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Abstract

Modern functional neurosurgery for movement disorders such as Parkinson's disease, tremor, and dystonia involves the placement of focal lesions or the application of deep brain stimulation (DBS) within circuits that modulate motor function. Precise targeting of these motor structures can be further refined by the use of electrophysiological approaches. In particular, microelectrode recordings enable the delineation of neuroanatomic structures. In the course of these operations, there is an opportunity not only to map basal ganglia structures but also to gain insights into how disturbances in neural activity produce movement disorders. In this review, we aim to highlight what the field has uncovered thus far about movement disorders through DBS. The work to date lays the foundation for future studies that will shed further light on dysfunctional circuits mediating diseases of the nervous system and how we might modulate these circuits therapeutically.

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... At the site of electrode implantation, DBS may modulate local neuronal activity by direct stimulation of axons and dendrites. 3 Alterations in local firing patterns could also have important effects on the synchronization of neuronal networks by disrupting pathological oscillatory activity in diseased brain regions (e.g. excessive b oscillations in the basal ganglia of PD patients). ...
... excessive b oscillations in the basal ganglia of PD patients). 3 This electrical modulation relieves motor symptoms within seconds of current onset, as shown by the immediate relief of essential tremor when current is delivered through a DBS electrode in the ventral intermediate nucleus of the thalamus (VIM). 4 However, growing evidence suggests that DBS is more than just a "neuromodulatory switch" to control debilitating motor symptoms. ...
... 6 The mechanism underlying DBS-mediated motor symptom control remains uncertain, however it is likely to involve both local effects on neuronal firing patterns and network-wide effects on pathological oscillatory activity. 3,7 In addition to effective relief of motor symptoms, emerging evidence from preclinical models suggests that long-term DBS may have the potential to protect against neuronal loss and limit motor dysfunction. However it remains uncertain whether this occurs by mitigating pathological oscillatory activity or through other mechanisms. ...
Article
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Over the last two decades there has been an exponential rise in the number of patients receiving deep brain stimulation (DBS) to manage debilitating neurological symptoms in conditions such as Parkinson's disease, essential tremor, and dystonia. Novel applications of DBS continue to emerge including treatment of various psychiatric conditions (e.g. obsessive‐compulsive disorder, major depression) and cognitive disorders such as Alzheimer's disease. Despite widening therapeutic applications, our understanding of the mechanisms underlying DBS remains limited. In addition to modulation of local and network‐wide neuronal activity, growing evidence suggests that DBS may also have important neuroprotective effects in the brain by limiting synaptic dysfunction and neuronal loss in neurodegenerative disorders. In this review, we consider evidence from preclinical and clinical studies of DBS in Parkinson's disease, Alzheimer's disease, and epilepsy that suggest chronic stimulation has the potential to mitigate neuronal loss and disease progression.
... Deep brain stimulation (DBS) is a standard treatment for medication-refractory movement disorders such as Parkinson's disease and essential tremor (Kalia et al., 2013;Lozano et al., 2017). Electrical fields induced by DBS can directly modulate the activity of target neurons as well as indirectly affect distant neuronal populations within the same circuitry to alter electrical oscillations of brain networks (Lozano et al., 2017). ...
... Deep brain stimulation (DBS) is a standard treatment for medication-refractory movement disorders such as Parkinson's disease and essential tremor (Kalia et al., 2013;Lozano et al., 2017). Electrical fields induced by DBS can directly modulate the activity of target neurons as well as indirectly affect distant neuronal populations within the same circuitry to alter electrical oscillations of brain networks (Lozano et al., 2017). Previous studies have demonstrated that DBS also modulates endogenous gene expression at the stimulation target, as well as in distant synaptically-connected brain regions (Gondard et al., 2015;Mann et al., 2017). ...
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Background Mechanisms of deep brain stimulation (DBS) remain controversial, and spatiotemporal control of brain-wide circuits remains elusive. Adeno-associated viral (AAV) vectors have emerged as vehicles for spatiotemporal expression of exogenous transgenes in several tissues, including specific nuclei in the brain. Coupling DBS with viral vectors to modulate exogenous transgene expression remains unexplored. Objective This study examines whether DBS of the medial septal nucleus (MSN) can regulate gene expression of AAV-transduced neurons in a brain region anatomically remote from the stimulation target: the hippocampal dentate gyrus. Methods Rats underwent unilateral hippocampal injection of an AAV vector with c-Fos promoter-driven expression of TdTomato (TdT), followed by medial septal nucleus (MSN) electrode implantation. Rodents received no stimulation, 7.7 Hz (theta), or 130 Hz (gamma) DBS for 1 hour one week after surgery. In a repeat stimulation experiment, rodents received either no stimulation, or two 1 hour MSN DBS over 2 weeks. Results No significant differences in hippocampal TdT expression between controls and acute MSN DBS were found. With repeat DBS we found c-Fos protein expression was induced and we could detect increased TdT with either gamma or theta stimulation. Conclusion We demonstrate that viral vector-mediated gene expression can be regulated spatially and temporally using DBS. Control of gene expression by DBS warrants further investigation into stimulation-responsive promoters for clinical applications.
... Understanding the brain's distinct response to stimulation during different states not only improves our understanding of the mechanisms of consciousness but also has therapeutic implications, as chronic neuromodulation is increasingly common for movement disorders (18)(19)(20)(93)(94)(95)(96), epilepsy (22,24), and psychiatric disorders (25,97,98). Moreover, deep brain stimulation using stimulation trains affects sleep (99)(100)(101). ...
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The neural basis of consciousness remains a major unresolved issue in human neuroscience, with theories of consciousness and experimental studies differing concerning which brain regions are necessary for consciousness. Direct experimental evidence to resolve this debate requires identifying the global, network, and regional involvement during different states of consciousness in humans. We utilized multi-region intracranial single-pulse direct electrical stimulation to examine circuit and network interactions during three canonical states of consciousness: wake vs. arousable unconsciousness (sleep) vs. non-arousable unconsciousness (e.g., propofol-induced general anesthesia). Increased variability in cortical responses, reduced information transfer, and reduced complexity characterized states of diminished consciousness. Notably, however, these metrics differed in different brain regions and types of unconscious states.Anesthesia induced more overall changes in brain responses than sleep, but cortical network engagement depended on the kind of unconsciousness. Brain activity changes were largely anatomically uniform during sleep, contrasting with a substantial and selective disconnection of the prefrontal cortices during anesthesia. These results provide direct evidence from human intracranial recordings during the loss of consciousness, suggesting that the obliteration of consciousness during anesthesia results not from just altered overall physiology but from a disconnection between prefrontal areas and other brain areas. Significance What happens in the human brain when we are unconscious? Despite substantial work, we are still unsure which brain regions are involved and how they are impacted when consciousness is disrupted. Using intracranial recordings and direct electrical stimulation, we mapped global, network, and regional involvement during wake vs. arousable unconsciousness (sleep) vs. non-arousable unconsciousness (propofol-induced general anesthesia). Information integration and complex processing were reduced, while variability increased during the loss of consciousness. These changes were more pronounced during anesthesia than sleep. They also involved different cortical engagement; During sleep, changes were mostly uniformly distributed across the brain while during anesthesia the prefrontal cortex was the most disrupted. These findings indicate different neural signatures for different types of unconsciousness. Highlights · Sleep and anesthesia showed decreased complexity, connectivity, and response amplitude with increased response variability compared to wake states in the human brain. · These changes in brain response to stimulation were more pronounced during propofol-induced general anesthesia than during natural sleep. · During sleep, changes were homogeneously distributed across the brain. · During anesthesia, there was a substantial disconnection of the frontal cortices.
... However, long-term therapy is complicated by motor fluctuations and levodopa-induced dyskinesias, which represent a substantial source of disability in some patients (Nutt, 1990;Obeso et al., 2000). Subsequently, deep brain stimulation (DBS) of the STN or GPi has been widely adapted as a conventional alternative management option (Benabid et al., 1994;Limousin et al., 1995;Kumar et al., 1998Kumar et al., , 2000Kleiner-Fisman et al., 2006;Perlmutter and Mink, 2006;Lozano et al., 2017); as well as recent promising studies demonstrating the efficacy of SNr-DBS, or combined STN/SNr-DBS for the treatment of axial motor symptoms in Parkinson's disease (Chastan et al., 2009;Weiss et al., 2011aWeiss et al., , b, 2013. DBS mimics the effect of beneficial lesions (Bergman et al., 1990;Aziz et al., 1991;Heywood and Gill, 1997) or inactivation by injections of muscimol and lidocaine (Wichmann et al., 1994;Levy et al., 2001), suggesting that DBS may work by inhibition of neuronal activity. ...
Article
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Deep brain stimulation of certain target structures within the basal ganglia is an effective therapy for the management of the motor symptoms of Parkinson’s disease. However, its mechanisms, as well as the pathophysiology of Parkinson’s disease, are varied and complex. The classical model of Parkinson’s disease states that symptoms may arise as a result of increased neuronal activity in the basal ganglia output nuclei due to downregulated GABAergic striato-nigral/-pallidal projections. We sought to investigate the stimulation and levodopa induced effects on inhibitory synaptic plasticity in these basal ganglia output nuclei, and to determine the clinical relevance of altered plasticity with respect to patients’ symptoms. Two closely spaced microelectrodes were advanced into the substantia nigra pars reticulata (potential novel therapeutic target for axial motor symptoms) or globus pallidus internus (conventional therapeutic target) in each of 28 Parkinson’s disease patients undergoing subthalamic or pallidal deep brain stimulation surgery. Sets of 1Hz test-pulses were delivered at different cathodal pulse widths (25, 50, 100, 150, 250us) in randomized order, before and after a train of continuous high frequency stimulation at 100Hz. Increasing the pulse width led to progressive increases in both the amplitudes of extracellular focally evoked inhibitory field potentials and durations of neuronal silent periods. Both of these effects were augmented after a train of continuous high frequency stimulation. Additionally, reductions in the baseline neuronal firing rate persisted beyond one minute after high frequency stimulation. We found greater enhancements of plasticity in the globus pallidus internus compared to the substantia nigra pars reticulata, and that intraoperative levodopa administration had a potent effect on the enhancement of nigral plasticity. We also found that lower levels of nigral plasticity were associated with higher severity motor symptoms. The findings of this study demonstrate that the efficacy of inhibitory synaptic transmission may be involved in the pathophysiology of Parkinson’s disease, and furthermore may have implications for the development of novel stimulation protocols, and advancement of DBS technologies.
... Knowledge of spinal cord stimulation mechanisms will also enhance our overall understanding of the multiple unique and specialized areas in the brain. 117 The brain presents a challenge to researchers because invasive techniques require a high degree of skill, noninvasive imaging lacks spatial detail and temporal resolution, and in vivo experimentation with brain manipulation is problematic. Emerging technologies in neuroscience, such as single-cell RNA sequencing, optogenetics, dynamic imaging, and brain recording, may help overcome these obstacles. ...
Article
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The field of spinal cord stimulation is expanding rapidly, with new waveform paradigms asserting supraspinal sites of action. The scope of treatment applications is also broadening from chronic pain to include cerebral ischemia, dystonia, tremor, multiple sclerosis, Parkinson disease, neuropsychiatric disorders, memory, addiction, cognitive function, and other neurologic diseases. The role of neurostimulation as an alternative strategy to opioids for chronic pain treatment is under robust discussion in both scientific and public forums. An understanding of the supraspinal mechanisms underlying the beneficial effects of spinal cord stimulation will aid in the appropriate application and development of optimal stimulation strategies for modulating pain signaling pathways. In this review, the authors focus on clinical and preclinical studies that indicate the role of supraspinal mechanisms in spinal cord stimulation-induced pain inhibition, and explore directions for future investigations.
... As one of the most successful clinical interventions, deep brain stimulation (DBS) has demonstrated remarkable symptomatic amelioration in a wide range of neurological [1,2] and psychiatric conditions [3,4]. However, the clinical efficacy of brain stimulation is unpredictable on a case-by-case basis, which may be partially due to inter-individual differences in stimulationinduced effects [5,6], and our incomplete understanding of their neural circuit-level mechanisms [2,[7][8][9][10]. To date, Xiaoyu Chen, Chencheng Zhang and Yuxin Li contributed equally to this work. ...
Article
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Neurostimulation remarkably alleviates the symptoms in a variety of brain disorders by modulating the brain-wide network. However, how brain-wide effects on the direct and indirect pathways evoked by focal neurostimulation elicit therapeutic effects in an individual patient is unknown. Understanding this remains crucial for advancing neural circuit-based guidance to optimize candidate patient screening, pre-surgical target selection, and post-surgical parameter tuning. To address this issue, we propose a functional brain connectome-based modeling approach that simulates the spreading effects of stimulating different brain regions and quantifies the rectification of abnormal network topology in silico. We validated these analyses by pinpointing nuclei in the basal ganglia circuits as top-ranked targets for 43 local patients with Parkinson's disease and 90 patients from a public database. Individual connectome-based analysis demonstrated that the globus pallidus was the best choice for 21.1% and the subthalamic nucleus for 19.5% of patients. Down-regulation of functional connectivity (up to 12%) at these prioritized targets optimally maximized the therapeutic effects. Notably, the priority rank of the subthalamic nucleus significantly correlated with motor symptom severity (Unified Parkinson's Disease Rating Scale III) in the local cohort. These findings underscore the potential of neural network modeling for advancing personalized brain stimulation therapy, and warrant future experimental investigation to validate its clinical utility.
... Since its inception, deep brain stimulation (DBS) has revolutionized the management of a broad range of neurological and psychiatric diseases, from movement disorders to epilepsy and obsessive-compulsive disorder. Promising clinical trials have shown preliminary safety and efficacy of DBS as a treatment for disabling symptoms of Alzheimer's disease, depression, and many other conditions (Lozano and Lipsman, 2013;Lozano et al., 2017). The unique ability of electrical modulation of the brain circuits with spatial and temporal accuracy enabled a completely new treatment paradigm complementing pharmacological approaches and lesioning procedures, which lack spatial and temporal control, respectively. ...
Article
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Deep brain stimulation (DBS) represents an important treatment modality for movement disorders and other circuitopathies. Despite their miniaturization and increasing sophistication, DBS systems share a common set of components of which the implantable pulse generator (IPG) is the core power supply and programmable element. Here we provide an overview of key hardware and software specifications of commercially available IPG systems such as rechargeability, MRI compatibility, electrode configuration, pulse delivery, IPG case architecture, and local field potential sensing. We present evidence-based approaches to mitigate hardware complications, of which infection represents the most important factor. Strategies correlating positively with decreased complications include antibiotic impregnation and co-administration and other surgical considerations during IPG implantation such as the use of tack-up sutures and smaller profile devices.Strategies aimed at maximizing battery longevity include patient-related elements such as reliability of IPG recharging or consistency of nightly device shutoff, and device-specific such as parameter delivery, choice of lead configuration, implantation location, and careful selection of electrode materials to minimize impedance mismatch. Finally, experimental DBS systems such as ultrasound, magnetoelectric nanoparticles, and near-infrared that use extracorporeal powered neuromodulation strategies are described as potential future directions for minimally invasive treatment.
... Studies on PPN are also of clinical importance. Application of PPN deep brain stimulation (DBS) (Lozano et al., 2017) to ameliorate parkinsonian gait and balance symptoms yields diverse findings (Nowacki et al., 2019;Thevathasan et al., 2018;Tubert et al., 2019). A recent review article stresses the fact that functional diversity in the PPN area is likely the key reason for the lack of consensus on applied strategies to ameliorate Parkinson's disease (PD) symptoms, despite ongoing clinical work over many years (Garcia-Rill et al., 2019). ...
Article
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The mesencephalic locomotor region (MLR) is a key midbrain center with roles in locomotion. Despite extensive studies and clinical trials aimed at therapy-resistant Parkinson’s disease (PD), debate on its function remains. Here, we reveal the existence of functionally diverse neuronal populations with distinct roles in control of body movements. We identify two spatially intermingled glutamatergic populations separable by axonal projections, mouse genetics, neuronal activity profiles, and motor functions. Most spinally projecting MLR neurons encoded the full-body behavior rearing. Loss- and gain-of-function optogenetic perturbation experiments establish a function for these neurons in controlling body extension. In contrast, Rbp4-transgene-positive MLR neurons project in an ascending direction to basal ganglia, preferentially encode the forelimb behaviors handling and grooming, and exhibit a role in modulating movement. Thus, the MLR contains glutamatergic neuronal subpopulations stratified by projection target exhibiting roles in action control not restricted to locomotion.
... Functional neurosurgery is unique in its focus on altering specific central nervous system (CNS) circuitry. Altering circuitry enables clinicians to offer lasting treatments for diseases and disorders that are continually evolving [1][2][3]. This dynamic field of neurosurgery concentrates on new evolving technologies to improve and add precision and accuracy. ...
Article
Functional disorders of the central nervous system (CNS) are diverse in terms of their etiology and symptoms, however, they can be quite debilitating. Many functional neurological disorders can progress to a level where pharmaceuticals and other early lines of treatment can no longer optimally treat the condition, therefore requiring surgical intervention. A variety of stereotactic and functional neurosurgical approaches exist, including deep brain stimulation, implantation, stereotaxic lesions, and radiosurgery, among others. Most techniques are invasive or minimally invasive forms of surgical intervention and require immense precision to effectively modulate CNS circuitry. Focused ultrasound (FUS) is a relatively new, safe, non-invasive neurosurgical approach that has demonstrated efficacy in treating a range of functional neurological diseases. It can function reversibly, through mechanical stimulation causing circuitry changes, or irreversibly, through thermal ablation at low and high frequencies respectively. In preliminary studies, magnetic resonance imaging-guided high-intensity focused ultrasound (MRgHIFU) has been shown to have long-lasting treatment effects in several disease types. The technology has been approved by the FDA and internationally for a number of treatment-resistant neurological disorders and currently clinical trials are underway for several other neurological conditions. In this review, the authors discuss the potential applications and emerging role of MRgHIFU in functional neurosurgery in the coming years.
... depending on the stimulus parameters applied (Posporelis et al., 2018). It has been shown that chronic DBS modulates local neuronal activity and stimulates gradual reorganization of neuronal circuits through enhancing synaptic plasticity and neurogenesis (Herrington et al., 2016;Lozano et al., 2017). Even though DBS is now a routine treatment for movement disorders, its efficacy and safety in cognitive and neuropsychiatric disorders is still under investigation (Posporelis et al., 2018). ...
Article
Aging is associated with alterations in cognitive processing and brain neurophysiology. Whereas the primary symptom of amnestic mild cognitive impairment (aMCI) is memory problems greater than normal for age and education, patients with Alzheimer’s disease (AD) show impairments in other cognitive domains in addition to memory dysfunction. Resting-state electroencephalography (rsEEG) studies in physiological aging indicate a global increase in low-frequency oscillations’ power and the reduction and slowing of alpha activity. The enhancement of slow and the reduction of fast oscillations, and the disruption of brain functional connectivity, however, are characterized as major rsEEG changes in AD. Recent rodent studies also support human evidence of age- and AD-related changes in resting-state brain oscillations, and the neuroprotective effect of brain stimulation techniques through gamma-band stimulations. Cumulatively, current evidence moves toward optimizing rsEEG features as reliable predictors of people with aMCI at risk for conversion to AD and mapping neural alterations subsequent to brain stimulation therapies. The present paper reviews the latest evidence of changes in rsEEG oscillations in physiological aging, aMCI, and AD, as well as findings of various brain stimulation therapies from both human and non-human studies.
... Understanding the brain's distinct response to stimulation during different states not only improves our understanding of the mechanisms of consciousness but also has therapeutic implications, as chronic neuromodulation is increasingly common for movement disorders [18][19][20][93][94][95][96] , epilepsy 22,24 , and psychiatric disorders 25,97,98 . Moreover, deep brain stimulation using stimulation trains affects sleep [99][100][101] . ...
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The neural basis of consciousness remains a major unresolved issue in human neuroscience. To better understand how cortical networks are engaged during different states of consciousness, we utilized multi-region intracranial single-pulse direct electrical stimulation to examine circuit and network interactions during three canonical states of consciousness: wake, sleep, and under propofol-induced general anesthesia. Increased variability in cortical responses, reduced information transfer, and reduced complexity characterized states of diminished consciousness. Notably, however, these metrics differed in different brain regions and types of unconscious states. Anesthesia induced more overall changes in brain responses than sleep. Brain activity changes were largely anatomically uniform during sleep, contrasting with a substantial and selective disconnection of the prefrontal cortices during anesthesia. These results suggest that the obliteration of consciousness during anesthesia results not from just altered overall physiology but from a disconnection between prefrontal areas and other brain areas.
... DBS is an invasive neuromodulation technique that consists of the placement of electrodes in deep brain targets, followed by the delivery of electrical stimulation to modulate local and neural activity [50]. DBS has been extensively used to treat movement disorders [51][52][53] and is currently delivered through a humanitarian exemption for the treatment of obsessive-compulsive disorder in the USA, while it has CE marking and is approved in Europe [54,55]. There is one case report using DBS for the treatment of PTSD (Table 3). ...
Article
Post-traumatic stress disorder (PTSD) is a prevalent and debilitating illness. While standard treatment with pharmacotherapy and psychotherapy may be effective, approximately 20 to 30% of patients remain symptomatic. These individuals experience depression, anxiety, and elevated rates of suicide. For treatment-resistant patients, there is a growing interest in the use of neuromodulation therapies, including transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and deep brain stimulation (DBS). We conducted a systematic review on the use of neuromodulation strategies for PTSD and pooled 13 randomized clinical trials (RCTs), 11 case series, and 6 case reports for analysis. Overall, most studies reported favorable outcomes in alleviating both PTSD and depressive symptoms. Although several RCTs described significant differences when active and sham stimulations were compared, others found marginal or nonsignificant differences between groups. Also positive were studies comparing PTSD symptoms before and after treatment. The side effect profile with all 3 modalities was found to be low, with mostly mild adverse events being reported. Despite these encouraging data, several aspects remain unknown. Given that PTSD is a highly heterogeneous condition that can be accompanied by distinct psychiatric diagnoses, defining a unique treatment for this patient population can be quite challenging. There has also been considerable variation across trials regarding stimulation parameters, symptomatic response, and the role of adjunctive psychotherapy. Future studies are needed to address these issues.
Chapter
The basal ganglia are a group of closely connected cell masses, forming a more or less continuum, extending from the telencephalon to the midbrain tegmentum (Sect. 11.3). A few notes on the development of the basal ganglia are presented in Sect. 11.2. This complex comprises the striatum (the nucleus caudatus and the putamen, largely separated by the internal capsule), the globus pallidus, the subthalamic nucleus and the substantia nigra. The output of the basal ganglia is aimed at the ventral anterior (VA) and ventrolateral (VL) thalamic nuclei or VA-VL complex, the centromedian thalamic nucleus, the habenula, the pedunculopontine tegmental nucleus and the superior colliculus. In most non-primate mammals, the caudate and putamen are not clearly separated by an internal capsule and are known as the caudate-putamen complex or striatum. In primates, the globus pallidus consists of external or lateral and internal or medial segments. In other mammals, the entopeduncular nucleus is the homologue of the internal segment. The caudate nucleus, the putamen and the globus pallidus form the dorsal part of the striatal complex. The nucleus accumbens and the olfactory tubercle form the ventral striatum. The rostral part of the substantia innominata forms a ventral extension of the globus pallidus and is known as the ventral pallidum.
Article
Objective: The effectiveness of deep brain stimulation (DBS) therapy strongly depends on precise surgical targeting of intracranial leads and on clinical optimization of stimulation settings. Recent advances in surgical targeting, multi-electrode designs, and multi-channel independent current-controlled stimulation are poised to enable finer control in modulating pathways within the brain. However, the large stimulation parameter space enabled by these technologies also poses significant challenges for efficiently identifying the most therapeutic DBS setting for a given patient. Here, we present a computational approach for programming directional DBS leads that is based on a non-convex optimization framework for neural pathway targeting. Approach: The algorithm integrates patient-specific pre-operative 7 T MR imaging, post-operative CT scans, and multi-objective particle swarm optimization (MOPSO) methods using dominance based-criteria and incorporating multiple neural pathways simultaneously. The algorithm was evaluated on eight patient-specific models of subthalamic nucleus (STN) DBS to identify electrode configurations and stimulation amplitudes to optimally activate or avoid six clinically relevant pathways: motor territory of STN, non-motor territory of STN, internal capsule, superior cerebellar peduncle, thalamic fasciculus, and hyperdirect pathway. Main results: Across the patient-specific models, single-electrode stimulation showed significant correlations across modeled pathways, particularly for motor and non-motor STN efferents. The MOPSO approach was able to identify multi-electrode configurations that achieved improved targeting of motor STN efferents and hyperdirect pathway afferents than that achieved by any single-electrode monopolar setting at equivalent power levels. Significance: These results suggest that pathway targeting with patient-specific model-based optimization algorithms can efficiently identify non-trivial electrode configurations for enhancing activation of clinically relevant pathways. However, the results also indicate that inter-pathway correlations can limit selectivity for certain pathways even with directional DBS leads.
Chapter
Die Tiefe Hirnstimulation (deep brain stimulation: DBS) hat sich in den letzten drei Jahrzehnten zu eine der erfolgreichsten neuroprothetischen Anwendung zur neuromodulatorischen Behandlung von Hirnerkrankungen im Alter entwickelt und führt zu nachweislichen Verbesserungen der Lebensqualität, z.B. bei Patientinnen und Patienten mit der Parkinson-Erkrankung. Hierzu wird eine neurochirurgische Hochpräzisionsoperation durchgeführt, die auf unterschiedlichen neurotechnologischen Verfahren basiert. Innovative physiologische Verfahren zur Lokalisation der Zielregion können helfen, die Implantation der Elektroden im Gehirn sicherer, genauer und schneller durchzuführen und die Therapieeffekte zu verbessern. Neue Stimulationszielorte und -parameter werden aktuell erforscht, um auch diejenigen Krankheitssymptome, die bisher nicht ausreichend auf diese Therapie ansprechen, wie Gang- und Schlafstörungen, erfolgreich zu behandeln.
Article
Traumatic brain injury (TBI) has been associated with several lasting impairments that affect the quality of life. Pre-clinical models of TBI have been studied to further our understanding of the underlying short-term and long-term symptomatology. Neuromodulation techniques have become of great interest in recent years as potential rehabilitative therapies following injury due to their capacity to alter neuronal activity and neural circuits in targeted brain regions. This systematic review aims to provide an overlook of the behavioural and neurochemical effects of transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), and vagus nerve stimulation (VNS) in preclinical TBI models. After screening 629 abstracts, 30 articles were pooled for review. These studies showed that tDCS, TMS, DBS or VNS delivered to rodents restored TBI-induced deficits in coordination, balance, locomotor activity and improved cognitive impairments in memory, learning and impulsivity. Potential mechanisms for these effects included neuroprotection, a decrease in apoptosis, neuroplasticity, and the restoration of neural circuits abnormalities. The translational value, potential applicability and the interpretation of these findings in light of outcome data from clinical trials in TBI patients are discussed.
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People with Parkinson's disease (PD) show impaired decision-making when sensory and memory information must be combined. This recently identified impairment results from an inability to accumulate the proper amount of information needed to make a decision and appears to be independent of dopamine tone and reinforcement learning mechanisms. Although considerable work focuses on PD and decisions involving risk and reward, in this Opinion article we propose that the emerging findings in perceptual decision-making highlight the multisystem nature of PD, and that unraveling the neuronal circuits underlying perceptual decision-making impairment may help in understanding other cognitive impairments in people with PD. We also discuss how a decision-making framework may be extended to gain insights into mechanisms of motor impairments in PD.
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Background: Rapid action stopping leads to global motor suppression. This is shown by studies using transcranial magnetic stimulation to measure corticospinal excitability of task-unrelated effectors (e.g., from the hand during speech stopping). We hypothesize that this global suppression relates to the STN of the basal ganglia. Several STN local field potential studies in PD patients have shown increased ß-band power during successful stopping. Objectives: Here, we aimed to test whether this STN ß-band activity indexes global motor suppression measured by transcranial magnetic stimulation. Methods: We studied 9 medicated PD patients (age, 47-67 years; mean, 55.8; 3 female) who were implanted with STN-DBS electrodes. Participants performed a vocal stop-signal task (i.e., they had to occasionally stop a vocal response) while we simultaneously recorded local field potentials from right STN and delivered transcranial magnetic stimulation to primary motor cortex to measure corticospinal excitability from a task-unrelated hand muscle (first dorsal interosseous). Results: Replicating previous results, STN ß-band power was increased (P < 0.005) and corticospinal excitability was reduced (P = 0.024; global motor suppression) during successful stopping. As hypothesized, global motor suppression was greater for successful stop trials with higher STN ß-power (median split: P = 0.043), which was further evident in a negative correlation between single-trial STN ß-power and corticospinal excitability (mean, r = -0.176; P = 0.011). Conclusion: These findings link stopping-related global motor suppression to STN ß-band activity through simultaneous recordings of STN and corticospinal excitability. The results support models of basal ganglia function that propose the STN has broad motor suppressive effects. © 2016 International Parkinson and Movement Disorder Society.
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Deep brain stimulation (DBS) is increasingly applied for the treatment of brain disorders, but its mechanism of action remains unknown. Here we evaluate the effect of basal ganglia DBS on cortical function using invasive cortical recordings in Parkinson's disease (PD) patients undergoing DBS implantation surgery. In the primary motor cortex of PD patients, neuronal population spiking is excessively synchronized to the phase of network oscillations. This manifests in brain surface recordings as exaggerated coupling between the phase of the beta rhythm and the amplitude of broadband activity. We show that acute therapeutic DBS reversibly reduces phase-amplitude interactions over a similar time course as that of the reduction in parkinsonian motor signs. We propose that DBS of the basal ganglia improves cortical function by alleviating excessive beta phase locking of motor cortex neurons.
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The subthalamic nucleus (STN) has been shown to be implicated in the control of voluntary action, especially during tasks involving conflicting choice alternatives or rapid response suppression. However, the precise role of the STN during nonmotor functions remains controversial. First, we tested whether functionally distinct neuronal populations support different executive control functions (such as inhibitory control or error monitoring) even within a single subterritory of the STN. We used microelectrode recordings during deep brain stimulation surgery to study extracellular activity of the putative associative-limbic part of the STN while patients with severe obsessive-compulsive disorder performed a stop-signal task. Second, 2-4 days after the surgery, local field potential recordings of STN were used to test the hypothesis that STN oscillations may also reflect executive control signals. Extracellular recordings revealed three functionally distinct neuronal populations: the first one fired selectively before and during motor responses, the second one selectively increased their firing rate during successful inhibitory control, and the last one fired selectively during error monitoring. Furthermore, we found that beta band activity (15-35 Hz) rapidly increased during correct and incorrect behavioral stopping. Taken together, our results provide critical electrophysiological support for the hypothesized role of the STN in the integration of motor and cognitive-executive control functions.
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We provide a historic outlook on the development of the concept of bioelectricity, with emphasis on the neuromuscular junction as a model that revolutionized our thinking of the nerve, nervous, and muscle tissue excitability. We abridge some crucial experiments in defining the electrical excitability of biological cells. We also provide an insight into developments of tools and methods, which gradually yielded a contemporary "palette" of electrophysiology approaches, including the patch clamp. Pioneering steps in this journey, ranging from Galvani's experiments using the Leyden jar to those of Neher and Sakmann using a gigaseal patch-clamp approach, are pictorially illustrated. This chapter is meant to be a perspective to the following sections in this volume dedicated to patch-clamp methods and protocols.
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Deep brain stimulation (DBS) is highly effective for both hypo- and hyperkinetic movement disorders of basal ganglia origin. The clinical use of DBS is, in part, empiric, based on the experience with prior surgical ablative therapies for these disorders, and, in part, driven by scientific discoveries made decades ago. In this review, we consider anatomical and functional concepts of the basal ganglia relevant to our understanding of DBS mechanisms, as well as our current understanding of the pathophysiology of two of the most commonly DBS-treated conditions, Parkinson's disease and dystonia. Finally, we discuss the proposed mechanism(s) of action of DBS in restoring function in patients with movement disorders. The signs and symptoms of the various disorders appear to result from signature disordered activity in the basal ganglia output, which disrupts the activity in thalamocortical and brainstem networks. The available evidence suggests that the effects of DBS are strongly dependent on targeting sensorimotor portions of specific nodes of the basal ganglia-thalamocortical motor circuit, that is, the subthalamic nucleus and the internal segment of the globus pallidus. There is little evidence to suggest that DBS in patients with movement disorders restores normal basal ganglia functions (e.g., their role in movement or reinforcement learning). Instead, it appears that high-frequency DBS replaces the abnormal basal ganglia output with a more tolerable pattern, which helps to restore the functionality of downstream networks.
Article
During procedures for parkinsonian tremor, neurons in the thalamic ventral nuclear group show periodic activity at tremor frequency (tremor-frequency activity). The tremor-frequency activity of some cells is significantly correlated with tremor. Cells in this region also display functional properties defined by activity related to somatosensory stimuli and to active movement. Cells with activity related to somatosensory stimulation were termed sensory cells while those with activity related to active movement were termed voluntary cells. Cells with activity related to both somatosensory stimulation and active movement were termed combined cells. Those with activity related to neither somatosensory stimulation nor active movement were termed no-response cells. Combined, voluntary and no-response cells were located in the region of thalamus where a lesion stops tremor and anterior to the region where sensory cells were found. Spectral cross-correlation analysis demonstrated that many combined, voluntary and no-response cells had a peak of activity at tremor frequency which was significantly correlated with electromyogram (EMG). Analysis of the phase of thalamic activity relative to EMG activity indicated that voluntary and combined cell activity usually led EMG during tremor. These results suggest that thalamic cells unresponsive to somatosensory stimulation (voluntary and no-response cells) and those responsive to somatosensory stimulation (combined cells) are involved in the mechanism of parkinsonian tremor. The activity of sensory cells frequently lagged behind tremor while activity of combined cells often led tremor. This finding suggests that the activity of these two cell types, both responding to sensory input, is related to tremor by different mechanisms.
Article
In Parkinson's disease the loss of dopaminergic neurons in the substantia nigra is associated with global disorganization of basal ganglia activity and, in particular, with increased activity of the excitatory glutamatergic neurons of the subthalamic nucleus. Recent experimental studies have shown that parkinsonian symptoms can be alleviated by selective lesioning of the subthalamic nucleus in monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We measured the effect of high-frequency stimulation of the subthalamic nucleus in two unilaterally MPTP-treated monkeys in order to determine whether it was possible to obtain reversible, gradual and controllable functional impairment of this structure. Clinical, mechanographic and electromyographic results demonstrate that this technique can alleviate parkinsonian rigidity and bradykinesia without causing dyskinesia or hemiballismus. This study supports the hypothesis that the subthalamic nucleus and its excitatory projections have an important role in the mechanisms sustaining the expression of parkinsonian motor changes, and suggests that high-frequency stimulation of the subthalamic nucleus could be included in treatment for parkinsonism.
Article
Our aim was to compare in a prospective blinded study the cognitive and mood effects of subthalamic nucleus (STN) vs. globus pallidus interna (GPi) deep brain stimulation (DBS) in Parkinson disease. Fifty-two subjects were randomized to unilateral STN or GPi DBS. The co-primary outcome measures were the Visual Analog Mood Scale, and verbal fluency (semantic and letter) at 7 months post-DBS in the optimal setting compared to pre-DBS. At 7 months post-DBS, subjects were tested in four randomized/counterbalanced conditions (optimal, ventral, dorsal, and off DBS). Forty-five subjects (23 GPi, 22 STN) completed the protocol. The study revealed no difference between STN and GPi DBS in the change of co-primary mood and cognitive outcomes pre- to post-DBS in the optimal setting (Hotelling's T(2) test: p = 0.16 and 0.08 respectively). Subjects in both targets were less "happy", less "energetic" and more "confused" when stimulated ventrally. Comparison of the other 3 DBS conditions to pre-DBS showed a larger deterioration of letter verbal fluency in STN, especially when off DBS. There was no difference in UPDRS motor improvement between targets. There were no significant differences in the co-primary outcome measures (mood and cognition) between STN and GPi in the optimal DBS state. Adverse mood effects occurred ventrally in both targets. A worsening of letter verbal fluency was seen in STN. The persistence of deterioration in verbal fluency in the off STN DBS state was suggestive of a surgical rather than a stimulation-induced effect. Similar motor improvement were observed with both STN and GPi DBS.
Article
Resting tremor in idiopathic Parkinson's disease (PD) is associated with an oscillatory network comprising cortical as well as subcortical brain areas. To shed light on the effect of levodopa on these network interactions, we investigated 10 patients with tremor-dominant PD and reanalyzed data in 11 healthy volunteers mimicking PD resting tremor. To this end, we recorded surface electromyograms of forearm muscles and neuromagnetic activity using a 122-channel whole-head magnetometer (MEG). Measurements were performed after overnight withdrawal of levodopa (OFF) and 30 min after oral application of fast-acting levodopa (ON). During OFF, patients showed the typical antagonistic resting tremor. Using the analysis tool Dynamic Imaging of Coherent Sources, we identified the oscillatory network associated with tremor comprising contralateral primary sensorimotor cortex (S1/M1), supplementary motor area (SMA), contralateral premotor cortex (PMC), thalamus, secondary somatosensory cortex (S2), posterior parietal cortex (PPC), and ipsilateral cerebellum oscillating at 8 to 10 Hz. After intake of levodopa, we found a significant decrease of cerebro-cerebral coupling between thalamus and motor cortical areas. Similarly, in healthy controls mimicking resting tremor, we found a significant decrease of functional interaction within a thalamus-premotor-motor network during rest. However, in patients with PD, decrease of functional interaction between thalamus and PMC was significantly stronger when compared with healthy controls. These data support the hypothesis that (1) in patients with PD the basal ganglia and motor cortical structures become more closely entrained and (2) levodopa is associated with normalization of the functional interaction between thalamus and motor cortical areas.