Dataset Information

Neurodegeneration of the Globus Pallidus Internus as a Neural Correlate to Dopa-Response in Freezing of Gait.

ABSTRACT:

Background

Background: Parkinson's disease (PD) patients who develop freezing of gait (FOG) have reduced mobility and independence. While some patients experience improvement in their FOG symptoms with dopaminergic therapies, a subset of patients have little to no response. To date, it is unknown what changes in brain structure underlie dopa-response and whether this can be measured using neuroimaging approaches.

Objective

We tested the hypothesis that structural integrity of brain regions (subthalamic nucleus and globus pallidus internus, GPi) which link basal ganglia to the mesencephalic locomotor region (MLR), a region involved in automatic gait, would be associated with FOG response to dopaminergic therapy.

Methods

In this observational study, thirty-six participants with PD and definite FOG were recruited to undergo diffusion kurtosis imaging (DKI) and multiple assessments of dopa responsiveness (UPDRS scores, gait times ON versus OFF medication).

Results

The right GPi in participants with dopa-unresponsive FOG showed reduced fractional anisotropy, mean kurtosis (MK), and increased radial diffusivity relative to those with dopa-responsive FOG. Furthermore, using probabilistic tractography, we observed reduced MK and increased mean diffusivity along the right GPi-MLR tract in dopa-unresponsive FOG. MK in the right GPi was associated with a subjective dopa-response for FOG (r = -0.360, df = 30, p = 0.043) but not overall motor dopa-response.

Conclusion

These results support structural integrity of the GPi as a correlate to dopa-response in FOG. Additionally, this study suggests DKI metrics may be a sensitive biomarker for clinical studies targeting dopaminergic circuitry and improvements in FOG behavior.

SUBMITTER: Lench DH

PROVIDER: S-EPMC10792667 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Neurodegeneration of the Globus Pallidus Internus as a Neural Correlate to Dopa-Response in Freezing of Gait.

Lench Daniel H DH Keith Kathryn K Wilson Sandra S Padgett Lucas L Benitez Andreana A Ramakrishnan Viswanathan V Jensen Jens H JH Bonilha Leonardo L Revuelta Gonzalo J GJ

Journal of Parkinson's disease 20220101 4

<h4>Background</h4>Background: Parkinson's disease (PD) patients who develop freezing of gait (FOG) have reduced mobility and independence. While some patients experience improvement in their FOG symptoms with dopaminergic therapies, a subset of patients have little to no response. To date, it is unknown what changes in brain structure underlie dopa-response and whether this can be measured using neuroimaging approaches.<h4>Objective</h4>We tested the hypothesis that structural integrity of brai ...[more]

PMID: 35367969

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Project description:BackgroundFreezing of gait (FOG) is a common motor symptom in advanced Parkinson's disease (PD). However, the pathophysiology mechanism of FOG is not fully understood. The purpose of this study was to investigate microstructural abnormalities in subcortical gray matter and alterations in functional connectivity of the nuclei with microstructural changes. In addition, the correlations between these microstructural and functional changes and the severity of FOG were measured.Materials and methodsTwenty-four patients with FOG (PD-FOG), 22 PD patients without FOG (PD-nFOG), and 27 healthy controls (HC) were recruited. FOG Questionnaire (FOGQ) and Gait and Falling Questionnaire (GFQ) were assessed, and Timed Up and Go (TUG) tests were performed in PD-FOG patients. All subjects underwent diffusion tensor imaging (DTI) and resting-state functional MRI scanning. The DTI measures, including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD), were extracted and measured from basal ganglia, thalamus, and substantia nigra. The nuclei with microstructural alterations were selected as seed regions to perform the seed-based resting-state functional connectivity.ResultsThe MD and RD values of the right globus pallidus internus (GPi) were significantly higher in patients with PD-FOG compared with PD-nFOG patients and HC. In PD-FOG patients, the MD and RD values of the right GPi were significantly correlated with the time of the TUG test in both ON and OFF states. The MD values were also correlated with the GFQ scores in PD-FOG patients. Resting-state functional connectivity between the right GPi and left middle occipital gyri decreased significantly in PD-FOG patients compared to PD-nFOG patients, and was negatively correlated with GFQ scores as well as the time of ON state TUG in PD-FOG patients.ConclusionMicrostructural alterations in the right GPi and functional connectivity between the right GPi and visual cortex may be associated with the pathophysiological mechanisms of FOG in PD patients.

Project description:Abstract Globus pallidus internus deep brain stimulation is an established therapy for patients with medication-refractory Parkinson’s disease. Clinical outcomes are highly dependent on applying stimulation to precise locations in the brain. However, robust neurophysiological markers are needed to determine the optimal electrode location and to guide postoperative stimulation parameter selection. In this study, we evaluated evoked resonant neural activity in the pallidum as a potential intraoperative marker to optimize targeting and stimulation parameter selection to improve outcomes of deep brain stimulation for Parkinson’s disease. Intraoperative local field potential recordings were acquired in 22 patients with Parkinson’s disease undergoing globus pallidus internus deep brain stimulation implantation (N = 27 hemispheres). A control group of patients undergoing implantation in the subthalamic nucleus (N = 4 hemispheres) for Parkinson’s disease or the thalamus for essential tremor (N = 9 patients) were included for comparison. High-frequency (135 Hz) stimulation was delivered from each electrode contact sequentially while recording the evoked response from the other contacts. Low-frequency stimulation (10 Hz) was also applied as a comparison. Evoked resonant neural activity features, including amplitude, frequency and localization were measured and analysed for correlation with empirically derived postoperative therapeutic stimulation parameters. Pallidal evoked resonant neural activity elicited by stimulation in the globus pallidus internus or externus was detected in 26 of 27 hemispheres and varied across hemispheres and across stimulating contacts within individual hemispheres. Bursts of high-frequency stimulation elicited evoked resonant neural activity with similar amplitudes (P = 0.9) but a higher frequency (P = 0.009) and a higher number of peaks (P = 0.004) than low-frequency stimulation. We identified a ‘hotspot’ in the postero-dorsal pallidum where stimulation elicited higher evoked resonant neural activity amplitudes (P < 0.001). In 69.6% of hemispheres, the contact that elicited the maximum amplitude intraoperatively matched the contact empirically selected for chronic therapeutic stimulation by an expert clinician after 4 months of programming sessions. Pallidal and subthalamic nucleus evoked resonant neural activity were similar except for lower pallidal amplitudes. No evoked resonant neural activity was detected in the essential tremor control group. Given its spatial topography and correlation with postoperative stimulation parameters empirically selected by expert clinicians, pallidal evoked resonant neural activity shows promise as a potential marker to guide intraoperative targeting and to assist the clinician with postoperative stimulation programming. Importantly, evoked resonant neural activity may also have the potential to guide directional and closed-loop deep brain stimulation programming for Parkinson’s disease. Objective markers are needed to guide deep brain stimulation (DBS) for Parkinson’s disease. Johnson et al. established pallidal evoked resonant neural activity as a potential neurophysiological marker to verify the DBS electrode location intraoperatively and identify effective postoperative stimulation parameters. See Steiner and Milosevic (https://doi.org/10.1093/braincomms/fcad033) for a scientific commentary on this article. Graphical Abstract Graphical abstract

Project description:IntroductionThe globus pallidus internus (GPi) region has evolved as a potential target for deep brain stimulation (DBS) in Parkinson's disease (PD). DBS of the GPi (GPi DBS) is an established, safe and effective method for addressing many of the motor symptoms associated with advanced PD. It is important that clinicians fully understand this target when considering GPi DBS for individual patients.MethodsThe literature on GPi DBS in PD has been comprehensively reviewed, including the anatomy, physiology and potential pitfalls that may be encountered during surgical targeting and post-operative management. Here, we review and address the implications of lead location on GPi DBS outcomes. Additionally, we provide a summary of randomized controlled clinical trials conducted on DBS in PD, together with expert commentary on potential applications of the GPi as target. Finally, we highlight future technologies that will likely impact GPi DBS, including closed-loop adaptive approaches (e.g. sensing-stimulating capabilities), advanced methods for image-based targeting and advances in DBS programming, including directional leads and pulse shaping.ResultsThere are important disease characteristics and factors to consider prior to selecting the GPi as the DBS target of PD surgery. Prior to and during implantation of the leads it is critical to consider the neuroanatomy, which can be defined through the combination of image-based targeting and intraoperative microelectrode recording strategies. There is an increasing body of literature on GPi DBS in patients with PD suggesting both short- and long-term benefits. Understanding the GPi target can be useful in choosing between the subthalamic (STN), GPi and ventralis intermedius nucleus as lead locations to address the motor symptoms and complications of PD.ConclusionGPi DBS can be effectively used in select cases of PD. As the ongoing DBS target debate continues (GPi vs. STN as DBS target), clinicians should keep in mind that GPi DBS has been shown to be an effective treatment strategy for a variety of symptoms, including bradykinesia, rigidity and tremor control. GPi DBS also has an important, direct anti-dyskinetic effect. GPi DBS is easier to program in the outpatient setting and will allow for more flexibility in medication adjustments (e.g. levodopa). Emerging technologies, including GPi closed-loop systems, advanced tractography-based targeting and enhanced programming strategies, will likely be future areas of GPi DBS expansion. We conclude that although the GPi as DBS target may not be appropriate for all PD patients, it has specific clinical advantages.

Project description:IntroductionDystonic opisthotonus is defined as a backward arching of the neck and trunk, which ranges in severity from mild backward jerks to life-threatening prolonged severe muscular spasms. It can be associated with generalized dystonic syndromes or, rarely, present as a form of axial truncal dystonia. The etiologies vary from idiopathic, genetic, tardive, hereditary-degenerative, or associated with parkinsonism. We report clinical cases of dystonic opisthotonus associated with adult-onset dystonic syndromes, that benefitted from globus pallidus internus (GPi) deep brain stimulation (DBS).MethodsClinical data from patients with dystonic syndromes who underwent comprehensive medical review, multidisciplinary assessment, and tailored medical and neurosurgical managements were prospectively analyzed. Quantification of dystonia severity pre- and postoperatively was performed using the Burke-Fahn-Marsden Dystonia Rating Scale and quantification of overall pain severity was performed using the Visual Analog Scale.ResultsThree male patients, with age of onset of the dystonic symptoms ranging from 32 to 51 years old, were included. Tardive dystonia, adult-onset dystonia-parkinsonism and adult-onset idiopathic axial dystonia were the etiologies identified. Clinical investigation and management were tailored according to the complexity of the individual presentations. Although they shared common clinical features of adult-onset dystonia, disabling dystonic opisthotonus, refractory to medical management, was the main indication for GPi-DBS in all patients presented. The severity of axial dystonia ranged from disturbance of daily function to life-threatening truncal distortion. All three patients underwent bilateral GPi DBS at a mean age of 52 years (range 48-55 years), after mean duration of symptoms prior to DBS of 10.7 years (range 4-16 years). All patients showed a rapid and sustained clinical improvement of their symptoms, notably of the dystonic opisthotonos, at postoperative follow-up ranging from 20 to 175 months. In some, the ability to resume activities of daily living and reintegration into the society was remarkable.ConclusionAdult-onset dystonic syndromes predominantly presenting with dystonic opisthotonus are relatively rare. The specific nature of dystonic opisthotonus remains a treatment challenge, and thorough investigation of this highly disabling condition with varying etiologies is often necessary. Although patients may be refractory to medical management and botulinum toxin injection, Globus pallidus stimulation timed and tailored provided symptomatic control in this cohort and may be considered in other carefully selected cases.

Dataset Information

Neurodegeneration of the Globus Pallidus Internus as a Neural Correlate to Dopa-Response in Freezing of Gait.

Background

Objective

Methods

Results

Conclusion

Publications

Neurodegeneration of the Globus Pallidus Internus as a Neural Correlate to Dopa-Response in Freezing of Gait.

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