Neural representations of anxiety in adolescents with anorexia nervosa: a multivariate approach.

Anorexia nervosa (AN) is characterized by low body weight, fear of gaining weight, and distorted body image. Anxiety may play a role in the formation and course of the illness, especially related to situations involving food, eating, weight, and body image. To understand distributed patterns and consistency of neural responses related to anxiety, we enrolled 25 female adolescents with AN and 22 non-clinical female adolescents with mild anxiety who underwent two fMRI sessions in which they saw personalized anxiety-provoking word stimuli and neutral words. Consistency in brain response patterns across trials was determined using a multivariate representational similarity analysis (RSA) approach within anxiety circuits and in a whole-brain voxel-wise searchlight analysis. In the AN group there was higher representational similarity for anxiety-provoking compared with neutral stimuli predominantly in prefrontal regions including the frontal pole, medial prefrontal cortex, dorsolateral prefrontal cortex, and medial orbitofrontal cortex, although no significant group differences. Severity of anxiety correlated with consistency of brain responses within anxiety circuits and in cortical and subcortical regions including the frontal pole, middle frontal gyrus, orbitofrontal cortex, thalamus, lateral occipital cortex, middle temporal gyrus, and cerebellum. Higher consistency of activation in those with more severe anxiety symptoms suggests the possibility of a greater degree of conditioned brain responses evoked by personally-relevant emotional stimuli. Anxiety elicited by disorder-related stimuli may activate stereotyped, previously-learned neural responses within- and outside of classical anxiety circuits. Results have implications for understanding consistent and automatic responding to environmental stimuli that may play a role in maintenance of AN.

Neural Systems for Own-body Processing Align with Gender Identity Rather Than Birth-assigned Sex.

Gender identity is a core aspect of self-identity and is usually congruent with birth-assigned sex and own body sex-perception. The neuronal circuits underlying gender identity are unknown, but greater awareness of transgenderism has sparked interest in studying these circuits. We did this by comparing brain activation and connectivity in transgender individuals (for whom gender identity and birth-assigned sex are incongruent) with that in cisgender controls (for whom they are congruent) when performing a body self-identification task during functional magnetic resonance imaging. Thirty transgender and 30 cisgender participants viewed images of their own bodies and bodies morphed in sex toward or opposite to birth-assigned sex, rating each image to the degree they identified with it. While controls identified with images of themselves, transgender individuals identified with images morphed "opposite" to their birth-assigned sex. After covarying out the effect of self-similarity ratings, both groups activated similar self- and body-processing systems when viewing bodies that aligned with their gender identity rather than birth-assigned sex. Additionally, transgender participants had greater limbic involvement when viewing ambiguous, androgynous images of themselves morphed toward their gender identity. These results shed light on underlying self-processing networks specific to gender identity and uncover additional involvement of emotional processing in transgender individuals.

One-year changes in brain microstructure differentiate preclinical Huntington's disease stages.

OBJECTIVE: To determine whether brain imaging markers of tissue microstructure can detect the effect of disease progression across the preclinical stages of Huntington's disease. METHODS: Longitudinal microstructural changes in diffusion imaging metrics (mean diffusivity and fractional anisotropy) were investigated in participants with presymptomatic Huntington's disease (N = 35) stratified into three preclinical subgroups according to their estimated time until onset of symptoms, compared with age- and gender-matched healthy controls (N = 19) over a 1y period. RESULTS: Significant differences were found over the four groups in change of mean diffusivity in the posterior basal ganglia and the splenium of the corpus callosum. This overall effect was driven by significant differences between the group far-from-onset (FAR) of symptoms and the groups midway- (MID) and near-the-onset (NEAR) of symptoms. In particular, an initial decrease of mean diffusivity in the FAR group was followed by a subsequent increase in groups closer to onset of symptoms. The seemingly counter-intuitive decrease of mean diffusivity in the group furthest from onset of symptoms might be an early indicator of neuroinflammatory process preceding the neurodegenerative phase. In contrast, the only clinical measure that was able to capture a difference in 1y changes between the preclinical stages was the UHDRS confidence in motor score. CONCLUSIONS: With sensitivity to longitudinal changes in brain microstructure within and between preclinical stages, and potential differential response to distinct pathophysiological mechanisms, diffusion imaging is a promising state marker for monitoring treatment response and identifying the optimal therapeutic window of opportunity in preclinical Huntington's disease.

Sex differences in own and other body perception.

Own body perception, and differentiating and comparing one's body to another person's body, are common cognitive functions that have relevance for self-identity and social interactions. In several psychiatric conditions, including anorexia nervosa, body dysmorphic disorder, gender dysphoria, and autism spectrum disorder, self and own body perception, as well as aspects of social communication are disturbed. Despite most of these conditions having skewed prevalence sex ratios, little is known about whether the neural basis of own body perception differs between the sexes. We addressed this question by investigating brain activation using functional magnetic resonance imaging during a Body Perception task in 15 male and 15 female healthy participants. Participants viewed their own body, bodies of same-sex, or opposite-sex other people, and rated the degree that they appeared like themselves. We found that men and women did not differ in the pattern of brain activation during own body perception compared to a scrambled control image. However, when viewing images of other bodies of same-sex or opposite-sex, men showed significantly stronger activations in attention-related and reward-related brain regions, whereas women engaged stronger activations in striatal, medial-prefrontal, and insular cortices, when viewing the own body compared to other images of the opposite sex. It is possible that other body images, particularly of the opposite sex, may be of greater salience for men, whereas images of own bodies may be more salient for women. These observations provide tentative neurobiological correlates to why women may be more vulnerable than men to conditions involving own body perception.

Training voluntary motor suppression with real-time feedback of motor evoked potentials.

Training people to suppress motor representations voluntarily could improve response control. We evaluated a novel training procedure of real-time feedback of motor evoked potentials (MEPs) generated by transcranial magnetic stimulation (TMS) over motor cortex. On each trial, a cue instructed participants to use a mental strategy to suppress a particular finger representation without overt movement. A single pulse of TMS was delivered over motor cortex, and an MEP-derived measure of hand motor excitability was delivered visually to the participant within 500 ms. In experiment 1, we showed that participants learned to reduce the excitability of a particular finger beneath baseline (selective motor suppression) within 30 min of practice. In experiment 2, we performed a double-blind study with 2 training groups (1 with veridical feedback and 1 with matched sham feedback) to show that selective motor suppression depends on the veridical feedback itself. Experiment 3 further demonstrated the importance of veridical feedback by showing that selective motor suppression did not arise from mere mental imagery, even when incentivized with reward. Thus participants can use real-time feedback of TMS-induced MEPs to discover an effective mental strategy for selective motor suppression. This high-temporal-resolution, trial-by-trial-feedback training method could be used to help people better control response tendencies and may serve as a potential therapy for motor disorders such as Tourette's and dystonia.

Proactive selective response suppression is implemented via the basal ganglia.

In the welter of everyday life, people can stop particular response tendencies without affecting others. A key requirement for such selective suppression is that subjects know in advance which responses need stopping. We hypothesized that proactively setting up and implementing selective suppression relies on the basal ganglia and, specifically, regions consistent with the inhibitory indirect pathway for which there is scant functional evidence in humans. Consistent with this hypothesis, we show, first, that the degree of proactive motor suppression when preparing to stop selectively (indexed by transcranial magnetic stimulation) corresponds to striatal, pallidal, and frontal activation (indexed by functional MRI). Second, we demonstrate that greater striatal activation at the time of selective stopping correlates with greater behavioral selectivity. Third, we show that people with striatal and pallidal volume reductions (those with premanifest Huntington's disease) have both absent proactive motor suppression and impaired behavioral selectivity when stopping. Thus, stopping goals are used to proactively set up specific basal ganglia channels that may then be triggered to implement selective suppression. By linking this suppression to the striatum and pallidum, these results provide compelling functional evidence in humans of the basal ganglia's inhibitory indirect pathway.

Stability of resting fMRI interregional correlations analyzed in subject-native space: a one-year longitudinal study in healthy adults and premanifest Huntington's disease.

The pattern of interregional functional MRI correlations at rest is being actively considered as a potential noninvasive biomarker in multiple diseases. Before such methods can be used in clinical studies it is important to establish their usefulness in three ways. First, the long-term stability of resting correlation patterns should be characterized, but there have been very few such studies. Second, analysis of resting correlations should account for the unique neuroanatomy of each subject by taking measurements in native space and avoiding transformation of functional data to a standard volume space (e.g., Talairach-Tournox or Montreal Neurological Institute atlases). Transformation to a standard volume space has been shown to variably influence the measurement of functional correlations, and this is a particular concern in diseases which may cause structural changes in the brain. Third, comparisons within the patient population of interest and comparisons between patients and age-matched controls, should demonstrate sensitivity to any disease-related disruption of resting functional correlations. Here we examine the test-retest stability of resting fMRI correlations over a period of one year in a group of healthy adults and in a group of cognitively intact individuals who are gene-positive for Huntington's disease. A recently-developed method is used to measure functional correlations in the native space of individual subjects. The utility of resting functional correlations as a biomarker in premanifest Huntington's disease is also investigated. Results in control and premanifest Huntington's populations were both highly consistent at the group level over one year. We thus show that when resting fMRI analysis is performed in native space (to reduce confounds in registration between subjects and groups) it has good long-term stability at the group level. Individual-subject level results were less consistent between visit 1 and visit 2, suggesting further work is required before resting fMRI correlations can be useful diagnostically for individual patients. No significant effect of premanifest Huntington's disease on prespecified interregional fMRI correlations was observed relative to the control group using either baseline or longitudinal measures. Within the premanifest Huntington's group, though, there was evidence that decreased striatal functional correlations might be associated with disease severity, as gauged by estimated years to symptom onset or by striatal volume.

Transcranial magnetic stimulation reveals dissociable mechanisms for global versus selective corticomotor suppression underlying the stopping of action.

Stopping an initiated response is an essential function, investigated in many studies with go/no-go and stop-signal paradigms. These standard tests require rapid action cancellation. This appears to be achieved by a suppression mechanism that has "global" effects on corticomotor excitability (i.e., affecting task-irrelevant muscles). By contrast, stopping action in everyday life may require selectivity (i.e., targeting a specific response tendency without affecting concurrent action). We hypothesized that while standard stopping engages global suppression, behaviorally selective stopping engages a selective suppression mechanism. Accordingly, we measured corticomotor excitability of the task-irrelevant leg using transcranial magnetic stimulation while subjects stopped the hand. Experiment 1 showed that for standard (i.e., nonselective) stopping, the task-irrelevant leg was suppressed. Experiment 2 showed that for behaviorally selective stopping, there was no mean leg suppression. Experiment 3 directly compared behaviorally nonselective and selective stopping. Leg suppression occurred only in the behaviorally nonselective condition. These results argue that global and selective suppression mechanisms are dissociable. Participants may use a global suppression mechanism when speed is stressed; however, they may recruit a more selective suppression mechanism when selective stopping is behaviorally necessary and preparatory information is available. We predict that different fronto-basal-ganglia pathways underpin these different suppression mechanisms.

Basal ganglia atrophy in prodromal Huntington's disease is detectable over one year using automated segmentation.

Future clinical trials of neuroprotection in prodromal Huntington's (known as preHD) will require sensitive in vivo imaging biomarkers to track disease progression over the shortest period. Since basal ganglia atrophy is the most prominent structural characteristic of Huntington's pathology, systematic assessment of longitudinal subcortical atrophy holds great potential for future biomarker development. We studied 36 preHD and 22 age-matched controls using a novel method to quantify regional change from T(1) -weighted structural images acquired 1 year apart. We assessed cross-sectional volume differences and longitudinal volumetric change in 7 subcortical structures-the accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. At baseline, accumbens, caudate, pallidum, and putamen volumes were reduced in preHD versus controls (all P < .01). Longitudinally, atrophy was greater in preHD than controls in the caudate, pallidum, and putamen (all P < .01). Each structure showed a large between-group effect size, especially the pallidum where Cohen's d was 1.21. Using pallidal atrophy as a biomarker, we estimate that a hypothetical 1-year neuroprotection study would require only 35 preHD per arm to detect a 50% slowing in atrophy and only 138 preHD per arm to detect a 25% slowing in atrophy. The effect sizes calculated for preHD basal ganglia atrophy over 1 year are some of the largest reported to date. Consequently, this translates to strikingly small sample size estimates that will greatly facilitate any future neuroprotection study. This underscores the utility of this automatic image segmentation and longitudinal nonlinear registration method for upcoming studies of preHD and other neurodegenerative disorders.

Automated structural imaging analysis detects premanifest Huntington's disease neurodegeneration within 1 year.

Intense efforts are underway to evaluate neuroimaging measures as biomarkers for neurodegeneration in premanifest Huntington's disease (preHD). We used a completely automated longitudinal analysis method to compare structural scans in preHD individuals and controls. Using a 1-year longitudinal design, we analyzed T(1) -weighted structural scans in 35 preHD individuals and 22 age-matched controls. We used the SIENA (Structural Image Evaluation, using Normalization, of Atrophy) software tool to yield overall percentage brain volume change (PBVC) and voxel-level changes in atrophy. We calculated sample sizes for a hypothetical disease-modifying (neuroprotection) study. We found significantly greater yearly atrophy in preHD individuals versus controls (mean PBVC controls, -0.149%; preHD, -0.388%; P = .031, Cohen's d = .617). For a preHD subgroup closest to disease onset, yearly atrophy was more than 3 times that of controls (mean PBVC close-to-onset preHD, -0.510%; P = .019, Cohen's d = .920). This atrophy was evident at the voxel level in periventricular regions, consistent with well-established preHD basal ganglia atrophy. We estimated that a neuroprotection study using SIENA would only need 74 close-to-onset individuals in each arm (treatment vs placebo) to detect a 50% slowing in yearly atrophy with 80% power. Automated whole-brain analysis of structural MRI can reliably detect preHD disease progression in 1 year. These results were attained with a readily available imaging analysis tool, SIENA, which is observer independent, automated, and robust with respect to image quality, slice thickness, and different pulse sequences. This MRI biomarker approach could be used to evaluate neuroprotection in preHD.