Morphometric alterations of the mesocorticolimbic network in Parkinson's disease with impulse control disorders.

Impulse control disorders (ICDs) are a group of non-motor symptoms of Parkinson disease (PD) leading to significant psychosocial detrimental outcome. The mesocorticolimbic network plays a distinctive role in reward learning and executive decision making and has been suggested to be involved in ICDs in PD. To study morphometric changes of the mesocorticolimbic network in PD with ICD. A total of 18 patients of PD with ICD (PD + ICD), 19 patients of PD without ICD (PD - ICD) and 19 healthy controls (HC) were included in the study. ICDs were diagnosed using Questionnaire for Impulsive-Compulsive Disorders in PD-Rating Scale (QUIP-RS). MRI was done using a 3T scanner and assessment of cortical thickness and subcortical volumes were done using FreeSurfer. Brain regions known to be part of the mesocorticolimbic network were extracted and included for statistical analysis. There was no difference between PD + ICD and PD - ICD with regard to duration of illness or total dopaminergic medication. In comparison to HC, patients with PD + ICD demonstrated atrophy of the left frontal pole, and this atrophy neared significance in comparison to PD - ICD. The QUIP-RS had a negative correlation with left caudate volume in PD + ICD. The PD + ICD group showed distinct morphometric changes in regions involved in the mesocorticolimbic system which may contribute to the presence of ICD.

False recall is associated with larger caudate in males but not in females.

After learning semantically related words, some people are more likely than others to incorrectly recall unstudied but semantically related lures (i.e., Deese-Roediger-McDermott [DRM] false recall). Previous studies have suggested that neural activity in subcortical regions (e.g., the caudate) is involved in false memory, and that there may be sex differences in the neural basis of false memory. However, sex-specific associations between subcortical volumes and false memory are not well understood. This study investigated whether sex modulates the associations between subcortical volumes and DRM false recall in 400 healthy college students. Volumes of subcortical regions including the caudate, accumbens, amygdala, hippocampus, pallidum, putamen and thalamus were obtained from structural magnetic resonance images and measured using FreeSurfer. The results showed that males had lower true and false recall but larger subcortical volumes than females. Interestingly, higher false recall was associated with a larger caudate in males, but not in females. This association was significant after controlling for age and intracranial volume. This study provides new evidence on the neural basis of false recall. It suggests that the caudate plays a role in false recall in young men, and that future studies of the neural correlates of false memory should consider sex differences.

Shared genetic effects of emotion and subcortical volumes in healthy adults.

Ample studies have reported a strong association between emotion and subcortical volumes; still, the underlying mechanism regarding this relation remains unclear. Using a twin design, the current study aimed to explore the intrinsic association between emotion and subcortical volumes by examining their phenotypic, genetic, and environmental correlations. We used a group dataset of 960 individuals from the Human Connectome Project (234 monozygotic twins, 145 dizygotic twins, 581 not twins, males = 454, age = 22-37 years). We found that both emotion and subcortical volumes were heritable. Of the 17 emotional traits, 13 were significantly phenotypically correlated with the volumes of multiple subcortical regions. There was no environmental correlation between emotion and subcortical volumes; however, we found a genetic overlap between overall emotional traits and caudate volume. Taken together, our results showed that emotion and subcortical volumes were heritable and closely related. Although the caudate has been often studied with execution of movement, given that the caudate volume is genetically associated with diverse emotional domains, such as negative affect, psychological well-being, and social relationships, it may suggest that the caudate volume might also be an important factor when studying the brain basis of emotion.

Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: The ENIGMA adventure.

Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case-control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case-control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.

Larger bilateral amygdalar volumes are associated with affective loss experiences.

Affective loss (AL) (i.e., bereavement, relationship breakup) is a stressful life event leading to a heightened risk of developing a psychiatric disorder, for example, depression and anxiety disorder. These disorders have been associated with altered subcortical brain volumes. Little is known though, how AL in healthy subjects is linked to subcortical volumes. In a study with 196 healthy young adults, we probed the association between AL across the individual entire life span, assessed via the List of Threatening Experiences Questionnaire, and magnetic resonance imaging brain gray matter volumes (a priori selected: bilateral amygdalae, hippocampi, thalami; exploratory analyses: nuclei accumbens, caudate, putamina), segmented by use of volBrain. AL was defined as death of a first-degree relative/spouse, close relative/friend, and breakup of a marriage or steady relationship. AL was associated with larger bilateral amygdalar volumes and, after taking into account the total number of ALs, with smaller right hippocampal volumes, both irrespective of sex. Exploratory analyses of striatal volumes yielded an association of AL with larger right nucleus accumbens volumes in men, and increased caudate volumes after the loss of a first-degree relative irrespective of sex. Our data suggest that AL engenders alterations in limbic structures that likely involve processes of chronic stress and amygdala- and hippocampus-dependent fear conditioning, and resemble those observed in general anxiety disorder, childhood maltreatment, and major depressive disorder. Our exploratory findings of striatal volume alterations hint at a modulation of reward processing by AL.

Adjusting for allometric scaling in ABIDE I challenges subcortical volume differences in autism spectrum disorder.

Inconsistencies across studies investigating subcortical correlates of autism spectrum disorder (ASD) may stem from small sample size, sample heterogeneity, and omitting or linearly adjusting for total brain volume (TBV). To properly adjust for TBV, brain allometry-the nonlinear scaling relationship between regional volumes and TBV-was considered when examining subcortical volumetric differences between typically developing (TD) and ASD individuals. Autism Brain Imaging Data Exchange I (ABIDE I; N = 654) data was analyzed with two methodological approaches: univariate linear mixed effects models and multivariate multiple group confirmatory factor analyses. Analyses were conducted on the entire sample and in subsamples based on age, sex, and full scale intelligence quotient (FSIQ). A similar ABIDE I study was replicated and the impact of different TBV adjustments on neuroanatomical group differences was investigated. No robust subcortical allometric or volumetric group differences were observed in the entire sample across methods. Exploratory analyses suggested that allometric scaling and volume group differences may exist in certain subgroups defined by age, sex, and/or FSIQ. The type of TBV adjustment influenced some reported volumetric and scaling group differences. This study supports the absence of robust volumetric differences between ASD and TD individuals in the investigated volumes when adjusting for brain allometry, expands the literature by finding no group difference in allometric scaling, and further suggests that differing TBV adjustments contribute to the variability of reported neuroanatomical differences in ASD.

No associations between medial temporal lobe volumes and verbal learning/memory in emerging psychosis.

Grey matter (GM) volume alterations have been repeatedly demonstrated in patients with first episode psychosis (FEP). Some of these neuroanatomical abnormalities are already evident in the at-risk mental state (ARMS) for psychosis. Not only GM alterations but also neurocognitive impairments predate the onset of frank psychosis with verbal learning and memory (VLM) being among the most impaired domains. Yet, their interconnection with alterations in GM volumes remains ambiguous. Thus, we evaluated associations of different subcortical GM volumes in the medial temporal lobe with VLM performance in antipsychotic-naïve ARMS and FEP patients. Data from 59 ARMS and 31 FEP patients, collected within the prospective Früherkennung von Psychosen study, were analysed. Structural T1-weighted images were acquired using a 3 Tesla magnetic resonance imaging scanner. VLM was assessed using the California Verbal Learning Test and its factors Attention Span, Learning Efficiency, Delayed Memory and Inaccurate Memory. FEP patients showed significantly enlarged volumes of hippocampus, pallidum, putamen and thalamus compared to ARMS patients. A significant negative association between amygdala and pallidum volume and Attention Span was found in ARMS and FEP patients combined, which however did not withstand correction for multiple testing. Although we found significant between-group differences in subcortical volumes and VLM is among the most impaired cognitive domains in emerging psychosis, we could not demonstrate an association between low performance and subcortical GM volumes alterations in antipsychotic-naïve patients. Hence, deficits in this domain do not appear to stem from alterations in subcortical structures.

Grey matter structural differences in alcohol-dependent individuals with and without comorbid depression/anxiety-an MRI study.

Although depression and anxiety disorders are common comorbid conditions in alcohol dependence, few structural brain imaging studies have compared alcohol-dependent subjects with and without such comorbidity. In the current study, brain scans of 35 alcohol-dependent with and 40 individuals without diagnosis of a comorbid ICD-10 depressive or anxiety disorder receiving detoxification inpatient treatment were evaluated. Thickness and volumes of automatically segmented neuroanatomical structures were measured in FreeSurfer. Furthermore, associations of brain structure with biological markers and clinical severity markers of alcohol dependence were assessed. Despite comparable addiction severity, the non-comorbid group had evidence of higher cytotoxic effects of alcohol use on hepatic and haematological markers, and showed significantly smaller volumes of total cerebral, and cerebellar grey matter. Similarly, they showed unexpected smaller hippocampal and nucleus accumbens volumes, and thinner frontal, temporal and occipital cortices. Smaller brain volumes correlated with increased markers of hepatic and haematological dysfunction, and with longer duration of alcohol dependence in the non-comorbid group. Evidence of higher biomarkers of alcohol use may be indicative of more severe alcohol dependence or higher vulnerability to ethanol toxicity in this group. Furthermore, psychopathology-related drug treatment, which occurred in 53% of the comorbid group over the recent years, or tissue inflammation may have a moderate effect on the grade of cerebral atrophy in alcohol-dependent patients. Longitudinal studies are needed to investigate this issue more fully.

Combining multiple anatomical MRI measures improves Alzheimer's disease classification.

Several anatomical MRI markers for Alzheimer's disease (AD) have been identified. Hippocampal volume, cortical thickness, and grey matter density have been used successfully to discriminate AD patients from controls. These anatomical MRI measures have so far mainly been used separately. The full potential of anatomical MRI scans for AD diagnosis might thus not yet have been used optimally. In this study, we therefore combined multiple anatomical MRI measures to improve diagnostic classification of AD. For 21 clinically diagnosed AD patients and 21 cognitively normal controls, we calculated (i) cortical thickness, (ii) cortical area, (iii) cortical curvature, (iv) grey matter density, (v) subcortical volumes, and (vi) hippocampal shape. These six measures were used separately and combined as predictors in an elastic net logistic regression. We made receiver operating curve plots and calculated the area under the curve (AUC) to determine classification performance. AUC values for the single measures ranged from 0.67 (cortical thickness) to 0.94 (grey matter density). The combination of all six measures resulted in an AUC of 0.98. Our results demonstrate that the different anatomical MRI measures contain complementary information. A combination of these measures may therefore improve accuracy of AD diagnosis in clinical practice. Hum Brain Mapp 37:1920-1929, 2016. © 2016 Wiley Periodicals, Inc.

Maturation of Cortico-Subcortical Structural Networks-Segregation and Overlap of Medial Temporal and Fronto-Striatal Systems in Development.

The brain consists of partly segregated neural circuits within which structural convergence and functional integration occurs during development. The relationship of structural cortical and subcortical maturation is largely unknown. We aimed to study volumetric development of the hippocampus and basal ganglia (caudate, putamen, pallidum, accumbens) in relation to volume changes throughout the cortex. Longitudinal MRI data were obtained across a mean interval of 2.6 years in 85 participants with an age range of 8-19 years at study start. Left and right subcortical changes were related to cortical change vertex-wise in the ipsilateral hemisphere with general linear models with age, sex, interval between scans, and mean cortical volume change as covariates. Hippocampal-cortical change relationships centered on parts of the Papez circuit, including entorhinal, parahippocampal, and isthmus cingulate areas, and lateral temporal, insular, and orbitofrontal cortices in the left hemisphere. Basal ganglia-cortical change relationships were observed in mostly nonoverlapping and more anterior cortical areas, all including the anterior cingulate. Other patterns were unique to specific basal ganglia structures, including pre-, post-, and paracentral patterns relating to putamen change. In conclusion, patterns of cortico-subcortical development as assessed by morphometric analyses in part map out segregated neural circuits at the macrostructural level.

Neuroanatomical Correlates of the Late Positive Potential in Youth with Pediatric Bipolar Disorder.

BACKGROUND: The late positive potential (LPP) could be a marker of emotion dysregulation in youth with pediatric bipolar disorder (PBD). However, the neuroanatomical correlates of the LPP are still not clarified. OBJECTIVE: To provide cortical and deep gray matter correlates of the LPP in youth, specifically, youth with PBD. METHODS: Twenty-four 7 to 17 years-old children with PBD and 28 healthy controls (HC) underwent cortical thickness and deep gray matter volumes measurements through magnetic resonance imaging and LPP measurement elicited by passively viewing emotional faces through electroencephalography. T-tests compared group differences in LPP, cortical thickness, and deep gray matter volumes. Linear regressions tested the relationship between LPP amplitude and cortical thickness/deep gray matter volumes. RESULTS: PBD had a more pronounced LPP amplitude for happy faces and a thinner cortex in prefrontal areas than HC. While considering both groups, a higher LPP amplitude was associated with a thicker cortex across occipital and frontal lobes, and with a smaller right globus pallidus volume. In addition, a higher LPP amplitude for happy faces was associated with smaller left caudate and left globus pallidus volumes across both groups. Finally, the LPP amplitude correlated negatively with right precentral gyrus thickness across youth with PBD, but positively across HC. CONCLUSION: Neural correlates of LPP in youth included fronto-occipital areas that have been associated also with emotion processing and control. The opposite relationship between BPD and HC of LPP amplitude and right precentral gyrus thickness might explain the inefficacy of the emotional control system in PBD.

Genomic Studies Across the Lifespan Point to Early Mechanisms Determining Subcortical Volumes.

BACKGROUND: Subcortical brain structures play a key role in pathological processes of age-related neurodegenerative disorders. Mounting evidence also suggests that early-life factors may have an impact on the development of common late-life neurological diseases, including genetic factors that can influence both brain maturation and neurodegeneration. METHODS: Using large population-based brain imaging datasets across the lifespan (N ≤ 40,628), we aimed to 1) estimate the heritability of subcortical volumes in young (18-35 years), middle (35-65 years), and older (65+ years) age, and their genetic correlation across age groups; 2) identify whether genetic loci associated with subcortical volumes in older persons also show associations in early adulthood, and explore underlying genes using transcriptome-wide association studies; and 3) explore their association with neurological phenotypes. RESULTS: Heritability of subcortical volumes consistently decreased with increasing age. Genetic risk scores for smaller caudate nucleus, putamen, and hippocampus volume in older adults were associated with smaller volumes in young adults. Individually, 10 loci associated with subcortical volumes in older adults also showed associations in young adults. Within these loci, transcriptome-wide association studies showed that expression of several genes in brain tissues (especially MYLK2 and TUFM) was associated with subcortical volumes in both age groups. One risk variant for smaller caudate nucleus volume (TUFM locus) was associated with lower cognitive performance. Genetically predicted Alzheimer's disease was associated with smaller subcortical volumes in middle and older age. CONCLUSIONS: Our findings provide novel insights into the genetic determinants of subcortical volumes across the lifespan. More studies are needed to decipher the underlying biology and clinical impact.

Associations of medication with subcortical morphology across the lifespan in OCD: Results from the international ENIGMA Consortium.

BACKGROUND: Widely used psychotropic medications for obsessive-compulsive disorder (OCD) may change the volumes of subcortical brain structures, and differently in children vs. adults. We measured subcortical volumes cross-sectionally in patients finely stratified for age taking various common classes of OCD drugs. METHODS: The ENIGMA-OCD consortium sample (1081 medicated/1159 unmedicated OCD patients and 2057 healthy controls aged 6-65) was divided into six successive 6-10-year age-groups. Individual structural MRIs were parcellated automatically using FreeSurfer into 8 regions-of-interest (ROIs). ROI volumes were compared between unmedicated and medicated patients and controls, and between patients taking serotonin reuptake inhibitors (SRIs), tricyclics (TCs), antipsychotics (APs), or benzodiazepines (BZs) and unmedicated patients. RESULTS: Compared to unmedicated patients, volumes of accumbens, caudate, and/or putamen were lower in children aged 6-13 and adults aged 50-65 with OCD taking SRIs (Cohen's d = -0.24 to -0.74). Volumes of putamen, pallidum (d = 0.18-0.40), and ventricles (d = 0.31-0.66) were greater in patients aged 20-29 receiving APs. Hippocampal volumes were smaller in patients aged 20 and older taking TCs and/or BZs (d = -0.27 to -1.31). CONCLUSIONS: Results suggest that TCs and BZs could potentially aggravate hippocampal atrophy of normal aging in older adults with OCD, whereas SRIs may reduce striatal volumes in young children and older adults. Similar to patients with psychotic disorders, OCD patients aged 20-29 may experience subcortical nuclear and ventricular hypertrophy in relation to APs. Although cross-sectional, present results suggest that commonly prescribed agents exert macroscopic effects on subcortical nuclei of unknown relation to therapeutic response.

Smaller spared subcortical nuclei are associated with worse post-stroke sensorimotor outcomes in 28 cohorts worldwide.

Up to two-thirds of stroke survivors experience persistent sensorimotor impairments. Recovery relies on the integrity of spared brain areas to compensate for damaged tissue. Deep grey matter structures play a critical role in the control and regulation of sensorimotor circuits. The goal of this work is to identify associations between volumes of spared subcortical nuclei and sensorimotor behaviour at different timepoints after stroke. We pooled high-resolution T1-weighted MRI brain scans and behavioural data in 828 individuals with unilateral stroke from 28 cohorts worldwide. Cross-sectional analyses using linear mixed-effects models related post-stroke sensorimotor behaviour to non-lesioned subcortical volumes (Bonferroni-corrected, P < 0.004). We tested subacute (≤90 days) and chronic (≥180 days) stroke subgroups separately, with exploratory analyses in early stroke (≤21 days) and across all time. Sub-analyses in chronic stroke were also performed based on class of sensorimotor deficits (impairment, activity limitations) and side of lesioned hemisphere. Worse sensorimotor behaviour was associated with a smaller ipsilesional thalamic volume in both early (n = 179; d = 0.68) and subacute (n = 274, d = 0.46) stroke. In chronic stroke (n = 404), worse sensorimotor behaviour was associated with smaller ipsilesional putamen (d = 0.52) and nucleus accumbens (d = 0.39) volumes, and a larger ipsilesional lateral ventricle (d = -0.42). Worse chronic sensorimotor impairment specifically (measured by the Fugl-Meyer Assessment; n = 256) was associated with smaller ipsilesional putamen (d = 0.72) and larger lateral ventricle (d = -0.41) volumes, while several measures of activity limitations (n = 116) showed no significant relationships. In the full cohort across all time (n = 828), sensorimotor behaviour was associated with the volumes of the ipsilesional nucleus accumbens (d = 0.23), putamen (d = 0.33), thalamus (d = 0.33) and lateral ventricle (d = -0.23). We demonstrate significant relationships between post-stroke sensorimotor behaviour and reduced volumes of deep grey matter structures that were spared by stroke, which differ by time and class of sensorimotor measure. These findings provide additional insight into how different cortico-thalamo-striatal circuits support post-stroke sensorimotor outcomes.

Cognitive reappraisal and expressive suppression relate differentially to longitudinal structural brain development across adolescence.

Emotional disorders commonly emerge in adolescence, a period characterized by changes in emotion-related processes. Thus, the ability to regulate emotions is crucial for well-being and adaptive social functioning during this period. Concurrently, the brain undergoes large structural and functional changes. We investigated relations between tendencies to use two emotion regulation strategies, cognitive reappraisal and expressive suppression, and structural development of the cerebral cortex and subcortical structures (specifically amygdala and nucleus accumbens given these structures are frequently associated with emotion regulation). A total of 112 participants (59 females) aged 8-26 were followed for up to 3 times over a 7-year period, providing 272 observations. Participants completed the Emotion Regulation Questionnaire (ERQ), yielding a measure of tendencies to use cognitive reappraisal and expressive suppression at the final time point. Linear mixed model analyses were performed to account for the longitudinal nature of the data. Contrary to expectations, volumetric growth of the amygdala and nucleus accumbens was not associated with either emotion regulation strategy. However, frequent use of expressive suppression was linked to greater regionally-specific apparent cortical thinning in both sexes, while tendency to use cognitive reappraisal was associated with greater regionally-specific apparent thinning in females and less thinning in males. Although cognitive reappraisal is traditionally associated with cognitive control regions of the brain, our results suggest it is also associated with regions involved in social cognition and semantics. The continued changes in cortical morphology and their associations with habitual use of different emotion regulation strategies indicate continued plasticity during this period, and represent an opportunity for interventions targeting emotion regulation for adolescents at risk.

Cortical surface thickness, subcortical volumes and disability between races in relapsing-remitting multiple sclerosis.

BACKGROUND: The interplay between cortical surface thickness (CTh), subcortical volumes (SCV) and disability in patients with relapsing remitting multiple sclerosis (RRMS) is still not clear. OBJECTIVE: To examine the relationship between CTh, SCV, and disability and investigate differences in CTh, SCV and disability between African Americans (AA) and Caucasian Americans (CA). METHODS: Sixty-five RRMS (33AA, 32 CA) participants underwent Expanded Disability Status Scale and Multiple Sclerosis Functional Composite (MSFC) assessments, including timed 25-foot walk (T25FW), nine-hole peg test (9HPT) on dominant (D) and non-dominant hand (ND) and paced auditory serial addition test (PASAT-3). Symbol digit modalities test (SDMT) was also administered. All participants underwent 3T brain MRI. CTh was measured in the Frontal (FA), Parietal (PA), Temporal (TA), Occipital (OA), Cingulate (CA), and Global (GA) cortical surface areas (CSA). SCV measurements included Thalamus (TV), Caudate (CV), Putamen (PV), Pallidum (PaV), Hippocampus (HV), Amygdala (AV), Accumbens (AcV), Brain Stem (BSV), and Deep Gray Matter Total Volume (DGMTV). A general linear model with multivariate analysis (MANOVA) was used to determine the differences between the two cohorts (SPSS vs 25). Spearman rank correlation analysis was performed to investigate the relationship between CTh and MSFC. RESULTS: AA have significantly decreased FA, PA, TA, GA CTh compared to CA (p = 0.004, p = 0.018, p = 0.013, p = 0.015, respectively). SCV measurements were not significantly different. Only in CA, the MSFC measures correlate significantly with regional CSA CTh. In both races and in the entire group, T25FW correlates with TV, PV, AV, AcV and DGMTV (p < 0.05). Only in AA and the entire cohort, PASAT-3 correlates with TV and AcV(p = 0.041, p = 0.006, p = 0.006, p = 0.000 respectively). CONCLUSIONS: Differences in CSA CTh reinforce the different disease pathobiology between AA and CA. Regional CTh may represent a useful biomarker related to multi-domain disability only in CA, while in AA DGM injury might be a more important contributor to disability. Longitudinal, large-scale studies are warranted to confirm our findings.

Validity of automated FreeSurfer segmentation compared to manual tracing in detecting prenatal alcohol exposure-related subcortical and corpus callosal alterations in 9- to 11-year-old children.

In recent years a number of semi-automated and automated segmentation tools and brain atlases have been developed to facilitate morphometric analyses of large MRI datasets. These tools are much faster than manual tracing and demonstrate excellent test-retest reliabilities. Reliabilities of automated segmentations relative to "gold standard" manual tracings have, however, been shown to vary by brain region and in different cohorts. It remains uncertain to what extent smaller brain volumes and potential changes in grey/white matter contrasts in paediatric brains impact on the performance of automated methods, and how pathology may influence performance. This study examined whether using data from automated FreeSurfer segmentation would alter our ability, compared to manual segmentation, to detect prenatal alcohol exposure (PAE)-related volume changes in subcortical regions and the corpus callosum (CC) in pre-adolescent children. High-resolution T1-weighted images were acquired, using a sequence optimized for morphometric neuroanatomical analysis, on a Siemens 3T Allegra MRI scanner in 71 right-handed, 9- to 11-year-old children (27 fetal alcohol syndrome (FAS) and partial FAS (PFAS), 25 non-syndromal heavily exposed (HE) and 19 non-exposed controls) from a high-risk community in Cape Town, South Africa. Data from timeline follow-back interviews administered to the mothers prospectively during pregnancy were used to quantify the amount of alcohol (in ounces absolute alcohol per day, AA/day) that the children had been exposed to prenatally. Volumes of corpus callosum (CC) and bilateral caudate nuclei, hippocampi and nucleus accumbens (NA) were obtained by manual tracing and automated segmentation using both FreeSurfer versions 5.1 and 6.0. Reliability across methods was assessed using intraclass correlation (ICC) estimates for consistency and absolute agreement, and Cronbach's α. Ability to detect regions showing PAE effects was assessed separately for each segmentation method using ANOVA and linear regression of regional volumes with AA/day. Our results support findings from other studies showing excellent reliability across methods for easy-to-segment structures, such as the CC and caudate nucleus. Volumes from FreeSurfer 6.0 were smaller than those from version 5.1 in all regions except the right caudate, for which they were similar, and right hippocampus and CC, for which they were larger. Despite poor absolute agreement between methods in the NA and hippocampus, all three segmentation methods detected dose-dependent volume reductions in regions for which reliabilities on ICC consistency across methods reached at least 0.70, namely the CC, and bilateral caudate nuclei and hippocampi. PAE-related changes in the NA for which ICC consistency did not reach this minimum were inconsistent across methods and should be interpreted with caution. This is the first study to demonstrate in a pre-adolescent cohort the ability of automated segmentation with FreeSurfer to detect regional volume changes associated with pathology similar to those found using manual tracing.

Whole Exome Sequencing Study of Parkinson Disease and Related Endophenotypes in the Italian Population.

Parkinson Disease (PD) is a complex neurodegenerative disorder characterized by large genetic heterogeneity and missing heritability. Since the genetic background of PD can partly vary among ethnicities and neurological scales have been scarcely investigated in a PD setting, we performed an exploratory Whole Exome Sequencing (WES) analysis of 123 PD patients from mainland Italy, investigating scales assessing motor (UPDRS), cognitive (MoCA), and other non-motor symptoms (NMS). We performed variant prioritization, followed by targeted association testing of prioritized variants in 446 PD cases and 211 controls. Then we ran Exome-Wide Association Scans (EWAS) within sequenced PD cases (N = 113), testing both motor and non-motor PD endophenotypes, as well as their associations with Polygenic Risk Scores (PRS) influencing brain subcortical volumes. We identified a variant associated with PD, rs201330591 in GTF2H2 (5q13; alternative T allele: OR [CI] = 8.16[1.08; 61.52], FDR = 0.048), which was not replicated in an independent cohort of European ancestry (1,148 PD cases, 503 controls). In the EWAS, polygenic analyses revealed statistically significant multivariable associations of amygdala- [ß(SE) = -0.039(0.013); FDR = 0.039] and caudate-PRS [0.043(0.013); 0.028] with motor symptoms. All subcortical PRSs in a multivariable model notably increased the variance explained in motor (adjusted-R2 = 38.6%), cognitive (32.2%) and other non-motor symptoms (28.9%), compared to baseline models (~20%). Although, the small sample size warrants further replications, these findings suggest shared genetic architecture between PD symptoms and subcortical structures, and provide interesting clues on PD genetic and neuroimaging features.

Sexually divergent effect of COMT Val/met genotype on subcortical volumes in schizophrenia.

Structural and functional alterations of subcortical areas have been observed in schizophrenia. COMT Val108/158Met has been associated with schizophrenia and implicated in different cognitive and neurofunctional alterations. Recent studies suggested that COMT genotype influences neuronal growth. Genetic variations in COMT were associated with sexually dimorphic effects on enzymatic activity, brain anatomy and behavior suggesting that gender might be crucial in interpreting COMT-dependent effects. Based on these data, we investigated possible effects of the interaction between COMT Val108/158Met genotype and gender on subcortical volumes among 79 patients with schizophrenia. All patients were genotyped for COMT Val108/158Met polymorphism and underwent 3 T-MRI. Volumetric segmentation of subcortical structures was performed with Freesurfer 5.3. The general linear model yielded no significant effect of COMT genotype alone, thus revealing a significant interaction of gender and COMT gene on subcortical volumes. The overall significance of the interaction was driven by significant effects in the right caudate, and bilaterally in putamen, pallidum, and nucleus accumbens. Post-hoc analyses showed that female Met/Met patients had smaller volumes, whereas male subjects homozygous for the Met allele showed higher or not different subcortical volumes compared to the other groups. This study reports a sexually divergent effect of COMT polymorphism on subcortical structures in schizophrenia. These results support the hypothesis of a sexually dimorphic effect of COMT genetic variations on brain morphology.

Cortical and subcortical changes in patients with premenstrual syndrome.

BACKGROUND: Premenstrual syndrome (PMS) is characterized by a series of emotional, physical and behavioral symptoms. Although PMS is related to dysfunctions of the central nervous system, the neuropathological mechanism of PMS still has not been clearly established. The aim of this study is to evaluate potential differences in both cortical thickness and subcortical volumes in PMS patients compared to healthy controls (HCs). METHODS: Twenty PMS patients and twenty HCs underwent a structural magnetic resonance imaging scan and clinical assessment. Cortical thickness and subcortical volumes were computed using the FreeSurfer image analysis suite. Relationships between cortical thickness/subcortical volumes and the daily rating of severity of problems (DRSP) score were then measured in patients. RESULTS: Compared to HCs, PMS patients exhibited reduced cortical thickness in the medial prefrontal cortex (MPFC), orbitofrontal cortex (OFC) and insula, and increased subcortical volumes of the amygdala, thalamus and pallidum. Furthermore, negative correlations were detected between the DRSP and cortical thickness in the anterior cingulate cortex and precuneus. LIMITATIONS: The study is limited by a small sample size and narrow age range of participants. CONCLUSIONS: Our findings indicate that the abnormal morphological changes are mainly implicated in emotional regulation and visceral perception in PMS patients. We hope that our study may contribute to a better understanding of PMS.