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...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.展开更多
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 d...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.展开更多
The fornix,which connects the medial temporal lobe and the medial diencephalon,is involved in episodic memory as an important part of the Papez circuit.The mechanisms of recovery of an injured fornix revealed by diffu...The fornix,which connects the medial temporal lobe and the medial diencephalon,is involved in episodic memory as an important part of the Papez circuit.The mechanisms of recovery of an injured fornix revealed by diffusion tensor tractography in the five studies are summarized as follows：1） recovery through the nerve tract from an injured fornical crus to the medial temporal lobe via the normal pathway of the fornical crus;2）recovery through the nerve tract originating from an ipsi-lesional fornical body connected to the ipsi-lesional medial temporal lobe via the splenium of the corpus callosum;3） recovery through the nerve tract from the ipsi-lesional fornical body extending to the contra-lesional medial temporal lobe via the splenium of the corpus callosum;4） recovery through the nerve tract originating from the ipsi-lesional fornical column connected to the ipsi-lesional medial temporal lobe;and 5） recovery through the nerve tract originating from the contra-lesional fornical column connected to the ipsi-lesional medial temporal lobe via the contra-lesional medial temporal lobe and the splenium of the corpus callosum.These diffusion tensor tractography studies on mechanisms of recovery of injured fornical crus appeared to provide useful information for clinicians caring for patients with brain injury,however,studies on this topic are still in the beginning stages.展开更多
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 h...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.展开更多
It has been known that four cholinergic nuclei are located in the septal region and basal forebrain （Ch 1： medial septal nucleus, Ch 2： vertical nucleus of the diagonal band, Ch 3： horizontal limb of the diagonal ...It has been known that four cholinergic nuclei are located in the septal region and basal forebrain （Ch 1： medial septal nucleus, Ch 2： vertical nucleus of the diagonal band, Ch 3： horizontal limb of the diagonal band and Ch 4： nucleus basalis of Meynert） and two are located in the brainstem （Ch 5： pedunculopontine nucleus and Ch 6： laterodorsal tegmental nucleus） （Selden et al., 1998; Lucas-Meunier et al., 2003; Mesulam, 2004; Nieuwenhuys et al., 2007）. The fornix transfers information on episodic mem- ory between the medial diencephalon and the medial temporal lobe （Afifi and Bergman, 2005; Wolk and Budson, 2010）. The fornix is known to obtain cholinergic innervation from Ch 1 and Ch 2, and to project to the hippocampal formation （Selden et al., 1998; Lucas-Meunier et al., 2003; Mesulam, 2004; Nieu- wenhuys et al., 2007; Dere et al., 2008; Naidich and Duvernoy, 2009; Isaacson and Pribram, 2013）.展开更多
Alzheimer's disease is the most common type of cognitive disorder,and there is an urgent need to develop more effective,targeted and safer therapies for patients with this condition.Deep brain stimulation is an in...Alzheimer's disease is the most common type of cognitive disorder,and there is an urgent need to develop more effective,targeted and safer therapies for patients with this condition.Deep brain stimulation is an invasive surgical treatment that modulates abnormal neural activity by implanting electrodes into specific brain areas followed by electrical stimulation.As an emerging therapeutic approach,deep brain stimulation shows significant promise as a potential new therapy for Alzheimer's disease.Here,we review the potential mechanisms and therapeutic effects of deep brain stimulation in the treatment of Alzheimer's disease based on existing clinical and basic research.In clinical studies,the most commonly targeted sites include the fornix,the nucleus basalis of Meynert,and the ventral capsule/ventral striatum.Basic research has found that the most frequently targeted areas include the fornix,nucleus basalis of Meynert,hippocampus,entorhinal cortex,and rostral intralaminar thalamic nucleus.All of these individual targets exhibit therapeutic potential for patients with Alzheimer's disease and associated mechanisms of action have been investigated.Deep brain stimulation may exert therapeutic effects on Alzheimer's disease through various mechanisms,including reducing the deposition of amyloid-β,activation of the cholinergic system,increasing the levels of neurotrophic factors,enhancing synaptic activity and plasticity,promoting neurogenesis,and improving glucose metabolism.Currently,clinical trials investigating deep brain stimulation for Alzheimer's disease remain insufficient.In the future,it is essential to focus on translating preclinical mechanisms into clinical trials.Furthermore,consecutive follow-up studies are needed to evaluate the long-term safety and efficacy of deep brain stimulation for Alzheimer's disease,including cognitive function,neuropsychiatric symptoms,quality of life and changes in Alzheimer's disease biomarkers.Researchers must also prioritize the initiation of multi-center clinical trials of deep brain stimulation with large sample sizes and target earlier therapeutic windows,such as the prodromal and even the preclinical stages of Alzheimer's disease.Adopting these approaches will permit the efficient exploration of more effective and safer deep brain stimulation therapies for patients with Alzheimer's disease.展开更多
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...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.展开更多
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...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 mice by promoting cellular aerobic respiration activity.展开更多
基金supported by the National Natural Science Foundation of China,No.8187052509(to XGY)the National Key Research and Development Plan of China,No.2017YFC0114005(to ZPL)
文摘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.
文摘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.
基金supported by the National Research Foundation(NRF)of Korea Grant funded by the Korean Government(MSIP)(2015R1A2A2A01004073)
文摘The fornix,which connects the medial temporal lobe and the medial diencephalon,is involved in episodic memory as an important part of the Papez circuit.The mechanisms of recovery of an injured fornix revealed by diffusion tensor tractography in the five studies are summarized as follows：1） recovery through the nerve tract from an injured fornical crus to the medial temporal lobe via the normal pathway of the fornical crus;2）recovery through the nerve tract originating from an ipsi-lesional fornical body connected to the ipsi-lesional medial temporal lobe via the splenium of the corpus callosum;3） recovery through the nerve tract from the ipsi-lesional fornical body extending to the contra-lesional medial temporal lobe via the splenium of the corpus callosum;4） recovery through the nerve tract originating from the ipsi-lesional fornical column connected to the ipsi-lesional medial temporal lobe;and 5） recovery through the nerve tract originating from the contra-lesional fornical column connected to the ipsi-lesional medial temporal lobe via the contra-lesional medial temporal lobe and the splenium of the corpus callosum.These diffusion tensor tractography studies on mechanisms of recovery of injured fornical crus appeared to provide useful information for clinicians caring for patients with brain injury,however,studies on this topic are still in the beginning stages.
基金supported by Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Education,Science and Technology,No.2012R1A1A4A01001873
文摘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.
基金supported by the Medical Research Center Program(2015R1A5A2009124)through the National Research Foundation of Korea(NRF)funded by the Ministry of Science,ICT and Future Planning
文摘It has been known that four cholinergic nuclei are located in the septal region and basal forebrain （Ch 1： medial septal nucleus, Ch 2： vertical nucleus of the diagonal band, Ch 3： horizontal limb of the diagonal band and Ch 4： nucleus basalis of Meynert） and two are located in the brainstem （Ch 5： pedunculopontine nucleus and Ch 6： laterodorsal tegmental nucleus） （Selden et al., 1998; Lucas-Meunier et al., 2003; Mesulam, 2004; Nieuwenhuys et al., 2007）. The fornix transfers information on episodic mem- ory between the medial diencephalon and the medial temporal lobe （Afifi and Bergman, 2005; Wolk and Budson, 2010）. The fornix is known to obtain cholinergic innervation from Ch 1 and Ch 2, and to project to the hippocampal formation （Selden et al., 1998; Lucas-Meunier et al., 2003; Mesulam, 2004; Nieu- wenhuys et al., 2007; Dere et al., 2008; Naidich and Duvernoy, 2009; Isaacson and Pribram, 2013）.
基金supported by the Capital Fund for Health Improvement and Research,No.2022-2-2048(to WZ)the National Natural Science Foundation of China,No.81970992(to WZ)+3 种基金Capital Clinical Characteristic Application Research,No.Z121107001012161(to WZ)the Natural Science Foundation of Beijing,No.7082032(to WZ)the Key Technology R&D Program of Beijing Municipal Education Commission,No.KZ201610025030(to WZ)Project of Scientific and Technological Development of Traditional Chinese Medicine in Beijing,No.JJ2018-48(to WZ)。
文摘Alzheimer's disease is the most common type of cognitive disorder,and there is an urgent need to develop more effective,targeted and safer therapies for patients with this condition.Deep brain stimulation is an invasive surgical treatment that modulates abnormal neural activity by implanting electrodes into specific brain areas followed by electrical stimulation.As an emerging therapeutic approach,deep brain stimulation shows significant promise as a potential new therapy for Alzheimer's disease.Here,we review the potential mechanisms and therapeutic effects of deep brain stimulation in the treatment of Alzheimer's disease based on existing clinical and basic research.In clinical studies,the most commonly targeted sites include the fornix,the nucleus basalis of Meynert,and the ventral capsule/ventral striatum.Basic research has found that the most frequently targeted areas include the fornix,nucleus basalis of Meynert,hippocampus,entorhinal cortex,and rostral intralaminar thalamic nucleus.All of these individual targets exhibit therapeutic potential for patients with Alzheimer's disease and associated mechanisms of action have been investigated.Deep brain stimulation may exert therapeutic effects on Alzheimer's disease through various mechanisms,including reducing the deposition of amyloid-β,activation of the cholinergic system,increasing the levels of neurotrophic factors,enhancing synaptic activity and plasticity,promoting neurogenesis,and improving glucose metabolism.Currently,clinical trials investigating deep brain stimulation for Alzheimer's disease remain insufficient.In the future,it is essential to focus on translating preclinical mechanisms into clinical trials.Furthermore,consecutive follow-up studies are needed to evaluate the long-term safety and efficacy of deep brain stimulation for Alzheimer's disease,including cognitive function,neuropsychiatric symptoms,quality of life and changes in Alzheimer's disease biomarkers.Researchers must also prioritize the initiation of multi-center clinical trials of deep brain stimulation with large sample sizes and target earlier therapeutic windows,such as the prodromal and even the preclinical stages of Alzheimer's disease.Adopting these approaches will permit the efficient exploration of more effective and safer deep brain stimulation therapies for patients with Alzheimer's disease.
基金This study was supported by grants from the National Natural Science Foundation of China，the Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding，the Scientific Research Common Program of Beijing Municipal Commission of Education （No.KZ201510025029）.Conflict of Interest：None declared
文摘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.
基金This work was supported by grants from the Scientific Research Common Program of Beijing Municipal Commission of Education （No. KZ201510025029）, the National Natural Science Foundation of China （No. 81301183）, and the Beijing Municipal Administration of Hospitals＇ Ascent Plan （No. DFL20150503）.
文摘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 mice by promoting cellular aerobic respiration activity.
