Fornix-Region Deep Brain Stimulation-Induced Memory Flashbacks in Alzheimer's Disease.
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ABSTRACT:
SUBMITTER: Deeb W
PROVIDER: S-EPMC7313538 | biostudies-literature | 2019 Aug
REPOSITORIES: biostudies-literature
Publications
Fornix-Region Deep Brain Stimulation-Induced Memory Flashbacks in Alzheimer's Disease.
Deeb Wissam W Salvato Bryan B Almeida Leonardo L Foote Kelly D KD Amaral Robert R Germann Jurgen J Rosenberg Paul B PB Tang-Wai David F DF Wolk David A DA Burke Anna D AD Salloway Stephen S Sabbagh Marwan N MN Chakravarty M Mallar MM Smith Gwenn S GS Lyketsos Constantine G CG Lozano Andres M AM Okun Michael S MS
The New England journal of medicine 20190801 8
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Project description:Deep brain stimulation (DBS) to the fornix is an investigational treatment for patients with mild Alzheimer's Disease. Outcomes from randomized clinical trials have shown that cognitive function improved in some patients but deteriorated in others. This could be explained by variance in electrode placement leading to differential engagement of neural circuits. To investigate this, we performed a post-hoc analysis on a multi-center cohort of 46 patients with DBS to the fornix (NCT00658125, NCT01608061). Using normative structural and functional connectivity data, we found that stimulation of the circuit of Papez and stria terminalis robustly associated with cognitive improvement (R = 0.53, p < 0.001). On a local level, the optimal stimulation site resided at the direct interface between these structures (R = 0.48, p < 0.001). Finally, modulating specific distributed brain networks related to memory accounted for optimal outcomes (R = 0.48, p < 0.001). Findings were robust to multiple cross-validation designs and may define an optimal network target that could refine DBS surgery and programming.
| S-EPMC9751139 | biostudies-literature
Project description:BackgroundDeep brain stimulation (DBS) is used to modulate the activity of dysfunctional brain circuits. The safety and efficacy of DBS in dementia is unknown.ObjectiveTo assess DBS of memory circuits as a treatment for patients with mild Alzheimer's disease (AD).MethodsWe evaluated active "on" versus sham "off" bilateral DBS directed at the fornix-a major fiber bundle in the brain's memory circuit-in a randomized, double-blind trial (ClinicalTrials.gov NCT01608061) in 42 patients with mild AD. We measured cognitive function and cerebral glucose metabolism up to 12 months post-implantation.ResultsSurgery and electrical stimulation were safe and well tolerated. There were no significant differences in the primary cognitive outcomes (ADAS-Cog 13, CDR-SB) in the "on" versus "off" stimulation group at 12 months for the whole cohort. Patients receiving stimulation showed increased metabolism at 6 months but this was not significant at 12 months. On post-hoc analysis, there was a significant interaction between age and treatment outcome: in contrast to patients <65 years old (n = 12) whose results trended toward being worse with DBS ON versus OFF, in patients≥65 (n = 30) DBS-f ON treatment was associated with a trend toward both benefit on clinical outcomes and a greater increase in cerebral glucose metabolism.ConclusionDBS for AD was safe and associated with increased cerebral glucose metabolism. There were no differences in cognitive outcomes for participants as a whole, but participants aged≥65 years may have derived benefit while there was possible worsening in patients below age 65 years with stimulation.
| S-EPMC5026133 | biostudies-literature
Project description:IntroductionFornix 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.MethodsThirty-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.ResultsA 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.DiscussionThese results clarify the neuroanatomical substrates of stimulation-evoked flashbacks.
| S-EPMC8247976 | biostudies-literature
Project description:OBJECT This report describes the stereotactic technique, hospitalization, and 90-day perioperative safety of bilateral deep brain stimulation (DBS) of the fornix in patients who underwent DBS for the treatment of mild, probable Alzheimer's disease (AD). METHODS The ADvance Trial is a multicenter, 12-month, double-blind, randomized, controlled feasibility study being conducted to evaluate the safety, efficacy, and tolerability of DBS of the fornix in patients with mild, probable AD. Intraoperative and perioperative data were collected prospectively. All patients underwent postoperative MRI. Stereotactic analyses were performed in a blinded fashion by a single surgeon. Adverse events (AEs) were reported to an independent clinical events committee and adjudicated to determine the relationship between the AE and the study procedure. RESULTS Between June 6, 2012, and April 28, 2014, a total of 42 patients with mild, probable AD were treated with bilateral fornix DBS (mean age 68.2 ± 7.8 years; range 48.0-79.7 years; 23 men and 19 women). The mean planned target coordinates were x = 5.2 ± 1.0 mm (range 3.0-7.9 mm), y = 9.6 ± 0.9 mm (range 8.0-11.6 mm), z = -7.5 ± 1.2 mm (range -5.4 to -10.0 mm), and the mean postoperative stereotactic radial error on MRI was 1.5 ± 1.0 mm (range 0.2-4.0 mm). The mean length of hospitalization was 1.4 ± 0.8 days. Twenty-six (61.9%) patients experienced 64 AEs related to the study procedure, of which 7 were serious AEs experienced by 5 patients (11.9%). Four (9.5%) patients required return to surgery: 2 patients for explantation due to infection, 1 patient for lead repositioning, and 1 patient for chronic subdural hematoma. No patients experienced neurological deficits as a result of the study, and no deaths were reported. CONCLUSIONS Accurate targeting of DBS to the fornix without direct injury to it is feasible across surgeons and treatment centers. At 90 days after surgery, bilateral fornix DBS was well tolerated by patients with mild, probable AD. Clinical trial registration no.: NCT01608061 ( clinicaltrials.gov ).
| S-EPMC4912949 | biostudies-literature
Project description:Deep brain stimulation is a therapy for Alzheimer's disease (AD) that has previously been used for mainly mild to moderate cases. This study provides the first evidence of early alterations in performance induced by stimulation targeted at the fornix in severe AD patients. The performance of the five cases enrolled in this study was scored with specialized assessments including the Mini-Mental State Examination and Clinical Dementia Rating, both before and at an early stage after deep brain stimulation. The burden of caregivers was also evaluated using the Zarit Caregiver Burden Interview. As a whole, the cognitive performance of patients remained stable or improved to varying degrees, and caregiver burden was decreased. Individually, an improved mental state or social performance was observed in three patients, and one of these three patients showed remarkable improvement in long-term memory. The conditions of another patient deteriorated because of inappropriate antipsychotic medications that were administered by his caregivers. Taken together, deep brain stimulation was capable of improving some cognitive aspects in patients with severe AD, and of ameliorating their emotional and social performance, at least at an early stage. However, long-term effects induced by deep brain stimulation in patients with severe AD need to be further validated. More research should focus on clarifying the mechanism of deep brain stimulation. This study was registered with ClinicalTrials.gov (NCT03115814) on April 14, 2017.
| S-EPMC6199932 | biostudies-literature
Project description:BackgroundDeep Brain Stimulation (DBS) is thought to improve the symptoms of selected neurological disorders by modulating activity within dysfunctional brain circuits. To date, there is no evidence that DBS counteracts progressive neurodegeneration in any particular disorder.Objective/hypothesisWe hypothesized that DBS applied to the fornix in patients with Alzheimer's Disease (AD) could have an effect on brain structure.MethodsIn six AD patients receiving fornix DBS, we used structural MRI to assess one-year change in hippocampal, fornix, and mammillary body volume. We also used deformation-based morphometry to identify whole-brain structural changes. We correlated volumetric changes to hippocampal glucose metabolism. We also compared volumetric changes to those in an age-, sex-, and severity-matched group of AD patients (n = 25) not receiving DBS.ResultsWe observed bilateral hippocampal volume increases in the two patients with the best clinical response to fornix DBS. In one patient, hippocampal volume was preserved three years after diagnosis. Overall, mean hippocampal atrophy was significantly slower in the DBS group compared to the matched AD group, and no matched AD patients demonstrated bilateral hippocampal enlargement. Across DBS patients, hippocampal volume change correlated strongly with hippocampal metabolism and with volume change in the fornix and mammillary bodies, suggesting a circuit-wide effect of stimulation. Deformation-based morphometry in DBS patients revealed local volume expansions in several regions typically atrophied in AD.ConclusionWe present the first in-human evidence that, in addition to modulating neural circuit activity, DBS may influence the natural course of brain atrophy in a neurodegenerative disease.
| S-EPMC5659851 | biostudies-literature
Project description:Recent studies have identified an association between memory deficits and defects of the integrated neuronal cortical areas known collectively as the default mode network. It is conceivable that the amyloid deposition or other molecular abnormalities seen in patients with Alzheimer's disease may interfere with this network and disrupt neuronal circuits beyond the localized brain areas. Therefore, Alzheimer's disease may be both a degenerative disease and a broader system-level disorder affecting integrated neuronal pathways involved in memory. In this paper, we describe the rationale and provide some evidence to support the study of deep brain stimulation of the hippocampal fornix as a novel treatment to improve neuronal circuitry within these integrated networks and thereby sustain memory function in early Alzheimer's disease.
| S-EPMC3552463 | biostudies-literature
Project description:Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Deep brain stimulation (DBS) has been used to treat a variety of brain disorders and shows promise in alleviating cognitive symptoms in some AD patients (Laxton et al, 2010). We previously showed that DBS of the entorhinal cortex (EC) enhances spatial memory formation in normal (wild-type) mice (Stone et al, 2011). Here we tested the effects of EC-DBS on the progressive cognitive deficits in a genetically-based mouse model of AD. TgCRND8 (Tg) transgenic mice express human amyloid precursor protein harboring the Swedish and Indiana familial AD mutations. These mice exhibit age-related increases in Aβ production, plaque deposition, as well as contextual fear and spatial memory impairments. Here, we found EC stimulation in young mice (6 weeks old) rescued the early contextual fear and spatial memory deficits and decreased subsequent plaque load in Tg mice. Moreover, stimulation in older mice (6 months old) was also sufficient to rescue the memory deficits in Tg mice. The memory enhancement induced by DBS emerged gradually (over the course of weeks) and was both persistent and specific to hippocampal-based memories. These results provide further support for the development of novel therapeutics aimed to resolve the cognitive decline and memory impairment in AD using DBS of hippocampal afferents.
| S-EPMC5686482 | biostudies-literature
Project description:IntroductionDeep brain stimulation (DBS) is a circuit-based treatment shown to relieve symptoms from multiple neurologic and neuropsychiatric disorders. In order to treat the memory deficit associated with Alzheimer's disease (AD), several clinical trials have tested the efficacy of DBS near the fornix. Early results from these studies indicated that patients who received fornix DBS experienced an improvement in memory and quality of life, yet the mechanisms behind this effect remain controversial. It is known that transmission between the medial limbic and corticolimbic circuits plays an integral role in declarative memory, and dysfunction at the circuit level results in various forms of dementia, including AD. Here, we aimed to determine the potential underlying mechanism of fornix DBS by examining the functional circuitry and brain structures engaged by fornix DBS.MethodsA multimodal approach was employed to examine global and local temporal changes that occur in an anesthetized swine model of fornix DBS. Changes in global functional activity were measured by functional MRI (fMRI), and local neurochemical changes were monitored by fast scan cyclic voltammetry (FSCV) during electrical stimulation of the fornix. Additionally, intracranial microinfusions into the nucleus accumbens (NAc) were performed to investigate the global activity changes that occur with dopamine and glutamate receptor-specific antagonism.ResultsHemodynamic responses in both medial limbic and corticolimbic circuits measured by fMRI were induced by fornix DBS. Additionally, fornix DBS resulted in increases in dopamine oxidation current (corresponding to dopamine efflux) monitored by FSCV in the NAc. Finally, fornix DBS-evoked hemodynamic responses in the amygdala and hippocampus decreased following dopamine and glutamate receptor antagonism in the NAc.ConclusionsThe present findings suggest that fornix DBS modulates dopamine release on presynaptic dopaminergic terminals in the NAc, involving excitatory glutamatergic input, and that the medial limbic and corticolimbic circuits interact in a functional loop.
| S-EPMC4764383 | biostudies-literature
Project description:Telomere length is a reliable biomarker for health and longevity prediction in both humans and animals. The common neuromodulation techniques, including deep brain stimulation (DBS) and optogenetics, have excellent spatial resolution and depth penetration but require implementation of electrodes or optical fibers. Therefore, it is important to develop methods for noninvasive modulation of telomere length. Herein, we reported on a new method for decelerating telomere shortening using noninvasive ultrasound deep brain stimulation (UDBS). Firstly, we found that UDBS could activate the telomerase-associated proteins in normal mice. Then, in the Alzheimer's disease mice, UDBS was observed to decelerate telomere shortening of the cortex and myocardial tissue and to effectively improve spatial learning and memory abilities. Similarly, UDBS was found to significantly slow down telomere shortening of the cortex and peripheral blood, and improve motor and cognitive functions in aging mice. Finally, transcriptome analysis revealed that UDBS upregulated the neuroactive ligand-receptor interaction pathway. Overall, the present findings established the critical role of UDBS in delaying telomere shortening and indicated that ultrasound modulation of telomere length may constitute an effective therapeutic strategy for aging and aging-related diseases.
| S-EPMC11197585 | biostudies-literature