Clusters Of Voxels Research Articles

P11.11.A VOLUMETRIC AND SPATIAL ANALYSES OF TREATMENT-RELATED INJURY IN GLIOMA

Abstract BACKGROUND As diffuse glioma cannot yet be cured, benefits of therapeutic strategies should be carefully balanced against their burden. Postoperative ischemia is a relatively common adverse event of surgery, which can lead to serious neurological deficits. Radiation therapy (RT) can cause post-RT lesions, which may cause clinical symptoms and can create a therapeutic impasse since they mimic tumor progression. We aimed to explore the spatial and volumetric tumor and treatment characteristics in relation to development of treatment-related effects in glioma. Materials and METHODS We retrospectively included 144 WHO grade II-IV supratentorial glioma cases, which were resected from 2012 till 2014 and had early postoperative MRI with diffusion-weighted imaging (DWI). Tumors were delineated on preoperative contrast-enhanced T1 MRI for high grade gliomas and FLAIR for low grade gliomas. Postoperative ischemia was defined as new, confluent diffusion restriction on postoperative DWI. Post-RT injury was investigated in patients who received RT after first surgery and had at least 6 months of follow-up (FU), and was defined as new or increasing contrast-enhancement that subsequently stabilized or decreased during FU. After manual delineation and non-linear registration to MNI stereotaxic space, all lesions were investigated with regard to size and location of pre-operative tumor, resection cavity, residual tumor and extent of resection (EOR). Voxel-based analysis (VBA) was performed with family-wise error correction for multiple comparisons. RESULTS Postoperative ischemia occurred in 93 of 144 cases and was associated with a larger EOR (P=0.02). Ischemic volume was correlated with a larger preoperative tumor volume (P=0.009) and resection volume (P=0.001). Post-RT injury was found in 25 of 67 analyzed cases and was associated with a larger residual tumor volume (P=0.021) and a smaller EOR (P=0.005). VBA showed an association of the occurrence of post-RT lesions with a cluster of preoperative tumor voxels in the left temporal lobe and clusters of residual tumor voxels in the left temporal and right frontal region. No association in volume or location was found between postoperative ischemia and post-RT lesions. CONCLUSION Adverse events of glioma treatment may be influenced by tumor and treatment volumes. In our population, a larger EOR was associated with the occurrence of postoperative ischemia, and larger tumor and resection volumes were correlated with the volume of ischemia. Additionally, the occurrence of post-RT injury was associated with a larger residual tumor and a smaller EOR, as well as a left temporal preoperative tumor location and a right frontal or left temporal residual tumor location. A thorough examination of spatial and volumetric characteristics of the tumor, treatment and subsequent complications can help elucidate the etiology and guide treatment decisions.

Investigation of Brain Iron in Niemann-Pick Type C: A 7T Quantitative Susceptibility Mapping Study.

While brain iron dysregulation has been observed in several neurodegenerative disorders, its association with the progressive neurodegeneration in Niemann-Pick type C is unknown. Systemic iron abnormalities have been reported in patients with Niemann-Pick type C and in animal models of Niemann-Pick type C. In this study, we examined brain iron using quantitative susceptibility mapping MR imaging in individuals with Niemann-Pick type C compared with healthy controls. A cohort of 10 patients with adolescent- and adult-onset Niemann-Pick type C and 14 age- and sex-matched healthy controls underwent 7T brain MR imaging with T1 and quantitative susceptibility mapping acquisitions. A probing whole-brain voxelwise comparison of quantitative susceptibility mapping between groups was conducted. Mean quantitative susceptibility mapping in the ROIs (thalamus, hippocampus, putamen, caudate nucleus, and globus pallidus) was further compared. The correlations between regional volume, quantitative susceptibility mapping values, and clinical features, which included disease severity on the Iturriaga scale, cognitive function, and the Social and Occupational Functioning Assessment Scale, were explored as secondary analyses. We observed lower volume in the thalamus and voxel clusters of higher quantitative susceptibility mapping in the pulvinar nuclei bilaterally in patients with Niemann-Pick type C compared with the control group. In patients with Niemann-Pick type C, higher quantitative susceptibility mapping in the pulvinar nucleus clusters correlated with lower volume of the thalamus on both sides. Moreover, higher quantitative susceptibility mapping in the right pulvinar cluster was associated with greater disease severity. Our findings suggest iron deposition in the pulvinar nucleus in Niemann-Pick type C disease, which is associated with thalamic atrophy and disease severity. This preliminary evidence supports the link between iron and neurodegeneration in Niemann-Pick type C, in line with existing literature on other neurodegenerative disorders.

The long-term effects of adolescent Δ9-tetrahydrocannabinol on brain structure and function assessed through neuroimaging techniques in male and female rats

Several studies performed on human subjects have examined the effects of adolescent cannabis consumption on brain structure or function using brain imaging techniques. However, the evidence from these studies is usually heterogenous and affected by several confounding variables. Animal models of adolescent cannabinoid exposure may help to overcome these difficulties. In this exploratory study, we aim to increase our understanding of the protracted effects of adolescent Δ9-tetrahydrocannabinol (THC) in rats of both sexes using magnetic resonance (MR) to obtain volumetric data, assess grey and white matter microstructure with diffusion tensor imaging (DTI) and measure brain metabolites with 1H-MR spectroscopy (MRS); in addition, we studied brain function using positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-d-glucose as the tracer. THC-exposed rats exhibited volumetric and microstructural alterations in the striatum, globus pallidus, lateral ventricles, thalamus, and septal nuclei in a sex-specific manner. THC administration also reduced fractional anisotropy in several white matter tracts, prominently in rostral sections, while in vivo MRS identified lower levels of cortical choline compounds. THC-treated males had increased metabolism in the cerebellum and olfactory bulb and decreased metabolism in the cingulate cortex. By contrast, THC-treated females showed hypermetabolism in a cluster of voxels comprising the entorhinal piriform cortices and in the cingulate cortex. These results indicate that mild THC exposure during adolescence leaves a lingering mark on brain structure and function in a sex-dependant manner. Some of the changes found here resemble those observed in human studies and highlight the importance of studying sex-specific effects in cannabinoid research.

Permutation-based true discovery proportions for functional magnetic resonance imaging cluster analysis.

We propose a permutation-based method for testing a large collection of hypotheses simultaneously. Our method provides lower bounds for the number of true discoveries in any selected subset of hypotheses. These bounds are simultaneously valid with high confidence. The methodology is particularly useful in functional Magnetic Resonance Imaging cluster analysis, where it provides a confidence statement on the percentage of truly activated voxels within clusters of voxels, avoiding the well-known spatial specificity paradox. We offer a user-friendly tool to estimate the percentage of true discoveries for each cluster while controlling the family-wise error rate for multiple testing and taking into account that the cluster was chosen in a data-driven way. The method adapts to the spatial correlation structure that characterizes functional Magnetic Resonance Imaging data, gaining power over parametric approaches.

Altered neuronal response to visual food stimuli in adolescents undergoing chronic sleep restriction.

Poor sleep in adolescents can increase the risk of obesity, possibly due to changes in dietary patterns. Prior neuroimaging evidence, mostly in adults, suggests that lacking sleep results in increased response to food cues in reward-processing brain regions. Needed is a clarification of the mechanisms by which food reward processing is altered by the kind of chronic sleep restriction (SR) typically experienced by adolescents. This study aimed to elucidate the impact of sleep duration on response to visual food stimuli in healthy adolescents using functional neuroimaging, hypothesizing increased reward processing response after SR compared to a well-rested condition. Thirty-nine healthy adolescents, 14-17 years old, completed a 3-week protocol: (1) sleep phase stabilization; (2) SR (~6.5 h nightly); and (3) healthy sleep (HS) duration (~9 h nightly). Participants underwent functional MRI while performing a visual food paradigm. Contrasts of food versus nonfood responses were compared within-subject between conditions of SR and HS. Under SR, there was a greater response to food stimuli compared to HS in a voxel cluster including the left ventral tegmental area and substantia nigra. No change in food appeal rating due to the sleep manipulation was detected. Outcomes of this study suggest that SR, as commonly experienced by healthy adolescents, results in the elevated dopaminergic drive of the reward network that may augment motivation to seek food in the context of individual food appeal and inhibitory profiles. Countermeasures that reduce food salience could include promoting consistent HS habits.

Parental education, cognition and functional connectivity of the salience network

The aim was to investigate the association of parental education at birth with cognitive ability in childhood and young adulthood and determine, whether functional connectivity of the salience network underlies this association. We studied participants of the Czech arm of the European Longitudinal Study of Pregnancy and Childhood who underwent assessment of their cognitive ability at age 8 (Wechsler Intelligence Scale for Children) and 28/29 years (Wechsler Adult Intelligence Scale) and measurement with resting state functional MRI at age 23/24. We estimated the associations of parental education with cognitive ability and functional connectivity between the seeds in the salience network and other voxels in the brain. We found that lower education of both mothers and fathers was associated with lower verbal IQ, performance IQ and full-scale IQ of the offspring at age 8. Only mother´s education was associated with performance IQ at age 28/29. Lower mother´s education correlated with greater functional connectivity between the right rostral prefrontal cortex and a cluster of voxels in the occipital cortex, which, in turn, was associated with lower performance IQ at age 28/29. We conclude that the impact of parental education, particularly father´s, on offspring´s cognitive ability weakens during the lifecourse. Functional connectivity between the right rostral prefrontal cortex and occipital cortex may be a biomarker underlying the transmission of mother´s education on performance IQ of their offspring.

Diffusion Tensor and Kurtosis Imaging Findings the First Year following Mild Traumatic Brain Injury.

Despite enormous research interest in diffusion tensor imaging and diffusion kurtosis imaging (DTI; DKI) following mild traumatic brain injury (MTBI), it remains unknown how diffusion in white matter evolves post-injury and relates to acute MTBI characteristics. This prospective cohort study aimed to characterize diffusion changes in white matter the first year after MTBI. Patients with MTBI (n = 193) and matched controls (n = 83) underwent 3T magnetic resonance imaging (MRI) within 72 h and 3- and 12-months post-injury. Diffusion data were analyzed in three steps: 1) voxel-wise comparisons between the MTBI and control group were performed with tract-based spatial statistics at each time-point; 2) clusters of significant voxels identified in step 1 above were evaluated longitudinally with mixed-effect models; 3) the MTBI group was divided into: (A) complicated (with macrostructural findings on MRI) and uncomplicated MTBI; (B) long (1-24 h) and short (< 1 h) post-traumatic amnesia (PTA); and (C) other and no other concurrent injuries to investigate if findings in step 1 were driven mainly by aberrant diffusion in patients with a more severe injury. At 72 h, voxel-wise comparisons revealed significantly lower fractional anisotropy (FA) in one tract and significantly lower mean kurtosis (Kmean) in 11 tracts in the MTBI compared with control group. At 3 months, the MTBI group had significantly higher mean diffusivity in eight tracts compared with controls. At 12 months, FA was significantly lower in four tracts and Kmean in 10 tracts in patients with MTBI compared with controls. There was considerable overlap in affected tracts across time, including the corpus callosum, corona radiata, internal and external capsule, and cerebellar peduncles. Longitudinal analyses revealed that the diffusion metrics remained relatively stable throughout the first year after MTBI. The significant group*time interactions identified were driven by changes in the control rather than the MTBI group. Further, differences identified in step 1 did not result from greater diffusion abnormalities in patients with complicated MTBI, long PTA, or other concurrent injuries, as standardized mean differences in diffusion metrics between the groups were small (0.07 ± 0.11) and non-significant. However, follow-up voxel-wise analyses revealed that other concurrent injuries had effects on diffusion metrics, but predominantly in other metrics and at other time-points than the effects observed in the MTBI versus control group analysis. In conclusion, patients with MTBI differed from controls in white matter integrity already 72 h after injury. Diffusion metrics remained relatively stable throughout the first year after MTBI and were not driven by deviating diffusion in patients with a more severe MTBI.

MRI Statistical region of interest best differentiates impaired from non‐impaired in the Study of Latinos‐Investigation of Neurocognitive Aging‐MRI (SOL‐INCA‐MRI)

AbstractBackgroundWe developed a statistical region of interest (sROI) of gray matter (GM) for which cortical thickness (CT) significantly differed in a “training set” of 100 cognitively normal and 100 individuals with incident dementia in the Framingham Heart Study. sROI significantly predicts incident cognitive impairment and dementia in both FHS and the highly diverse UC Davis Alzheimer’s disease longitudinal cohort. Here we describe a similar analysis of participants of Study of Latinos‐Investigation of Neurocognitive Aging‐MRI (SOL‐INCA‐MRI).MethodsHispanics/Latinos (n=6,377 ages 50‐86) were enrolled in the Study of Latinos ‐ Investigation of Neurocognitive Aging (SOL‐INCA) of which 1,143 also participated in SOL‐INCA‐MRI ancillary study. Cognitive impairment (CI) was defined as any cognitive domain score falling below (&lt;‐1.0 SD) the SOL‐INCA robust internal normative mean and significant cognitive decline (‐0.055 SD/yr), self‐reported cognitive decline and no or minimal functional impairment over 7 years. Participants with dementia were excluded.MRI CT was computed by the DiReCT method. sROI was derived from statistically significant (via 1,000 non‐parametric permutations) clusters of GM voxels having CT group difference t &gt; 2 over the training set (Fig. 1). Extents of sROI overlap with standard atlas GM regions appear in Table 3.Group differences in variables were assessed by t‐test. Logistic regression assessed the impact on cognitive status of MRI factors: total brain, hippocampal, white matter hyperintensities (WMH), sROI volumes and infarction occurrence, controlling for age, sex, education, and background.ResultsThe cohort was 64.4 + 7 years of age, 69% female. Nearly 60% with high school or less education, and 21% CI. Table 1 summarizes demographic and MRI measures for CI and cognitively normal (CN). CI individuals were older, had less education, smaller brains, and greater amounts of WMH. Table 2 summarizes results of logistic regression. Education and sROI mean CT were the only significant predictors of cognitive status.ConclusionCortical thickness within the sROI was strongly associated with cognitive status, even when other commonly used MRI measures were not. sROI may therefore be a sensitive indicator of incipient CI within SOL‐INCA‐MRI where more traditional measures of Alzheimer’s pathology and vascular disease appear insensitive.

Quantifying Extent, the Spatial Distribution of Flortaucipir PET Uptake, in an Autopsy Cohort and its Correspondence to Post‐Mortem Staining of Alzheimer’s Disease Biomarkers

AbstractBackgroundIn Alzheimer’s disease, neurofibrillary tangle (NFT) burden can be characterized in postmortem staining and in vivo NFT‐specific flortaucipir PET by increases in intensity and spatial distribution. Previous work compared intensity based standard uptake value ratios (SUVRs) from Early Tau and MUBADA volumes of interest (VOIs) in detecting Braak stage pathology. We propose a measure called Extent to quantify the spatial distribution of NFT‐specific uptake in flortaucipir PET from the Phase III study AV‐1451‐A16 and compare against Early Tau and MUBADA SUVRs in detecting Braak stage pathology and post‐mortem amyloid burden.MethodsThis retrospective analysis of the AV‐1451‐A16 study included 60 subjects that underwent ante‐mortem flortaucipir imaging and post‐mortem assignment of Braak stages and Thal/CERAD scoring for amyloid burden. The processing of the flortaucipir scans and the recording of neuropathological findings were performed as previously described except cerebellum crustaneous was used as a reference region. Extent was calculated by 1) creating a Z‐score image using 16 young cognitively normal controls, 2) retaining voxel clusters with Z‐scores smaller than a false discovery corrected p‐value of 0.01, and 3) calculating the ratio of the number of surviving voxels against the total number of voxels in the mask. Flortaucipir positivity was defined as greater than 2.5 SD of the mean of young controls for Early Tau and MUBADA SUVRs and as non‐zero for Extent. Amyloid positivity was defined by a Thal/CERAD scoring of 2 or higher and compared to flortaucipir positivity using sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).ResultsExtent detected subjects with flortaucipir positivity comparably to Early Tau in Braak stages I, II, and III while detecting more subjects with flortaucipir positivity in Braak stages V and VI than Early Tau and MUBADA (Table 1 and Figure 1). For amyloid positivity, Extent had the highest sensitivity (79.62%) and NPV (29.42%) while MUBADA had the highest specificity (87.50%) and PPV (97.06%) (Table 2).ConclusionBased on the Correspondence to post‐mortem staining, the Extent measure of flortaucipir spatial distribution may provide benefit over intensity based SUVRs in detecting flortaucipir and amyloid positive subjects for inclusion in future studies.

Neurobiological substrates of chronic low back pain (CLBP): a brain [99mTc]Tc-ECD SPECT study

BackgroundRecent neuroimaging studies have demonstrated pathological mechanisms related to cerebral neuroplasticity in chronic low back pain (CLBP). Few studies have compared cerebral changes between patients with and without pain in the absence of an experimentally induced stimulus. We investigated the neurobiological substrates associated with chronic low back pain using [99mTc]Tc-ECD brain SPECT and correlated rCBF findings with the numeric rating scale (NRS) of pain and douleur neuropathique en 4 questions (DN4). Ten healthy control volunteers and fourteen patients with neuropathic CLBP due to lumbar disc herniation underwent cerebral SPECT scans. A quantitative comparison of rCBF findings between patients and controls was made using the Statistical Parametric Mapping (SPM), revealing clusters of voxels with a significant increase or decrease in rCBF. The intensity of CLBP was assessed by NRS and by DN4. RESULTS: The results demonstrated an rCBF increase in clusters A (occipital and posterior cingulate cortex) and B (right frontal) and a decrease in cluster C (superior parietal lobe and middle cingulate cortex). NRS scores were inversely and moderately correlated with the intensity of rCBF increase in cluster B, but not to rCBF changes in clusters A and C. DN4 scores did not correlate with rCBF changes in all three clusters. CONCLUSIONS: This study will be important for future therapeutic studies that aim to validate the association of rCBF findings with the pharmacokinetic and pharmacodynamic profiles of therapeutic challenges in pain.

Molecular imaging of the brain–heart axis provides insights into cardiac dysfunction after cerebral ischemia

Ischemic stroke imparts elevated risk of heart failure though the underlying mechanisms remain poorly described. We aimed to characterize the influence of cerebral ischemic injury on cardiac function using multimodality molecular imaging to investigate brain and cardiac morphology and tissue inflammation in two mouse models of variable stroke severity. Transient middle cerebral artery occlusion (MCAo) generated extensive stroke damage (56.31 ± 40.39 mm3). Positron emission tomography imaging of inflammation targeting the mitochondrial translocator protein (TSPO) revealed localized neuroinflammation at 7 days after stroke compared to sham (3.8 ± 0.8 vs 2.6 ± 0.7 %ID/g max, p < 0.001). By contrast, parenchyma topical application of vasoconstrictor endothelin-1 did not generate significant stroke damage or neuroinflammatory cell activity. MCAo evoked a modest reduction in left ventricle ejection fraction at both 1 weeks and 3 weeks after stroke (LVEF at 3 weeks: 54.3 ± 5.7 vs 66.1 ± 3.5%, p < 0.001). This contractile impairment was paralleled by elevated cardiac TSPO PET signal compared to sham (8.6 ± 2.4 vs 5.8 ± 0.7%ID/g, p = 0.022), but was independent of leukocyte infiltration defined by flow cytometry. Stroke size correlated with severity of cardiac dysfunction (r = 0.590, p = 0.008). Statistical parametric mapping identified a direct association between neuroinflammation at 7 days in a cluster of voxels including the insular cortex and reduced ejection fraction (ρ = − 0.396, p = 0.027). Suppression of microglia led to lower TSPO signal at 7 days which correlated with spared late cardiac function after MCAo (r = − 0.759, p = 0.029). Regional neuroinflammation early after cerebral ischemia influences subsequent cardiac dysfunction. Total body TSPO PET enables monitoring of neuroinflammation, providing insights into brain–heart inter-organ communication and may guide therapeutic intervention to spare cardiac function post-stroke.

P01.19.A The temporo-parieto-occipital junction in the non-dominant hemisphere as a challenging hub for glioma surgery: functional and oncological outcomes

Abstract Background The temporo-parieto-occipital junction (TPOJ) in the non-dominant hemisphere is a complex region intersected by multiple white matter bundles (Optic radiations, Inferior-fronto-occipital tract, inferior-longitudinalis-tract, superior-longitudinalis-tract, vertical-occipital-tract, medial-dorsal-longitudinal-tract, parietal-aslant-tract), subserving several high-level neurological functions such as spatial recognition, visual agnosia, visual field, attention and working memory. Few data are available on the optimum brain mapping strategy to be adopted for resecting tumors involving this area. Ideally it should allow surgeon to effectively identify several tracts and safely preserve all functions. Material and Methods We developed a proper protocol to approach this complex area integrating, in awake condition, intraoperative visual test (iVT) to mapping visual field, semantic association test (SRAT) to prevent visual agnosia and preserve working memory, hand manipulation task (hMT) to preserve spatial abilities. We reviewed its efficacy in a series of 38 patients with tumors involving non-dominant TPOJ, looking to functional (neurologic-neuropsychological) and oncological (EOR) outcomes. we perform a lesion symptom map and a disconnectome analysis to evaluate what region predict a decline in neuropsychological function and which tract of white brain matter are correlated in the decline of performance. Results Feasibility was high and all patients were able to perform and complete the protocol, which lasted, on the average11 min cortically and 25 min subcortically. Specificity was &amp;gt;95%. Immediate post-operative deficits were documented in 87.4% of patients, permanent in 3.9% (visual field, visual spatial abilities). Attentive and emotional domains were those mostly affected in the neuropsychological evaluation. Lesion symptom mapping and disconnectomic analysis showed that the postoperative decrease in neuropsychological performance was associated with resection of a cluster of voxels corresponding to the anterior portion of the temporo-parietal junction. The white matter tracts mainly involved were the anterior and posterior segment of the middle longitudinal fasciculus (aMdLF and pMdLF) and the parietal aslant tract (PAT). Conclusion Effective and safe resection of tumors involving non-dominant TPOJ is feasible. The adoption of a specific brain mapping protocol in awake setting is recommended to achieve a full functional preservation and extend tumor resection. Further analysis should be performed to assess the role of this subcortical tracts.

Orbito-Frontal Cortex Hypometabolism in Children With Post-COVID Condition (Long COVID): A Preliminary Experience.

We describe 3 children with new-onset neurocognitive problems after coronavirus disease 2019 (COVID-19), that showed, at the brain [18F]-fluorodeoxyglucose positron emission tomography/computed tomography, hypometabolism in the left orbito-frontal region. The voxel-wise analysis confirmed a cluster of hypometabolic voxels in this region with a peak at −18/46/−4mm (179 voxels, T-Score 8.1). These findings may explain neurocognitive symptoms that some children develop after COVID-19 and require further investigations

New Cluster Analysis Method for Quantitative Dynamic Contrast-Enhanced MRI Assessing Tumor Heterogeneity Induced by a Tumor-Microenvironmental Ameliorator (E7130) Treatment to a Breast Cancer Mouse Model.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can provide insight into tumor perfusion. However, a method that can quantitatively measure the intra-tumor distribution of tumor voxel clusters with a distinct range of Ktrans and ve values remains insufficiently explored. Two-dimensional cluster analysis may quantify the distribution of a tumor voxel subregion with a distinct range of Ktrans and ve values in human breast cancer xenografts. Prospective longitudinal study. Twenty-two female athymic nude mice with MCF-7 xenograft, treated with E7130, a tumor-microenvironmental ameliorator, or saline. 9.4 Tesla, turbo rapid acquisition with relaxation enhancement, and spoiled gradient-echo sequences. We performed two-dimensional k-means clustering to identify tumor voxel clusters with a distinct range of Ktrans and ve values on Days 0, 2, and 5 after treatment, calculated the ratio of the number of tumor voxels in each cluster to the total number of tumor voxels, and measured the normalized distances defined as the ratio of the distance between each tumor voxel and the nearest tumor margin to a tumor radius. Unpaired t-tests, Dunnett's multiple comparison tests, and Chi-squared test were used. The largest and second largest clusters constituted 44.4% and 27.5% of all tumor voxels with cluster centroid values of Ktrans at 0.040 min-1 and 0.116 min-1 , and ve at 0.131 and 0.201, respectively. At baseline (Day 0), the average normalized distances for the largest and second largest clusters were 0.33 and 0.24, respectively. E7130-treated group showed the normalized distance of the initial largest cluster decreasing to 0.25, while that of the second largest cluster increasing to 0.31. Saline-treated group showed no change. A two-dimensional cluster analysis might quantify the spatial distribution of a tumor subregion with a distinct range of Ktrans and ve values. 1 TECHNICAL EFFICACY: Stage 1.

Effect of Low-Dose Statins in Addition to Standard Therapy on Brain Perfusion and Neurocognitive Performance in Patients with Major Depressive Disorder

Introduction: Major depressive disorder (MDD) is a prevalent condition which has a well-known association with ischemic cardiomyopathy, probably explained by an inflammatory mediator mechanism. Statins, besides reducing cholesterol production, have pleiotropic effects including anti-inflammatory activity. The goal was to evaluate the effect of statins as an addition to standard therapy on mood status, brain perfusion, and neurocognitive performance in MDD. Methods: We studied 20 MDD patients with brain single-photon emission tomography and Cambridge Neuropsychological Test Automated Battery (CANTAB), half randomized to 10 mg of Rosuvastatin or placebo, in addition to selective serotonin reuptake inhibitors (SSRIs) therapy and being reevaluated 3 months later. The images were compared using Statistical Parametric Mapping; clinical scores (Hamilton Depression Score with 17 items and Beck’s Depression Inventory) as well as neurocognitive parameters were applied as covariances (CoV) to estimate regional cerebral blood flow (rCBF) changes with both therapies. Results: Clinical scores decreased in both groups (p = 0.0001); Beck’s presented a larger decrease with statins. We observed significantly rCBF changes expressed as significant larger clusters of voxels (p < 0.05) in the pre/subgenual anterior cingulate plus orbitofrontal cortex and a small area in the posterior cingulate gyrus in the statins group, whereas it was not observed with placebo, when using clinical scores as CoV. A similar pattern of rCBF changes was present with emotions recognition, attentional, paired associates learning, spatial planning, and working memory tasks. Conclusion: Short-term use of low-dose statins in MDD patients under SSRIs results in important rCBF changes in key mood associated areas to improvement in neurocognitive performance. These findings, even though demonstrated in a small sample, could open a new therapeutic tool in the comprehensive management of this disorder.

Lesion symptom mapping of domain-specific cognitive impairments using routine imaging in stroke

IntroductionThis large-scale lesion-symptom mapping study investigates the necessary neuro-anatomical substrates of 5 cognitive domains frequently affected post stroke: Language, Attention, Praxis, Number, and Memory. This study aims to demonstrate the validity of using routine clinical brain imaging and standard bedside cognitive screening data from a large, real-world patient cohort for lesion-symptom mapping. Patients and methodsBehavioural cognitive screening data from the Oxford Cognitive Screen and routine clinical neuroimaging from 573 acute patients was used in voxel-based lesion-symptom mapping analyses. Patients were classed as impaired or not on each of the subtests within 5 cognitive domains. ResultsDistinct patterns of lesion damage were associated with different domains. Language functions were associated with damage to left hemisphere fronto-temporal areas. Visuo-spatial functions were associated with damage to posterior occipital areas (Visual Field) and the right temporo-parietal region (Visual Neglect). Different memory impairments were linked to distinct voxel clusters within the left insular and opercular cortices. Deficits which were not associated with localised voxels (e.g. executive function, praxis) represent distributed, bilateral functions. DiscussionThe standardised, brief Oxford Cognitive Screen was able to reliably differentiate distinct neural correlates critically involved in supporting domain-specific cognitive abilities. ConclusionBy demonstrating and replicating known brain anatomy correlates within real-life clinical cohorts using routinely collected scans and standard bedside screens, we open up VLSM techniques to a wealth of clinically relevant studies which can capitalise on using existing clinical data.

Enhancing cognitive restructuring with concurrent fMRI-guided neurostimulation for emotional dysregulation–A randomized controlled trial

BackgroundTransdiagnostic clinical emotional dysregulation is a key component of many mental health disorders and offers an avenue to address multiple disorders with one transdiagnostic treatment. In the current study, we pilot an intervention that combines a one-time teaching and practice of cognitive restructuring (CR) with repetitive transcranial magnetic stimulation (rTMS), targeted based on functional magnetic resonance imaging (fMRI). MethodsThirty-seven clinical adults who self-reported high emotional dysregulation were enrolled in this randomized, double-blind, placebo-controlled trial. fMRI was collected as participants were reminded of lifetime stressors and asked to downregulate their distress using CR tactics. fMRI BOLD data were analyzed to identify the cluster of voxels within the left dorsolateral prefrontal cortex (dlPFC) with the highest activation when participants attempted to downregulate, versus passively remember, distressing memories. Participants underwent active or sham rTMS (10 Hz) over the left dlPFC target while practicing CR following emotional induction using recent autobiographical stressors. ResultsReceiving active versus sham rTMS led to significantly higher high frequency heart rate variability during regulation, lower regulation duration during the intervention, and higher likelihood to use CR during the week following the intervention. There were no differences between conditions when administering neurostimulation alone without the CR skill and compared to sham. Participants in the sham versus active condition experienced less distress the week after the intervention. There were no differences between conditions at the one-month follow up. ConclusionThis study demonstrated that combining active rTMS with emotion regulation training for one session significantly enhances emotion regulation and augments the impact of training for as long as a week. These findings are a promising step towards a combined intervention for transdiagnostic emotion dysregulation.

Socioeconomic and cognitive roots of trait anxiety in young adults.

In 54 participants (41% women) from the Czech arm of the European Longitudinal Study of Pregnancy and Childhood, a national birth cohort with prospectively collected data from their birth until young adulthood, we aimed to study the association between early-life socioeconomic deprivation (ELSD), cognitive ability in adolescence, trait anxiety and resting state functional connectivity of the lateral prefrontal cortex (LPFC) in young adulthood. We found that ELSD was associated with lower cognitive ability in adolescence (at age 13) as well as higher trait anxiety in young adulthood (at age 23/24). Higher cognitive ability in adolescence predicted lower trait anxiety in young adulthood. Resting state functional connectivity between the right LPFC and a cluster of voxels including left precentral gyrus, left postcentral gyrus and superior frontal gyrus mediated the relationship between lower cognitive ability in adolescence and higher trait anxiety in young adulthood. These findings indicate that lower cognitive ability and higher trait anxiety may be both consequences of socioeconomic deprivation in early life. The recruitment of the right LPFC may be the underlying mechanism, through which higher cognitive ability may ameliorate trait anxiety.

Fully automated detection of focal cortical dysplasia: Comparison of MPRAGE and MP2RAGE sequences.

The detection of focal cortical dysplasia (FCD) in magnetic resonance imaging is challenging. Voxel-based morphometric analysis and automated FCD detection using an artificial neural network (ANN) integrated into the Morphometric Analysis Program (MAP18) have been shown to facilitate FCD detection. This study aimed to evaluate whether the detection of FCD can be further improved by feeding this approach with magnetization prepared two rapid acquisition gradient echoes (MP2RAGE) instead of magnetization-prepared rapid acquisition gradient echo (MPRAGE) datasets. MPRAGE and MP2RAGE datasets were acquired in a consecutive sample of 32 patients with FCD and postprocessed using MAP18. Visual analysis and, if available, histopathology served as the gold standard for assessing the sensitivity and specificity of FCD detection. Out-of-sample specificity was evaluated in a cohort of 32healthy controls. The sensitivity and specificity of FCD detection were 82.4% and 62.5% for the MPRAGE and 97.1% and 34.4% for the MP2RAGE sequences, respectively. Median volumes of true-positive voxel clusters were .16ml for the MPRAGE and .52ml for the MP2RAGE sequences compared to .08- and .04-ml volumes of false-positive clusters. With regard to cluster volumes, FCD detection was substantially improved for the MP2RAGE data when the estimated optimal threshold of .23ml was applied (sensitivity = 72.9%, specificity = 83.0%). In contrast, the estimated optimal threshold of .37ml for the MPRAGE data did not improve FCD lesion detection (sensitivity = 42.9%, specificity = 79.5%). In this study, the sensitivity of FCD detection by morphometric analysis and an ANN integrated into MAP18 was higher for MP2RAGE than for MPRAGE sequences. Additional usage of cluster volume information helped to discriminate between true- and false-positive MP2RAGE results.

Soundtrack of life: An fMRI study

Most people have a soundtrack of life, a set of special musical pieces closely linked to certain biographical experiences. Autobiographical memories (AM) and music listening (ML) involve complex mental processes ruled by differentiate brain networks. The aim of the paper was to determine the way both networks interact in linked occurrences. We performed an fMRI experiment on 31 healthy participants (age: 32.4 ± 7.6, 11 men, 4 left-handers). Participants had to recall AMs prompted by music they reported to be associated with personal biographical events (LMM: linked AM-ML events). In the main control task, participants were prompted to recall emotional AMs while listening known tracks from a pool of popular music (UMM: unlinked AM-ML events). We wanted to investigate to what extent LMM network exceeded the overlap of AM and ML networks by contrasting the activation obtained in LMM versus UMM. The contrast LMM>UMM showed the areas (at P < 0.05 FWE corrected at voxel level and cluster size>20): right frontal inferior operculum, frontal middle gyrus, pars triangularis of inferior frontal gyrus, occipital superior gyrus and bilateral basal ganglia (caudate, putamen and pallidum), occipital (middle and inferior), parietal (inferior and superior), precentral and cerebellum (6, 7 L, 8 and vermis 6 and 7). Complementary results were obtained from additional control tasks. Provided part of tLMM>UMM areas might not be related to ML-AM linkage, we assessed LMM brain network by an independent component analysis (ICA) on contrast images. Results from ICA suggest the existence of a cortico-ponto-cerebellar network including left precuneus, bilateral anterior cingulum, parahippocampal gyri, frontal inferior operculum, ventral anterior part of the insula, frontal medial orbital gyri, caudate nuclei, cerebellum 6 and vermis, which might rule the ML-induced retrieval of AM in closely linked AM-ML events. This topography may suggest that the pathway by which ML is linked to AM is attentional and directly related to perceptual processing, involving salience network, instead of the natural way of remembering typically associated with default mode network.