Fornix Deep Brain Stimulation Research Articles

Deep Brain Stimulation for Alzheimer’s Disease and the Human Memory Circuit

AbstractBackgroundBrain lesions causing amnesia are in a memory circuit centered on the subiculum. Deep brain stimulation (DBS) sites connected to this circuit are linked to cognitive decline in Parkinson’s disease but cognitive improvement in Alzheimer’s Disease (AD). Insight into this paradox may come from directly comparing the topography of lesion and DBS‐induced effects.MethodsWe studied 53 amnesia‐causing lesion locations and 46 patients (92 DBS sites) from Phase 1 and Phase 2 randomized controlled trials of fornix DBS for AD. Connectivity between lesions and DBS sites was computed using a normative atlas of functional connectivity data from 1000 healthy subjects. Baseline cognitive scores were compared to 1‐year post‐DBS activation scores.ResultsConnectivity between AD patients' DBS sites and a subiculum region derived from amnesia‐causing brain lesions correlated with cognitive improvement (Spearman’s rho = 0.33, p = 0.027). There was a difference between sham‐first (Spearman’s rho = 0.33, p = 0.027) and stimulation‐first (Spearman’s rho = 0.25, p = 0.27) cohorts. Whole‐brain connectivity maps of the subiculum region and AD response fingerprints were aligned: 17/19 local maxima appeared in both maps, dice coefficient 0.71 (p<0.00001). Both maps showed data‐driven peaks in an overlapping subiculum region. However, DBS data showed a significant interaction effect between patient age and subiculum connectivity upon outcome in a general linear model (p = 0.031). Randomization status was controlled as a covariate and was not significant. Specifically, higher subiculum connectivity in older patients led to improved cognition, while higher connectivity in younger patients resulted in worsening cognition. The data‐driven inflection point for this interaction effect was at age 65 at any subiculum connectivity value.ConclusionOur findings suggest that lesions causing amnesia and DBS sites modulating cognition converge on common neuroanatomy. However, patient age appears to be critical variable in determining whether DBS sites connected to the subiculum result in cognitive improvement or decline. Our results provide insight into the paradox of mixed outcomes across DBS cohorts and support restricting ADvance II enrollment of fornix‐targeted DBS to patients over 65. The underlying mechanisms remain unclear, and this study must be replicated in additional datasets.

Deep brain stimulation of fornix in Alzheimer's disease: From basic research to clinical practice.

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.

Brain structures and networks responsible for stimulation‐induced memory flashbacks during forniceal deep brain stimulation for Alzheimer's disease

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.

Chapter 28 - Electrical stimulation of the fornix for the treatment of brain diseases

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.

Deep brain stimulation in Alzheimer's disease.

Benefits from symptomatic and etiologic treatments in Alzheimer's Disease (AD), the most frequent dementia, are still insufficient. During the last decade, several studies showed that electrical stimulation of memory circuits could enhance memory in humans without memory impairment. First, improvement of verbal recollection was reported after deep brain stimulation (DBS) of the fornix in the hypothalamus in a patient treated for morbid obesity. Several studies in epileptic patients explored by deep electrodes reported that visuo-spatial memorization was facilitated by electrical stimulation of the entorhinal cortex or theta burst stimulation of the fornix. Recent studies suggested that DBS could be useful to modulate memory circuits in patients with cognitive decline. Phase I and II studies (about 50 patients) showed that chronic fornix DBS was safe and could achieved to stabilize or slow the memory decline of some patients with mild to moderate AD, especially older ones with less severe and/or advanced disease. DBS of the cholinergic nucleus of Meynert also has been explored in phase I studies in AD and Parkinson-related dementia. Growing experimental data suggest several mechanisms of action: restoration of hippocampal theta rhythms, enhanced long term potentiation, increase of hippocampal neurogenesis, neuroprotection by release of neurotrophic factors, diffuse reactivation of hypoactive neocortical associative regions. However, DBS in AD is still investigational and numerous issues remain to be solved before envisaging its use in clinical practice, including optimal anatomical DBS target, stimulation modalities (continuous, intermittent, theta-bursts, closed loop stimulation), best candidate patients, relevant targeted symptoms, ethical considerations.

Correction to: The effect of fornix deep brain stimulation in brain diseases.

After publication of the original article it came to the authors' attention that there was an error under the subheading Traumatic Brain Injury (TBI) as well as Table 1.

Fornix Stimulation Induces Metabolic Activity and Dopaminergic Response in the Nucleus Accumbens.

The Papez circuit, including the fornix white matter bundle, is a well-known neural network that is involved in multiple limbic functions such as memory and emotional expression. We previously reported a large-animal study of deep brain stimulation (DBS) in the fornix that found stimulation-induced hemodynamic responses in both the medial limbic and corticolimbic circuits on functional resonance imaging (fMRI) and evoked dopamine responses in the nucleus accumbens (NAc), as measured by fast-scan cyclic voltammetry (FSCV). The effects of DBS on the fornix are challenging to analyze, given its structural complexity and connection to multiple neuronal networks. In this study, we extend our earlier work to a rodent model wherein we characterize regional brain activity changes resulting from fornix stimulation using fludeoxyglucose (18F-FDG) micro positron emission tomography (PET) and monitor neurochemical changes using FSCV with pharmacological confirmation. Both global functional changes and local changes were measured in a rodent model of fornix DBS. Functional brain activity was measured by micro-PET, and the neurochemical changes in local areas were monitored by FSCV. Micro-PET images revealed increased glucose metabolism within the medial limbic and corticolimbic circuits. Neurotransmitter efflux induced by fornix DBS was monitored at NAc by FSCV and identified by specific neurotransmitter reuptake inhibitors. We found a significant increase in the metabolic activity in several key regions of the medial limbic circuits and dopamine efflux in the NAc following fornix stimulation. These results suggest that electrical stimulation of the fornix modulates the activity of brain memory circuits, including the hippocampus and NAc within the dopaminergic pathway.

Fornix deep brain stimulation induces reduction of hippocampal synaptophysin levels

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.

Chronic fornix deep brain stimulation in a transgenic Alzheimer’s rat model reduces amyloid burden, inflammation, and neuronal loss

Recent studies have suggested deep brain stimulation (DBS) as a promising therapy in patients with Alzheimer's disease (AD). Particularly, the stimulation of the forniceal area was found to slow down the cognitive decline of some AD patients, but the biochemical and anatomical modifications underlying these effects remain poorly understood. We evaluated the effects of chronic forniceal stimulation on amyloid burden, inflammation, and neuronal loss in a transgenic Alzheimer rat model TgF344-AD, as well as in age-matched control rats. 18-month-old rats were surgically implanted with electrodes in stereotactic conditions and connected to a portable microstimulator for chronic DBS in freely moving rats. The stimulation was continuous during 5 weeks and animals were immediately sacrificed for immunohistochemical analysis of pathological markers. Implanted, but non-stimulated rats were used as controls. We found that chronic forniceal DBS in the Tg-AD rat significantly reduces amyloid deposition in the hippocampus and cortex, decreases astrogliosis and microglial activation and lowers neuronal loss, as determined by NeuN staining. In control animals, the stimulation neither affects neuroinflammation nor neuronal count. In the Tg-F344-AD rat model, 5 weeks of forniceal DBS decreased amyloidosis, inflammatory responses, and neuronal loss in both cortex and hippocampus. These findings strongly suggest a neuroprotective effect of DBS and support the beneficial effects of targeting the fornix in Alzheimer's disease patients.

Acute Fornix Deep Brain Stimulation Improves Hippocampal Glucose Metabolism in Aged Mice.

Background:A beneficial memory effect of acute fornix deep brain stimulation (DBS) has been reported in clinical studies. The aim of this study was to investigate the acute changes in glucose metabolism induced by fornix DBS.Methods:First, the Morris water maze test and novel object recognition memory test were used to confirm declined memory in aged mice (C57BL/6, 20–22 months old). Then, four groups of mice were used as follows: aged mice with stimulation (n = 12), aged mice with sham-stimulation (n = 8), adult mice (3–4 months old) with stimulation (n = 12), and adult mice with sham-stimulation (n = 8). Ipsilateral hippocampal glucose metabolism and glutamate levels were measured in vivo by microdialysis before, during, and after fornix DBS treatment. Histological staining was used to verify the localization of electrodes and mice with inaccurate placement were excluded from subsequent analyses. The effects of fornix DBS on extracellular glucose, lactate, pyruvate, and glutamate levels over time were analyzed by repeated-measures analysis of variance followed by Fisher's least significant difference post hoc test.Results:The aged mice had a higher basal lactate/pyruvate ratio (LPR) and lactate/glucose ratio (LGR) than the adult mice (LPR: 0.34 ± 0.04 vs. 0.13 ± 0.02, t = 4.626, P < 0.0001; LGR: 6.06 ± 0.59 vs. 4.14 ± 0.36, t = 2.823, P < 0.01). Fornix DBS decreased the ipsilateral hippocampal pyruvate and lactate levels (P < 0.05), but the glucose levels were not obviously changed in aged mice. Similarly, the LGR and LPR also decreased in aged mice after fornix DBS treatment (P < 0.05). Glucose metabolism in adult mice was not significantly influenced by fornix DBS. In addition, fornix DBS significantly decreased the ipsilateral hippocampal extracellular levels of glutamate in aged mice (P < 0.05), while significant alterations were not found in the adult mice.Conclusions:The present study provides experimental evidence that fornix DBS could significantly improve hippocampal glucose metabolism in aged mice by promoting cellular aerobic respiration activity.

Partial improvement in performance of patients with severe Alzheimer's disease at an early stage of fornix deep brain stimulation.

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.

Modulation of hippocampal activity with fornix Deep Brain Stimulation

BackgroundDeep Brain Stimulation (DBS) within the Papez circuit is under investigation as a treatment for epilepsy and Alzheimer's disease. We previously reported the effects of stimulation at nodes within this network (anterior thalamic nucleus and hippocampus) on hippocampal activity in a large animal model, using a chronic implantable, clinical-grade system that permits concurrent stimulation and recording. ObjectiveIn this study we extended earlier work to compare the effects of fornix DBS on evoked potentials (EPs) and local field potential (LFP) activity within the hippocampus, and to assess closed-loop stimulation. MethodsUnilateral fornix and hippocampal DBS leads were implanted in three ovine subjects using image-guided, frameless stereotaxy. Chronic, awake recordings of EPs and LFPs in response to fornix and hippocampal stimulation were collected with the implanted device and analyzed off-line. ResultsStimulation of the fornix produced robust, short latency hippocampal EPs. High frequency fornix stimulation generated parameter-dependent effects. At low amplitudes, short lasting inhibition of LFP activity occurred. Above a specific amplitude threshold, DBS elicited pronounced bursts of theta activity, followed by a marked state shift in hippocampal activity. These effects persisted for minutes post-DBS and were reflected as changes in LFP spectral content and phase-amplitude coupling. Real-time modulation of hippocampal activity via the implanted device was demonstrated using LFPs as the control signal for closed-loop stimulation. ConclusionsThe current results expand earlier findings and demonstrate target-specific effects produced by DBS within this neural circuit. These changes in network activity may provide insights into stimulation targets and parameter selection for clinical investigations.

EP 28. Fornix DBS enhances long-term spatial memory independent of hippocampal neuroplasticity

Deep brain stimulation (DBS) of the fornix can restore memory functions in animals with experimental dementia. We have shown that one potential underlying mechanism is the enhanced release of acetylcholine in the hippocampus. Another suggested mechanism of action is neuronal plasticity. Here, we have tested the hypothesis that acute fornix DBS can have long-term beneficial effects on memory by enhancing histological parameters of neuronal and synaptic plasticity. Rats were implanted with bilateral electrodes at the site of the fornix and received DBS at 100 Hz, 100 μA and 100 μs pulse width for 4 h. Three days after stimulation, rats received BrdU injections twice daily for a period of 3 days. After 5 weeks, fornix DBS and sham rats were tested in the water maze task. Probe trials were given after 1 h and 48 h. About 6.5 weeks after DBS, rats were sacrificed and their brains processed for BrdU/NeuN, p-CREB or synaptophysin immunohistochemistry. Fornix DBS rats visited the target annulus more frequently than sham rats in the probe trial with 1 h delay. We did not find any differences for the number of double-labelled BrdU/NeuN or p-CREB cells for fornix DBS rats when compared to sham. Synaptophysin-immunoreactive presynaptic boutons, however, were significantly decreased in the CA1 and CA3 subfield of the hippocampus for fornix DBS rats when compared to sham. Fornix DBS enhances long-term spatial memory independent of the neuroplasticity markers, which were used in the present study. An interesting finding is the decrease in the synaptic-neuroplasticity marker, which might suggest a long-term depression related mechanism.

Fornix deep brain stimulation circuit effect is dependent on major excitatory transmission via the nucleus accumbens

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.

Bilateral deep brain stimulation of the fornix for Alzheimer's disease: surgical safety in the ADvance trial.

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 ).

Fornix deep brain stimulation enhances acetylcholine levels in the hippocampus.

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.

Rapid Modulation of Protein Expression in the Rat Hippocampus Following Deep Brain Stimulation of the Fornix.

The forniceal area is currently being evaluated as a target for deep brain stimulation (DBS) to improve cognitive function in patients with Alzheimer's disease. The molecular changes at downstream targets within the stimulated circuit are unknown. To analyze the modulation of hippocampal protein expression following 1h of fornix DBS in the rat. Animals underwent bilateral forniceal DBS for 1h and sacrificed at different time-points after the initiation of the stimulation (1h, 2.5h, 5h, 25h). Bilateral hippocampi were isolated for western blot analyses. Forniceal DBS led to a dramatic elevation of cFos post-stimulation, suggesting that forniceal DBS activates the hippocampus. There was also a significant increase in candidate proteins including several trophic factors, such as brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) but not glial cell-derived neurotrophic factor (GDNF). There was in addition, increased expression of the synaptic markers growth associated protein 43 (GAP-43), synaptophysin and α-synuclein. No changes were observed at the studied time-points in Alzheimer's-related proteins including amyloid precursor protein (APP), tau, phosphorylated tau (ptau), or selected chaperone proteins (HSP40, HSP70 and CHIP). Forniceal DBS triggers hippocampal activity and rapidly modulate the expression of neurotrophic factors and markers of synaptic plasticity known to play key roles in memory processing. The clinical effects of DBS of the fornix may, in part, be mediated by producing changes in the expression of these proteins.

Alzheimer's disease and the fornix.

Alzheimer’s disease (AD) is the most common form of neurodegenerative dementia. Researchers have long been focused on the cortical pathology of AD, since the most important pathologic features are the senile plaques found in the cortex, and the neurofibrillary tangles and neuronal loss that begin in the entorhinal cortex and the hippocampus. In addition to these gray matter (GM) structures, histopathological studies indicate that the white matter (WM) is also a good target for both the early diagnosis of AD and for monitoring disease progression. The fornix is a WM bundle that constitutes a core element of the limbic circuits, and is one of the most important anatomical structures related to memory. Functional and anatomical features of the fornix have naturally captured researchers’ attention as possible diagnostic and prognostic markers of AD. Indeed, neurodegeneration of the fornix has been histologically observed in AD, and growing evidence indicates that the alterations seen in the fornix are potentially a good marker to predict future conversion from mild cognitive impairment (MCI) to AD, and even from cognitively normal individuals to AD. The degree of alteration is correlated with the degree of memory impairment, indicating the potential for the use of the fornix as a functional marker. Moreover, there have been attempts to stimulate the fornix using deep brain stimulation (DBS) to augment cognitive function in AD, and ongoing research has suggested positive effects of DBS on brain glucose metabolism in AD patients. On the other hand, disease specificity for fornix degeneration, methodologies to evaluate fornix degeneration, and the clinical significance of the fornix DBS, especially for the long-term impact on the quality of life, are mostly unknown and need to be elucidated.

Detection of Dopamine Efflux in the Nucleus Accumbens caused by Electrical Stimulation of the Rat Fornix by Fast Scan Cyclic Voltammetry

Introduction: Deep Brain Stimulation (DBS) has been recently suggested as a potential therapy for improving memory functions in Alzheimer’s Disease, as the improvement of certain memory functions was shown when DBS on fornix, The goal of this study is to investigate the relationship between fornix stimulation and neurochemical change in rat brain. Methods: We stereotactically implanted carbon fiber microelectrode (CFM) into nucleus accumbens of the rat to measure neurotransmitter changes during DBS of fornix using WINCS based fast scan cyclic voltammetry. DBS was applied with changes of stimulation amplitudes and frequencies under general anesthesia. Results: Dopamine efflux change was measured in the core of nucleus accumbens, but not in the shell of nucleus accumbens. The dopamine changes became highest at 120Hz stimulating frequency and also get higher when increasing the stimulation amplitude. Conclusion: In this study, the possible relationship between fornix and nuclueus accumbens was demonstrated with fast scan cyclic voltammetry. The dopamine releases in nucleus accumbens during fornix DBS could be utilized for explain the mechanism of the fornix DBS.

Symptomatic Treatment of Memory Decline in Alzheimer's Disease by Deep Brain Stimulation: A Feasibility Study

Recent studies have suggested that memory circuits can be modulated by deep brain stimulation (DBS). This propriety might be used to slow down cognitive decline in patients suffering from Alzheimer's disease (AD). We conducted a prospective study to evaluate the feasibility and safety of DBS in AD patients with mild cognitive decline. Inclusion criteria were: patients (<70 years old) with AD diagnosed for less than 2 years, predominant impairment of episodic memory, and Mini-Mental Status Exam (MMSE) score between 20 and 24. The fornix was stimulated bilaterally by electrodes implanted stereotactically in the hypothalamus. Clinical, biological, neuropsychological, and imaging evaluations were conducted 3 months before surgery and 3, 6, and 12 months thereafter. During the one year-period of inclusion, 110 patients with recently diagnosed AD and predominant impairment of episodic memory were screened. Only 9 patients (8.2%) fulfilled all the inclusion criteria. Finally, just one patient accepted to be operated (acceptance rate 11.1%) and completed the study. No complications occurred and the stimulation was perfectly tolerated. After one year of stimulation, the memory scores (MMSE, ADAS-Cog, Free and Cued Selective Reminding Test) were stabilized compared to baseline, and mesial temporal lobes metabolism increased. This pilot study provides new data about the safety of fornix DBS in the hypothalamus. However, it suggests that only a small proportion of AD patients might be interested in this approach and that the acceptance of DBS by AD patients was low, raising questions about the relevance of this approach to meet the expectations of these patients.