Linking Impulsivity to Activity Levels in Pre-Supplementary Motor Area during Sequential Gambling.

Impulsivity refers to the tendency to act prematurely or without forethought, and excessive impulsivity is a key problem in many neuropsychiatric disorders. Since the pre-supplementary motor area (pre-SMA) has been implicated in inhibitory control, this region may also contribute to impulsivity. Here, we examined whether functional recruitment of pre-SMA may contribute to risky choice behavior (state impulsivity) during sequential gambling and its relation to self-reported trait impulsivity. To this end, we performed task-based functional MRI (fMRI) after low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) of the pre-SMA. We expected low-frequency rTMS to modulate task-related engagement of the pre-SMA and, hereby, tune the tendency to make risky choices. Twenty-four healthy volunteers (12 females; age range, 19-52 years) received real or sham-rTMS on separate days in counterbalanced order. Thereafter, participants performed a sequential gambling task with concurrently increasing stakes and risk during whole-brain fMRI. In the sham-rTMS session, self-reported trait impulsivity scaled positively with state impulsivity (riskier choice behavior) during gambling. The higher the trait impulsivity, the lower was the task-related increase in pre-SMA activity with increasingly risky choices. Following real-rTMS, low-impulsivity participants increased their preference for risky choices, while the opposite was true for high-impulsivity participants, resulting in an overall decoupling of trait impulsivity and state impulsivity during gambling. This rTMS-induced behavioral shift was mirrored in the rTMS-induced change in pre-SMA activation. These results provide converging evidence for a causal link between the level of task-related pre-SMA activity and the propensity for impulsive risk-taking behavior in the context of sequential gambling.SIGNIFICANCE STATEMENT Impulsivity is a personal trait characterized by a tendency to act prematurely or without forethought, and excessive impulsivity is a key problem in many neuropsychiatric disorders. Here we provide evidence that the pre-supplementary motor area (pre-SMA) is causally involved in implementing general impulsive tendencies (trait impulsivity) into actual behavior (state impulsivity). Participants' self-reported impulsivity levels (trait impulsivity) were reflected in their choice behavior (state impulsivity) when involved in a sequential gambling task. This relationship was uncoupled after perturbing the pre-SMA with repetitive transcranial stimulation (rTMS). This effect was contingent on trait impulsivity and was echoed in rTMS-induced changes in pre-SMA activity. Pre-SMA is key in translating trait impulsivity into behavior, possibly by integrating prefrontal goals with corticostriatal motor control.

Using neuroimaging to assess brain activity and areas associated with surgical skills: a systematic review.

BACKGROUND: Surgical skills acquisition is under continuous development due to the emergence of new technologies, and there is a need for assessment tools to develop along with these. A range of neuroimaging modalities has been used to map the functional activation of brain networks while surgeons acquire novel surgical skills. These have been proposed as a method to provide a deeper understanding of surgical expertise and offer new possibilities for the personalized training of future surgeons. With studies differing in modalities, outcomes, and surgical skills there is a need for a systematic review of the evidence. This systematic review aims to summarize the current knowledge on the topic and evaluate the potential use of neuroimaging in surgical education. METHODS: We conducted a systematic review of neuroimaging studies that mapped functional brain activation while surgeons with different levels of expertise learned and performed technical and non-technical surgical tasks. We included all studies published before July 1st, 2023, in MEDLINE, EMBASE and WEB OF SCIENCE. RESULTS: 38 task-based brain mapping studies were identified, consisting of randomized controlled trials, case-control studies, and observational cohort or cross-sectional studies. The studies employed a wide range of brain mapping modalities, including electroencephalography, functional magnetic resonance imaging, positron emission tomography, and functional near-infrared spectroscopy, activating brain areas involved in the execution and sensorimotor or cognitive control of surgical skills, especially the prefrontal cortex, supplementary motor area, and primary motor area, showing significant changes between novices and experts. CONCLUSION: Functional neuroimaging can reveal how task-related brain activity reflects technical and non-technical surgical skills. The existing body of work highlights the potential of neuroimaging to link task-related brain activity patterns with the individual level of competency or improvement in performance after training surgical skills. More research is needed to establish its validity and usefulness as an assessment tool.

Dynamic involvement of premotor and supplementary motor areas in bimanual pinch force control.

Many activities of daily living require quick shifts between symmetric and asymmetric bimanual actions. Bimanual motor control has been mostly studied during continuous repetitive tasks, while little research has been carried out in experimental settings requiring dynamic changes in motor output generated by both hands. Here, we performed functional magnetic resonance imaging (MRI) while healthy volunteers performed a visually guided, bimanual pinch force task. This enabled us to map functional activity and connectivity of premotor and motor areas during bimanual pinch force control in different task contexts, requiring mirror-symmetric or inverse-asymmetric changes in discrete pinch force exerted with the right and left hand. The bilateral dorsal premotor cortex showed increased activity and effective coupling to the ipsilateral supplementary motor area (SMA) in the inverse-asymmetric context compared to the mirror-symmetric context of bimanual pinch force control while the SMA showed increased negative coupling to visual areas. Task-related activity of a cluster in the left caudal SMA also scaled positively with the degree of synchronous initiation of bilateral pinch force adjustments, irrespectively of the task context. The results suggest that the dorsal premotor cortex mediates increasing complexity of bimanual coordination by increasing coupling to the SMA while SMA provides feedback about motor actions to the sensory system.

Multipulse transcranial magnetic stimulation of human motor cortex produces short-latency corticomotor facilitation via two distinct mechanisms.

Single-pulse transcranial magnetic stimulation (TMS) of the precentral hand representation (M1HAND) can elicit indirect waves in the corticospinal tract at a periodicity of ∼660 Hz, called I-waves. These descending volleys are produced by transsynaptic excitation of fast-conducting corticospinal axons in M1HAND. Paired-pulse TMS can induce short-interval intracortical facilitation (SICF) of motor evoked potentials (MEPs) at interpulse intervals that match I-wave periodicity. This study examined whether short-latency corticospinal facilitation engages additional mechanisms independently of I-wave periodicity. In 19 volunteers, one to four biphasic TMS pulses were applied to left M1HAND with interpulse intervals adjusted to the first peak or trough of the individual SICF curve at different intensities to probe the intensity-response relationship. Multipulse TMSHAND at individual peak latency facilitated MEP amplitudes and reduced resting motor threshold (RMT) compared with single pulses. Multipulse TMSHAND at individual trough latency also produced a consistent facilitation of MEPs and a reduction of RMT. Short-latency facilitation at trough latency was less pronounced, but the relative difference in facilitation decreased with increasing stimulus intensity. Increasing the pulse number had only a modest effect. Two mechanisms underlie short-latency facilitation caused by biphasic multipulse TMSHAND. One intracortical mechanism is related to I-wave periodicity and engages fast-conducting direct projections to spinal motoneurons. A second corticospinal mechanism does not rely on I-wave rhythmicity and may be mediated by slower-conducting indirect pyramidal tract projections from M1HAND to spinal interneurons. The latter mechanism deserves more attention in studies of the corticomotor system and its link to manual motor control using the MEP.NEW & NOTEWORTHY TMS pairs evoke SICF at interpulse intervals (IPIs) that match I-wave periodicity. Biphasic bursts with IPIs at the latency of the first peak facilitate MEPs and reduce corticomotor threshold. Bursts at the latency of the first trough facilitate MEPs and reduce corticomotor threshold to a lesser extent. TMS bursts facilitate corticomotor excitability via two mechanisms: SICF-dependently via fast-conducting direct projections from M1HAND to spinal motoneurons and SICF-independently, probably through slower-conducting indirect pyramidal tract projections.

Stability of associations between neuroticism and microstructural asymmetry of the cingulum during late childhood and adolescence: Insights from a longitudinal study with up to 11 waves.

Adolescence is characterized by significant brain development and marks a period of the life span with an increased incidence of mood disorders, especially in females. The risk of developing mood disorders is also higher in individuals scoring high on neuroticism, a personality trait characterized by a tendency to experience negative and anxious emotions. We previously found in a cross-sectional study that neuroticism is associated with microstructural left-right asymmetry of the fronto-limbic white matter involved in emotional processing, with opposite effects in female and male adolescents. We now have extended this work collecting longitudinal data in 76 typically developing children and adolescents aged 7-18 years, including repeated MRI sampling up to 11 times. This enabled us, for the first time, to address the critical question, whether the association between neuroticism and frontal-limbic white matter asymmetry changes or remains stable across late childhood and adolescence. Neuroticism was assessed up to four times and showed good intraindividual stability and did not significantly change with age. Conforming our cross-sectional results, females scoring high on neuroticism displayed increased left-right cingulum fractional anisotropy (FA), while males showed decreased left-right cingulum FA asymmetry. Despite ongoing age-related increases in FA in cingulum, the association between neuroticism and cingulum FA asymmetry was already expressed in females in late childhood and remained stable across adolescence. In males, the association appeared to become more prominent during adolescence. Future longitudinal studies need to cover an earlier age span to elucidate the time point at which the relationship between neuroticism and cingulum FA asymmetry arises.

Is it all in the baseline? Trajectories of chair stand performance over 4 years and their association with grey matter structure in older adults.

Understanding individual variability in response to physical activity is key to developing more effective and personalised interventions for healthy ageing. Here, we aimed to unpack individual differences by using longitudinal data from a randomised-controlled trial of a 12-month muscle strengthening intervention in older adults. Physical function of the lower extremities was collected from 247 participants (66.3 ± 2.5 years) at four time-points. At baseline and at year 4, participants underwent 3 T MRI brain scans. K-means longitudinal clustering was used to identify patterns of change in chair stand performance over 4 years, and voxel-based morphometry was applied to map structural grey matter volume at baseline and year 4. Results identified three groups showing trajectories of poor (33.6%), mid (40.1%), and high (26.3%) performance. Baseline physical function, sex, and depressive symptoms significantly differed between trajectory groups. High performers showed greater grey matter volume in the motor cerebellum compared to the poor performers. After accounting for baseline chair stand performance, participants were re-assigned to one of four trajectory-based groups: moderate improvers (38.9%), maintainers (38.5%), improvers (13%), and decliners (9.7%). Clusters of significant grey matter differences were observed between improvers and decliners in the right supplementary motor area. Trajectory-based group assignments were unrelated to the intervention arms of the study. In conclusion, patterns of change in chair stand performance were associated with greater grey matter volumes in cerebellar and cortical motor regions. Our findings emphasise that how you start matters, as baseline chair stand performance was associated with cerebellar volume 4 years later.

Volumetric measurements of weak current-induced magnetic fields in the human brain at high resolution.

PURPOSE: Clinical use of transcranial electrical stimulation (TES) requires accurate knowledge of the injected current distribution in the brain. MR current density imaging (MRCDI) uses measurements of the TES-induced magnetic fields to provide this information. However, sufficient sensitivity and image quality in humans in vivo has only been documented for single-slice imaging. METHODS: A recently developed, optimally spoiled, acquisition-weighted, gradient echo-based 2D-MRCDI method has now been advanced for volume coverage with densely or sparsely distributed slices: The 3D rectilinear sampling (3D-DENSE) and simultaneous multislice acquisition (SMS-SPARSE) were optimized and verified by cable-loop experiments and tested with 1-mA TES experiments for two common electrode montages. RESULTS: Comparisons between the volumetric methods against the 2D-MRCDI showed that relatively long acquisition times of 3D-DENSE using a single slab with six slices hindered the expected sensitivity improvement in the current-induced field measurements but improved sensitivity by 61% in the Laplacian of the field, on which some MRCDI reconstruction methods rely. Also, SMS-SPARSE acquisition of three slices, with a factor 2 CAIPIRINHA (controlled aliasing in parallel imaging results in higher acceleration) acceleration, performed best against the 2D-MRCDI with sensitivity improvements for the ∆ B z , c $$ \Delta {B}_{z,c} $$ and Laplacian noise floors of 56% and 78% (baseline without current flow) as well as 43% and 55% (current injection into head). SMS-SPARSE reached a sensitivity of 67 pT for three distant slices at 2 × 2 × 3 mm3 resolution in 10 min of total scan time, and consistently improved image quality. CONCLUSION: Volumetric MRCDI measurements with high sensitivity and image quality are well suited to characterize the TES field distribution in the human brain.

X-linked creatine transporter (SLC6A8) deficiency in females: Difficult to recognize, but a potentially treatable disease.

Creatine transporter deficiency (CTD), caused by pathogenic variants in SLC6A8, is the second most common cause of X-linked intellectual disability. Symptoms include intellectual disability, epilepsy, and behavioral disorders and are caused by reduced cerebral creatine levels. Targeted treatment with oral supplementation is available, however the treatment efficacy is still being investigated. There are clinical and theoretical indications that heterozygous females with CTD respond better to supplementation treatment than hemizygous males. Unfortunately, heterozygous females with CTD often have more subtle and uncharacteristic clinical and biochemical phenotypes, rendering diagnosis more difficult. We report a new female case who presented with learning disabilities and seizures. After determining the diagnosis with molecular genetic testing confirmed by proton magnetic resonance spectroscopy (1H-MRS), the patient was treated with supplementation treatment including creatine, arginine, and glycine. After 28 months of treatment, the patient showed prominent clinical improvement and increased creatine levels in the brain. Furthermore, we provide a review of the 32 female cases reported in the current literature including a description of phenotypes, genotypes, diagnostic approaches, and effects of supplementation treatment. Based on this, we find that supplementation treatment should be tested in heterozygous female patients with CTD, and a prospective treatment underlines the importance of diagnosing these patients. The diagnosis should be suspected in a broad clinical spectrum of female patients and can only be made by molecular genetic testing. 1H-MRS of cerebral creatine levels is essential for establishing the diagnosis in females, and especially valuable when assessing variants of unknown significance.

Lack of reproducibility of resting-state functional MRI findings in migraine with aura.

BACKGROUND: Several studies have applied resting-state functional MRI to examine whether functional brain connectivity is altered in migraine with aura patients. These studies had multiple limitations, including small sample sizes, and reported conflicting results. Here, we performed a large, cross-sectional brain imaging study to reproduce previous findings. METHODS: We recruited women aged 30-60 years from the nationwide Danish Twin Registry. Resting-state functional MRI of women with migraine with aura, their co-twins, and unrelated migraine-free twins was performed at a single centre. We carried out an extensive series of brain connectivity data analyses. Patients were compared to migraine-free controls and to co-twins. RESULTS: Comparisons were based on data from 160 patients, 30 co-twins, and 136 controls. Patients were similar to controls with regard to age, and several lifestyle characteristics. We replicated clear effects of age on resting-state networks. In contrast, we failed to detect any differences, and to replicate previously reported differences, in functional connectivity between migraine patients with aura and non-migraine controls or their co-twins in any of the analyses. CONCLUSION: Given the large sample size and the unbiased population-based design of our study, we conclude that women with migraine with aura have normal resting-state brain connectivity outside of migraine attacks.

Investigations of the subarachnoid space as a potential link between aura and headache in migraine: A case-control MRI study.

BACKGROUND: The connection between migraine aura and headache is poorly understood. Some patients experience migraine aura without headache, and patients with migraine aura with headache commonly experience milder headaches with age. The distance between the cerebral cortex and the overlying dura mater has been hypothesized to influence development of headache following aura. We tested this hypothesis by comparing approximated distances between visual cortical areas and overlying dura mater between female patients with migraine aura without headache and female patients with migraine aura with headache. METHODS: Twelve cases with migraine aura without headache and 45 age-matched controls with migraine aura with headache underwent 3.0 T MRI. We calculated average distances between the occipital lobes, between the calcarine sulci, and between the skull and visual areas V1, V2 and V3a. We also measured volumes of corticospinal fluid between the occipital lobes, between the calcarine sulci, and overlying visual areas V2 and V3a. We investigated the relationship between headache status, distances and corticospinal fluid volumes using conditional logistic regression. RESULTS: Distances between the occipital lobes, calcarine sulci and between the skull and V1, V2 and V3a did not differ between patients with migraine aura with headache and patients with migraine aura without headache. We found no differences in corticospinal fluid volumes between groups. CONCLUSION: We found no indication for a connection between visual migraine aura and headache based on cortico-cortical, cortex-to-skull distances, or corticospinal fluid volumes overlying visual cortical areas. Longitudinal studies with imaging sequences optimized for measuring the cortico-dural distance and a larger sample of patients are needed to further investigate the hypothesis.

Linking lesions in sensorimotor cortex to contralateral hand function in multiple sclerosis: a 7†T MRI study.

Cortical lesions constitute a key manifestation of multiple sclerosis and contribute to clinical disability and cognitive impairment. Yet it is unknown whether local cortical lesions and cortical lesion subtypes contribute to domain-specific impairments attributable to the function of the lesioned cortex. In this cross-sectional study, we assessed how cortical lesions in the primary sensorimotor hand area relate to corticomotor physiology and sensorimotor function of the contralateral hand. Fifty relapse-free patients with relapsing-remitting or secondary-progressive multiple sclerosis and 28 healthy age- and sex-matched participants underwent whole-brain 7 T MRI to map cortical lesions. Brain scans were also used to estimate normalized brain volume, pericentral cortical thickness, white matter lesion fraction of the corticospinal tract, infratentorial lesion volume and the cross-sectional area of the upper cervical spinal cord. We tested sensorimotor hand function and calculated a motor and sensory composite score for each hand. In 37 patients and 20 healthy controls, we measured maximal motor-evoked potential amplitude, resting motor threshold and corticomotor conduction time with transcranial magnetic stimulation and the N20 latency from somatosensory-evoked potentials. Patients showed at least one cortical lesion in the primary sensorimotor hand area in 47 of 100 hemispheres. The presence of a lesion was associated with worse contralateral sensory (P = 0.014) and motor (P = 0.009) composite scores. Transcranial magnetic stimulation of a lesion-positive primary sensorimotor hand area revealed a decreased maximal motor-evoked potential amplitude (P < 0.001) and delayed corticomotor conduction (P = 0.002) relative to a lesion-negative primary sensorimotor hand area. Stepwise mixed linear regressions showed that the presence of a primary sensorimotor hand area lesion, higher white-matter lesion fraction of the corticospinal tract, reduced spinal cord cross-sectional area and higher infratentorial lesion volume were associated with reduced contralateral motor hand function. Cortical lesions in the primary sensorimotor hand area, spinal cord cross-sectional area and normalized brain volume were also associated with smaller maximal motor-evoked potential amplitude and longer corticomotor conduction times. The effect of cortical lesions on sensory function was no longer significant when controlling for MRI-based covariates. Lastly, we found that intracortical and subpial lesions had the largest effect on reduced motor hand function, intracortical lesions on reduced motor-evoked potential amplitude and leucocortical lesions on delayed corticomotor conduction. Together, this comprehensive multilevel assessment of sensorimotor brain damage shows that the presence of a cortical lesion in the primary sensorimotor hand area is associated with impaired corticomotor function of the hand, after accounting for damage at the subcortical level. The results also provide preliminary evidence that cortical lesion types may affect the various facets of corticomotor function differentially.

Midlife perceived stress is associated with cognitive decline across three decades.

BACKGROUND: Research indicates detrimental effects of stress on brain health and cognitive functioning, but population-based studies using comprehensive measures of cognitive decline is lacking. The present study examined the association of midlife perceived stress with cognitive decline from young adulthood to late midlife, controlling for early life circumstances, education and trait stress (neuroticism). METHODS: The sample consisted of 292 members of the Copenhagen Perinatal Cohort (1959-1961) with continued participation in two subsequent follow-up studies. Cognitive ability was assessed in young adulthood (mean age 27 years) and midlife (mean age 56 years) using the full Wechsler Adult Intelligence Scale (WAIS), and perceived stress was measured at midlife using the Perceived Stress Scale. The association of midlife perceived stress with decline in Verbal, Performance and Full-Scale IQ was assessed in multiple regression models based on Full Information Maximum Likelihood estimation. RESULTS: Over a mean retest interval of 29 years, average decline in IQ score was 2.42 (SD 7.98) in Verbal IQ and 8.87 (SD 9.37) in Performance IQ. Mean decline in Full-scale IQ was 5.63 (SD 7.48), with a retest correlation of 0.83. Controlling for parental socio-economic position, education and young adult IQ, higher perceived stress at midlife was significantly associated with greater decline in Verbal (ß = - 0.012), Performance (ß = - 0.025), and Full-scale IQ (ß = - 0.021), all p < .05. Across IQ scales, additionally controlling for neuroticism in young adulthood and change in neuroticism had only minor effects on the association of midlife perceived stress with decline. CONCLUSIONS: Despite very high retest correlations, decline was observed on all WAIS IQ scales. In fully adjusted models, higher midlife perceived stress was associated with greater decline on all scales, indicating a negative association of stress with cognitive ability. The association was strongest for Performance and Full-scale IQ, perhaps reflecting the greater decline on these IQ scales compared to Verbal IQ.

The Myelin Content of the Human Precentral Hand Knob Reflects Interindividual Differences in Manual Motor Control at the Physiological and Behavioral Level.

The primary motor cortex hand area (M1HAND) and adjacent dorsal premotor cortex (PMd) form the so-called motor hand knob in the precentral gyrus. M1HAND and PMd are critical for dexterous hand use and are densely interconnected via corticocortical axons, lacking a sharp demarcating border. In 24 young right-handed volunteers, we performed multimodal mapping to delineate the relationship between structure and function in the right motor hand knob. Quantitative structural magnetic resonance imaging (MRI) at 3 tesla yielded regional R1 maps as a proxy of cortical myelin content. Participants also underwent functional MRI (fMRI). We mapped task-related activation and temporal precision, while they performed a visuomotor synchronization task requiring visually cued abduction movements with the left index or little finger. We also performed sulcus-aligned transcranial magnetic stimulation of the motor hand knob to localize the optimal site (hotspot) for evoking a motor evoked potential (MEP) in two intrinsic hand muscles. Individual motor hotspot locations varied along the rostrocaudal axis. The more rostral the motor hotspot location in the precentral crown, the longer were corticomotor MEP latencies. "Hotspot rostrality" was associated with the regional myelin content in the precentral hand knob. Cortical myelin content also correlated positively with task-related activation of the precentral crown and temporal precision during the visuomotor synchronization task. Together, our results suggest a link among cortical myelination, the spatial cortical representation, and temporal precision of finger movements. We hypothesize that the myelination of cortical axons facilitates neuronal integration in PMd and M1HAND and, hereby, promotes the precise timing of movements.SIGNIFICANCE STATEMENT Here we used magnetic resonance imaging and transcranial magnetic stimulation of the precentral motor hand knob to test for a link among cortical myelin content, functional corticomotor representations, and manual motor control. A higher myelin content of the precentral motor hand knob was associated with more rostral corticomotor presentations, with stronger task-related activation and a higher precision of movement timing during a visuomotor synchronization task. We propose that a high precentral myelin content enables fast and precise neuronal integration in M1 (primary motor cortex) and dorsal premotor cortex, resulting in higher temporal precision during dexterous hand use. Our results identify the degree of myelination as an important structural feature of the neocortex that is tightly linked to the function and behavior supported by the cortical area.

Mapping cortico-subcortical sensitivity to 4 Hz amplitude modulation depth in human auditory system with functional MRI.

Temporal modulations in the envelope of acoustic waveforms at rates around 4 Hz constitute a strong acoustic cue in speech and other natural sounds. It is often assumed that the ascending auditory pathway is increasingly sensitive to slow amplitude modulation (AM), but sensitivity to AM is typically considered separately for individual stages of the auditory system. Here, we used blood oxygen level dependent (BOLD) fMRI in twenty human subjects (10 male) to measure sensitivity of regional neural activity in the auditory system to 4 Hz temporal modulations. Participants were exposed to AM noise stimuli varying parametrically in modulation depth to characterize modulation-depth effects on BOLD responses. A Bayesian hierarchical modeling approach was used to model potentially nonlinear relations between AM depth and group-level BOLD responses in auditory regions of interest (ROIs). Sound stimulation activated the auditory brainstem and cortex structures in single subjects. BOLD responses to noise exposure in core and belt auditory cortices scaled positively with modulation depth. This finding was corroborated by whole-brain cluster-level inference. Sensitivity to AM depth variations was particularly pronounced in the Heschl's gyrus but also found in higher-order auditory cortical regions. None of the sound-responsive subcortical auditory structures showed a BOLD response profile that reflected the parametric variation in AM depth. The results are compatible with the notion that early auditory cortical regions play a key role in processing low-rate modulation content of sounds in the human auditory system.

The recent history of afferent stimulation modulates corticospinal excitability.

BACKGROUND: Transcranial magnetic stimulation (TMS) is widely used to probe corticospinal excitability and fast sensorimotor integration in the primary motor hand area (M1-HAND). A conditioning electrical stimulus, applied to the contralateral hand, can suppress the motor evoked potential (MEP) elicited by TMS of M1-HAND when the afferent stimulus arrives in M1-HAND at the time of TMS. The magnitude of this short-latency afferent inhibition (SAI) is expressed as the ratio between the conditioned and unconditioned MEP amplitude. OBJECTIVE/HYPOTHESIS: We hypothesized that corticospinal excitability and SAI are influenced by the recent history of peripheral electrical stimulation. METHODS: In twenty healthy participants, we recorded MEPs from the right first dorsal interosseus muscle. MEPs were evoked by single-pulse TMS of the left M1-HAND alone (unconditioned TMS) or by TMS preceded by electrical stimulation of the right index finger ("homotopic" conditioning) or little finger ("heterotopic" conditioning). The three conditions were either pseudo-randomly intermixed or delivered in blocks in which a single condition was repeated five or ten times. MEP amplitudes and SAI magnitudes were compared using linear mixed-effect models and one-way ANOVAs. RESULTS: All stimulation protocols consistently produced SAI, which was stronger after homotopic stimulation. Randomly intermingling the three stimulation conditions reduced the relative magnitude of homotopic and heterotopic SAI as opposed to blocked stimulation. The apparent attenuation of SAI was caused by a suppression of the unconditioned but not the conditioned MEP amplitude during the randomly intermixed pattern. CONCLUSION(S): The recent history of afferent stimulation modulates corticospinal excitability. This "history effect" impacts on the relative magnitude of SAI depending on how conditioned and unconditioned responses are intermixed and needs to be taken into consideration when probing afferent inhibition and corticospinal excitability.

Locus Coeruleus Shows a Spatial Pattern of Structural Disintegration in Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) causes a loss of neuromelanin-positive, noradrenergic neurons in the locus coeruleus (LC), which has been implicated in nonmotor dysfunction. OBJECTIVES: We used "neuromelanin sensitive" magnetic resonance imaging (MRI) to localize structural disintegration in the LC and its association with nonmotor dysfunction in PD. METHODS: A total of 42 patients with PD and 24 age-matched healthy volunteers underwent magnetization transfer weighted (MTw) MRI of the LC. The contrast-to-noise ratio of the MTw signal (CNRMTw ) was used as an index of structural LC integrity. We performed slicewise and voxelwise analyses to map spatial patterns of structural disintegration, complemented by principal component analysis (PCA). We also tested for correlations between regional CNRMTw and severity of nonmotor symptoms. RESULTS: Mean CNRMTw of the right LC was reduced in patients relative to controls. Voxelwise and slicewise analyses showed that the attenuation of CNRMTw was confined to the right mid-caudal LC and linked regional CNRMTw to nonmotor symptoms. CNRMTw attenuation in the left mid-caudal LC was associated with the orthostatic drop in systolic blood pressure, whereas CNRMTw attenuation in the caudal most portion of right LC correlated with apathy ratings. PCA identified a bilateral component that was more weakly expressed in patients. This component was characterized by a gradient in CNRMTw along the rostro-caudal and dorso-ventral axes of the nucleus. The individual expression score of this component reflected the overall severity of nonmotor symptoms. CONCLUSION: A spatially heterogeneous disintegration of LC in PD may determine the individual expression of specific nonmotor symptoms such as orthostatic dysregulation or apathy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with differences in uncinate fasciculus microstructure.

BACKGROUND: Evidence suggests that fronto-limbic brain regions and connecting white matter fibre tracts in the left hemisphere are more sensitive to glucocorticoids than in the right hemisphere. It is unknown whether treatment with glucocorticoids in childhood is associated with microstructural differences of the uncinate fasciculus and cingulum bundle, which connect fronto-limbic brain regions. Here, we tested the hypothesis that prior glucocorticoid treatment would be associated with differences in fractional anisotropy (FA) of the left relative to right uncinate fasciculus and cingulum bundle. METHODS: We performed diffusion-weighted imaging in 28 children and adolescents aged 7-16 years previously treated with glucocorticoids for nephrotic syndrome or rheumatic disease and 28 healthy controls. RESULTS: Patients displayed significantly different asymmetry in the microstructure of uncinate fasciculus with higher left but similar right uncinate fasciculus FA and axial diffusivity compared to controls. No apparent differences were observed for the cingulum. Notably, higher cumulative glucocorticoid doses were significantly associated with higher uncinate fasciculus FA and axial diffusivity bilaterally. CONCLUSIONS: Our findings indicate that previous glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with long-term changes in the microstructure of the uncinate fasciculi, and that higher cumulative glucocorticoid doses have a proportional impact on the microstructure. IMPACT: It is unknown if treatment with glucocorticoids in childhood have long-term effects on fronto-limbic white matter microstructure. The study examined if children and adolescents previously treated with glucocorticoids for nephrotic syndrome or rheumatic disorder differed in fronto-limbic white matter microstructure compared to healthy controls. The nephrotic and rheumatic patients had higher left but similar right uncinate fasciculus FA and axial diffusivity. Higher bilateral uncinate fasciculus FA and axial diffusivity was associated with higher cumulative glucocorticoid doses. We revealed new evidence suggesting that previous glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with long-term changes in uncinate fasciculi microstructure.

Ergodicity-breaking reveals time optimal decision making in humans.

Ergodicity describes an equivalence between the expectation value and the time average of observables. Applied to human behaviour, ergodic theories of decision-making reveal how individuals should tolerate risk in different environments. To optimize wealth over time, agents should adapt their utility function according to the dynamical setting they face. Linear utility is optimal for additive dynamics, whereas logarithmic utility is optimal for multiplicative dynamics. Whether humans approximate time optimal behavior across different dynamics is unknown. Here we compare the effects of additive versus multiplicative gamble dynamics on risky choice. We show that utility functions are modulated by gamble dynamics in ways not explained by prevailing decision theories. Instead, as predicted by time optimality, risk aversion increases under multiplicative dynamics, distributing close to the values that maximize the time average growth of in-game wealth. We suggest that our findings motivate a need for explicitly grounding theories of decision-making on ergodic considerations.

Sense of agency as synecdoche: Multiple neurobiological mechanisms may underlie the phenomenon summarized as sense of agency.

Functional magnetic resonance imaging (fMRI) studies on the sense of agency (SoA) have yielded heterogeneous findings identifying regional brain activity during tasks that probed SoA. In this review, we argue that the reason behind this between-study heterogeneity is a "synecdochic" way the field conceptualizes and studies SoA. Typically, a single feature is experimentally manipulated and then this is interpreted as covering all aspects of SoA. The purpose of this paper is to give an overview of the fMRI studies of SoA and attempt to provide meaningful categories whereby the heterogeneous findings may be classified. This classification is based on a separation of the experimental paradigms (Feedback Manipulations of ongoing movements, Action-Effect, and Sensory Attenuation) and type of report employed (implicit, explicit reports of graded or dichotic nature, and whether these concern self-other distinctions or sense of control). We only find that Feedback Manipulation and Action-Effect share common activation in supplementary motor area, insula and cerebellum in positive SoA and inferior frontal gyrus in the negative SoA, but observe large networks related to SoA only in Feedback Manipulation studies. To illustrate the advantages of this approach, we discuss the findings from an fMRI study which we conducted, within this framework.

Family-based cognitive behavioural therapy versus family-based relaxation therapy for obsessive-compulsive disorder in children and adolescents: protocol for a randomised clinical trial (the TECTO trial).

BACKGROUND: Cognitive behavioural therapy (CBT) is the recommended first-line treatment for children and adolescents with obsessive-compulsive disorder (OCD), but evidence concerning treatment-specific benefits and harms compared with other interventions is limited. Furthermore, high risk-of-bias in most trials prevent firm conclusions regarding the efficacy of CBT. We investigate the benefits and harms of family-based CBT (FCBT) versus family-based psychoeducation and relaxation training (FPRT) in youth with OCD in a trial designed to reduce risk-of-bias. METHODS: This is an investigator-initiated, independently funded, single-centre, parallel group superiority randomised clinical trial (RCT). Outcome assessors, data managers, statisticians, and conclusion drawers are blinded. From child and adolescent mental health services we include patients aged 8-17 years with a primary OCD diagnosis and an entry score of ≥16 on the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). We exclude patients with comorbid illness contraindicating trial participation; intelligence quotient < 70; or treatment with CBT, PRT, antidepressant or antipsychotic medication within the last 6 months prior to trial entry. Participants are randomised 1:1 to the experimental intervention (FCBT) versus the control intervention (FPRT) each consisting of 14 75-min sessions. All therapists deliver both interventions. Follow-up assessments occur in week 4, 8 and 16 (end-of-treatment). The primary outcome is OCD symptom severity assessed with CY-BOCS at end-of-trial. Secondary outcomes are quality-of-life and adverse events. Based on sample size estimation, a minimum of 128 participants (64 in each intervention group) are included. DISCUSSION: In our trial design we aim to reduce risk-of-bias, enhance generalisability, and broaden the outcome measures by: 1) conducting an investigator-initiated, independently funded RCT; 2) blinding investigators; 3) investigating a representative sample of OCD patients; 3) using an active control intervention (FPRT) to tease apart general and specific therapy effects; 4) using equal dosing of interventions and therapist supervision in both intervention groups; 5) having therapists perform both interventions decided by randomisation; 6) rating fidelity of both interventions; 7) assessing a broad range of benefits and harms with repeated measures. The primary study limitations are the risk of missing data and the inability to blind participants and therapists to the intervention. TRIAL REGISTRATION: ClinicalTrials.gov : NCT03595098, registered July 23, 2018.