PURPOSE: Clinical outcomes of patients with CNS lymphomas (CNSLs) are remarkably heterogeneous, yet identification of patients at high risk for treatment failure is challenging. Furthermore, CNSL diagnosis often remains unconfirmed because of contraindications for invasive stereotactic biopsies. Therefore, improved biomarkers are needed to better stratify patients into risk groups, predict treatment response, and noninvasively identify CNSL. PATIENTS AND METHODS: We explored the value of circulating tumor DNA (ctDNA) for early outcome prediction, measurable residual disease monitoring, and surgery-free CNSL identification by applying ultrasensitive targeted next-generation sequencing to a total of 306 tumor, plasma, and CSF specimens from 136 patients with brain cancers, including 92 patients with CNSL. RESULTS: Before therapy, ctDNA was detectable in 78% of plasma and 100% of CSF samples. Patients with positive ctDNA in pretreatment plasma had significantly shorter progression-free survival (PFS, P < .0001, log-rank test) and overall survival (OS, P = .0001, log-rank test). In multivariate analyses including established clinical and radiographic risk factors, pretreatment plasma ctDNA concentrations were independently prognostic of clinical outcomes (PFS HR, 1.4; 95% CI, 1.0 to 1.9; P = .03; OS HR, 1.6; 95% CI, 1.1 to 2.2; P = .006). Moreover, measurable residual disease detection by plasma ctDNA monitoring during treatment identified patients with particularly poor prognosis following curative-intent immunochemotherapy (PFS, P = .0002; OS, P = .004, log-rank test). Finally, we developed a proof-of-principle machine learning approach for biopsy-free CNSL identification from ctDNA, showing sensitivities of 59% (CSF) and 25% (plasma) with high positive predictive value. CONCLUSION: We demonstrate robust and ultrasensitive detection of ctDNA at various disease milestones in CNSL. Our findings highlight the role of ctDNA as a noninvasive biomarker and its potential value for personalized risk stratification and treatment guidance in patients with CNSL. [Media: see text]

Hippocampal theta cycles provide a means to maintain and segregate different goal representations during human wayfinding.

Associative memory enables the encoding and retrieval of relations between different stimuli. To better understand its neural basis, we investigated whether associative memory involves temporally correlated spiking of medial temporal lobe (MTL) neurons that exhibit stimulus-specific tuning. Using single-neuron recordings from patients with epilepsy performing an associative object–location memory task, we identified the object-specific and place-specific neurons that represented the separate elements of each memory. When patients encoded and retrieved particular memories, the relevant object-specific and place-specific neurons activated together during hippocampal ripples. This ripple-locked coactivity of stimulus-specific neurons emerged over time as the patients’ associative learning progressed. Between encoding and retrieval, the ripple-locked timing of coactivity shifted, suggesting flexibility in the interaction between MTL neurons and hippocampal ripples according to behavioral demands. Our results are consistent with a cellular account of associative memory, in which hippocampal ripples coordinate the activity of specialized cellular populations to facilitate links between stimuli.

BACKGROUND AND PURPOSE: New deep brain stimulation leads with electrode contacts that are split along their circumference allow steering of the electrical field in a predefined direction. However, imaging-assisted directional stimulation requires detailed knowledge of the exact orientation of the electrode array. The purpose of this study was to evaluate whether this information can be obtained by rotational 3D fluoroscopy. MATERIALS AND METHODS: Two directional leads were inserted into a 3D-printed plaster skull filled with gelatin. The torsion of the lead tip versus the lead at the burr-hole level was investigated. Then, 3 blinded raters evaluated 12 3D fluoroscopies with random lead orientations. They determined the lead orientation considering the x-ray marker only and considering the overlap of the gaps between the contact segments. Intraclass correlation coefficients and an extended version of the Bland-Altman plot were used to determine interrater reliability and agreement of the measurements of the different raters. RESULTS: Electrode torsion of up to 35° could be demonstrated. Evaluation of the lead rotation considering the x-ray marker only revealed limits of agreement of ±9.37° and an intraclass correlation coefficient of 0.9975. In addition, taking into account the lines resulting from overlapping of the gaps between the electrode segments, the limits of agreement to the mean were ±2.44° and an intraclass correlation coefficient of 0.9998. CONCLUSIONS: In directional deep brain stimulation systems, rotational 3D fluoroscopy combined with the described evaluation method allows for determining the exact orientation of the leads, enabling the full potential of imaging-assisted personalized programming.

Although the free water content within the perilesional T2 hyperintense region should differ between glioblastomas (GBM) and brain metastases based on histological differences, the application of classical MR diffusion models has led to inconsistent results regarding the differentiation between these two entities. Whereas diffusion tensor imaging (DTI) considers the voxel as a single compartment, multicompartment approaches such as neurite orientation dispersion and density imaging (NODDI) or the recently introduced diffusion microstructure imaging (DMI) allow for the calculation of the relative proportions of intra- and extra-axonal and also free water compartments in brain tissue. We investigate the potential of water-sensitive DTI, NODDI and DMI metrics to detect differences in free water content of the perilesional T2 hyperintense area between histopathologically confirmed GBM and brain metastases. Respective diffusion metrics most susceptible to alterations in the free water content (MD, V-ISO, V-CSF) were extracted from T2 hyperintense perilesional areas, normalized and compared in 24 patients with GBM and 25 with brain metastases. DTI MD was significantly increased in metastases (p = 0.006) compared to GBM, which was corroborated by an increased DMI V-CSF (p = 0.001), while the NODDI-derived ISO-VF showed only trend level increase in metastases not reaching significance (p = 0.060). In conclusion, diffusion MRI metrics are able to detect subtle differences in the free water content of perilesional T2 hyperintense areas in GBM and metastases, whereas DMI seems to be superior to DTI and NODDI.