-
Brain : a Journal of Neurology Jul 2023The parkinsonian gait disorder and freezing of gait are therapeutically demanding symptoms with considerable impact on quality of life. The aim of this study was to...
The parkinsonian gait disorder and freezing of gait are therapeutically demanding symptoms with considerable impact on quality of life. The aim of this study was to assess the role of subthalamic and nigral neurons in the parkinsonian gait control using intraoperative microelectrode recordings of basal ganglia neurons during a supine stepping task. Twelve male patients (56 ± 7 years) suffering from moderate idiopathic Parkinson's disease (disease duration 10 ± 3 years, Hoehn and Yahr stage 2), undergoing awake neurosurgery for deep brain stimulation, participated in the study. After 10 s resting, stepping at self-paced speed for 35 s was followed by short intervals of stepping in response to random 'start' and 'stop' cues. Single- and multi-unit activity was analysed offline in relation to different aspects of the stepping task (attentional 'start' and 'stop' cues, heel strikes, stepping irregularities) in terms of firing frequency, firing pattern and oscillatory activity. Subthalamic nucleus and substantia nigra neurons responded to different aspects of the stepping task. Of the subthalamic nucleus neurons, 24% exhibited movement-related activity modulation as an increase of the firing rate, suggesting a predominant role of the subthalamic nucleus in motor aspects of the task, while 8% of subthalamic nucleus neurons showed a modulation in response to the attentional cues. In contrast, responsive substantia nigra neurons showed activity changes exclusively associated with attentional aspects of the stepping task (15%). The firing pattern of subthalamic nucleus neurons revealed gait-related firing regularization and a drop of beta oscillations during the stepping performance. During freezing episodes instead, there was a rise of beta oscillatory activity. This study shows for the first time specific, task-related subthalamic nucleus and substantia nigra single-unit activity changes during gait-like movements in humans with differential roles in motor and attentional control of gait. The emergence of perturbed firing patterns in the subthalamic nucleus indicates a disrupted information transfer within the gait network, resulting in freezing of gait.
Topics: Humans; Male; Deep Brain Stimulation; Gait; Gait Disorders, Neurologic; Neurons; Parkinson Disease; Parkinsonian Disorders; Quality of Life; Substantia Nigra
PubMed: 36730026
DOI: 10.1093/brain/awad006 -
The Journal of Neuroscience : the... Nov 2021Tremor, a common and often primary symptom of Parkinson's disease, has been modeled with distinct onset and maintenance dynamics. To identify the neurophysiologic...
Tremor, a common and often primary symptom of Parkinson's disease, has been modeled with distinct onset and maintenance dynamics. To identify the neurophysiologic correlates of each state, we acquired intraoperative cortical and subthalamic nucleus recordings from 10 patients (9 male, 1 female) performing a naturalistic visual-motor task. From this task, we isolated short epochs of tremor onset and sustained tremor. Comparing these epochs, we found that the subthalamic nucleus was central to tremor onset, as it drove both motor cortical activity and tremor output. Once tremor became sustained, control of tremor shifted to cortex. At the same time, changes in directed functional connectivity across sensorimotor cortex further distinguished the sustained tremor state. Tremor is a common symptom of Parkinson's disease (PD). While tremor pathophysiology is thought to involve both basal ganglia and cerebello-thalamic-cortical circuits, it is unknown how these structures functionally interact to produce tremor. In this article, we analyzed intracranial recordings from the subthalamic nucleus and sensorimotor cortex in patients with PD undergoing deep brain stimulation surgery. Using an intraoperative task, we examined tremor in two separate dynamic contexts: when tremor first emerged, and when tremor was sustained. We believe that these findings reconcile several models of Parkinson's tremor, while describing the short-timescale dynamics of subcortical-cortical interactions during tremor for the first time. These findings may describe a framework for developing proactive and responsive neurostimulation models for specifically treating tremor.
Topics: Aged; Electrocorticography; Female; Humans; Male; Middle Aged; Neural Pathways; Parkinson Disease; Sensorimotor Cortex; Subthalamic Nucleus; Tremor
PubMed: 34702744
DOI: 10.1523/JNEUROSCI.0854-21.2021 -
Brain Communications 2023Freezing of gait is a common and debilitating symptom in Parkinson's disease. Although high-frequency subthalamic deep brain stimulation is an effective treatment for...
Freezing of gait is a common and debilitating symptom in Parkinson's disease. Although high-frequency subthalamic deep brain stimulation is an effective treatment for Parkinson's disease, post-operative freezing of gait severity has been reported to alleviate, deteriorate or remain constant. We conducted this study to explore the optimal stimulation sites and related connectivity networks for high-frequency subthalamic deep brain stimulation treating freezing of gait in Parkinson's disease. A total of 76 Parkinson's disease patients with freezing of gait who underwent bilateral high-frequency subthalamic stimulation were retrospectively included. The volumes of tissue activated were estimated based on individual electrode reconstruction. The optimal and sour stimulation sites were calculated at coordinate/voxel/mapping level and mapped to anatomical space based on patient-specific images and stimulation settings. The structural and functional predictive connectivity networks for the change of the post-operative Freezing of Gait-Questionnaire were also identified based on normative connectomes derived from the Parkinson's Progression Marker Initiative database. Leave-one-out cross-validation model validated the above results, and the model remained significant after including covariates. The dorsolateral two-thirds of the subthalamic nucleus was identified as the optimal stimulation site, while the ventrocentral portion of the right subthalamic nucleus and internal capsule surrounding the left central subthalamic nucleus were considered as the sour stimulation sites. Modulation of the fibre tracts connecting to the supplementary motor area, pre-supplementary motor area and pedunculopontine nucleus accounted for the alleviation of freezing of gait, whereas tracts connecting to medial and ventrolateral prefrontal cortices contributed to the deterioration of freezing of gait. The optimal/sour stimulation sites and structural/functional predictive connectivity networks for high-frequency subthalamic deep brain stimulation treating freezing of gait are identified and validated through sizable Parkinson's disease patients in this study. With the growing understanding of stimulation sites and related networks, individualized deep brain stimulation treatment with directional leads will become an optimal choice for Parkinson's disease patients with freezing of gait in the future.
PubMed: 37701817
DOI: 10.1093/braincomms/fcad238 -
Turkish Neurosurgery 2023To investigate the surgical value of MER recordings and improve surgical technique by demonstrating the consistency between preoperative radiological STN volume and...
AIM
To investigate the surgical value of MER recordings and improve surgical technique by demonstrating the consistency between preoperative radiological STN volume and intraoperative neurophysiological STN length.
MATERIAL AND METHODS
Sixty-one patients with PD were enrolled. The volumes of the STN were measured using magnetic resonance images 3-dimensional volume reconstructions of stereotactic magnetic resonance images. MER were performed in all patient and the maximal electrophysiologic length of the STN was recorded each patient. In the postoperative period, the permanent electrode was modeled and reconstructed in 3D, and the longest distance traveled in the STN was calculated.
RESULTS
A total of 61 patients who underwent surgery between 2012-2022 were included in the study. Thirty-six (59%) of the patients were male, and 25 (41%) were female. A total of 122 STNs were performed with 166 electrodes. The most common end alignment used was center with 86. STN length averaged 4.9 mm (0-10.5 mm). The mean STN volume was 0.11 cm3. The STN Volume of men were significantly higher than women. The STN Length, Volume, and the target MER length showed a positive correlation significantly.
CONCLUSION
With radiological advances, it is possible to better visualize the target points and define the boundaries better, and direct methods can be used more in making targeting plans. MER records obtained during surgery and STN dimensions in presurgical planning show compatibility, and it is seen that there may be differences between the right and left sides because of brain shifting. Although radiology is increasingly providing better support, electrophysiological recordings provides real-time information on the electrodes? locations and give the opportunity to surgical team choosing alternative target.
Topics: Humans; Male; Female; Parkinson Disease; Subthalamic Nucleus; Deep Brain Stimulation; Radiography; Magnetic Resonance Imaging; Radiology; Electrodes, Implanted; Microelectrodes
PubMed: 36128921
DOI: 10.5137/1019-5149.JTN.42157-22.1 -
CNS Neuroscience & Therapeutics Jul 2023Patients with Parkinson's disease (PD) have various motor difficulties, including standing up, gait initiation and freezing of gait. These abnormalities are associated...
AIMS
Patients with Parkinson's disease (PD) have various motor difficulties, including standing up, gait initiation and freezing of gait. These abnormalities are associated with cortico-subthalamic dysfunction. We aimed to reveal the characteristics of cortico-subthalamic activity in PD patients during different motor statuses.
METHODS
Potentials were recorded in the superior parietal lobule (SPL), the primary motor cortex (M1), premotor cortex (PMC), and the bilateral subthalamic nucleus (STN) in 18 freely walking patients while sitting, standing, walking, dual-task walking, and freezing in medication "off" (Moff) and "on" (Mon) states. Different motor status activities were compared in band power, and a machine learning classifier was used to differentiate the motor statuses.
RESULTS
SPL beta power was specifically inhibited from standing to walking, and negatively correlated with walking speed; M1 beta power reflected the degree of rigidity and was reversed by medication; XGBoost algorithm classified the five motor statuses with acceptable accuracy (68.77% in Moff, 60.58% in Mon). SPL beta power ranked highest in feature importance in both Moff and Mon states.
CONCLUSION
SPL beta power plays an essential role in walking status classification and could be a physiological biomarker for walking speed, which would aid the development of adaptive DBS.
Topics: Humans; Parkinson Disease; Gait Disorders, Neurologic; Deep Brain Stimulation; Subthalamic Nucleus; Gait
PubMed: 37017365
DOI: 10.1111/cns.14155 -
Frontiers in Neuroanatomy 2020The Subthalamic Nucleus (STh) is an oval-shaped diencephalic structure located ventrally to the thalamus, playing a fundamental role in the circuitry of the basal... (Review)
Review
The Subthalamic Nucleus (STh) is an oval-shaped diencephalic structure located ventrally to the thalamus, playing a fundamental role in the circuitry of the basal ganglia. In addition to being involved in the pathophysiology of several neurodegenerative disorders, such as Huntington's and Parkinson's disease, the STh is one of the target nuclei for deep brain stimulation. However, most of the anatomical evidence available derives from non-human primate studies. In this review, we will present the topographical and morphological organization of the nucleus and its connections to structurally and functionally related regions of the basal ganglia circuitry. We will also highlight the importance of additional research in humans focused on validating STh connectivity, cytoarchitectural organization, and its functional subdivision.
PubMed: 32390807
DOI: 10.3389/fnana.2020.00013 -
ENeuro 2022The subthalamic nucleus (STN) is a small, excitatory nucleus that regulates the output of basal ganglia motor circuits. The functions of the STN and its role in the... (Review)
Review
The subthalamic nucleus (STN) is a small, excitatory nucleus that regulates the output of basal ganglia motor circuits. The functions of the STN and its role in the pathophysiology of Parkinson's disease are now well established. However, some basic characteristics like the developmental origin and molecular phenotype of neuronal subpopulations are still being debated. The classical model of forebrain development attributed the origin of STN within the diencephalon. Recent studies of gene expression patterns exposed shortcomings of the classical model. To accommodate these findings, the prosomeric model was developed. In this concept, STN develops within the hypothalamic primordium, which is no longer a part of the diencephalic primordium. This concept is further supported by the expression patterns of many transcription factors. It is interesting to note that many transcription factors involved in the development of the STN are also involved in the pathogenesis of neurodevelopmental disorders. Thus, the study of neurodevelopmental disorders could provide us with valuable information on the roles of these transcription factors in the development and maintenance of STN phenotype. In this review, we summarize historical theories about the developmental origin of the STN and interpret the gene expression data within the prosomeric conceptual framework. Finally, we discuss the importance of neurodevelopmental disorders for the development of the STN and its potential role in the pathophysiology of neurodevelopmental disorders.
Topics: Humans; Subthalamic Nucleus; Basal Ganglia; Neurons; Parkinson Disease; Transcription Factors
PubMed: 36257692
DOI: 10.1523/ENEURO.0193-22.2022 -
Frontiers in Neuroscience 2022The human Subthalamic Nucleus (STh) is a diencephalic lens-shaped structure located ventrally to the thalamus and functionally implicated in the basal ganglia circuits....
The human Subthalamic Nucleus (STh) is a diencephalic lens-shaped structure located ventrally to the thalamus and functionally implicated in the basal ganglia circuits. Despite recent efforts to characterize the neurochemical and functional anatomy of the STh, little to no information is available concerning the expression and distribution of receptors belonging to the dopaminergic and purinergic system in the human STh. Both systems are consistently implicated in basal ganglia physiology and pathology, especially in Parkinson's Disease, and represent important targets for the pharmacological treatment of movement disorders. Here, we investigate the topography and distribution of A adenosine and D dopamine receptors in the human basal ganglia and subthalamic nucleus. Our findings indicate a peculiar topographical distribution of the two receptors throughout the subthalamic nucleus, while colocalization between the receptors opens the possibility for the presence of AR- DR heterodimers within the dorsal and medial aspects of the structure. However, further investigation is required to confirm these findings.
PubMed: 36017181
DOI: 10.3389/fnins.2022.945574 -
Cell Reports Nov 2023The subthalamic nucleus (STN) is critical for behavioral control; its dysregulation consequently correlated with neurological and neuropsychiatric disorders, including...
The subthalamic nucleus (STN) is critical for behavioral control; its dysregulation consequently correlated with neurological and neuropsychiatric disorders, including Parkinson's disease. Deep brain stimulation (DBS) targeting the STN successfully alleviates parkinsonian motor symptoms. However, low mood and depression are affective side effects. STN is adjoined with para-STN, associated with appetitive and aversive behavior. DBS aimed at STN might unintentionally modulate para-STN, causing aversion. Alternatively, the STN mediates aversion. To investigate causality between STN and aversion, affective behavior is addressed using optogenetics in mice. Selective promoters allow dissociation of STN (e.g., Pitx2) vs. para-STN (Tac1). Acute photostimulation results in aversion via both STN and para-STN. However, only STN stimulation-paired cues cause conditioned avoidance and only STN stimulation interrupts on-going sugar self-administration. Electrophysiological recordings identify post-synaptic responses in pallidal neurons, and selective photostimulation of STN terminals in the ventral pallidum replicates STN-induced aversion. Identifying STN as a source of aversive learning contributes neurobiological underpinnings to emotional affect.
Topics: Animals; Mice; Subthalamic Nucleus; Avoidance Learning; Deep Brain Stimulation; Parkinson Disease; Parkinsonian Disorders
PubMed: 37925641
DOI: 10.1016/j.celrep.2023.113328 -
Movement Disorders : Official Journal... Aug 2023Gait freezing is a common, disabling symptom of Parkinson's disease characterized by sudden motor arrest during walking. Adaptive deep brain stimulation devices that...
BACKGROUND
Gait freezing is a common, disabling symptom of Parkinson's disease characterized by sudden motor arrest during walking. Adaptive deep brain stimulation devices that detect freezing and deliver real-time, symptom-specific stimulation are a potential treatment strategy. Real-time alterations in subthalamic nucleus firing patterns have been demonstrated with lower limb freezing, however, whether similar abnormal signatures occur with freezing provoked by cognitive load, is unknown.
METHODS
We obtained subthalamic nucleus microelectrode recordings from eight Parkinson's disease patients performing a validated virtual reality gait task, requiring responses to on-screen cognitive cues while maintaining motor output.
RESULTS
Signal analysis during 15 trials containing freezing or significant motor output slowing precipitated by dual-tasking demonstrated reduced θ frequency (3-8 Hz) firing compared to 18 unaffected trials.
CONCLUSIONS
These preliminary results reveal a potential neurobiological basis for the interplay between cognitive factors and gait disturbances including freezing in Parkinson's disease, informing development of adaptive deep brain stimulation protocols. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Subthalamic Nucleus; Parkinson Disease; Gait Disorders, Neurologic; Deep Brain Stimulation; Gait; Cognition
PubMed: 37226972
DOI: 10.1002/mds.29455