Causal network localization of brain stimulation targets for trait anxiety.

Transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) can treat some neuropsychiatric disorders, but there is no consensus approach for identifying new targets. We localized causal circuit-based targets for anxiety that converged across multiple natural experiments. Lesions (n=451) and TMS sites (n=111) that modify anxiety mapped to a common normative brain circuit (r=0.68, p=0.01). In an independent dataset (n=300), individualized TMS site connectivity to this circuit predicted anxiety change (p=0.02). Subthalamic DBS sites overlapping the circuit caused more anxiety (n=74, p=0.006), thus demonstrating a network-level effect, as the circuit was derived without any subthalamic sites. The circuit was specific to trait versus state anxiety in datasets that measured both (p=0.003). Broadly, this illustrates a pathway for discovering novel circuit-based targets across neuropsychiatric disorders.

Endoscopic endonasal approach for olfactory groove meningioma resection: Strategies and outcomes in a retrospective case series.

OBJECTIVE: Though the endoscopic endonasal approach (EEA) is a widely accepted treatment for skull base tumors, the specific use of EEA for olfactory groove meningiomas (OGMs) is debated, with variable outcomes reported in the literature. We review the surgical results of OGM resections for one surgeon including the operative approach, surgical nuances, and outcomes, with a focus on factors relating to patient selection which favor EEA over transcranial approaches. METHODS: We retrospectively reviewed thirteen cases of endoscopic endonasal resection of olfactory groove meningiomas. Patient characteristics, clinical characteristics, surgical outcomes, and complications were analyzed. Extent of resection was determined based on volumetric analysis of pre- and postoperative MRI. RESULTS: Anatomic characteristics that render a tumor difficult to access fully are lateral extension beyond the mid-orbit and anterior extension to the falx. Simpson Grade I resection was achieved in 11/13 (84.6 %) cases. Mean pre-operative tumor volume was 8.99 cm3 (range 2.19-16.79 cm3), and 92 % of tumors were WHO grade I. We demonstrate 2 cases of smell preservation, possible with small unilateral tumors and tumors that are confined to either the anterior or posterior portion of the cribriform plate. The post-operative CSF leak rate was 7.7 %, without prophylactic lumbar CSF drainage. The mortality rate was 7.7 % (n = 1) after infectious complications following CSF leak. CONCLUSIONS: Endoscopic endonasal resection of olfactory groove meningiomas is an effective and safe operative method with outcomes and complication rates comparable to transcranial approaches. Key considerations include careful patient selection and familiarity with technical nuances of endoscopic endonasal approach for this specific tumor type.

Changes in deep brain stimulation surgeries between 2019 and 2020: A national inpatient sample analysis.

Background: Deep brain stimulation (DBS) surgery is a neurosurgical procedure that implants electrodes into the brain to treat a variety of neurological and psychiatric conditions. The COVID-19 pandemic resulted in significant disruptions in elective surgeries, but the impact on DBS surgeries remains largely unknown. Methods: The National Inpatient Sample (NIS), an all-payors database of inpatient hospitalizations in the US, was queried for DBS implantation procedural codes in 2019 and 2020. Results: There were a total of 7,625 hospitalizations (95% CI: 6,664 to 8,586) for the implantation of a DBS lead in the 2019 NIS, which reduced by 11.9% to 6,715 hospitalizations (95% CI: 5,872 to 7,558) in the 2020 NIS. Procedural numbers declined in March 2020, with a peak 92.7% decline in volume in April of 2020 relative to 2019. Case numbers for July through December 2020 were 96.1% of the 2019 volume. Overall patient demographics and primary discharge diagnoses for hospitalizations involving DBS implantation were similar in the two study years. Conclusions: Surgical volume for DBS implantation reduced by 92.7% in April of 2020 relative to 2019, which is among the highest declines reported for any surgical procedure. While procedural volume increased in the second half of 2020, this did not make up for the reduction in procedures earlier in the year, highlighting the disruption in DBS surgeries in 2020.

Choroid plexus-targeted NKCC1 overexpression to treat post-hemorrhagic hydrocephalus.

Post-hemorrhagic hydrocephalus (PHH) refers to a life-threatening accumulation of cerebrospinal fluid (CSF) that occurs following intraventricular hemorrhage (IVH). An incomplete understanding of this variably progressive condition has hampered the development of new therapies beyond serial neurosurgical interventions. Here, we show a key role for the bidirectional Na-K-Cl cotransporter, NKCC1, in the choroid plexus (ChP) to mitigate PHH. Mimicking IVH with intraventricular blood led to increased CSF [K+] and triggered cytosolic calcium activity in ChP epithelial cells, which was followed by NKCC1 activation. ChP-targeted adeno-associated viral (AAV)-NKCC1 prevented blood-induced ventriculomegaly and led to persistently increased CSF clearance capacity. These data demonstrate that intraventricular blood triggered a trans-choroidal, NKCC1-dependent CSF clearance mechanism. Inactive, phosphodeficient AAV-NKCC1-NT51 failed to mitigate ventriculomegaly. Excessive CSF [K+] fluctuations correlated with permanent shunting outcome in humans following hemorrhagic stroke, suggesting targeted gene therapy as a potential treatment to mitigate intracranial fluid accumulation following hemorrhage.

Magnetic resonance spectroscopy outperforms perfusion in distinguishing between pseudoprogression and disease progression in patients with glioblastoma.

Background: There is a need to establish biomarkers that distinguish between pseudoprogression (PsP) and true tumor progression in patients with glioblastoma (GBM) treated with chemoradiation. Methods: We analyzed magnetic resonance spectroscopic imaging (MRSI) and dynamic susceptibility contrast (DSC) MR perfusion data in patients with GBM with PsP or disease progression after chemoradiation. MRSI metabolites of interest included intratumoral choline (Cho), myo-inositol (mI), glutamate + glutamine (Glx), lactate (Lac), and creatine on the contralateral hemisphere (c-Cr). Student T-tests and area under the ROC curve analyses were used to detect group differences in metabolic ratios and their ability to predict clinical status, respectively. Results: 28 subjects (63 ± 9 years, 19 men) were evaluated. Subjects with true progression (n = 20) had decreased enhancing region mI/c-Cr (P = .011), a marker for more aggressive tumors, compared to those with PsP, which predicted tumor progression (AUC: 0.84 [0.76, 0.92]). Those with true progression had elevated Lac/Glx (P = .0009), a proxy of the Warburg effect, compared to those with PsP which predicted tumor progression (AUC: 0.84 [0.75, 0.92]). Cho/c-Cr did not distinguish between PsP and true tumor progression. Despite rCBV (AUC: 0.70 [0.60, 0.80]) and rCBF (AUC: 0.75 [0.65, 0.84]) being individually predictive of tumor response, they added no additional predictive value when combined with MRSI metabolic markers. Conclusions: Incorporating enhancing lesion MRSI measures of mI/c-Cr and Lac/Glx into brain tumor imaging protocols can distinguish between PsP and true progression and inform patient management decisions.

Magnetic resonance spectroscopic imaging for detecting metabolic changes in glioblastoma after anti-angiogenic therapy-a systematic literature review.

Background: The impact of anti-angiogenic therapy (AAT) on patients with glioblastoma (GBM) is unclear due to a disconnect between radiographic findings and overall survivorship. MR spectroscopy (MRS) can provide clinically relevant information regarding tumor metabolism in response to AAT. This review explores the use of MRS to track metabolic changes in patients with GBM treated with AAT. Methods: We conducted a systematic literature review in accordance with PRISMA guidelines to identify primary research articles that reported metabolic changes in GBMs treated with AAT. Collected variables included single or multi-voxel MRS acquisition parameters, metabolic markers, reported metabolic changes in response to AAT, and survivorship data. Results: Thirty-five articles were retrieved in the initial query. After applying inclusion and exclusion criteria, 11 studies with 262 patients were included for qualitative synthesis with all studies performed using multi-voxel 1H MRS. Two studies utilized 31P MRS. Post-AAT initiation, shorter-term survivors had increased choline (cellular proliferation marker), increased lactate (a hypoxia marker), and decreased levels of the short echo time (TE) marker, myo-inositol (an osmoregulator and gliosis marker). MRS detected metabolic changes as soon as 1-day after AAT, and throughout the course of AAT, to predict survival. There was substantial heterogeneity in the timing of scans, which ranged from 1-day to 6-9 months after AAT initiation. Conclusions: Multi-voxel MRS at intermediate and short TE can serve as a robust prognosticator of outcomes of patients with GBM who are treated with AAT.

Myo-Inositol Levels Measured with MR Spectroscopy Can Help Predict Failure of Antiangiogenic Treatment in Recurrent Glioblastoma.

Background Patients with recurrent glioblastoma (GBM) are often treated with antiangiogenic agents, such as bevacizumab (BEV). Despite therapeutic promise, conventional MRI methods fail to help determine which patients may not benefit from this treatment. Purpose To use MR spectroscopic imaging (MRSI) with intermediate and short echo time to measure corrected myo-inositol (mI)normalized by contralateral creatine (hereafter, mI/c-Cr) in participants with recurrent GBM treated with BEV and to investigate whether such measurements can help predict survivorship before BEV initiation (baseline) and at 1 day, 4 weeks, and 8 weeks thereafter. Materials and Methods In this prospective longitudinal study (2016-2020), spectroscopic data on mI-a glial marker and osmoregulator within the brain-normalized by contralateral creatine in the intratumoral, contralateral, and peritumoral volumes of patients with recurrent GBM were evaluated. Area under the receiver operating characteristic curve (AUC) was calculated for all volumes at baseline and 1 day, 4 weeks, and 8 weeks after treatment to determine the ability of mI/c-Cr to help predict survivorship. Results Twenty-one participants (median age ± standard deviation, 62 years ± 12; 15 men) were evaluated. Lower mI/c-Cr in the tumor before and during BEV treatment was predictive of poor survivorship, with receiver operating characteristic analyses showing an AUC of 0.75 at baseline, 0.87 at 1 day after treatment, and 1 at 8 weeks after. A similar result was observed in contralateral normal-appearing tissue and the peritumoral volume, with shorter-term survivors having lower levels of mI/c-Cr. In the contralateral volume, a lower ratio of mI to creatine (hereafter, mI/Cr) predicted shorter-term survival at baseline and all other time points. Within the peritumoral volume, lower mI/c-Cr levels were predictive of shorter-term survival at baseline (AUC, 0.80), at 1 day after treatment (AUC, 0.93), and at 4 weeks after treatment (AUC, 0.68). Conclusion Lower levels of myo-inositol normalized by contralateral creatine within intratumoral, contralateral, and peritumoral volumes were predictive of poor survivorship and antiangiogenic treatment failure as early as before bevacizumab treatment. Adapting MR spectroscopic imaging alongside conventional MRI modalities conveys critical information regarding the biologic characteristics of tumors to help better treat individuals with recurrent glioblastoma. Clinical trial registration no. NCT02843230 © RSNA, 2021 Online supplemental material is available for this article.

MR spectroscopic imaging predicts early response to anti-angiogenic therapy in recurrent glioblastoma.

BACKGROUND: Determining failure to anti-angiogenic therapy in recurrent glioblastoma (GBM) (rGBM) remains a challenge. The purpose of the study was to assess treatment response to bevacizumab-based therapy in patients with rGBM using MR spectroscopy (MRS). METHODS: We performed longitudinal MRI/MRS in 33 patients with rGBM to investigate whether changes in N-acetylaspartate (NAA)/Choline (Cho) and Lactate (Lac)/NAA from baseline to subsequent time points after treatment can predict early failures to bevacizumab-based therapies. RESULTS: After stratifying based on 9-month survival, longer-term survivors had increased NAA/Cho and decreased Lac/NAA levels compared to shorter-term survivors. ROC analyses for intratumoral NAA/Cho correlated with survival at 1 day, 2 weeks, 8 weeks, and 16 weeks. Intratumoral Lac/NAA ROC analyses were predictive of survival at all time points tested. At the 8-week time point, 88% of patients with decreased NAA/Cho did not survive 9 months; furthermore, 90% of individuals with an increased Lac/NAA from baseline did not survive at 9 months. No other metabolic ratios tested significantly predicted survival. CONCLUSIONS: Changes in metabolic levels of tumoral NAA/Cho and Lac/NAA can serve as early biomarkers for predicting treatment failure to anti-angiogenic therapy as soon as 1 day after bevacizumab-based therapy. The addition of MRS to conventional MR methods can provide better insight into how anti-angiogenic therapy affects tumor microenvironment and predict patient outcomes.

Neurophysiologic Mapping of Thalamocortical Tract in Asleep Craniotomies: Promising Results From an Early Experience.

BACKGROUND: Subcortical mapping of the corticospinal tract has been extensively used during craniotomies under general anesthesia to achieve maximal resection while avoiding postoperative motor deficits. To our knowledge, similar methods to map the thalamocortical tract (TCT) have not yet been developed. OBJECTIVE: To describe a neurophysiologic technique for TCT identification in 2 patients who underwent resection of frontoparietal lesions. METHODS: The central sulcus (CS) was identified using the somatosensory evoked potentials (SSEP) phase reversal technique. Furthermore, monitoring of the cortical postcentral N20 and precentral P22 potentials was performed during resection. Subcortical electrical stimulation in the resection cavity was done using the multipulse train (case #1) and Penfield (case #2) techniques. RESULTS: Subcortical stimulation within the postcentral gyrus (case #1) and in depth of the CS (case #2), resulted in a sudden drop in amplitudes in N20 (case #1) and P22 (case #2), respectively. In both patients, the potentials promptly recovered once the stimulation was stopped. These results led to redirection of the surgical plane with avoidance of damage of thalamocortical input to the primary somatosensory (case #1) and motor regions (case #2). At the end of the resection, there were no significant changes in the median SSEP. Both patients had no new long-term postoperative sensory or motor deficit. CONCLUSION: This method allows identification of TCT in craniotomies under general anesthesia. Such input is essential not only for preservation of sensory function but also for feedback modulation of motor activity.

Hyperactivity and Reduced Activation of Anterior Hippocampus in Early Psychosis.

OBJECTIVE: In schizophrenia, the anterior hippocampus is hyperactive and shows reduced task-related recruitment, but the relationship between these two findings is unclear. The authors tested the hypothesis that hyperactivity impairs recruitment of the anterior hippocampus during scene processing. METHODS: Functional MRI data from 45 early-psychosis patients and 35 demographically matched healthy control subjects were analyzed using a block-design 1-back scene-processing task. Hippocampal activation in response to scenes and faces compared with scrambled images was measured. In a subset of 20 early-psychosis patients and 31 healthy control subjects, baseline hippocampal activity using cerebral blood volume (CBV) mapping was measured. Correlation analyses were used to examine the association between baseline hippocampal activity and task-related hippocampal activation. RESULTS: Activation of the anterior hippocampus was significantly reduced and CBV in the anterior hippocampus was significantly increased in the early stages of psychosis. Increased CBV in early-psychosis patients was inversely correlated with task-related activation during scene processing in the anterior hippocampus. CONCLUSIONS: Anterior hippocampal hyperactivity in early-psychosis patients appears to limit effective recruitment of this region during task performance. These findings provide novel support for the anterior hippocampus as a therapeutic target in the treatment of cognitive deficits in psychosis.

Regionally specific volume deficits along the hippocampal long axis in early and chronic psychosis.

Previous studies in psychosis patients have shown hippocampal volume deficits across anterior and posterior regions or across subfields, but subfield specific changes in volume along the hippocampal long axis have not been examined. Here, we tested the hypothesis that volume changes exist across the hippocampus in chronic psychosis but only the anterior CA region is affected in early psychosis patients. We analyzed structural MRI data from 179 patients with a non-affective psychotic disorder (94 chronic psychosis; 85 early psychosis) and 167 heathy individuals demographically matched to the chronic and early psychosis samples respectively (82 matched to chronic patients; 85 matched to early patients). We measured hippocampal volumes using Freesurfer 6-derived automated segmentation of both anterior and posterior regions and the CA, dentate gyrus, and subiculum subfields. We found a hippocampal volume deficit in both anterior and posterior regions in chronic psychosis, but this deficit was limited to the anterior hippocampus in early psychosis patients. This volume change was more pronounced in the anterior CA subfield of early psychosis patients than in the dentate gyrus or subiculum. Our findings support existing models of psychosis implicating initial CA dysfunction with later progression to other hippocampal regions and suggest that the anterior hippocampus may be an important target for early interventions.

Hippocampal arterial cerebral blood volume in early psychosis.

Recent studies of patients in the early stage of psychosis have revealed increased cerebral blood volume (CBV) in specific subfields of the anterior hippocampus. These studies required injection of a contrast agent to measure steady state CBV. Here we used a novel, non-invasive method, inflow-based-vascular-space-occupancy with dynamic subtraction (iVASO-DS), to measure the arterial component of CBV (aCBV) in a single slice of the hippocampus. Based on evidence from contrast-enhanced CBV studies, we hypothesized increased aCBV in the anterior hippocampus in early psychosis. We used 3T MRI to generate iVASO-derived aCBV maps in 17 medicated patients (average duration of illness = 7.6 months) and 25 matched controls. We did not find hemispheric or regional group differences in hippocampal aCBV. The limited spatial resolution of the iVASO-DS method did not allow us to test for aCBV differences in specific subfields of the hippocampus. Future studies should investigate venous and arterial CBV changes in the hippocampus of early psychosis patients.

Inflow-vascular space occupancy (iVASO) reproducibility in the hippocampus and cortex at different blood water nulling times.

PURPOSE: Inflow-vascular space occupancy (iVASO) measures arterial cerebral blood volume (aCBV) using accurate blood water nulling (inversion time [TI]) when arterial blood reaches the capillary, i.e., at the arterial arrival time. This work assessed the reproducibility of iVASO measurements in the hippocampus and cortex at multiple TIs. METHODS: The iVASO approach was implemented at multiple TIs in 10 healthy volunteers at 3 Tesla. aCBV values were measured at each TI in the left and right hippocampus, and the cortex. Reproducibility of aCBV measurements within scans (same day) and across sessions (different days) was assessed using the intraclass correlation coefficient (ICC). RESULTS: Overall hippocampal aCBV was significantly higher than cortical aCBV, likely due to higher gray matter volume. Hippocampal ICC values were high at short TIs (≤914 ms; intrascan values = 0.80-0.96, interscan values = 0.61-0.91). Cortically, high ICC values were observed at intermediate TIs of 914 (intra: 0.93, inter: 0.87) and 1034 ms (intra: 0.96, inter: 0.86). The ICC values were comparable to established contrast-based CBV measures. CONCLUSION: iVASO measurements are reproducible within and across sessions. TIs for iVASO measurements should be chosen carefully, taking into account heterogeneous arterial arrival times in different brain regions. Magn Reson Med 75:2379-2387, 2016. © 2015 Wiley Periodicals, Inc.

Increased Amplitude of Low Frequency Fluctuations but Normal Hippocampal-Default Mode Network Connectivity in Schizophrenia.

BACKGROUND: Clinical and preclinical studies have established that the hippocampus is hyperactive in schizophrenia, making it a possible biomarker for drug development. Increased hippocampal connectivity, which can be studied conveniently with resting state imaging, has been proposed as a readily accessible corollary of hippocampal hyperactivity. Here, we tested the hypothesis that hippocampal activity and connectivity are increased in patients with schizophrenia. METHODS: Sixty-three schizophrenia patients and 71 healthy control subjects completed a resting state functional magnetic resonance imaging scan. We assessed hippocampal activity with the amplitude of low frequency fluctuations. We analyzed hippocampal functional connectivity with the default mode network using three common methods: group and single subject level independent component analysis, and seed-based functional connectivity. RESULTS: In patients with schizophrenia, we observed increased amplitude of low frequency fluctuations but normal hippocampal connectivity using independent component and seed-based analyses. CONCLUSION: Our results indicate that although intrinsic hippocampal activity may be increased in schizophrenia, this finding does not extend to functional connectivity. Neuroimaging methods that directly assess hippocampal activity may be more promising for the identification of a biomarker for schizophrenia.

Increased hippocampal blood volume and normal blood flow in schizophrenia.

Neuroimaging studies have provided compelling evidence for abnormal hippocampal activity in schizophrenia. Most studies made inferences about baseline hippocampal activity using a single hemodynamic parameter (e.g., blood volume or blood flow). Here we studied several hemodynamic measures in the same cohort to test the hypothesis of increased hippocampal activity in schizophrenia. We used dynamic susceptibility contrast- (DSC-) magnetic resonance imaging (MRI) to assess blood volume, blood flow, and mean transit time in the hippocampus of 15 patients with chronic schizophrenia and 15 healthy controls. Left and right hippocampal measurements were combined for absolute measures of cerebral blood volume (CBV), cerebral blood flow (CBF), and mean transit time (MTT). We found significantly increased hippocampal CBV, but normal CBF and MTT, in schizophrenia. The uncoupling of CBV and CBF could be due to several factors, including antipsychotic medication, loss of cerebral perfusion pressure, or angiogenesis. Further studies need to incorporate several complementary imaging modalities to better characterize hippocampal dysfunction in schizophrenia.

Increased hippocampal CA1 cerebral blood volume in schizophrenia.

Hippocampal hyperactivity has been proposed as a biomarker in schizophrenia. However, there is a debate whether the CA1 or the CA2/3 subfield is selectively affected. We studied 15 schizophrenia patients and 15 matched healthy control subjects with 3T steady state, gadolinium-enhanced, absolute cerebral blood volume (CBV) maps, perpendicular to the long axis of the hippocampus. The subfields of the hippocampal formation (subiculum, CA1, CA2/3, and hilus/dentate gyrus) were manually segmented to establish CBV values. Comparing anterior CA1 and CA2/3 CBV between patients and controls revealed a significant subfield-by-diagnosis interaction. This interaction was due to the combined effect of a trend of increased CA1 CBV (p = .06) and non-significantly decreased CA2/3 CBV (p = 0.14) in patients relative to healthy controls. These results support the emerging hypothesis of increased hippocampal activity as a biomarker of schizophrenia and highlight the importance of subfield-level investigations.

Anterior-posterior cerebral blood volume gradient in human subiculum.

The human hippocampal formation is characterized by anterior-posterior gradients of cell density, neurochemistry, and hemodynamics. In addition, some functions are associated with specific subfields (subiculum, CA1-4, dentate gyrus) and regions (anterior and posterior). We performed contrast-enhanced, high-resolution T1-weighted 3T steady state (SS) imaging to investigate cerebral blood volume (CBV) gradients of the hippocampal formation. We studied 14 healthy subjects and found significant CBV gradients (anterior > posterior) in the subiculum but not in other hippocampal subfields. Since CBV is a marker of basal metabolism, these results indicate a greater baseline activity in the anterior compared with the posterior subiculum. This gradient might be related to the role of the subiculum as the main outflow station of the hippocampal formation and might have implications for the mechanisms of neuropsychiatric disorders.

Identification of novel targets for PGC-1alpha and histone deacetylase inhibitors in neuroblastoma cells.

Recent evidence suggests that the transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator 1alpha (PGC-1alpha) is involved in the pathology of Huntington's Disease (HD). While animals lacking PGC-1alpha express lower levels of genes involved in antioxidant defense and oxidative phosphorylation in the brain, little is known about other targets for PGC-1alpha in neuronal cells and whether there are ways to pharmacologically target PGC-1alpha in neurons. Here, PGC-1alpha overexpression in SH-SY5Y neuroblastoma cells upregulated expression of genes involved in mitochondrial function, glucose transport, fatty acid metabolism, and synaptic function. Overexpression also decreased vulnerability to hydrogen peroxide-induced cell death and caspase 3 activation. Treatment of cells with the histone deacetylase inhibitors (HDACi's) trichostatin A and valproic acid upregulated PGC-1alpha and glucose transporter 4 (GLUT4). These results suggest that PGC-1alpha regulates multiple pathways in neurons and that HDACi's may be good candidates to target PGC-1alpha and GLUT4 in HD and other neurological disorders.