Bilateral Hippocampus Research Articles

Abstract 106: CHANTER Syndrome: A Case Report Of A 59 Year Old Man With Positive Outcome

Introduction Cerebellar, Hippocampal, and Basal Nuclei Transient Edema with Restricted Diffusion (CHANTER) syndrome was first described in 2019 [1] as a pattern of radiographic findings that are distinct from ischemic, anoxic, or toxic brain injury. Pathophysiology is still uncertain, but some proposed theories include a primary metabolic etiology or a mitochondrial failure of gray matter. Clinically, patients typically present with altered level of consciousness. Radiographically, diffusion weighted imaging shows restriction in the bilateral hippocampi, bilateral cerebelli, and basal nuclei. The cerebral cortex, thalamus, and subcortical white matter are usually spared. Despite the morbid clinical picture on presenation, positive outcomes were reported with early intervention. We describe a case of CHANTER syndrome in a 59 year old man with history of illicit substance abuse. Methods Case report with electronic medical record review. Results 59‐year‐old man with history of illicit substance abuse including cocaine, opioid, and phencyclidine presented to the hospital after being found down at a drug store. Patient did not respond to Naloxone and was eventually intubated due to respiratory compromise. Non‐contrast CT head showed hypoattenuation of the bilateral cerebellar hemispheres with mild effacement of the fourth ventricle. MRI brain showed diffusion signal abnormalities with corresponding T2 FLAIR hyperintensities in the bilateral cerebellar hemispheres, bilateral hippocampi, and bilateral basal ganglia with some involvement of the left occipital lobe suggestive of CHANTER syndrome. As vasogenic edema worsened, hydrocephalus ensued requiring administration of hypertonic saline and eventual external ventricular drain (EVD) insertion in the neurocritical care unit. Despite initial improvement in his level of consciousness after the EVD insertion, his intracranial pressure (ICP) continued to increase and midazolam and ketamine infusion drips were added. A fine balance between lowering the ICP and avoiding respiratory suppresion with sedating infusions was maintained. Consecutive MRI brain images over the course of the following 4 weeks of his stay showed decrease of the abnormal diffusion weighted imaging signal along with improvement in his overall mental status and eventual discharge 12 weeks from his initial presentation. Conclusion This case further strengthens the relationship between CHANTER syndrome and illicit substance use as a likely etiology along with other cases in the literature. Aggressive management in the neurocritical care to control vasogenic edema and avoid ICP elevation is essential to give patients the highest chance of recovery. Clinical improvement At least partial reversal of the radiographic findings of CHANTER syndrome can be attained with treatment, however, unclear if complete reversal is possible.

5 Cross-cultural Diagnostic Validity of the Multilingual Naming Test (MINT) in a Sample of Older Adults.

Objective:The current study aimed to evaluate the psychometric properties and diagnostic accuracy of the 32-item version of the Multilingual Naming Test (MINT) in a sample of English and Spanish monolinguals and bilingual older adults from two ethnic groups (EA; European Americans and HA; Hispanic American) with typical and atypical aging. An IRT model was used to identify 24 MINT Items assessed across ethnicity and language testing groups (Spanish and English). We analyzed the discriminant and predictive validity of the 32-item and 24-item scales across diagnostic groups (cognitively normal [CN], mild cognitive impairment [MCI], and dementia [AD]). Diagnostic accuracy was then assessed with both versions applying ROC (Receiver Operating Characteristics) curve reporting using AUC (Area Under the Curve). We expected the MINT to distinguish between the CN and AD groups but not between CN and MCI and the MCI and AD. We conducted IRT analyses to evaluate the cross-language validity of the items from the 32-item MINT in English and Spanish through Rasch Analysis across our two ethnic groups. Finally, we tested the association between MINT scores and MRI volumetric measures of language-related areas in both cerebral hemispheres’ temporal and frontal lobes.Participants and Methods:The sample comprised 281 participants (178 females) enrolled in the 1Florida Alzheimer’s Disease Research Center (ADRC), with 175 participants self-identified as HA (51 tested in English and 124 in Spanish) and 106 EA, all of them monolingual English speakers. The participants were classified into three diagnostic groups: 1. CN (n = 94); 2. MCI (n = 148); and 3. AD (n = 39). Participants are evaluated yearly through a comprehensive neuropsychological battery, including the MINT is a standard CN task that requires patients to retrieve words upon presentation of a line drawing.Results:We obtained a ceiling effect in four items (Butterfly, Glove, Watch, and Candle). Four items were easier in English (Blind, Gauge, Porthole, and Pestle) and four in Spanish (Dustpan, Funnel, Anvil, and Mortar). In the 32-item version of the MINT, EA scored significantly higher than HA, but when removing those eight items, the ethnic difference was attenuated and no longer statistically significant (controlling for education). The ROC curves showed that both versions of the MINT had poor accuracy when identifying CN participants and were acceptable in identifying dementia participants but unacceptable for classifying MCI participants. The 32-item MINT in English and Spanish and the 24-item MINT in Spanish were significantly correlated with the bilateral MTG. However, the 24-item MINT in English was only correlated with this area’s volume in the right hemisphere. The left FG correlated with MINT scores regardless of language and MINT version. We also found some differential correlations depending on the language of administration. The bilateral hippocampi, STG, MTG and FG, and right ITG were significantly correlated only with MINT Spanish scores, while the left ITG was significant only when either version of the MINT was administered in English.Conclusions:Our results highlight the importance of analyzing cross-cultural samples when implementing neuropsychological tests.

48 Should I Stay or Should I Go? Neural Circuits Underlying Decisions to Explore or Exploit

Objective:Adaptive decision-making is necessary to sustain functional independence. Maladaptive decisions are among the most prevalent features of psychological and neurological disorders. One crucial aspect of decision-making involves arbitrating between exploring new avenues with risky but potentially lucrative outcomes or exploiting prior knowledge and endorsing predictable outcomes. Balancing this dichotomy creates a behavioral tension that shapes all decisions and is termed the exploration-exploitation trade-off. This trade-off has been linked to reward and affective drives and associated neural circuitry as well as neuropsychological dysfunction. However, the neural mechanisms underlying the exploration-exploitation trade-off are still uncertain, due to the scarcity of literature and the heterogeneity of paradigms. This study aimed to systematically quantify and disambiguate neuroanatomical correlates of the exploration-exploitation tradeoff in a normative adult sample. These findings provide a necessary starting point for future investigations of this fundamental aspect of decision-making across clinical populations, with potential implications for assessment and intervention.Participants and Methods:We used the effect-location method of meta-analysis to analyze data from 10 functional neuroimaging studies investigating the exploration-exploitation tradeoff in non-clinical samples. We analyzed the location and frequency of significant neural activations across studies for both explorative and exploitative decisions and characterized them as core and non-core regions. Core activations were defined as those reported in over 50% of studies. Secondary and tertiary activations were defined as those reported in 40% and 30% of studies, respectively. The present review was conducted in accordance with the guidelines of the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.Results:The results revealed that explorative and exploitative choice behaviours differed markedly with respect to associated patterns of task-related brain activity. Exploration was associated with activity in brain regions implicated in externally directed, goal-based attentional processing and reward-related uncertainty, mainly tapping bilateral parietal and frontal circuitry, with relatively high consistency across studies. A core explorative network was revealed, consisting of activity in the frontal polar cortex, the dorsal anterior cingulate cortex, the bilateral medial frontal gyrus, the bilateral precuneus, and the bilateral intraparietal sulcus. Secondary and tertiary regions were also detected, including the bilateral anterior insula, the left precentral gyrus, the bilateral superior frontal gyrus, the right inferior frontal gyrus, the left supplementary motor area, the bilateral superior parietal lobule, and the bilateral thalamus. Exploitation was associated with brain regions implicated in internally directed processes including reward valuation, motivation, and memory. Core exploitative activations included the ventromedial prefrontal cortex, the bilateral anterior cingulate cortex, and the bilateral orbitofrontal cortex. Secondary and tertiary activations included the bilateral hippocampus, the left middle temporal gyrus, the bilateral angular gyrus, the left posterior cingulate cortex, the left superior frontal gyrus, and the bilateral superior temporal gyrus.Conclusions:The exploration-exploitation trade-off provides a novel paradigmatic approach to study adaptive and maladaptive decision-making behaviour in humans. Our findings support the neural dichotomization of exploration and exploitation and illuminate potential neural networks underlying this fundamental feature of decision-making. Understanding these mechanistic networks opens a new avenue of inquiry into decision-making deficits in clinical populations, including neurodegenerative, neurodevelopmental, and neuropsychiatric syndromes.

The remodeling of metabolic brain pattern in patients with extracranial diffuse large B-cell lymphoma

BackgroundOwing to the advances in diagnosis and therapy, survival or remission rates for lymphoma have improved prominently. Apart from the lymphoma- and chemotherapy-related somatic symptom burden, increasing attention has been drawn to the health-related quality of life. The application of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) has been routinely recommended for the staging and response assessment of FDG-avid lymphoma. However, up till now, only a few researches have investigated the brain metabolic impairments in patients with pre-treatment lymphoma. The determination of the lymphoma-related metabolic brain pattern would facilitate exploring the tailored therapeutic regimen to alleviate not only the physiological, but also the psychological symptoms. In this retrospective study, we aimed to establish the diffuse large B-cell lymphoma-related pattern (DLBCLRP) of metabolic brain network and investigate the correlations between DLBCLRP and several indexes of the staging and response assessment.ResultsThe established DLBCLRP was characterized by the increased metabolic activity in bilateral cerebellum, brainstem, thalamus, striatum, hippocampus, amygdala, parahippocampal gyrus and right middle temporal gyrus and by the decreased metabolic activity in bilateral occipital lobe, parietal lobe, anterior cingulate gyrus, midcingulate cortex and medial frontal gyrus. Significant difference in the baseline expression of DLBCLRP was found among complete metabolic response (CMR), partial metabolic response (PMR) and progressive metabolic disease (PMD) groups (P < 0.01). DLBCLRP expressions were also significantly or tended to be positively correlated with international prognostic index (IPI) (rs = 0.306, P < 0.05), lg(total metabolic tumor volume, TMTV) (r = 0.298, P < 0.05) and lg(total lesion glycolysis, TLG) (r = 0.233, P = 0.064). Though no significant correlation of DLBCLRP expression was found with Ann Arbor staging or tumor SUVmax (P > 0.05), the post-treatment declines of DLBCLRP expression were significantly positively correlated with Ann Arbor staging (rs = 0.284, P < 0.05) and IPI (rs = 0.297, P < 0.05).ConclusionsThe proposed DLBCLRP would lay the foundation for further investigating the cerebral dysfunction related to DLBCL itself and/or treatments. Besides, the expression of DLBCLRP was associated with the tumor burden of lymphoma, implying a potential biomarker for prognosis.

Altered single-subject gray matter structural networks in first-episode drug-naïve adolescent major depressive disorder

Although previous studies have demonstrated regional gray matter (GM) structural abnormalities in adolescents with major depressive disorder (MDD), how the topological organization of GM networks is affected in these patients is still unclear. Structural magnetic resonance imaging data were acquired from 100 first-episode drug-naïve adolescent MDD patients and 80 healthy controls (HCs). Whole-brain GM structural network was constructed for each subject, and a graph theory analysis was used to calculate the topological metrics of GM networks. Adolescent MDD patients showed significantly lower cluster coefficient and local efficiency compared to HCs. Compared to controls, adolescent MDD patients showed higher nodal centralities in the bilateral cuneus, left lingual gyrus, and right middle occipital gyrus and lower nodal centralities in the bilateral dorsolateral superior frontal gyrus, bilateral middle frontal gyrus, right anterior cingulate and paracingulate gyri, bilateral hippocampus, bilateral amygdala, bilateral caudate nucleus, and bilateral thalamus. Nodal centralities of the hippocampus were negatively associated with symptom severity and illness duration. Our findings suggest disrupted topological organization of GM structural networks in adolescent MDD patients. Impaired local segregation and abnormal nodal centralities in the prefrontal-subcortical-limbic areas and visual cortex regions may play important roles in the neurobiology of adolescent-onset MDD.

Fronto-striatal alterations correlate with apathy severity in behavioral variant frontotemporal dementia

Structural and functional changes in cortical and subcortical regions have been reported in behavioral variant frontotemporal dementia (bvFTD), however, a multimodal approach may provide deeper insights into the neural correlates of neuropsychiatric symptoms. In this multicenter study, we measured cortical thickness (CTh) and subcortical volumes to identify structural abnormalities in 37 bvFTD patients, and 37 age- and sex-matched healthy controls. For seed regions with significant structural changes, whole-brain functional connectivity (FC) was examined in a sub-cohort of N = 22 bvFTD and N = 22 matched control subjects to detect complementary alterations in brain network organization. To explore the functional significance of the observed structural and functional deviations, correlations with clinical and neuropsychological outcomes were tested where available. Significantly decreased CTh was observed in the bvFTD group in caudal middle frontal gyrus, left pars opercularis, bilateral superior frontal and bilateral middle temporal gyrus along with subcortical volume reductions in bilateral basal ganglia, thalamus, hippocampus, and amygdala. Resting-state functional magnetic resonance imaging showed decreased FC in bvFTD between: dorsal striatum and left caudal middle frontal gyrus; putamen and fronto-parietal regions; pallidum and cerebellum. Conversely, bvFTD showed increased FC between: left middle temporal gyrus and paracingulate gyrus; caudate nucleus and insula; amygdala and parahippocampal gyrus. Additionally, cortical thickness in caudal, lateral and superior frontal regions as well as caudate nucleus volume correlated negatively with apathy severity scores of the Neuropsychiatry Inventory Questionnaire. In conclusion, multimodal structural and functional imaging indicates that fronto-striatal regions have a considerable influence on the severity of apathy in bvFTD.

Preliminary MRS study of critical values of relevant brain metabolites in elderly Chinese patients with post-stroke cognitive impairment

ObjectiveProton magnetic resonance spectroscopy (1H-MRS) was applied in this study to detect metabolite changes in the brain of post-stroke cognitive impairment (PSCI) and normal volunteers. The levels of N-acetylaspartate (NAA) and creatinine (Cr) and in the frontal lobe, hippocampus and cingulate gyrus were measured to distinguish patients with post-stroke cognitive impairment (PSCI) and normal control group (NC). The relationship between them and cognitive function was explored and a critical value of the metabolite ratio was predicted. This study may serve as a reference for the diagnosis of cognitive dysfunction after stroke. MethodsA total of 46 patients with PSCI (PSCI group, all patients are unilateral cerebral infarction or intracerebral haemorrhage) were screened by the Mini-Mental Status Examination (MMSE), and 35 healthy volunteers were selected as normal control group (NC group). The general information of gender, age, and education level was matched between the two groups. Two groups of subjects were examined using MRS and evaluated for cognitive function using the MMSE test and the Montreal Cognitive Assessment Scale (MoCA). The correlation between MRS and neurobehavioral scale (MMSE test and MoCA scale) was analysed, and the possible demarcation points of the brain metabolism of PSCI were evaluated. ResultThe MMSE and MoCA scores of patients with PSCI were lower significantly when compared with those of the NC group (P < 0.05). The NAA/Cr values of the bilateral hippocampus, bilateral frontal lobe and bilateral anterior and posterior cingulate gyrus in the PSCI group were lower than those in the NC group (P < 0.05). The NAA/Cr cut-off value for the right frontal lobe was 1.533, and the NAA/Cr sensitivity, specificity and Youden index for the right frontal lobe were 0.943, 0.935, and 0.878. ConclusionNAA/Cr values in the MRS bilateral frontal, bilateral hippocampus and bilateral anterior and posterior cingulate gyrus were reduced in the cognitively impaired post-stroke patients compared to the normal control group. MRS was also found to be correlated with the score of neurobehavioral scale (MMSE test and MoCA scale) and the combination of the two could evaluate cognitive dysfunction more comprehensively and objectively. NAA/Cr value of the right frontal lobe < 1.533 indicated that PSCI may occur. In accordance with this cut-off point, PSCI could be detected as early as possible and timely intervention could be carried out.

B - 76 Neurobehavioral Sequela Following Hypoxic-Ischemic Brain Injury to the Bilateral Hippocampi and Globus Pallidus: a Clinical Case Study.

Hypoxic-ischemic brain injury (HIBI) occurs when there is deficient oxygen supply and blood flow to the brain. HIBI can be precipitated by various factors including drug overdose. Brain regions that have high vulnerability to HIBI include the hippocampus and basal ganglia. Even when damage is limited to these two regions, research suggests that diffuse cognitive deficits and changes in behavior-emotional functioning can be observed. This case study presents on a 29-year-old female who sustained HIBI to the bilateral hippocampi and globus pallidus secondary to an opioid overdose which required a 3-day hospitalization. The patient was discharged from the hospital on suboxone therapy and completed outpatient interventions which included physical therapy as well as speech-language therapy with cognitive rehab. Although improvements in her functional status were noted, she reported having persisting difficulties with cognition in addition to post-injury behavioral-emotional changes. As such, she was referred for neuropsychological testing and the evaluation was completed 6months after her hospitalization. Testing showed prominent memory impairments along with deficits in language, visuospatial skills, executive functioning, and attention. On questionnaires, she endorsed having concerns for depression, attention, and executive functioning in daily life whereas her mother endorsed concerns for executive functioning. The patient's neurobehavioral profile was consistent with broad ranging sequela that can be observed with HIBI. Recommendations included medication consultation for mood, compensatory cognitive strategies, and vocational rehab for individuals with neurological disabilities. Overall, this case study demonstrates the important role of neuropsychologists in the assessment and treatment of individuals recovering from HIBI.

Neuron-derived exosomes mediate sevoflurane-induced neurotoxicity in neonatal mice via transferring lncRNA Gas5 and promoting M1 polarization of microglia.

Sevoflurane exposure during rapid brain development induces neuronal apoptosis and causes memory and cognitive deficits in neonatal mice. Exosomes that transfer genetic materials including long non-coding RNAs (lncRNAs) between cells play a critical role in intercellular communication. However, the lncRNAs found in exosomes derived from neurons treated with sevoflurane and their potential role in promoting neurotoxicity remain unknown. In this study, we investigated the role of cross-talk of newborn mouse neurons with microglial cells in sevoflurane-induced neurotoxicity. Mouse hippocampal neuronal HT22 cells were exposed to sevoflurane, and then co-cultured with BV2 microglial cells. We showed that sevoflurane treatment markedly increased the expression of the lncRNA growth arrest-specific 5 (Gas5) in neuron-derived extracellular vesicles, which inhibited neuronal proliferation and induced neuronal apoptosis by promoting M1 polarization of microglia and the release of inflammatory cytokines. We further revealed that the exosomal lncRNA Gas5 significantly upregulated Foxo3 as a competitive endogenous RNA of miR-212-3p in BV2 cells, and activated the NF-κB pathway to promote M1 microglial polarization and the secretion of inflammatory cytokines, thereby exacerbating neuronal damage. In neonatal mice, intracranial injection of the exosomes derived from sevoflurane-treated neurons into the bilateral hippocampi significantly increased the proportion of M1 microglia, inhibited neuronal proliferation and promoted apoptosis, ultimately leading to neurotoxicity. Similar results were observed in vitro in BV2 cells treated with the CM from HT22 cells after sevoflurane exposure. We conclude that sevoflurane induces the transfer of lncRNA Gas5-containing exosomes from neurons, which in turn regulates the M1 polarization of microglia and contributes to neurotoxicity. Thus, modulating the expression of lncRNA Gas5 or the secretion of exosomes could be a strategy for addressing sevoflurane-induced neurotoxicity.

Brain-aging related protein expression and imaging characteristics of mice exposed to chronic hypoxia at high altitude.

To determine changes in protein expression related to brain aging and imaging features in mice after chronic hypoxia exposure at high altitude. A total of 24 healthy 4-week-old mice were randomly divided into high altitude hypoxia (HH) and plain control (PC) groups (n = 8 per group). HH mice were transported from Xi'an (450 m above sea level) to Maduo (4,300 m above sea level) while PC mice were raised in Xi'an. After 6 months, 7.0T magnetic resonance imaging (MRI) was performed. All mice completed T2-weighted imaging (T2WI), diffusion tensor imaging (DTI), resting-state functional MRI (rs-fMRI), arterial spin labeling (ASL), and magnetic resonance angiography (MRA) examinations. Next, brain slices were prepared and Nissl staining was used to observe morphological changes in neurons. Ultrastructural changes in neurons were observed by transmission electron microscopy. Expression changes of Caspase-3, klotho, P16, P21, and P53 at the gene and protein levels were detected by real-time PCR (RT-PCR) and Western blot. The number of neuronal Nissl bodies in the hippocampus and frontal cortex was significantly decreased in the HH group compared to the PC group. Some hippocampal and frontal cortical neurons were apoptotic, the nuclei were wrinkled, chromatin was aggregated, and most mitochondria were mildly swollen (crista lysis, fracture). Compared with the PC group, the HH group showed elevated expression of caspase-3 mRNA, P16 mRNA, P21 mRNA, and P53 mRNA in the hippocampus and frontal cortex. Expression of Klotho mRNA in the frontal cortex was also significantly decreased. Western blot results showed that caspase-3 protein expression in the hippocampus and frontal cortex of the HH group was increased compared with the PC group. Moreover, there was decreased Klotho protein expression and significantly increased P-P53 protein expression. Compared with the PC group, expression of P16 protein in the frontal cortex of the HH group was increased and the gray matter (GM) volume in the left visceral area, left caudate nucleus, and left piriform cortex was decreased. Furthermore, the amplitude of low frequency fluctuation was decreased in the left posterior nongranular insular lobe, right small cell reticular nucleus, left flocculus, left accessory flocculus, and left primary auditory area, but increased in the GM layer of the left superior colliculus. Regional homogeneity was decreased in the left and right olfactory regions, but increased in the left bed nucleus. After exposure to high altitude, functional connectivity (FC) between the bilateral caudate nucleus and thalamus, corpus callosum, cingulate gyrus, anterior limbic cortex, globus pallidus, and hippocampus was weakened. FC between the right caudate nucleus and hypothalamus and entorhinal cortex was also weakened. The fractional anisotropy value of the left hippocampus was decreased in the HH group. Compared with the PC group, the HH group showed significantly increased inner diameters of the bilateral common carotid artery and left internal carotid artery. The cerebral blood flow values of the bilateral cortex and bilateral hippocampus in the HH group did not change significantly. Taken together, our findings show that chronic hypoxia exposure at high altitude may promote neuronal apoptosis and abnormal expression of related proteins, changing the structure and function of brain. These changes may contribute to brain aging.

Application of a Novel Methodology for Efficient Optimization of Hippocampal Avoidance Whole-Brain Radiotherapy

A growing awareness of the long-term neurocognitive toxicity associated with whole-brain radiotherapy (WBRT) has led to the development of newer delivery methods to achieve relative hippocampal sparing. In order to accomplish the required target coverage and dose constraints, however, hippocampal-avoidance WBRT (HA-WBRT) can prove labor intensive and time-consuming. We therefore developed a simplified and efficient planning model for generating optimized HA-WBRT treatment. Target volumes and organs at risk (OARs) were contoured per the NRG-CC001 protocol, including the whole-brain parenchyma, bilateral hippocampi, and optic apparatus. Treatment was planned using Eclipse 16.1 for a TrueBeam STx 2.7 LINAC, applying customizable optimization and clinical goals templates to rapidly generate uniform plans. An isocenter was placed at the point corresponding to the center of mass between the bilateral contoured 3-dimensional hippocampi. Volumetric modulated arc therapy (VMAT) using 6MV photons was designed using two sets of bi-directional full arcs, with collimator rotations of 85° and 95°. The two paired sets independently covered the superior and inferior portions of the treatment volume, respectively. Arcs shared a total 2cm overlap in the superior-inferior (X Jaws) direction. A total of 10 consecutive cases of HA-WBRT were retrospectively re-optimized using the described planning model. All plans were normalized to cover 95% of the treatment volume with prescription dose (V30Gy = 95%). The model achieved favorable dosimetry relative to NRG-CC001 per protocol constraints. Average maximal dose to the hottest 2% and minimal dose to 98% of the volume were 32.22 ± 0.26 Gy and 29.82 ± 1.46 Gy, well within protocol limits of 37.5 Gy and 25 Gy, respectively. The average maximal dose to 100% of the hippocampi (D100%) and to its hottest 0.03cc (Dmax) were 8.50 ± 0.34 Gy and 12.85 ± 0.70 Gy, compared to protocol limits of 9Gy and 16Gy, respectively. Mean Dmax to the total optic apparatus was 29.67 ± 0.52 Gy, with a maximum value within the cohort of 30 Gy, matching protocol constraints. The above presented methodology for optimizing HA-WBRT can consistently and efficiently generate plans with excellent target coverage and strict hippocampal avoidance per current collaborative group constraints. This method can be broadly applied to decrease the burden and heterogeneity across HA-WBRT planning.

Hippocampal Avoidance Whole BRAIN Radiotherapy (HA-WBRT) with Simultaneous Integrated BOOST (SIB) vs. HA-WBRT in Multiple Brain Metastases: A Dosimetric Comparison

There has been a paradigm shift in managing multiple brain metastases. Various options include SRS, WBRT, and WBRT with Hippocampal avoidance (HA-WBRT). There is no consensus for the treatment of multiple brain metastases (>3 brain metastases). A new technique that has proven feasible is dose escalation in the form of simultaneous integrated boost. The aim of this study was to compare the dosimetry parameters of HA-WBRT plus simultaneous integrated boost versus HA-WBRT alone in multiple brain metastases. In a prospective trial,16 patients with multiple brain metastasis (≥ 3) from various primaries with good performance scores (ECOG PS ≤ 2) are recruited. All patients underwent CT simulation (1.5 mm slice thickness) and RT plans for HA-WBRT with (SIB) and HA-WBRT alone were made. A 5 mm margin was given to the bilateral hippocampus for Hippocampal Avoidance. In the HA-WBRT plan for the PTV i.e., whole brain plus 3 mm margin minus hippocampal avoidance region (H.A.), a dose of 30 Gy in 10 fractions is prescribed over two weeks. In HA-WBRT with SIB, a dose of 30 Gy in 10 fractions over two weeks is prescribed for the PTV, which is the clinical target volume, minus the hippocampal avoidance region (H.A.) minus the PTV Mets (1 mm margin to the GTV). A simultaneous Integrated Boost of 42.5 Gy in 10 # over two weeks is prescribed for PTVmets. Planning was done using a VMAT technique with 6MV F.F.F. beam energy in a treatment planning software. The mean B/L hippocampus volume is 3.47 cc. The mean dose of PTV D98% in HA-WBRT plans is 27.45 Gy, whereas in HA-WBRT with S.I.B. is 27.36 Gy (p = 0.90). V30 mean dose in HA-WBRT plans is 93.35%, and the mean dose in HA-WBRT SIB is 91.87% (p = 0.12). PTV D2% mean dose in HA-WBRT Is 36.06 Gy, and in HA-WBRT -S.I.B., it is 40.58 (p< 0.001). The mean bilateral hippocampus Dmax in HA-WBRT is 14.85 Gy, and in HA-WBRT-SIB is 14.25 Gy (p = 0.35). The mean Bilateral hippocampus D100% is 9.14 Gy in HA-WBRT and 9.01 Gy in HA-WBRT-SIB (p = 0.54). The mean brainstem Dmax in HA-WBRT is 36.82 Gy compared to 38.55 Gy in HA-WBRT-SIB (p = 0.02). In patients planned for a simultaneous boost along with hippocampal sparing whole brain radiotherapy, the mean dose to the hippocampal region did not increase. The Dmax of Brainstem, optic chiasma is significantly higher in HA-WBRT-). Our study, the mean dose to PTVmets is more than 45 Gy and more than 50 Gy to GTV with a BED of more than 65 Gy (α/ß = 10) to the metastases, which is equivalent to some ablative dose regimens. Simultaneous integrated boost along with hippocampal sparing radiotherapy thus helps in sparing the hippocampus and delivering higher doses to the metastases and intermediate doses to the rest of the brain, addressing the microscopic disease.

Feasibility of Cognitive-Sparing Stereotactic Radiosurgery for Brain Metastases: Initial Report of Phase II COG-SRS Trial

Radiotherapy at high doses leads to white matter (WM) and hippocampal injury which can cause cognitive decline. We designed the first, to our knowledge, evidence-based cognitive sparing brain SRS trial for patients with limited brain metastases. In this report we analyze feasibility of cognitive-sparing SRS, utilizing dose constraints for eloquent WM tracts and bilateral hippocampi. This is a single-institution phase II NCI-funded clinical trial (NCT04343157) of cognitive-sparing brain SRS; eloquent regions of interest (ROI) and associated cognitive domains are outlined in Table 1. Patients underwent high-resolution quantitative diffusion and volumetric MRI at baseline and post-SRS follow-up. Comprehensive neurocognitive assessment was performed at baseline and 3 months post-SRS by a neuropsychologist evaluating different neurocognitive domains (Table 1). Clinical processing/workflow was largely automated with robust, validated segmentation tools of eloquent WM tracts and the hippocampi. Single fraction dose constraints to WM tracts were 12 Gy Dmax and 8.4 Gy to hippocampi with 3 and 5 fraction equivalent doses, based on our prior NTCP studies. Patient accrual, follow up imaging and neurocognitive testing is still active. To date, n = 59 patients and 114 lesions have been treated with cognitive-sparing Linac-based SRS on trial. Median age is 63 years. Lung cancer was the most common primary (35.6%), along with breast cancer (23.7%) and melanoma (15.3%). Patients had 1-4 brain metastases; median prescription dose was 24 Gy/1, 27 Gy/3, or 30 Gy/5 depending on target volume. Most patients were treated < 7 business days from MRI. Cognitive endpoints have been collected on 89.5% of patients. Cognitive sparing constraints were met in 79.3% of plans while maintaining standard clinical SRS plan indices and coverage benchmarks. 38.9% of the plans that failed to meet the Dmax constraint kept D0.03cc under constraints. Plans going over constraints had tumors overlying or within 1 mm of eloquent ROIs. Local control for treated lesions at 6 months was 97.9% and 95.7% at 12 months. Distant intracranial control was 68.1% at 6 and 12 months. Median OS was 18 months. Cognitive-sparing SRS treatment planning was successfully implemented for the majority of treated lesions with excellent local control. Mitigation of damage to eloquent structures has potential to further reduce cognitive decline after SRS. Full neurocognitive outcomes will be reported after accrual and testing are complete.

Identifying and Re-Planning Challenging Retrospective SRS Patients to Evaluate the Potential for a White Matter Tract Sparing Knowledge-Based Planning Model

Diffusion tensor imaging (DTI) with automated tractography, along with auto-parcellation of volumetric MRI (vMRI), allows for reliable parcellation of critical white matter (WM) and hippocampal structures in the brain. Knowledge-based planning (KBP) may facilitate the optimization of new brain SRS plans that highly prioritize WM tracts and hippocampal sparing, allowing for cognitive preservation. However, building a high-performing model is challenging as the geometry of WM tracts and their proximity to planning target volumes (PTVs) can vary substantially. In this work we propose an iterative step for creating a KBP model where we used a preliminary model to identify challenging plans and worked on improving their dosimetry to refine the model predictions. Tractography of eloquent deep WM was obtained from high resolution DTI, along with auto-segmentation of bilateral hippocampi from vMRI and an open-source software for processing and analyzing brain MRI images. These ROIs were imported to the treatment planning system as organs-at-risk (OARsDTI). A preliminary KBP model was built from an IRB-approved cohort of 30 consecutive patients (75 plans total) treated for brain metastasis with non-coplanar SRS with total dose from 20 to 30 Gy in one to five fractions using a LINAC. This preliminary model was used to identify the 7 plans with the highest doses to the OARsDTI. These plans were re-optimized with new objectives on the OARsDTI that were partially or totally overlapped with the isodose line representing 30% of the prescription dose (as a surrogate for proximity to the PTV). The OARsDTI that were overlapping with the PTV were excluded from this analysis. We evaluated the re-optimized plans (PlanNew) by comparing maximum and mean dose (Dmax and Dmean, respectively) of OARsDTI to the initial values from the preliminary plans (PlanPre). In order to verify that the PlanNew were not compromising other structures or treatment goals, we also evaluated conformity index (CI), PTV coverage and the dosimetry of OARs included in the PlanPre. Additionally, the PlanNew were normalized to our clinical standard used for the PlanPre (100% of prescription dose to 98% of the PTV). In the 7 plans, there were 30 OARsDTI overlapping with the 30% isodose line. Refining the dosimetric objectives for the OARsDTI decreased the Dmean on average 31% when comparing PlanNew to Planpre (p<0.05, Wilcoxon rank-sum test). The CI of the PlanNew were not statistically different from the PlanPre. Although Dmax of PlanNew was 12% lower than Dmax of Planpre, the difference was not statistically different. The addition of a plan refinement step was shown to improve dose to the OARsDTI in 7 challenging SRS plans. The generation of these plans are a necessary step to creating a refined KBP model capable of accounting for the high variability in WM tracts geometry and their proximity with PTV.

Disentangling in-vivo microstructural changes of white and gray matter in mild cognitive impairment and Alzheimer's disease: a systematic review and meta-analysis.

The microstructural characteristics of white and gray matter in mild cognitive impairment (MCI) and the early-stage of Alzheimer's disease (AD) remain unclear. This study aimed to systematically identify the microstructural damages of MCI/AD in studies using neurite orientation dispersion and density imaging (NODDI), and explore their correlations with cognitive performance. Multiple databases were searched for eligible studies. The 10 eligible NODDI studies were finally included. Patients with MCI/AD showed overall significant reductions in neurite density index (NDI) of specific white matter structures in bilateral hemispheres (left hemisphere: -0.40 [-0.53, -0.27], P < 0.001; right: -0.33 [-0.47, -0.19], P < 0.001), involving the bilateral superior longitudinal fasciculus (SLF), uncinate fasciculus (UF), the left posterior thalamic radiation (PTR), and the left cingulum. White matter regions exhibited significant increased orientation dispersion index (ODI) (left: 0.25 [0.02, 0.48], P < 0.05; right: 0.27 [0.07, 0.46], P < 0.05), including the left cingulum, the right UF, and the bilateral parahippocampalcingulum (PHC), and PTR. Additionally, the ODI of gray matter showed significant reduction in bilateral hippocampi (left: -0.97 [-1.42, -0.51], P < 0.001; right: -0.90 [-1.35, -0.45], P < 0.001). The cognitive performance in MCI/AD was significantly associated with NDI (r = 0.50, P < 0.001). Our findings highlight the microstructural changes in MCI/AD were characterized by decreased fiber orientation dispersion in the hippocampus, and decreased neurite density and increased fiber orientation dispersion in specific white matter tracts, including the cingulum, UF, and PTR. Moreover, the decreased NDI may indicate the declined cognitive level of MCI/AD patients.

Dynamic alterations in the amplitude of low-frequency fluctuation in patients with cerebral small vessel disease.

Previous studies have focused on the changes of dynamic and static functional connections in cerebral small vessel disease (CSVD). However, the dynamic characteristics of local brain activity are poorly understood. The purpose of this study was to investigate the dynamic cerebral activity changes in patients with CSVD using the dynamic amplitude of low-frequency fluctuation (d-ALFF). A total of 104 CSVD patients with cognitive impairment (CSVD-CI, n = 52) or normal cognition (CSVD-NC, n = 52) and 63 matched healthy controls (HCs) were included in this study. Every participant underwent magnetic resonance imaging scans and a battery of neuropsychological examinations. The dynamics of spontaneous brain activity were assessed using dynamic changes in the amplitude of low-frequency fluctuation (ALFF) with the sliding-window method. We used voxel-wise one-way analysis of variance (ANOVA) to compare dynamic ALFF variability among the three groups. Post-hoc t-tests were used to evaluate differences between each group pair. Finally, the brain regions with d-ALFF values with differences between CSVD subgroups were taken as regions of interest (ROI), and the d-ALFF values corresponding to the ROI were extracted for partial correlation analysis with memory. (1) There was no significant difference in age (p = 0.120), sex (p = 0.673) and education (p = 0.067) among CSVD-CI, CSVD-NC and HC groups, but there were significant differences Prevalence of hypertension and diabetes mellitus among the three groups (p < 10-3). There were significant differences in scores of several neuropsychological scales among the three groups (p < 10-3). (2) ANOVA and post-hoc t-test showed that there were dynamic abnormalities of spontaneous activity in several brain regions in three groups, mainly located in bilateral parahippocampal gyrus and bilateral hippocampus, bilateral insular and frontal lobes, and the static activity abnormalities in bilateral parahippocampal gyrus and bilateral hippocampal regions were observed at the same time, suggesting that bilateral parahippocampal gyrus and bilateral hippocampus may be the key brain regions for cognitive impairment caused by CSVD. (3) The correlation showed that d-ALFF in the bilateral insular was slightly correlated with the Mini-Mental State Examination (MMSE) score and disease progression rate. The d-ALFF value of the left postcentral gyrus was negatively correlated with the Clock Drawing Test (CDT) score (r = -0.416, p = 0.004), and the d-ALFF value of the right postcentral gyrus was negatively correlated with the Rey's Auditory Verbal Learning Test (RAVLT) word recognition (r = -0.320, p = 0.028). There is a wide range of dynamic abnormalities of spontaneous brain activity in patients with CSVD, in which the abnormalities of this activity in specific brain regions are related to memory and execution or emotion.

Long period changes of hippocampal cerebral blood flow and its correlation with anxiety-like behavior and inflammation after incomplete cerebral ischemia reperfusion in rats.

This study was designed to summarize the changes of cerebral blood flow (CBF) in the bilateral hippocampal CA1 region of the hemorrhagic shock reperfusion (HSR) model of rats and their correlation with anxiety-like behavior and inflammation. Rats were randomly divided into the HSR group and the Sham group. 30 rats in each group were subdivided into 5 time points (1 w, 2 w, 4 w, 8 w, and 12 w) for examination. 3D-arterial spin labeling (3D-ASL) was performed. Long period anxiety-like behaviors were analyzed through the open field test. Histopathology was used to detect astrocytic activation in bilateral hippocampus. The concentrations of pro-inflammatory cytokines were analyzed by ELISA. At 1, 2, 4, and 8 weeks, CBF in bilateral hippocampus CA1 area of the rats in the Sham group was significantly higher than the rats in the HSR group. The rats in the HSR group had significantly shorter total traveled distance, lower velocity, and less rearing counts than those in the Sham group at 1, 2, 4, 8, and 12 weeks after the surgery. The CBF at 1, 2, 4, 8, and 12 weeks after the surgery had positive correlation with the total traveled distance, velocity, and rearing counts in the open field test. The rats in the HSR group had significantly higher GFAP intensity and the concentrations of IL-6, IL-1β, and TNF-α than those in the Sham group at 1, 2, 4, 8, and 12 weeks after the surgery. The CBF at 1, 2, 4, 8 and 12 weeks after the surgery had significantly negative correlation with the GFAP intensity and the concentrations of IL-6, IL-1β, and TNF-α. In conclusion, CBF in bilateral hippocampus CA1 area, spatial exploration ability in rats with HSR were decreased while the astrocyte activation was enhanced. During the long period after the induction of HSR, the value of CBF in bilateral hippocampus CA1 area was proved to have significant correlation with anxiety-like behaviors and astrocyte activation.

Evaluation of whole-brain oxygen metabolism in Alzheimer's disease using QSM and quantitative BOLD

ObjectiveThe objective of this study was to evaluate the whole-brain pattern of oxygen extraction fraction (OEF), cerebral blood flow (CBF), and cerebral metabolic rate of oxygen consumption (CMRO2) perturbation in Alzheimer's disease (AD) and investigate the relationship between regional cerebral oxygen metabolism and global cognition. MethodsTwenty-six AD patients and 25 age-matched healthy controls (HC) were prospectively recruited in this study. Mini-Mental State Examination (MMSE) was used to evaluate cognitive status. We applied the QQ-CCTV algorithm which combines quantitative susceptibility mapping and quantitative blood oxygen level-dependent models (QQ) for OEF calculation. CBF map was computed from arterial spin labeling and CMRO2 was generated based on Fick's principle. Whole-brain and regional OEF, CBF, and CMRO2 analyses were performed. The associations between these measures in substructures of deep brain gray matter and MMSE scores were assessed. ResultsWhole brain voxel-wise analysis showed that CBF and CMRO2 values significantly decreased in AD predominantly in the bilateral angular gyrus, precuneus gyrus and parieto-temporal regions. Regional analysis showed that CBF value decreased in the bilateral caudal hippocampus and left rostral hippocampus and CMRO2 value decreased in left caudal and rostral hippocampus in AD patients. Considering all subjects in the AD and HC groups combined, the mean CBF and CMRO2 values in the bilateral hippocampus positively correlated with the MMSE score. ConclusionCMRO2 mapping with the QQ-CCTV method - which is readily available in MR systems for clinical practice - can be a potential biomarker for AD. In addition, CMRO2 in the hippocampus may be a useful tool for monitoring cognitive impairment.

Identifying Alzheimer's disease and mild cognitive impairment with atlas-based multi-modal metrics.

Multi-modal neuroimaging metrics in combination with advanced machine learning techniques have attracted more and more attention for an effective multi-class identification of Alzheimer's disease (AD), mild cognitive impairment (MCI) and health controls (HC) recently. In this paper, a total of 180 subjects consisting of 44 AD, 66 MCI and 58 HC subjects were enrolled, and the multi-modalities of the resting-state functional magnetic resonance imaging (rs-fMRI) and the structural MRI (sMRI) for all participants were obtained. Then, four kinds of metrics including the Hurst exponent (HE) metric and bilateral hippocampus seed independently based connectivity metrics generated from fMRI data, and the gray matter volume (GMV) metric obtained from sMRI data, were calculated and extracted in each region of interest (ROI) based on a newly proposed automated anatomical Labeling (AAL3) atlas after data pre-processing. Next, these metrics were selected with a minimal redundancy maximal relevance (MRMR) method and a sequential feature collection (SFC) algorithm, and only a subset of optimal features were retained after this step. Finally, the support vector machine (SVM) based classification methods and artificial neural network (ANN) algorithm were utilized to identify the multi-class of AD, MCI and HC subjects in single modal and multi-modal metrics respectively, and a nested ten-fold cross-validation was utilized to estimate the final classification performance. The results of the SVM and ANN based methods indicated the best accuracies of 80.36 and 74.40%, respectively, by utilizing all the multi-modal metrics, and the optimal accuracies for AD, MCI and HC were 79.55, 78.79 and 82.76%, respectively, in the SVM based method. In contrast, when using single modal metric, the SVM based method obtained a best accuracy of 72.62% with the HE metric, and the accuracies for AD, MCI and HC subjects were just 56.82, 80.30 and 75.86%, respectively. Moreover, the overlapping abnormal brain regions detected by multi-modal metrics were mainly located at posterior cingulate gyrus, superior frontal gyrus and cuneus. Taken together, the SVM based method with multi-modal metrics could provide effective diagnostic information for identifying AD, MCI and HC subjects.

Apamin, an SK2 Inhibitor, Attenuated Neonatal Sevoflurane Exposures Caused Cognitive Deficits in Mice through the Regulation of Hippocampal Neuroinflammation.

Cognitive dysfunction induced by anesthesia in the infant is a crucial clinical issue that is still being debated and the focus of concern for the parents. However, the mechanism of cognitive decline caused by anesthesia and the corresponding treatment methods remain unclear. Postnatal day 7 (PND7) C57BL/6 mice included in the study were randomly divided into a control group (Control), a group with repeated exposure to sevoflurane (Sevo), and an Apamin intervention group (Sevo + Apamin). Apamin (0.5 μL at the concentration of 100 nmol/L) was injected into the bilateral hippocampus of mice. qRT-PCR, enzyme-linked immunosorbent assay (ELISA), and western blotting assay were used to evaluate the protein levels in the hippocampus. Object location memory (OLM) and novel object recognition (NOR) tasks, as well as elevated plus maze and contextual and cued fear conditioning tasks were used to evaluate the cognitive function of mice. Apamin mitigated sevoflurane-induced cognitive impairment of mice, sevoflurane-induced neuronal injury, and sevoflurane-induced activation of microglial in the hippocampus of the mice. Apamin inhibited M1-type polarization but promoted M2-type polarization of microglia after neonatal sevoflurane exposures in the hippocampus. In conclusion, Apamin attenuates neonatal sevoflurane exposures that cause cognitive deficits in mice through regulating hippocampal neuroinflammation.