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Significant evidence suggests that misfolded alpha‐synuclein (aSyn), a major component of Lewy bodies, propagates in a prion‐like manner contributing to disease progression in Parkinson's disease (PD) and other synucleinopathies. In fact, timed inoculation of M83 hemizygous mice with recombinant human aSyn preformed fibrils (PFF) has shown symptomatic deficits after substantial spreading of pathogenic alpha‐synuclein, as detected by markers for the phosphorylation of S129 of aSyn. However, whether accumulated toxicity impact human‐relevant cognitive and structural neuroanatomical measures is not fully understood. Here we performed a single unilateral striatal PFF injection in M83 hemizygous mice, and using two assays with translational potential, ex vivo magnetic resonance imaging (MRI) and touchscreen testing, we examined the combined neuroanatomical and behavioral impact of aSyn propagation. In PFF‐injected mice, we observed widespread atrophy in bilateral regions that project to or receive input from the injection site using MRI. We also identified early deficits in reversal learning prior to the emergence of motor symptoms. Our findings highlight a network of regions with related cellular correlates of pathology that follow the progression of aSyn spreading, and that affect brain areas relevant for reversal learning. Our experiments suggest that M83 hemizygous mice injected with human PFF provides a model to understand how misfolded aSyn affects human‐relevant pre‐clinical measures and suggest that these pre‐clinical biomarkers could be used to detect early toxicity of aSyn and provide better translational measures between mice and human disease. [ABSTRACT FROM AUTHOR]

Background: Growing evidence suggests Alzheimer's disease (AD) develops from a complex cascade of events that vary between individuals. Multivariate approaches have the potential to capture the complexity and heterogeneity of pathologies underlying AD in a more holistic manner compared to univariate approaches. Method: The MRI data of 105 older adults with a family history of AD from the PREVENT‐AD dataset were analysed. Forty six of these individuals had the APOE4‐3 genotype (greater risk of developing AD), while 59 subjects had the APOE3‐3 genotype (normal risk). Diffusion‐weighted imaging and multi‐echo magnetization transfer, proton density and T1‐weighted data were used to compute several WM metrics (Fig1 b‐c). We computed the voxel‐wise Mahalanobis distance (D2) in WM between APOE4‐3 individuals and a reference group (APOE3‐3) (Fig1). D2 is a multivariate measure that combines several MRI metrics, accounting for their covariance, and yielding a score indicative of the degree of abnormality at each WM voxel (Fig2). Associations between WM D2 and cognitive performance were then investigated (Fig3). Independent component analysis (ICA) was performed on spatial dimensions and linear regression analyses were conducted between D2 in ICA components and scores on items of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). We then extracted the contribution of each MRI feature to D2 in the regions where significant associations were found. Result: A significant negative association (R = ‐0.36, p = 0.014) was found between D2 in a component corresponding to the splenium of the corpus callosum (CC) and scores on RBANS‐immediate memory (Fig3), indicating a link between a greater degree of WM abnormality and poorer performance. Proton density (MPM_PD) and longitudinal relaxation rate (MPM_R1), potentially indicative of WM loss, contributed most to D2 in this region. Conclusion: Our findings suggest that microstructural alterations in the posterior part of the CC may play a role in memory deficit in older adults who are at greater risk of developing AD. This is in line with other studies that showed a link between CC degeneration and memory impairments in early AD stages.1 1. Qiu et al. (2016). Inter‐hemispheric dysconnectivity in AD and aMCI. Sci.Rep. [ABSTRACT FROM AUTHOR]

Statistical effects of cortical metrics derived from standard T1‐ and T2‐weighted magnetic resonance imaging (MRI) images, such as gray–white matter contrast (GWC), boundary sharpness coefficient (BSC), T1‐weighted/T2‐weighted ratio (T1w/T2w), and cortical thickness (CT), are often interpreted as representing or being influenced by intracortical myelin content with little empirical evidence to justify these interpretations. We first examined spatial correspondence with more biologically specific microstructural measures, and second compared between‐marker age‐related trends with the underlying hypothesis that different measures primarily driven by similar changes in myelo‐ and microstructural underpinnings should be highly related. Cortical MRI markers were derived from MRI images of 127 healthy subjects, aged 18–81, using cortical surfaces that were generated with the CIVET 2.1.0 pipeline. Their gross spatial distributions were compared with gene expression‐derived cell‐type densities, histology‐derived cytoarchitecture, and quantitative R1 maps acquired on a subset of participants. We then compared between‐marker age‐related trends in their shape, direction, and spatial distribution of the linear age effect. The gross anatomical distributions of cortical MRI markers were, in general, more related to myelin and glial cells than neuronal indicators. Comparing MRI markers, our results revealed generally high overlap in spatial distribution (i.e., group means), but mostly divergent age trajectories in the shape, direction, and spatial distribution of the linear age effect. We conclude that the microstructural properties at the source of spatial distributions of MRI cortical markers can be different from microstructural changes that affect these markers in aging. [ABSTRACT FROM AUTHOR]

Background: The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS‐ND) cohort of the pan‐Canadian Consortium on Neurodegeneration in Aging (CCNA) provides imaging on participants following a standardized protocol. This imaging contribution to deep phenotyping is done to study the full spectrum of age‐related dementias in more than 1,100 individuals (50‐90y) with subjective or mild cognitive impairment, Alzheimer's disease, other dementias, or otherwise cognitively unimpaired. To accelerate discovery, we propose to release biomarkers extracted from these acquisitions. Here we present preliminary (N=385, AD=39) preprocessing methods, quality control, and available derivatives of the resting‐state functional (rsfMRI), diffusion weighted (DWI), and structural magnetic resonance images. Method: fMRI data was preprocessed using fMRIprep v20.2.1. Sørensen–Dice similarity measure was computed between individual masks and group templates using our internal BIDS app. Functional connectome of 101 regions from Dictionary of Functional Modes (DiFuMo) 64 dimension atlas were calculated with confounds removed. Mean network connectivity for the Yeo7 networks was summarized from connectomes. DWI data underwent robust quality control and preprocessing using Tractoflow. Bundle extraction and mean metric computation was done using freewater_flow, rbx_flow and tractometry_flow. Structural scans were preprocessed and segmented using iterativeN3 and MAGeT‐brain to obtain subcortical and cerebellar volumes. As a validation, a subset of variables associated with aging in the literature was tested for association with participant age using simple correlation. Result: The functional Dice score was 0.915 (SD=0.017, N=390) and structural was 0.988 (SD=0.004, N=381). Age was significantly associated with mean DMN connectivity (r=‐0.226, p<0.001), bilateral inferior fronto‐occipital fasciculus freewater (r=0.533, p<0.001), and bilateral thalamus volume (r=‐0.243, p<0.001). Conclusion: Derivatives obtained include: functional connectomes using DiFuMo64, network connectivity from Yeo7, DWI measures for major fiber tracts, and segmented subcortical and cerebellar volumes. The results of the quality and validity checks indicate the derivatives would be useful for the study of age‐related dementias. Full quality control and release of the complete COMPASS‐ND preprocessed imaging dataset and derivatives should be completed in 2022. For information on access see ccna‐ccnv.ca. [ABSTRACT FROM AUTHOR]

Progressive cortical volumetric loss following moderate–severe traumatic brain injury (TBI) has been observed; however, regionally specific changes in the structural determinants of cortical volume, namely, cortical thickness (CT) and cortical surface area (CSA), are unknown and may inform the patterns and neural substrates of neurodegeneration and plasticity following injury. We aimed to (a) assess differences in CT and CSA between TBI participants and controls in the early chronic stage post‐injury, (b) describe longitudinal changes in cortical morphometry following TBI, and (c) examine how regional changes in CT and CSA are associated. We acquired magnetic resonance images for 67 participants with TBI at up to 4 time‐points spanning 5 months to 7 years post‐injury, and 18 controls at 2 time‐points. In the early chronic stage, TBI participants displayed thinner cortices than controls, predominantly in frontal regions, but no CSA differences. Throughout the chronic period, TBI participants showed widespread CT reductions in posterior cingulate/precuneus regions and moderate CT increase in frontal regions. Additionally, CSA showed a significant decrease in the orbitofrontal cortex and circumscribed increase in posterior regions. No changes were identified in controls. Relationships between regional cortical changes in the same morphological measure revealed coordinated patterns within participants, whereas correlations between regions with CT and CSA change yielded bi‐directional relationships. This suggests that these measures may be differentially affected by neurodegenerative mechanisms such as transneuronal degeneration following TBI and that degeneration may be localized to the depths of cortical sulci. These findings emphasize the importance of dissecting morphometric contributions to cortical volume change. [ABSTRACT FROM AUTHOR]

Background and purpose: In an era of individualized multiple sclerosis (MS) patient management, biomarkers for accurate prediction of future clinical outcomes are needed. We aimed to evaluate the potential of short‐term magnetic resonance imaging (MRI) atrophy measures and serum neurofilament light chain (sNfL) as predictors of the dynamics of disability accumulation in relapse‐onset MS. Methods: Brain gray and white matter, thalamic, striatal, pallidal and cervical spinal cord volumes, and lesion load were measured over three available time points (mean time span 2.24 ± 0.70 years) for 183 patients (140 relapsing‐remitting [RRMS] and 43 secondary‐progressive MS (SPMS); 123 female, age 46.4 ± 11.0 years; disease duration 15.7 ± 9.3 years), and their respective annual changes were calculated. Baseline sNfL was also measured at the third available time point for each patient. Subsequently, patients underwent annual clinical examinations over 5.4 ± 3.7 years including Expanded Disability Status Scale (EDSS) scoring, the nine‐hole peg test and the timed 25‐foot walk test. Results: Higher annual spinal cord atrophy rates and lesion load increase predicted higher future EDSS score worsening over time in SPMS. Lower baseline thalamic volumes predicted higher walking speed worsening over time in RRMS. Lower baseline gray matter, as well as higher white matter and spinal cord atrophy rates, lesion load increase, baseline striatal volumes and baseline sNfL, predicted higher future hand dexterity worsening over time. All models showed reasonable to high prediction accuracy. Conclusion: This study demonstrates the capability of short‐term MRI metrics to accurately predict future dynamics of disability progression in a real‐world relapse‐onset MS cohort. The present study represents a step towards the utilization of structural MRI measurements in patient care. [ABSTRACT FROM AUTHOR]

Introduction: Fornix deep brain stimulation (fx‐DBS) is under investigation for treatment of Alzheimer's disease (AD). We investigated the anatomic correlates of flashback phenomena that were reported previously during acute diencephalic stimulation. Methods: Thirty‐nine patients with mild AD who took part in a prior fx‐DBS trial (NCT01608061) were studied. After localizing patients' implanted electrodes and modeling the volume of tissue activated (VTA) by DBS during systematic stimulation testing, we performed (1) voxel‐wise VTA mapping to identify flashback‐associated zones; (2) machine learning–based prediction of flashback occurrence given VTA overlap with specific structures; (3) normative functional connectomics to define flashback‐associated brain‐wide networks. Results: A distinct diencephalic region was associated with greater flashback likelihood. Fornix, bed nucleus of stria terminalis, and anterior commissure involvement predicted memory events with 72% accuracy. Flashback‐inducing stimulation exhibited greater functional connectivity to a network of memory‐evoking and autobiographical memory‐related sites. Discussion: These results clarify the neuroanatomical substrates of stimulation‐evoked flashbacks. [ABSTRACT FROM AUTHOR]

Hippocampal circuitry has been posited to be fundamental to positive symptoms in psychosis, but its contributions to other factors important for outcome remains unclear. We hypothesized that longitudinal changes in the hippocampal circuit and concomitant changes of intracortical microstructure are altered in first episode psychosis (FEP) patients and that such changes are associated with negative symptoms and verbal memory. Longitudinal brain scans (2–4 visits over 3–15 months) were acquired for 27 FEP and 29 age‐ and sex‐matched healthy controls. Quantitative T1 maps, sensitive to myelin content, were used to sample the microstructure of the hippocampal subfields and output circuitry (fimbria, alveus, fornix, mammillary bodies), and intracortical regions. Dynamic anatomical covariance in pair‐wise regional trajectories were assessed for each subject, and graph theory was used to calculate a participation coefficient metric that quantifies the similarity/divergence between hippocampal and intracortical microstructure. The mean participation coefficient of the hippocampus was significantly reduced in FEP patients compared with controls, reflecting differences in output hippocampal regions. Importantly, lower participation coefficient of the hippocampal circuit was associated with worse negative symptoms, a relationship that was mediated by changes in verbal memory. This study provides evidence for reduced hippocampal centrality in FEP and concomitant changes in intracortical anatomy. Myelin‐rich output regions of the hippocampus may be an important biological trigger in early psychosis, with cascading effects on broader cortical networks and resultant clinical profiles. [ABSTRACT FROM AUTHOR]

In multiple sclerosis (MS), cortical atrophy is correlated with clinical and neuropsychological measures. We aimed to examine the differences in the temporospatial evolution of cortical thickness (CTh) between MS‐subtypes and to study the association of CTh with T2‐weighted white matter lesions (T2LV) and clinical progression. Two hundred and forty‐three MS patients (180 relapsing–remitting [RRMS], 51 secondary‐progressive [SPMS], and 12 primary‐progressive [PPMS]) underwent annual clinical (incl. expanded disability status scale [EDSS]) and MRI‐examinations over 6 years. T2LV and CTh were measured. CTh did not differ between MS‐subgroups. Higher total T2LV was associated with extended bilateral CTh‐reduction on average, but did not correlate with CTh‐changes over time. In RRMS, CTh‐ and EDSS‐changes over time were negatively correlated in large bilateral prefrontal, frontal, parietal, temporal, and occipital areas. In SPMS, CTh was not associated with the EDSS. In PPMS, CTh‐ and EDSS‐changes over time were correlated in small clusters predominantly in left parietal areas. Increase of brain lesion load does not lead to an immediate CTh‐reduction. Although CTh did not differ between MS‐subtypes, a dissociation in the correlation between CTh‐ and EDSS‐changes over time between RRMS and progressive‐MS was shown, possibly underlining the contribution of subcortical pathology to clinical progression in progressive‐MS. [ABSTRACT FROM AUTHOR]

While numerous studies have used magnetic resonance imaging (MRI) to elucidate normative age‐related trajectories in subcortical structures across the human lifespan, there exists substantial heterogeneity among different studies. Here, we investigated the normative relationships between age and morphology (i.e., volume and shape), and microstructure (using the T1‐weighted/T2‐weighted [T1w/T2w] signal ratio as a putative index of myelin and microstructure) of the striatum, globus pallidus, and thalamus across the adult lifespan using a dataset carefully quality controlled, yielding a final sample of 178 for the morphological analyses, and 162 for the T1w/T2w analyses from an initial dataset of 253 healthy subjects, aged 18–83. In accordance with previous cross‐sectional studies of adults, we observed age‐related volume decrease that followed a quadratic relationship between age and bilateral striatal and thalamic volumes, and a linear relationship in the globus pallidus. Our shape indices consistently demonstrated age‐related posterior and medial areal contraction bilaterally across all three structures. Beyond morphology, we observed a quadratic inverted U‐shaped relationship between T1w/T2w signal ratio and age, with a peak value occurring in middle age (at around 50 years old). After permutation testing, the Akaike information criterion determined age relationships remained significant for the bilateral globus pallidus and thalamus, for both the volumetric and T1w/T2w analyses. Our findings serve to strengthen and expand upon previous volumetric analyses by providing a normative baseline of morphology and microstructure of these structures to which future studies investigating patients with various disorders can be compared. [ABSTRACT FROM AUTHOR]

There is a high prevalence of neurodevelopmental impairments in individuals living with congenital heart disease (CHD) and the neural correlates of these impairments are not yet fully understood. Recent studies have shown that hippocampal volume and shape differences may provide unique biomarkers for neurodevelopmental disorders. The hippocampus is vulnerable to early life injury, especially in populations at risk for hypoxemia or hemodynamic instability such as in neonates with CHD. We compared hippocampal gray and white matter volume and morphometry between youth born with CHD (n = 50) aged 16–24 years and healthy peers (n = 48). We also explored whether hippocampal gray and white matter volume and morphometry are associated with executive function and self‐regulation deficits. To do so, participants underwent 3T brain magnetic resonance imaging and completed the self‐reported Behavior Rating Inventory of Executive Function—Adult version. We found that youth with CHD had smaller hippocampal volumes (all statistics corrected for false discovery rate; q < 0.05) as compared to controls. We also observed significant smaller surface area bilaterally and inward displacement on the left hippocampus predominantly on the ventral side (q < 0.10) in the CHD group that were not present in the controls. Left CA1 and CA2/3 were negatively associated with working memory (p < .05). Here, we report, for the first‐time, hippocampal morphometric alterations in youth born with CHD when compared to healthy peers, as well as, structure–function relationships between hippocampal volumes and executive function. These differences may reflect long lasting alterations in brain development specific to individual with CHD. [ABSTRACT FROM AUTHOR]

Background: The medial temporal lobe (MTL, i.e. hippocampus and adjacent cortices) is particularly vulnerable to age‐related diseases: Alzheimer's disease, other age‐related proteinothies (TDP‐43, AGD, etc) and vascular injury. Yet, the subregional pattern of vulnerability is thought to differ across etiologies; characterizing these differences using high‐resolution MRI may provide more insight in disease processes and better biomarkers. However, substantial differences in subfield definition has hindered the ability to compare results across laboratories or draw robust conclusions (Figure 1). The Hippocampal Subfields Group (HSG) is an international group seeking to remedy this problem by developing a histologically‐valid, reliable, and freely available segmentation protocol for high‐resolution T2‐weighted 3T MRI (http://www.hippocampalsubfields.com) Method: Our workflow consists of five steps: 1) collecting histology samples labeled by multiple expert neuroanatomists to form a novel reference dataset to guide the development of the MRI segmentation protocol, 2) developing boundary definitions for each segment of the hippocampus, (head, body, and tail) and MTL cortices), 3) assessing HSG community agreement with boundary rules via online questionnaires and revising boundary rules based on questionnaire responses, and 4) testing reliability of the protocol definitions on multiple MRI datasets. Result: For both the hippocampal body and head, we have developed a preliminary subfield segmentation protocol (i.e. completed steps 1‐2, see Figure 2 for a histology slice segmented by three anatomists). Step 3 was piloted for the outer boundaries of the body (i.e., the anterior/posterior, medial/lateral, and superior/inferior boundaries) using an online questionnaire describing each of the proposed rules. 29 labs participated and consensus agreement was reached for all rules, with only minor changes being made to improve comprehension and clarity. We are now creating and administering additional questionnaires for assessing agreement of the hippocampal body and head inner boundary rules (e.g., between the CA fields and dentate gyrus). Upon completion of the assessment/revision process for each set of rules, the final phase – reliability testing of the protocol – should begin mid 2020 for the body. Conclusion: Once completed, the harmonized protocol will significantly facilitate cross‐study comparisons thus advancing insight in the role of hippocampal subfields across the lifespan in aging and disease. [ABSTRACT FROM AUTHOR]

Background: The TAUPS2APP Alzheimer's disease (AD) mouse model expresses mutant APPSWE, PSEN2N141I and TAUP301L mutations and displays age‐dependent accumulation of Aβ plaques and neurofibrillary tangles. In humans, abnormal protein accumulation and spreading are related to neurodegenerative processes, most stereotypically in the hippocampus and medial temporal lobe. Prior reports in different AD models have demonstrated various brain structural phenotypes (Grandjean et al.,2016). Here we assess neuroanatomical trajectories in the TAUPS2APP model of AD using longitudinal MRIs. Method: Thirteen C67BL/6 (11f/2m) and seventeen TAUPS2APP (10f/7m) mice underwent T2‐weighted MRI (voxel size 117x147x147 μm, matrix 256x102x120, FoV 3x1.5x1.5 cm, TR=2500 ms TE=50 ms) at 4,9,13,18, and 24 months of age. Data were analyzed following two‐level deformation‐based morphometry pipeline that uses ANTs SyN nonlinear registration. At the first level within subjects' minimum deformation averages are created and estimates of volume change are computed (log Jacobian determinants). Next, a second level average is created out of unbiased within‐subject averages and the Jacobians are resampled into the common space Result: A linear mixed‐effect model with subject as random effect (second order spline fit, sex as a covariate) revealed significant differences in interaction between age and genotype in neuroanatomical trajectory (absolute Jacobian) of bilateral hippocampus, lateral septal area (LSA) and isocortical areas (at False Discovery Rate of 5%, fig.1). TAUPS2APP showed an accelerated overgrowth of hippocampus at young age but larger volumetric decline with age in comparison to non‐TG animals (fig.2a). A similar pattern was observed in LSA (fig.2b). On the contrary in the isocortex, where non‐TG declined with age, TAUPS2APP mice showed volume enlargement (fig. 3c). Conclusion: These data suggest that TAUPS2APP model is characterized by abnormal neuroanatomical trajectory throughout its lifespan relative to controls. While hippocampal atrophy recapitulates clinical markers of late‐onset AD, enlarged cortex that had been reported earlier in some AD mouse models (TgCRND8, APP/J20 and PSAPP) does not. It was suggested that elevated APP levels may affect the rate of local region growth in adult mice ‐ due to space occupancy by amyloidosis and astrogliosis. In line with this Maheswaran et al. had reported a link between transgene expression, age, and volume increase over time (Maheswaran et al., 2009). [ABSTRACT FROM AUTHOR]

Objective: Motivational deficits are prevalent in patients with schizophrenia, persist despite antipsychotic treatment, and predict long-term outcomes. Evidence suggests that patients with greater amotivation have smaller ventral striatum (VS) volumes. We wished to replicate this finding in a sample of older, chronically medicated patients with schizophrenia. Using structural imaging and positron emission tomography, we examined whether amotivation uniquely predicted VS volumes beyond the effects of striatal dopamine D2/3 receptor (D2/3 R) blockade by antipsychotics.Methods: Data from 41 older schizophrenia patients (mean age: 60.2 ± 6.7; 11 female) were reanalysed from previously published imaging data. We constructed multivariate linear stepwise regression models with VS volumes as the dependent variable and various sociodemographic and clinical variables as the initial predictors: age, gender, total brain volume, and antipsychotic striatal D2/3 R occupancy. Amotivation was included as a subsequent step to determine any unique relationships with VS volumes beyond the contribution of the covariates. In a reduced sample (n = 36), general cognition was also included as a covariate.Results: Amotivation uniquely explained 8% and 6% of the variance in right and left VS volumes, respectively (right: β = -.38, t = -2.48, P = .01; left: β = -.31, t = -2.17, P = .03). Considering cognition, amotivation levels uniquely explained 9% of the variance in right VS volumes (β = -.43, t = -0.26, P = .03).Conclusion: We replicate and extend the finding of reduced VS volumes with greater amotivation. We demonstrate this relationship uniquely beyond the potential contributions of striatal D2/3 R blockade by antipsychotics. Elucidating the structural correlates of amotivation in schizophrenia may help develop treatments for this presently irremediable deficit. [ABSTRACT FROM AUTHOR]

Abstract: Neuropathological and in vivo brain imaging studies agree that the cornu ammonis 1 and subiculum subfields of the hippocampus are most vulnerable to atrophy in the prodromal phases of Alzheimer's disease (AD). However, there has been limited investigation of the structural integrity of the components of the hippocampal circuit, including subfields and extra‐hippocampal white matter structure, in relation to the progression of well‐accepted cerebrospinal fluid (CSF) biomarkers of AD, amyloid‐β 1‐42 (Aβ) and total‐tau (tau). We investigated these relationships in 88 aging asymptomatic individuals with a parental or multiple‐sibling familial history of AD. Apolipoprotein (APOE) ɛ4 risk allele carriers were identified, and all participants underwent cognitive testing, structural magnetic resonance imaging, and lumbar puncture for CSF assays of tau, phosphorylated‐tau (p‐tau) and Aβ. Individuals with a reduction in CSF Aβ levels (an indicator of amyloid accretion into neuritic plaques) as well as evident tau pathology (believed to be linked to neurodegeneration) exhibited lower subiculum volume, lower fornix microstructural integrity, and a trend towards lower cognitive score than individuals who showed only reduction in CSF Aβ. In contrast, persons with normal levels of tau showed an increase in structural MR markers in relation to declining levels of CSF Aβ. These results suggest that hippocampal subfield volume and extra‐hippocampal white matter microstructure demonstrate a complex pattern where an initial volume increase is followed by decline among asymptomatic individuals who, in some instances, may be a decade or more away from onset of cognitive or functional impairment. [ABSTRACT FROM AUTHOR]

Background Abnormalities in dopamine (DA) and brain morphology are observed in several neuropsychiatric disorders. However, it is not fully understood how these abnormalities may relate to one another. For such in vivo findings to be used as biomarkers for neuropsychiatric disease, it must be understood how variability in DA relates to brain structure under healthy conditions. We explored how the availability of striatal DA D2/3 receptors (D2/3R) is related to the volume of subcortical brain structures in a sample of healthy humans. Differences in D2/3R availability measured with an antagonist radiotracer ([11C]-raclopride) versus an agonist radiotracer ([11C]-(+)-PHNO) were examined. Methods Data from 62 subjects scanned with [11C]-raclopride (mean age = 38.98 ± 14.45; 23 female) and 68 subjects scanned with [11C]-(+)-PHNO (mean age = 38.54 ± 14.59; 25 female) were used. Subcortical volumes were extracted from T1-weighted images using the Multiple Automatically Generated Templates (MAGeT-Brain) algorithm. Partial correlations were used controlling for age, gender, and total brain volume. Results For [11C]-(+)-PHNO, ventral caudate volumes were positively correlated with BPND in the dorsal caudate and globus pallidus (GP). Ventral striatum (VS) volumes were positively correlated with BPND in the VS. With [11C]-raclopride, BPND in the VS was negatively correlated with subiculum volume of the hippocampus. Moreover, BPND in the GP was negatively correlated with the volume of the lateral posterior nucleus of the thalamus. Conclusion Findings are purely exploratory and presented corrected and uncorrected for multiple comparisons. We hope they will help inform the interpretation of future PET studies where concurrent changes in D2/3R and brain morphology are observed. Hum Brain Mapp 38:5519-5534, 2017. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The developing hippocampus is highly sensitive to chemotherapy and cranial radiation treatments for pediatric cancers, yet little is known about the effects that cancer treatents have on specific hippocampal subfields. Here, we examined hippocampal subfield volumes in 29 pediatric brain tumor survivors treated with cranial radiation and chemotherapy, and 30 healthy developing children and adolescents. We also examined associations between hippocampal subfield volumes and short-term verbal memory. Hippocampal subfields (Cornus Ammonis (CA) 1, CA2-3, dentate gyrus (DG)-CA4, stratum radiatum-lacunosum-moleculare, and subiculum) were segmented using the Multiple Automatically Generated Templates for Different Brains automated segmentation algorithm. Neuropsychological assessment of short-term verbal associative memory was performed in a subset of brain tumor survivors ( N = 11) and typically developing children ( N = 16), using the Children's Memory Scale or Wechsler's Memory Scale-third edition. Repeated measures analysis of variance showed that pediatric brain tumor survivors had significantly smaller DG-CA4, CA1, CA2-3, and stratum radiatum-lacunosum-moleculare volumes compared with typically developing children. Verbal memory performance was positively related to DG-CA4, CA1, and stratum radiatum-lacunosum-moleculare volumes in pediatric brain tumor survivors. Unlike the brain tumor survivors, there were no associations between subfield volumes and memory in typically developing children and adolescents. These data suggest that specific subfields of the hippocampus may be vulnerable to brain cancer treatments, and may contribute to impaired episodic memory following brain cancer treatment in childhood. [ABSTRACT FROM AUTHOR]

The hippocampus is composed of distinct subfields linked to diverse functions and disorders. The subfields can be mapped using high-resolution magnetic resonance images, and their volumes can potentially be used as quantitative phenotypes for genetic investigation of hippocampal function. We estimated the heritability of hippocampus subfield volumes of 465 subjects from the Human Connectome Project (twins and non-twin siblings) using two methods. The first used a univariate model to estimate heritability with and without adjustment for total brain volume (TBV) and ipsilateral hippocampal volume to determine if heritability was uniquely attributable to subfield volume rather than confounds that attributed to global volumes. We observed the right: subiculum, cornu ammonis 2/3, and cornu ammonis 4/dentate gyrus subfields had the highest significant heritability estimates after adjusting for ipsilateral hippocampal volume. In the second analysis, we used a bivariate model to investigate the shared heritability and genetic correlation of the subfield volumes with TBV and ipsilateral hippocampal volume. Genetic correlation demonstrates shared genetic architecture between phenotypes and shared heritability is what proportion of the genetic architecture of one trait is shared by the other. Highest genetic correlations were between subfield volumes and ipsilateral hippocampal volume than with TBV. The pattern was opposite for shared heritability suggesting that subfields share greater proportion of the genetic architecture with TBV than with ipsilateral hippocampal volume. The relationship between the genetic architecture of TBV, hippocampal volume, and of individual subfields should be accounted for when using hippocampal subfield volumes as quantitative phenotypes for imaging genetics studies. Hum Brain Mapp 38:4337-4352, 2017. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Threshold-free cluster enhancement (TFCE) is a sensitive means to incorporate spatial neighborhood information in neuroimaging studies without using arbitrary thresholds. The majority of methods have applied TFCE to voxelwise data. The need to understand the relationship among multiple variables and imaging modalities has become critical. We propose a new method of applying TFCE to vertexwise statistical images as well as cortexwise (either voxel- or vertexwise) mediation analysis. Here we present TFCE_mediation, a toolbox that can be used for cortexwise multiple regression analysis with TFCE, and additionally cortexwise mediation using TFCE. The toolbox is open source and publicly available (). We validated TFCE_mediation in healthy controls from two independent multimodal neuroimaging samples ( N = 199 and N = 183). We found a consistent structure-function relationship between surface area and the first independent component (IC1) of the N-back task, that white matter fractional anisotropy is strongly associated with IC1 N-back, and that our voxel-based results are essentially identical to FSL randomise using TFCE (all PFWE<0.05). Using cortexwise mediation, we showed that the relationship between white matter FA and IC1 N-back is mediated by surface area in the right superior frontal cortex ( PFWE < 0.05). We also demonstrated that the same mediation model is present using vertexwise mediation ( PFWE < 0.05). In conclusion, cortexwise analysis with TFCE provides an effective analysis of multimodal neuroimaging data. Furthermore, cortexwise mediation analysis may identify or explain a mechanism that underlies an observed relationship among a predictor, intermediary, and dependent variables in which one of these variables is assessed at a whole-brain scale. Hum Brain Mapp 38:2795-2807, 2017. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Hippocampal atrophy rate-measured using automated techniques applied to structural MRI scans-is considered a sensitive marker of disease progression in Alzheimer's disease, frequently used as an outcome measure in clinical trials. Using publicly accessible data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we examined 1-year hippocampal atrophy rates generated by each of five automated or semiautomated hippocampal segmentation algorithms in patients with Alzheimer's disease, subjects with mild cognitive impairment, or elderly controls. We analyzed MRI data from 398 and 62 subjects available at baseline and at 1 year at MRI field strengths of 1.5 T and 3 T, respectively. We observed a high rate of hippocampal segmentation failures across all algorithms and diagnostic categories, with only 50.8% of subjects at 1.5 T and 58.1% of subjects at 3 T passing stringent segmentation quality control. We also found that all algorithms identified several subjects (between 2.94% and 48.68%) across all diagnostic categories showing increases in hippocampal volume over 1 year. For any given algorithm, hippocampal 'growth' could not entirely be explained by excluding patients with flawed hippocampal segmentations, scan-rescan variability, or MRI field strength. Furthermore, different algorithms did not uniformly identify the same subjects as hippocampal 'growers,' and showed very poor concordance in estimates of magnitude of hippocampal volume change over time (intraclass correlation coefficient 0.319 at 1.5 T and 0.149 at 3 T). This precluded a meaningful analysis of whether hippocampal 'growth' represents a true biological phenomenon. Taken together, our findings suggest that longitudinal hippocampal volume change should be interpreted with considerable caution as a biomarker. Hum Brain Mapp 38:2875-2896, 2017. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Aβ deposition is a driving force of Alzheimer's disease pathology and can be detected early by amyloid positron emission tomography. Identifying presymptomatic structural brain changes associated with Aβ deposition might lead to a better understanding of its consequences and provide early diagnostic information. In this respect we analyzed measures of cortical thickness and subcortical volumes along with hippocampal, thalamic and striatal shape and surface area by applying novel analysis strategies for structural magnetic resonance imaging. We included 69 cognitively normal elderly subjects after careful clinical and neuropsychological workup. Standardized uptake value ratios (cerebellar reference) for uptake of 11-C-Pittsburgh Compound B (PiB) were calculated from positron emission tomographic data for a cortical measurement and for bilateral hippocampus, thalamus and striatum. Associations to shape, surface area, volume and cortical thickness were tested using regression models that included significant predictors as covariates. Left anterior hippocampal shape was associated with regional PiB uptake ( P < 0.05, FDR corrected), whereas volumes of the hippocampi and their subregions were not associated with cortical or regional PiB uptake (all P > 0.05, FDR corrected). Within the entorhinal cortical region of both hemispheres, thickness was negatively associated with cortical PiB uptake ( P < 0.05, FDR corrected). Hence, localized shape measures and cortical thickness may be potential biomarkers of presymptomatic Alzheimer's disease. [ABSTRACT FROM AUTHOR]

ABSTRACT The advent of high-resolution magnetic resonance imaging (MRI) has enabled in vivo research in a variety of populations and diseases on the structure and function of hippocampal subfields and subdivisions of the parahippocampal gyrus. Because of the many extant and highly discrepant segmentation protocols, comparing results across studies is difficult. To overcome this barrier, the Hippocampal Subfields Group was formed as an international collaboration with the aim of developing a harmonized protocol for manual segmentation of hippocampal and parahippocampal subregions on high-resolution MRI. In this commentary we discuss the goals for this protocol and the associated key challenges involved in its development. These include differences among existing anatomical reference materials, striking the right balance between reliability of measurements and anatomical validity, and the development of a versatile protocol that can be adopted for the study of populations varying in age and health. The commentary outlines these key challenges, as well as the proposed solution of each, with concrete examples from our working plan. Finally, with two examples, we illustrate how the harmonized protocol, once completed, is expected to impact the field by producing measurements that are quantitatively comparable across labs and by facilitating the synthesis of findings across different studies. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Objective: Very preterm-born neonates (24-32 weeks of gestation) are exposed to stressful and painful procedures during neonatal intensive care. Analgesic and sedation therapies are essential, and opiates and benzodiazepines are commonly used. These medications may negatively impact brain development. The hippocampus may be especially vulnerable to the effects of pain and analgesic and/or sedative therapies and contribute to adverse outcomes. The effect of invasive procedures and analgesic-sedative exposure on hippocampal growth was assessed, as was that of hippocampal growth on neurodevelopmental outcome.Methods: A total of 138 neonates (51% male, median gestational age = 27.7 weeks) underwent magnetic resonance imaging and diffusion tensor imaging (DTI) scans, early in life (postmenstrual age [PMA] = 32.3 weeks) and at term-equivalent age (PMA = 40.2 weeks). Volumes and DTI measures of axial diffusivity, radial diffusivity, and mean diffusivity (MD) were obtained from the hippocampus. Cognitive, language, and motor abilities were assessed using the Bayley Scales of Infant Development-III at 18.7 months median corrected age. Models testing the association of invasive procedures with hippocampal volumes and DTI measures accounted for birth gestational age, sex, PMA, dose of analgesics/sedatives (fentanyl, morphine, midazolam), mechanical ventilation, hypotension, and surgeries.Results: Total midazolam dose predicted decreased hippocampal volumes (β = -1.8, p < 0.001) and increased MD (β = 0.002, p = 0.02), whereas invasive procedures did not (β = 0, p > 0.5 each). Lower cognitive scores were associated with hippocampal growth (β = -0.31, p = 0.003), midazolam dose (β = -0.27, p = 0.03), and surgery (β = -8.32, p = 0.04).Interpretation: Midazolam exposure was associated with macro- and microstructural alterations in hippocampal development and poorer outcomes consistent with hippocampal dysmaturation. Use of midazolam in preterm neonates, particularly those not undergoing surgery, is cautioned. [ABSTRACT FROM AUTHOR]

Objective: Serum urate levels have been associated with risk for and progression of Parkinson's disease (PD). Urate-related compounds are therapeutic candidates in neuroprotective efforts to slow PD progression. A urate-elevating agent is currently under investigation as a potential disease-modifying strategy in people with PD. However, PD is a heterogeneous disorder, and genetic variation may explain divergence in disease severity and progression.Methods: We conducted a genome-wide association study to identify gene variant × serum urate interaction effects on the striatal (123) I-ioflupane (DaTscan) binding ratio measured using single photon emission computed tomography in patients with possible PD from the Parkinson's Progression Markers Initiative (PPMI, n = 360). Follow-up analyses were conducted to assess gene variant × serum urate interaction effects on magnetic resonance imaging-derived regional brain volumes and clinical status. We then attempted to replicate our primary analysis in patients who entered the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) with a clinical diagnosis of PD (n = 349).Results: Rs1109303 (T>G) variant within the INPP5K gene on chromosome 17p13.3 demonstrated a genome-wide significant interaction with serum urate level to predict striatal dopamine transporter density among all PPMI participants (n = 359) with possible PD (p = 2.01 × 10(-8) ; after excluding participants with SWEDD [scan without evidence of dopaminergic deficit]: p = 1.12 × 10(-9) ; n = 316). Independent of striatal dopamine transporter density, similar effects on brain atrophy, bradykinesia, anxiety, and depression were observed. No effect was present in the PRECEPT sample at baseline; however, in non-SWEDD PD participants in PRECEPT (n = 309), we observed a significant longitudinal genotype × serum urate interaction effect, consistent in direction with the PPMI sample, on progression of striatal dopamine transporter density over the 22-month follow-up.Interpretation: Genetic profile combined with serum urate level can be used to predict disease severity and potential disease progression in patients with PD. These results may be relevant to therapeutic efforts targeting the urate pathway. [ABSTRACT FROM AUTHOR]

Newer approaches to characterizing hippocampal morphology can provide novel insights regarding cognitive function across the lifespan. We comprehensively assessed the relationships among age, hippocampal morphology, and hippocampal-dependent cognitive function in 137 healthy individuals across the adult lifespan (18-86 years of age). They underwent MRI, cognitive assessments and genotyping for Apolipoprotein E status. We measured hippocampal subfield volumes using a new multiatlas segmentation tool (MAGeT-Brain) and assessed vertex-wise (inward and outward displacements) and global surface-based descriptions of hippocampus morphology. We examined the effects of age on hippocampal morphology, as well as the relationship among age, hippocampal morphology, and episodic and working memory performance. Age and volume were modestly correlated across hippocampal subfields. Significant patterns of inward and outward displacement in hippocampal head and tail were associated with age. The first principal shape component of the left hippocampus, characterized by a lengthening of the antero-posterior axis was prominently associated with working memory performance across the adult lifespan. In contrast, no significant relationships were found among subfield volumes and cognitive performance. Our findings demonstrate that hippocampal shape plays a unique and important role in hippocampal-dependent cognitive aging across the adult lifespan, meriting consideration as a biomarker in strategies targeting the delay of cognitive aging. Hum Brain Mapp 36:3020-3037, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

There are varying, often conflicting, reports with respect to altered striatal volume and morphometry in the major psychoses due to the influences of antipsychotic medications on striatal volume. Thus, disassociating disease effects from those of medication become exceedingly difficult. For the first time, using a longitudinally studied sample of structural magnetic resonance images from patients with childhood onset schizophrenia (COS; neurobiologically contiguous with the adult onset form of schizophrenia), their nonpsychotic siblings (COSSIBs), and novel shape mapping algorithms that are volume independent, we report the familial contribution of striatal morphology in schizophrenia. The results of our volumetric analyses demonstrate age-related increases in overall striatal volumes specific only to COS. However, both COS and COSSIBs showed overlapping shape differences in the striatal head, which normalized in COSSIBs by late adolescence. These results mirror previous studies from our group, demonstrating cortical thickness deficits in COS and COSSIBs as these deficits normalize in COSSIBs in the same age range as our striatal findings. Finally, there is a single region of nonoverlapping outward displacement in the dorsal aspect of the caudate body, potentially indicative of a response to medication. Striatal shape may be considered complimentary to volume as an endophenotype, and, in some cases may provide information that is not detectable using standard volumetric techniques. Our striatal shape findings demonstrate the striking localization of abnormalities in striatal the head. The neuroanatomical localization of these findings suggest the presence of abnormalities in the striatal-prefrontal circuits in schizophrenia and resilience mechanisms in COSSIBs with age dependent normalization. Hum Brain Mapp 36:1458-1469, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Impaired illness awareness or anosognosia is a common, but poorly understood feature of schizophrenia that contributes to medication nonadherence and poor treatment outcomes. Here we present a functional imaging study to measure brain activity at the moment of illness denial. To accomplish this, participants with schizophrenia ( n = 18) with varying degrees of illness awareness were confronted with their illness beliefs while undergoing functional MRI. To link structure with function, we explored the relationships among impaired illness awareness and brain activity during the illness denial task with cortical thickness. Impaired illness awareness was associated with increased brain activity in the left temporoparieto-occipital junction (TPO) and left medial prefrontal cortex (mPFC) at the moment of illness denial. Brain activity in the left mPFC appeared to be a function of participants' degree of self-reflectiveness, while the activity in the left TPO was associated with cortical thinning in this region and more specific to illness denial. Participants with impaired illness awareness had slower response times to illness related stimuli than those with good illness awareness. Increased left hemisphere brain activity in association with illness denial is consistent with the literature in other neuropsychiatric conditions attributing anosognosia or impaired illness awareness to left hemisphere dominance. The TPO and mPFC may represent putative targets for noninvasive treatment interventions, such as transcranial magnetic or direct current stimulation. Hum Brain Mapp, 36:391-414, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Deep gray matter (DGM) atrophy has been reported in patients with multiple sclerosis (MS) already at early stages of the disease and progresses throughout the disease course. We studied DGM volume and shape and their relation to disability in a large cohort of clinically well-described MS patients using new subcortical segmentation methods and shape analysis. Structural 3D magnetic resonance images were acquired at 1.5 T in 118 patients with relapsing remitting MS. Subcortical structures were segmented using a multiatlas technique that relies on the generation of an automatically generated template library. To localize focal morphological changes, shape analysis was performed by estimating the vertex-wise displacements each subject must undergo to deform to a template. Multiple linear regression analysis showed that the volume of specific thalamic nuclei (the ventral nuclear complex) together with normalized gray matter volume explains a relatively large proportion of expanded disability status scale (EDSS) variability. The deformation-based displacement analysis confirmed the relation between thalamic shape and EDSS scores. Furthermore, white matter lesion volume was found to relate to the shape of all subcortical structures. This novel method for the analysis of subcortical volume and shape allows depicting specific contributions of DGM abnormalities to neurological deficits in MS patients. The results stress the importance of ventral thalamic nuclei in this respect. Hum Brain Mapp 35:4193-4203, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Classically, model-based segmentation procedures match magnetic resonance imaging (MRI) volumes to an expertly labeled atlas using nonlinear registration. The accuracy of these techniques are limited due to atlas biases, misregistration, and resampling error. Multi-atlas-based approaches are used as a remedy and involve matching each subject to a number of manually labeled templates. This approach yields numerous independent segmentations that are fused using a voxel-by-voxel label-voting procedure. In this article, we demonstrate how the multi-atlas approach can be extended to work with input atlases that are unique and extremely time consuming to construct by generating a library of multiple automatically generated templates of different brains (MAGeT Brain). We demonstrate the efficacy of our method for the mouse and human using two different nonlinear registration algorithms (ANIMAL and ANTs). The input atlases consist a high-resolution mouse brain atlas and an atlas of the human basal ganglia and thalamus derived from serial histological data. MAGeT Brain segmentation improves the identification of the mouse anterior commissure (mean Dice Kappa values (κ = 0.801), but may be encountering a ceiling effect for hippocampal segmentations. Applying MAGeT Brain to human subcortical structures improves segmentation accuracy for all structures compared to regular model-based techniques (κ = 0.845, 0.752, and 0.861 for the striatum, globus pallidus, and thalamus, respectively). Experiments performed with three manually derived input templates suggest that MAGeT Brain can approach or exceed the accuracy of multi-atlas label-fusion segmentation (κ = 0.894, 0.815, and 0.895 for the striatum, globus pallidus, and thalamus, respectively). Hum Brain Mapp 34:2635-2654, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Introduction: Lack of illness awareness or anosognosia occurs in both schizophrenia and right hemisphere lesions due to stroke, dementia, and traumatic brain injury. In the latter conditions, anosognosia is thought to arise from unilateral hemispheric dysfunction or interhemispheric disequilibrium, which provides an anatomical model for exploring illness unawareness in other neuropsychiatric disorders, such as schizophrenia. Methods: Both voxel-based morphometry using Diffeomorphic Anatomical Registration through Exponentiated Lie Algebra (DARTEL) and a deformation-based morphology analysis of hemispheric asymmetry were performed on 52 treated schizophrenia subjects, exploring the relationship between illness awareness and gray matter volume. Analyses included age, gender, and total intracranial volume as covariates. Results: Hemispheric asymmetry analyses revealed illness unawareness was significantly associated with right < left hemisphere volumes in the anteroinferior temporal lobe ( t = 4.83, P = 0.051) using DARTEL, and the dorsolateral prefrontal cortex ( t = 5.80, P = 0.003) and parietal lobe ( t = 4.3, P = 0.050) using the deformation-based approach. Trend level associations were identified in the right medial prefrontal cortex ( t = 4.49, P = 0.127) using DARTEL. Lack of illness awareness was also strongly associated with reduced total white matter volume ( r = 0.401, P < 0.01) and illness severity ( r = 0.559, P < 0.01). Conclusion: These results suggest a relationship between anosognosia and hemispheric asymmetry in schizophrenia, supporting previous volume-based MRI studies in schizophrenia that found a relationship between illness unawareness and reduced right hemisphere gray matter volume. Functional imaging studies are required to examine the neural mechanisms contributing to these structural observations. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Ahdidan J, Hviid LB, Chakravarty MM, Ravnkilde B, Rosenberg R, Rodell A, Stødkilde-Jørgensen H, Videbech P. Longitudinal MR study of brain structure and hippocampus volume in major depressive disorder. To determine whether long-term course of treated major depression has an effect on the structure of the brain and the hippocampal volume. An 11-year follow-up procedure was used with data collection at baseline and again at follow-up. Tensor-based morphometry (TBM) and automatic hippocampal volume measure was performed on different datasets. The baseline dataset consisted of T1-weighted magnetic resonance images (MRIs) of 24 in-patients suffering from major depression and 33 healthy controls. The second dataset consisted of T1-weighted MRIs of 31 remitted depressive patients and 36 healthy controls. The longitudinal dataset consisted of 19 patients and 19 matched healthy controls present at both the first and the second dataset. Brain segmentation and hippocampal segmentation were fully automated and were based on a spatial normalization to the International Consortium of Brain Mapping (ICBM) non-linear model. Depressed patients were found to have smaller temporal lobes bilaterally, medulla and right hippocampus at baseline. However, these changes were not found at follow-up 11 years later. Moreover, these changes did not significantly correlate with the illness outcome. Brain structure changes seem to be state dependent in major depression, only occurring in acute episode of major depression and normalizing after remission. [ABSTRACT FROM AUTHOR]

Background and purpose: Previous volumetric magnetic resonance imaging (MRI) studies of Parkinson’s disease (PD) utilized primarily voxel-based morphometry (VBM), and investigated mostly patients with moderate- to late-stage disease. We now use deformation-based morphometry (DBM), a method purported to be more sensitive than VBM, to test for atrophy in patients with early-stage PD. Methods: T1-weighted MRI images from 24 early-stage PD patients and 26 age-matched normal control subjects were compared using DBM. Two separate studies were conducted, where two minimally-biased nonlinear intensity-average were created; one for all subjects and another for just the PD patients. The DBM technique creates an average population-based MRI-average in an iterative hierarchical fashion. The nonlinear transformations estimated to match each subject to the MRI-average were then analysed. Results: The DBM comparison between patients and controls revealed significant contraction in the left cerebellum, and non-significant trends towards frontal, temporal and cingulate sulcal expansions with frontal and temporal white matter contractions. Within the patient group, the unified PD rating scores were highly correlated with local expansions in or near sulci bordering on frontal and temporal cortex. Conclusion: Our results suggest that DBM could be a sensitive method for detecting morphological changes in early-stage PD. [ABSTRACT FROM AUTHOR]

Digital atlases are commonly used in pre-operative planning in functional neurosurgical procedures performed to minimize the symptoms of Parkinson's disease. These atlases can be customized to fit an individual patient's anatomy through atlas-to-patient warping procedures. Once fitted to pre-operative magnetic resonance imaging (MRI) data, the customized atlas can be used to plan and navigate surgical procedures. Linear, piece-wise linear and nonlinear registration methods have been used to customize different digital atlases with varying accuracies. Our goal was to evaluate eight different registration methods for atlas-to-patient customization of a new digital atlas of the basal ganglia and thalamus to demonstrate the value of nonlinear registration for automated atlas-based subcortical target identification in functional neurosurgery. In this work, we evaluate the accuracy of two automated linear techniques, two piece-wise linear techniques (requiring the identification of manually placed anatomical landmarks), and four different automated nonlinear atlas-to-patient warping techniques (where two of the four nonlinear techniques are variants of the ANIMAL algorithm). Since a gold standard of the subcortical anatomy is not available, manual segmentations of the striatum, globus pallidus, and thalamus are used to derive a silver standard for evaluation. Four different metrics, including the kappa statistic, the mean distance between the surfaces, the maximum distance between surfaces, and the total structure volume are used to compare the warping techniques. The results show that nonlinear techniques perform statistically better than linear and piece-wise linear techniques. In addition, the results demonstrate statistically significant differences between the nonlinear techniques, with the ANIMAL algorithm yielding better results. Hum Brain Mapp, 2009. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Morphologic measures have long been used to determine the patho-anatomical signature of different neurologic disorders. However, these measures can also be used to determine effects of specific learning tasks and quantifiable human abilities on cerebral structure. Musicians provide interesting opportunities for this type of analysis as their various skills, such as rhythmic ability and pitch and harmony discrimination (acquired through years of practicing and playing) can be quantified and compared using distinct morphologic analyses. Here, we review magnetic resonance imaging–based morphologic analyses in the music and neuroscience literature and provide some results from our own analysis of rhythmic ability in a cohort of musicians. [ABSTRACT FROM AUTHOR]

Functional magnetic resonance imaging (fMRI) is often used to enhance visualization and provide target localization during the planning phase of neurosurgical procedures. Although parametric maps have been used to identify areas of eloquent cortex such as the primary (S1) and secondary (S2) somatosensory areas for tumor surgery, to date, few fMRI methods exist to localize subcortical targets for surgical interventions used to treat movement disorders. The scanning time required to obtain statistically significant functional signals must be balanced against the possibility of movement artifacts and patient discomfort. We propose a vibrotactile stimulation technique to activate the somatosensory pathway for neurosurgical planning and perform a sensitivity analysis to determine the amount of time required to achieve significant activations of S1, S2, and sensory thalamus in individual subjects. Bilateral stimulation experiments were carried out on two MRI scanners ( n = 13 at 1.5 T; n = 5 at 3.0 T). The analysis demonstrates that statistically significant functional activations can be achieved in clinically acceptable times: 16 min at 1.5 T (26/26 experiments) and 6 min at 3.0 T (10/10) for S1 activations; 24 min at 1.5 T (22/26) and 18 min at 3.0 T for S2 activations (9/10); and 32 min at 1.5 T (15/26) and 18 min at 3.0 T (10/10) for activation of thalamic nuclei. These results demonstrate that S1 and S2 activations are robust at 1.5 and 3.0 T, and that robust thalamic activations in individual subjects are possible at 3.0 T. These techniques demonstrate that this technique can be used for preoperative planning for surgical candidates. Hum Brain Mapp, 2009. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Impulsivity is considered a vulnerability trait for addiction. Recently, we found trait non-planning impulsiveness measured with the Karolinska Scales of Personality was negatively correlated with dopamine D 2/3 receptor availability in the ventral striatum of healthy humans. While also observed in rodents, human studies have failed to find this association with other measures of trait impulsivity. We explored whether another rodent finding, reduced ventral striatum volume with greater impulsivity, could also be observed in humans using this scale. Non-planning impulsiveness was measured in 52 healthy subjects (21 female; mean age: 33.06 ± 9.69) using the Karolinska Scales of Personality. Striatal subregion volumes, including the globus pallidus, were acquired using the Multiple Automatically Generated Templates (MAGeT-Brain) algorithm. Although failing to support our a priori hypothesis, there was a significant sex interaction in the post-commissural putamen with impulsiveness. Exploratory analyses revealed impulsiveness was negatively correlated with post-commissural putamen volumes in males, but positively correlated in females. We replicated this finding in males in an increased sample (including all 52 previous subjects) who provided impulsiveness measured by the Temperament and Character Inventory (n = 73; 32 female; mean age: 33.48 ± 9.75). These correlations by sex were statistically different from one another, the main finding with the Kasolinksa Scales of Personality surviving correction for multiple comparisons. While impulsivity may be related to reduced ventral striatal D 2/3 receptors across sexes, males but not females may show significant reductions in post-commissural putamen volume. These findings have important implications for understanding biological markers underlying sex differences in drug addiction vulnerability., (© 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Objectives: Evidence from experimental animal models of Parkinson's disease (PD) suggests a characteristic pattern of metabolic perturbation in discrete, very small basal ganglia structures. These structures are generally too small to allow valid investigation by conventional positron emission tomography (PET) cameras. However, the high-resolution research tomograph (HRRT) PET system has a resolution of 2 mm, sufficient for the investigation of important structures such as the pallidum and thalamic subnuclei., Materials and Methods: Using the HRRT, we performed [(18)F]-fluorodeoxyglucose (FDG) scans on 21 patients with PD and 11 age-matched controls. We employed three types of normalization: white matter, global mean, and data-driven normalization. We performed volume-of-interest analyses of small subcortical gray matter structures. Voxel-based comparisons were performed to investigate the extent of cortical hypometabolism., Results: The most significant level of relative subcortical hypermetabolism was detected in the external pallidum (GPe), irrespective of normalization strategy. Hypermetabolism was suggested also in the internal pallidum, thalamic subnuclei, and the putamen. Widespread cortical hypometabolism was seen in a pattern very similar to previously reported patterns in patients with PD., Conclusion: The presence and extent of subcortical hypermetabolism in PD is dependent on type of normalization. However, the present findings suggest that PD, in addition to widespread cortical hypometabolism, is probably characterized by true hypermetabolism in the GPe. This finding was predicted by the animal 2-deoxyglucose autoradiography literature, in which high-magnitude hypermetabolism was also most robustly detected in the GPe., (© 2011 John Wiley & Sons A/S.)