Alexander Ksendzovsky

Brain tumors exhibit extensive metabolic reprogramming that supports proliferation, invasion, therapeutic resistance, and adaptation to dynamic microenvironmental conditions. These alterations provide opportunities for metabolic imaging approaches that extend beyond conventional anatomical neuroimaging. Hyperpolarized magnetic resonance imaging (hpMRI) has emerged as a novel metabolic imaging platform capable of non-invasively visualizing real-time cellular metabolism through dynamic nuclear polarization of carbon-13-labeled substrates. By dramatically enhancing magnetic resonance signal intensity, hpMRI enables interrogation of enzyme-specific metabolic pathways and provides unique insight into tumor energetics, metabolic heterogeneity, and treatment response. The distinct contribution of this review is an updated, brain tumor-specific, clinically oriented framework that integrates recent human evidence with longitudinal metabolic phenotyping, emerging pathway-specific probes, acquisition standardization, multimodal validation, and the remaining barriers to clinical implementation. Particular emphasis is placed on hyperpolarized [1-¹³C]pyruvate, which has demonstrated feasibility and safety in patients with gliomas and has enabled assessment of glycolytic metabolism, oxidative phosphorylation, tumor recurrence, and longitudinal treatment response. Serial changes in lactate and bicarbonate flux may also reflect evolution toward more glycolytic, heterogeneous, and treatment-resistant tumor phenotypes, supporting the potential prognostic value of hpMRI before conventional radiographic progression becomes evident. We also review emerging applications involving α-ketoglutarate metabolism, redox biology, glutathione cycling, perfusion imaging, and molecular characterization of clinically relevant alterations including IDH1, TERT, and c-MYC-associated metabolic programs. In addition, we discuss recent advances in acquisition methods, image standardization, and multimodal integration with conventional MRI and positron emission tomography. Although several technical and logistical challenges remain, hpMRI is an investigational, radiation-free metabolic imaging modality with potential applications in diagnosis, molecular stratification, and treatment monitoring; however, substantial technical, regulatory, logistical, and economic barriers currently limit routine clinical use, molecular stratification, therapeutic monitoring, and precision medicine approaches in neuro-oncology. Continued clinical translation and development of novel metabolic probes may further expand its role in brain tumors and other neurological diseases.

Thirty percent of epilepsy patients have seizures despite best medical therapy. While epilepsy surgery has emerged as a promising treatment option for these patients, surgical outcomes vary considerably between patients and have not significantly improved over the years. These stagnant outcomes can be attributed to poor seizure onset zone and epileptic network localization with currently available tools. Lactate production is a well-known consequence of metabolic reprogramming and biomarker in epilepsy. Detection of lactate elevations using conventional magnetic resonance spectroscopy has been extensively studied as an effective tool to non-invasively detect epileptic brain tissue. However, this method suffers from poor spatial resolution, which limits its clinical utility in pre-surgical resection mapping. In this study, we explore the utility of a recently developed approach, magnetic resonance spectroscopy and spectroscopic imaging of hyperpolarized [1-13C]pyruvate, to identify epileptic tissues via detection of increased lactate production. We found that this approach accurately identifies elevated lactate production in an in vitro model of chronic hyperactivity and in the gold standard mouse epilepsy model, pentylenetetrazol kindling. These data suggest that magnetic resonance spectroscopic imaging of hyperpolarized [1-13C]pyruvate has the potential to effectively and non-invasively map epileptic foci and should be further explored as a clinical tool to guide epilepsy resection surgery by identifying epileptic tissue in patients.

Over the last two decades, it has become increasingly clear that epilepsy is a network disorder. However, it is unclear whether these networks are established only during seizures or persist interictally. The goal of this study was to identify whether functional seizure networks exist interictally and evaluate if there is a structural basis to these networks. We identified four patients with mesial temporal lobe epilepsy who underwent resective epilepsy surgery. We estimated functional and structural connectivity across intracranial electrode contacts involved in seizure onset, early spread, and uninvolved controls. Across all interictal epochs considered, we found higher functional and white matter connectivity across cortical regions involved in seizure spread. Additionally, we observed that the patient in our cohort with the best seizure outcome had the highest functional connectivity across seizure contacts. Functional connectivity findings suggest the presence of an interictal seizure network that parallels underlying structural connectivity. Furthermore, our findings suggest that disruption or ablation of highly connected seizure regions may be necessary to achieve improved post-operative seizure freedom.

Objective Pentylenetetrazol (PTZ) kindling is a widely used model for inducing epileptogenesis and evaluating long-term seizure susceptibility differences among animals. This model is typically performed by chronic, repetitive exposures to a constant subconvulsive PTZ dose. However, the effectiveness of the commonly used subconvulsive dose (35mg/kg) varies among different animal groups and experimental conditions due to factors such as species, age, sex, and genetic background. The objective of this study was to characterize a novel model of kindling, the PTZ Dose Escalation (PTZ-DE) model, which assesses chronic seizure threshold with enhanced sensitivity by empirically determining the minimally effective dose to induce PTZ kindling for specific experimental conditions. Methods This study investigated the efficacy and validity of the PTZ-DE model by comparing its performance to the standard PTZ kindling approach across a series of conditions. First, the ability of the PTZ-DE model to produce the gradual increase in chronic seizure severity response characteristic of PTZ kindling was compared to the standard model across animal background characteristics (strain, sex). Next, the validity of this model was investigated by determining if the PTZ-DE model could replicate similar changes in chronic seizure susceptibility previously published using the standard approach after traumatic brain injury (TBI). Lastly, the PTZ-DE model’s efficacy to detect seizure differences was measured in a condition (glyburide treatment) in which alterations to chronic seizure susceptibility were not detected with standard kindling. Results This study found that the PTZ-DE model corrects for background differences in PTZ susceptibility, replicates known differences in chronic seizure thresholds after TBI, and identifies new alterations in seizure threshold not detected with traditional kindling methods. Significance The PTZ-DE model may prove to be a superior tool to standard PTZ kindling for discovering new pathological mechanisms of epileptogenesis and for developing targeted therapies for chronic seizure management, as evidenced by its ability to detect subtle differences in seizure susceptibility across various experimental conditions.

Recent technological advances in intracranial brain stimulation have enhanced the potential of neuromodulation for addressing neuropsychiatric disorders. We present a review of the methodology and the preliminary outcomes of the pioneering studies exploring intracranial biomarker detection and closed-loop neuromodulation to modulate high-symptom severity states in neuropsychiatric disorders. We searched PubMed, Scopus, Web of Science, Embase, and PsycINFO/PsycNet, followed by the reference and citation lists of retrieved articles. This search strategy yielded a total of 583 articles, of which 5 articles met the inclusion criteria, focusing on depression, obsessive-compulsive disorder, post-traumatic stress disorder, and binge eating disorder. We discuss the methodology of biomarker identification, the biomarkers identified, and the preliminary treatment outcomes for closed-loop neuromodulation. Successful biomarker identification hinges on investigating across various setting. Targeted neuromodulation, either directed at the biomarker or within its associated neural network, offers a promising treatment approach. Future research should seek to understand the mechanisms underlying the effects of neuromodulation as well as the long-term viability of these treatment effects across different neuropsychiatric conditions.

Trauma to the brain can induce a contusion characterized by a discrete intracerebral or diffuse interstitial hemorrhage. In humans, “computed tomography-positive,” that is, hemorrhagic, temporal lobe contusions (tlCont) have unique sequelae. TlCont confers significantly increased odds for moderate or worse disability and the inability to return to baseline work capacity compared to intra-axial injuries in other locations. Patients with tlCont are at elevated risks of memory dysfunction, anxiety, and post-traumatic epilepsy due to involvement of neuroanatomical structures unique to the temporal lobe including the amygdala, hippocampus, and ento-/perirhinal cortex. Because of the relative inaccessibility of the temporal lobe in rodents, no preclinical model of tlCont has been described, impeding progress in elucidating the specific pathophysiology unique to tlCont. Here, we present a minimally invasive mouse model of tlCont with the contusion characterized by a traumatic interstitial hemorrhage. Mortality was low and sensorimotor deficits (beam walk, accelerating rotarod) resolved completely within 3–5 days. However, significant deficits in memory (novel object recognition, Morris water maze) and anxiety (elevated plus maze) persisted at 14–35 days and nonconvulsive electroencephalographic seizures and spiking were significantly increased in the hippocampus at 7–21 days. Immunohistochemistry showed widespread astrogliosis and microgliosis, bilateral hippocampal sclerosis, bilateral loss of hippocampal and cortical inhibitory parvalbumin neurons, and evidence of interhemispheric connectional diaschisis involving the fiber bundle in the ventral corpus callosum that connects temporal lobe structures. This model may be useful to advance our understanding of the unique features of tlCont in humans.

Glioma-related epilepsy (GRE) is a hallmark clinical presentation of gliomas with significant impacts on patient quality of life. The current standard of care for seizure management is comprised of anti-seizure medications (ASMs) and surgical resection. Seizures in glioma patients are often drug-resistant and can often recur after surgery despite total tumor resection. Therefore, current research is focused on the pro-epileptic pathological changes occurring in tumor cells and the peritumoral environment. One important contribution to seizures in GRE patients is metabolic reprogramming in tumor and surrounding cells. This is most evident by the significantly heightened seizure rate in patients with isocitrate dehydrogenase mutated (IDH^mut) tumors compared to patients with IDH wildtype (IDH^wt) gliomas. To gain further insight into glioma metabolism in epileptogenesis, this review compares the metabolic changes inherent to IDH^mut vs. IDH^wt tumors and describes the pro-epileptic effects these changes have on both the tumor cells and the peritumoral environment. Understanding alterations in glioma metabolism can help to uncover novel therapeutic interventions for seizure management in GRE patients.