Brain structures and networks responsible for stimulation-induced memory flashbacks during forniceal deep brain stimulation for Alzheimer's disease

Jürgen Germann; Gavin J.B. Elias; Alexandre Boutet; Keshav Narang; Clemens Neudorfer; Andreas Horn; Aaron Loh; Wissam Deeb; Bryan Salvato; Leonardo Almeida; Kelly D. Foote; Paul B. Rosenberg; David F. Tang-Wai; David A. Wolk; Anna D. Burke; Stephen Salloway; Marwan N. Sabbagh; M. Mallar Chakravarty; Gwenn S. Smith; Constantine G. Lyketsos; Michael S. Okun; Andres M. Lozano

doi:10.1002/alz.12238

Brain structures and networks responsible for stimulation-induced memory flashbacks during forniceal deep brain stimulation for Alzheimer's disease

Jürgen Germann, Gavin J.B. Elias, Alexandre Boutet, Keshav Narang, Clemens Neudorfer, Andreas Horn, Aaron Loh, Wissam Deeb, Bryan Salvato, Leonardo Almeida, Kelly D. Foote, Paul B. Rosenberg, David F. Tang-Wai, David A. Wolk, Anna D. Burke, Stephen Salloway, Marwan N. Sabbagh, M. Mallar Chakravarty, Gwenn S. Smith, Constantine G. LyketsosMichael S. Okun, Andres M. Lozano

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

Introduction: Fornix deep brain stimulation (fx-DBS) is under investigation for treatment of Alzheimer's disease (AD). We investigated the anatomic correlates of flashback phenomena that were reported previously during acute diencephalic stimulation. Methods: Thirty-nine patients with mild AD who took part in a prior fx-DBS trial (NCT01608061) were studied. After localizing patients’ implanted electrodes and modeling the volume of tissue activated (VTA) by DBS during systematic stimulation testing, we performed (1) voxel-wise VTA mapping to identify flashback-associated zones; (2) machine learning–based prediction of flashback occurrence given VTA overlap with specific structures; (3) normative functional connectomics to define flashback-associated brain-wide networks. Results: A distinct diencephalic region was associated with greater flashback likelihood. Fornix, bed nucleus of stria terminalis, and anterior commissure involvement predicted memory events with 72% accuracy. Flashback-inducing stimulation exhibited greater functional connectivity to a network of memory-evoking and autobiographical memory-related sites. Discussion: These results clarify the neuroanatomical substrates of stimulation-evoked flashbacks.

Original language	English (US)
Pages (from-to)	777-787
Number of pages	11
Journal	Alzheimer's and Dementia
Volume	17
Issue number	5
DOIs	https://doi.org/10.1002/alz.12238
State	Published - May 2021

Keywords

Alzheimer's disease
brain connectivity
deep brain stimulation
fornix
magnetic resonance imaging
memory

ASJC Scopus subject areas

Clinical Neurology
Geriatrics and Gerontology
Psychiatry and Mental health
Cellular and Molecular Neuroscience
Health Policy
Developmental Neuroscience
Epidemiology

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10.1002/alz.12238

Cite this

Germann, J., Elias, G. J. B., Boutet, A., Narang, K., Neudorfer, C., Horn, A., Loh, A., Deeb, W., Salvato, B., Almeida, L., Foote, K. D., Rosenberg, P. B., Tang-Wai, D. F., Wolk, D. A., Burke, A. D., Salloway, S., Sabbagh, M. N., Chakravarty, M. M., Smith, G. S., ... Lozano, A. M. (2021). Brain structures and networks responsible for stimulation-induced memory flashbacks during forniceal deep brain stimulation for Alzheimer's disease. Alzheimer's and Dementia, 17(5), 777-787. https://doi.org/10.1002/alz.12238

Germann, J, Elias, GJB, Boutet, A, Narang, K, Neudorfer, C, Horn, A, Loh, A, Deeb, W, Salvato, B, Almeida, L, Foote, KD, Rosenberg, PB, Tang-Wai, DF, Wolk, DA, Burke, AD, Salloway, S, Sabbagh, MN, Chakravarty, MM, Smith, GS , Lyketsos, CG, Okun, MS & Lozano, AM 2021, 'Brain structures and networks responsible for stimulation-induced memory flashbacks during forniceal deep brain stimulation for Alzheimer's disease', Alzheimer's and Dementia, vol. 17, no. 5, pp. 777-787. https://doi.org/10.1002/alz.12238

@article{e3496c4145be4388bf3decebf5569232,

title = "Brain structures and networks responsible for stimulation-induced memory flashbacks during forniceal deep brain stimulation for Alzheimer's disease",

abstract = "Introduction: Fornix deep brain stimulation (fx-DBS) is under investigation for treatment of Alzheimer's disease (AD). We investigated the anatomic correlates of flashback phenomena that were reported previously during acute diencephalic stimulation. Methods: Thirty-nine patients with mild AD who took part in a prior fx-DBS trial (NCT01608061) were studied. After localizing patients{\textquoteright} implanted electrodes and modeling the volume of tissue activated (VTA) by DBS during systematic stimulation testing, we performed (1) voxel-wise VTA mapping to identify flashback-associated zones; (2) machine learning–based prediction of flashback occurrence given VTA overlap with specific structures; (3) normative functional connectomics to define flashback-associated brain-wide networks. Results: A distinct diencephalic region was associated with greater flashback likelihood. Fornix, bed nucleus of stria terminalis, and anterior commissure involvement predicted memory events with 72% accuracy. Flashback-inducing stimulation exhibited greater functional connectivity to a network of memory-evoking and autobiographical memory-related sites. Discussion: These results clarify the neuroanatomical substrates of stimulation-evoked flashbacks.",

keywords = "Alzheimer's disease, brain connectivity, deep brain stimulation, fornix, magnetic resonance imaging, memory",

author = "J{\"u}rgen Germann and Elias, {Gavin J.B.} and Alexandre Boutet and Keshav Narang and Clemens Neudorfer and Andreas Horn and Aaron Loh and Wissam Deeb and Bryan Salvato and Leonardo Almeida and Foote, {Kelly D.} and Rosenberg, {Paul B.} and Tang-Wai, {David F.} and Wolk, {David A.} and Burke, {Anna D.} and Stephen Salloway and Sabbagh, {Marwan N.} and Chakravarty, {M. Mallar} and Smith, {Gwenn S.} and Lyketsos, {Constantine G.} and Okun, {Michael S.} and Lozano, {Andres M.}",

note = "Funding Information: This work was supported by the RR Tasker Chair in Functional Neurosurgery at University Health Network (AML), the Canadian Institutes of Health Research (reference # 164235: GJBE), and the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG NE 2276/1‐1: CN; DFG grant 410169619: AH). Publisher Copyright: {\textcopyright} 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association",

year = "2021",

month = may,

doi = "10.1002/alz.12238",

language = "English (US)",

volume = "17",

pages = "777--787",

journal = "Alzheimer's and Dementia",

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T1 - Brain structures and networks responsible for stimulation-induced memory flashbacks during forniceal deep brain stimulation for Alzheimer's disease

AU - Germann, Jürgen

AU - Elias, Gavin J.B.

AU - Boutet, Alexandre

AU - Narang, Keshav

AU - Neudorfer, Clemens

AU - Horn, Andreas

AU - Loh, Aaron

AU - Deeb, Wissam

AU - Salvato, Bryan

AU - Almeida, Leonardo

AU - Foote, Kelly D.

AU - Rosenberg, Paul B.

AU - Tang-Wai, David F.

AU - Wolk, David A.

AU - Burke, Anna D.

AU - Salloway, Stephen

AU - Sabbagh, Marwan N.

AU - Chakravarty, M. Mallar

AU - Smith, Gwenn S.

AU - Lyketsos, Constantine G.

AU - Okun, Michael S.

AU - Lozano, Andres M.

N1 - Funding Information: This work was supported by the RR Tasker Chair in Functional Neurosurgery at University Health Network (AML), the Canadian Institutes of Health Research (reference # 164235: GJBE), and the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG NE 2276/1‐1: CN; DFG grant 410169619: AH). Publisher Copyright: © 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association

PY - 2021/5

Y1 - 2021/5

N2 - Introduction: Fornix deep brain stimulation (fx-DBS) is under investigation for treatment of Alzheimer's disease (AD). We investigated the anatomic correlates of flashback phenomena that were reported previously during acute diencephalic stimulation. Methods: Thirty-nine patients with mild AD who took part in a prior fx-DBS trial (NCT01608061) were studied. After localizing patients’ implanted electrodes and modeling the volume of tissue activated (VTA) by DBS during systematic stimulation testing, we performed (1) voxel-wise VTA mapping to identify flashback-associated zones; (2) machine learning–based prediction of flashback occurrence given VTA overlap with specific structures; (3) normative functional connectomics to define flashback-associated brain-wide networks. Results: A distinct diencephalic region was associated with greater flashback likelihood. Fornix, bed nucleus of stria terminalis, and anterior commissure involvement predicted memory events with 72% accuracy. Flashback-inducing stimulation exhibited greater functional connectivity to a network of memory-evoking and autobiographical memory-related sites. Discussion: These results clarify the neuroanatomical substrates of stimulation-evoked flashbacks.

AB - Introduction: Fornix deep brain stimulation (fx-DBS) is under investigation for treatment of Alzheimer's disease (AD). We investigated the anatomic correlates of flashback phenomena that were reported previously during acute diencephalic stimulation. Methods: Thirty-nine patients with mild AD who took part in a prior fx-DBS trial (NCT01608061) were studied. After localizing patients’ implanted electrodes and modeling the volume of tissue activated (VTA) by DBS during systematic stimulation testing, we performed (1) voxel-wise VTA mapping to identify flashback-associated zones; (2) machine learning–based prediction of flashback occurrence given VTA overlap with specific structures; (3) normative functional connectomics to define flashback-associated brain-wide networks. Results: A distinct diencephalic region was associated with greater flashback likelihood. Fornix, bed nucleus of stria terminalis, and anterior commissure involvement predicted memory events with 72% accuracy. Flashback-inducing stimulation exhibited greater functional connectivity to a network of memory-evoking and autobiographical memory-related sites. Discussion: These results clarify the neuroanatomical substrates of stimulation-evoked flashbacks.

KW - Alzheimer's disease

KW - brain connectivity

KW - deep brain stimulation

KW - fornix

KW - magnetic resonance imaging

KW - memory

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JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

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ER -

Brain structures and networks responsible for stimulation-induced memory flashbacks during forniceal deep brain stimulation for Alzheimer's disease

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