Background

Deep Brain Stimulation (DBS) is an invasive treatment where pairs of electrodes are surgically implanted in the brain, and connected to a pulse generator placed under the skin on the chest. DBS-fornix places electrodes in the fiber tract that connects the hippocampus to other parts of the limbic system, and is intended to modulate or ease dysfunction of memory circuits in the brain. A large body of evidence links fornix pathology, amnestic mild cognitive impairment, and the development of Alzheimer’s dementia (reviewed in Benear et al., 2020).

The memory-enhancing effects of fornix stimulation were observed incidentally in a patient undergoing DBS to treat obesity at Toronto Western Hospital in Canada (Hamani et al., 2008). Instead of affecting appetite, the stimulation induced a flashback to a decades-old memory during surgery, and improvement in verbal and spatial memory assessments afterwards. After this, the Toronto investigator founded Functional Neuromodulation to pursue DBS-fornix (DBS-f) as a potential treatment for AD (for rationale, see Mirzadeh et al., 2015). This study, and other single-case reports, have been criticized as potentially misleading (Jun 2010 news).

Several preclinical studies documented improved memory after DBS-f stimulation in rats (e.g., Hescham et al., 2012; reviewed in Senova et al., 2020). In rats, one hour of fornix stimulation elevated markers of neuronal activity, trophic factor expression, and synaptic markers in the hippocampus (Gondard et al., 2015). Multiple labs have reported that DBS-f improves cognition in rat and mouse models of AD (e.g., Leplus et al., 2019; Gallino et al., 2019; Zhang et al., 2015).

Findings

In March 2007-June 2010, an open-label pilot study of bilateral DBS-f ran at the Toronto Western Hospital. Six volunteers with clinically diagnosed probable AD had electrodes implanted and received continuous stimulation for one year. Results were published after peer review (Laxton et al., 2010). The treatment was safe, with no serious adverse effects. Stimulation led to increased glucose uptake in temporal and parietal brain regions, suggesting successful modulation of brain activity. Cognitive testing indicated possible improvements, although there was no placebo control in this open-label study. Additional analyses found enhancements in functional connectivity that correlated with clinical improvement (Smith et al., 2012). Three of the six patients showed a preservation or increase in bilateral hippocampal volume, and the group averaged slower hippocampal volume loss than age-, sex-, and severity-matched AD patients not receiving DBS (Sankar et al., 2015).

In May 2012, the placebo-controlled ADvance DBS-f study began to evaluate the safety, efficacy, and tolerability of the procedure in patients clinically diagnosed mild AD. Participants were allowed to be on acetylcholinesterase inhibitors, but could not change regimens during the study. In this study, all 42 participants had a Medtronics neurostimulator surgically implanted, but only half had the stimulator turned on. Outcomes were acute safety 30 days after surgery, and long-term safety one year later, with secondary outcomes of the ADAS-Cog13 and CDR-SB. Results of the study, at seven locations in the U.S. and Canada, were first reported at the CTAD conference in November 2015 (Nov 2015 conference news) and subsequently published after peer review (Lozano et al., 2016; Ponce et al., 2015). Five patients experienced serious adverse events due to surgery. Two had infection that necessitated lead removal, one needed surgery to reposition leads, and one needed surgery for chronic subdural bleeding. No patients developed neurological issues due to surgery, and adverse events were similar between the ON and OFF groups after lead activation. After one year, there was no difference in cognition between the ON and OFF groups. At six months, the ON group showed increased brain glucose uptake, but the difference was not significant at one year. In a post hoc analysis, patients older than 65 in the ON group trended to improvement in glucose metabolism and cognition, while patients younger than 65 trended to worse cognition with DBS ON (see also Targum et al., 2021).

One year after surgery, everyone had the stimulator turned on in an open-label extension. The treatment continued to be safe and well-tolerated, but did not change clinical trajectory (Leoutsakos et al., 2018).

In this study, about half of patients reported spontaneous, vivid memory flashbacks during initial programming of the stimulator, and some memories became more detailed as the voltage was increased (Deeb et al., 2019). Trial data was used to identify the brain regions and circuits responsible for these flashbacks (Germann et al., 2021), and for eliciting side effects including rapid heart rate, warmth, flushing, and high blood pressure (Neudorfer et al., 2021).

An analysis of electrode placement versus clinical outcomes identified a “sweet spot” in the fornix, at the interface between the circuit of Papez and stria terminalis, where stimulation was significantly associated with cognitive improvement (Rios et al., 2022).

A report has been published on potential brain damage due to DBS-f lead placement (McMullen et al., 2015).

In December 2014, a one-year biomarker and dose-finding study began at the University of Toronto, assessing clinical and imaging outcomes in 12 patients with mild Alzheimer’s dementia. After implantation of the DBS device, the participants receive personalized fornix stimulation, optimized by cognitive testing. Primary outcomes are the ADAS-Cog, CDR, amyloid PET, CSF Aβ and tau, and MRI. Secondary and other outcomes include activities of daily living, verbal and visual memory tests, neuropsychiatric symptoms, and measures of depression, suicidality, and mania. The study is to finish in December 2023.

In August 2019, Functional Neuromodulation began the ADvance II study for U.S. regulatory approval. The 210 participants must be at least 65 years old with CSF biomarker-confirmed AD and mild dementia. They can be taking acetylcholinesterase inhibitors or not, but may not change their regimen during the one-year study. All participants will have the Boston Scientific Vercise™ Directional DBS System surgically implanted, and then be randomized to low- or high-frequency stimulation, or no stimulation. A three-year open label extension is planned. The primary outcome is a composite of scores from ADAS-COG and ADCS-ADL. CDR-SB serves as a secondary outcome. The study is ongoing at 23 locations in the U.S., Canada, and Germany, with primary completion expected in October 2027.

In December 2017, the Beijing Pins Medical Company began testing their implantable neurostimulator for DBS of the fornix or the nucleus basalis of Meynert. The latter is the major source of acetylcholine in the brain, and degenerates early in AD. The study, at one hospital in Beijing, is enrolling 30 participants with amyloid-PET-confirmed AD, a clinical dementia rating of 1.0 or 2.0, and on stable donepezil. Stimulator ON and OFF groups will be compared against a primary outcome of ADAS-COG13. The study was to be completed in December 2020, but its status is unknown. A pilot study of 1.5 to three months of DBS-f with this device in five patients in China produced varying results. Several improved their mood and social function, while one got worse (Mao et al., 2018).

Two small academic trials have reported difficulty recruiting for DBS-f trials. In an open-label trial planned for five patients in France, 110 patients were screened, nine were eligible, two gave consent, and only one underwent surgery (Fontaine et al., 2013). A small study planned for six patients in Spain ultimately published a single-patient case report claiming cognitive stabilization over two years stimulation (Barcia et al., 2022).

A meta-analysis of trials of DBS-f involving a total of 53 people with AD found no evidence for improved cognition (Majdi et al., 2023). Besides the small number of participants, the studies differed in their stimulation parameters, and the authors cite the need for larger, standardized trials.

DBS-f is being tested for additional indications. A Mayo Clinic study is testing dual stimulation of the subthalamic nucleus and fornix/hypothalamus to improve cognitive function in people with Parkinson’s disease. Beginning in April 2012, the open-label study is enrolling 12 participants, and plans to finish in January 2025. Acute DBS-f also has been reported to improve memory and reduce the risk of seizure in people with temporal lobe epilepsy (Koubeissi et al., 2013; Koubeissi et al., 2022).

Other studies evaluating DBS for AD are targeting the nucleus basalis of Meynert (e.g., Hardenacke et al., 2016), and the ventral capsule/ventral striatum, a modulator of frontal lobe networks (Scharre et al., 2018).

For details on DBS-f trials, see clinicaltrials.gov.