-
Rinsho Shinkeigaku = Clinical Neurology Jun 2024Malfunction of the basal ganglia leads to movement disorders such as Parkinson's disease, dystonia, Huntington's disease, dyskinesia, and hemiballism, but their... (Review)
Review
Malfunction of the basal ganglia leads to movement disorders such as Parkinson's disease, dystonia, Huntington's disease, dyskinesia, and hemiballism, but their underlying pathophysiology is still subject to debate. To understand their pathophysiology in a unified manner, we propose the "dynamic activity model", on the basis of alterations of cortically induced responses in individual nuclei of the basal ganglia. In the normal state, electric stimulation in the motor cortex, mimicking cortical activity during initiation of voluntary movements, evokes a triphasic response consisting of early excitation, inhibition, and late excitation in the output stations of the basal ganglia of monkeys, rodents, and humans. Among three components, cortically induced inhibition, which is mediated by the direct pathway, releases an appropriate movement at an appropriate time by disinhibiting thalamic and cortical activity, whereas early and late excitation, which is mediated by the hyperdirect and indirect pathways, resets on-going cortical activity and stops movements, respectively. Cortically induced triphasic response patterns are systematically altered in various movement disorder models and could well explain the pathophysiology of their motor symptoms. In monkey and mouse models of Parkinson's disease, cortically induced inhibition is reduced and prevents the release of movements, resulting in akinesia/bradykinesia. On the other hand, in a mouse model of dystonia, cortically induced inhibition is enhanced and releases unintended movements, inducing involuntary muscle contractions. Moreover, after blocking the subthalamic nucleus activity in a monkey model of Parkinson's disease, cortically induced inhibition is recovered and enables voluntary movements, explaining the underlying mechanism of stereotactic surgery to ameliorate parkinsonian motor signs. The "dynamic activity model" gives us a more comprehensive view of the pathophysiology underlying motor symptoms of movement disorders and clues for their novel therapies.
Topics: Humans; Animals; Movement Disorders; Mice; Basal Ganglia; Disease Models, Animal; Parkinson Disease
PubMed: 38811203
DOI: 10.5692/clinicalneurol.cn-001957 -
Journal of Neurology May 2024Autonomic dysfunction is common and disabling in Parkinson's disease (PD). The effects of deep brain stimulation (DBS) on the cardiovascular system in PD remain poorly... (Review)
Review
BACKGROUND
Autonomic dysfunction is common and disabling in Parkinson's disease (PD). The effects of deep brain stimulation (DBS) on the cardiovascular system in PD remain poorly understood. We aimed to assess the effect of DBS on cardiovascular symptoms and objective measures in PD patients.
METHODS
We conducted a systematic literature search in PubMed/MEDLINE.
RESULTS
36 out of 472 studies were included, mostly involving DBS of the subthalamic nucleus, and to a lesser extent the globus pallidus pars interna and pedunculopontine nucleus. Seventeen studies evaluated the effect of DBS on patient-reported or clinician-rated cardiovascular symptoms, showing an improvement in the first year after surgery but not with longer-term follow-up. DBS has no clear direct effects on blood pressure during an orthostatic challenge (n = 10 studies). DBS has inconsistent effects on heart rate variability (n = 10 studies).
CONCLUSION
Current evidence on the impact of DBS on cardiovascular functions in PD is inconclusive. DBS may offer short-term improvement of cardiovascular symptoms in PD, particularly orthostatic hypotension, which may be attributed to dopaminergic medication reduction after surgery. There is insufficient evidence to draw conclusions on the direct effect of DBS on blood pressure and heart rate variability.
PubMed: 38809271
DOI: 10.1007/s00415-024-12459-1 -
Journal of Neural Transmission (Vienna,... May 2024Interactions with others need social adjustment (i.e., the constant accommodation to changing social situations). Mixed evidence indicates positive as well as negative... (Review)
Review
Interactions with others need social adjustment (i.e., the constant accommodation to changing social situations). Mixed evidence indicates positive as well as negative changes in social adjustment after subthalamic nucleus deep brain stimulation (STN-DBS) in people with Parkinson's Disease (PwPD). To date, however, no meta-analysis of these changes exists. Thus, the study aim was to review evidence of the effects of STN-DBS on social adjustment in PwPD. For this purpose, a systematic literature search in MEDLINE was conducted. The meta-analysis was performed using a random effects model and standardized mean differences (SMDs) with 95% confidence intervals (CIs). The MINORS tool was used to assess the methodological quality of the studies. The initial literature search identified 13,124 articles, of which 1,550 full texts were assessed for eligibility. Eight studies were finally included; for seven articles sufficient data for a meta-analysis was available. Most studies found mild impairment in social adjustment impairment pre-surgery. The meta-analysis revealed no significant changes but a statistical trend towards improvement in social adjustment up to six months (SMD = 0.25; 95%CI=-0.03,0.53; P = 0.08) and over 12 months (SMD = 0.26; 95%CI=-0.03,0.55; P = 0.07) post-surgery. Methodological quality was moderate in 87.5% of the studies and good in 12.5%. While mild impairment in social adjustment pre-surgery was reported in most studies, the data indicate that STN-DBS might yield beneficial effects toward this outcome. However, not enough data yet exists to draw firm conclusions. As a crucial skill for everyday functioning, social adjustment should be more often defined as an outcome in STN-DBS trials in PwPD and should be considered in clinical routines.
PubMed: 38795178
DOI: 10.1007/s00702-024-02787-x -
Neuropharmacology Sep 2024Neuromodulation such as deep brain stimulation (DBS) is advancing as a clinical intervention in several neurological and neuropsychiatric disorders, including... (Review)
Review
Concerning neuromodulation as treatment of neurological and neuropsychiatric disorder: Insights gained from selective targeting of the subthalamic nucleus, para-subthalamic nucleus and zona incerta in rodents.
Neuromodulation such as deep brain stimulation (DBS) is advancing as a clinical intervention in several neurological and neuropsychiatric disorders, including Parkinson's disease, dystonia, tremor, and obsessive-compulsive disorder (OCD) for which DBS is already applied to alleviate severely afflicted individuals of symptoms. Tourette syndrome and drug addiction are two additional disorders for which DBS is in trial or proposed as treatment. However, some major remaining obstacles prevent this intervention from reaching its full therapeutic potential. Side-effects have been reported, and not all DBS-treated individuals are relieved of their symptoms. One major target area for DBS electrodes is the subthalamic nucleus (STN) which plays important roles in motor, affective and associative functions, with impact on for example movement, motivation, impulsivity, compulsivity, as well as both reward and aversion. The multifunctionality of the STN is complex. Decoding the anatomical-functional organization of the STN could enhance strategic targeting in human patients. The STN is located in close proximity to zona incerta (ZI) and the para-subthalamic nucleus (pSTN). Together, the STN, pSTN and ZI form a highly heterogeneous and clinically important brain area. Rodent-based experimental studies, including opto- and chemogenetics as well as viral-genetic tract tracings, provide unique insight into complex neuronal circuitries and their impact on behavior with high spatial and temporal precision. This research field has advanced tremendously over the past few years. Here, we provide an inclusive review of current literature in the pre-clinical research fields centered around STN, pSTN and ZI in laboratory mice and rats; the three highly heterogeneous and enigmatic structures brought together in the context of relevance for treatment strategies. Specific emphasis is placed on methods of manipulation and behavioral impact.
Topics: Subthalamic Nucleus; Animals; Deep Brain Stimulation; Zona Incerta; Mental Disorders; Humans; Nervous System Diseases; Rodentia
PubMed: 38789078
DOI: 10.1016/j.neuropharm.2024.110003 -
Heliyon May 2024Neurogenesis, play a vital role in neuronal plasticity of adult mammalian brains, and its dysregulation is present in the pathophysiology of Parkinson's disease (PD)....
Neurogenesis, play a vital role in neuronal plasticity of adult mammalian brains, and its dysregulation is present in the pathophysiology of Parkinson's disease (PD). While subthalamic nucleus deep brain stimulation (STN-DBS) at various frequencies has been proven effective in alleviating PD symptoms, its influence on neurogenesis remains unclear. This study aimed to investigate the effects of 1-week electrical stimulation at frequencies of 60Hz, 130Hz, and 180Hz on neurogenesis in the subventricular zone (SVZ) of PD rats. A hemiparkinsonian rat model was established using 6-hydroxydopamine and categorized into six groups: control, PD, sham stimulation, 60Hz stimulation, 130Hz stimulation, and 180Hz stimulation. Motor function was assessed using the open field test and rotarod test after one week of STN-DBS at different frequencies. Tyrosine hydroxylase (TH) expression in brain tissue was analyzed via Western blot and immunohistochemistry. Immunofluorescence analysis was conducted to evaluate the expression of BrdU/Sox2, BrdU/GFAP, Ki67/GFAP, and BrdU/DCX in bilateral SVZ and the rostral migratory stream (RMS). Our findings revealed that high-frequency STN-DBS improved motor function. Specifically, stimulation at 130Hz increased dopaminergic neuron survival in the PD rat model, while significantly enhancing the proliferation of neural stem cells (NSCs) and neuroblasts in bilateral SVZ. Moreover, this stimulation effectively facilitated the generation of new NSCs in the ipsilateral RMS and triggered the emergence of fresh neuroblasts in bilateral RMS, with notable presence within the lesioned striatum. Conversely, electrical stimulation at 60Hz and 180Hz did not exhibit comparable effects. The observed promotion of neurogenesis in PD rats following STN-DBS provides valuable insights into the mechanistic basis of this therapeutic approach for PD.
PubMed: 38784548
DOI: 10.1016/j.heliyon.2024.e30730 -
Heliyon May 2024Parkinson's disease (PD), even though generally perceived as a dominantly motor disorder, is associated with a wide range of non-motor symptoms, including mixed...
BACKGROUND
Parkinson's disease (PD), even though generally perceived as a dominantly motor disorder, is associated with a wide range of non-motor symptoms, including mixed anxiety-depressive disorder (MADD).
OBJECTIVES
The aim of the presented study was to determine whether deep brain stimulation (DBS) of the subthalamic nucleus (STN) brings the functional characteristics of non-motor networks closer to the condition detected in healthy population and whether pre-DBS presence of MADD in PD patients was associated with different reaction to this therapeutic modality.
METHODS
Resting-state fMRI signature elicited by STN DBS activation and deactivation in 81 PD patients was compared against healthy controls, with the focus on measures of efficiency of information processing and localised subnetwork differences.
RESULTS
While all the MRI metrics showed statistically significant differences between PD patients in DBS OFF condition and healthy controls, none were detected in such a comparison against DBS ON condition. Furthermore, in the post-DBS evaluation, PD patients with MADD in the pre-DBS stage showed no differences in depression scales compared to pre-DBS psychiatrically intact PD patients, but still exhibited lower DBS-related connectivity in a subnetwork encompassing anterior and posterior cingulate, dorsolateral prefrontal and medial temporal cortices.
CONCLUSIONS
STN DBS improved all the metrics of interest towards the healthy state, normalising the resting-state MRI signature of PD. Furthermore, pre-DBS presence of MADD, even though clinically silent at post-DBS MRI acquisition, was associated with lower DBS effect in areas highly relevant for depression. This finding points to a possibly latent nature of post-DBS MADD, calling for caution in further follow-up of these patients.
PubMed: 38778942
DOI: 10.1016/j.heliyon.2024.e30698 -
Proceedings of the National Academy of... May 2024Speech impediments are a prominent yet understudied symptom of Parkinson's disease (PD). While the subthalamic nucleus (STN) is an established clinical target for...
Speech impediments are a prominent yet understudied symptom of Parkinson's disease (PD). While the subthalamic nucleus (STN) is an established clinical target for treating motor symptoms, these interventions can lead to further worsening of speech. The interplay between dopaminergic medication, STN circuitry, and their downstream effects on speech in PD is not yet fully understood. Here, we investigate the effect of dopaminergic medication on STN circuitry and probe its association with speech and cognitive functions in PD patients. We found that changes in intrinsic functional connectivity of the STN were associated with alterations in speech functions in PD. Interestingly, this relationship was characterized by altered functional connectivity of the dorsolateral and ventromedial subdivisions of the STN with the language network. Crucially, medication-induced changes in functional connectivity between the STN's dorsolateral subdivision and key regions in the language network, including the left inferior frontal cortex and the left superior temporal gyrus, correlated with alterations on a standardized neuropsychological test requiring oral responses. This relation was not observed in the written version of the same test. Furthermore, changes in functional connectivity between STN and language regions predicted the medication's downstream effects on speech-related cognitive performance. These findings reveal a previously unidentified brain mechanism through which dopaminergic medication influences speech function in PD. Our study sheds light into the subcortical-cortical circuit mechanisms underlying impaired speech control in PD. The insights gained here could inform treatment strategies aimed at mitigating speech deficits in PD and enhancing the quality of life for affected individuals.
Topics: Humans; Parkinson Disease; Subthalamic Nucleus; Male; Speech; Female; Middle Aged; Language; Aged; Magnetic Resonance Imaging; Dopamine; Nerve Net; Cognition; Dopamine Agents
PubMed: 38768342
DOI: 10.1073/pnas.2316149121 -
Research Square May 2024Subthalamic nucleus deep brain stimulation (STN-DBS) alleviates motor symptoms of Parkinson's disease (PD), thereby improving quality of life. However, quantitative...
Subthalamic nucleus deep brain stimulation (STN-DBS) alleviates motor symptoms of Parkinson's disease (PD), thereby improving quality of life. However, quantitative brain markers to evaluate DBS responses and select suitable patients for surgery are lacking. Here, we used metabolic brain imaging to identify a reproducible STN-DBS network for which individual expression levels increased with stimulation in proportion to motor benefit. Of note, measurements of network expression from metabolic and BOLD imaging obtained preoperatively predicted motor outcomes determined after DBS surgery. Based on these findings, we computed network expression in 175 PD patients, with time from diagnosis ranging from 0 to 21 years, and used the resulting data to predict the outcome of a potential STN-DBS procedure. While minimal benefit was predicted for patients with early disease, the proportion of potential responders increased after 4 years. Clinically meaningful improvement with stimulation was predicted in 18.9 - 27.3% of patients depending on disease duration.
PubMed: 38766007
DOI: 10.21203/rs.3.rs-4178280/v1 -
Psychiatry and Clinical... Dec 2023The aim of the study was to investigatie apathy and cognitive functions in Parkinson's disease patients who underwent deep brain stimulation surgery on bilateral...
BACKGROUND
The aim of the study was to investigatie apathy and cognitive functions in Parkinson's disease patients who underwent deep brain stimulation surgery on bilateral subthalamic nuclei.
METHODS
This study included 18 patients with Parkinson's disease who were accommodated in the Parkinson's and Movement Disorders Center of Adana City Training and Research Hospital for treatment in 2022. Patients were evaluated by psychiatry, neurology and neurosurgery specialists with a multidisciplinary approach and found to be surgically appropriate. Standardized Mini-Mental Test and Montreal Cognitive Assessment Scale, Apathy Evaluation Scale, and Hamilton Anxiety and Depression Scale were administered to each patient before the operation and at 6 months after effective stimulation parameters were reached.
RESULTS
The mean apathy score at the preoperative zeroth month was 47.77 ± 15.83 in patients having deep brain stimulation surgery and 30.83 ± 13.59 in the postoperative sixth month. Statistically that reduction was significant ( = .003) and showed clinical development. The average Hamilton Anxiety Scale scores at the preoperative zeroth month was 11.50 ± 5.14 and 10.22 ± 5.57 at the postoperative sixth month, with no clinical significance ( = .280). The determined value for the Unified Parkinson's Disease Rating Scale, on treatment, was 22.55 ± 7.53 in the preoperative zeroth month and 14.50 ± 6.99 in the postoperative sixth month, with statistical significance (). The Unified Parkinson's Disease Rating Scale, off treatment, score was revealed to be significant in the preoperative zeroth month (37.44 ± 9.85) in comparison to that of the postoperative sixth month (23.44 ± 7.86; < .001).
CONCLUSION
This study showed that bilateral subthalamic stimulation improves nonmotor and motor symptoms in patients having Parkinson's disease. The mechanism is complex, and we believe that future studies focusing on pharmacological and nonpharmacological treatments involving more patient groups will be useful for clinicians.
PubMed: 38765847
DOI: 10.5152/pcp.2023.23621 -
NPJ Parkinson's Disease May 2024Deep brain stimulation of the subthalamic nucleus (STN-DBS) effectively treats motor and non-motor symptoms in advanced Parkinson's disease (PD). As considerable...
Deep brain stimulation of the subthalamic nucleus (STN-DBS) effectively treats motor and non-motor symptoms in advanced Parkinson's disease (PD). As considerable interindividual variability of outcomes exists, neuroimaging-based biomarkers, including microstructural metrics, have been proposed to anticipate treatment response. In this prospective open-label study, we sought to detect microstructural properties of brain areas associated with short-term non-motor outcomes following STN-DBS. Thirty-seven PD patients underwent diffusion MRI and clinical assessments at preoperative baseline and 6-month follow-up. Whole brain voxel-wise analysis assessed associations between microstructural metrics and non-motor outcomes. Intact microstructure within specific areas, including the right insular cortex, right putamen, right cingulum, and bilateral corticospinal tract were associated with greater postoperative improvement of non-motor symptom burden. Furthermore, microstructural properties of distinct brain regions were associated with postoperative changes in sleep, attention/memory, urinary symptoms, and apathy. In conclusion, diffusion MRI could support preoperative patient counselling by identifying patients with above- or below-average non-motor responses.
PubMed: 38762510
DOI: 10.1038/s41531-024-00717-y