation parameters, less need for post-operative dopaminergic medication, and / or less development of levodopa associated dyskinesia or other motor fluctuations.

15. The method of any one of claims 1 and 3-14, wherein step (a) comprises:464932-4302-8600, v. 1identifying the patient-specific location of the tracts defined in (a)(i) and (a)(ii) from a normative connectome by using inverse normalization to warp the tracts from the template space into the patient’s brain space; orwherein step (a) comprises identifying the patient-specific location of the tracts defined in (a)(i) and (a)(ii) from a normative connectome by normalizing the patient’s brain to the template space which includes the tracts.

16. The method of any one of claims 1 and 3-14, wherein step (a) comprises utilizing patient-specific tractography data collected from diffusion-weighted brain imaging of the patient’s brain to identify (a)(i) and (a)(ii) using the following regions of interest (ROI):1) from the supplementary motor area projecting to the STN;2) from the primary motor area projecting to the STN; and3) from the pre-SMA projecting to the STN.

17. The method of any one of claims 1 and 3-16, further comprising performing a postoperative scan of the patient’s brain.

18. The method of claim 2 or claim 3, wherein mapping comprises:identifying the patient-specific location of the tracts defined in (b)(i) and (b)(ii) from a normative connectome by using inverse normalization to warp the tracts from the template space into the patient's brain space; orwherein step (b) comprises identifying the patient-specific location of the tracts defined in (b)(i) and (b)(ii) from a normative connectome by normalizing the patient’s brain to the template space which includes the tracts.

19. The method of claim 2 or claim 3, wherein mapping comprises utilizing patient-specific tractography data collected from diffusion- weighted brain imaging of the patient’s brain to identify (b)(i) and (b)(ii) using the following regions of interest (ROI):1) from the supplementary motor area projecting to the STN;2) from the primary motor area projecting to the STN; and3) from the pre-SMA projecting to the STN.474932-4302-8600, v.

120. The method of claim 18. determining whether said DBS electrode has achieved intended preoperative targeting of (b)(i) and non-targeting of (b)(ii).

21. The method of claims 18 or 19, wherein said DBS electrode comprises a plurality of contacts or segments and said method further comprises determining which contact(s) or segment(s) provide(s) the maximal stimulation of (b)(i) and avoids (b)(ii).

22. The method of claims 18 or 19, wherein said DBS electrode comprises a plurality of contacts or segments, and said method further comprises determining a field shape for said contact(s) or segment(s) that provide(s) maximal stimulation of (b)(i) and that avoids (b)(ii).

23. The method of claim 2, wherein said DBS electrode comprises a plurality of contacts or segments and said method further comprises determining which contact(s) or segment(s) provide(s) the maximal stimulation of (b)(i) and avoids (b)(ii).

24. The method of claim 2, wherein said DBS electrode comprises a plurality of contacts or segments, and said method further comprises determining a field shape for said contact(s) or segment(s) that provide(s) maximal stimulation of (b)(i) and that avoids (b)(ii).

25. A Parkinson’s Disease (PD) therapeutic agent for use in treating mid- to late-stage PD in a subject, wherein the subject separately, simultaneously or sequentially receives subthalamic nucleus (STN) deep brain stimulation (DBS) by a method as defined by any of claims 1-7 or 13-20.

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

27. The PD therapeutic agent for use in treating PD in a mid- to late-stage PD subject according to claim 25, wherein the PD therapeutic agent is administered at the same time as STN-DBS.

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

29. The PD therapeutic agent for use in treating PD in a mid- to late-stage PD subject according to any one of claims 25-28, wherein the PD therapeutic agent is levodopa,484932-4302-8600, v. 1optionally 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, and an anticholinergics cholinesterase inhibitor, or combinations thereof.

30. A computer implemented method for identifying deep brain stimulation (DBS) electrode placement locations for DBS treatment of a patient having mid- to late-stage Parkinson’s Disease (PD) comprising the steps of:(a) receiving brain image data for the patient;(b) processing the brain image data to identify fiber tracts (i) from the supplementary motor area and / or primary motor area to the subthalamic nucleus (STN) of the patient, and (ii) from the pre-supplementary motor area to the STN of the patient; and(c) generating an electrode placement map for the treatment of the patient using DBS, such that the implanted electrodes will target (b)(i) and avoid targeting (b)(ii).

31. A computer implemented method for identifying deep brain stimulation (DBS) electrode placement programming for DBS treatment of a patient having mid- to latestage Parkinson’s Disease (PD) comprising the steps of:(a) receiving brain image data for the patient;(b) processing the brain image data to identify fiber tracts (i) from the supplementary motor area and / or primary motor area to the subthalamic nucleus (STN) of the patient, and (ii) from the pre-supplementary motor area to the STN of the patient; and(c) generating an electrode programming map for the treatment of the patient using DBS, such that the implanted electrodes will target (b)(i) and avoid targeting (b)(ii).

32. The computer-implemented method of claims 30 or 31, further comprising identifying the patient-specific location of the tracts defined in (b)(i) and (b)(ii) from a normative494932-4302-8600, v. 1connectome by using inverse normalization to warp the tracts from the template space into the patient’s brain space.

33. The computer-implemented method of claims 30 or 31, further comprising utilizing patient-specific tractography data collected from diffusion-weighted brain imaging of the patient’s brain to identify (b)(i) and (b)(ii) using the following regions of interest (ROT):from the supplementary motor area projecting to the STN:from the primary motor area projecting to the STN; andfrom the pre-SMA projecting to the STN.

34. The computer-implemented method of claims 30 or 31 , further comprising the steps of:receiving postoperative brain image data for the patient; andprocessing the postoperative brain image data to determine whether said DBS electrode has achieved the intended preoperative targeting of (b)(i) and non-targeting of (b)(ii).4932-4302-8600, v. 1

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