The role of the locus coeruleus/norepinephrine system in the pathogenesis of neurodegenerative disorders: An update.

PURPOSE OF REVIEW: The aim of this review was to provide an update on current and emerging knowledge of the neuropathological processes affecting the locus coeruleus/norepinephrine (LC/NE) system, their effect on Alzheimer's disease and Parkinson's disease symptomatology, including efforts to translate these notions into therapeutic actions targeting the noradrenergic system. RECENT FINDINGS: Over the past 2 years, work from multiple groups has contributed to support an early role of locus coeruleus degeneration and/or hyperactivation in the neurodegenerative process, including a trigger of neuroinflammation. Imaging advances are allowing the quantification of locus coeruleus structural features in vivo, which is critical in the early stages of disease. Nonmotor and noncognitive symptoms, often secondary to the involvement of the LC/NE system, are becoming more important in the definition of these diseases and their treatment. SUMMARY: The diverse symptomatology of Parkinson's disease and Alzheimer's disease, which is not limited to cardinal motor and cognitive abnormalities, strongly suggests a multisystem neurodegenerative process. In this context, it is increasingly clear how the LC/NE system plays a key role in the initiation and maintenance of the neurodegenerative process.

Three-dimensional simultaneous brain mapping of T1, T2, T2∗ and magnetic susceptibility with MR Multitasking.

PURPOSE: To develop a new technique that enables simultaneous quantification of whole-brain T1 , T2 , T2∗ , as well as susceptibility and synthesis of six contrast-weighted images in a single 9.1-minute scan. METHODS: The technique uses hybrid T2 -prepared inversion-recovery pulse modules and multi-echo gradient-echo readouts to collect k-space data with various T1, T2, and T2∗ weightings. The underlying image is represented as a six-dimensional low-rank tensor consisting of three spatial dimensions and three temporal dimensions corresponding to T1 recovery, T2 decay, and multi-echo behaviors, respectively. Multiparametric maps were fitted from reconstructed image series. The proposed method was validated on phantoms and healthy volunteers, by comparing quantitative measurements against corresponding reference methods. The feasibility of generating six contrast-weighted images was also examined. RESULTS: High quality, co-registered T1 , T2 , and T2∗ susceptibility maps were generated that closely resembled the reference maps. Phantom measurements showed substantial consistency (R2 > 0.98) with the reference measurements. Despite the significant differences of T1 (p < .001), T2 (p = .002), and T2∗ (p = 0.008) between our method and the references for in vivo studies, excellent agreement was achieved with all intraclass correlation coefficients greater than 0.75. No significant difference was found for susceptibility (p = .900). The framework is also capable of synthesizing six contrast-weighted images. CONCLUSION: The MR Multitasking-based 3D brain mapping of T1 , T2 , T2∗ , and susceptibility agrees well with the reference and is a promising technique for multicontrast and quantitative imaging.

Long-Term Outcomes of Deep Brain Stimulation for Pediatric Dystonia.

BACKGROUND: Deep brain stimulation (DBS) has been utilized for over two decades to treat medication-refractory dystonia in children. Short-term benefit has been demonstrated for inherited, isolated, and idiopathic cases, with less efficacy in heredodegenerative and acquired dystonia. The ongoing publication of long-term outcomes warrants a critical assessment of available information as pediatric patients are expected to live most of their lives with these implants. SUMMARY: We performed a review of the literature for data describing motor and neuropsychiatric outcomes, in addition to complications, 5 or more years after DBS placement in patients undergoing DBS surgery for dystonia at an age younger than 21. We identified 20 articles including individual data on long-term motor outcomes after DBS for a total of 78 patients. In addition, we found five articles reporting long-term outcomes after DBS in 9 patients with status dystonicus. Most patients were implanted within the globus pallidus internus, with only a few cases targeting the subthalamic nucleus and ventrolateral posterior nucleus of the thalamus. The average follow-up was 8.5 years, with a range of up to 22 years. Long-term outcomes showed a sustained motor benefit, with median Burke-Fahn-Marsden dystonia rating score improvement ranging from 2.5% to 93.2% in different dystonia subtypes. Patients with inherited, isolated, and idiopathic dystonias had greater improvement than those with heredodegenerative and acquired dystonias. Sustained improvements in quality of life were also reported, without the development of significant cognitive or psychiatric comorbidities. Late adverse events tended to be hardware-related, with minimal stimulation-induced effects. KEY MESSAGES: While data regarding long-term outcomes is somewhat limited, particularly with regards to neuropsychiatric outcomes and adverse events, improvement in motor outcomes appears to be preserved more than 5 years after DBS placement.

Differential response to pallidal deep brain stimulation among monogenic dystonias: systematic review and meta-analysis.

OBJECTIVE: Genetic subtypes of dystonia may respond differentially to deep brain stimulation of the globus pallidus pars interna (GPi DBS). We sought to compare GPi DBS outcomes among the most common monogenic dystonias. METHODS: This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology guidelines. We searched PubMed for studies on genetically confirmed monogenic dystonia treated with GPi DBS documenting pre-surgical and post-surgical assessments using the Burke-Fahn-Marsden Dystonia Rating Scale Motor Score (BFMMS) and Burke-Fahn-Marsden Disability Score (BFMDS). We performed (i) meta-analysis for each gene mutation; (ii) weighted ordinary linear regression analyses to compare BFMMS and BFMDS outcomes between DYT-TOR1A and other monogenic dystonias, adjusting for age and disease duration and (iii) weighted linear regression analysis to estimate the effect of age, sex and disease duration on GPi DBS outcomes. Results were summarised with mean change and 95% CI. RESULTS: DYT-TOR1A (68%, 38.4 points; p<0.001), DYT-THAP1 (37% 14.5 points; p<0.001) and NBIA/DYT-PANK2 (27%, 21.4 points; p<0.001) improved in BFMMS; only DYT-TOR1A improved in BFMDS (69%, 9.7 points; p<0.001). Improvement in DYT-TOR1A was significantly greater than in DYT-THAP1 (BFMMS -31%), NBIA/DYT-PANK2 (BFMMS -35%; BFMDS -53%) and CHOR/DYT-ADCY5 (BFMMS -36%; BFMDS -42%). Worse motor outcomes were associated with longer dystonia duration and older age at dystonia onset in DYT-TOR1A, longer dystonia duration in DYT/PARK-TAF1 and younger age at dystonia onset in DYT-SGCE. CONCLUSIONS: GPi DBS outcomes vary across monogenic dystonias. These data serve to inform patient selection and prognostic counselling.

Sustained quality-of-life improvements over 10 years after deep brain stimulation for dystonia.

BACKGROUND: Little is known about the quality of life of people with dystonia and DBS beyond 5 years. The objectives of this study were (1) to examine the long-term quality-of-life outcomes in a large cohort of people with dystonia and DBS, (2) to determine the incidence of stimulation-induced parkinsonism, and (3) to elucidate the potential long-term cognitive impact of DBS in this cohort. METHODS: Fifty-four subjects with dystonia and DBS for more than 5 years were contacted via social media and were offered to complete a quality-of-life survey comparing current-day life and life prior to DBS. The primary study outcomes were the Short Form survey, a parkinsonian symptoms questionnaire, the Telephone Montreal Cognitive Assessment, and the Measurement of Every Day Cognition. RESULTS: Thirty-seven of 54 subjects consented to the study. Average age was 39.7 ± 16.6 years, 16 were female, and 23 were DYT1+. Average time from implantation was 10.5 years. Average total Short Form survey scores improved, from 43.7 pre-DBS to 69.5 current day (P < 0.0005). Mean total self-reported parkinsonian symptom score was 13.8 ± 14.7, with worsening balance and hypophonia the most common. Average Telephone Montreal Cognitive Assessment was 20.1 ± 1.6, with 3 of 29 scores (10.3%) in the impaired range (score of 18 or less). Average total Every Day Cognition score was 1.25 ± 0.35, with 3 subjects (10.3%) scoring in the range of impaired cognition (>1.81). CONCLUSIONS: DBS for dystonia results in long-term quality-of-life improvements that persist on average 10 years or more after surgery. The prevalence of stimulation-induced parkinsonism and cognitive impairment is low. © 2018 International Parkinson and Movement Disorder Society.

GRIN1 mutation associated with intellectual disability alters NMDA receptor trafficking and function.

N-methyl-d-aspartate receptors (NMDARs) play important roles in brain development and neurological disease. We report two individuals with similar dominant de novo GRIN1 mutations (c.1858 G>A and c.1858 G>C; both p.G620R). Both individuals presented at birth with developmental delay and hypotonia associated with behavioral abnormalities and stereotypical movements. Recombinant NMDARs containing the mutant GluN1-G620R together with either GluN2A or GluN2B were evaluated for changes in their trafficking to the plasma membrane and their electrophysiological properties. GluN1-G620R/GluN2A complexes showed a mild reduction in trafficking, a ~2-fold decrease in glutamate and glycine potency, a strong decrease in sensitivity to Mg2+ block, and a significant reduction of current responses to a maximal effective concentration of agonists. GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface associated with similarly altered electrophysiology. These results indicate these individuals may have suffered neurodevelopmental deficits as a result of the decreased presence of GluN1-G620R/GluN2B complexes on the neuronal surface during embryonic brain development and reduced current responses of GluN1-G620R-containing NMDARs after birth. These cases emphasize the importance of comprehensive functional characterization of de novo mutations and illustrates how a combination of several distinct features of NMDAR expression, trafficking and function can be present and influence phenotype.

Neuropsychological outcomes from constant current deep brain stimulation for Parkinson's disease.

OBJECTIVE: The aim of this study was to evaluate the neurobehavioral safety of constant-current subthalamic deep brain stimulation and to compare the neuropsychological effects of stimulation versus electrode placement alone. METHODS: A total of 136 patients with Parkinson's disease underwent bilateral subthalamic device implantation in this randomized trial. Patients received stimulation either immediately after device implantation (n = 101; active stimulation) or beginning 3 months after surgery (n = 35; delayed activation control). Patients were administered neuropsychological tests before, 3, and 12 months after device implantation. RESULTS: Neuropsychological change in stimulation and control groups were comparable. Within-group analyses revealed declines in category and switching verbal fluency in both groups, but only the stimulation group had letter verbal fluency and Stroop task declines. Depression symptom improvements occurred in both groups, but more often in the stimulation group. Letter fluency declines were associated with worse Parkinson's Disease Questionnaire Communication subscale scores. Baseline and 12-month comparisons (in the combined group) revealed gains in verbal and visual delayed recall scores and improvement in depression symptoms, but decrements in verbal fluency and Stroop scores. CONCLUSIONS: Constant-current bilateral subthalamic stimulation had a good cognitive safety profile except for decrements in verbal fluency and on the Stroop task. These abnormalities are related to device implantation, but stimulation likely had an additive effect. One year after surgery, the cognitive changes did not exert a detrimental effect on quality of life, although letter fluency declines were associated with communication dissatisfaction at 12 months. Improvement in depressive symptom severity appears dependent on stimulation and not placebo or lesion effects. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Deep Brain Stimulation for Status Dystonicus: A Case Series and Review of the Literature.

BACKGROUND: Status dystonicus (SD) is a rare and potentially life-threatening complication of primary or secondary dystonia, characterized by acute worsening of dystonic movements. There is no consensus regarding optimal treatment, which may be medical and/or surgical. METHODS: We present our experience with pallidal deep brain stimulation (DBS) in 5 DYT1-positive patients with SD and provide a review of the literature to examine optimal management. RESULTS: Of the 5 patients treated with pallidal DBS, all experienced postoperative resolution of their dystonic crisis within a range of 1-21 days. Long-term follow-up resulted in 1 patient returning to preoperative baseline, 3 patients improving from baseline, and 1 patient making a complete recovery. Of the 28 SD patients (including our 5 patients) reported in the literature who were treated with DBS or ablative surgery, 26 experienced cessation of their dystonic crisis with a return to baseline function and, in most cases, clinical improvement. CONCLUSION: DBS is an effective therapeutic modality for the treatment of SD. In addition to the long-term benefits of stimulation, early and aggressive treatment may improve the overall outcome.

Defining a therapeutic target for pallidal deep brain stimulation for dystonia.

OBJECTIVE: To create a data-driven computational model that identifies brain regions most frequently influenced by successful deep brain stimulation (DBS) of the globus pallidus (GP) for advanced, medication-resistant, generalized dystonia. METHODS: We studied a retrospective cohort of 21 DYT1 primary dystonia patients treated for at least 1 year with bilateral pallidal DBS. We first created individual volume of tissue activation (VTA) models utilizing neuroimaging and postoperative stimulation and clinical data. These models were then combined into a standardized probabilistic dystonia stimulation atlas (DSA). Finally, we constructed a candidate target volume from electrodes demonstrating at least 75% improvement in contralateral symptoms, utilizing voxels stimulated by least 75% of these electrodes. RESULTS: Pallidal DBS resulted in a median contralateral hemibody improvement of 90% (mean = 83%, standard deviation [SD] = 20) after 1 year of treatment. Individual VTA models of the 42 active electrodes included in the study demonstrated a mean stimulation volume of 501mm ([SD] = 284). The resulting DSA showed that areas most frequently stimulated were located squarely in the middle of the posterior GP, with a common target volume measuring 153mm(3) . INTERPRETATION: Our results provide a map of the region of influence of therapeutic DBS for dystonia and represent a potential target to refine current methods of surgical planning and stimulation parameters selection. Based on their role in alleviating symptoms, these regions may also provide anatomical and physiological information relevant to disease models of dystonia. Further experimental and clinical studies will be needed to validate their importance.

Cholinesterase inhibitors for Parkinson's disease: a systematic review and meta-analysis.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative movement disorder frequently associated with a wide variety of non-motor symptoms related to non-dopaminergic pathways. Although the depletion of dopamine is the key neurochemical impairment in PD and anticholinergic medications are used for symptomatic treatment, significant deficits in cholinergic transmission are also present and have been associated with cognitive decline and gait dysfunction. Therefore, use of a cholinesterase inhibitor (ChI) might improve cognitive function and reduce the risk of falls in patients with PD, although it could plausibly worsen motor features. Our objective was to conduct a systematic review of prospective, randomised controlled trials, in order to assess the efficacy and safety of ChIs compared with placebo in patients with PD. METHODS AND RESULTS: MEDLINE, Web of Science, CENTRAL and Scopus databases were searched to identify studies published before 5 May 2014 and including patients with PD treated with ChIs. From 945 references identified and screened, 19 were assessed for eligibility and 4 trials were included for a total of 941 patients with PD. ChIs significantly slowed Mini-Mental State Examination decline without effect on risk of falls. Tremor rates and adverse drug reactions favoured the placebo group. Alzheimer Disease Assessment Scale-cognitive subscale, global assessment and behavioural disturbance improved in the ChI group without effect on disability. There was no significant difference between the groups for Unified Parkinson Disease Rating Scale III. A significantly reduced death rate was observed in the treated cohort as compared with placebo. CONCLUSIONS: ChIs are effective in the treatment of cognitive impairment in patients with PD, but do not affect risk of falls. The choice of treatment has to be balanced considering the increased tremor and adverse drug reactions.

The rationale driving the evolution of deep brain stimulation to constant-current devices.

OBJECTIVE: Deep brain stimulation (DBS) is an effective therapy for the treatment of a number of movement and neuropsychiatric disorders. The effectiveness of DBS is dependent on the density and location of stimulation in a given brain area. Adjustments are made to optimize clinical benefits and minimize side effects. Until recently, clinicians would adjust DBS settings using a voltage mode, where the delivered voltage remained constant. More recently, a constant-current mode has become available where the programmer sets the current and the stimulator automatically adjusts the voltage as impedance changes. METHODS: We held an expert consensus meeting to evaluate the current state of the literature and field on constant-current mode versus voltage mode in clinical brain-related applications. RESULTS/CONCLUSIONS: There has been little reporting of the use of constant-current DBS devices in movement and neuropsychiatric disorders. However, as impedance varies considerably between patients and over time, it makes sense that all new devices will likely use constant current.

What's special about task in dystonia? A voxel-based morphometry and diffusion weighted imaging study.

Numerous brain imaging studies have demonstrated structural changes in the basal ganglia, thalamus, sensorimotor cortex, and cerebellum across different forms of primary dystonia. However, our understanding of brain abnormalities contributing to the clinically well-described phenomenon of task specificity in dystonia remained limited. We used high-resolution magnetic resonance imaging (MRI) with voxel-based morphometry and diffusion weighted imaging with tract-based spatial statistics of fractional anisotropy to examine gray and white matter organization in two task-specific dystonia forms, writer's cramp and laryngeal dystonia, and two non-task-specific dystonia forms, cervical dystonia and blepharospasm. A direct comparison between both dystonia forms indicated that characteristic gray matter volumetric changes in task-specific dystonia involve the brain regions responsible for sensorimotor control during writing and speaking, such as primary somatosensory cortex, middle frontal gyrus, superior/inferior temporal gyrus, middle/posterior cingulate cortex, and occipital cortex as well as the striatum and cerebellum (lobules VI-VIIa). These gray matter changes were accompanied by white matter abnormalities in the premotor cortex, middle/inferior frontal gyrus, genu of the corpus callosum, anterior limb/genu of the internal capsule, and putamen. Conversely, gray matter volumetric changes in the non-task-specific group were limited to the left cerebellum (lobule VIIa) only, whereas white matter alterations were found to underlie the primary sensorimotor cortex, inferior parietal lobule, and middle cingulate gyrus. Distinct microstructural patterns in task-specific and non-task-specific dystonias may represent neuroimaging markers and provide evidence that these two dystonia subclasses likely follow divergent pathophysiological mechanisms precipitated by different triggers.

Sustained relief of generalized dystonia despite prolonged interruption of deep brain stimulation.

BACKGROUND: Pallidal deep brain stimulation (DBS) is an established treatment for disabling, medication-refractory generalized dystonia. Patients typically regress to their preoperative baseline when stimulation is discontinued. METHODS: Presented are case reports of 2 dystonia patients. RESULTS: Two patients with primary generalized dystonia (1 with the DYT1 mutation) who were treated successfully with bilateral pallidal DBS for periods of 18 months and 5 years retained motor benefit for several months after inadvertent interruption of stimulation. Stimulation was interrupted unilaterally for 3 and 7 months and bilaterally for 2 days and 2 months, respectively. Symptoms of dystonia returned only partially during the period of therapy interruption and rapidly and completely resolved after resuming stimulation. CONCLUSIONS: We report unexpected and prolonged retention of motor benefits despite transient cessation of pallidal DBS in 2 dystonia patients. Factors that appear to differentiate these individuals are young age, short duration of disease, and chronic DBS therapy with relatively low energy of stimulation.

Pallidal deep brain stimulation for DYT6 dystonia.

BACKGROUND: Mutations of the THAP1 gene were recently shown to underlie DYT6 torsion dystonia. Little is known about the response of this dystonia subtype to deep brain stimulation (DBS) at the internal globus pallidus (GPi). METHODS: Retrospective analysis of the medical records of three DYT6 patients who underwent pallidal DBS by one surgical team. The Burke-Fahn-Marsden Dystonia Rating scale served as the primary outcome measure. Comparison is made to 23 patients with DYT1 dystonia also treated with GPi-DBS by the same team. RESULTS: In contrast with the DYT1 patients who exhibited a robust and sustained clinical response to DBS, the DYT6 patients exhibited more modest gains during the first 2 years of therapy, and some symptom regression between years 2 and 3 despite adjustments to the stimulation parameters and repositioning of one stimulating lead. Microelectrode recordings made during the DBS procedures demonstrated no differences in the firing patterns of GPi neurons from DYT1 and DYT6 patients. DISCUSSION: Discovery of the genetic mutations responsible for the DYT6 phenotype allows for screening and analysis of a new homogeneous group of dystonia patients. DYT6 patients appear to respond less robustly to GPi-DBS than their DYT1 counterparts, most likely reflecting differences in the underlying pathophysiology of these distinct genetic disorders. CONCLUSIONS: While early results of pallidal DBS for DYT6 dystonia are encouraging, further research and additional subjects are needed both to optimise stimulation parameters for this population and to elucidate more accurately their response to surgical treatment.

Improvement of both dystonia and tics with 60 Hz pallidal deep brain stimulation.

Deep brain stimulation has been utilized in both dystonia and in medication refractory Tourette syndrome. We present an interesting case of a patient with a mixture of disabling dystonia and Tourette syndrome whose coexistent dystonia and tics were successfully treated with 60 Hz-stimulation of the globus pallidus region.

Sustained chemogenetic activation of locus coeruleus norepinephrine neurons promotes dopaminergic neuron survival in synucleinopathy.

Dopaminergic neuron degeneration in the midbrain plays a pivotal role in motor symptoms associated with Parkinson's disease. However, non-motor symptoms of Parkinson's disease and post-mortem histopathology confirm dysfunction in other brain areas, including the locus coeruleus and its associated neurotransmitter norepinephrine. Here, we investigate the role of central norepinephrine-producing neurons in Parkinson's disease by chronically stimulating catecholaminergic neurons in the locus coeruleus using chemogenetic manipulation. We show that norepinephrine neurons send complex axonal projections to the dopaminergic neurons in the substantia nigra, confirming physical communication between these regions. Furthermore, we demonstrate that increased activity of norepinephrine neurons is protective against dopaminergic neuronal depletion in human α-syn A53T missense mutation over-expressing mice and prevents motor dysfunction in these mice. Remarkably, elevated norepinephrine neurons action fails to alleviate α-synuclein aggregation and microgliosis in the substantia nigra suggesting the presence of an alternate neuroprotective mechanism. The beneficial effects of high norepinephrine neuron activity might be attributed to the action of norepinephrine on dopaminergic neurons, as recombinant norepinephrine treatment increased primary dopaminergic neuron cultures survival and neurite sprouting. Collectively, our results suggest a neuroprotective mechanism where noradrenergic neurons activity preserves the integrity of dopaminergic neurons, which prevents synucleinopathy-dependent loss of these cells.

Early postoperative management of DBS in dystonia: programming, response to stimulation, adverse events, medication changes, evaluations, and troubleshooting.

Early postoperative management in deep brain stimulation-treated patients with dystonia differs from that of patients with essential tremor and Parkinson's disease, mainly due to the usually delayed effects of deep brain stimulation and the heterogenous clinical manifestation and etiologies of dystonia. The present chapter summarizes the available data about and concentrates on practical clinical aspects of early postoperative management in deep brain stimulation-treated patients with dystonia.

Long-Term management of DBS in dystonia: response to stimulation, adverse events, battery changes, and special considerations.

Multiple independent case series have documented sustained benefit of bilateral pallidal deep brain stimulation (DBS) up to 3 years in patients with primary dystonia. Growing evidence exists for positive outcomes extending up to 10 years. The beneficial effects from DBS are usually reported to be stable, thus requiring little long-term modifications of the parameters of stimulation. Speech and swallowing abnormalities are less responsive than other dystonic symptoms. Symptom exacerbation after initial benefit has been reported in a few cases. It is not known whether this is related to potential tolerance or habituation to stimulation or to progression of the underlying disease. Failures of pallidal DBS, at least in primary dystonia patients, should not be accepted without further re-evaluation of each individual case, including possible revisions of the electrode location. Both hardware- and stimulation-related adverse effects, including insufficient relief of speech function, have been reported in the long-term. Despite early reports suggesting that hardware problems might be more frequent in dystonia, more recent studies did not confirm these observations. In patients with severe segmental (e.g., axial) or generalized dystonia, sudden cessation of stimulation may become a medical emergency and should be anticipated changing the neurostimulator before its natural end of life.

Short- and Long-Term Effects of DBS on Gait in Parkinson's Disease.

The aim was to compare the short and long-term effects of subthalamic nucleus (STN) deep brain stimulation (DBS) on gait dysfunction and other cardinal symptoms of Parkinson's disease (PD). Two groups of patients were studied. The first group (short-term DBS, n = 8) included patients recently implanted with STN DBS (mean time since DBS 15.8 months, mean age 58.8 years, PD duration 13 years); the second group (long-term DBS, n = 10) included patients with at least 5 years of DBS therapy (mean time since DBS 67.6 months, mean age 61.7 years, PD duration 17.1 years). Both groups were examined using the Unified Parkinson's Disease Rating Scale (UPDRS) and Gait and Balance scale (GABS) during four stimulation/medication states (ON/OFF; OFF/OFF; OFF/ON; ON/ON). Data were analyzed using repeated measures ANOVA with time since implantation (years) between groups and medication or DBS effect (ON, OFF) within groups. In the short-term DBS group, stimulation improved all UPDRS subscores similar to dopaminergic medications. In particular, average gait improvement was over 40% (p = 0.01), as measured by the UPDRS item 29 and GABS II. In the long-term DBS group, stimulation consistently improved all clinical subscores with the exception of gait and postural instability. In these patients, the effect of levodopa on gait was partially preserved. Short-term improvement of gait abnormalities appears to significantly decline after 5 years of STN DBS in PD patients, while effectiveness for other symptoms remains stable. Progressive non-dopaminergic (non-DBS responsive) mechanisms or deleterious effects of high frequency STN stimulation on gait function may play a role.