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’ 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.

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“…Additionally, as no native resting state functional MRI data were available, the functional connectivity analysis was performed using high-resolution and high-fidelity normative data from healthy individuals. Although normative data may not fully represent patient or pathology-specific functional connectivity, it has been shown to yield similar results to patient-specific data in prior analyses [7,12].…”

“…Retrospective imaging analysis was performed to elucidate the neurocircuitry underlying response to stimulation. This involved DBS electrode localization (https://www.lead-dbs.org/), volume of activated tissue (VAT) modelling, and mapping of areas functionally connected to the VATs using a normative connectome [7] (see supplementary materials for detailed description).…”

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“…The connectome is key for understanding how the brain works. Over the last years, multiple studies have demonstrated that neurological and psychiatric symptoms can be mapped to a common distributed brain network [19][20][21][22][23][24][25][26][27][28][29][30]. The brain connectome can be assessed using different MRI acquisitions: (1) diffusion-weighted MRI (dMRI) to estimate the structural connectivity using the directionality of water diffusion to evaluate tracts and projections [31]; (2) resting state functional MRI (rsfMRI) to estimate functional connectivity making use of the lowfrequency blood oxygen level-dependent (BOLD) fluctuations found in brain regions that are functionally related to each other [32].…”

“…Using the segmented feature in the template space as the input in the normative functional and structural connectomes, one can then identify the brain-wide network of functionally and structurally connected areas (Figure 2). This allows identification of networks involved in clinical symptoms or disease processes (Figure 1) [22,[25][26][27]46]. For Using the segmented feature in the template space as the input in the normative functional and structural connectomes, one can then identify the brain-wide network of functionally and structurally connected areas (Figure 2).…”

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“…Recognizing these remote effects of DBS, one can also conceptualize that connectomic analysis may provide insight into the underlying basis of adverse effects or undesirable symptoms occurring secondary to DBS. Such an approach has been used to map the underlying connectivity of DBS-associated flashback phenomena following forniceal DBS, panic attacks induced by inferior thalamic peduncle DBS, and seizures following subcallosal cingulate DBS for refractory anorexia nervosa [ 30 , 31 , 32 ]. Similarly, connectivity-derived models can guide effective DBS for less well-understood pathologies, such as central post-stroke pain and neuropsychiatric indications, including obsessive-compulsive disorder [ 8 , 33 ].…”