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1.
Handb Clin Neurol ; 175: 179-193, 2020.
Article in English | MEDLINE | ID: mdl-33008524

ABSTRACT

Sex differences are observed at many distinct biologic levels, such as in the anatomy and functioning of the brain, behavior, and susceptibility to neuropsychiatric disorders. Previously, these differences were believed to entirely result from the secretion of gonadal hormones; however, recent research has demonstrated that differences are also the consequence of direct or nonhormonal effects of genes located on the sex chromosomes. This chapter reviews the four core genotype model that separates the effects of hormones and sex chromosomes and highlights a few genes that are believed to be partly responsible for sex dimorphism of the brain, in particular, the Sry gene. Genetics of the brain's neurochemistry is discussed and the susceptibility to certain neurologic and psychiatric disorders is reviewed. Lastly, we discuss the sex-specific genetic contribution in disorders of sexual development. The precise molecular mechanisms underlying these differences are currently not entirely known. An increased knowledge and understanding of the role of candidate genes will undeniably be of great aid in elucidating the molecular basis of sex-biased disorders and potentially allow for more sex-specific therapies.


Subject(s)
Neuroanatomy , Sex Characteristics , Brain , Female , Genes, sry , Humans , Male , Sex Chromosomes/genetics
2.
Brain Imaging Behav ; 14(2): 477-484, 2020 Apr.
Article in English | MEDLINE | ID: mdl-31598826

ABSTRACT

Previous evidence indicates that transcranial direct stimulation (tDCS) is a neuromodulatory brain stimulation technique. Easy applicability, low side-effects and negligible costs facilitated its wide-spread application in efforts to modulate brain function, however neuronal mechanisms of tDCS are insufficiently understood. Hence, we investigated the immediate impact of tDCS on the brain's glucose consumption in a continuous infusion protocol with the radioligand 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) and positron emission tomography (PET). This novel functional PET (fPET) method is capable to reliably detect area-specific and dynamic absolute glucose demand related to neuronal activity in a single molecular imaging session. Fifteen healthy subjects underwent tDCS at 0.5, 1 and 2 mA (mA) at the bilateral dorsolateral prefrontal cortex (dlPFC, cathodal right) for 10 min during functional [18F]FDG-PET lasting 70 min. Active stimulation compared to sham did not yield significant changes in glucose consumption at any tested stimulation intensity in this paradigm. Exploratory investigation of aftereffects provided hints for increased glucose consumption with a delay of 5 min at 1 mA in the right posterior temporal cortex. This is the first study investigating changes of glucose consumption in the brain during tDCS. The lack of immediately increased glucose consumption indicates that energy demanding processes in the brain such as glutamatergic signaling might not be immediately increased by tDCS. However, our results implicate the need of fPET investigations for medium-term and long-term effects.


Subject(s)
Glucose/metabolism , Prefrontal Cortex/diagnostic imaging , Adult , Brain/metabolism , Female , Fluorodeoxyglucose F18/metabolism , Humans , Male , Motor Cortex/physiology , Positron-Emission Tomography/methods , Transcranial Direct Current Stimulation/methods
3.
Front Physiol ; 10: 1422, 2019.
Article in English | MEDLINE | ID: mdl-31824335

ABSTRACT

BACKGROUND: Several MR-based attenuation correction (AC) approaches were developed to conquer the challenging AC in hybrid PET/MR imaging. These AC methods are commonly evaluated on standardized uptake values or tissue concentration. However, in neurotransmitter system studies absolute quantification is more favorable due to its accuracy. Therefore, our aim was to investigate the accuracy of segmentation- and atlas-based MR AC approaches on serotonin transporter (SERT) distribution volumes and occupancy after a drug challenge. METHODS: 18 healthy subjects (7 male) underwent two [11C]DASB PET/MRI measurements in a double-blinded, placebo controlled, cross-over design. After 70 min the selective serotonin reuptake inhibitor (SSRI) citalopram or a placebo was infused. The parameters total and specific volume of distribution (VT, VS = BPP) and occupancy were quantified. All subjects underwent a low-dose CT scan as reference AC method. Besides the standard AC approaches DIXON and UTE, a T1-weighted structural image was recorded to estimate a pseudo-CT based on an MR/CT database (pseudoCT). Another evaluated AC approach superimposed a bone model on AC DIXON. Lastly, an approach optimizing the segmentation of UTE images was analyzed (RESOLUTE). PET emission data were reconstructed with all 6 AC methods. The accuracy of the AC approaches was evaluated on a region of interest-basis for the parameters VT, BPP, and occupancy with respect to the results of AC CT. RESULTS: Variations for VT and BPP were found with all AC methods with bias ranging from -15 to 17%. The smallest relative errors for all regions were found with AC pseudoCT (<|5%|). Although the bias between BPP SSRI and BPP placebo varied markedly with AC DIXON (<|12%|) and AC UTE (<|9%|), a high correlation to AC CT was obtained (r 2∼1). The relative difference of the occupancy for all tested AC methods was small for SERT high binding regions (<|4%|). CONCLUSION: The high correlation might offer a rescaling from the biased parameters VT and BPP to the true values. Overall, the pseudoCT approach yielded smallest errors and the best agreement with AC CT. For SERT occupancy, all AC methods showed little bias in high binding regions, indicating that errors may cancel out in longitudinal assessments.

4.
Cereb Cortex ; 29(1): 372-382, 2019 01 01.
Article in English | MEDLINE | ID: mdl-30357321

ABSTRACT

Parcellation of distinct areas in the cerebral cortex has a long history in neuroscience and is of great value for the study of brain function, specialization, and alterations in neuropsychiatric disorders. Analysis of cytoarchitectonical features has revealed their close association with molecular profiles based on protein density. This provides a rationale for the use of in vivo molecular imaging data for parcellation of the cortex with the advantage of whole-brain coverage. In the current work, parcellation was based on expression of key players of the serotonin neurotransmitter system. Positron emission tomography was carried out for the quantification of serotonin 1A (5-HT1A, n = 30) and 5-HT2A receptors (n = 22), the serotonin-degrading enzyme monoamine oxidase A (MAO-A, n = 32) and the serotonin transporter (5-HTT, n = 24) in healthy participants. Cortical protein distribution maps were obtained using surface-based quantification. Based on k-means clustering, silhouette criterion and bootstrapping, five distinct clusters were identified as the optimal solution. The defined clusters proved of high explanatory value for the effects of psychotropic drugs acting on the serotonin system, such as antidepressants and psychedelics. Therefore, the proposed method constitutes a sensible approach towards integration of multimodal imaging data for research and development in neuropharmacology and psychiatry.


Subject(s)
Cerebral Cortex/metabolism , Monoamine Oxidase/metabolism , Positron-Emission Tomography/methods , Receptor, Serotonin, 5-HT1A/metabolism , Receptor, Serotonin, 5-HT2A/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Adult , Cerebral Cortex/diagnostic imaging , Female , Humans , Male , Middle Aged , Molecular Imaging/methods , Serotonin/metabolism , Young Adult
5.
Brain Struct Funct ; 223(3): 1369-1378, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29134288

ABSTRACT

Except for task-specific functional MRI, the vast majority of imaging studies assessed human brain function at resting conditions. However, tracking task-specific neuronal activity yields important insight how the brain responds to stimulation. We specifically investigated changes in glucose metabolism, functional connectivity and white matter microstructure during task performance using several recent methodological advancements. Opening the eyes and right finger tapping had elicited an increased glucose metabolism in primary visual and motor cortices, respectively. Furthermore, a decreased metabolism was observed in the regions of the default mode network, which allowed absolute quantification of commonly described deactivations during cognitive tasks. These brain regions showed widespread task-specific changes in functional connectivity, which stretched beyond their primary resting-state networks and presumably reflected the level of recruitment of certain brain regions for each task. Finally, the corresponding white matter fiber pathways exhibited changes in axial and radial diffusivity during the tasks, which were regionally distinctive for certain tract groups. These results highlight that even simple task performance leads to substantial changes of entire brain networks. Exploiting the complementary nature of the different imaging modalities may reveal novel insights how the brain processes external stimuli and which networks are involved in certain tasks.


Subject(s)
Brain/diagnostic imaging , Brain/physiology , Magnetic Resonance Imaging , Neural Pathways/diagnostic imaging , Positron-Emission Tomography , Psychomotor Performance/physiology , Adult , Analysis of Variance , Blood Glucose/metabolism , Female , Fluorodeoxyglucose F18/pharmacokinetics , Humans , Image Processing, Computer-Assisted , Male , Neuropsychological Tests , Oxygen/blood , Rest , Time Factors , White Matter/diagnostic imaging , White Matter/metabolism , Young Adult
6.
Hum Brain Mapp ; 38(2): 792-802, 2017 02.
Article in English | MEDLINE | ID: mdl-27770470

ABSTRACT

Altered serotonergic neurotransmission has been found to cause impulsive and aggressive behavior, as well as increased motor activity, all exemplifying key symptoms of ADHD. The main objectives of this positron emission tomography (PET) study were to investigate the serotonin transporter binding potential (SERT BPND ) in patients with ADHD and to assess associations of SERT BPND between the brain regions. 25 medication-free patients with ADHD (age ± SD; 32.39 ± 10.15; 10 females) without any psychiatric comorbidity and 25 age and sex matched healthy control subjects (33.74 ± 10.20) were measured once with PET and the highly selective and specific radioligand [11 C]DASB. SERT BPND maps in nine a priori defined ROIs exhibiting high SERT binding were compared between groups by means of a linear mixed model. Finally, adopted from structural and functional connectivity analyses, we performed correlational analyses using regional SERT binding potentials to examine molecular interregional associations between all selected ROIs. We observed significant differences in the interregional correlations between the precuneus and the hippocampus in patients with ADHD compared to healthy controls, using SERT BPND of the investigated ROIs (P < 0.05; Bonferroni corrected). When correlating SERT BPND and age in the ADHD and the healthy control group, we confirmed an age-related decline in brain SERT binding in the thalamus and insula (R2 = 0.284, R2 = 0.167, Ps < 0.05; Bonferroni corrected). The results show significantly different interregional molecular associations of the SERT expression for the precuneus with hippocampus in patients with ADHD, indicating presumably altered functional coupling. Altered interregional coupling between brain regions might be a sensitive approach to demonstrate functional and molecular alterations in psychiatric conditions. Hum Brain Mapp 38:792-802, 2017. © 2016 Wiley Periodicals, Inc.


Subject(s)
Attention Deficit Disorder with Hyperactivity/diagnostic imaging , Attention Deficit Disorder with Hyperactivity/metabolism , Brain/diagnostic imaging , Positron-Emission Tomography , Serotonin Plasma Membrane Transport Proteins/metabolism , Adult , Brain/metabolism , Case-Control Studies , Female , Humans , Linear Models , Male , Psychiatric Status Rating Scales , Young Adult
7.
J Nucl Med ; 57(12): 1933-1940, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27390156

ABSTRACT

The investigation of cerebral metabolic rate of glucose (CMRGlu) at baseline and during specific tasks previously required separate scans with the drawback of high intrasubject variability. We aimed to validate a novel approach to assessing baseline glucose metabolism and task-specific changes in a single measurement with a constant infusion of 18F-FDG. METHODS: Fifteen healthy subjects underwent two PET measurements with arterial blood sampling. As a reference, baseline CMRGlu was quantified from a 60-min scan after 18F-FDG bolus application using the Patlak plot (eyes closed). For the other scan, a constant radioligand infusion was applied for 95 min, during which the subjects opened their eyes at 10-20 min and 60-70 min and tapped their right thumb to their fingers at 35-45 min and 85-95 min. The constant-infusion scan was quantified in two steps. First, the general linear model was used to fit regional time-activity curves with regressors for baseline metabolism, task-specific changes for the eyes-open and finger-tapping conditions, and movement parameters. Second, the Patlak plot was used for quantification of CMRGlu. Multiplication of the baseline regressor by ß-values from the general linear model yielded regionally specific time-activity curves for baseline metabolism. Further, task-specific changes in metabolism are directly proportional to changes in the slope of the time-activity curve and hence to changes in CMRGlu. RESULTS: Baseline CMRGlu from the constant-infusion scan matched that from the bolus application (test-retest variability, 1.1% ± 24.7%), which was not the case for a previously suggested approach (variability, -39.9% ± 25.2%, P < 0.001). Task-specific CMRGlu increased in the primary visual and motor cortices for eyes open and finger tapping, respectively (P < 0.05, familywise error-corrected), with absolute changes of up to 2.1 µmol/100 g/min and 6.3% relative to baseline. For eyes open, a decreased CMRGlu was observed in default-mode regions (P < 0.05, familywise error-corrected). CMRGlu quantified with venous blood samples (n = 6) showed excellent agreement with results obtained from arterial samples (r > 0.99). CONCLUSION: Baseline glucose metabolism and task-specific changes can be quantified in a single measurement with constant infusion of 18F-FDG and venous blood sampling. The high sensitivity and regional specificity of the approach offer novel possibilities for functional and multimodal brain imaging.


Subject(s)
Fluorodeoxyglucose F18/administration & dosage , Glucose/metabolism , Positron-Emission Tomography/methods , Adult , Brain/diagnostic imaging , Brain/metabolism , Female , Humans , Male
8.
Hum Brain Mapp ; 37(3): 884-95, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26678348

ABSTRACT

Attention deficit hyperactivity disorder (ADHD) is a heterogeneous disorder with a strong genetic component. The norepinephrine transporter (NET) is a key target for ADHD treatment and the NET gene has been of high interest as a possible modulator of ADHD pathophysiology. Therefore, we conducted an imaging genetics study to examine possible effects of single nucleotide polymorphisms (SNPs) within the NET gene on NET nondisplaceable binding potential (BPND ) in patients with ADHD and healthy controls (HCs). Twenty adult patients with ADHD and 20 HCs underwent (S,S)-[18F]FMeNER-D2 positron emission tomography (PET) and were genotyped on a MassARRAY MALDI-TOF platform using the Sequenom iPLEX assay. Linear mixed models analyses revealed a genotype-dependent difference in NET BPND between groups in the thalamus and cerebellum. In the thalamus, a functional promoter SNP (-3081 A/T) and a 5'-untranslated region (5'UTR) SNP (-182 T/C), showed higher binding in ADHD patients compared to HCs depending on the major allele. Furthermore, we detected an effect of genotype in HCs, with major allele carriers having lower binding. In contrast, for two 3'UTR SNPs (*269 T/C, *417 A/T), ADHD subjects had lower binding in the cerebellum compared to HCs depending on the major allele. Additionally, symptoms of hyperactivity and impulsivity correlated with NET BPND in the cerebellum depending on genotype. Symptoms correlated positively with cerebellar NET BPND for the major allele, while symptoms correlated negatively to NET BPND in minor allele carriers. Our findings support the role of genetic influence of the NE system on NET binding to be pertubated in ADHD.


Subject(s)
Attention Deficit Disorder with Hyperactivity/genetics , Attention Deficit Disorder with Hyperactivity/metabolism , Brain/diagnostic imaging , Brain/metabolism , Norepinephrine Plasma Membrane Transport Proteins/genetics , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Adult , Attention Deficit Disorder with Hyperactivity/diagnostic imaging , Brain Mapping , Cohort Studies , Female , Genotyping Techniques , Humans , Linkage Disequilibrium , Male , Morpholines , Polymorphism, Single Nucleotide , Positron-Emission Tomography , Promoter Regions, Genetic , Radiopharmaceuticals , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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