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

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.

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Common therapeutic mechanisms of pallidal deep brain stimulation for hypo- and hyperkinetic movement disorders

Journal of Neurophysiology ◽

10.1152/jn.00223.2015 ◽

2015 ◽

Vol 114 (4) ◽

pp. 2090-2104 ◽

Cited By ~ 8

Author(s):

Kevin W. McCairn ◽

Atsushi Iriki ◽

Masaki Isoda

Keyword(s):

Deep Brain Stimulation ◽

Basal Ganglia ◽

Brain Stimulation ◽

Movement Disorders ◽

Information Transfer ◽

Motor Behavior ◽

Global Network ◽

Symptom Profiles ◽

Stimulus Effect ◽

Deep Brain

Abnormalities in cortico-basal ganglia (CBG) networks can cause a variety of movement disorders ranging from hypokinetic disorders, such as Parkinson's disease (PD), to hyperkinetic conditions, such as Tourette syndrome (TS). Each condition is characterized by distinct patterns of abnormal neural discharge (dysrhythmia) at both the local single-neuron level and the global network level. Despite divergent etiologies, behavioral phenotypes, and neurophysiological profiles, high-frequency deep brain stimulation (HF-DBS) in the basal ganglia has been shown to be effective for both hypo- and hyperkinetic disorders. The aim of this review is to compare and contrast the electrophysiological hallmarks of PD and TS phenotypes in nonhuman primates and discuss why the same treatment (HF-DBS targeted to the globus pallidus internus, GPi-DBS) is capable of ameliorating both symptom profiles. Recent studies have shown that therapeutic GPi-DBS entrains the spiking of neurons located in the vicinity of the stimulating electrode, resulting in strong stimulus-locked modulations in firing probability with minimal changes in the population-scale firing rate. This stimulus effect normalizes/suppresses the pathological firing patterns and dysrhythmia that underlie specific phenotypes in both the PD and TS models. We propose that the elimination of pathological states via stimulus-driven entrainment and suppression, while maintaining thalamocortical network excitability within a normal physiological range, provides a common therapeutic mechanism through which HF-DBS permits information transfer for purposive motor behavior through the CBG while ameliorating conditions with widely different symptom profiles.

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Deep brain stimulation changes basal ganglia output nuclei firing pattern in the dystonic hamster

Neurobiology of Disease ◽

10.1016/j.nbd.2010.01.020 ◽

2010 ◽

Vol 38 (2) ◽

pp. 288-298 ◽

Cited By ~ 10

Author(s):

Arthur Leblois ◽

René Reese ◽

David Labarre ◽

Melanie Hamann ◽

Angelika Richter ◽

...

Keyword(s):

Deep Brain Stimulation ◽

Basal Ganglia ◽

Brain Stimulation ◽

Firing Pattern ◽

Deep Brain

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Deep Brain Stimulation of the Center Median-Parafascicular Complex of the Thalamus Has Efficient Anti-Parkinsonian Action Associated with Widespread Cellular Responses in the Basal Ganglia Network in a Rat Model of Parkinson's Disease

Journal of Neuroscience ◽

10.1523/jneurosci.1404-10.2010 ◽

2010 ◽

Vol 30 (29) ◽

pp. 9919-9928 ◽

Cited By ~ 39

Author(s):

L. Jouve ◽

P. Salin ◽

C. Melon ◽

L. K.-L. Goff

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Deep Brain Stimulation ◽

Basal Ganglia ◽

Brain Stimulation ◽

Rat Model ◽

Cellular Responses ◽

Parafascicular Complex ◽

Deep Brain ◽

Stimulation Of

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

Journal of Neurophysiology ◽

10.1152/jn.00822.2015 ◽

2016 ◽

Vol 115 (6) ◽

pp. 2791-2802 ◽

Cited By ~ 19

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.

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