Connectivity and dynamics underlying synaptic control of the Subthalamic Nucleus

Steiner, Leon Amadeus; Tomás, Federico José Barreda; Planert, Henrike; Alle, Henrik; Vida, Imre; Geiger, Jörg R. P.

doi:10.1523/jneurosci.1642-18.2019

Cited by 35 publications

(35 citation statements)

References 59 publications

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“…In contrast, phase alignment of cortical and GPe neurons, corresponding to coincident firing, desynchronized STN neurons (Figure 8C). These findings are in agreement with recent experimental observations which demonstrate that co-stimulation of GABAergic and glutamergic STN afferents disperses STN spiking and has a desynchronizing effect on the population (Amadeus Steiner et al, 2019). Overall, the simulation results are consistent with the hypothesis of cortical patterning and resonance of beta activity within the STN-GPe network through feedback inhibition, whereby GPe inhibition arriving in anti-phase to cortical excitation promotes phase locking of STN neurons to beta-band cortical inputs (Baufreton et al, 2005).…”

Section: Discussionsupporting

confidence: 93%

Beta-Band Resonance and Intrinsic Oscillations in a Biophysically Detailed Model of the Subthalamic Nucleus-Globus Pallidus Network

Koelman

Lowery

2019

Front. Comput. Neurosci.

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Increased beta-band oscillatory activity in the basal ganglia network is associated with Parkinsonian motor symptoms and is suppressed with medication and deep brain stimulation (DBS). The origins of the beta-band oscillations, however, remains unclear with both intrinsic oscillations arising within the subthalamic nucleus (STN)—external globus pallidus (GPe) network and exogenous beta-activity, originating outside the network, proposed as potential sources of the pathological activity. The aim of this study was to explore the relative contribution of autonomous oscillations and exogenous oscillatory inputs in the generation of pathological oscillatory activity in a biophysically detailed model of the parkinsonian STN-GPe network. The network model accounts for the integration of synaptic currents and their interaction with intrinsic membrane currents in dendritic structures within the STN and GPe. The model was used to investigate the development of beta-band synchrony and bursting within the STN-GPe network by changing the balance of excitation and inhibition in both nuclei, and by adding exogenous oscillatory inputs with varying phase relationships through the hyperdirect cortico-subthalamic and indirect striato-pallidal pathways. The model showed an intrinsic susceptibility to beta-band oscillations that was manifest in weak autonomously generated oscillations within the STN-GPe network and in selective amplification of exogenous beta-band synaptic inputs near the network's endogenous oscillation frequency. The frequency at which this resonance peak occurred was determined by the net level of excitatory drive to the network. Intrinsic or endogenously generated oscillations were too weak to support a pacemaker role for the STN-GPe network, however, they were considerably amplified by sparse cortical beta inputs and were further amplified by striatal beta inputs that promoted anti-phase firing of the cortex and GPe, resulting in maximum transient inhibition of STN neurons. The model elucidates a mechanism of cortical patterning of the STN-GPe network through feedback inhibition whereby intrinsic susceptibility to beta-band oscillations can lead to phase locked spiking under parkinsonian conditions. These results point to resonance of endogenous oscillations with exogenous patterning of the STN-GPe network as a mechanism of pathological synchronization, and a role for the pallido-striatal feedback loop in amplifying beta oscillations.

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Section: Discussionsupporting

confidence: 93%

Beta-Band Resonance and Intrinsic Oscillations in a Biophysically Detailed Model of the Subthalamic Nucleus-Globus Pallidus Network

Koelman

Lowery

2019

Front. Comput. Neurosci.

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“…It is only conjecturable how the muscular oscillations would reflect those changes of brain activity. However, since the interaction of STN and cortex is relevant in motor control 51,52 , it is conceivable that the changes in power distribution of brain activity might be somehow visible in the mechanical output of muscles already in a premotor state.…”

Section: Discussionmentioning

confidence: 99%

Parkinson patients without tremor show changed patterns of mechanical muscle oscillations during a specific bilateral motor task compared to controls

Schaefer

Bittmann

2020

Sci Rep

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the pathophysiology of parkinson's disease (pD) is still not understood. there are investigations which show a changed oscillatory behaviour of brain circuits or changes in variability of, e.g., gait parameters in PD. The aim of this study was to investigate whether or not the motor output differs between PD patients and healthy controls. Thereby, patients without tremor are investigated in the medication off state performing a special bilateral isometric motor task. The force and accelerations (ACC) were recorded as well as the Mechanomyography (MMG) of the biceps brachii, the brachioradialis and of the pectoralis major muscles using piezoelectric-sensors during the bilateral motor task at 60% of the maximal isometric contraction. The frequency, a specific power ratio, the amplitude variation and the slope of amplitudes were analysed. The results indicate that the oscillatory behaviour of motor output in PD patients without tremor deviates from controls: thereby, the 95%-confidence-intervals of power ratio and of amplitude variation of all signals are disjoint between PD and controls and show significant differences in group comparisons (power ratio: p = 0.000-0.004, r = 0.441-0.579; amplitude variation: p = 0.000-0.001, r = 0.37-0.67). The mean frequency shows a significant difference for ACC (p = 0.009, r = 0.43), but not for MMG. It remains open, whether this muscular output reflects changes of brain circuits and whether the results are reproducible and specific for PD.The pathogenesis and pathomechanism of Parkinson's disease (PD) are not clarified yet 1-4 . A damage or death of neuronal cells through aggregation of misfolded alpha-synuclein in Lewy bodies is reported to be necessary 5,6 . The occurrence of those Lewy bodies in PD are reported for brain and other nerval structures as the spinal cord, peripheral nervous system, cervical sympathetic trunk and vagal nerve 6 , but also for the submandibular gland or the upper gastrointestinal tract 4 . The misfolded alpha-synuclein spread in diverse cells and lead to several deficits of bodily functions as e.g. mitochondrial function 5,6 . However, also other proteins than alpha-synuclein and other pathological changes are discussed to be relevant in PD 6,7 . This emphasises the complexity of PD and explains the different symptom appearances in patients, which complicates the diagnosis.PD is characterized by the presence of multiple motor and nonmotor symptoms 1,6,7 . The motor symptoms are not limited to tremor, but also appear as postural instability or gait impairment 6,8,9 . In addition, the tremor appears not only as resting tremor, but also as holding or postural tremor 10 . The motor symptoms are primarily explained by the loss of dopaminergic cells in the substantia nigra 2,5-7 . If the motor stage is reached, already around 50% of the dopaminergic neurons of the total substantia nigra are lost 11,12 and around 80% of the striatal dopamine is reduced [12][13][14] . If the amount of loss is lower, the patients are in the so called premotor state. Especial...

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“…Several of these functional regions are components of the motor circuit in which increased synchronization of beta band power has been linked to PD (Obeso et al, 2008;Steiner et al, 2019). This motor pathway is well-understood and thought to originate in dorsolateral STN and send output to the globus pallidus pars interna (GPi) which is connected to cortex through the thalamus (Obeso et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Effect of Directional Deep Brain Stimulation on Sensory Thresholds in Parkinson’s Disease

Sabourin

Khazen

DiMarzio

et al. 2020

Front. Hum. Neurosci.

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Objective: Previous studies showed that deep brain stimulation (DBS) relieves pain symptoms in Parkinson disease (PD) patients when programmed for motor-symptom relief. One factor involved in pain processing is sensory perception of stimuli. With the advent of directional leads, we explore whether directional DBS affects quantitative sensory testing (QST) metrics acutely. Methods: PD patients with subthalamic (STN) DBS and directional leads were tested in 5 settings (DBS-OFF, DBS-ON with omnidirectional stimulation, and DBS-ON) for each of three directional segments of contact used for clinical programming. The Unified Parkinson's Disease Rating Scale (UPDRS-III) assessed patient's motor skills at time of study visit at clinical contact and at contact which produced optimal sensory threshold (defined by the greatest tolerance to mechanical stimuli). Correlation analyses were performed between stimulation parameters [amplitude, frequency, pulse width (PW), total electrical energy delivered (TEED)] and outcome metrics. Results: Sensory thresholds were obtained in nine patients. Directional stimulation did not significantly alter patient perceptions of sensory stimulus [cold pain (p = 0.69), warm pain (p = 0.99), Von frey fibers (p = 0.09), pin-prick (p = 0.88), vibration (p = 0.40), pressure (p = 0.98)]. With correlation analysis, increasing PW at the posterior contact increased pin prick and vibration sensitivity (p < 0.001). Additionally, an increase in TEED caused a decrease in sensitivity to warm detection when using the anterior (p = 0.04), lateral (p = 0.02), and medial contacts (p = 0.03), and also caused a decrease in sensitivity to cold detection when using the medial contact (p = 0.03). UPDRS-III remained stable during testing. Conclusion: Motor benefit can be acutely maintained at directional contacts, whereas directional stimulation can modulate thermal and mechanical sensitivity. Further investigation will determine whether these changes are maintained chronically or can be improved with optimized programming.

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Connectivity and dynamics underlying synaptic control of the Subthalamic Nucleus

Cited by 35 publications

References 59 publications

Beta-Band Resonance and Intrinsic Oscillations in a Biophysically Detailed Model of the Subthalamic Nucleus-Globus Pallidus Network

Beta-Band Resonance and Intrinsic Oscillations in a Biophysically Detailed Model of the Subthalamic Nucleus-Globus Pallidus Network

Parkinson patients without tremor show changed patterns of mechanical muscle oscillations during a specific bilateral motor task compared to controls

Effect of Directional Deep Brain Stimulation on Sensory Thresholds in Parkinson’s Disease

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