Papers by Anderson Winkler
Nature Neuroscience, 2016
Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and fu... more Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and function differ, on average, between people with schizophrenia and healthy individuals. As common genetic associations are emerging for both schizophrenia and brain imaging phenotypes, we can now use genome-wide data to investigate genetic overlap. Here we integrated results from common variant studies of schizophrenia (33,636 cases, 43,008 controls) and volumes of several (mainly subcortical) brain structures (11,840 subjects). We did not find evidence of genetic overlap between schizophrenia risk and subcortical volume measures either at the level of common variant genetic architecture or for single genetic markers. These results provide a proof of concept (albeit based on a limited set of structural brain measures) and define a roadmap for future studies investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders.
in the middle and inferior frontal gyri and in the precentral gyrus. Vestibular-and somatosensory... more in the middle and inferior frontal gyri and in the precentral gyrus. Vestibular-and somatosensory-related areas show negative BOLD responses (NBR) during simultaneous stimulation. NBR areas were also observed in the calcarine gyrus, lingual gyrus, cuneus and precuneus during simultaneous and single visual stimulations. For static visual and galvanic vestibular simultaneous stimulation, the reciprocal inhibitory visual–vestibular interaction pattern is observed in our results. The experimental results revealed interactions in frontal areas during concurrent visual–vestibular stimuli, which are affected by intermodal association areas in occipital, parietal, and temporal lobes.
Introduction: Areas of the brain that are associated with the vestibular system can be activated ... more Introduction: Areas of the brain that are associated with the vestibular system can be activated using galvanic vestibular stimulation. These areas can be studied through a combination of galvanic vestibular stimulation with functional magnetic resonance imaging (fMRI). In order to provide an appropriate sequence of galvanic stimulation synchronous with the MRI pulse sequence, a specific electronic device that was built and assessed is presented. Methods: The electronic project of the GVS is divided in analog and digital circuits. The analog circuits are mounted in an aluminum case, supplied by sealed batteries, and goes inside the MRI room near to the feet of the subject. The digital circuits are placed in the MRI control room. Those circuits communicate through each other by an optical fiber. Tests to verify the GVS-MRI compatibility were conducted. Silicone (in-house) and Ag/AgCl (commercial) electrodes were evaluated for maximum balance and minimal pain sensations. fMRI experiments were conducted in eight human volunteers. Results: GVS-MRI compatibility experiments demonstrate that the GVS did not interfere with the MRI scanner functionality and vice versa. The circular silicone electrode was considered the most suitable to apply the galvanic vestibular stimulation. The 1 Hz stimulation sinusoid frequency produced the biggest balance and the less pain sensations when compared to 2 Hz. The GVS was capable of eliciting activation in the precentral and postcentral gyri, in the central sulcus, in the supplementary motor area, in the middle and inferior frontal gyri, in the inferior parietal lobule, in the insula, in the superior temporal gyrus, in the middle cingulate cortex, and in the cerebellum. Conclusion: This study shows the development and description of a neurovestibular stimulator that can be safely used inside the MRI scanner room without interfering on its operation and vice versa. The developed GVS could successfully activate the major areas involved with multimodal functions of the vestibular system, demonstrating its validity as a stimulator for neurovestibular research. To the best of our knowledge, this is the first work that shows the development and the construction of a galvanic vestibular stimulator that could be safely used inside the MRI room.
Frontiers in Genetics, 2015
Obesity is a chronic metabolic disorder that may also lead to reduced white matter integrity, pot... more Obesity is a chronic metabolic disorder that may also lead to reduced white matter integrity, potentially due to shared genetic risk factors. Genetic correlation analyses were conducted in a large cohort of Mexican American families in San Antonio (N = 761, 58% females, ages 18-81 years; 41.3 ± 14.5) from the Genetics of Brain Structure and Function Study. Shared genetic variance was calculated between measures of adiposity [(body mass index (BMI; kg/m 2 ) and waist circumference (WC; in)] and whole-brain and regional measurements of cerebral white matter integrity (fractional anisotropy). Whole-brain average and regional fractional anisotropy values for 10 major white matter tracts were calculated from high angular resolution diffusion tensor imaging data (DTI; 1.7 × 1.7 ×3 mm; 55 directions). Additive genetic factors explained intersubject variance in BMI (heritability, h 2 = 0.58), WC (h 2 = 0.57), and FA (h 2 = 0.49). FA shared significant portions of genetic variance with BMI in the genu (ρG = −0.25), body (ρG = −0.30), and splenium (ρG = −0.26) of the corpus callosum, internal capsule (ρG = −0.29), and thalamic radiation (ρG = −0.31) (all p's = 0.043). The strongest evidence of shared variance was between BMI/WC and FA in the superior fronto-occipital fasciculus (ρG = −0.39, p = 0.020; ρG = −0.39, p = 0.030), which highlights region-specific variation in neural correlates of obesity. This may suggest that increase in obesity and reduced white matter integrity share common genetic risk factors.
Arquivos Brasileiros de Cardiologia, 2005
To assess mortality trends due to ischemic heart diseases, per sex, and acute myocardial infarcti... more To assess mortality trends due to ischemic heart diseases, per sex, and acute myocardial infarction, per sex and age range, from 1980 to 1998, in the city of Curitiba. Methods Data of death due to ischemic heart disease and acute myocardial infarction from Sistema de Informação sobre Mortalidade do Ministério da Saúde (Information System on Mortality of Ministry of Health), per sex, age range and domicile location in Curitiba were used. Population data were obtained from Fundação Instituto Brasileiro de Geografia e Estatística (Brazilian Institute of Geography and Statistics Foundation). Mortality rates were adjusted per age through direct method, by using the population of Curitiba, in 1980, as reference. The analysis of trend was calculated through simple linear regression, with a significance level of 5%.
Cerebral Cortex
Schizophrenia is a devastating neuropsychiatric syndrome associated with distributed brain dyscon... more Schizophrenia is a devastating neuropsychiatric syndrome associated with distributed brain dysconnectivity that may involve large-scale thalamo-cortical systems. Incomplete characterization of thalamic connectivity in schizophrenia limits our understanding of its relationship to symptoms and to diagnoses with shared clinical presentation, such as bipolar illness, which may exist on a spectrum. Using resting-state functional magnetic resonance imaging, we characterized thalamic connectivity in 90 schizophrenia patients versus 90 matched controls via: (1) Subject-specific anatomically defined thalamic seeds; (2) anatomical and data-driven clustering to assay within-thalamus dysconnectivity; and (3) machine learning to classify diagnostic membership via thalamic connectivity for schizophrenia and for 47 bipolar patients and 47 matched controls. Schizophrenia analyses revealed functionally related disturbances: Thalamic over-connectivity with bilateral sensory–motor cortices, which pred...
Human Brain Mapping
Individuals with a family history of substance use disorders (FH+) are at a greater risk of devel... more Individuals with a family history of substance use disorders (FH+) are at a greater risk of developing substance use disorders than their peers with no such family histories (FH-) and this vulnerability is proportional to the number of affected relatives (FH density). The risk for developing substance use disorders peaks during adolescence to early adulthood in the general population, and that is thought to be related to delayed maturation of frontocortical and frontostriatal functional circuits. We hypothesized that FH+ youth and young adults have impaired myelination of frontocortical and frontostriatal white matter tracts. We examined fractional anisotropy (FA) data in 80 FH+ and 34 FH- youths (12.9 ± 1.0 years) and in 25 FH+ and 30 FH- young adults (24.3 ± 3.4 years). FH+ youths had lower FA values in both frontocortical and frontostriatal tracts as well as parietocortical tracts including the anterior, superior and posterior corona radiata and the superior frontal-occipital fas...
Brain and Behavior, 2015
Youths with a family history of alcohol and other drug use disorders (FH+) are at greater risk of... more Youths with a family history of alcohol and other drug use disorders (FH+) are at greater risk of developing substance-use disorders relative to those with no such family histories (FH-). We previously reported that FH+ youths have elevated activity in the supplementary motor area (SMA) and dorsal striatum while performing go/no-go tasks and have reduced frontal white matter integrity. A better understanding of relationships between these variables would provide insight into how frontostriatal circuitry is altered in FH+ youths, which may be an important contributor to their elevated risk. In this study, we used structural equation modeling (SEM) to test interactions between activity in the SMA and dorsal striatum in 72 FH+ and 32 FH- youths during go/no-go task performance and to determine whether increased activity in these regions in FH+ youths can be at least partially explained by reduced frontal white matter integrity, as indexed by anterior corona radiata fractional anisotropy and N-acetylaspartate. Increased dorsal striatum activity explained most (∽75%) of the elevated SMA activity in FH+ youths, and the combined contributions of increased dorsal striatal activity, and decreased white matter integrity fully explained the elevated SMA activity. These results suggest the elevated frontal cortical activity in FH+ youths is driven both by their increased striatal activity via downstream projections and reduced white matter integrity in frontal cortical projections, the latter likely increasing frontal cortical activity due to increased energy demands required for action potential propagation. As part of our ongoing longitudinal studies we will examine how these frontostriatal alterations relate to risk for developing substance-use disorders.
Human brain mapping, Jan 24, 2015
Reduced speed of cerebral information processing is a cognitive deficit associated with schizophr... more Reduced speed of cerebral information processing is a cognitive deficit associated with schizophrenia. Normal information processing speed (PS) requires intact white matter (WM) physiology to support information transfer. In a cohort of 107 subjects (47/60 patients/controls), we demonstrate that PS deficits in schizophrenia patients are explained by reduced WM integrity, which is measured using diffusion tensor imaging, mediated by the mismatch in WM/gray matter blood perfusion, and measured using arterial spin labeling. Our findings are specific to PS, and testing this hypothesis for patient-control differences in working memory produces no explanation. We demonstrate that PS deficits in schizophrenia can be explained by neurophysiological alterations in cerebral WM. Whether the disproportionately low WM integrity in schizophrenia is due to illness or secondary due to this disorder deserves further examination. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc.
Executive function deficits are observed in many psychiatric disorders. Executive functions decli... more Executive function deficits are observed in many psychiatric disorders. Executive functions decline with age and are an early indicator of most forms of dementia. Thus, executive function is a construct with high clinical relevance for which genetic underpinnings need to be explored.
NeuroImage, Jan 23, 2015
Heritability estimation has become an important tool for imaging genetics studies. The large numb... more Heritability estimation has become an important tool for imaging genetics studies. The large number of voxel- and vertex-wise measurements in imaging genetics studies presents a challenge both in terms of computational intensity and the need to account for elevated false positive risk because of the multiple testing problem. There is a gap in existing tools, as standard neuroimaging software cannot estimate heritability, and yet standard quantitative genetics tools cannot provide essential neuroimaging inferences, like family-wise error corrected voxel-wise or cluster-wise P-values. Moreover, available heritability tools rely on P-values that can be inaccurate with usual parametric inference methods. In this work we develop fast estimation and inference procedures for voxel-wise heritability, drawing on recent methodological results that simplify heritability likelihood computations (Blangero et al., 2013). We review the family of score and Wald tests and propose novel inference met...
Genome Mapping and Genomics in Human and Non-Human Primates, 2015
ABSTRACT Despite rapid advancements and widespread interest, the field of imaging-genetics is nei... more ABSTRACT Despite rapid advancements and widespread interest, the field of imaging-genetics is neither mature nor secure. Although single-gene implications related to prevalent disorders continue to attract the lion’s share of attention, of far greater importance for the maturation and longevity of the field is an established foundation regarding how genes influence basic neuroscience. The genetic search space is finite and defined; the neuroscience component is anything but. Therefore, the greatest limitation is our ability to translate image-based features into neuroscientific phenotypes. The field will fully emerge only if laboratories capable of doing imaging-genetics research perceive the need to define fundamental neuroscience in terms of genetic elements. To make progress toward this overarching goal, there is urgent need for a systematic program of discovery based on genetic underpinnings of brain function. This chapter details the efforts of the Genetics of Brain Structure and Function (GOBS) project to build such a program of discovery.
NeuroImage, Jan 3, 2015
The degree to which genetic factors influence brain connectivity is beginning to be understood. L... more The degree to which genetic factors influence brain connectivity is beginning to be understood. Large-scale efforts are underway to map the profile of genetic effects in various brain regions. The NIH-funded Human Connectome Project (HCP) is providing data valuable for analyzing the degree of genetic influence underlying brain connectivity revealed by state-of-the-art neuroimaging methods. We calculated the heritability of the fractional anisotropy (FA) measure derived from diffusion tensor imaging (DTI) reconstruction in 481 HCP subjects (194/287M/F) consisting of 57/60 pairs of mono- and dizygotic twins, and 246 siblings. FA measurements were derived using (Enhancing NeuroImaging Genetics through Meta-Analysis) ENIGMA DTI protocols and heritability estimates were calculated using the SOLAR-Eclipse imaging genetic analysis package. We compared heritability estimates derived from HCP data to those publicly available through the ENIGMA-DTI consortium, which were pooled together from ...
Frontiers in Genetics, 2015
Obesity is a chronic metabolic disorder that may also lead to reduced white matter integrity, pot... more Obesity is a chronic metabolic disorder that may also lead to reduced white matter integrity, potentially due to shared genetic risk factors. Genetic correlation analyses were conducted in a large cohort of Mexican American families in San Antonio (N = 761, 58% females, ages 18-81 years; 41.3 ± 14.5) from the Genetics of Brain Structure and Function Study. Shared genetic variance was calculated between measures of adiposity [(body mass index (BMI; kg/m 2 ) and waist circumference (WC; in)] and whole-brain and regional measurements of cerebral white matter integrity (fractional anisotropy). Whole-brain average and regional fractional anisotropy values for 10 major white matter tracts were calculated from high angular resolution diffusion tensor imaging data (DTI; 1.7 × 1.7 ×3 mm; 55 directions). Additive genetic factors explained intersubject variance in BMI (heritability, h 2 = 0.58), WC (h 2 = 0.57), and FA (h 2 = 0.49). FA shared significant portions of genetic variance with BMI in the genu (ρG = −0.25), body (ρG = −0.30), and splenium (ρG = −0.26) of the corpus callosum, internal capsule (ρG = −0.29), and thalamic radiation (ρG = −0.31) (all p's = 0.043). The strongest evidence of shared variance was between BMI/WC and FA in the superior fronto-occipital fasciculus (ρG = −0.39, p = 0.020; ρG = −0.39, p = 0.030), which highlights region-specific variation in neural correlates of obesity. This may suggest that increase in obesity and reduced white matter integrity share common genetic risk factors.
Experimental Brain Research, 2014
Static body equilibrium is an essential requisite for human daily life. It is known that visual a... more Static body equilibrium is an essential requisite for human daily life. It is known that visual and vestibular systems must work together to support equilibrium. However, the relationship between these two systems is not fully understood. In this work, we present the results of a study which identify the interaction of brain areas that are involved with concurrent visual and vestibular inputs. The visual and the vestibular systems were individually and simultaneously stimulated, using flickering checkerboard (without movement stimulus) and galvanic current, during experiments of functional magnetic resonance imaging. Twenty-four right-handed and non-symptomatic subjects participated in this study. Single visual stimulation shows positive blood-oxygen-level-dependent (BOLD) responses (PBR) in the primary and associative visual cortices. Single vestibular stimulation shows PBR in the parieto-insular vestibular cortex, inferior parietal lobe, superior temporal gyrus, precentral gyrus and lobules V and VI of the cerebellar hemisphere. Simultaneous stimulation shows PBR in the middle and inferior frontal gyri and in the precentral gyrus. Vestibular- and somatosensory-related areas show negative BOLD responses (NBR) during simultaneous stimulation. NBR areas were also observed in the calcarine gyrus, lingual gyrus, cuneus and precuneus during simultaneous and single visual stimulations. For static visual and galvanic vestibular simultaneous stimulation, the reciprocal inhibitory visual-vestibular interaction pattern is observed in our results. The experimental results revealed interactions in frontal areas during concurrent visual-vestibular stimuli, which are affected by intermodal association areas in occipital, parietal, and temporal lobes.
Journal of Clinical Medicine, 2014
Background: There is increasing evidence that bipolar disorder (BD) and conduct disorder (CD) are... more Background: There is increasing evidence that bipolar disorder (BD) and conduct disorder (CD) are co-occurring disorders. Magnetic resonance imaging has revealed differences in the structure and function of the frontal cortex in these disorders when studied separately; however, the impact of BD comorbidity on brain structure in adolescents with CD has not yet been examined. Method: We conducted an optimized voxel based morphometry (VBM) study of juvenile offenders with the following diagnoses: conduct disorder with comorbid bipolar disorder (CD-BD; n = 24), conduct disorder without bipolar disorder (CD; n = 24) and healthy controls (HC, n = 24). Participants were 13-17 years of age, in a residential treatment facility for repeat offenders. The three groups in this study were similar in age, gender, socioeconomic status and OPEN ACCESS ethnicity. Results: We found CD-BD subjects had decreased volume relative to controls at the voxel level in the right medial prefrontal cortex (PFC). Using a Threshold-Free Cluster Enhancement (TFCE) technique, the CD-BD subjects had significantly decreased volumes of the right medial prefrontal cortex and portions of the superior and inferior frontal gyrus, anterior cingulate and temporal gyrus. The CD subjects did not have differences in brain volume compared to control subjects or CD-BD subjects. Conclusions: Our findings suggest the comorbidity between CD and BD is associated with neurobiological impact namely volumetric differences from healthy controls. Furthermore subjects with this comorbidity had poorer lifetime functioning, more mood and attentional dysfunction, and more medication exposure than subjects with CD who were not BD.
Biological Psychiatry, 2015
Background: Although case-control approaches are beginning to disentangle schizophrenia's complex... more Background: Although case-control approaches are beginning to disentangle schizophrenia's complex polygenic burden, other methods will likely be necessary to fully identify and characterize risk genes. Endophenotypes, traits genetically correlated with an illness, can help characterize the impact of risk genes by providing genetically relevant traits that are more tractable than the behavioral symptoms that classify mental illness. Here, we present an analytic approach for discovering and empirically validating endophenotypes in extended pedigrees with very few affected individuals. Our approach indexes each family member's risk as a function of shared genetic kinship with an affected individual, often referred to as the coefficient of relatedness. To demonstrate the utility of this approach, we search for neurocognitive and neuroanatomic endophenotypes for schizophrenia in large unselected multigenerational pedigrees.
Jornal Brasileiro de Doenças Sexualmente Transmissíveis, 2013
Introduction: Many evidences have demonstrated the association between human papillomavirus (HPV)... more Introduction: Many evidences have demonstrated the association between human papillomavirus (HPV) infection and cervical cancer, and prophylactic vaccines have been effective to prevent this infection. In relation to the vaccination program of the population, it is important to study the sexual behavior of adolescent students, especially the onset age of sexual activity. Objective: To evaluate the sexual behavior of adolescent students from public schools in relation to some associated variables and to link the onset age of sexual activity with HPV vaccination of the population. Methods: The study was based on the application of a questionnaire to 500 students of public high schools of the city of Curitiba, aged between 13 and 19 years, to assess their sexual behavior and related questions. Of the 500 questionnaires, 488 were answered and analyzed by statistical methodology. The study was approved by local regulatory bodies. Results: Regarding sexual activity, it was observed that it was most frequent along male than female students. It is noticed that 47.8% of boys and 24.6% of girls answered positively to this question. Similarly, 38.7% of boys reported having initiated sexual activity before age 14 compared to only 8.5% of the girls. Other data about the perceived risk of contracting a sexually transmitted infection and contraception condom were assessed. The relation between drug use (tobacco, alcohol and marijuana) and sexual activity was demonstrated. About 45% of sexually active students stated regular use of drugs, compared with less than 20% of those who reported not having initiated sexual activity (p < 0.001), whereas this proportion was even more evident when analyzed only the use of marijuana. The "protector" effect of family environment shows an interesting finding: the adolescents who lived with their parents were less sexually active than those who did not report such situation with a percentage of 31.3% versus 59.4% (p = 0.003). Conclusion: We concluded that sexual activity was more evident among male participants as sexual initiation was earlier among boys. Use of drugs and independence of family environment were related to higher rate of earlier and current sexual activity. According to researches, 90% of the students who already are 17 years old had initiated sexual activity; therefore, we can conclude that the age of vaccination proposed by most governmental authorities and the Brazilian Federation of Gynecology and Obstetrics (Febrasgo) is adequately when it comes to prevent HPV infection. Keywords: adolescence, sexual behavior, HPV vaccine.
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Papers by Anderson Winkler