scholarly journals Failure to suppress low-frequency neuronal oscillatory activity underlies the reduced effectiveness of random patterns of deep brain stimulation

2016 ◽  
Vol 115 (6) ◽  
pp. 2791-2802 ◽  
Author(s):  
George C. McConnell ◽  
Rosa Q. So ◽  
Warren M. Grill
Keyword(s):  
Deep Brain Stimulation ◽  
Basal Ganglia ◽  
Brain Stimulation ◽  
High Frequency ◽  
Single Unit ◽  
Low Frequency ◽  
Neuronal Firing ◽  
Motor Symptoms ◽  
Firing Patterns ◽  
Deep Brain

Subthalamic nucleus (STN) deep brain stimulation (DBS) is an established treatment for the motor symptoms of Parkinson's disease (PD). However, the mechanisms of action of DBS are unknown. Random temporal patterns of DBS are less effective than regular DBS, but the neuronal basis for this dependence on temporal pattern of stimulation is unclear. Using a rat model of PD, we quantified the changes in behavior and single-unit activity in globus pallidus externa and substantia nigra pars reticulata during high-frequency STN DBS with different degrees of irregularity. Although all stimulus trains had the same average rate, 130-Hz regular DBS more effectively reversed motor symptoms, including circling and akinesia, than 130-Hz irregular DBS. A mixture of excitatory and inhibitory neuronal responses was present during all stimulation patterns, and mean firing rate did not change during DBS. Low-frequency (7–10 Hz) oscillations of single-unit firing times present in hemiparkinsonian rats were suppressed by regular DBS, and neuronal firing patterns were entrained to 130 Hz. Irregular patterns of DBS less effectively suppressed 7- to 10-Hz oscillations and did not regularize firing patterns. Random DBS resulted in a larger proportion of neuron pairs with increased coherence at 7–10 Hz compared with regular 130-Hz DBS, which suggested that long pauses (interpulse interval >50 ms) during random DBS facilitated abnormal low-frequency oscillations in the basal ganglia. These results suggest that the efficacy of high-frequency DBS stems from its ability to regularize patterns of neuronal firing and thereby suppress abnormal oscillatory neural activity within the basal ganglia.

scholarly journals Deep Brain Stimulation Alleviates Parkinsonian Bradykinesia by Regularizing Pallidal Activity

2010 ◽  
Vol 104 (2) ◽  
pp. 911-921 ◽  
Author(s):  
Alan D. Dorval ◽  
Alexis M. Kuncel ◽  
Merrill J. Birdno ◽  
Dennis A. Turner ◽  
Warren M. Grill
Keyword(s):  
Deep Brain Stimulation ◽  
Basal Ganglia ◽  
Brain Stimulation ◽  
High Frequency ◽  
High Frequency Stimulation ◽  
Motor Symptoms ◽  
Transmission Errors ◽  
Symptom Alleviation ◽  
Frequency Stimulation ◽  
Deep Brain

Deep brain stimulation (DBS) of the basal ganglia can alleviate the motor symptoms of Parkinson's disease although the therapeutic mechanisms are unclear. We hypothesize that DBS relieves symptoms by minimizing pathologically disordered neuronal activity in the basal ganglia. In human participants with parkinsonism and clinically effective deep brain leads, regular (i.e., periodic) high-frequency stimulation was replaced with irregular (i.e., aperiodic) stimulation at the same mean frequency (130 Hz). Bradykinesia, a symptomatic slowness of movement, was quantified via an objective finger tapping protocol in the absence and presence of regular and irregular DBS. Regular DBS relieved bradykinesia more effectively than irregular DBS. A computational model of the relevant neural structures revealed that output from the globus pallidus internus was more disordered and thalamic neurons made more transmission errors in the parkinsonian condition compared with the healthy condition. Clinically therapeutic, regular DBS reduced firing pattern disorder in the computational basal ganglia and minimized model thalamic transmission errors, consistent with symptom alleviation by clinical DBS. However, nontherapeutic, irregular DBS neither reduced disorder in the computational basal ganglia nor lowered model thalamic transmission errors. Thus we show that clinically useful DBS alleviates motor symptoms by regularizing basal ganglia activity and thereby improving thalamic relay fidelity. This work demonstrates that high-frequency stimulation alone is insufficient to alleviate motor symptoms: DBS must be highly regular. Descriptive models of pathophysiology that ignore the fine temporal resolution of neuronal spiking in favor of average neural activity cannot explain the mechanisms of DBS-induced symptom alleviation.

scholarly journals Patterned low-frequency deep brain stimulation induces motor deficits and modulates cortex-basal ganglia neural activity in healthy rats

2018 ◽  
Vol 120 (5) ◽  
pp. 2410-2422 ◽  
Author(s):  
Chintan S. Oza ◽  
David T. Brocker ◽  
Christina E. Behrend ◽  
Warren M. Grill
Keyword(s):  
Deep Brain Stimulation ◽  
Basal Ganglia ◽  
Brain Stimulation ◽  
Movement Disorders ◽  
Neural Activity ◽  
Low Frequency ◽  
Oscillatory Activity ◽  
Motor Deficits ◽  
Motor Symptoms ◽  
Deep Brain

Deep brain stimulation (DBS) is an effective therapy for movement disorders, including Parkinson’s disease (PD), although the mechanisms of action remain unclear. Abnormal oscillatory neural activity is correlated with motor symptoms, and pharmacological or DBS treatment that alleviates motor symptoms appears to suppress abnormal oscillations. However, whether such oscillatory activity is causal of motor deficits such as tremor remains unclear. Our goal was to generate abnormal oscillatory activity in the cortex-basal ganglia loop using patterned subthalamic nucleus DBS and to quantify motor behavior in awake healthy rats. Stimulation patterns were designed via model-based optimization to increase power in the low-frequency (7–11 Hz) band because these oscillations are associated with the emergence of motor symptoms in the 6-hydroxydopamine lesioned rat model of parkinsonism. We measured motor activity using a head-mounted accelerometer, as well as quantified neural activity in cortex and globus pallidus (GP), in response to 5 stimulation patterns that generated a range of 7- to 11-Hz spectral power. Stimulation patterns induced oscillatory activity in the low-frequency band in the cortex and GP and caused tremor, whereas control patterns and regular 50-Hz DBS did not generate any such effects. Neural and motor-evoked responses observed during stimulation were synchronous and time-locked to stimulation bursts within the patterns. These results identified elements of irregular patterns of stimulation that were correlated with tremor and tremor-related neural activity in the cortex and basal ganglia and may lead to the identification of the oscillatory activity and structures associated with the generation of tremor activity. NEW & NOTEWORTHY Subthalamic nucleus deep brain stimulation is a promising therapy for movement disorders such as Parkinson’s disease. Several groups reported correlation between suppression of abnormal oscillatory activity in the cortex-basal ganglia and motor symptoms, but it remains unclear whether such oscillations play a causal role in the emergence of motor symptoms. We demonstrate generation of tremor and pathological oscillatory activity in otherwise healthy rats by stimulation with patterns that produced increases in low-frequency oscillatory activity.

The Effect of Neural Entropy during Deep Brain Stimulation of Cortex-Basal Ganglia Network Model.

2021 ◽  
pp. 16089-16097
Author(s):  
Aditya Robin Singh, Vikash Yadav
Keyword(s):  
Deep Brain Stimulation ◽  
Basal Ganglia ◽  
Brain Stimulation ◽  
High Frequency ◽  
Low Frequency ◽  
Field Potentials ◽  
Single Unit Recordings ◽  
High Frequency Stimulus ◽  
Deep Brain ◽  
Stimulation Of

Researchers reported decreased nerve entropy Patients with Parkinson's disease (PD) have abnormalities in their basal ganglia (BG). Studies of local field potentials (LFPs) recorded from the hypothalamus and single unit recordings of GP neurons showed this reduction to be significant. According to this hypothesis, these changes are consistent with changes in the ability of the basal ganglion network to encode PD information. Our deep brain stimulation of cortical basal ganglia (DBS) model includes single LFP recordings and shows how entropy changes during DBS. In addition to the extracellular stimulation of supplied STN fibers and LFP mimetics, which are detected differently on a registered electrode, this model includes osteoclast activation and anti-apoptosis. In the DBS network, the firing pattern fluctuated between high-frequency and low-frequency stimuli, since gp neurons in the network showed a decrease in entropy when a high-frequency stimulus was applied and an increase in entropy when a low-frequency stimulus was applied. Second hand. Changes in neural entropy after DBS have been reported experimentally. The simulation results were consistent

scholarly journals Deep Brain Stimulation of the Posterior Insula in Chronic Pain: A Theoretical Framework

2021 ◽  
Vol 11 (5) ◽  
pp. 639
Author(s):  
David Bergeron ◽  
Sami Obaid ◽  
Marie-Pierre Fournier-Gosselin ◽  
Alain Bouthillier ◽  
Dang Khoa Nguyen
Keyword(s):  
Chronic Pain ◽  
Electrical Stimulation ◽  
Deep Brain Stimulation ◽  
Brain Stimulation ◽  
High Frequency ◽  
Brain Lesion ◽  
Low Frequency ◽  
Posterior Insula ◽  
Deep Brain ◽  
Stimulation Of

Introduction: To date, clinical trials of deep brain stimulation (DBS) for refractory chronic pain have yielded unsatisfying results. Recent evidence suggests that the posterior insula may represent a promising DBS target for this indication. Methods: We present a narrative review highlighting the theoretical basis of posterior insula DBS in patients with chronic pain. Results: Neuroanatomical studies identified the posterior insula as an important cortical relay center for pain and interoception. Intracranial neuronal recordings showed that the earliest response to painful laser stimulation occurs in the posterior insula. The posterior insula is one of the only regions in the brain whose low-frequency electrical stimulation can elicit painful sensations. Most chronic pain syndromes, such as fibromyalgia, had abnormal functional connectivity of the posterior insula on functional imaging. Finally, preliminary results indicated that high-frequency electrical stimulation of the posterior insula can acutely increase pain thresholds. Conclusion: In light of the converging evidence from neuroanatomical, brain lesion, neuroimaging, and intracranial recording and stimulation as well as non-invasive stimulation studies, it appears that the insula is a critical hub for central integration and processing of painful stimuli, whose high-frequency electrical stimulation has the potential to relieve patients from the sensory and affective burden of chronic pain.

scholarly journals Deep brain stimulation of the subthalamic nucleus reestablishes neuronal information transmission in the 6-OHDA rat model of parkinsonism

2014 ◽  
Vol 111 (10) ◽  
pp. 1949-1959 ◽  
Author(s):  
Alan D. Dorval ◽  
Warren M. Grill
Keyword(s):  
Deep Brain Stimulation ◽  
Basal Ganglia ◽  
Information Transmission ◽  
Brain Stimulation ◽  
Rat Model ◽  
Information Transfer ◽  
Firing Pattern ◽  
Signal Propagation ◽  
Neuronal Firing ◽  
Deep Brain

Pathophysiological activity of basal ganglia neurons accompanies the motor symptoms of Parkinson's disease. High-frequency (>90 Hz) deep brain stimulation (DBS) reduces parkinsonian symptoms, but the mechanisms remain unclear. We hypothesize that parkinsonism-associated electrophysiological changes constitute an increase in neuronal firing pattern disorder and a concomitant decrease in information transmission through the ventral basal ganglia, and that effective DBS alleviates symptoms by decreasing neuronal disorder while simultaneously increasing information transfer through the same regions. We tested these hypotheses in the freely behaving, 6-hydroxydopamine-lesioned rat model of hemiparkinsonism. Following the onset of parkinsonism, mean neuronal firing rates were unchanged, despite a significant increase in firing pattern disorder (i.e., neuronal entropy), in both the globus pallidus and substantia nigra pars reticulata. This increase in neuronal entropy was reversed by symptom-alleviating DBS. Whereas increases in signal entropy are most commonly indicative of similar increases in information transmission, directed information through both regions was substantially reduced (>70%) following the onset of parkinsonism. Again, this decrease in information transmission was partially reversed by DBS. Together, these results suggest that the parkinsonian basal ganglia are rife with entropic activity and incapable of functional information transmission. Furthermore, they indicate that symptom-alleviating DBS works by lowering the entropic noise floor, enabling more information-rich signal propagation. In this view, the symptoms of parkinsonism may be more a default mode, normally overridden by healthy basal ganglia information. When that information is abolished by parkinsonian pathophysiology, hypokinetic symptoms emerge.

scholarly journals Deep Brain Stimulation Frequency of the Subthalamic Nucleus Affects Phonemic and Action Fluency in Parkinson’s Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Valéria de Carvalho Fagundes ◽  
Carlos R. M. Rieder ◽  
Aline Nunes da Cruz ◽  
Bárbara Costa Beber ◽  
Mirna Wetters Portuguez
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Deep Brain Stimulation ◽  
Subthalamic Nucleus ◽  
Brain Stimulation ◽  
High Frequency ◽  
Verbal Fluency ◽  
Low Frequency ◽  
Stn Dbs ◽  
Deep Brain

Introduction.Deep brain stimulation of the subthalamic nucleus (STN-DBS) in Parkinson’s disease (PD) has been linked to a decline in verbal fluency. The decline can be attributed to surgical effects, but the relative contributions of the stimulation parameters are not well understood. This study aimed to investigate the impact of the frequency of STN-DBS on the performance of verbal fluency tasks in patients with PD.Methods.Twenty individuals with PD who received bilateral STN-DBS were evaluated. Their performances of verbal fluency tasks (semantic, phonemic, action, and unconstrained fluencies) upon receiving low-frequency (60 Hz) and high-frequency (130 Hz) STN-DBS were assessed.Results.The performances of phonemic and action fluencies were significantly different between low- and high-frequency STN-DBS. Patients showed a decrease in these verbal fluencies for high-frequency STN-DBS.Conclusion.Low-frequency STN-DBS may be less harmful to the verbal fluency of PD patients.

scholarly journals Deep brain stimulation entrains local neuronal firing in human globus pallidus internus

2013 ◽  
Vol 109 (4) ◽  
pp. 978-987 ◽  
Author(s):  
Daniel R. Cleary ◽  
Ahmed M. Raslan ◽  
Jonathan E. Rubin ◽  
Diaa Bahgat ◽  
Ashwin Viswanathan ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Deep Brain Stimulation ◽  
Globus Pallidus ◽  
Neuronal Activity ◽  
Brain Stimulation ◽  
Spike Trains ◽  
Neuronal Firing ◽  
Firing Patterns ◽  
Deep Brain

Deep brain stimulation (DBS) in the internal segment of the globus pallidus (GPi) relieves the motor symptoms of Parkinson's disease, yet the mechanism of action remains uncertain. To address the question of how therapeutic stimulation changes neuronal firing in the human brain, we studied the effects of GPi stimulation on local neurons in unanesthetized patients. Eleven patients with idiopathic Parkinson's disease consented to participate in neuronal recordings during stimulator implantation surgery. A recording microelectrode and a DBS macroelectrode were advanced through the GPi in parallel until a single neuron was isolated. After a baseline period, stimulation was initiated with varying voltages and different stimulation sites. The intra-operative stimulation parameters (1–8 V, 88–180 Hz, 0.1-ms pulses) were comparable with the postoperative DBS settings. Stimulation in the GPi did not silence local neuronal activity uniformly, but instead loosely entrained firing and decreased net activity in a voltage-dependent fashion. Most neurons had decreased activity during stimulation, although some increased or did not change firing rate. Thirty-three of 45 neurons displayed complex patterns of entrainment during stimulation, and burst-firing was decreased consistently after stimulation. Recorded spike trains from patients were used as input into a model of a thalamocortical relay neuron. Only spike trains that occurred during therapeutically relevant voltages significantly reduced transmission error, an effect attributable to changes in firing patterns. These data indicate that DBS in the human GPi does not silence neuronal activity, but instead disrupts the pathological firing patterns through loose entrainment of neuronal activity.

scholarly journals Therapeutic Deep Brain Stimulation Disrupts Subthalamic Nucleus Activity Dynamics in Parkinsonian Mice

2021 ◽  
Author(s):  
Jonathan S Schor ◽  
Isabelle Gonzalez Montalvo ◽  
Perry W.E. Spratt ◽  
Rea J Brakaj ◽  
Jasmine A Stansil ◽  
...  
Keyword(s):  
Deep Brain Stimulation ◽  
Basal Ganglia ◽  
Subthalamic Nucleus ◽  
Brain Stimulation ◽  
Electrophysiological Recording ◽  
Free Calcium ◽  
Motor Symptoms ◽  
Antidromic Activation ◽  
Stn Dbs ◽  
Deep Brain

Subthalamic nucleus deep brain stimulation (STN DBS) relieves many motor symptoms of Parkinson Disease (PD), but its underlying therapeutic mechanisms remain unclear. Since its advent, three major theories have been proposed: (1) DBS inhibits the STN and basal ganglia output; (2) DBS antidromically activates motor cortex; and (3) DBS disrupts firing dynamics within the STN. Previously, stimulation-related electrical artifacts limited mechanistic investigations using electrophysiology. We used electrical artifact-free calcium imaging to investigate activity in basal ganglia nuclei during STN DBS in parkinsonian mice. To test whether the observed changes in activity were sufficient to relieve motor symptoms, we then combined electrophysiological recording with targeted optical DBS protocols. Our findings suggest that STN DBS exerts its therapeutic effect through the disruption of STN dynamics, rather than inhibition or antidromic activation. These results provide insight into optimizing PD treatments and establish an approach for investigating DBS in other neuropsychiatric conditions.

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