Anterior insula and inferior frontal gyrus: where ventral and dorsal visual attention systems meet

The clinical link between spatial and non-spatial attentional aspects in patients with hemispatial neglect is well known; in particular, an increase in alerting can transitorily help to allocate attention towards the contralesional side. In models of attention, this phenomenon is postulated to rely on an interaction between ventral and dorsal cortical networks, subtending non-spatial and spatial attentional aspects, respectively. However, the exact neural underpinnings of the interaction between these two networks are still poorly understood. In the present study, we included 80 right-hemispheric patients with subacute stroke (50% women; age range: 24–96), 33 with and 47 without neglect, as assessed by paper–pencil cancellation tests. The patients performed a computerized task in which they were asked to respond as quickly as possible by button-press to central targets, which were either preceded or not preceded by non-spatial, auditory warning tones. Reaction times in the two different conditions were measured. In neglect patients, a warning tone, enhancing activity within the ventral attentional ‘alerting’ network, could boost the reaction (in terms of shorter reaction times) of the dorsal attentional network to a visual stimulus up to the level of patients without neglect. Critically, using voxel-based lesion-symptom mapping analyses, we show that this effect significantly depends on the integrity of the right anterior insula and adjacent inferior frontal gyrus, i.e., right-hemispheric patients with lesions involving these areas were significantly less likely to show shorter reaction times when a warning tone was presented prior to visual target appearance. We propose that the right anterior insula and inferior frontal gyrus are a critical hub through which the ventral attentional network can ‘alert’ and increase the efficiency of the activity of the dorsal attentional network.

Cortical Thinning and Neuropsychologic Measures Predict CD19 CAR T Cell Therapy-Associated Neurotoxicity

Introduction: CD19-directed chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), inducing complete remission in 70-90% of patients. Importantly, 40% of patients receiving CD19 CAR T cell therapy develop immune effector cell-associated neurotoxicity syndrome (ICANS), which manifests clinically as confusion, delirium, aphasia and seizures. The neurologic and immune mechanisms of ICANS remain poorly understood, and identifying biomarkers of ICANS are critical to develop strategies to mitigate or prevent this serious side effect. Methods: In an ongoing prospective, longitudinal study, we report on 11 patients with relapsed ALL (ages 6-19 years, 7 males) who received CD19 CAR T cell therapy and underwent serial comprehensive assessments including multimodal magnetic resonance imaging (MRI) of the brain (anatomical, perfusion, diffusion tensor imaging and MR spectroscopy) and neuropsychological testing. Extensive neuropsychological testing of a wide range of cognitive functions was performed. Time points for data collection included: 1) at baseline, prior to lymphodepleting (LD) chemotherapy, consisting of fludarabine and cyclophosphamide, and post-CD19 CAR T cell infusion, 2) on day 10, at peak ICANS (if applicable), and 3) at day 28, upon resolution of cytokine release syndrome (CRS) and ICANS. In addition, multimodal MRI and neuropsychological tests were acquired in 14 healthy controls (ages 5-20 years, 5 males), at one time point as baseline. The MRI data were acquired on a 3T Philips MR scanner using a 32 channel head coil without the use of sedatives or contrast agents. All MRI data were processed blinded to the participant diagnosis and the order of data acquisition. Results: In our cohort of 11 patients, 7 developed cytokine release syndrome and 4 developed ICANS (Table 1). At baseline, patients relative to controls had thinner cortices across the entire brain (Fig.1A). Patients who developed ICANS, compared to those who did not, had additional cortical thinning in the frontal, anterior cingulate, anterior temporal, dorsal parietal, and posterior cingulate cortices (Fig.1B), which together constitute the dorsal attentional network. Consistent with the thinning of attentional cortices, baseline neuropsychological assessments of patients who developed ICANS relative to those who did not revealed worse scores in the measures of inattention (p=0.025), ADHD (p=0.038), and panic disorder (p=0.016), as well as impaired working memory represented by poorer performance on the backward digit span (p=0.038) and digit total (p=0.01) tasks. Regions in the dorsal attentional network demonstrated further cortical thinning on day 10 post-infusion and rebounded to baseline values by day 28 post-infusion in most, but not all patients (Fig.1B). Conclusions: MRI findings revealed that all patients demonstrated global thinning of the cortex at baseline, likely secondary to prior chemotherapy and/or radiation therapy for ALL. These findings were more pronounced in patients who later developed ICANS and were concentrated in the area of the dorsal attentional network of the brain. This was recapitulated in baseline neuropsychological assessments which revealed deficits in attention and working memory in patients who later developed ICANS. In addition, patients with ICANS had additional cortical thinning by day 10 post-CAR T cell infusion, yet had the least cortical reserve to withstand such changes. Although most patients returned to baseline cortical thickness by day 28, which was coincident with ICANS resolution, a subset of patients failed to return to baseline cortical thickness, and we predict that these may be the patients at highest risk for long term brain changes and associated cognitive disturbances. We anticipate that the combination of MRI changes in cortical thickness, especially in the dorsal attentional network, and neuropsychologic impairments at baseline could serve as predictive biomarkers for patients who develop ICANS which in turn could allow for future interventional trials designed to mitigate or prevent ICANS in at-risk individuals. Disclosures Pulsipher: Novartis: Honoraria; Jasper: Honoraria; Bellicum: Honoraria; Mesoblast: Honoraria; Miltenyi: Honoraria, Research Funding; Adaptive: Research Funding. Wayne:Kite, a Gilead Company: Research Funding; Servier: Research Funding.

Neuroimaging Studies on Disorders of Consciousness: A Meta-Analytic Evaluation

Neuroimaging tools could open a window on residual neurofunctional activity in the absence of detectable behavioural responses in patients with disorders of consciousness (DOC). Nevertheless, the literature on this topic is characterised by a large heterogeneity of paradigms and methodological approaches that can undermine the reproducibility of the results. To explicitly test whether task-related functional magnetic resonance imaging (fMRI) can be used to systematically detect neurofunctional differences between different classes of DOC, and whether these differences are related with a specific category of cognitive tasks (either active or passive), we meta-analyzed 22 neuroimaging studies published between 2005 and 2017 using the Activation Likelihood Estimate method. The results showed that: (1) active and passive tasks rely on well-segregated patterns of activations; (2) both unresponsive wakeful syndrome and patients in minimally conscious state activated a large portion of the dorsal-attentional network; (3) shared activations between patients fell mainly in the passive activation map (7492 voxels), while only 48 voxels fell in a subcortical region of the active-map. Our results suggest that DOCs can be described along a continuum—rather than as separated clinical categories—and characterised by a widespread dysfunction of brain networks rather than by the impairment of a well functionally anatomically defined one.

Brain activity at rest: a multiscale hierarchical functional organization

Spontaneous brain activity was mapped with functional MRI (fMRI) in a sample of 180 subjects while in a conscious resting-state condition. With the use of independent component analysis (ICA) of each individual fMRI signal and classification of the ICA-defined components across subjects, a set of 23 resting-state networks (RNs) was identified. Functional connectivity between each pair of RNs was assessed using temporal correlation analyses in the 0.01- to 0.1-Hz frequency band, and the corresponding set of correlation coefficients was used to obtain a hierarchical clustering of the 23 RNs. At the highest hierarchical level, we found two anticorrelated systems in charge of intrinsic and extrinsic processing, respectively. At a lower level, the intrinsic system appears to be partitioned in three modules that subserve generation of spontaneous thoughts (M1a; default mode), inner maintenance and manipulation of information (M1b), and cognitive control and switching activity (M1c), respectively. The extrinsic system was found to be made of two distinct modules: one including primary somatosensory and auditory areas and the dorsal attentional network (M2a) and the other encompassing the visual areas (M2b). Functional connectivity analyses revealed that M1b played a central role in the functioning of the intrinsic system, whereas M1c seems to mediate exchange of information between the intrinsic and extrinsic systems.