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

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Neural Regeneration Research 2018年第12期13卷 2164-2172页

作者： Zhi-Qi Mao Xin Wang Xin Xu Zhi-Qiang Cui Long-Sheng Pan Xiao-Jing Ning Bai-Xuan Xu Lin Ma Zhi-Pei Ling Jian-Jun Jia Xin-Guang Yu Department of Neurosurgery Chinese PLA General Hospital School of Medicine Nankai University Department of Nuclear Medicine Chinese PLA General Hospital Department of Radiology Chinese PLA General Hospital Department of Neurology Chinese PLA General Hospital

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.

关键词： Alzheimer＇s disease deep brain stimulation Fornix cognition memory mood performance early stage functional neurosurgery dementia

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

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Chinese Medical Journal 2018年第5期131卷 594-599页

作者： Xiu Wang Wen-Hart HU Kai Zhang Jun-Jian Zhou De-Feng Liu Mei-Yu Zhang Jian-Guo Zhang Department of Neurosurgery Beijing Tian Tan Hospital Capital Medical University Beijing 100050 China Stereotactic and Functional Neurosurgery Laboratory Beijing Neurosurgical Institute Capital Medical University Beijing 100050 China Beijing Key Laboratory of Neurostimulation Beijing 100050 China Experimental Research Center China Academy of Traditional Chinese Medicine Beijing 100700 China

Background： A beneficial memory effect of acute formix 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）. lpsilateral 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 ）. Fomix 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 tbrnix 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 bippocampal glucose metabolism in aged m

关键词： Deep Brain Stimulation Fornix Glucose Metabolism Memory Decline

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Behavioral Effects of Deep Brain Stimulation of the Anterior Nucleus of Thalamus, Entorhinal Cortex and Fornix in a Rat Model of Alzheimer＇s Disease

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Chinese Medical Journal 2015年第9期128卷 1190-1195页

作者： Chao Zhang Wen-Han Hu De-Long Wu Kai Zhang Jian-Guo Zhang Department of Neurosurgery Beijing Tian Tan Hospital Capital Medical University Beijing 100050 China Beijing Key Laboratory of Neurostimulation Beijing 100050 China Stereotactic and Functional Neurosurgery Laboratory Beijing Neurosurgical Institute Capital Medical University Beijing 100050 China Department of Neurosurgery Xiamen Fifth Hospital Xiamen University Xiamen Fujian 361101 China

Background：Recent clinical and preclinical studies have suggested that deep brain stimulation （DBS） can be used as a tool to enhance cognitive functions.The aim of the present study was to investigate the impact of DBS at three separate targets in the Papez circuit,including the anterior nucleus of thalamus （ANT）,the entorhinal cortex （EC）,and the Fornix （FX）,on cognitive behaviors in an Alzheimer＇s disease （AD） rat model.Methods：Forty-eight rats were subjected to an intrahippocampal injection ofamyloid peptides 1-42 to induce an AD model.Rats were divided into six groups：DBS and sham DBS groups of ANT,EC,and FX.Spatial learning and memory were assessed by the Morris water maze （MWM）.Recognition memory was investigated by the novel object recognition memory test （NORM）.Locomotor and anxiety-related behaviors were detected by the open field test （OF）.By using two-way analysis of variance （ANOVA）,behavior differences between the six groups were analyzed.Results：In the MWM,the ANT,EC,and FX DBS groups performed differently in terms of the time spent in the platform zone （F（2.23） =6.04,P ＜ 0.01）,the frequency of platform crossing （F（2,23） =11.53,P ＜ 0.001）,and the percent time spent within the platform quadrant （F（2,23） =6.29,P ＜ 0.01）.In the NORM,the EC and FX DBS groups spent more time with the novel object,although the ANT DBS group did not （F（2,23） =10.03,P ＜ 0.001）.In the OF,all of the groups showed a similar total distance moved （F（1.42） =1.14,P =0.29）and relative time spent in the center （F（2,42） =0.56,P =0.58）.Conclusions：Our results demonstrated that DBS of the EC and FX facilitated hippocampus-dependent spatial memory more prominently thanANT DBS.In addition,hippocampus-independent recognition memory was enhanced by EC and FX DBS.None of the targets showed side-effects of anxiety or locomotor behaviors.

关键词： Anterior Thalamic Nuclei Deep Brain Stimulation Entorhinal Cortex Fornix Memory

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Perspectives on the neural connectivity of the Fornix in the human brain

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Neural Regeneration Research 2014年第15期9卷 1434-1436页

作者： Sung Ho Jang Hyeok Gyu Kwon Department of Physical Medicine and Rehabilitation College of MedicineYeungnam UniversityTaeguRepublic of Korea

The Fornix is involved in the transfer of information on episodic memory as a part of the Papez circuit. Diffusion tensor imaging enables to estimate the neural connectivity of the Fornix. The anterior fornical body has high connectivity with the anterior commissure, and brain areas rele- vant to cholinergic nuclei （septal forebrain region and brainstem） and memory function （medial temporal lobe）. In the normal subjects, by contrast, the posterior fornical body has connectivity with the cerebral cortex and brainstem through the splenium of the corpus callosum. We believe that knowledge of the neural connectivity of the Fornix would be helpful in investigation of the neural network associated with memory and recovery mechanisms following injury of the Fornix.

关键词： Fornix neural connectivity diffusion tensor imaging anterior commissure corpus callo-sum cholinergic nucleus

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Acute amnesia during pregnancy due to bilateral Fornix infarction: A case report

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World Journal of Clinical Cases 2020年第19期8卷 4494-4498页

作者： Min Jai Cho Dong-Ick Shin Moon-Ku Han Kyu Sun Yum Department of Neurosurgery Chungbuk National University HospitalCheongju-si 28644South Korea Department of Neurology Chungbuk National University HospitalCheongju-si 28644South Korea Department of Neurology Seoul National University Bundang HospitalSeongnam-si 463-707South Korea

BACKGROUND Stroke is an important cause of maternal morbidity and mortality during pregnancy and puerperium.Isolated amnesia is a rare clinical symptom caused by ischemic stroke during pregnancy.We present the first documented case of acute amnesia during pregnancy due to bilateral Fornix infarction.CASE SUMMARY A 32-year-old nullipara presented at 35 wk of gestation with acute amnesia and headache.Brain magnetic resonance imaging and angiography revealed acute infarction in the bilateral anterior Fornix.There was no evidence of causative abnormality after extensive work-up,including for vascular abnormality,cardiac disease,coagulopathy,and pregnancy-related conditions.The patient was diagnosed with cryptogenic stroke.Aspirin was administered immediately,and the patient recovered fully without recurrence.CONCLUSION Acute isolated amnesia due to stroke is rare during pregnancy.Early diagnosis of stroke and immediate treatment prevent neurologic sequelae.

关键词： Fornix Brain Amnesia Cerebral infarction Pregnancy Stroke Case report

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Intermittent vs Continuous Administration of Nerve Growth Factor to Injured Medial Septal Cholinergic Neurons in Rat Basal Forebrain

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Neuroscience & Medicine 2014年第2期5卷 109-118页

作者： Kenneth E. Miller Gregory E. Frierdich Robert H. Dillard Robert H. Soriano Dikla G. Roufa Department of Anatomy and Cell Biology Oklahoma State University Center for Health Sciences Tulsa USA

Many medial septal neurons of the basal forebrain are dependent on nerve growth factor (NGF) from the hippocampus for survival and maintenance of a cholinergic phenotype. When deprived of their source of NGF by axotomy, medial septal neuronal cell bodies atrophy and lose their cholinergic markers. This is similar to what is observed in the basal forebrain during Alzheimer’s disease (AD). In the present study, medial septal neurons were axotomized in female rats by way of a fimbria/Fornix lesion. For fourteen days following axotomy, varying NGF doses (1 - 250 μg/ml) were administered to the lateral cerebral ventricle with either mini-osmotic infusion or daily injection. The responsiveness of medial septal neurons was evaluated with choline acetyltransferase immunohistochemistry. Within the mini-osmotic pumps, NGF activity diminished greatly during the first five days of implantation, but increased dramatically in the CSF after five days of infusion. The responsiveness of medial septal neurons to NGF was dose dependent and the ED50 for NGF injection was determined to be 14.08 μg/ml compared to 27.60 μg/ml for NGF infusion. Intermittent injections at varying intervals were evaluated with 30 μg/ml NGF over a fourteen-day time period (2, 3, 6, or 12 injections). No differences occurred in the number of choline acetyltransferase neurons from rats that received weekly injections to those that received daily injections of NGF. NGF administration has been suggested as a therapy for AD. The results of these studies continue to highlight the need for NGF stability within the delivery system and AD patient CSF, the choice of delivery system, frequency of administration, and the NGF dose for maintaining basal forebrain cholinergic neurons during AD.

关键词： Nerve Growth Factor Medial Septal Nucleus Choline Acetyltransferase Alzheimer’s Fimbria Fornix

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