Presurgical structural imaging and clinical outcome in combined bed nucleus of the stria terminalis-nucleus accumbens deep brain stimulation for treatment-resistant depression

Background Structural imaging holds great potential for precise targeting and stimulation for deep brain stimulation(DBS).The anatomical information it provides may serve as potential biomarkers for predicting the efficacy of DBS in treatment-resistant depression(TRD).Aims The primary aim is to identify preoperative imaging biomarkers that correlate with the efficacy of DBS in patients with TRD.Methods Preoperative imaging parameters were estimated and correlated with the 6-month clinical outcome of patients with TRD receiving combined bed nucleus of the stria terminalis(BNST)-nucleus accumbens(NAc)DBS.White matter(WM)properties were extracted and compared between the response/non-response and remission/non-remission groups.Structural connectome was constructed and analysed using graph theory.Distances of the volume of activated tissue(VAT)to the main modulating tracts were also estimated to evaluate the correlations.Results Differences in fibre bundle properties of tracts,including superior thalamic radiation and reticulospinal tract,were observed between the remission and nonremission groups.Distance of the centre of the VAT to tracts connecting the ventral tegmental area and the anterior limb of internal capsule on the left side varied between the remission and non-remission groups(p=0.010,t=3.07).The normalised clustering coefficient(γ)and the small-world property(σ)in graph analysis correlated with the symptom improvement after the correction of age.Conclusions Presurgical structural alterations in WM tracts connecting the frontal area with subcortical regions,as well as the distance of the VAT to the modulating tracts,may influence the clinical outcome of BNST-NAc DBS.These findings provide potential imaging biomarkers for the DBS treatment for patients with TRD.

Clinical safety and efficacy of allogenic human adipose mesenchymal stromal cells-derived exosomes in patients with mild to moderate Alzheimer’s disease:a phaseⅠ/Ⅱclinical trial

Background There have been no effective treatments for slowing or reversing Alzheimer’s disease(AD)until now.Growing preclinical evidence,including this study,suggests that mesenchymal stem cells-secreted exosomes(MSCs-Exos)have the potential to cure AD.Aims The first three-arm,drug-intervention,phase I/II clinical trial was conducted to explore the safety and efficacy of allogenic human adipose MSCs-Exos(ahaMSCs-Exos)in patients with mild to moderate AD.Methods The eligible subjects were assigned to one of three dosage groups,intranasally administrated with ahaMSCs-Exos two times per week for 12 weeks,and underwent follow-up visits at weeks 16,24,36 and 48.Results No adverse events were reported.In the medium-dose arm,Alzheimer’s Disease Assessment Scale–Cognitive section(ADAS-cog)scores decreased by 2.33(1.19)and the basic version of Montreal Cognitive Assessment scores increased by 2.38(0.58)at week 12 compared with baseline levels,indicating improved cognitive function.Moreover,the ADAS-cog scores in the medium-dose arm decreased continuously by 3.98 points until week 36.There were no significant differences in altered amyloid or tau deposition among the three arms,but hippocampal volume shrank less in the medium-dose arm to some extent.Conclusions Intranasal administration of ahaMSCs-Exos was safe and well tolerated,and a dose of at least 4×10^(8)particles could be selected for further clinical trials.

Low-intensity focused ultrasound stimulation promotes stroke recovery via astrocytic HMGB1 and CAMK2N1 in mice

Background Low-intensity focused ultrasound stimulation(LIFUS)has been developed to enhance neurological repair and remodelling during the late acute stage of ischaemic stroke in rodents.However,the cellular and molecular mechanisms of neurological repair and remodelling after LIFUS in ischaemic stroke are unclear.Methods Ultrasound stimulation was treated in adult male mice 7 days after transient middle cerebral artery occlusion.Angiogenesis was measured by laser speckle imaging and histological analyses.Electromyography and fibre photometry records were used for synaptogenesis.Brain atrophy volume and neurobehaviour were assessed 0–14 days after ischaemia.iTRAQ proteomic analysis was performed to explore the differentially expressed protein.scRNA-seq was used for subcluster analysis of astrocytes.Fluorescence in situ hybridisation and Western blot detected the expression of HMGB1 and CAMK2N1.Results Optimal ultrasound stimulation increased cerebral blood flow,and improved neurobehavioural outcomes in ischaemic mice(p<0.05).iTRAQ proteomic analysis revealed that the expression of HMGB1 increased and CAMK2N1 decreased in the ipsilateral hemisphere of the brain at 14 days after focal cerebral ischaemia with ultrasound treatment(p<0.05).scRNA-seq revealed that this expression pattern belonged to a subcluster of astrocytes after LIFUS in the ischaemic brain.LIFUS upregulated HMGB1 expression,accompanied by VEGFA elevation compared with the control group(p<0.05).Inhibition of HMGB1 expression in astrocytes decreased microvessels counts and cerebral blood flow(p<0.05).LIFUS reduced CAMK2N1 expression level,accompanied by increased extracellular calcium ions and glutamatergic synapses(p<0.05).CAMK2N1 overexpression in astrocytes decreased dendritic spines,and aggravated neurobehavioural outcomes(p<0.05).Conclusion Our results demonstrated that LIFUS promoted angiogenesis and synaptogenesis after focal cerebral ischaemia by upregulating HMGB1 and downregulating CAMK2N1 in a subcluster of astrocytes,suggesting that LIFUS activated specific astrocyte subcluster could be a key target for ischaemic brain therapy.

Plasma from healthy donors protects blood-brain barrier integrity via FGF21 and improves the recovery in a mouse model of cerebral ischaemia

Background Healthy plasma therapy reverses cognitive deficits and promotes neuroplasticity in ageing brain disease.However,whether healthy plasma therapy improve blood-brain barrier integrity after stroke remains unknown.Methods Here,we intravenously injected healthy female mouse plasma into adult female ischaemic stroke C57BL/6 mouse induced by 90 min transient middle cerebral artery occlusion for eight consecutive days.Infarct volume,brain atrophy and neurobehavioural tests were examined to assess the outcomes of plasma treatment.Cell apoptosis,blood-brain barrier integrity and fibroblast growth factor 21 knockout mice were used to explore the underlying mechanism.Results Plasma injection improved neurobehavioural recovery and decreased infarct volume,brain oedema and atrophy after stroke.Immunostaining showed that the number of transferase dUTP nick end labelling+/NeuN+cells decreased in the plasma-injected group.Meanwhile,plasma injection reduced ZO-1,occluding and claudin-5 tight junction gap formation and IgG extravasation at 3 days after ischaemic stroke.Western blot results showed that the FGF21 expression increased in the plasma-injected mice.However,using FGF21 knockout mouse plasma injecting to the ischaemic wild-type mice diminished the neuroprotective effects.Conclusions Our study demonstrated that healthy adult plasma treatment protected the structural and functional integrity of blood-brain barrier,reduced neuronal apoptosis and improved functional recovery via FGF21,opening a new avenue for ischaemic stroke therapy.

Rationale,design,and baseline characteristics of Chinese registry in early detection and risk stratification of coronary plaques(C-STRAT)study

To the Editor:Coronary computed tomographic angiography(CCTA)has been considered as one of the most important noninvasive imaging modalities in diagnosing coronary artery disease(CAD).[1]Modern scanner of CCTA can provide precise coronary atherosclerotic plaque information,showing improved diagnostic accuracy and sensitivity for identifying obstructive CAD with a preferable temporal and spatial resolution.Several studies have demonstrated the prognosis value of CCTA for the prediction of future adverse CAD events.