The Neuroanatomy of Transgender Identity: Mega-Analytic Findings From the ENIGMA Transgender Persons Working Group.

BACKGROUND: In contrast to cisgender persons, transgender persons identify with a different gender than the one assigned at birth. Although research on the underlying neurobiology of transgender persons has been accumulating over the years, neuroimaging studies in this relatively rare population are often based on very small samples resulting in discrepant findings. AIM: To examine the neurobiology of transgender persons in a large sample. METHODS: Using a mega-analytic approach, structural MRI data of 803 non-hormonally treated transgender men (TM, n = 214, female assigned at birth with male gender identity), transgender women (TW, n = 172, male assigned at birth with female gender identity), cisgender men (CM, n = 221, male assigned at birth with male gender identity) and cisgender women (CW, n = 196, female assigned at birth with female gender identity) were analyzed. OUTCOMES: Structural brain measures, including grey matter volume, cortical surface area, and cortical thickness. RESULTS: Transgender persons differed significantly from cisgender persons with respect to (sub)cortical brain volumes and surface area, but not cortical thickness. Contrasting the 4 groups (TM, TW, CM, and CW), we observed a variety of patterns that not only depended on the direction of gender identity (towards male or towards female) but also on the brain measure as well as the brain region examined. CLINICAL TRANSLATION: The outcomes of this large-scale study may provide a normative framework that may become useful in clinical studies. STRENGTHS AND LIMITATIONS: While this is the largest study of MRI data in transgender persons to date, the analyses conducted were governed (and restricted) by the type of data collected across all participating sites. CONCLUSION: Rather than being merely shifted towards either end of the male-female spectrum, transgender persons seem to present with their own unique brain phenotype. Mueller SC, Guillamon A, Zubiaurre-Elorza L, et al. The Neuroanatomy of Transgender Identity: Mega-Analytic Findings From the ENIGMA Transgender Persons Working Group. J Sex Med 2021;18:1122-1129.

Functional Magnetic Resonance Imaging of Inhibitory Control Reveals Decreased Blood Oxygen Level Dependent Effect in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

Background and Purpose- Small-vessel damage in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is associated with impaired vascular constriction and dilation. We used a functional magnetic resonance imaging task with an event-related design of stimulus to explore the anticipated abnormally decreased blood oxygen level dependent effect in CADASIL. Methods- Twenty-one CADASIL patients and 16 healthy controls performed a Go/No-go task exploring reactive and proactive phases of inhibition control in a 3-T magnet. Results- Error number and reaction times were not different between patients and controls. Analysis of the reactive inhibition (No-go/baseline contrast) did not show clusters of lower or higher blood oxygen level dependent effect in patients or controls. Analysis of the proactive inhibition (alertness contrast) in CADASIL patients revealed a lower blood oxygen level dependent effect in the alerting network (anterior cingulate cortex and insula, thalamus), lower brain stem and left cerebellar hemisphere (crus I) that is involved in executive functions. Conclusions- In CADASIL patients, an event-related Go/No-go task reveals a lower blood oxygen level dependent effect in the alerting network and areas involved in executive functions possibly reflecting the altered hemodynamic response secondary to small-vessel changes. Our observation extends the role of MR in demonstrating one of the fundamental pathophysiological changes of CADASIL.

Impulsivity trait and proactive cognitive control: An fMRI study.

The ability to flexibly regulate our behavior is a fundamental feature of human cognition and requires efficient functioning of cognitive control. During movement preparation, proactive inhibitory control plays a crucial role in regulating the excitatory activity carried out by alertness. The balance between alertness and proactive inhibition could be altered in people with motor impulsivity trait, determining the typical failure in the inhibition of prepotent motor responses. To test this hypothesis, 36 young adults were administered the Barratt Impulsiveness Scale to assess motor impulsivity trait and underwent fMRI acquisition during the execution of an event-related Go/Nogo task. To investigate motor preparation processes, we analyzed the "readiness" period, in which subjects were waiting and preparing for the upcoming stimulus (Go or Nogo). We found a positive significant correlation between motor impulsivity scores and the activation of left sensorimotor cortices. This result indicates that motor impulsivity trait might be associated with a disinhibition of the motor system, characterized by a diminished reactivity threshold and a reduced control over covert urges. Furthermore, we observed a positive significant correlation between motor impulsivity scores and the activation in left inferior and superior parietal lobule, which might be related to a more pronounced proactive control, probably reflecting a compensatory mechanism implemented by participants with a higher degree of motor impulsivity trait to reach a correct inhibition. Current findings provide a rationale for further studies aiming to better understand proactive control functioning in healthy impulsive subjects and under clinical conditions.

Characterizing cardiac autonomic dynamics of fear learning in humans.

Understanding transient dynamics of the autonomic nervous system during fear learning remains a critical step to translate basic research into treatment of fear-related disorders. In humans, it has been demonstrated that fear learning typically elicits transient heart rate deceleration. However, classical analyses of heart rate variability (HRV) fail to disentangle the contribution of parasympathetic and sympathetic systems, and crucially, they are not able to capture phasic changes during fear learning. Here, to gain deeper insight into the physiological underpinnings of fear learning, a novel frequency-domain analysis of heart rate was performed using a short-time Fourier transform, and instantaneous spectral estimates extracted from a point-process modeling algorithm. We tested whether spectral transient components of HRV, used as a noninvasive probe of sympathetic and parasympathetic mechanisms, can dissociate between fear conditioned and neutral stimuli. We found that learned fear elicited a transient heart rate deceleration in anticipation of noxious stimuli. Crucially, results revealed a significant increase in spectral power in the high frequency band when facing the conditioned stimulus, indicating increased parasympathetic (vagal) activity, which distinguished conditioned and neutral stimuli during fear learning. Our findings provide a proximal measure of the involvement of cardiac vagal dynamics into the psychophysiology of fear learning and extinction, thus offering new insights for the characterization of fear in mental health and illness.

The fMRI correlates of visuo-spatial abilities: sex differences and gender dysphoria.

The contribution of brain regions to visuospatial abilities according to sex differences and gender identity is inconsistently described. One potential explaining factor may be the different tasks employed requiring a variable load of working memory and other cognitive resources. Here we asked to 20 cis and 20 transgender participants to undergo functional Magnetic Resonance Imaging during performance of a judgement line of orientation test that was adapted to explore the basic visuospatial processing while minimizing the working memory load. We show that V1 activation may be viewed as a brain area with enhanced activation in males, regardless of participants' gender identity. On its turn, gender identity exclusively influences the visuospatial processing of extrastriate visual areas (V5) in women with gender dysphoria. They showed enhanced V5 activation and an increased functional connectivity between V5 and V1. Overall our neuroimaging results suggest that the basic visuospatial abilities are associated with different activations pattern of cortical visual areas depending on the sex assigned at birth and gender identity.

Wireless Electrocardiography and Impedance Cardiography Devices Using a Network Time Protocol for Synchronized Data.

During minimally invasive and image-guided procedures, vital parameters have to be recorded for patient safety. In the Magnetic Resonance Tomograph (MRT) environment the Magneto Hydrodynamic (MHD) effect emerges, under the high magnetic field strength in the signal recording of an Electrocardiography (ECG) system. To allow the investigation of this effect, newly developed wireless ECG and Impedance cardiography (ICG) devices using a network time protocol for accurate synchronization of the collected data will be presented. The developed ICG and tetrapolar electrodes were designed to comply with the IEC 60601-1 standard. One subject was instructed to alternate phases of end-inspiration breath hold with the regular breathing cycle and concurrent synchronized ECG and ICG were collected.

Altered Regional Brain Homogeneity of BOLD Signal in CADASIL: A Resting State fMRI Study.

BACKGROUND AND PURPOSE: The cognitive decline in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is assumed to be due to a cortical-subcortical disconnection secondary to damage to the cerebral white matter (WM). Using resting state functional MRI (rsfMRI) and analysis of the regional homogeneity (ReHo), we examined a group of CADASIL patients and a group of healthy subjects in order to: (1) explore possible differences between the two groups; and (2) to assess, in CADASIL patients, whether any ReHo abnormalities correlate with individual burdens of WM T2 -weighted hyperintensity and diffusion tensor imaging (DTI)-derived index of mean diffusivity (MD) of the cerebral WM, an index reflecting microstructural damage in CADASIL. METHODS: Twenty-three paucisymptomatic CADASIL patients (13 females; age mean ± standard deviation = 43.6 ± 11.1 years; three symptomatic and 20 with no or few symptoms) and 16 healthy controls (nine females; age 46.6 ± 11.0 years) were examined with T1 -weighted, T2 -weighted fluid attenuated inversion recovery images, DTI, and rsfMRI. RESULTS: When compared to controls, CADASIL patients showed four clusters of significantly lower ReHo values in cortical areas belonging to networks involved in inhibition and attention, including the right insula, the left superior frontal gyrus, and the bilateral anterior cingulated cortex. ReHo changes did not correlate with an individual patient's lesion burden or MD. CONCLUSIONS: This study reveals decreased ReHo of rsfMRI signals in cortical areas involved in inhibition and attention processes, suggesting a potential role for these functional cortical changes in CADASIL.

Corrigendum to "Handedness Side and Magnetization Transfer Ratio in the Primary Sensorimotor Cortex Central Sulcus".

[This corrects the article DOI: 10.1155/2019/5610849.].

Neural Correlates of Gender Face Perception in Transgender People.

To date, MRI studies focused on brain sexual dimorphism have not explored the presence of specific neural patterns in gender dysphoria (GD) using gender discrimination tasks. Considering the central role of body image in GD, the present study aims to evaluate brain activation patterns with 3T-scanner functional MRI (fMRI) during gender face discrimination task in a sample of 20 hormone-naïve transgender and 20 cisgender individuals. Additionally, participants were asked to complete psychometric measures. The between-group analysis of average blood oxygenation level dependent (BOLD) activations of female vs. male face contrast showed a significant positive cluster in the bilateral precuneus in transmen when compared to the ciswomen. In addition. the transwomen group compared to the cismen showed higher activations also in the precuneus, as well as in the posterior cingulate gyrus, the angular gyrus and the lateral occipital cortices. Moreover, the activation of precuneus, angular gyrus, lateral occipital cortices and posterior cingulate gyrus was significantly associated with higher levels of body uneasiness. These results show for the first time the existence of a possible specific GD-neural pattern. However, it remains unclear if the differences in brain phenotype of transgender people may be the result of a sex-atypical neural development or of a lifelong experience of gender non-conformity.

Central modulation of parasympathetic outflow is impaired in de novo Parkinson's disease patients.

Task- and stimulus-based neuroimaging studies have begun to unveil the central autonomic network which modulates autonomic nervous system activity. In the present study, we aimed to evaluate the central autonomic network without the bias constituted by the use of a task. Additionally, we assessed whether this circuitry presents signs of dysregulation in the early stages of Parkinson's disease (PD), a condition which may be associated with dysautonomia. We combined heart-rate-variability based methods for time-varying assessments of the autonomic nervous system outflow with resting-state fMRI in 14 healthy controls and 14 de novo PD patients, evaluating the correlations between fMRI time-series and the instantaneous high-frequency component of the heart-rate-variability power spectrum, a marker of parasympathetic outflow. In control subjects, the high-frequency component of the heart-rate-variability power spectrum was significantly anti-correlated with fMRI time-series in several cortical, subcortical and brainstem regions. This complex central network was not detectable in PD patients. In between-group analysis, we found that in healthy controls the brain activation related to the high-frequency component of the heart-rate-variability power spectrum was significantly less than in PD patients in the mid and anterior cingulum, sensorimotor cortex and supplementary motor area, insula and temporal lobe, prefrontal cortex, hippocampus and in a region encompassing posterior cingulum, precuneus and parieto-occipital cortex. Our results indicate that the complex central network which modulates parasympathetic outflow in the resting state is impaired in the early clinical stages of PD.

DTI-derived indexes of brain WM correlate with cognitive performance in vascular MCI and small-vessel disease. A TBSS study.

Indexes derived from diffusion tensor imaging (DTI) are sensitive to changes of both T2-hyperintense and normal-appearing brain white matter (WM) in elderly subjects with variable cognitive status. We investigated correlations between global cognitive performance and DTI-derived indexes along the WM tracts in the brain of patients with vascular mild cognitive impairment (MCI) and small vessel disease (SVD). Seventy-six patients with vascular MCI and SVD were assessed through Montreal Cognitive Assessment (MoCA) and Mini Mental State Examination (MMSE) test and underwent DTI examination on a 1.5 T MR scanner. We used Tract Based Spatial Statistics (TBSS) to assess voxel-wise in the entire brain the spatial distribution of the correlation between values of fractional anisotropy, mean, axial/radial diffusivity and global cognitive performance as assessed with MoCA and MMSE tests. All correlations were statistically tested with a significant p-value <0.05 using a family-wise error correction for multiple comparisons. The MoCA score significantly correlated with fractional anisotropy (positive correlation) and mean, axial and radial diffusivity (negative correlations) in WM tracts of cerebral hemispheres and corpus callosum, as well as in the intra-thalamic WM tracts and the superior cerebellar peduncle decussation in the midbrain. No significant correlations were observed for MMSE score. Global cognitive performance, as measured by the MoCA score, in patients with vascular MCI and SVD is associated with microstructural changes in WM tracts underlying intra- and inter-hemispheric cerebral, thalamo-cortical and cerebello-thalamic connections.

Handedness Side and Magnetization Transfer Ratio in the Primary Sensorimotor Cortex Central Sulcus.

Left-handers show lower asymmetry in manual ability when compared to right-handers. Unlike right-handers, left-handers do not show larger deactivation of the ipsilateral primary sensorimotor (SM1) cortex on functional magnetic resonance imaging when moving their dominant than their nondominant hand. However, it should be noted that morphometric MRI studies have reported no differences between right-handers and left-handers in volume, thickness, or surface area of the SM1 cortex. In this regard, magnetization transfer (MT) imaging is a technique with the potential to provide information on microstructural organization and macromolecular content of tissue. In particular, MT ratio index of the brain gray matter is assumed to reflect the variable content of afferent or efferent myelinated fibers, with higher MT ratio values being associated with increased fibers number or degree of myelination. The aim of this study was hence to assess, for the first time, through quantitative MT ratio measurements, potential differences in microstructural organization/characteristics of SM1 cortex between left- and right-handers, which could underlay handedness side. Nine left-handed and 9 right-handed healthy subjects, as determined by the Edinburgh handedness inventory, were examined with T1-weighted and MT-weighted imaging on a 3 T scanner. The hands of subjects were kept still during all acquisitions. Using FreeSurfer suite and the automatic anatomical labeling parcellations defined by the Destrieux atlas, we measured MT ratio, as well as cortical thickness, in three regions of interests corresponding to the precentral gyrus, the central sulcus, and the postcentral gyrus in the bilateral SM1 cortex. No significant difference between left- and right-handers was revealed in the thickness of the three partitions of the SM1 cortex. However, left-handers showed a significantly (p = 0.007) lower MT ratio (31.92% ± 0.96%) in the right SM1 central sulcus (i.e., the hand representation area for left-handers) as compared to right-handers (33.28% ± 0.94%). The results of this preliminary study indicate that quantitative MT imaging, unlike conventional morphometric MRI measurements, can be a useful tool to reveal, in SM1 cortex, potential microstructural correlates of handedness side.

Alexithymic trait is associated with right IFG and pre-SMA activation in non-emotional response inhibition in healthy subjects.

Event-related fMRI studies have explored emotion inhibitory processes in alexithymic individuals and have demonstrated abnormal BOLD activations in the processing of emotional stimuli. So far, no study has explored the relationship between the alexithymic trait and the general inhibition process, namely utilizing stimuli devoid of emotional valence. In this study 26 healthy subjects were administered the Toronto Alexithymic Scale (TAS-20) questionnaire to measure the alexithymic trait and performed an event related Go/Nogo task build up with letters during fMRI acquisition. We found no correlation between the TAS-20 z-score and the reaction times during the Go/Nogo task. Conversely, we observed a positive correlation between the degree of alexithymic trait -measured with the TAS-20 and the Nogo-Go activation of the right Inferior Frontal Gyrus and the right pre-Supplementary Motor Area. These data suggest that the general process of response inhibition may be modulated by the individual degree of alexithymic trait. We propose that such a relationship could reflect a compensatory mechanism implemented by participants with higher degree of alexithymic trait to reach a correct inhibition.

Effect of Attention Training in Mild Cognitive Impairment Patients with Subcortical Vascular Changes: The RehAtt Study.

BACKGROUND AND OBJECTIVE: Mild cognitive impairment (MCI) patients with small vessel disease (SVD) are at high dementia risk. We tested the effects of cognitive rehabilitation in these patients using the Attention Process Training-II (APT-II) program in a single-blinded, randomized clinical trial. METHODS: Patients were randomized to APT-II or standard care and evaluated at baseline, 6, and 12 months with functional, quality of life, cognitive tests, and resting state functional MRI (rsfMRI). RESULTS: Forty-six patients were enrolled and 43 (mean±SD age 75.1±6.8) completed the study. No change was seen in functionality and quality of life between treated and non-treated patients. However, the Rey Auditory-Verbal Learning Test immediate recall showed a significant improvement in treated compared to non-treated group (change score 6 versus 12 months: 1.8±4.9 and -1.4±3.8, p = 0.021; baseline versus 12 months: 3.8±6.1 and 0.2±4.4, p = 0.032). A higher proportion of treated patients had stable/better evaluation compared to non-treated group on Visual search test (6 versus 12 months: 95% versus 71%, p = 0.038) and Rey-Osterrieth Complex Figure copy (6 versus 12 months: 95% versus 67%, p = 0.027). RsfMRI, performed in a subsample, showed that the difference between follow-up and baseline in synchronization of activity in cerebellar areas was significantly greater in treated than in non-treated patients. CONCLUSION: We were unable to show a significant effect in quality of life or functional status in treated patients with MCI and SVD. However, APT-II produces some beneficial effects in focused attention and working memory and seems to increase activity in brain circuits involved in cognitive processes.

Diffusion Tensor Imaging to Map Brain Microstructural Changes in CADASIL.

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) is sensitive to brain microstructural changes. The aims of this DTI study were to map voxelwise the spatial distribution of brain microstructural changes in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and to investigate any correlation between DTI-derived indices and extension of T2 hyperintensity. METHODS: Eighteen patients with CADASIL and 18 age-, sex-, and education-level-matched healthy controls underwent magnetic resonance imaging at 3 T. Differences in DTI-derived indices (mean diffusivity [MD], fractional anisotropy [FA], axial [AD] and radial [RD] diffusivities, and mode of anisotropy [MO]) of brain white matter (WM) between CADASIL patients and healthy subjects were assessed through tract-based spatial statistics. Then, DTI-derived indices were correlated with the patient's score on the extended Fazekas visual scale of the T2 hyperintensity. RESULTS: When compared to healthy controls, CADASIL patients showed extensive symmetric areas of increased MD/RD and decreased AD/FA/MO that involved almost the entire hemispheric cerebral WM (internal and external capsule, WM of the temporal poles, superior and inferior longitudinal fasciculus, inferior frontal-occipital fasciculus, uncinate fasciculus, cingulum, forceps major and minor, corticospinal tracts, and thalamic radiations), thalami, and corpus callosum. Additional areas of increased RD were observed in pons, midbrain, cerebellar peduncles, and cerebellar WM. Only FA was negatively correlated with extended Fazekas visual score. CONCLUSIONS: Our results indicate that brain damage in CADASIL is associated with extensive microstructural changes implying impairment of intra- and inter-hemispheric cerebral, thalamocortical, and cerebrocerebellar connections. Severity of microstructural changes correlates with extension of T2 hyperintensity.

Resting state fMRI regional homogeneity correlates with cognition measures in subcortical vascular cognitive impairment.

BACKGROUND: The hyperintensity of cerebral white matter (WM) in T2-weighted MR images of elderly subjects due to small vessel disease (SVD) is associated with variable clinical features including mild cognitive impairment (MCI), also termed subcortical vascular cognitive impairment (SVCI). The latter is typically characterized by psychomotor slowing, attention deficits, and executive dysfunctions. We hypothesized that functional brain changes might be associated with these distinctive cognitive deficits in patients with SVCI. METHODS: Resting-state fMRI (rsfMRI) signal was assessed in conjunction with performance on the Montreal Cognitive Assessment battery (MoCA) and Stroop test in 67 subjects with MCI and moderate to severe extension of cerebral WM T2 hyperintensities qualifying for SVCI. We performed a whole-brain analysis of regional homogeneity (ReHo) of rsfMRI in conjunction with cognitive test scores. RESULTS: We observed a significant (p<0.05) negative association between ReHo and MoCA scores, with higher ReHo in the left posterior cerebellum (crus I) of patients with greater global cognitive impairment, and a significant positive association between ReHo and Stroop scores, with higher ReHo in the middle cingulate cortex bilaterally of patients with worse executive functions. CONCLUSION: ReHo of rsfMRI is significantly correlated with measurements of the cognitive deficits which are distinctive of SVCI. The increased activity could have a maladaptive or compensatory significance towards specific aspects of cognition.