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Communications Biology Jan 2024The subthalamic nucleus (STN) is a major neuromodulation target for the alleviation of neurological and neuropsychiatric symptoms using deep brain stimulation (DBS).... (Review)
Review
The subthalamic nucleus (STN) is a major neuromodulation target for the alleviation of neurological and neuropsychiatric symptoms using deep brain stimulation (DBS). STN-DBS is today applied as treatment in Parkinson´s disease, dystonia, essential tremor, and obsessive-compulsive disorder (OCD). STN-DBS also shows promise as a treatment for refractory Tourette syndrome. However, the internal organization of the STN has remained elusive and challenges researchers and clinicians: How can this small brain structure engage in the multitude of functions that renders it a key hub for therapeutic intervention of a variety of brain disorders ranging from motor to affective to cognitive? Based on recent gene expression studies of the STN, a comprehensive view of the anatomical and cellular organization, including revelations of spatio-molecular heterogeneity, is now possible to outline. In this review, we focus attention to the neurobiological architecture of the STN with specific emphasis on molecular patterns discovered within this complex brain area. Studies from human, non-human primate, and rodent brains now reveal anatomically defined distribution of specific molecular markers. Together their spatial patterns indicate a heterogeneous molecular architecture within the STN. Considering the translational capacity of targeting the STN in severe brain disorders, the addition of molecular profiling of the STN will allow for advancement in precision of clinical STN-based interventions.
Topics: Animals; Humans; Subthalamic Nucleus; Brain; Parkinson Disease; Research Personnel
PubMed: 38200143
DOI: 10.1038/s42003-023-05691-4 -
The Journal of Neuroscience : the... Jun 2022The cortico-basal ganglia circuit is needed to suppress prepotent actions and to facilitate controlled behavior. Under conditions of response conflict, the frontal...
The cortico-basal ganglia circuit is needed to suppress prepotent actions and to facilitate controlled behavior. Under conditions of response conflict, the frontal cortex and subthalamic nucleus (STN) exhibit increased spiking and theta band power, which are linked to adaptive regulation of behavioral output. The electrophysiological mechanisms underlying these neural signatures of impulse control remain poorly understood. To address this lacuna, we constructed a novel large-scale, biophysically principled model of the subthalamopallidal (STN-globus pallidus externus) network and examined the mechanisms that modulate theta power and spiking in response to cortical input. Simulations confirmed that theta power does not emerge from intrinsic network dynamics but is robustly elicited in response to cortical input as burst events representing action selection dynamics. Rhythmic burst events of multiple cortical populations, representing a state of conflict where cortical motor plans vacillate in the theta range, led to prolonged STN theta and increased spiking, consistent with empirical literature. Notably, theta band signaling required NMDA, but not AMPA, currents, which were in turn related to a triphasic STN response characterized by spiking, silence, and bursting periods. Finally, theta band resonance was also strongly modulated by architectural connectivity, with maximal theta arising when multiple cortical populations project to individual STN "conflict detector" units because of an NMDA-dependent supralinear response. Our results provide insights into the biophysical principles and architectural constraints that give rise to STN dynamics during response conflict, and how their disruption can lead to impulsivity and compulsivity. The subthalamic nucleus exhibits theta band power modulation related to cognitive control over motor actions during conditions of response conflict. However, the mechanisms of such dynamics are not understood. Here we developed a novel biophysically detailed and data-constrained large-scale model of the subthalamopallidal network, and examined the impacts of cellular and network architectural properties that give rise to theta dynamics. Our investigations implicate an important role for NMDA receptors and cortico-subthalamic nucleus topographical connectivities in theta power modulation.
Topics: Basal Ganglia; Globus Pallidus; Motor Cortex; N-Methylaspartate; Subthalamic Nucleus
PubMed: 35477903
DOI: 10.1523/JNEUROSCI.2433-19.2022 -
Brain Structure & Function Sep 2023The Subthalamic Nucleus (STh) is a lens-shaped subcortical structure located ventrally to the thalamus, that despite being embryologically derived from the diencephalon,... (Review)
Review
The Subthalamic Nucleus (STh) is a lens-shaped subcortical structure located ventrally to the thalamus, that despite being embryologically derived from the diencephalon, is functionally implicated in the basal ganglia circuits. Because of this strict structural and functional relationship with the circuits of the basal ganglia, the STh is a current target for deep brain stimulation, a neurosurgical procedure employed to alleviate symptoms in movement disorders, such as Parkinson's disease and dystonia. However, despite the great relevance of this structure for both basal ganglia physiology and pathology, the neurochemical and molecular anatomy of the STh remains largely unknown. Few studies have specifically addressed the detection of neurotransmitter systems and their receptors within the structure, and even fewer have investigated their topographical distribution. Here, we have reviewed the scientific literature on neurotransmitters relevant in the STh function of rodents, non-human primates and humans including glutamate, GABA, dopamine, serotonin, noradrenaline with particular focus on their subcellular, cellular and topographical distribution. Inter-species differences were highlighted to provide a framework for further research priorities, particularly in humans.
Topics: Animals; Humans; Subthalamic Nucleus; Basal Ganglia; Thalamus; Dopamine; Parkinson Disease
PubMed: 37479801
DOI: 10.1007/s00429-023-02678-z -
Brain : a Journal of Neurology Jun 2021Pain is a frequent and poorly treated symptom of Parkinson's disease, mainly due to scarce knowledge of its basic mechanisms. In Parkinson's disease, deep brain... (Review)
Review
Pain is a frequent and poorly treated symptom of Parkinson's disease, mainly due to scarce knowledge of its basic mechanisms. In Parkinson's disease, deep brain stimulation of the subthalamic nucleus is a successful treatment of motor symptoms, but also might be effective in treating pain. However, it has been unclear which type of pain may benefit and how neurostimulation of the subthalamic nucleus might interfere with pain processing in Parkinson's disease. We hypothesized that the subthalamic nucleus may be an effective access point for modulation of neural systems subserving pain perception and processing in Parkinson's disease. To explore this, we discuss data from human neurophysiological and psychophysical investigations. We review studies demonstrating the clinical efficacy of deep brain stimulation of the subthalamic nucleus for pain relief in Parkinson's disease. Finally, we present some of the key insights from investigations in animal models, healthy humans and Parkinson's disease patients into the aberrant neurobiology of pain processing and consider their implications for the pain-relieving effects of subthalamic nucleus neuromodulation. The evidence from clinical and experimental studies supports the hypothesis that altered central processing is critical for pain generation in Parkinson's disease and that the subthalamic nucleus is a key structure in pain perception and modulation. Future preclinical and clinical research should consider the subthalamic nucleus as an entry point to modulate different types of pain, not only in Parkinson's disease but also in other neurological conditions associated with abnormal pain processing.
Topics: Animals; Deep Brain Stimulation; Humans; Pain; Parkinson Disease; Subthalamic Nucleus
PubMed: 34037696
DOI: 10.1093/brain/awab001 -
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 -
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 -
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 -
Science (New York, N.Y.) Oct 2021Symptoms of neurological diseases emerge through the dysfunction of neural circuits whose diffuse and intertwined architectures pose serious challenges for delivering...
Symptoms of neurological diseases emerge through the dysfunction of neural circuits whose diffuse and intertwined architectures pose serious challenges for delivering therapies. Deep brain stimulation (DBS) improves Parkinson’s disease symptoms acutely but does not differentiate between neuronal circuits, and its effects decay rapidly if stimulation is discontinued. Recent findings suggest that optogenetic manipulation of distinct neuronal subpopulations in the external globus pallidus (GPe) provides long-lasting therapeutic effects in dopamine-depleted (DD) mice. We used synaptic differences to excite parvalbumin-expressing GPe neurons and inhibit lim-homeobox-6–expressing GPe neurons simultaneously using brief bursts of electrical stimulation. In DD mice, circuit-inspired DBS provided long-lasting therapeutic benefits that far exceeded those induced by conventional DBS, extending several hours after stimulation. These results establish the feasibility of transforming knowledge of circuit architecture into translatable therapeutic approaches.
Topics: Animals; Deep Brain Stimulation; Disease Models, Animal; Dopamine; Female; Globus Pallidus; Male; Mice; Mice, Inbred C57BL; Neurons; Optogenetics; Parkinson Disease; Subthalamic Nucleus; Synapses; Transcutaneous Electric Nerve Stimulation
PubMed: 34618556
DOI: 10.1126/science.abi7852 -
Acta Neurologica Belgica Aug 2021Standard treatment of Parkinson's disease involves the dopaminergic medications. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an important... (Review)
Review
Standard treatment of Parkinson's disease involves the dopaminergic medications. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an important neurosurgical intervention often used as alternative treatment to drug therapy; however, it can be associated with increase of impulsive behaviors. This descriptive review focused on studies investigating the correlation between Deep brain stimulation of the subthalamic nucleus and impulsivity in Parkinson's disease patients, arguing, the action's mechanism and the specific role of the subthalamic nucleus. We searched on PubMed and Web of Science databases and screening references of included studies and review articles for additional citations. From initial 106 studies, only 15 met the search criteria. Parkinson's Disease patients with and without Deep Brain Stimulation were compared with healthy controls, through 16 different tasks that assessed some aspects of impulsivity. Both Deep brain stimulation of the subthalamic nucleus and medication were associated with impulsive behavior and influenced decision-making processes. Moreover, findings demonstrated that: Impulse Control Disorders (ICDs) occurred soon after surgery, while, in pharmacological treatment, they appeared mainly after the initiation of treatment or the increase in dosage, especially with dopamine agonists. The subthalamic nucleus plays a part in the fronto-striato-thalamic-cortical loops mediating motor, cognitive, and emotional functions: this could explain the role of the Deep Brain Stimulation in behavior modulation in Parkinson's Disease patients. Indeed, increase impulsivity has been reported also after deep brain stimulation of the subthalamic nucleus independently by dopaminergic medication status.
Topics: Deep Brain Stimulation; Dopamine; Dopamine Agents; Humans; Impulsive Behavior; Parkinson Disease; Subthalamic Nucleus
PubMed: 33961279
DOI: 10.1007/s13760-021-01684-4