Neuroanatomical Substrates Research Articles

Morphine-responsive neurons that regulate mechanical antinociception.

Opioids are widely used, effective analgesics to manage severe acute and chronic pain, although they have recently come under scrutiny because of epidemic levels of abuse. While these compounds act on numerous central and peripheral pain pathways, the neuroanatomical substrate for opioid analgesia is not fully understood. By means of single-cell transcriptomics and manipulation of morphine-responsive neurons, we have identified an ensemble of neurons in the rostral ventromedial medulla (RVM) that regulates mechanical nociception in mice. Among these, forced activation or silencing of excitatory RVMBDNF projection neurons mimicked or completely reversed morphine-induced mechanical antinociception, respectively, via a brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)-dependent mechanism and activation of inhibitory spinal galanin-positive neurons. Our results reveal a specific RVM-spinal circuit that scales mechanical nociception whose function confers the antinociceptive properties of morphine.

Inhibition of Thyroid Hormone Signaling in the Zona Incerta Alters Basal Metabolic Rate, Behavior, and Serum Glucocorticoids in Male Mice.

Background: It has long been known that thyroid disease can lead to changes in energy metabolism, thermoregulation, and anxiety behavior. While these actions have been partially attributed to thyroid hormone (TH) receptor α1 (TRα1) action in the brain, the precise neuroanatomical substrates have remain elusive. Methods: We used PET-CT scans to identify brain regions affected by TH. We then inhibited TRα1 signaling specifically in the most affected region, the zona incerta (ZI), a still mysterious region previously implicated in thermogenesis and anxiety. To this end, we used an adeno-associated virus (AAV) expressing a dominant-negative TRα1R384C in wild-type mice and phenotyped the animals. Finally, we used tyrosine hydroxylase-Cre mice to test specifically the contribution of ZI dopaminergic neurons. Results: Our data showed that AAV-mediated inhibition of TRα1 signaling in the ZI lead to increased energy expenditure at thermoneutrality, while body temperature regulation remained unaffected. Moreover, circulating glucocorticoid levels were increased, and a mild habituation problem was observed in the open field test. No effects were observed when TRα1 signaling was selectively inhibited in dopaminergic neurons. Conclusions: Our findings suggest that altered TH signaling in the ZI is not involved in body temperature regulation but can affect basal metabolism and modulates stress responses.

Clinical symptoms and neuroanatomical substrates of daytime sleepiness in Parkinson’s disease

Clinical and neuroanatomical correlates of daytime sleepiness in Parkinson’s disease (PD) remain inconsistent in the literature. Two studies were conducted here. The first evaluated the interrelation between non-motor and motor symptoms, using a principal component analysis, associated with daytime sleepiness in PD. The second identified the neuroanatomical substrates associated with daytime sleepiness in PD using magnetic resonance imaging (MRI). In the first study, 77 participants with PD completed an extensive clinical, cognitive testing and a polysomnographic recording. In the second study, 29 PD participants also underwent MRI acquisition of T1-weighted images. Vertex-based cortical and subcortical surface analysis, deformation-based morphometry, and voxel-based morphometry were performed to assess the association between daytime sleepiness severity and structural brain changes in participants. In both studies, the severity of daytime sleepiness and the presence of excessive daytime sleepiness (EDS; total score >10) were measured using the Epworth Sleepiness Scale. We found that individuals with EDS had a higher score on a component including higher dosage of dopamine receptor agonists, motor symptoms severity, shorter sleep latency, and greater sleep efficiency. Moreover, increased daytime sleepiness severity was associated with a larger surface area in the right insula, contracted surfaces in the right putamen and right lateral amygdala, and a larger surface in the right posterior amygdala. Hence, daytime sleepiness in PD was associated with dopaminergic receptor agonists dosage, motor impairment, and objective sleep measures. Moreover, neuroanatomical changes in cortical and subcortical regions related to vigilance, motor, and emotional states were associated with more severe daytime sleepiness.

Oxytocin receptors in the nucleus accumbens shell are necessary for the onset of maternal behavior.

In rodents, oxytocin (Oxt) contributes to the onset of maternal care by shifting the perception of pups from aversive to attractive. Both Oxt receptor knockout (Oxtr -/-) and forebrain-specific Oxtr knockout (FB/FB) dams abandon their first litters, likely due to a failure of the brain to 'switch' to a more maternal state. Whether this behavioral shift is neurochemically similar in virgin females, who can display maternal behaviors when repeatedly exposed to pups, or what neuroanatomical substrate is critical for the onset of maternal care remains unknown. To understand similarities and differences in Oxtr signaling in virgin pup-sensitized Oxtr FB/FB as opposed to post-parturient Oxtr -/- and Oxtr FB/FB dams, maternal behavior (pup-sensitized females only) and immediate early gene activation were assessed. Pup-sensitized Oxtr FB/FB females retrieved pups faster on day one of testing and had reduced c-Fos expression in the dorsal lateral septum as compared to virgin pup-sensitized Oxtr +/+ females. This differs from what was observed in post-parturient Oxtr -/- and Oxtr FB/FB dams, where increased c-Fos expression was observed in the nucleus accumbens (NAcc) shell. Based on these data, we then disrupted Oxtr signaling in the NAcc shell or the posterior paraventricular thalamus (pPVT) (control region) of female Oxtr floxed mice using a Cre recombinase expressing adeno-associated virus. Knockout of the Oxtr only in the NAcc shell prevented the onset of maternal care post-parturient females. Our data suggest that a pup-sensitized brain may differ from a post-parturient brain and that Oxtr signaling in the NAcc shell is critical to the onset of maternal behavior.

Post-stroke urinary incontinence is associated with behavior control deficits and overactive bladder

BackgroundAlthough urinary incontinence in stroke survivors can substantially impact the patient's quality of life, the underlying neuropsychological mechanisms and its neural basis have not been adequately investigated. Therefore, we investigated this topic via neuropsychological assessment and neuroimaging in a cross-sectional study. MethodsWe recruited 71 individuals with cerebrovascular disease. The relationship between urinary incontinence and neuropsychological indices was investigated using simple linear regression analysis or Mann-Whitney U test, along with other explanatory variables, e.g., severity of overactive bladder. Variables with a p-value of <0.1 in the simple regression analysis were entered in the final multiple linear regression model to control for potential confounding factors. To carry out an in-depth examination of the neuroanatomical substrate for urinary incontinence, voxel-based lesion-behavior mapping was performed using MRIcron software. ResultsBehavioral control deficits and severity of overactive bladder were closely related to severity of urinary incontinence. The voxel-based lesion-behavior mapping suggests a potential role for ventromedial prefrontal cortex lesioning in the severity of urinary incontinence, although this association is not statistically significant. ConclusionsPost-stroke urinary incontinence is closely related to two factors: neurogenic overactive bladder, a physiological disinhibition of micturition reflex, and cognitive dysfunction, characterized by behavior control deficits.

Case Report: Callosal disconnection syndrome manifesting as mixed frontal-callosal-posterior alien hand syndrome following extensive corpus callosum infarct

Alien hand syndrome (AHS) is a rare neurological phenomenon first described by Van Vleuten over a century ago. The most widely recognized variants in literature are frontal, callosal, and posterior AHS. AHS due to the corpus callosum lesion can occur alone or as part of callosal disconnection syndrome (CDS). This report presents a unique CDS case manifesting clinical features from all three AHS variants, resulting from an extensive corpus callosum infarct. Our patient exhibited various clinical features from the three AHS variants, which include grasping, groping, and difficulty releasing objects from the hand (anterior); intermanual conflict (callosal); arm levitation, mild hemiparesis, and hemisensory loss (posterior). Additionally, the extensive disruption of the corpus callosal fibers produced neurological manifestations of CDS, such as cognitive impairment, ideomotor and constructional apraxia, behavioral disorder, and transcortical motor aphasia. We employed a range of rehabilitation interventions, such as mirror box therapy, limb restraint strategy, verbal cue training, cognitive behavioral therapy, bimanual hand training, speech and language therapy, and pharmacological treatment with clonazepam. The patient showed almost complete resolution of CDS and AHS features by nine months post-stroke Our case report highlights distinctive clinical variations of AHS and the challenging correlation between clinical manifestations and neuroanatomical substrates. Future studies are necessary to explore the intricate neural connections and the precise function of the corpus callosum. This can be achieved by combining comprehensive neuropsychological testing with diffusion tensor tractography studies. It is also essential to develop a validated tool to standardize AHS assessment. Finally, the scarcity of evidence in rehabilitation interventions necessitates further studies to address the wide knowledge gap in AHS and CDS management.

DNA metabarcoding technology for the identification of the fecal microbiome in patients with chronic stress

In the latest research, the concept of stress is associated with the deregulation of several biological systems sensitive to stress, such as the immune system, the microbiome, the endocrine system and neuroanatomical substrates. The objective of the research was to identify the fecal microbiome in patients diagnosed with chronic stress and in healthy patients through a metabarcoding analysis. The methodology used fecal samples collected from 20 patients with stress and 20 healthy patients. For the diagnosis of stress, psychological tools previously validated by external researchers were used. For metabarcoding analysis, metagenomic DNA extraction was performed from the fecal samples. Next Generation Illumina genetic sequencing targeting the 16S rDNA gene was then performed, followed by bioinformatic analysis using QUIME II software. The results, at the psychological test level, 20 people with chronic stress were diagnosed, on the other hand, at the metabarcoding level, specifically at the Gender level, the Asteroleplasma bacteria present only in the 20 healthy patients was molecularly identified. On the other hand, the bacteria Alistipes and Bifidobacterium were identified with greater predominance in the 20 patients with stress. Concluding, the bacteria Alistipes and Bifidobacterium are candidates as possible markers of the intestinal microbiome in patients with chronic stress, and the bacteria Asteroleplasma are candidates as a bacterial marker of the intestinal microbiome in healthy people. Finally, the identification of the microbiome in patients with stress opens a new path to understanding stress and its relationship to dysregulation with the microbiome.

Localization of stuttering based on causal brain lesions.

Stuttering affects approximately 1 in 100 adults and can result in significant communication problems and social anxiety. It most often occurs as a developmental disorder but can also be caused by focal brain damage. These latter cases may lend unique insight into the brain regions causing stuttering. Here, we investigated the neuroanatomical substrate of stuttering using three independent datasets: (i) case reports from the published literature of acquired neurogenic stuttering following stroke (n = 20, 14 males/six females, 16-77 years); (ii) a clinical single study cohort with acquired neurogenic stuttering following stroke (n = 20, 13 males/seven females, 45-87 years); and (iii) adults with persistent developmental stuttering (n = 20, 14 males/six females, 18-43 years). We used the first two datasets and lesion network mapping to test whether lesions causing acquired stuttering map to a common brain network. We then used the third dataset to test whether this lesion-based network was relevant to developmental stuttering. In our literature dataset, we found that lesions causing stuttering occurred in multiple heterogeneous brain regions, but these lesion locations were all functionally connected to a common network centred around the left putamen, including the claustrum, amygdalostriatal transition area and other adjacent areas. This finding was shown to be specific for stuttering (PFWE < 0.05) and reproducible in our independent clinical cohort of patients with stroke-induced stuttering (PFWE < 0.05), resulting in a common acquired stuttering network across both stroke datasets. Within the common acquired stuttering network, we found a significant association between grey matter volume and stuttering impact for adults with persistent developmental stuttering in the left posteroventral putamen, extending into the adjacent claustrum and amygdalostriatal transition area (PFWE < 0.05). We conclude that lesions causing acquired neurogenic stuttering map to a common brain network, centred to the left putamen, claustrum and amygdalostriatal transition area. The association of this lesion-based network with symptom severity in developmental stuttering suggests a shared neuroanatomy across aetiologies.

Gender Differences in Cognitive Abilities in Human Adults

Modern world of globalization and unification is of particular interest considering the rapid changes in men's and women's dispositions and engagement in societal institutions. According to these contemporary developments of the psychosocial context, cognitive differences between females and males may also be changing. The aim of this study was to update findings from the last two decades regarding gender differences in cognitive abilities. Major updated results confirm earlier studies and demonstrate relevant gender differences in spatial abilities, verbal skills, emotional processing and executive functions. Like earlier studies, the new data also show small to trivial gender differences in mathematics performance, yet gender effects on complex problem solving are found to be smaller than in 1990 meta-analyses. The updated data confirm that gender differences in cognitive abilities do exist despite the increasing unification of men's and women's involvement in psychosocial contexts. Moreover, new scientific approaches demonstrate that these gender-specific cognitive differences are grounded on hormonal, neuroanatomical and neurofunctional substrates emphasizing their biological origin. Although the psychosocial interaction is of relevance, the primary biological basis of gender differences should be very strongly and carefully considered.

Volumetric and diffusion MRI abnormalities associated with dysarthria in multiple sclerosis

Abstract Up to half of all people with multiple sclerosis experience communication difficulties due to dysarthria, a disorder that impacts the motor aspects of speech production. Dysarthria in multiple sclerosis is linked to cerebellar dysfunction, disease severity and lesion load, but the neuroanatomical substrates of these symptoms remain unclear. In this study, 52 participants with multiple sclerosis and 14 age- and sex-matched healthy controls underwent structural and diffusion MRI, clinical assessment of disease severity and cerebellar dysfunction, and a battery of motor speech tasks. Assessments of regional brain volume and white matter integrity, and their relationships with clinical and speech measures, were undertaken. White matter tracts of interest included the interhemispheric sensorimotor tract, cerebello-thalamo-cortical tract, and arcuate fasciculus, based on their roles in motor and speech behaviours. Volumetric analyses were targeted to Broca’s area, Wernicke’s area, the corpus callosum, thalamus, and cerebellum. Our results indicated that multiple sclerosis participants scored worse on all motor speech tasks. Fixel-based diffusion MRI analyses showed significant evidence of white matter tract atrophy in each tract of interest. Correlational analyses further indicated that higher speech naturalness - a perceptual measure of dysarthria – and lower reading rate were associated with axonal damage in the interhemispheric sensorimotor tract and left arcuate fasciculus in people with multiple sclerosis. Axonal damage in all tracts of interest also correlated with clinical scales sensitive to cerebellar dysfunction. Participants with multiple sclerosis had lower volumes of the thalamus and corpus callosum compared to controls, though no brain volumetrics correlated with measures of dysarthria. These findings indicate that axonal damage, particularly when measured using diffusion metrics, underpin dysarthria in multiple sclerosis.

Neuroanatomical substrates of depression in dementia with Lewy bodies and Alzheimer's disease.

Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are often associated with depressive symptoms from the prodromal stage. The aim of the present study was to investigate the neuroanatomical correlates of depression in prodromal to mild DLB patients compared with AD patients. Eighty-three DLB patients, 37 AD patients, and 18 healthy volunteers were enrolled in this study. Depression was evaluated with the Mini International Neuropsychiatric Interview (MINI), French version 5.0.0. T1-weighted three-dimensional anatomical images were acquired for all participants. Regression and comparison analyses were conducted using a whole-brain voxel-based morphometry (VBM) approach on the grey matter volume (GMV). DLB patients presented a significantly higher mean MINI score than AD patients (p = 0.004), 30.1% of DLB patients had clinical depression, and 56.6% had a history of depression, while 0% of AD patients had clinical depression and 29.7% had a history of depression. VBM regression analyses revealed negative correlations between the MINI score and the GMV of right prefrontal regions in DLB patients (p < 0.001, uncorrected). Comparison analyses between DLB patients taking and those not taking an antidepressant mainly highlighted a decreased GMV in the bilateral middle/inferior temporal gyrus (p < 0.001, uncorrected) in treated DLB patients. In line with the literature, our behavioral analyses revealed higher depression scores in DLB patients than in AD patients. We also showed that depressive symptoms in DLB are associated with decreased GMV in right prefrontal regions. Treated DLB patients with long-standing depression would be more likely to experience GMV loss in the bilateral middle/inferior temporal cortex. These findings should be taken into account when managing DLB patients.

Assessment of white matter microstructure integrity in subacute postconcussive vestibular dysfunction using NODDI

Abstract Vestibular symptoms, such as dizziness and balance impairment, are frequently reported following mild traumatic brain injury (mTBI) and are associated with a protracted recovery, yet the underlying neuroanatomical substrates remain unclear. The present study utilized advanced diffusion MRI (dMRI) techniques including both conventional diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) to investigate microstructural white matter integrity in individuals with postconcussive vestibular dysfunction (PCVD) within the subacute injury period (median of 35 days from injury; IQR of 23). Study participants included 23 individuals with subacute PCVD and 37 healthy control subjects who underwent imaging and comprehensive clinical vestibular testing. Between-group voxelwise analysis of differences in white matter revealed areas of higher intra-neurite volume fraction (VIn) and isotropic volume fraction (VIso) within PCVD subjects compared to controls, which involved overlapping regions within the left hemisphere of the brain. Affected areas of higher VIn and VIso included the superior longitudinal fasciculus (SLF) and superior and posterior corona radiata (SCR and PCR, respectively). We examined the relationship between clinical vestibular measures and diffusion metrics including DTI (fractional anisotropy [FA], mean diffusivity [MD], radial diffusivity [RD] and axial diffusivity [AD]) and NODDI (intraneurite volume fraction [VIn], isotropic volume fraction [VIso], dispersion anisotropy [DA], orientation dispersion indexTotal/Primary/Secondary [ODIT/P/S]) within 32 regions-of-interest. Clinical vestibular measures included self-reported measures, including the Dizziness Handicap Inventory, Visual Vertigo Analog Scale, and Vestibular/Ocular-Motor Screening, as well as objective vestibular testing using the sensory organization test. Significant correlations were found with clinical measures across all diffusion maps (except DA), within various regions of interest (ROIs), including SLF, SCR, and PCR. These results implicate several important association bundles that may potentiate sensory processing dysfunction related to PCVD. Whether these neuroanatomical differences found within the subacute phase of PCVD are in response to injury or represent preexisting structural variations that increase vulnerability to sensory processing dysfunction is unclear and remains an active area of study.

Radionuclide Imaging of the Neuroanatomical and Neurochemical Substrate of Cognitive Decline in Parkinson's Disease.

Cognitive impairment is a frequent manifestation of Parkinson's disease (PD), resulting in decrease in patients' quality of life and increased societal and economic burden. However, cognitive decline in PD is highly heterogenous and the mechanisms are poorly understood. Radionuclide imaging techniques like positron emission tomography (PET) and single photon emission computed tomography (SPECT) have been used to investigate the neurochemical and neuroanatomical substrate of cognitive decline in PD. These techniques allow the assessment of different neurotransmitter systems, changes in brain glucose metabolism, proteinopathy, and neuroinflammation in vivo in PD patients. Here, we review current radionuclide imaging research on cognitive deficit in PD with a focus on predicting accelerating cognitive decline. This research could assist in the development of prognostic biomarkers for patient stratification and have utility in the development of ameliorative or disease-modifying therapies targeting cognitive deficit in PD.

Hypothalamic Thyroid Hormone Receptor α1 Signaling Controls Body Temperature.

Background: The importance of thyroid hormones (THs) for peripheral body temperature regulation has been long recognized, as medical conditions such as hyper- and hypothyroidism lead to alterations in body temperature and energy metabolism. In the past decade, the brain actions of THs and their respective nuclear receptors, thyroid hormone receptor α1 (TRα1) and thyroid hormone receptor beta (TRβ), coordinating body temperature regulation have moved into focus. However, the exact roles of the individual TR isoforms and their precise neuroanatomical substrates remain poorly understood. Methods: Here we used mice expressing a mutant TRα1 (TRα1+m) as well as TRβ knockouts to study body temperature regulation using radiotelemetry in conscious and freely moving animals at different ambient temperatures, including their response to oral 3,3',5-triiodothyronine (T3) treatment. Subsequently, we tested the effects of a dominant-negative TRα1 on body temperature after adeno-associated virus (AAV)-mediated expression in the hypothalamus, a region known to be involved in thermoregulation. Results: While TRβ seems to play a negligible role in body temperature regulation, TRα1+m mice had lower body temperature, which was surprisingly not entirely normalized at 30°C, where defects in facultative thermogenesis or tail heat loss are eliminated as confounding factors. Only oral T3 treatment fully normalized the body temperature profile of TRα1+m mice, suggesting that the mutant TRα1 confers an altered central temperature set point in these mice. When we tested this hypothesis more directly by expressing the dominant-negative TRα1 selectively in the hypothalamus via AAV transfection, we observed a similarly reduced body temperature at room temperature and 30°C. Conclusion: Our data suggest that TRα1 signaling in the hypothalamus is important for maintaining body temperature. However, further studies are needed to dissect the precise neuroanatomical substrates and the downstream pathways mediating this effect.

Amusia e afasia expressiva: a história de Maurice Ravel

ABSTRACT The French composer, Maurice Ravel, at the peak of his career, showed signs of a progressive disorder that affected his ability to function with verbal and musical language, as noted by the neurologist Théophile Alajouanine. The worsening of the disease led to a craniotomy, performed in 1937, which failed to reveal the cause of his illness, and he died shortly thereafter. A lack of post-mortem neuropathological evidence precluded a definitive diagnosis of the illness, which remained enigmatic. Speculations about the precise diagnosis of Ravel's neurological disease have been largely based on Alajouanine's observations, which included aphasia and amusia, mostly expressive, and ideomotor apraxia, while musical judgement, taste, and memory remained relatively intact, implying different neuroanatomical substrates. A possible subform of frontotemporal lobar degeneration complex was the diagnostic suggestion of many authors. His untimely death deprived the world of this remarkable musician, and the music that remained trapped in his mind.

Network Localization of Spontaneous Confabulation.

Spontaneous confabulation is a symptom in which false memories are conveyed by the patient as true. The purpose of the study was to identify the neuroanatomical substrate of this complex symptom and evaluate the relationship to related symptoms, such as delusions and amnesia. Twenty-five lesion locations associated with spontaneous confabulation were identified in a systematic literature search. The network of brain regions functionally connected to each lesion location was identified with a large connectome database (N=1,000) and compared with networks derived from lesions associated with nonspecific (i.e., variable) symptoms (N=135), delusions (N=32), or amnesia (N=53). Lesions associated with spontaneous confabulation occurred in multiple brain locations, but they were all part of a single functionally connected brain network. Specifically, 100% of lesions were connected to the mammillary bodies (familywise error rate [FWE]-corrected p<0.05). This connectivity was specific for lesions associated with confabulation compared with lesions associated with nonspecific symptoms or delusions (FWE-corrected p<0.05). Lesions associated with confabulation were more connected to the orbitofrontal cortex than those associated with amnesia (FWE-corrected p<0.05). Spontaneous confabulation maps to a common functionally connected brain network that partially overlaps, but is distinct from, networks associated with delusions or amnesia. These findings lend new insight into the neuroanatomical bases of spontaneous confabulation.

Mechanisms of infantile epileptic spasms syndrome: Whathave we learned from animal models?

The devastating developmental and epileptic encephalopathy of infantile epileptic spasms syndrome (IESS) has numerous causes, including, but not limited to, brain injury, metabolic, and genetic conditions. Given the stereotyped electrophysiologic, age-dependent, and clinical findings, there likely exists one or more final common pathways in the development of IESS. The identity of this final common pathway is unknown, but it may represent a novel therapeutic target for infantile spasms. Previous research on IESS has focused largely on identifying the neuroanatomic substrate using specialized neuroimaging techniques and cerebrospinal fluid analysis in human patients. Over the past three decades, several animal models of IESS were created with an aim to interrogate the underlying pathogenesis of IESS, to identify novel therapeutic targets, and to test various treatments. Each of these models have been successful at recapitulating multiple aspects of the human IESS condition. These animal models have implicated several different molecular pathways in the development of infantile spasms. In this review we outline the progress that has been made thus far using these animal models and discuss future directions to help researchers identify novel treatments for drug-resistant IESS.

Cortical and subcortical structural differences in psychostimulant-free ADHD youth with and without a family history of bipolar I disorder: a cross-sectional morphometric comparison

Although attention-deficit/hyperactivity disorder (ADHD) and a family history of bipolar I disorder (BD) are associated with increased risk for developing BD, their neuroanatomical substrates remain poorly understood. This study compared cortical and subcortical gray matter morphology in psychostimulant-free ADHD youth with and without a first-degree relative with BD and typically developing healthy controls. ADHD youth (ages 10-18 years) with (‘high-risk’, HR) or without (‘low-risk’, LR) a first-degree relative with BD and healthy comparison youth (HC) were enrolled. High-resolution 3D T1-weighted images were acquired using a Philips 3.0 T MR scanner. The FreeSurfer image analysis suite was used to measure cortical thickness, surface area, and subcortical volumes. A general linear model evaluated group differences in MRI features with age and sex as covariates, and exploratory correlational analyses evaluated associations with symptom ratings. A total of n = 142 youth (mean age: 14.16 ± 2.54 years, 35.9% female) were included in the analysis (HC, n = 48; LR, n = 49; HR, n = 45). The HR group exhibited a more severe symptom profile, including higher mania and dysregulation scores, compared to the LR group. For subcortical volumes, the HR group exhibited smaller bilateral thalamic, hippocampal, and left caudate nucleus volumes compared to both LR and HC, and smaller right caudate nucleus compared with LR. No differences were found between LR and HC groups. For cortical surface area, the HR group exhibited lower parietal and temporal surface area compared with HC and LR, and lower orbitofrontal and superior frontal surface area compared to LR. The HR group exhibited lower left anterior cingulate surface area compared with HC. LR participants exhibited greater right pars opercularis surface area compared with the HC. Some cortical alterations correlated with symptom severity ratings. These findings suggest that ADHD in youth with a BD family history is associated with a more a severe symptom profile and a neuroanatomical phenotype that distinguishes it from ADHD without a BD family history.

Repetitive Low-Intensity Vestibular Noise Stimulation Partly Reverses Behavioral and Brain Activity Changes following Bilateral Vestibular Loss in Rats.

Low-intensity noisy galvanic vestibular stimulation (nGVS) can improve static and dynamic postural deficits in patients with bilateral vestibular loss (BVL). In this study, we aimed to explore the neurophysiological and neuroanatomical substrates underlying nGVS treatment effects in a rat model of BVL. Regional brain activation patterns and behavioral responses to a repeated 30 min nGVS treatment in comparison to sham stimulation were investigated by serial whole-brain 18F-FDG-PET measurements and quantitative locomotor assessments before and at nine consecutive time points up to 60 days after the chemical bilateral labyrinthectomy (BL). The 18F-FDG-PET revealed a broad nGVS-induced modulation on regional brain activation patterns encompassing biologically plausible brain networks in the brainstem, cerebellum, multisensory cortex, and basal ganglia during the entire observation period post-BL. nGVS broadly reversed brain activity adaptions occurring in the natural course post-BL. The parallel behavioral locomotor assessment demonstrated a beneficial treatment effect of nGVS on sensory-ataxic gait alterations, particularly in the early stage of post-BL recovery. Stimulation-induced locomotor improvements were finally linked to nGVS brain activity responses in the brainstem, hemispheric motor, and limbic networks. In conclusion, combined 18F-FDG-PET and locomotor analysis discloses the potential neurophysiological and neuroanatomical substrates that mediate previously observed therapeutic nGVS effects on postural deficits in patients with BVL.

Differential effects of reward and punishment on reinforcement-based motor learning and generalization.

Reward and punishment have long been recognized as potent modulators of human behavior. Although reinforcement learning is a significant motor learning process, the exact mechanisms underlying how the brain learns movements through reward and punishment are not yet fully understood. Beyond the memory of specific examples, investigating the ability to generalize to new situations offers a better understanding of motor learning. This study hypothesizes that reward and punishment engage qualitatively different motivational systems with different neurochemical and neuroanatomical substrates, which would have differential effects on reinforcement-based motor learning and generalization. To test this hypothesis, two groups of participants learn a motor task in one direction and then relearn the same task in a new direction, receiving only performance-based reward or punishment score feedback. Our findings support our hypothesis, showing that reward led to slower learning but promoted generalization. On the other hand, punishment led to faster learning but impaired generalization. These behavioral differences may be due to different tendencies of movement variability in each group. The punishment group tended to explore more actively than the reward group during the initial learning phase, possibly due to loss aversion. In contrast, the reward group tended to explore more actively than the initial learning phase during the generalization test phase, seemingly recalling back the strategy that led to reward. These results suggest that reward and punishment may engage different neural mechanisms during reinforcement-based motor learning and generalization, with important implications for practical applications such as sports training and motor rehabilitation.