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Background Reducing radiation dose to the hippocampus with hippocampal avoidance prophylactic cranial irradiation (HA-PCI) is proposed to prevent cognitive decline. It has, however, not been investigated whether hippocampal atrophy is actually mitigated by this approach. Here, we determined whether HA-PCI reduces hippocampal atrophy. Additionally, we evaluated neurotoxicity of (HA-)PCI to other brain regions. Finally, we evaluated associations of hippocampal atrophy and brain neurotoxicity with memory decline. Methods High-quality research MRI scans were acquired in the multicenter, randomized phase 3 trial NCT01780675. Hippocampal atrophy was evaluated for 4 months (57 HA-PCI patients and 46 PCI patients) and 12 months (28 HA-PCI patients and 27 PCI patients) after (HA-)PCI. We additionally studied multimodal indices of brain injury. Memory was assessed with the Hopkins Verbal Learning Test–Revised (HVLT-R). Results HA-PCI reduced hippocampal atrophy at 4 months (1.8% for HA-PCI and 3.0% for PCI) and at 12 months (3.0% for HA-PCI and 5.8% for PCI). Both HA-PCI and PCI were associated with considerable reductions in gray matter and normal-appearing white matter, increases in white matter hyperintensities, and brain aging. There were no significant associations between hippocampal atrophy and memory. Conclusions HA-PCI reduces hippocampal atrophy at 4 and 12 months compared to regular PCI. Both types of radiotherapy are associated with considerable brain injury. We did not find evidence for excessive brain injury after HA-PCI relative to PCI. Hippocampal atrophy was not associated with memory decline in this population as measured with HVLT-R. The usefulness of HA-PCI is still subject to debate.

Objective As preservation of cognitive functioning increasingly becomes important in the light of ameliorated survival after intracranial tumor treatments, identification of eloquent brain areas would enable optimization of these treatments. Methods This cohort study enrolled adult intracranial tumor patients who received neuropsychological assessments pre-irradiation, estimating processing speed, verbal fluency and memory. Anatomical magnetic resonance imaging scans were used for multivariate voxel-wise lesion-symptom predictions of the test scores (corrected for age, gender, educational level, histological subtype, surgery, and tumor volume). Potential effects of histological and molecular subtype and corresponding WHO grades on the risk of cognitive impairment were investigated using Chi square tests. P-values were adjusted for multiple comparisons (p Results A cohort of 179 intracranial tumor patients was included [aged 19–85 years, median age (SD) = 58.46 (14.62), 50% females]. In this cohort, test-specific impairment was detected in 20–30% of patients. Higher WHO grade was associated with lower processing speed, cognitive flexibility and delayed memory in gliomas, while no acute surgery-effects were found. No grading, nor surgery effects were found in meningiomas. The voxel-wise analyses showed that tumor locations in left temporal areas and right temporo-parietal areas were related to verbal memory and processing speed, respectively. Interpretation Patients with intracranial tumors affecting the left temporal areas and right temporo-parietal areas might specifically be vulnerable for lower verbal memory and processing speed. These specific patients at-risk might benefit from early-stage interventions. Furthermore, based on future validation studies, imaging-informed surgical and radiotherapy planning could further be improved.

Background and ObjectivesThe risk of developing Alzheimer disease is increased after stroke, and this association may not solely be driven by traditional vascular risk factors. Neuronal death leads to the release of tau proteins, which can become dephosphorylated, rephosphorylated, or hyperphosphorylated in the setting of ischemia, possibly leading to formation of neurofibrillary tangles (NFT). Therefore, a potential synergistic effect between development of tauopathy and cerebrovascular lesion burden may contribute to cognitive decline after stroke. We explored the spatial and temporal distribution of NFT after ischemic stroke in vivo by using18F-MK-6240 PET.MethodsWe included patients with a first ischemic stroke to undergo longitudinal18F-MK-6240 PET/MR within 2–4 weeks and 6 months after stroke. For cross-sectional analyses, we also included age-matched healthy controls. We delineated 5 volumes of interest based on T2 FLAIR and T1 MR data: the ischemic lesion, 3 consecutive peri-ischemic areas, and the remaining ipsilesional hemisphere. We performed region-based voxel-wise partial volume correction on the PET data and calculated standardized uptake value ratios (SUVRs) with the cerebellum as the reference region.ResultsWe did not quantify PET scans of patients within the first month after stroke (n = 17; median age 73 years [interquartile range {IQR}: 62–82 years]) because the signal intensity was influenced by blood-brain barrier breakdown hampering a reliable data analysis. At 6 months after the event (n = 13; median age 71 years [IQR: 60–79 years]),18F-MK-6240 SUVR was increased in the ischemic lesion compared with 20 age-matched healthy controls (median age 71.5 years [IQR: 66–76 years]; ratiolesion/controls= 1.62 ± 0.54; 1-samplettest:p= 0.0015) and gradually decreased in the surrounding tissue (1-way within-subject analysis of variance [F{1.2, 14.8} = 18.0,p= 0.00043]).DiscussionThese findings suggest that NFT may form after ischemic stroke and spread in the peri-ischemic brain parenchyma. Further follow-up is required to gain more insight into the spatial and temporal dynamics of this tauopathy after ischemic stroke.

BACKGROUND: The connectome, constituting a unique fingerprint of a person's brain, may be influenced by its prenatal environment, potentially affecting later-life resilience and mental health. METHODS: We conducted a prospective resting-state functional Magnetic Resonance Imaging study in 28-year-old offspring (N = 49) of mothers whose anxiety was monitored during pregnancy. Two offspring anxiety subgroups were defined: "High anxiety" (n = 13) group versus "low-to-medium anxiety" (n = 36) group, based on maternal self-reported state anxiety at 12-22 weeks of gestation. To predict resting-state functional connectivity of 32 by 32 ROIs, maternal state anxiety during pregnancy was included as a predictor in general linear models for both ROI-to-ROI and graph theoretical metrics. Sex, birth weight and postnatal anxiety were included as covariates. RESULTS: Higher maternal anxiety was associated with weaker functional connectivity of medial prefrontal cortex with left inferior frontal gyrus (t = 3.45, pFDR < 0.05). Moreover, network-based statistics (NBS) confirmed our finding and revealed an additional association of weaker connectivity between left lateral prefontal cortex with left somatosensory motor gyrus in the offspring. While our results showed a general pattern of lower functional connectivity in adults prenatally exposed to maternal anxiety, we did not observe significant differences in global brain networks between groups. CONCLUSIONS: Weaker (medial) prefrontal cortex functional connectivity in the high anxiety adult offspring group suggests a long-term negative impact of prenatal exposure to high maternal anxiety, extending into adulthood. To prevent mental health problems at population level, universal primary prevention strategies should aim at lowering maternal anxiety during pregnancy. ispartof: Brain Imaging And Behavior pages:1-13 ispartof: location:United States status: Published online

Introduction: Machine learning could play a key role in the development of new interventions for bulimia nervosa (BN) and alcohol use disorder (AUD) as it can be used to predict and identify specific triggers of binge behavior in daily life. Therefore, this study has the following two aims. First, to evaluate person-specific and pooled prediction models for binge eating (BE), alcohol use and binge drinking (BD) in daily life. Second, to identify important predictors for these behaviors. Methods: A total of 120 patients (BN: 50; AUD: 51; BN/AUD: 19) participated in an experience sampling study, where over a period of 12 months they reported on their eating and drinking behaviors as well as on several other emotional, behavioral and contextual factors in daily life. The study had a burst-measurement design, where assessments occurred 8 times a day on Thursdays, Fridays, and Saturdays in 7 bursts of 3 weeks. Afterwards, person-specific and pooled models were fit with elastic net regularized regression and evaluated with cross-validation. From these models, the variables with the 10% highest estimates were identified. Results: The person-specific models had a median AUC of 0.61, 0.80, and 0.85 for BE, alcohol use and BD respectively, while the pooled models had a median AUC of 0.70, 0.90, and 0.93. The most important predictors across the different behaviors were craving, and time of day. However, predictors concerning social context and affect differed between BE, alcohol use and BD.Conclusion: This study shows that BE, alcohol use and BD can be predicted in daily life, but that pooled models outperformed person-specific models and that models for alcohol use and BD outperformed those for BE. Future studies should investigate how model performance can be improved and how these models can be used to deliver interventions in daily life.

Introduction: Studies in daily life report that higher levels of positive affect (PA), but not negative affect (NA) are related to craving and alcohol consumption. However, these studies have mostly been performed in non-problematic drinkers. Therefore, this study compares how NA and PA are related to craving, non-heavy alcohol use, and binge drinking (BD) in patients with alcohol use disorder (AUD) and controls.Methods: A total of 53 female patients with AUD and 75 female controls were included in an experience sampling study where they reported on momentary NA, PA, craving, and alcohol use in daily life in a burst-measurement design over a period of 12 months. Assessments occurred eight times a day on Thursdays, Fridays, and Saturdays in seven bursts of three weeks, all separated by 5-week periods of no assessment.Results: Subsequent craving was predicted by NA and PA in a quadratic fashion in patients with AUD, but not in controls. Future non-heavy alcohol use was predicted by lower levels of NA and higher levels of PA in patients with AUD and controls, but also by lower levels of PA in patients with AUD. Subsequent BD was predicted by PA in a quadratic manner in patients with AUD and controls, but also predicted by NA in a quadratic fashion in patients with AUD. Non-heavy alcohol use predicted subsequent lower levels of NA and PA, but this was not the case for BD.Conclusions: These results suggest that the relation between affect and craving or alcohol use is often non-linear in daily life. Furthermore, they show that a worse mood can indeed predict subsequent alcohol use in patients with AUD. However, this could be more pronounced for BD than for non-heavy alcohol use.

A large number of patients with COVID-19 will suffer from long-term smell and taste disorders (STD). These STD symptoms could have a significant impact on patients with an eating disorder (ED). To highlight this issue, a case is presented of a patient with bulimia nervosa who experienced COVID-19-relate STD symptoms. Clinicians should reassess patients with an ED who suffer from COVID-19 with STD symptomatology and potentially redirect treatment. More research is needed on STD symptoms in patients with an ED to improve our knowledge on the role of smell and taste in disordered eating behaviors and improve treatment guidelines.

Deep brain stimulation is an established treatment option for both essential tremor (ET) and Parkinson’s disease (PD), although typically targeting different brain structures. Some patients are diagnosed with comorbid ET and PD. Selecting the optimal stimulation target in these patients is challenging. We present a patient with comorbid ET and PD in whom we used bilaterally a single parietal trajectory to align the dentato-rubro-thalamic tract and the subthalamic nucleus. Although parietal trajectories are challenging, we reached satisfactory outcomes for both conditions without complications. Single-electrode deep brain stimulation of the dentato-rubro-thalamic tract and the subthalamic nucleus through a parietal approach may represent a feasible treatment option in this patient group.

Recent studies suggest an important role of the principal inhibitory neurotransmitter GABA for motor performance in the context of aging. Nonetheless, as previous magnetic resonance spectroscopy (MRS) studies primarily reported resting-state GABA levels, much less is known about transient changes in GABA levels during motor task performance and how these relate to behavior and brain activity patterns. Therefore, we investigated GABA+ levels of left primary sensorimotor cortex (SM1) acquired before, during, and after execution of a unimanual/bimanual action selection task in 30 (human) young adults (YA; age 24.5 ± 4.1, 15 male) and 30 older adults (OA; age 67.8 ± 4.9, 14 male). In addition to task-related MRS data, task-related functional magnetic resonance imaging (fMRI) data were acquired. Behavioral results indicated lower motor performance in OA as opposed to YA, particularly in complex task conditions. MRS results demonstrated lower GABA+ levels in OA as compared with YA. Furthermore, a transient task-related decrease of GABA+ levels was observed, regardless of age. Notably, this task-induced modulation of GABA+ levels was linked to task-related brain activity patterns in SM1 such that a more profound task-induced instantaneous lowering of GABA+ was related to higher SM1 activity. Additionally, higher brain activity was related to better performance in the bimanual conditions, despite some age-related differences. Finally, the modulatory capacity of GABA+ was positively related to motor performance in OA but not YA. Together, these results underscore the importance of transient dynamical changes in neurochemical content for brain function and behavior, particularly in the context of aging.SIGNIFICANCE STATEMENT Emerging evidence designates an important role to regional GABA levels in motor control, especially in the context of aging. However, it remains unclear whether changes in GABA levels emerge when executing a motor task and how these changes relate to brain activity patterns and performance. Here, we identified a transient decrease of sensorimotor GABA+ levels during performance of an action selection task across young adults (YA) and older adults (OA). Interestingly, whereas a more profound GABA+ modulation related to higher brain activity across age groups, its association with motor performance differed across age groups. Within OA, our results highlighted a functional merit of a task-related release from inhibitory tone, i.e. lowering regional GABA+ levels was associated with task-relevant brain activity. ispartof: JOURNAL OF NEUROSCIENCE vol:42 issue:6 pages:1119-1130 ispartof: location:United States status: published

Language dysfunction is common in Alzheimer’s disease. There is increasing interest in the preclinical or asymptomatic phase of Alzheimer’s disease. Here we examined in 35 cognitively intact older adults (age range 52–78 years at baseline, 17 male) in a longitudinal study design the association between accumulation of amyloid over a 5–6-year period, measured using PET, and functional changes in the language network measured over the same time period using task-related functional MRI. In the same participants, we also determined the association between the longitudinal functional MRI changes and a cross-sectional measure of tau load as measured with 18F-AV1451 PET. As predicted, the principal change occurred in posterior temporal cortex. In the cortex surrounding the right superior temporal sulcus, the response amplitude during the associative-semantic versus visuo-perceptual task increased over time as amyloid load accumulated (Pcorrected = 0.008). In a whole-brain voxel-wise analysis, amyloid accumulation was also associated with a decrease in response amplitude in the left inferior frontal sulcus (Pcorrected = 0.009) and the right dorsomedial prefrontal cortex (Pcorrected = 0.005). In cognitively intact older adults, cross-sectional tau load was not associated with longitudinal changes in functional MRI response amplitude. Our findings confirm the central role of the neocortex surrounding the posterior superior temporal sulcus as the area of predilection within the language network in the earliest stages of Alzheimer’s disease. Amyloid accumulation has an impact on cognitive brain circuitry in the asymptomatic phase of Alzheimer’s disease., Using fMRI and amyloid PET in a longitudinal multimodal study, Reinartz et al. reveal functional changes in the language network occurring with increasing amyloid accumulation in an early asymptomatic phase of Alzheimer's disease.

BACKGROUND: Electroconvulsive therapy (ECT) applies electric currents to the brain to induce seizures for therapeutic purposes. ECT increases gray matter (GM) volume, predominantly in the medial temporal lobe (MTL). The contribution of induced seizures to this volume change remains unclear. METHODS: T1-weighted structural MRI was acquired from thirty patients with late-life depression (mean age 72.5 ± 7.9 years, 19 female), before and one week after one course of right unilateral ECT. Whole brain voxel-/deformation-/surface-based morphometry analyses were conducted to identify tissue-specific (GM, white matter: WM), and cerebrospinal fluid (CSF) and cerebral morphometry changes following ECT. Whole-brain voxel-wise electric field (EF) strength was estimated to investigate the association of EF distribution and regional brain volume change. The association between percentage volume change in the right MTL and ECT-related parameters (seizure duration, EF, and number of ECT sessions) was investigated using multiple regression. RESULTS: ECT induced widespread GM volume expansion with corresponding contraction in adjacent CSF compartments, and limited WM change. The regional EF was strongly correlated with the distance from the electrodes, but not with regional volume change. The largest volume expansion was identified in the right MTL, and this was correlated with the total seizure duration. CONCLUSIONS: Right unilateral ECT induces widespread, bilateral regional volume expansion and contraction, with the largest change in the right MTL. This dynamic volume change cannot be explained by the effect of electrical stimulation alone and is related to the cumulative effect of ECT-induced seizures. ispartof: BRAIN STIMULATION vol:14 issue:4 pages:1038-1047 ispartof: location:United States status: published

Background and objectivesBrain damage during early development impacts the brain structural network and its coinciding functions. Here, we explored structural brain connectomes in children with unilateral cerebral palsy and its relation to sensory-motor function using a novel semi-automated graph theory analysis, investigating both hemispheres.MethodsIn 46 children with spastic unilateral cerebral palsy (mean age 10y7m±2y9m, 27 boys, 25 right-sided hemiplegia; Manual Ability Classification System I=15, II=16, III=15) we assessed upper limb somatosensory (two-point discrimination and stereognosis) and motor function (grip force, Assisting Hand Assessment and Jebsen-Taylor Hand Function Test). We collected multi-shell diffusion-weighted, T1-weighted and T2-FLAIR MRI and performed transcranial magnetic stimulation to identify the corticospinal tract (CST) wiring pattern. Structural connectomes were constructed using Desikan-Killiany parcellations with Virtual Brain Grafting and FreeSurfer, and Multi-Shell Multi-Tissue Constrained Spherical Deconvolution diffusion modelling with anatomically constrained tractography. Graph metrics (characteristic path length, global/local efficiency and clustering coefficient) were calculated for the whole brain, the ipsilesional/contralesional hemisphere, and the full/ipsilesional/contralesional sensory-motor network, and were compared between lesion types (periventricular white matter (PWM)=28, cortical and deep grey matter (CDGM)=18) and CST-wiring patterns (ipsilateral=14, bilateral=14, contralateral=12, unknown=6) using ANCOVA with age as covariate. We used elastic-net regularized regression to investigate how graph metrics, lesion volume, lesion type, CST-wiring pattern and age predicted sensory-motor function.ResultsIn both the whole brain and subnetworks, we observed a hyperconnectivity pattern in children with CDGM-lesions compared to PWM-lesions, with higher clustering coefficient (p=[), characteristic path length (p=0.003, ) and local efficiency (p=[0.001-0.02], ), as well as a faster decrease in global efficiency with age (p=[0.01-0.04], ). No differences were found between CST-wiring groups. In general, good predictions of sensory-motor function were obtained with elastic-net regression (R2=0.40-0.87). For motor function, the CST-wiring pattern was identified as the strongest predictor. For somatosensory function all independent variables contributed equally to the model.DiscussionWith this study, we demonstrated the feasibility and potential of structural connectomes using graph theory analysis in understanding disease severity and brain development in children with unilateral cerebral palsy. Hence, this exploratory study could support and direct future research.

Background We examined in cognitively intact older adults the relative weight of cognitive, genetic, structural and amyloid brain imaging variables for predicting cognitive change over a 4-year time course. Methods One hundred-eighty community-recruited cognitively intact older adults (mean age 68 years, range 52–80 years, 81 women) belonging to the Flemish Prevent Alzheimer’s Disease Cohort KU Leuven (F-PACK) longitudinal observational cohort underwent a baseline evaluation consisting of detailed cognitive assessment, structural MRI and 18F-flutemetamol PET. At inclusion, subjects were stratified based on Apolipoprotein E (APOE) ε4 and Brain-Derived Neurotrophic Factor (BDNF) val66met polymorphism according to a factorial design. At inclusion, 15% were amyloid-PET positive (Centiloid >23.4). All subjects underwent 2-yearly follow-up of cognitive performance for a 4-year time period. Baseline cognitive scores were analysed using factor analysis. The slope of cognitive change over time was modelled using latent growth curve analysis. Using correlation analysis, hierarchical regression and mediation analysis, we examined the effect of demographic (age, sex, education) and genetic variables, baseline cognition, MRI volumetric (both voxelwise and region-based) as well as amyloid imaging measures on the longitudinal slope of cognitive change. Results A base model of age and sex explained 18.5% of variance in episodic memory decline. This increased to 41.6% by adding baseline episodic memory scores. Adding amyloid load or volumetric measures explained only a negligible additional amount of variance (increase to 42.2%). A mediation analysis indicated that the effect of age on episodic memory scores was partly direct and partly mediated via hippocampal volume. Amyloid load did not play a significant role as mediator between age, hippocampal volume and episodic memory decline. Conclusion In cognitively intact older adults, the strongest baseline predictor of subsequent episodic memory decline was the baseline episodic memory score. When this score was included, only very limited explanatory power was added by brain volume or amyloid load measures. The data warn against classifications that are purely biomarker-based and highlight the value of baseline cognitive performance levels in predictive models.

It has been argued that symptom onset in neurodegeneration reflects the overload of compensatory mechanisms. The present study aimed to investigate whether neural functional compensation can be observed in the manifest neurodegenerative disease stage, by focusing on a core deficit in frontotemporal dementia, i.e. social cognition, and by combining psychophysical assessment, structural MRI and functional MRI with multidimensional neural markers that allow quantification of neural computations.Nineteen patients with clinically manifest behavioral variant frontotemporal dementia (bvFTD) and 20 controls performed facial expression recognition tasks in the MRI-scanner and offline. Group differences in grey matter volume, neural response amplitude and neural patterns were assessed via a combination of voxel-wise whole-brain, searchlight, and ROI-analyses and these measures were correlated with psychophysical measures of emotion, valence and arousal ratings.Significant group effects were observed only outside task-relevant regions, converging in the caudate nucleus. This area showed a diagnostic neural pattern as well as hyperactivation and stronger neural representation of facial expressions in the bvFTD sample. Furthermore, response amplitude was associated with behavioral arousal ratings.The combined findings reveal converging support for compensatory processes in clinically manifest neurodegeneration, complementing accounts that clinical onset synchronizes with the breakdown of compensatory processes. Furthermore, active compensation may proceed along nodes in intrinsically connected networks, rather than along the more task-specific networks. The findings underscore the potential of distributed multidimensional functional neural characteristics that may provide a novel class of biomarkers with both diagnostic and therapeutic implications, including biomarkers for clinical trials.

Aging may be associated with motor decline that is attributed to deteriorating white matter microstructure of the corpus callosum (CC), among other brain-related factors. Similar to motor functioning, executive functioning (EF) typically declines during aging, with age-associated changes in EF likewise being linked to altered white matter connectivity in the CC. Given that both motor and executive functions rely on white matter connectivity via the CC, and that bimanual control is thought to rely on EF, the question arises whether EF can at least party account for the proposed link between CC-connectivity and motor control in older adults. To address this, diffusion magnetic resonance imaging data were obtained from 84 older adults. A fiber-specific approach was used to obtain fiber density (FD), fiber cross-section (FC), and a combination of both metrics in eight transcallosal white matter tracts. Motor control was assessed using a bimanual coordination task. EF was determined by a domain-general latent EF-factor extracted from multiple EF tasks, based on a comprehensive test battery. FD of transcallosal prefrontal fibers was associated with cognitive and motor performance. EF partly accounted for the relationship between FD of prefrontal transcallosal pathways and motor control. Our results underscore the multidimensional interrelations between callosal white matter connectivity (especially in prefrontal brain regions), EF across multiple domains, and motor control in the older population. They also highlight the importance of considering EF when investigating brain-motor behavior associations in older adults. ispartof: AGING-US vol:14 issue:18 pages:7263-7281 ispartof: location:United States status: published