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Optimal Deep Brain Stimulation Sites and Networks for Stimulation of the Fornix in Alzheimer's Disease

Key findings

  • Deep brain stimulation (DBS) to the fornix is an emerging investigational treatment for Alzheimer's disease but clinical outcomes vary widely, perhaps because of variance in electrode placement
  • This study investigated relationships between electrode placement and clinical outcome in a multicenter series of 46 patients with mild Alzheimer's disease who underwent DBS to the fornix
  • At the structural level, modulating the circuit of Papez and stria terminalis was a strong driver of clinical improvement; at a localized voxel level, the optimal stimulation site was at the border of the fornix and the bed nucleus of the stria terminalis
  • At the network connectivity level, DBS stimulation sites in patients with optimal cognitive response fell onto a network comprised of regions of the default mode network and premotor cortical sites involved in memory, working memory, and retrieval
  • With optimization of electrode placement, future trials may be able to show greater efficacy of DBS for Alzheimer's disease

Deep brain stimulation (DBS) to the fornix is an emerging investigational treatment for Alzheimer's disease (AD). The fornix is essential to memory formation and consolidation, and although other DBS targets have been proposed for AD, it's the most studied region.

The benefit of DBS in AD remains unproven because clinical outcomes vary—and cognition deteriorates in some patients. One explanation may be variance in electrode placement, especially since the precise target hasn't been defined yet and the neural substrates that drive results are still poorly understood.

Now, Andreas Horn, MD, PhD, director of Connectomic Neuromodulation Research at Massachusetts General Hospital, and director of DBS research at the Center for Brain Circuit Therapeutics in the Department of Neurology at Brigham and Women's Hospital, and colleagues have identified what seems to be an optimal site for DBS for AD. Their results appear in Nature Communications.


The post hoc analysis included data on 46 patients with mild AD who participated in a phase 1 or phase 2 trial of bilateral DBS targeting the fornix. The two trials were performed at seven international centers between 2007 and 2019 with a standardized DBS protocol.

The researchers investigated the effects of electrode localization at three levels: structural connectivity, the localized voxel level, and functional connectivity.

White Matter Analysis

The researchers first examined which white matter tracts were modulated in top responders to DBS and not poor responders. Stimulation of the circuit of Papez and stria terminalis were strongly associated with cognitive improvement (r=0.53; P<0.001).

The circuit of Papez has a crucial role in episodic memory, and changes have been detected as early as in prodromal AD. The stria terminalis is involved in behavior and emotional expression.

Focal Analysis

The anatomic "sweet spot" target for DBS was identified as a circumscribed region between the fornix and the bed nucleus of the stria terminalis (r=0.48; P<0.001).

The authors caution, however, that they used indirect coordinate systems to determine that site, a method unsuitable for DBS in patients who have cerebral atrophy. Accurate targeting will require direct imaging and fiber-tracking results.

Network Analysis

Modulating certain whole-brain networks was crucial to positive effects of DBS on cognition. In patients with an optimal cognitive response, DBS stimulation sites were functionally connected with the precuneus, prefrontal regions, cingulate, thalamus, basal ganglia, and insula.

Refining Trial Design

The results of all three levels of analysis were highly robust in multiple cross-validation methods. The findings can potentially refine and guide surgical targeting and DBS optimization in future AD clinical trials.

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