The rostro-caudal gradient in the prefrontal cortex and its modulation by subthalamic deep brain stimulation in Parkinson’s disease

F. Konrad Schumacher; Lena V. Schumacher; Florian Amtage; Andreas  Horn; Karl Egger; Tobias Piroth; Cornelius Weiller; Bjoern Schelter; Volker A.  Coenen; Christoph Kaller

doi:10.1038/s41598-021-81535-7

The rostro-caudal gradient in the prefrontal cortex and its modulation by subthalamic deep brain stimulation in Parkinson’s disease

F. Konrad Schumacher, Lena V. Schumacher, Florian Amtage, Andreas Horn, Karl Egger, Tobias Piroth, Cornelius Weiller, Bjoern Schelter, Volker A. Coenen, Christoph Kaller

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Abstract

Deep brain stimulation of the subthalamic nucleus (STN-DBS) alleviates motor symptoms in Parkinson’s disease (PD) but also affects the prefrontal cortex (PFC), potentially leading to cognitive side effects. The present study tested alterations within the rostro-caudal hierarchy of neural processing in the PFC induced by STN-DBS in PD. Granger-causality analyses of fast functional near-infrared spectroscopy (fNIRS) measurements were used to infer directed functional connectivity from intrinsic PFC activity in 24 PD patients treated with STN-DBS. Functional connectivity was assessed ON stimulation, in steady-state OFF stimulation and immediately after the stimulator was switched ON again. Results revealed that STN-DBS significantly enhanced the rostro-caudal hierarchical organization of the PFC in patients who had undergone implantation early in the course of the disease, whereas it attenuated the rostro-caudal hierarchy in late-implanted patients. Most crucially, this systematic network effect of STN-DBS was reproducible in the second ON stimulation measurement. Supplemental analyses demonstrated the significance of prefrontal networks for cognitive functions in patients and matched healthy controls. These findings show that the modulation of prefrontal functional networks by STN-DBS is dependent on the disease duration before DBS implantation and suggest a neurophysiological mechanism underlying the side effects on prefrontally-guided cognitive functions observed under STN-DBS.

Original language	English
Article number	2138
Number of pages	13
Journal	Scientific Reports
Volume	11
DOIs	https://doi.org/10.1038/s41598-021-81535-7
Publication status	Published - 22 Jan 2021

Bibliographical note

Acknowledgements
The authors thank Benjamin Rahm (University of Freiburg) and Michael Fox (Harvard Medical School) for valuable comments on a previous version of this manuscript. This work was supported by a grant of the BrainLinks-BrainTools Cluster of Excellence funded by the German Research Foundation (DFG, grant number EXC 1086) to C.P.K., F.A., T.P., B.O.S., C.W, and V.A.C.; A.H. was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, Emmy Noether Stipend 410169619 and 424778381 – TRR 295) as well as Deutsches Zentrum für Luft- und Raumfahrt (DynaSti grant within the EU Joint Programme Neurodegenerative Disease Research, JPND).

Funding
Open Access funding enabled and organized by Projekt DEAL.

Keywords

cognitive control
Parkinson disease
ORGANIZATION
ACTIVATION
NEUROSTIMULATION
CONNECTIVITY
NUCLEUS
MOTOR CORTEX
OUTCOMES
COGNITIVE CONTROL
OSCILLATIONS
LEVODOPA

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Cite this

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title = "The rostro-caudal gradient in the prefrontal cortex and its modulation by subthalamic deep brain stimulation in Parkinson{\textquoteright}s disease",

abstract = "Deep brain stimulation of the subthalamic nucleus (STN-DBS) alleviates motor symptoms in Parkinson{\textquoteright}s disease (PD) but also affects the prefrontal cortex (PFC), potentially leading to cognitive side effects. The present study tested alterations within the rostro-caudal hierarchy of neural processing in the PFC induced by STN-DBS in PD. Granger-causality analyses of fast functional near-infrared spectroscopy (fNIRS) measurements were used to infer directed functional connectivity from intrinsic PFC activity in 24 PD patients treated with STN-DBS. Functional connectivity was assessed ON stimulation, in steady-state OFF stimulation and immediately after the stimulator was switched ON again. Results revealed that STN-DBS significantly enhanced the rostro-caudal hierarchical organization of the PFC in patients who had undergone implantation early in the course of the disease, whereas it attenuated the rostro-caudal hierarchy in late-implanted patients. Most crucially, this systematic network effect of STN-DBS was reproducible in the second ON stimulation measurement. Supplemental analyses demonstrated the significance of prefrontal networks for cognitive functions in patients and matched healthy controls. These findings show that the modulation of prefrontal functional networks by STN-DBS is dependent on the disease duration before DBS implantation and suggest a neurophysiological mechanism underlying the side effects on prefrontally-guided cognitive functions observed under STN-DBS.",

keywords = "cognitive control, Parkinson disease, ORGANIZATION, ACTIVATION, NEUROSTIMULATION, CONNECTIVITY, NUCLEUS, MOTOR CORTEX, OUTCOMES, COGNITIVE CONTROL, OSCILLATIONS, LEVODOPA",

author = "Schumacher, {F. Konrad} and Schumacher, {Lena V.} and Florian Amtage and Andreas Horn and Karl Egger and Tobias Piroth and Cornelius Weiller and Bjoern Schelter and Coenen, {Volker A.} and Christoph Kaller",

note = "Acknowledgements The authors thank Benjamin Rahm (University of Freiburg) and Michael Fox (Harvard Medical School) for valuable comments on a previous version of this manuscript. This work was supported by a grant of the BrainLinks-BrainTools Cluster of Excellence funded by the German Research Foundation (DFG, grant number EXC 1086) to C.P.K., F.A., T.P., B.O.S., C.W, and V.A.C.; A.H. was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, Emmy Noether Stipend 410169619 and 424778381 – TRR 295) as well as Deutsches Zentrum f{\"u}r Luft- und Raumfahrt (DynaSti grant within the EU Joint Programme Neurodegenerative Disease Research, JPND). Funding Open Access funding enabled and organized by Projekt DEAL.",

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AU - Schumacher, F. Konrad

AU - Schumacher, Lena V.

AU - Amtage, Florian

AU - Horn, Andreas

AU - Egger, Karl

AU - Piroth, Tobias

AU - Weiller, Cornelius

AU - Schelter, Bjoern

AU - Coenen, Volker A.

AU - Kaller, Christoph

N1 - Acknowledgements The authors thank Benjamin Rahm (University of Freiburg) and Michael Fox (Harvard Medical School) for valuable comments on a previous version of this manuscript. This work was supported by a grant of the BrainLinks-BrainTools Cluster of Excellence funded by the German Research Foundation (DFG, grant number EXC 1086) to C.P.K., F.A., T.P., B.O.S., C.W, and V.A.C.; A.H. was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, Emmy Noether Stipend 410169619 and 424778381 – TRR 295) as well as Deutsches Zentrum für Luft- und Raumfahrt (DynaSti grant within the EU Joint Programme Neurodegenerative Disease Research, JPND). Funding Open Access funding enabled and organized by Projekt DEAL.

PY - 2021/1/22

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N2 - Deep brain stimulation of the subthalamic nucleus (STN-DBS) alleviates motor symptoms in Parkinson’s disease (PD) but also affects the prefrontal cortex (PFC), potentially leading to cognitive side effects. The present study tested alterations within the rostro-caudal hierarchy of neural processing in the PFC induced by STN-DBS in PD. Granger-causality analyses of fast functional near-infrared spectroscopy (fNIRS) measurements were used to infer directed functional connectivity from intrinsic PFC activity in 24 PD patients treated with STN-DBS. Functional connectivity was assessed ON stimulation, in steady-state OFF stimulation and immediately after the stimulator was switched ON again. Results revealed that STN-DBS significantly enhanced the rostro-caudal hierarchical organization of the PFC in patients who had undergone implantation early in the course of the disease, whereas it attenuated the rostro-caudal hierarchy in late-implanted patients. Most crucially, this systematic network effect of STN-DBS was reproducible in the second ON stimulation measurement. Supplemental analyses demonstrated the significance of prefrontal networks for cognitive functions in patients and matched healthy controls. These findings show that the modulation of prefrontal functional networks by STN-DBS is dependent on the disease duration before DBS implantation and suggest a neurophysiological mechanism underlying the side effects on prefrontally-guided cognitive functions observed under STN-DBS.

AB - Deep brain stimulation of the subthalamic nucleus (STN-DBS) alleviates motor symptoms in Parkinson’s disease (PD) but also affects the prefrontal cortex (PFC), potentially leading to cognitive side effects. The present study tested alterations within the rostro-caudal hierarchy of neural processing in the PFC induced by STN-DBS in PD. Granger-causality analyses of fast functional near-infrared spectroscopy (fNIRS) measurements were used to infer directed functional connectivity from intrinsic PFC activity in 24 PD patients treated with STN-DBS. Functional connectivity was assessed ON stimulation, in steady-state OFF stimulation and immediately after the stimulator was switched ON again. Results revealed that STN-DBS significantly enhanced the rostro-caudal hierarchical organization of the PFC in patients who had undergone implantation early in the course of the disease, whereas it attenuated the rostro-caudal hierarchy in late-implanted patients. Most crucially, this systematic network effect of STN-DBS was reproducible in the second ON stimulation measurement. Supplemental analyses demonstrated the significance of prefrontal networks for cognitive functions in patients and matched healthy controls. These findings show that the modulation of prefrontal functional networks by STN-DBS is dependent on the disease duration before DBS implantation and suggest a neurophysiological mechanism underlying the side effects on prefrontally-guided cognitive functions observed under STN-DBS.

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KW - NEUROSTIMULATION

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KW - NUCLEUS

KW - MOTOR CORTEX

KW - OUTCOMES

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KW - OSCILLATIONS

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The rostro-caudal gradient in the prefrontal cortex and its modulation by subthalamic deep brain stimulation in Parkinson’s disease

Abstract

Bibliographical note

Keywords

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