Exercise-induced calf muscle hyperemia quantified with dynamic blood oxygen level-dependent (BOLD) imaging.

Muscle hyperemia in exercise is usually the combined result of increased cardiac output and local muscle vasodilation, with the latter reflecting muscle's capacity for increased blood perfusion to support exercise. In this study, we aim to quantify muscle's vasodilation capability with dynamic BOLD imaging. A deoxyhemoglobin-kinetics model is proposed to analyze dynamic BOLD signals acquired during exercise recovery, deriving a hyperemia index (HI) for a muscle group of interest. We demonstrated the method's validity with calf muscles of healthy subjects who performed plantar flexion for muscle stimulation. In a test with exercise load incrementally increasing from 0 to 16 lbs., gastrocnemius HI showed considerable variance among the 4 subjects, but with a consistent trend, i.e. low at light load (e.g. 0-6 lbs) and linearly increasing at heavy load. The high variability among different subjects was confirmed with the other 10 subjects who exercised with a same moderate load of 8 lbs., with coefficient of variance among subjects' medial gastrocnemius 87.8%, lateral gastrocnemius 111.8% and soleus 132.3%. These findings align with the fact that intensive exercise induces high muscle hyperemia, but a comparison among different subjects is hard to make, presumably due to the subjects' different rate of oxygen utilization. For the same 10 subjects who exercised with load of 8 lbs., we also performed dynamic contrast enhanced (DCE) MRI to measure muscle perfusion (F). With a moderate correlation of 0.654, HI and F displayed three distinctive responses of calf muscles: soleus of all the subjects were in the cluster of low F and low HI, and gastrocnemius of most subjects had high F and either low or high HI. This finding suggests that parameter F encapsulates blood flow through vessels of all sizes, but BOLD-derived HI focuses on capillary flow and therefore is a more specific indicator of muscle vasodilation. In conclusion, the proposed hyperemia index has the potential of quantitatively assessing muscle vasodilation induced with exercise.

Bevacizumab and gamma knife radiosurgery for first-recurrence glioblastoma.

INTRODUCTION: Glioblastoma (GBM) is the most common central nervous system malignancy in adults. Despite decades of developments in surgical management, radiation treatment, chemotherapy, and tumor treating field therapy, GBM remains an ultimately fatal disease. There is currently no definitive standard of care for patients with recurrent glioblastoma (rGBM) following failure of initial management. OBJECTIVE: In this retrospective cohort study, we set out to examine the relative effects of bevacizumab and Gamma Knife radiosurgery on progression-free survival (PFS) and overall survival (OS) in patients with GBM at first-recurrence. METHODS: We conducted a retrospective review of all patients with rGBM who underwent treatment with bevacizumab and/or Gamma Knife radiosurgery at Roswell Park Comprehensive Cancer Center between 2012 and 2022. Mean PFS and OS were determined for each of our three treatment groups: Bevacizumab Only, Bevacizumab Plus Gamma Knife, and Gamma Knife Only. RESULTS: Patients in the combined treatment group demonstrated longer post-recurrence median PFS (7.7 months) and median OS (11.5 months) compared to glioblastoma patients previously reported in the literature, and showed improvements in total PFS (p=0.015), total OS (p=0.0050), post-recurrence PFS (p=0.018), and post-recurrence OS (p=0.0082) compared to patients who received either bevacizumab or Gamma Knife as monotherapy. CONCLUSION: This study demonstrates that the combined use of bevacizumab with concurrent stereotactic radiosurgery can have improve survival in patients with rGBM.

Accurate exclusion of kidney regions affected by susceptibility artifact in blood oxygenation level-dependent (BOLD) images using deep-learning-based segmentation.

Susceptibility artifact (SA) is common in renal blood oxygenation level-dependent (BOLD) images, and including the SA-affected region could induce much error in renal oxygenation quantification. In this paper, we propose to exclude kidney regions affected by SA in gradient echo images with different echo times (TE), based on a deep-learning segmentation approach. For kidney segmentation, a ResUNet was trained with 4000 CT images and then tuned with 60 BOLD images. Verified by a Monte Carlo simulation, the presence of SA leads to a bilinear pattern for the segmented area of kidney as function of TE, and the segmented kidney in the image of turning point's TE would exclude SA-affected regions. To evaluate the accuracy of excluding SA-affected regions, we compared the SA-free segmentations by the proposed method against manual segmentation by an experienced user for BOLD images of 35 subjects, and found DICE of 93.9% ± 3.4%. For 10 kidneys with severe SA, the DICE was 94.5% ± 1.7%, for 14 with moderate SA, 92.8% ± 4.7%, and for 46 with mild or no SA, 94.3% ± 3.8%. For the three sub-groups of kidneys, correction of SA led to a decrease of R2* of 8.5 ± 2.8, 4.7 ± 1.8, and 1.6 ± 0.9 s-1, respectively. In conclusion, the proposed method is capable of segmenting kidneys in BOLD images and at the same time excluding SA-affected region in a fully automatic way, therefore can potentially improve both speed and accuracy of the quantification procedure of renal BOLD data.

Lymph node targeted multi-epitope subunit vaccine promotes effective immunity to EBV in HLA-expressing mice.

The recent emergence of a causal link between Epstein-Barr virus (EBV) and multiple sclerosis has generated considerable interest in the development of an effective vaccine against EBV. Here we describe a vaccine formulation based on a lymph node targeting Amphiphile vaccine adjuvant, Amphiphile-CpG, admixed with EBV gp350 glycoprotein and an engineered EBV polyepitope protein that includes 20 CD8+ T cell epitopes from EBV latent and lytic antigens. Potent gp350-specific IgG responses are induced in mice with titers >100,000 in Amphiphile-CpG vaccinated mice. Immunization including Amphiphile-CpG also induces high frequencies of polyfunctional gp350-specific CD4+ T cells and EBV-specific CD8+ T cells that are 2-fold greater than soluble CpG and are maintained for >7 months post immunization. This combination of broad humoral and cellular immunity against multiple viral determinants is likely to provide better protection against primary infection and control of latently infected B cells leading to protection against the development of EBV-associated diseases.

Cervical spine flexion-extension radiography versus magnetic resonance imaging in pediatric patients following blunt traumatic injury.

Background: In pediatric trauma patients, 60-80% of spinal cord injuries involve the cervical vertebrae. While the American College of Radiology offers guidelines for best imaging practices in the setting of acute pediatric trauma, there is a lack of uniformity in imaging-decision protocols across institutions. MRI has been shown to demonstrate high sensitivity for both bony and ligamentous injuries while also avoiding unnecessary radiation exposure in the pediatric patient population. However, the efficacy of flexion-extension (FE) radiography following initial MRI has not been evaluated in children. Our hypothesis is that FE radiography conducted following an initial MRI does not contribute significant diagnostic information or reduce time to cervical collar removal and thus can be removed from institutional protocols in order to avoid unnecessary testing and reduce pediatric radiation exposure. Methods: Trauma data were collected for pediatric patients presenting with suspected acute cervical spine injury from 2014 to 2021. A total of 108 patients were subdivided into 41 patients who received "MRI Only" and 67 patients who received both "MRI and FE" diagnostic cervical spine imaging. Chi-square testing and t-tests were performed to determine differences between MRI and FE radiographic detection rates of bony and ligamentous injuries in the subgroups. Results: In patients for whom FE did not find any injury, MRI detected bony and ligamentous injuries in 9/63 and 12/65 cases, respectively. In 3/21 (14.3%) cases in which MRI detected a bony and/or ligamentous injury and FE did not, patients eventually required surgical intervention for c-spine stabilization. No patients required surgical fixation when FE radiography showed an abnormality and MRI was normal. Addition of follow-up FE radiography after initial MRI did not have a significant effect on overall hospital length of stay (MRI Only vs MRI+FE: 9.2±12.0 days vs 8.6±13.5 days, p=0.816) or on rates of collar removal at discharge or greater than 48 hours after imaging (MRI Only vs MRI+FE: 41.5% vs 56.7%, p=0.124). Conclusions: FE radiography following initial MRI did not have a significant effect on reducing time to cervical collar removal or overall hospital length of stay. In addition, in 3 of 6 cases (50.0%) in which surgical fixation was required, MRI detected ligamentous and/or bony injury while FE radiography was normal. Level of Evidence: This study contributes Level 2b scientific evidence consistent with a well-designed cohort or case-control analytic study.

Postoperative Morbidity and Mortality in Lumbar Spine Surgery Patients With Chronic Kidney Disease and Chronic Steroid Use.

BACKGROUND: Perioperative steroids have traditionally been administered during lumbar spine surgery in order to decrease local inflammation and prevent scar tissue formation, which can otherwise contribute to significant, long-lasting postoperative pain due to the formation of epidural fibrosis around lumbar nerve roots. However, the use of steroids in lumbar spine patients has raised concerns of postoperative wound complications caused by corticosteroid-induced immunomodulatory effects and changes in collagen synthesis. Patients with chronic kidney disease (CKD) undergoing spine surgery are at a particularly elevated risk of various complications due to chronic CKD-related systemic inflammation and endothelial dysfunction. It is currently uncertain whether chronic steroid use in CKD patients exerts a protective effect postoperatively due to decreased systemic inflammation or instead is correlated with increased rates of wound complications. RESULTS: Using adjusted odds ratios to control for CKD-related comorbidities, our study of lumbar spine fusion patients who were chronic steroid users vs nonusers found no significant differences in rates of postoperative wound infections in later stage CKD patients. However, we also did not observe statistically significant reductions in hospital length of stay or rates of 30-day mortality, sepsis, or cardiac, pulmonary, and renal events. CONCLUSIONS: Our results indicate chronic steroid use neither contributes significantly to rates of wound infections nor exerts a protective effect against postoperative inflammatory complications in lumbar spine patients with CKD. CLINICAL RELEVANCE: Our findings do not support the practice of holding steroids in chronic users prior to lumbar spine surgery. Perioperative steroids do not appear to increase the risk of postoperative complications, but neither do they improve lumbar spine patient outcomes.

Infantile-onset Pompe disease with neutropenia: Treatment decisions in the face of a unique phenotype.

Infantile-onset Pompe disease manifests with early signs of cardiomyopathy during the first few days to weeks of life. We present the case of a newborn born via emergency cesarean section with atrial flutter and moderate biventricular hypertrophy who was diagnosed with Pompe disease on New York State newborn screen. Diagnosis was confirmed with repeat leukocyte acid alpha-glucosidase (GAA) enzyme activity, GAA gene sequencing, urine Hex4, and evaluation of Cross-Reactive Immunological Material (CRIM) status. The patient was also found to be persistently neutropenic which to our knowledge has not been previously reported in the literature in association with Pompe disease. This report highlights the impact that newborn screening had on time to diagnosis and initiation of treatment with enzyme replacement therapy. We also discuss how our patient's concurrent neutropenia impacted decision making related to immune tolerance induction prior to starting enzyme replacement therapy.

Macroglossia Associated With Clobazam Administration: A Case Report and Literature Review.

Clobazam is a benzodiazepine derivative used as an antiepileptic agent for the treatment of focal and generalized seizures and drug-resistant epilepsy associated with Lennox-Gastaut Syndrome. While somnolence and mood-related side effects are commonly observed, acute macroglossia following initiation of Clobazam therapy has not been previously reported in the medical literature. In this case report, we present a female pediatric patient who developed significant tongue swelling with protrusion beyond the oral cavity after initiation of Clobazam for treatment-resistant epilepsy. Symptoms were unresponsive to antihistamines and steroids but resolved gradually in the days following discontinuation of Clobazam with no lingering sequelae.

Cerebral Proliferative Angiopathy Presenting as Subdural Hematoma: A Case Report and Systematic Literature Review.

Cerebral proliferative angiopathy (CPA) is a rare cerebrovascular pathology that presents with unique clinical features due to distinct histologic, angiographic, and pathophysiologic characteristics that separate it from classical arteriovenous malformation. The disorder is characterized by uncontrolled angiogenesis in which functional brain parenchyma is interspersed with abnormal vascular channels without a distinct nidus. Common presenting symptoms include headache, seizures, and stroke-like symptoms. Hemorrhagic presentations are rare in contrast to the typical presentations of classical arteriovenous malformation. Here, we report a young woman with a history of a suspected connective tissue disorder who presented to the emergency department with worsening headaches in a delayed fashion after experiencing minor head trauma and was found to have a left-sided subdural hematoma. Angiography confirmed a diagnosis of CPA after abnormal cortical vasculature was noted during the patient's craniotomy. A systematic review of CPA cases described in the literature was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, with the findings discussed.

Pan-Cancer Characterization of Intratumoral Autonomic Innervation in 32 Cancer Types in the Cancer Genome Atlas.

Over the past two decades, multiple studies have demonstrated the important role that the autonomic nervous system (ANS) plays in tumorigenesis and cancer progression. However, the mechanisms by which this process occurs have only recently begun to be elucidated. Further, the extent of autonomic innervation in various cancer types and its effects on tumor molecular, immunological, and histopathological features, as well as on patient outcomes, are not yet fully characterized. In this study, we analyzed intratumoral ANS gene expression signatures, including overall intratumoral neuron growth and sympathetic and parasympathetic markers, across 32 cancer types using tumor transcriptomic and clinical annotation data available from The Cancer Genome Atlas (TCGA). Our analysis revealed wide variations in intratumoral ANS expression both within and across cancer types. The association of ANS signatures with tumor histopathological characteristics and survival outcomes also varied by cancer type. We found intratumoral ANS expression to be commonly correlated with angiogenesis, TGF-ß signaling, and immunosuppression in the tumor microenvironment of many cancer types, which provide mechanistic insights into the involvement of intratumoral innervation in cancer development and progression. Our findings suggest that the potential benefits of cancer therapies targeting ß-adrenergic receptor-mediated stress signaling pathways are likely dependent on cancer type.

Levetiracetam-induced aggression and acute behavioral changes: A case report and literature review.

Levetiracetam is a second-generation antiepileptic medication used to treat a wide range of partial and generalized seizure disorders. While Levetiracetam is generally well-tolerated, mild mood-related side effects (e.g., anxiety, agitation, and depression) have been observed in a minority of patients in the days following initiation of therapy or changes in dosing. The development of acute aggression requiring termination of Levetiracetam therapy has been rarely reported in the medical literature but poses a limiting effect on treatment options for refractory epilepsy in pediatric patients. In this report, we present a teenage male patient with a history of seizure disorder who developed sudden, severe behavioral abnormalities and aggression following increases in his Levetiracetam dosing. His symptoms resolved rapidly after return of his medication dosing to baseline, with no further sequelae noted. Our observations suggest that Levetiracetam remains a safe and effective first-line antiepileptic whose adverse behavioral side effect profile can be properly managed with close patient monitoring and dose titration.

Acute-Onset Psychosis Following Prolonged Hospitalization for COVID-19 Pneumonia.

BACKGROUND SARS-CoV-2 infection presents with a variety of clinical manifestations, from asymptomatic courses to prolonged hospitalizations with severe systemic inflammatory responses and multiorgan failure. One particular sequela of the disease that has gained wider attention over the past year is the sudden onset of neuropsychiatric symptoms in the weeks following recovery from COVID-19 pneumonia. While the pathophysiology for the development of this condition is uncertain, symptoms ranging from mild confusion and anxiety to florid psychosis with manic delusions and auditory and visual hallucinations have been rarely, but increasingly, reported in the literature. The acute development of such symptoms in the post-recovery period can be devastating for patients, their caregivers, and clinicians who may be unaware of effective management options. CASE REPORT In this case report, we present a 23-year old man who developed psychotic symptoms, including acute mania, delusions of grandeur, and auditory and visual hallucinations, 1 week following an extended hospitalization for COVID-19 pneumonia. The patient was admitted to our psychiatric unit and treated with a combination of antipsychotic and mood stabilizer medications. After 2 weeks of treatment, the patient's psychotic and mood-related symptoms resolved, with normal mental status maintained at last follow-up 1 month following discharge from our unit. CONCLUSIONS The acute development of neuropsychiatric symptoms is a rare but increasingly recognized sequela of COVID-19. Despite the severity of initial presentation, patients can be successfully treated with short courses of typical antipsychotic medications with complete return to baseline, unimpaired functioning, and no lingering psychiatric sequela.

Discovery of the Clinical Candidate MAK683: An EED-Directed, Allosteric, and Selective PRC2 Inhibitor for the Treatment of Advanced Malignancies.

Polycomb Repressive Complex 2 (PRC2) plays an important role in transcriptional regulation during animal development and in cell differentiation, and alteration of PRC2 activity has been associated with cancer. On a molecular level, PRC2 catalyzes methylation of histone H3 lysine 27 (H3K27), resulting in mono-, di-, or trimethylated forms of H3K27, of which the trimethylated form H3K27me3 leads to transcriptional repression of polycomb target genes. Previously, we have shown that binding of the low-molecular-weight compound EED226 to the H3K27me3 binding pocket of the regulatory subunit EED can effectively inhibit PRC2 activity in cells and reduce tumor growth in mouse xenograft models. Here, we report the stepwise optimization of the tool compound EED226 toward the potent and selective EED inhibitor MAK683 (compound 22) and its subsequent preclinical characterization. Based on a balanced PK/PD profile, efficacy, and mitigated risk of forming reactive metabolites, MAK683 has been selected for clinical development.

Treatment of Morgellons disease with doxycycline.

Morgellons disease (MD) is a rare dermatopathy characterized by nonspecific symptoms and the production of multicolored fibers and granular tissue from diffuse skin ulcerations which are described as being either pruritic or painful. The etiology of MD is currently unknown; previous studies have suggested both psychiatric and infectious causes, with increasing interest over the previous decade in elaborating a possible pathogenesis for the disease secondary to infection by Borrelia species. We report a middle-aged Caucasian female who developed symptoms of MD in the days following exposure to a tick bite after spending an afternoon hiking through a wooded area. She was subsequently treated with a course of Doxycycline and found on two-week follow-up to have complete remission of her symptoms. This case report further supports the theory for an infectious etiology of MD and encourages future studies into its pathophysiology.

Radial first or patient first: a case series and meta-analysis of transradial versus transfemoral access for acute ischemic stroke intervention.

BACKGROUND: Few studies have compared technical success and effectiveness of transradial access (TRA) versus transfemoral access (TFA) for mechanical thrombectomy (MT) for acute ischemic stroke (AIS). We compared the two approaches for technical success, effectiveness, and outcomes. METHODS: We retrospectively compared TRA with TFA for AIS MT at our institute. We additionally performed a systematic review and meta-analysis of studies describing the use of TRA alone or in comparison with TFA for MT. Primary outcomes included rate of successful reperfusion (thrombolysis in cerebral infarction (TICI) >2b), number of passes, access-site complications, and 3- month mortality and favorable functional outcomes (modified Rankin Scale (mRS) score 0-2). RESULTS: A total of 222 consecutive patients (TRA=93, TFA=129) were included in our case series. The rate of successful reperfusion was significantly higher for the TFA cohort (91.4% vs 79.6%, P=0.01) with lower mean number of passes (1.8±1.2 vs 2.4±1.6, P=0.014). Three-month mortality in the TFA group was lower (22.1% vs 40.9% for the TRA cohort (P=0.004), with a higher rate of favorable functional outcomes (51.3% vs 34.1%, P=0.015). A meta-analysis of 10 studies showed significant heterogeneity in rates of successful reperfusion (57.1% to 95.6%, heterogeneity=67.55%, P=0.001). None of the previous comparative studies reported 3-month mortality and functional outcomes. CONCLUSIONS: This case series demonstrate a higher successful reperfusion rate, fewer passes, lower 3-month mortality, and improved 3-month functional outcomes with TFA. The systematic review highlights the inadequacy of existing evidence. Prospective comparative studies are needed before a 'radial-first' approach can be adopted for stroke intervention.

Exercise-induced calf muscle hyperemia: Rapid mapping of magnetic resonance imaging using deep learning approach.

Exercise-induced hyperemia in calf muscles was recently shown to be quantifiable with high-resolution magnetic resonance imaging (MRI). However, processing of the MRI data to obtain muscle-perfusion maps is time-consuming. This study proposes to substantially accelerate the mapping of muscle perfusion using a deep-learning method called artificial neural network (NN). Forty-eight MRI scans were acquired from 21 healthy subjects and patients with peripheral artery disease (PAD). For optimal training of NN, different training-data sets were compared, investigating the effect of data diversity and reference perfusion accuracy. Reference perfusion was estimated by tracer kinetic model fitting initialized with multiple values (multigrid model fitting). Result: The NN method was much faster than tracer kinetic model fitting. To generate a perfusion map of matrix 128 × 128 on a same computer, multigrid model fitting took about 80 min, single-grid or regular model fitting about 3 min, while the NN method took about 1 s. Compared to the reference values, NN trained with a diverse group gave estimates with mean absolute error (MAE) of 15.9 ml/min/100g and correlation coefficient (R) of 0.949, significantly more accurate than regular model fitting (MAE 22.3 ml/min/100g, R 0.889, p < .001). Conclusion: the NN method enables rapid perfusion mapping, and if properly trained, estimates perfusion with accuracy comparable to multigrid model fitting.

Renal perfusion imaging by MRI.

Renal perfusion can be quantitatively assessed by multiple magnetic resonance imaging (MRI) methods, including dynamic contrast enhanced (DCE), arterial spin labeling (ASL), and diffusion-weighted imaging with intravoxel incoherent motion (IVIM) analysis. In this review we summarize the advances in the field of renal-perfusion MRI over the past 5 years. The review starts with a brief introduction of relevant MRI methods, followed by a discussion of recent technical developments. In the main section of the review, we examine the clinical and preclinical applications for three disease populations: chronic kidney disease, renal transplant, and renal tumors. The DCE method has been routinely used for assessing renal tumors but not other renal diseases. As a noncontrast alternative, ASL was extensively explored in both preclinical and clinical applications and showed much promise. Protocol standardization for the methods is desperately needed, and then large-scale clinical trials for the methods can be initiated prior to their broad clinical use. Level of Evidence: 5 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019. J. Magn. Reson. Imaging 2020;52:369-379.

Consensus-based technical recommendations for clinical translation of renal BOLD MRI.

Harmonization of acquisition and analysis protocols is an important step in the validation of BOLD MRI as a renal biomarker. This harmonization initiative provides technical recommendations based on a consensus report with the aim to move towards standardized protocols that facilitate clinical translation and comparison of data across sites. We used a recently published systematic review paper, which included a detailed summary of renal BOLD MRI technical parameters and areas of investigation in its supplementary material, as the starting point in developing the survey questionnaires for seeking consensus. Survey data were collected via the Delphi consensus process from 24 researchers on renal BOLD MRI exam preparation, data acquisition, data analysis, and interpretation. Consensus was defined as ≥ 75% unanimity in response. Among 31 survey questions, 14 achieved consensus resolution, 12 showed clear respondent preference (65-74% agreement), and 5 showed equal (50/50%) split in opinion among respondents. Recommendations for subject preparation, data acquisition, processing and reporting are given based on the survey results and review of the literature. These technical recommendations are aimed towards increased inter-site harmonization, a first step towards standardization of renal BOLD MRI protocols across sites. We expect this to be an iterative process updated dynamically based on progress in the field.

Consensus-based technical recommendations for clinical translation of renal ASL MRI.

OBJECTIVES: This study aimed at developing technical recommendations for the acquisition, processing and analysis of renal ASL data in the human kidney at 1.5 T and 3 T field strengths that can promote standardization of renal perfusion measurements and facilitate the comparability of results across scanners and in multi-centre clinical studies. METHODS: An international panel of 23 renal ASL experts followed a modified Delphi process, including on-line surveys and two in-person meetings, to formulate a series of consensus statements regarding patient preparation, hardware, acquisition protocol, analysis steps and data reporting. RESULTS: Fifty-nine statements achieved consensus, while agreement could not be reached on two statements related to patient preparation. As a default protocol, the panel recommends pseudo-continuous (PCASL) or flow-sensitive alternating inversion recovery (FAIR) labelling with a single-slice spin-echo EPI readout with background suppression and a simple but robust quantification model. DISCUSSION: This approach is considered robust and reproducible and can provide renal perfusion images of adequate quality and SNR for most applications. If extended kidney coverage is desirable, a 2D multislice readout is recommended. These recommendations are based on current available evidence and expert opinion. Nonetheless they are expected to be updated as more data become available, since the renal ASL literature is rapidly expanding.

Vasoactive Intestinal Polypeptide-Expressing Interneurons in the Hippocampus Support Goal-Oriented Spatial Learning.

Diverse computations in the neocortex are aided by specialized GABAergic interneurons (INs), which selectively target other INs. However, much less is known about how these canonical disinhibitory circuit motifs contribute to network operations supporting spatial navigation and learning in the hippocampus. Using chronic two-photon calcium imaging in mice performing random foraging or goal-oriented learning tasks, we found that vasoactive intestinal polypeptide-expressing (VIP+), disinhibitory INs in hippocampal area CA1 form functional subpopulations defined by their modulation by behavioral states and task demands. Optogenetic manipulations of VIP+ INs and computational modeling further showed that VIP+ disinhibition is necessary for goal-directed learning and related reorganization of hippocampal pyramidal cell population dynamics. Our results demonstrate that disinhibitory circuits in the hippocampus play an active role in supporting spatial learning. VIDEO ABSTRACT.