{"count":5,"limit":50,"offset":0,"edits":[{"id":4993,"actor_id":null,"entity_type":"hypothesis","entity_id":"h-var-f110ef2e0a","action":"update","diff_json":{"after":"0d4b3d0810d06f9ecfce52a53026c59c750460281c98150a886bb832750e282e","before":"4f9882755e63f55201cf1c5644d166e1325cd74d5f5a01a5caea84534ac7a486"},"change_reason":"enrich EC-II vulnerability hypotheses with evidence addenda","created_at":"2026-04-21T02:54:50.595930+00:00"},{"id":4994,"actor_id":null,"entity_type":"hypothesis","entity_id":"h-var-f110ef2e0a","action":"update","diff_json":{"after":"## Molecular Mechanism and Rationale\n\nThe therapeutic strategy targets somatostatin-positive (SST) interneurons in entorhinal cortex layer II (EC-II), which serve as critical GABAergic regulators of tau propagation and gamma oscillatory activity. Early tau hyperphosphorylation selectively impairs SST interneuron function through disruption of microtubule-associated protein interactions and altered calcium homeostasis, leading to reduced GABA release and subsequent disinhibition of principal stellate cells. This disinhibition creates a permissive environment for pathological tau species to propagate along the perforant pathway while simultaneously disrupting the precise gamma-frequency inhibitory gating required for grid cell spatial navigation and object-vector cell memory encoding. Transcranial focused ultrasound (tFUS) delivers acoustic mechanostimulation that enhances SST interneuron membrane excitability through mechanosensitive ion channel activation, particularly PIEZO1 and TREK channels, thereby restoring synchronous GABAergic output and reestablishing proper excitatory-inhibitory balance in the entorhinal-hippocampal circuit.\n\n## Preclinical Evidence\n\nMultiple transgenic mouse models demonstrate selective vulnerability of EC-II SST interneurons to tau pathology, with P301S and rTg4510 mice showing early SST interneuron dysfunction coinciding with initial tau seeding events. Optogenetic restoration of SST interneuron activity in these models successfully prevents tau propagation from entorhinal cortex to hippocampus and preserves spatial memory performance, establishing causal relationships between SST dysfunction and disease progression. Electrophysiological studies reveal that SST interneuron stimulation specifically restores gamma oscillation coherence between entorhinal cortex and hippocampus, with power spectral analysis showing recovery of 30-80 Hz synchronization critical for memory consolidation. Recent ultrasound neuromodulation studies demonstrate that low-intensity focused ultrasound can selectively activate interneuron populations while preserving surrounding tissue integrity, with calcium imaging confirming enhanced GABA release and restored network inhibition.\n\n## Therapeutic Strategy\n\nThe closed-loop tFUS system utilizes real-time EEG monitoring to detect gamma desynchronization events and automatically delivers precisely targeted acoustic pulses to EC-II coordinates with sub-millimeter accuracy. Treatment protocols involve daily 20-minute sessions delivering low-intensity (0.3-0.5 W/cm²) ultrasound at 0.5-2 MHz frequency, optimized for EC-II penetration depth while minimizing heating effects through duty-cycled pulsing patterns. The closed-loop feedback mechanism ensures therapeutic intervention occurs specifically during periods of detected gamma disruption, maximizing efficacy while minimizing unnecessary exposure. Patient-specific MRI-guided targeting accounts for anatomical variability in entorhinal cortex positioning, with concurrent microbubble contrast agents potentially enhancing acoustic coupling and enabling more precise spatial resolution of SST interneuron populations.\n\n## Biomarkers and Endpoints\n\nPrimary endpoints include restoration of entorhinal-hippocampal gamma coherence measured through high-density EEG, with target coherence values >0.6 in the 30-80 Hz range during spatial navigation tasks. CSF biomarkers will monitor tau propagation through phosphorylated tau (p-tau181, p-tau217) levels and novel tau seed amplification assays to quantify pathological tau species reduction. Cognitive assessments focusing on spatial navigation performance, object-location memory, and pattern separation tasks will provide functional readouts of entorhinal-hippocampal circuit integrity, with neuroimaging measures including entorhinal cortex thickness and hippocampal volume preservation serving as structural endpoints.\n\n## Potential Challenges\n\nThe primary technical challenge involves achieving sufficient acoustic penetration to EC-II structures while maintaining spatial precision, as skull thickness variability and acoustic aberrations may compromise targeting accuracy in some patients. Off-target effects on adjacent temporal lobe structures, particularly the amygdala and temporal pole, could potentially induce mood or behavioral changes requiring careful monitoring and dose optimization. Safety concerns include the theoretical risk of acoustic heating or cavitation effects, though extensive preclinical safety studies suggest minimal risk at proposed therapeutic intensities when proper dosimetry protocols are followed.\n\n## Connection to Neurodegeneration\n\nSST interneuron dysfunction represents a critical early event in Alzheimer's pathogenesis, occurring before widespread neuronal loss and serving as both a consequence and driver of tau propagation throughout the brain. The selective vulnerability of these interneurons creates a cascade of network dysfunction that accelerates cognitive decline through loss of gamma oscillatory control over memory consolidation and spatial navigation processes. By targeting this early, mechanistically defined checkpoint in disease progression, the intervention addresses a fundamental driver of neurodegeneration rather than merely treating downstream symptoms, potentially offering disease-modifying therapeutic benefit.\n\n## Evidence enrichment addendum: ecii-sst-tau-propagation-gamma-synchrony\n\n        ### Mechanistic focus\n        SST-mediated inhibitory gating, tau propagation blockade, and entorhinal-hippocampal synchrony.\n\n\nThe shared evidence base for this EC layer II vulnerability family is now\nstronger than a generic \"entorhinal dysfunction\" claim. Neuropathology and\nsingle-cell evidence both place transentorhinal and entorhinal circuits at the\nfront of the Alzheimer cascade: Braak staging identified early neurofibrillary\nchange in these regions, modern tau-seeding work shows seeding activity can\nbegin in transentorhinal/entorhinal tissue before widespread cortical spread,\nand recent human cell-type profiling reports layer II entorhinal neurons as a\nselectively vulnerable population at the onset of AD neuropathology (PMID:\n39435008; PMID: 39803521). A 2023 review of entorhinal cortex dysfunction in AD\nalso links medial and lateral EC layer 2 output neurons to the perforant and\ntemporoammonic paths that feed dentate gyrus, CA3, and CA1, making EC-II a\nplausible upstream control point rather than a downstream bystander (PMID:\n36513524). In an EC-tau mouse model, tau pathology was sufficient to produce\nexcitatory neuron loss, degraded grid-cell tuning, altered network activity, and\nspatial memory deficits reminiscent of early AD (PMID: 28111080). The\nneuromodulation branch of this task is additionally supported by 40 Hz gamma\nentrainment studies: optogenetic or sensory gamma stimulation altered amyloid\nburden and microglial state in AD models (PMID: 27929004), and early feasibility\nclinical studies show that noninvasive gamma stimulation can entrain human\nneural activity with acceptable short-term tolerability while leaving efficacy\nas an open question (PMID: 34027028; PMID: 30155285).\n\nThe implication for SciDEX scoring is that EC-II hypotheses should be evaluated\non three separable axes: first, whether the proposed target maps to a layer II\ncell type or projection that is actually vulnerable in AD; second, whether the\nintervention can shift the network state without causing hyperexcitability,\nseizure risk, or nonspecific arousal; and third, whether the readout captures\nearly circuit rescue rather than only late global cognition. Strong support\nwould therefore require convergent biomarkers: tau or p-tau217 to confirm\ndisease stage, high-resolution structural or functional imaging of EC and\nhippocampal subfields, EEG/MEG evidence for theta-gamma coupling or gamma power\nchanges, and a behavioral assay sensitive to path integration, mnemonic\nseparation, or spatial remapping. Weak support would be any result that improves\na broad cognitive endpoint without demonstrating EC engagement, because such a\nsignal could come from attention, sleep, mood, or generalized cortical\nactivation rather than the specific layer II mechanism.\n\n\n        ### Hypothesis-specific interpretation\n        The disease-modifying version of this hypothesis is that restoring EC-II inhibitory timing reduces activity-dependent tau release and downstream seeding across perforant-path targets. That makes tau propagation the central endpoint and gamma synchrony the mechanistic mediator, not the final clinical claim.\n\n        ### Validation path\n        Use longitudinal tau-seeding assays, extracellular vesicle or interstitial tau measurements where feasible, and spatial-memory tasks that specifically load EC-hippocampal navigation rather than broad recognition memory.\n\n        ### Counterevidence and market caveats\n        The proposal should be penalized if it relies only on gamma improvement. Gamma restoration could be compensatory or epiphenomenal unless tied to reduced tau movement and preserved EC-II neuron survival. A reasonable Exchange price should increase only when\n        EC engagement, cell-type specificity, and disease-stage matching are\n        demonstrated together. The most informative near-term experiment is a\n        staged design that first confirms the circuit target in an ex vivo or\n        animal model, then tests a closed-loop intervention with blinded\n        oscillatory, pathology, and behavioral endpoints. This keeps the claim\n        falsifiable: failure to engage EC-II physiology, failure to alter tau or\n        amyloid-linked pathology, or benefit that disappears under sham-controlled\n        stimulation would all materially weaken the hypothesis.\n","before":"## Molecular Mechanism and Rationale\n\nThe therapeutic strategy targets somatostatin-positive (SST) interneurons in entorhinal cortex layer II (EC-II), which serve as critical GABAergic regulators of tau propagation and gamma oscillatory activity. Early tau hyperphosphorylation selectively impairs SST interneuron function through disruption of microtubule-associated protein interactions and altered calcium homeostasis, leading to reduced GABA release and subsequent disinhibition of principal stellate cells. This disinhibition creates a permissive environment for pathological tau species to propagate along the perforant pathway while simultaneously disrupting the precise gamma-frequency inhibitory gating required for grid cell spatial navigation and object-vector cell memory encoding. Transcranial focused ultrasound (tFUS) delivers acoustic mechanostimulation that enhances SST interneuron membrane excitability through mechanosensitive ion channel activation, particularly PIEZO1 and TREK channels, thereby restoring synchronous GABAergic output and reestablishing proper excitatory-inhibitory balance in the entorhinal-hippocampal circuit.\n\n## Preclinical Evidence\n\nMultiple transgenic mouse models demonstrate selective vulnerability of EC-II SST interneurons to tau pathology, with P301S and rTg4510 mice showing early SST interneuron dysfunction coinciding with initial tau seeding events. Optogenetic restoration of SST interneuron activity in these models successfully prevents tau propagation from entorhinal cortex to hippocampus and preserves spatial memory performance, establishing causal relationships between SST dysfunction and disease progression. Electrophysiological studies reveal that SST interneuron stimulation specifically restores gamma oscillation coherence between entorhinal cortex and hippocampus, with power spectral analysis showing recovery of 30-80 Hz synchronization critical for memory consolidation. Recent ultrasound neuromodulation studies demonstrate that low-intensity focused ultrasound can selectively activate interneuron populations while preserving surrounding tissue integrity, with calcium imaging confirming enhanced GABA release and restored network inhibition.\n\n## Therapeutic Strategy\n\nThe closed-loop tFUS system utilizes real-time EEG monitoring to detect gamma desynchronization events and automatically delivers precisely targeted acoustic pulses to EC-II coordinates with sub-millimeter accuracy. Treatment protocols involve daily 20-minute sessions delivering low-intensity (0.3-0.5 W/cm²) ultrasound at 0.5-2 MHz frequency, optimized for EC-II penetration depth while minimizing heating effects through duty-cycled pulsing patterns. The closed-loop feedback mechanism ensures therapeutic intervention occurs specifically during periods of detected gamma disruption, maximizing efficacy while minimizing unnecessary exposure. Patient-specific MRI-guided targeting accounts for anatomical variability in entorhinal cortex positioning, with concurrent microbubble contrast agents potentially enhancing acoustic coupling and enabling more precise spatial resolution of SST interneuron populations.\n\n## Biomarkers and Endpoints\n\nPrimary endpoints include restoration of entorhinal-hippocampal gamma coherence measured through high-density EEG, with target coherence values >0.6 in the 30-80 Hz range during spatial navigation tasks. CSF biomarkers will monitor tau propagation through phosphorylated tau (p-tau181, p-tau217) levels and novel tau seed amplification assays to quantify pathological tau species reduction. Cognitive assessments focusing on spatial navigation performance, object-location memory, and pattern separation tasks will provide functional readouts of entorhinal-hippocampal circuit integrity, with neuroimaging measures including entorhinal cortex thickness and hippocampal volume preservation serving as structural endpoints.\n\n## Potential Challenges\n\nThe primary technical challenge involves achieving sufficient acoustic penetration to EC-II structures while maintaining spatial precision, as skull thickness variability and acoustic aberrations may compromise targeting accuracy in some patients. Off-target effects on adjacent temporal lobe structures, particularly the amygdala and temporal pole, could potentially induce mood or behavioral changes requiring careful monitoring and dose optimization. Safety concerns include the theoretical risk of acoustic heating or cavitation effects, though extensive preclinical safety studies suggest minimal risk at proposed therapeutic intensities when proper dosimetry protocols are followed.\n\n## Connection to Neurodegeneration\n\nSST interneuron dysfunction represents a critical early event in Alzheimer's pathogenesis, occurring before widespread neuronal loss and serving as both a consequence and driver of tau propagation throughout the brain. The selective vulnerability of these interneurons creates a cascade of network dysfunction that accelerates cognitive decline through loss of gamma oscillatory control over memory consolidation and spatial navigation processes. By targeting this early, mechanistically defined checkpoint in disease progression, the intervention addresses a fundamental driver of neurodegeneration rather than merely treating downstream symptoms, potentially offering disease-modifying therapeutic benefit."},"change_reason":"enrich EC-II vulnerability hypotheses with evidence addenda","created_at":"2026-04-21T02:54:50.595930+00:00"},{"id":4995,"actor_id":null,"entity_type":"hypothesis","entity_id":"h-var-f110ef2e0a","action":"update","diff_json":{"after":0.78,"before":1.0},"change_reason":"enrich EC-II vulnerability hypotheses with evidence addenda","created_at":"2026-04-21T02:54:50.595930+00:00"},{"id":4996,"actor_id":null,"entity_type":"hypothesis","entity_id":"h-var-f110ef2e0a","action":"update","diff_json":{"after":"2026-04-20 19:54:50.595930-07:00","before":"2026-04-20 06:26:26.993470-07:00"},"change_reason":"enrich EC-II vulnerability hypotheses with evidence 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'base':751 'begin':805 'behavior':591,1096,1323 'benefit':722,1347 'biomark':435,470,1061 'blind':1319 'blockad':742 'braak':787 'brain':662 'branch':924 'broad':1116,1226 'burden':944 'bystand':885 'ca1':871 'ca3':869 'calcium':81,295 'captur':1045 'care':594 'cascad':671,786 'caus':1033 'causal':233 'caveat':1232 'cavit':609 'cell':94,124,131,772,817,907,1013,1276 'cell-typ':816,1275 'central':1183 'challeng':538,542 'chang':592,792,1093 'channel':150,156 'checkpoint':698 'circuit':174,520,779,1047,1302 'claim':767,1195,1328 'clinic':956,1194 'close':2,309,380,1315 'closed-loop':1,308,379,1314 'cognit':497,677,1054,1117 'coher':252,447,456 'coincid':203 'come':1128 'compensatori':1249 'compromis':565 'concern':600 'concurr':417 'confirm':297,1068,1300 'connect':629 'consequ':654 'consolid':272,687 'contrast':419 'control':684,879,1353 'converg':1060 'coordin':335 'cortex':44,224,255,414,527,845,1363 'cortic':811,1135 'could':586,1127,1247 'counterevid':1229 'coupl':424,1089 'creat':97,669 'critic':53,269,637 'csf':469 'cycl':375 'daili':344 'declin':678 'deficit':915 'defin':697 'degrad':904 'deliv':138,326,348 'demonstr':181,277,1120,1285 'densiti':452 'dentat':867 'depend':1167 'depth':367 'design':1297 'desynchron':322 'detect':320,392 'disappear':1349 'diseas':28,239,700,719,1069,1150,1281 'disease-modifi':718,1149 'disease-stag':1280 'disinhibit':90,96 'disrupt':72,113,394 'dose':597 'dosimetri':625 'downstream':714,884,1171 'driver':656,707 'duti':374 'duty-cycl':373 'dysfunct':202,237,634,674,766,846 'earli':25,63,199,638,695,790,918,954,1046 'ec':9,48,186,333,364,550,754,854,874,891,993,1079,1121,1160,1221,1261,1273,1334 'ec-hippocamp':1220 'ec-ii':8,47,185,332,363,549,873,992,1159,1260,1333 'ec-tau':890 'ecii':727 'ecii-sst-tau-propagation-gamma-synchroni':726 'eeg':317,453 'eeg/meg':1083 'effect':371,574,610 'efficaci':396,976 'electrophysiolog':241 'enabl':426 'encod':133 'endpoint':437,439,536,1118,1184,1324 'engag':1122,1274,1332 'enhanc':142,298,422 'enrich':724 'ensur':384 'entorhin':20,43,172,223,254,413,444,518,526,745,765,778,823,844,1362 'entorhinal-hippocamp':19,171,443,517,744 'entrain':935,964 'environ':100 'epiphenomen':1251 'establish':232 'evalu':998 'event':208,323,639 'evid':176,723,750,773,1084 'ex':1306 'exchang':1267 'excit':146 'excitatori':166,901 'excitatory-inhibitori':165 'experi':1293 'exposur':400 'extens':612 'extracellular':1204 'failur':1330,1337 'falsifi':1329 'famili':758 'feasibl':955,1211 'feed':866 'feedback':382 'final':1193 'first':1003,1299 'focus':5,135,282,499,734 'follow':628 'frequenc':118,360 'front':782 'function':70,514,1076 'fundament':706 'gaba':86,299 'gabaerg':54,160 'gamma':22,60,117,250,321,393,446,682,731,934,940,961,1088,1091,1186,1243,1245,1373 'gamma-frequ':116 'gate':120,739,1374 'general':1134 'generic':764 'global':1053 'grid':123,906 'grid-cel':905 'guid':406 'gyrus':868 'heat':370,607 'high':451,1072 'high-dens':450 'high-resolut':1071 'hippocamp':21,173,445,519,530,746,1081,1222 'hippocampus':226,257 'homeostasi':82 'human':815,965 'hyperexcit':1034 'hyperphosphoryl':65 'hypothes':995 'hypothesi':1145,1155,1360 'hypothesis-specif':1144 'hz':267,463,933 'identifi':789 'ii':10,46,49,187,334,365,551,756,822,875,994,1012,1142,1161,1262,1335,1365 'imag':296,1077 'impair':67 'implic':986 'improv':1114,1244 'includ':440,525,601 'increas':1270 'induc':588 'inform':1289 'inhibit':304 'inhibitori':119,167,738,1162 'initi':205 'integr':293,521,1101 'intens':281,351,622 'interact':78 'interneuron':12,41,69,144,189,201,213,246,287,433,633,668,1368 'interneuron-medi':1367 'interpret':1147 'interstiti':1207 'intervent':386,703,1026,1317 'involv':343,543 'ion':149 'keep':1326 'late':1052 'later':853 'layer':45,755,821,855,1011,1141,1364 'lead':83 'leav':975 'level':484 'link':850,1344 'load':1219 'lobe':578 'locat':506 'longitudin':1199 'loop':3,310,381,1316 'loss':648,680,903 'low':280,350 'low-intens':279,349 'maintain':554 'make':872,1179 'map':1008 'market':1231 'match':1283 'materi':1357 'maxim':395 'may':564 'measur':448,524,1209 'mechan':30,383,1143 'mechanist':696,733,1189 'mechanosensit':148 'mechanostimul':140 'medial':851 'mediat':737,1190,1369 'membran':145 'memori':132,230,271,507,686,914,1215,1228 'mere':712 'mhz':359 'mice':197 'microbubbl':418 'microgli':946 'microtubul':75 'microtubule-associ':74 'millimet':339 'minim':369,398,617 'minut':346 'mnemon':1102 'model':180,217,894,950,1310 'modern':796 'modifi':720,1151 'molecular':29 'monitor':318,472,595 'mood':589,1132 'mous':179,893 'movement':1257 'mri':405 'mri-guid':404 'multipl':177 'navig':126,467,502,690,1223 'near':1291 'near-term':1290 'network':303,673,910,1030 'neural':966 'neurodegener':631,709 'neurofibrillari':791 'neuroimag':523 'neuromodul':275,923 'neuron':647,824,858,902,1263 'neuropatholog':768,835 'noninvas':960 'nonspecif':1038 'novel':486 'object':129,505 'object-loc':504 'object-vector':128 'occur':387,644 'off-target':571 'offer':717 'onset':832 'open':979 'optim':361,598 'optogenet':209,937 'oscil':251 'oscillatori':61,683,1320 'output':161,857 'p':479,482,1065 'p-tau181':478 'p-tau217':481,1064 'p301s':194 'particular':152,580 'path':864,1100,1176,1197,1372 'pathogenesi':643 'patholog':102,192,493,896,1321,1345 'pathway':110 'patient':402,570 'patient-specif':401 'pattern':377,509 'penal':1237 'penetr':366,547 'perfor':109,861,1175,1371 'perforant-path':1174,1370 'perform':231,503 'period':390 'permiss':99 'phosphoryl':476 'physiolog':1336 'piezo1':153 'place':775 'plausibl':877 'pmid':836,838,886,920,951,981,983 'point':880 'pole':585 'popul':288,434,829 'posit':39,415 'potenti':421,537,587,716 'power':259,1092 'precis':115,327,428,556 'preclin':175,613 'preserv':228,290,532,1259 'prevent':14,219 'price':1268 'primari':438,540 'princip':92 'process':691 'produc':900 'profil':819 'progress':240,701 'project':1016 'propag':16,58,106,221,474,659,730,741,1181,1380 'proper':164,624 'propos':620,1006,1234 'protein':77 'protocol':342,626 'provid':513 'puls':330,376 'quantifi':492 'question':980 'rang':464 'rather':710,881,1049,1137,1224 'rational':32 'readout':515,1044 'real':315 'real-tim':314 'reason':1266 'recent':273,814 'recognit':1227 'recoveri':263 'reduc':85,1164,1255 'reduct':496 'reestablish':163 'region':795 'regul':55 'relationship':234 'releas':87,300,1169 'reli':1240 'remap':1106 'reminisc':916 'report':820 'repres':635 'requir':121,593,1059 'rescu':1048 'resolut':430,1073 'restor':18,158,210,249,302,441,1158,1246 'result':1112 'reveal':243 'review':842 'risk':604,618,1036 'rtg4510':196 'safeti':599,614 'scidex':988 'score':989 'second':1023 'seed':207,488,799,802,1172,1202 'seizur':1035 'select':66,182,285,664,827 'sensit':1098 'sensori':939 'separ':510,1001,1103 'serv':51,533,650 'session':347 'sham':1352 'sham-control':1351 'share':749 'shift':1028 'short':971 'short-term':970 'show':198,262,801,958 'signal':1126 'simultan':112 'singl':771 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'20':345 '30':265,461 'aberr':563 'acceler':676 'account':408 'accuraci':340,567 'achiev':544 'acoust':139,329,423,546,562,606 'activ':62,151,214,286 'address':704 'adjac':576 'agent':420 'along':107 'alter':80 'alzheim':26,641 'amplif':489 'amygdala':582 'analysi':261 'anatom':410 'assay':490 'assess':498 'associ':76 'automat':325 'balanc':168 'behavior':591 'benefit':722 'biomark':435,470 'brain':662 'calcium':81,295 'care':594 'cascad':671 'causal':233 'cavit':609 'cell':94,124,131 'challeng':538,542 'chang':592 'channel':150,156 'checkpoint':698 'circuit':174,520 'close':2,309,380 'closed-loop':1,308,379 'cognit':497,677 'coher':252,447,456 'coincid':203 'compromis':565 'concern':600 'concurr':417 'confirm':297 'connect':629 'consequ':654 'consolid':272,687 'contrast':419 'control':684 'coordin':335 'cortex':44,224,255,414,527,725 'could':586 'coupl':424 'creat':97,669 'critic':53,269,637 'csf':469 'cycl':375 'daili':344 'declin':678 'defin':697 'deliv':138,326,348 'demonstr':181,277 'densiti':452 'depth':367 'desynchron':322 'detect':320,392 'diseas':28,239,700,719 'disease-modifi':718 'disinhibit':90,96 'disrupt':72,113,394 'dose':597 'dosimetri':625 'downstream':714 'driver':656,707 'duti':374 'duty-cycl':373 'dysfunct':202,237,634,674 'earli':25,63,199,638,695 'ec':9,48,186,333,364,550 'ec-ii':8,47,185,332,363,549 'eeg':317,453 'effect':371,574,610 'efficaci':396 'electrophysiolog':241 'enabl':426 'encod':133 'endpoint':437,439,536 'enhanc':142,298,422 'ensur':384 'entorhin':20,43,172,223,254,413,444,518,526,724 'entorhinal-hippocamp':19,171,443,517 'environ':100 'establish':232 'event':208,323,639 'evid':176 'excit':146 'excitatori':166 'excitatory-inhibitori':165 'exposur':400 'extens':612 'feedback':382 'focus':5,135,282,499 'follow':628 'frequenc':118,360 'function':70,514 'fundament':706 'gaba':86,299 'gabaerg':54,160 'gamma':22,60,117,250,321,393,446,682,735 'gamma-frequ':116 'gate':120,736 'grid':123 'guid':406 'heat':370,607 'high':451 'high-dens':450 'hippocamp':21,173,445,519,530 'hippocampus':226,257 'homeostasi':82 'hyperphosphoryl':65 'hz':267,463 'ii':10,46,49,187,334,365,551,727 'imag':296 'impair':67 'includ':440,525,601 'induc':588 'inhibit':304 'inhibitori':119,167 'initi':205 'integr':293,521 'intens':281,351,622 'interact':78 'interneuron':12,41,69,144,189,201,213,246,287,433,633,668,730 'interneuron-medi':729 'intervent':386,703 'involv':343,543 'ion':149 'layer':45,726 'lead':83 'level':484 'lobe':578 'locat':506 'loop':3,310,381 'loss':648,680 'low':280,350 'low-intens':279,349 'maintain':554 'maxim':395 'may':564 'measur':448,524 'mechan':30,383 'mechanist':696 'mechanosensit':148 'mechanostimul':140 'mediat':731 'membran':145 'memori':132,230,271,507,686 'mere':712 'mhz':359 'mice':197 'microbubbl':418 'microtubul':75 'microtubule-associ':74 'millimet':339 'minim':369,398,617 'minut':346 'model':180,217 'modifi':720 'molecular':29 'monitor':318,472,595 'mood':589 'mous':179 'mri':405 'mri-guid':404 'multipl':177 'navig':126,467,502,690 'network':303,673 'neurodegener':631,709 'neuroimag':523 'neuromodul':275 'neuron':647 'novel':486 'object':129,505 'object-loc':504 'object-vector':128 'occur':387,644 'off-target':571 'offer':717 'optim':361,598 'optogenet':209 'oscil':251 'oscillatori':61,683 'output':161 'p':479,482 'p-tau181':478 'p-tau217':481 'p301s':194 'particular':152,580 'path':734 'pathogenesi':643 'patholog':102,192,493 'pathway':110 'patient':402,570 'patient-specif':401 'pattern':377,509 'penetr':366,547 'perfor':109,733 'perforant-path':732 'perform':231,503 'period':390 'permiss':99 'phosphoryl':476 'piezo1':153 'pole':585 'popul':288,434 'posit':39,415 'potenti':421,537,587,716 'power':259 'precis':115,327,428,556 'preclin':175,613 'preserv':228,290,532 'prevent':14,219 'primari':438,540 'princip':92 'process':691 'progress':240,701 'propag':16,58,106,221,474,659,742 'proper':164,624 'propos':620 'protein':77 'protocol':342,626 'provid':513 'puls':330,376 'quantifi':492 'rang':464 'rather':710 'rational':32 'readout':515 'real':315 'real-tim':314 'recent':273 'recoveri':263 'reduc':85 'reduct':496 'reestablish':163 'regul':55 'relationship':234 'releas':87,300 'repres':635 'requir':121,593 'resolut':430 'restor':18,158,210,249,302,441 'reveal':243 'risk':604,618 'rtg4510':196 'safeti':599,614 'seed':207,488 'select':66,182,285,664 'separ':510 'serv':51,533,650 'session':347 'show':198,262 'simultan':112 'skull':558 'somatostatin':38 'somatostatin-posit':37 'spatial':125,229,429,466,501,555,689 'speci':104,495 'specif':248,388,403 'spectral':260 'sst':11,40,68,143,188,200,212,236,245,432,632,723,728 'stellat':93 'stimul':247 'strategi':35,306 'structur':535,552,579 'studi':242,276,615 'sub':338 'sub-millimet':337 'subsequ':89 'success':218 'suffici':545 'suggest':616 'suppress':743 'surround':291 'symptom':715 'synapt':740 'synchron':159,268 'synchroni':23 'system':312 'target':7,36,328,407,455,566,573,693 'task':468,511 'tau':15,57,64,103,191,206,220,473,477,487,494,658,741 'tau181':480 'tau217':483 'technic':541 'tempor':577,584 'tfus':137,311 'theoret':603 'therapeut':34,305,385,621,721 'therebi':157 'thick':528,559 'though':611 'throughout':660 'time':316 'tissu':292 'tran':739 'trans-synapt':738 'transcrani':4,134 'transgen':178 'treat':713 'treatment':341 'trek':155 'ultrasound':6,136,274,283,355 'unnecessari':399 'util':313 'valu':457 'variabl':411,560 'vector':130 'volum':531 'vulner':183,665 'w/cm':354 'widespread':646"},"change_reason":"enrich EC-II vulnerability hypotheses with evidence addenda","created_at":"2026-04-21T02:54:50.595930+00:00"}]}