Catherine Oppenheim

Anorexia nervosa (AN) is a severe psychiatric disorder with high relapse rates despite successful weight restoration. Altered reward processing and an imbalance between goal-directed and habitual control within the striatum have been proposed to contribute to the persistence of maladaptive behaviours, but the striatal mechanisms underlying recovery and relapse remain unclear. Here, we combined cross-species structural MRI, including cross-sectional analyses in mice and longitudinal neuroimaging and clinical assessments in patients with AN, to investigate striatal alterations associated with recovery. Male mice with deletion of the vesicular acetylcholine transporter (VAChTcKO; n = 9), a model of maladaptive eating behaviour, showed reduced dorsolateral striatal volume compared with wild-type mice (n=9). At baseline, women with AN (n = 71) showed reduced striatal volumes compared with healthy controls (n = 30). Longitudinally, patients with AN (n = 41) and healthy controls (n = 28) were reassessed, revealing substantial recovery of striatal volumes following weight restoration in AN. Posterior-anterior putamen gradient changes differed according to subsequent remission status, with changes in the right putamen gradient predicting relapse. Striatal gradient changes were also associated with goal-directed and habitual behaviour during the slip-of-action task, response consistency during delay discounting, and circulating ghrelin and desacyl ghrelin concentrations. These findings identify longitudinal putamen reorganization as a candidate marker of vulnerability to relapse and link striatal plasticity, goal-directed and habitual control, reward processing, and metabolic processes in AN.

Background: Major Depressive Disorder is highly prevalent, and approximately 30% of patients develop treatment-resistant depression (TRD). Electroconvulsive therapy (ECT) remains the most effective treatment for TRD. Given the central role of the subcallosal cingulate (SCC) in depression, we investigated whether baseline SCC functional connectivity predicts ECT response and whether default mode network (DMN) connectivity changes are associated with clinical improvement.Methods: In this longitudinal study, 47 patients with TRD undergoing ECT and 25 matched healthy controls (HC) were recruited. Usable resting-state fMRI were available for 30 patients and 22 HC. Depression severity (Montgomery–Åsberg Depression Rating Scale, MADRS) and rs-fMRI were assessed at baseline, after five ECT sessions, and at the end of treatment. SCC functional connectivity was investigated using seed-based and region-of-interest analyses.Results: ECT was associated with a reduced SCC-medial prefrontal cortex connectivity, a core DMN region (pFDR = 0.001). Higher baseline SCC connectivity with a left prefrontal cluster (MNI:–22, 28, 28) was associated with greater clinical improvement (r = 0.59; p = 0.002). This connectivity was positive in remitters, negative in non-remitters, and near zero in HC. Complementary network-level analyses further identified baseline differences between remitters and non-remitters within a PCC-centered DMN subnetwork.Conclusion: SCC- and DMN-related connectivity patterns were associated with ECT responsiveness. The opposite baseline SCC connectivity observed in remitters and non-remitters suggests distinct functional network states linked to treatment outcome. If replicated, these findings may support the development of biomarker-guided neuromodulation strategies aimed at optimizing response to ECT.

A large MRI voxel-based atlas mapped intracranial meningioma distributions, linking location to symptoms, management, and malignancy grade, and provided a standardized spatial reference to anticipate presentation and guide clinical decision-making.

Catatonia is a severe psychomotor syndrome that occurs across psychiatric diagnoses and is increasingly conceptualized as reflecting neurodevelopmental vulnerability. The anterior cingulate cortex (ACC) plays a central role in motor initiation and cognitive–affective integration and displays substantial interindividual variability in its sulcal morphology, which is established prenatally and remains stable across life. In this MRI study, we examined whether ACC sulcal patterns represent a structural trait marker of catatonia. We analyzed high-resolution T1-weighted images from a hospital-based cohort comprising patients with catatonia (N = 109), psychiatric patients without catatonia (N = 323), and healthy controls (N = 91). The presence of the paracingulate sulcus (PCS) in each hemisphere was determined through blinded visual inspection, and regression analyses tested associations with diagnostic group, adjusting for age, sex, scanner type, intracranial volume, and benzodiazepine and antipsychotic exposure. Patients with catatonia exhibited a significantly reduced prevalence of the left PCS and diminished hemispheric asymmetry compared with both non-catatonic patients and healthy controls. These effects were independent of whether catatonia occurred within psychotic or mood disorders. PCS size did not differ across groups, and sulcal pattern did not correlate with catatonia severity among affected individuals. The findings demonstrate that ACC sulcal deviations are specifically associated with catatonia across diagnostic categories, supporting a neurodevelopmental etiology and reinforcing ACC involvement in its pathophysiology. Early-determined sulcal morphology may represent a trait-level marker contributing to vulnerability for catatonia, with implications for early identification, risk stratification, and targeted intervention strategies.

The widely used apparent diffusion coefficient (ADC) threshold of 620 × 10^-6 mm²/s to automatically delineate the ischemic core on diffusion-weighted imaging (DWI) was established in recanalized patients after IV thrombolysis. However, recanalization was assessed 3-6 hours after treatment, which may entail substantial core growth and in turn ADC threshold overestimation, while follow-up imaging was performed at day 30, implying potential infarct shrinkage. Other studies typically used follow-up MRI scans on days 2-5 but did not correct for vasogenic edema, implying potential infarct overestimation. We re-evaluated the ADC threshold in patients with very early recanalization after endovascular therapy (EVT), using 24-hour follow-up MRI and applying edema correction (EC). Consecutive patients with modified Treatment In Cerebral Infarction 2c-3 recanalization within 90 minutes after baseline MRI and who underwent follow-up MRI ≈24 hours were identified from our center's EVT registry (2012-2021). Basilar occlusions and small DWI lesions (24h) were manually delineated on initial DWI (DWI₀) and 24-hour DWI. EC was performed by applying nonlinear coregistration of follow-up MRI onto MRI₀. The intersection between DWI₀ and Infarct_24h was overlaid onto the baseline ADC map. A receiver operating characteristic analysis compared "core" with "noncore" voxels (obtained by varying the ADC threshold) across patients, and the Youden index was computed to determine the optimized ADC threshold (OptADC) without and with EC. Among 1,024 patients, 56 were eligible and included (median age 73 years; 52% female; median [interquartile range (IQR)] NIH Stroke Scale score 12 [8-19], median MRI₀-to-recanalization delay 70.5 [52-81] minutes). The OptADC was 611 × 10^-6 mm²/s (area under the curve = 0.704; sensitivity = 61.6%; specificity = 70.4%; Youden index = 0.320) and 612 × 10^-6 mm²/s without and with EC, respectively. The median (IQR) individual-OptADC was 621.5 (585.5-672.8) × 10^-6 mm²/s. The baseline core volume was significantly (p < 0.001), but only marginally, smaller using the optimized vs the reference ADC threshold (16.4 ± 25 mL and 17.0 ± 26 mL, respectively; volume difference larger than 3 mL in 1 patient only). We revisited the ADC core threshold using a stringent methodology, including EVT-induced ultra-early documented complete recanalization, ≈24-hour follow-up MRI, and EC. The resulting OptADC was marginally smaller than the reference threshold and, accordingly, modestly influenced the measured baseline core volume. The methodological refinements implemented here, including EC, seem essential for future research exploring core ADC.

Auditory–verbal hallucinations (AVHs) are among the most disabling symptoms of schizophrenia and often persist despite the use of adequate antipsychotic treatment. Conventional low-frequency repetitive transcranial magnetic stimulation (rTMS) targeting the T3P3 scalp site has demonstrated limited efficacy, likely due to interindividual variability in AVH-related brain networks. In this multicenter, randomized, double-blind phase 3 trial, 70 patients with drug-resistant AVHs received active 1-Hz rTMS targeted either with an individualized fMRI-based symptom-capture procedure or by using conventional T3P3 localization. fMRI-guided rTMS yielded a greater reduction in Auditory Hallucination Rating Scale (AHRS) scores at one month (mean difference, −5.43; 95% CI, −8.92 to −1.94), and the effects were sustained at three and six months. The number-needed-to-treat for neuroguided rTMS was 3.5. Clinical response was associated with greater E-field overlap with AVH-related networks. These findings demonstrate that fMRI-guided neuronavigation increases rTMS efficacy, thus supporting its use to optimize the treatment of drug-resistant AVHs in schizophrenia.

There is an important need for the development of neuroprotective therapeutic agents that could be combined to reperfusion strategies in acute ischemic stroke to improve patient prognosis. OTR4132 is a polymer of glucose engineered to mimic heparan sulfates (HS), which demonstrated neuroprotective effects in animal models. The aim of this study was to assess the safety of OTR4132 and to identify the highest, and well-tolerated, single dose of OTR4132 in patients with anterior circulation acute ischemic stroke who underwent endovascular thrombectomy (EVT). The MaTRISS study is a multi-center, first-in-man, open-label, dose-escalation study. OTR4132 was administered intra-arterially immediately after EVT recanalization. Dose levels were determined on the basis of preclinical studies. Six doses (from 0.2 to 2.5 mg) were planned to be administered in groups of at least three patients. Each dose escalation was authorized by the data safety monitoring board (DSMB) after reviewing all clinical, biological, and radiological data from a dose group up to 7 days post-administration. Key inclusion criteria were an acute ischemic stroke in the anterior circulation territory and endovascular thrombectomy performed with recanalization (thrombolysis in cerebral infarction [TICI] score of 2b-3) confirmed by angiography. The primary endpoint was the rate of investigational treatment-related severe adverse events occurring from baseline to 7 days after injection. All other safety and efficacy endpoints were exploratory and included all serious and non-serious adverse events, stroke lesion volumes, National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), Modified Barthel Index (BI), and Montreal Cognitive Assessment (MoCA) from baseline up to 3 months. In total, 19 patients were recruited from three centers in France between March 2022 and March 2024 and six different doses of OTR4132 were tested (in n patients): 0.2 mg (3), 0.5 mg (3), 1 mg (3), 1.5 mg (6), 2 mg (3), and 2.5 mg (1). No adverse drug events and no changes in vital signs or laboratory parameters were observed up to 3 months following administration, regardless of administered doses. Four patients presented at least one serious adverse event. None was considered linked to the investigational treatment on the basis of investigator and DSMB assessment. One patient died of intracranial hemorrhagic transformation at 24 h and the causality link between OTR4132 administration and death remained unknown. The highest tolerated dose of OTR4132 was the highest dose administered (i.e., 2.5 mg). These safety results need to be confirmed in a larger multicenter randomized placebo-controlled clinical trial. The trial was first registered in clinicaltrials.gov on 5 September 2019 (NCT04083001).

BACKGROUND: Diagnosing cerebral amyloid angiopathy (CAA) after spontaneous lobar intracerebral hemorrhage has significant clinical implications. A previous postmortem study found that the presence of both subarachnoid hemorrhage (SAH) and hematoma finger-like projections (FLP) on acute-stage computed tomography strongly rules in CAA. In the present study, we assessed the diagnostic value of these imaging markers against histopathologic diagnosis in less severe presentations. METHODS: This retrospective (2002–2022) multicenter study included patients aged ≥45 years with lobar intracerebral hemorrhage of unknown cause, for whom acute-stage computed tomography or magnetic resonance imaging and neuropathological samples from hematoma evacuation or biopsy were available. Centralized consensus reading (2 raters) of imaging and neuropathological data (including Aβ immunohistochemistry) were performed. Analysis was restricted to samples containing at least 10 vessels. The diagnostic performance was evaluated against the neuropathological reference, that is, CAA/no CAA. RESULTS: We analyzed data from 66 patients (age, 65±9 years; men, 33%; hematoma volume, 45±26 mL; death within 1 year, 14%) from 6 French centers. Neuropathological material included samples from hematoma evacuation (n=48) and biopsy (n=18). CAA was present in 38 patients (58%), and FLP and SAH were observed in 29 (44%) and 50 (76%) patients, respectively. FLP had a sensitivity of 0.58 (95% CI, 0.41–0.74) and a specificity of 0.74 (95% CI, 0.54–0.89) for the diagnosis of CAA. SAH demonstrated a high sensitivity of 0.92 (95% CI, 0.78–0.98; negative predictive value=0.80 [0.52–0.96]) but moderate specificity of 0.43 (95% CI, 0.24–0.63). The combined presence of FLP and SAH had a specificity of 0.54 (95% CI, 0.37–0.71) and a sensitivity of 0.79 (95% CI, 0.59–0.92). CONCLUSIONS: This study is the first to evaluate the diagnostic performance of FLP and SAH with histopathologic reference in nonautopsied patients. The results suggest these markers have lower diagnostic performance than previously reported in severe hematomas leading to early death. However, the high sensitivity of SAH suggests its potential clinical utility in ruling out CAA when absent.

Electroconvulsive therapy (ECT) induces hippocampal volume increases in depressed patients, potentially reflecting neuroplasticity. We hypothesized that Neurite Orientation Dispersion and Density Imaging (NODDI) could provide in vivo evidence of hippocampal neuroplasticity following ECT. This longitudinal study evaluated 43 depressed patients undergoing ECT and 24 controls. MRI and clinical assessments were performed at baseline (V1), after 5 sessions (V2), and post-treatment (V3). Evaluations included a 3 T MR-scan with 3DT1-weighted and multi-shell diffusion (b = 200/1500/2500 s/mm², 30/45/60directions) sequences. Q-ball, Diffusion Tensor, and NODDI models provided: axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD), fractional anisotropy (FA), generalized FA (GFA), neurite density index (NDI), isotropic fraction (Fiso), and orientation dispersion index (ODI). FreeSurfer extracted whole hippocampal and subfield volumes from T1-weighted images. Longitudinal changes were assessed with linear mixed-effect models. 107 MRIs from patients and 24 MRIs from controls were analyzed. ECT induced significant bilateral hippocampal volume increases (p < 0.001). Group comparisons showed consistently higher FA, lower GFA and ODI in patients compared to controls at all time-points. Following ECT, significant diffusion changes included decreased hippocampal GFA, FA, AD, MD and Fiso, along with increased ODI and NDI. NDI and Fiso changes were localized to the dentate gyrus but not the hippocampal tail. ECT responders showed a significant right hippocampal volume increase at V2 compared to non-responders. After ECT, hippocampal volume increases are accompanied by bilateral changes in NODDI parameters, particularly in the dentate gyrus, consistent with hippocampal neuroplasticity.

BACKGROUND: In ischemic cerebral small vessel diseases (cSVD), recurrent ischemic stroke is rare (2%–3% per year). Because acute ischemia may not always lead to stroke in cSVD due to the small size of lesions, acute stroke may not reliably reflect ischemic activity or the risk of further clinical worsening, as both incident lacunes and incidental diffusion-weighted imaging–positive lesions can occur without stroke symptoms. We aimed to evaluate the total ischemic activity by measuring the incidence of magnetic resonance imaging (MRI)–proven incident ischemia, independent of the presence of stroke symptoms in a large cohort of cSVD. METHODS: DHU-LAC is an ongoing French multicenter cohort study of MRI-proven ischemic stroke presumably due to cSVD. We report data on patients recruited between June 2018 and October 2023. In DHU-LAC, patients are enrolled within 15 days of stroke onset and are cared for according to current guidelines. During the first 6 months, patients are systematically reassessed clinically and by brain MRI: (1) at any time if stroke symptoms occur and (2) at the end of the period. We defined MRI-proven incident ischemia as either recurrent ischemic stroke or at least 1 incident lacune or incidental diffusion-weighted imaging–positive lesion on brain MRI at 6 months. RESULTS: Two hundred forty-nine patients were included, of whom 172 had available data at both inclusion and after 6 months. They were aged 63±6 years, 28% were women, and 65% had hypertension. Six (3%) had a recurrent ischemic stroke, but 25 more (15%) had at least 1 incident lacune or incidental diffusion-weighted imaging–positive lesion on brain MRI. MRI-proven ischemia occurs about 5× more frequently than ischemic stroke in cSVD. CONCLUSIONS: As data confirming the detrimental clinical effect of both incident lacunes and incidental diffusion-weighted imaging–positive lesions accumulate, MRI-proven incident ischemia may become a plausible outcome for future clinical trials in cSVD. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03552926.