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Cellular and Molecular Life Sciences :... Sep 2020Deep brain stimulation is used to alleviate symptoms of neurological and psychiatric disorders including Parkinson's disease, epilepsy, and... (Review)
Review
Deep brain stimulation is used to alleviate symptoms of neurological and psychiatric disorders including Parkinson's disease, epilepsy, and obsessive-compulsive-disorder. Electrically stimulating limbic structures has been of great interest, and in particular, the region of the fornix. We conducted a systematic search for studies that reported clinical and preclinical outcomes of deep brain stimulation within the fornix up to July 2019. We identified 13 studies (7 clinical, 6 preclinical) that examined the effects of fornix stimulation in Alzheimer's disease (n = 9), traumatic brain injury (n = 2), Rett syndrome (n = 1), and temporal lobe epilepsy (n = 1). Overall, fornix stimulation can lead to decreased rates of cognitive decline (in humans), enhanced memory (in humans and animals), visuo-spatial memorization (in humans and animals), and improving verbal recollection (in humans). While the exact mechanisms of action are not completely understood, studies suggest fornix DBS to be involved with increased functional connectivity and neurotransmitter levels, as well as enhanced neuroplasticity.
Topics: Alzheimer Disease; Animals; Brain Injuries, Traumatic; Deep Brain Stimulation; Epilepsy; Fornix, Brain; Humans; Memory; Memory Disorders; Rett Syndrome
PubMed: 31974655
DOI: 10.1007/s00018-020-03456-4 -
Handbook of Clinical Neurology 2021Deep brain stimulation (DBS) has proven to be safe and effective for both hypo- and hyperkinetic movement disorders of basal ganglia origin, while its application to... (Review)
Review
Deep brain stimulation (DBS) has proven to be safe and effective for both hypo- and hyperkinetic movement disorders of basal ganglia origin, while its application to other neural pathways such as the circuit of Papez is under investigation. In particular, the fornix has gained interest as potential DBS target to decrease rates of cognitive decline, enhance memory, aid visuospatial memorization, and improve verbal recollection. While the exact mechanisms of action of fornix DBS are not completely understood, studies found enhanced hippocampal acetylcholine release, synaptic plasticity, and decreased inflammatory responses in cortex and hippocampus. Nevertheless, it is still premature to conclude that fornix DBS can be used in the treatment of cognitive disorders, and the field needs sound, preclinically tested, and disease-specific a posteriori hypotheses.
Topics: Brain Diseases; Deep Brain Stimulation; Electric Stimulation; Fornix, Brain; Hippocampus; Humans
PubMed: 34225947
DOI: 10.1016/B978-0-12-820107-7.00028-8 -
Ageing Research Reviews Aug 2022Memory reflects the brain function in encoding, storage and retrieval of the data or information, which is a fundamental ability for any live organism. The development... (Review)
Review
Memory reflects the brain function in encoding, storage and retrieval of the data or information, which is a fundamental ability for any live organism. The development of approaches to improve memory attracts much attention due to the underlying mechanistic insight and therapeutic potential to treat neurodegenerative diseases with memory loss, such as Alzheimer's disease (AD). Deep brain stimulation (DBS), a reversible, adjustable, and non-ablative therapy, has been shown to be safe and effective in many clinical trials for neurodegenerative and neuropsychiatric disorders. Among all potential regions with access to invasive electrodes, fornix is considered as it is the major afferent and efferent connection of the hippocampus known to be closely associated with learning and memory. Indeed, clinical trials have demonstrated that fornix DBS globally improved cognitive function in a subset of patients with AD, indicating fornix can serve as a potential target for neurosurgical intervention in treating memory impairment in AD. The present review aims to provide a better understanding of recent progresses in the application of fornix DBS for ameliorating memory impairments in AD patients.
Topics: Alzheimer Disease; Deep Brain Stimulation; Fornix, Brain; Hippocampus; Humans; Learning
PubMed: 35705176
DOI: 10.1016/j.arr.2022.101668 -
European Journal of Clinical... Aug 2023Alzheimer's disease (AD) is one of the most common progressive neurodegenerative diseases associated with the degradation of memory and cognitive ability. Current... (Review)
Review
Alzheimer's disease (AD) is one of the most common progressive neurodegenerative diseases associated with the degradation of memory and cognitive ability. Current pharmacotherapies show little therapeutic effect in AD treatment and still cannot prevent the pathological progression of AD. Deep brain stimulation (DBS) has shown to enhance memory in morbid obese, epilepsy and traumatic brain injury patients, and cognition in Parkinson's disease (PD) patients deteriorates during DBS off. Some relevant animal studies and clinical trials have been carried out to discuss the DBS treatment for AD. Reviewing the fornix trials, no unified conclusion has been reached about the clinical benefits of DBS in AD, and the dementia ratings scale has not been effectively improved in the long term. However, some patients have presented promising results, such as improved glucose metabolism, increased connectivity in cognition-related brain regions and even elevated cognitive function rating scale scores. The fornix plays an important regulatory role in memory, attention, and emotion through its complex fibre projection to cognition-related structures, making it a promising target for DBS for AD treatment. Moreover, the current stereotaxic technique and various evaluation methods have provided references for the operator to select accurate stimulation points. Related adverse events and relatively higher costs in DBS have been emphasized. In this article, we summarize and update the research progression on fornix DBS in AD and seek to provide a reliable reference for subsequent experimental studies on DBS treatment of AD.
Topics: Animals; Humans; Alzheimer Disease; Deep Brain Stimulation; Fornix, Brain; Brain; Cognition
PubMed: 37004153
DOI: 10.1111/eci.13995 -
Nature Communications Dec 2022Deep brain stimulation (DBS) to the fornix is an investigational treatment for patients with mild Alzheimer's Disease. Outcomes from randomized clinical trials have...
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.
Topics: Humans; Alzheimer Disease; Brain; Deep Brain Stimulation; Fornix, Brain; Thalamus; Randomized Controlled Trials as Topic
PubMed: 36517479
DOI: 10.1038/s41467-022-34510-3 -
Journal of Chemical Neuroanatomy Mar 2019Fornix deep brain stimulation (DBS) has the ability to refurbish memory functions in animal models with experimental dementia. One of the possible underlying mechanisms...
Fornix deep brain stimulation (DBS) has the ability to refurbish memory functions in animal models with experimental dementia. One of the possible underlying mechanisms is the acute increase of acetylcholine in the hippocampus. Another suggested hypothesis is neuroplasticity. Recent work in rats has shown that acute fornix DBS can modulate neurotrophic factors as well as synaptic plasticity markers on the short-term. Here, we want to test the hypothesis that acute fornix DBS can also lead to long-term effects on neuroplasticity. Rats received DBS at 100 Hz, 100 μA and 100 μs pulse width for 4 h with electrodes placed bilaterally in the fornix. Seven weeks after stimulation, rats were sacrificed. BDNF, p-CREB, SV2 and synaptophysin immunohistochemistry was performed for their brains. No differences were found in the number of BDNF, p-CREB or SV2 positive cells for fornix DBS rats when compared to sham. Surprisingly, the density of synaptophysin immunoreactive presynaptic boutons was significantly decreased in the CA1 and CA3 subregion of the hippocampus for DBS rats. Therefore, fornix DBS might induce long-term depression related mechanisms.
Topics: Animals; Deep Brain Stimulation; Fornix, Brain; Hippocampus; Long-Term Synaptic Depression; Rats; Rats, Sprague-Dawley; Synaptophysin
PubMed: 30529072
DOI: 10.1016/j.jchemneu.2018.12.001 -
Neurosurgery Aug 2016
Review
Topics: Alzheimer Disease; Deep Brain Stimulation; Fornix, Brain; Humans; Male
PubMed: 27399356
DOI: 10.1227/NEU.0000000000001254 -
Brain Structure & Function Nov 2016Deep brain stimulation (DBS) of the fornix has gained interest as a potential therapy for advanced treatment-resistant dementia, yet the mechanism of action remains...
Deep brain stimulation (DBS) of the fornix has gained interest as a potential therapy for advanced treatment-resistant dementia, yet the mechanism of action remains widely unknown. Previously, we have reported beneficial memory effects of fornix DBS in a scopolamine-induced rat model of dementia, which is dependent on various brain structures including hippocampus. To elucidate mechanisms of action of fornix DBS with regard to memory restoration, we performed c-Fos immunohistochemistry in the hippocampus. We found that fornix DBS induced a selective activation of cells in the CA1 and CA3 subfields of the dorsal hippocampus. In addition, hippocampal neurotransmitter levels were measured using microdialysis before, during and after 60 min of fornix DBS in a next experiment. We observed a substantial increase in the levels of extracellular hippocampal acetylcholine, which peaked 20 min after stimulus onset. Interestingly, hippocampal glutamate levels did not change compared to baseline. Therefore, our findings provide first experimental evidence that fornix DBS activates the hippocampus and induces the release of acetylcholine in this region.
Topics: Acetylcholine; Animals; Deep Brain Stimulation; Fornix, Brain; Glutamic Acid; Hippocampus; Male; Neurons; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley
PubMed: 26597361
DOI: 10.1007/s00429-015-1144-2 -
Neurosurgical Review Apr 2022The historical evolution of the fornix has not been sufficiently reviewed in the literature. In this article, we follow this evolution from the first mention of the... (Review)
Review
The historical evolution of the fornix has not been sufficiently reviewed in the literature. In this article, we follow this evolution from the first mention of the fornix in animal dissections of the second century AD, to the legalization of cadaver dissection in the 1300 s, to the introduction of neural staining techniques and the microscope in the seventeenth century, to today. We summarize the focus of fornix studies on memory to reveal its relationship with the hippocampus. We then cover the detection of the fornix and its neural connections noninvasively with the advancement of radiological imaging techniques. Finally, we discuss the prominence of the fornix as a target for deep brain stimulation in Alzheimer's disease and post-traumatic brain injury memory disorders.
Topics: Alzheimer Disease; Animals; Deep Brain Stimulation; Fornix, Brain; Hippocampus; Humans
PubMed: 34498223
DOI: 10.1007/s10143-021-01635-w -
STAR Protocols Mar 2022Deep brain stimulation (DBS) entails neurosurgery to implant electrodes in specific brain structures to modulate the behavior of a particular neural circuit. DBS is best...
Deep brain stimulation (DBS) entails neurosurgery to implant electrodes in specific brain structures to modulate the behavior of a particular neural circuit. DBS is best known for treating advanced Parkinson disease and can potentially be applicable to other motor and even cognitive dysfunctions. Here, we describe a detailed protocol allowing for electrode preparation, surgical procedures, stimulation delivery, and field potential recordings in both anesthetized and behaving mice, and the benefit evaluation of DBS at the fimbria-fornix by using a fear conditioning test. For complete details on the use and execution of this protocol, please refer to Hao et al. (2015).
Topics: Animals; Deep Brain Stimulation; Electrodes; Fear; Fornix, Brain; Mice; Parkinson Disease
PubMed: 35005636
DOI: 10.1016/j.xpro.2021.101054