Cerebellar Volumetry in Ataxias: Relation to Ataxia Severity and Duration.

Cerebellar atrophy is the neuropathological hallmark of most ataxias. Hence, quantifying the volume of the cerebellar grey and white matter is of great interest. In this study, we aim to identify volume differences in the cerebellum between spinocerebellar ataxia type 1 (SCA1), SCA3 and SCA6 as well as multiple system atrophy of cerebellar type (MSA-C). Our cross-sectional data set comprised mutation carriers of SCA1 (N=12), SCA3 (N=62), SCA6 (N=14), as well as MSA-C patients (N=16). Cerebellar volumes were obtained from T1-weighted magnetic resonance images. To compare the different atrophy patterns, we performed a z-transformation and plotted the intercept of each patient group's model at the mean of 7 years of ataxia duration as well as at the mean ataxia severity of 14 points in the SARA sum score. In addition, we plotted the extrapolation at ataxia duration of 0 years as well as 0 points in the SARA sum score. Patients with MSA-C demonstrated the most pronounced volume loss, particularly in the cerebellar white matter, at the late time intercept. Patients with SCA6 showed a pronounced volume loss in cerebellar grey matter with increasing ataxia severity compared to all other patient groups. MSA-C, SCA1 and SCA3 showed a prominent atrophy of the cerebellar white matter. Our results (i) confirmed SCA6 being considered as a pure cerebellar grey matter disease, (ii) emphasise the involvement of cerebellar white matter in the neuropathology of SCA1, SCA3 and MSA-C, and (iii) reflect the rapid clinical progression in MSA-C.

Cerebellar volumetry in ataxias: Relation to ataxia severity and duration.

Background: Cerebellar atrophy is the neuropathological hallmark of most ataxias. Hence, quantifying the volume of the cerebellar grey and white matter is of great interest. In this study, we aim to identify volume differences in the cerebellum between spinocerebellar ataxia type 1 (SCA1), SCA3 and SCA6 as well as multiple system atrophy of cerebellar type (MSA-C). Methods: Our cross-sectional data set comprised mutation carriers of SCA1 (N=12), SCA3 (N=62), SCA6 (N=14), as well as MSA-C patients (N=16). Cerebellar volumes were obtained from T1-weighted magnetic resonance images. To compare the different atrophy patterns, we performed a z-transformation and plotted the intercept of each patient group's model at the mean of 7 years of ataxia duration as well as at the mean ataxia severity of 14 points in the SARA sum score. In addition, we plotted the extrapolation at ataxia duration of 0 years as well as 0 points in the SARA sum score. Results: Patients with MSA-C demonstrated the most pronounced volume loss, particularly in the cerebellar white matter, at the late time intercept. Patients with SCA6 showed a pronounced volume loss in cerebellar grey matter with increasing ataxia severity compared to all other patient groups. MSA-C, SCA1 and SCA3 showed a prominent atrophy of the cerebellar white matter. Conclusion: Our results (i) confirmed SCA6 being considered as a pure cerebellar gray matter disease, (ii) emphasise the involvement of cerebellar white matter in the neurophatology of SCA1, SCA3 and MSA-C, and (iii) reflect the rapid clinical progression in MSA-C.

Independent and combined effects of methamphetamine use disorders and APOEε4 allele on cognitive performance and brain morphometry.

AIMS: Prior studies showed that methamphetamine (METH) users had greater than normal age-related brain atrophy; whether having the apolipoprotein E (APOE)-ε4 allele may be a contributory factor has not been evaluated. We aimed to determine the independent and combined effects of chronic heavy METH use and having at least one copy of the APOE-ε4 allele (APOE-ε4+) on brain morphometry and cognition, especially in relation to aging. METHODS: We compared brain morphometry and cognitive performance in 77 individuals with chronic heavy METH use (26 APOE-ε4+, 51 APOE-ε4-) and 226 Non-METH users (66 APOE-ε4+, 160 APOE-ε4-), using a 2 × 2 design (two-way analysis of co-variance). Vertex-wise cortical volumes, thickness and seven subcortical volumes, were automatically measured using FreeSurfer. Linear regression between regional brain measures, and cognitive scores that showed group differences were evaluated. Group differences in age-related decline in brain and cognitive measures were also explored. RESULTS: Regardless of APOE-ε4 genotype, METH users had lower Motor Z-scores (P = 0.005), thinner right lateral-orbitofrontal cortices (P < 0.001), smaller left pars-triangularis gyrus volumes (P = 0.004), but larger pallida, hippocampi and amygdalae (P = 0.004-0.006) than nonusers. Across groups, APOE-ε4+ METH users had the smallest volumes of superior frontal cortical gyri bilaterally, and of the smallest volume in left rostral-middle frontal gyri (all P-values <0.001). Smaller right superior-frontal gyrus predicted poorer motor function only in APOE-ε4+ participants (interaction-P < 0.001). Cortical volumes and thickness declined with age similarly across all participants; however, APOE-ε4-carriers showed thinner right inferior parietal cortices than noncarriers at younger age (interaction-P < 0.001). CONCLUSIONS: Chronic heavy use and having at least one copy of the APOE-ε4 allele may have synergistic effects on brain atrophy, particularly in frontal cortices, which may contribute to their poorer cognitive function. However, the enlarged subcortical volumes in METH users replicated prior studies, and are likely due to METH-mediated neuroinflammation.

Fear conditioning is preserved in very preterm-born young adults despite increased anxiety levels.

Very preterm birth is associated with an increased risk for anxiety disorders. Abnormal brain development may result in disordered fear learning processes, which may be exacerbated by environmental risk factors and persist in adulthood. We tested the hypotheses that very preterm-born young adults displayed higher levels of fear conditioning, less differentiation between threat (CS+) and safety (CS-) signals, and stronger resistance to extinction relative to term-born controls. A group of 37 very preterm-born young adults and 31 age- and sex-matched term-born controls performed a differential fear conditioning paradigm on two consecutive days. Acquisition and extinction training were performed on day 1. Recall and reinstatement were tested on day 2. Preterm-born participants showed significantly higher levels of anxiety in the Depression-Anxiety-Stress-Scale-21 questionnaire. The fear conditioning outcome measures, skin conductance response amplitudes and anxiety ratings, were overall higher in the preterm-born group compared to controls. Awareness of CS-US contingencies was mildly reduced in preterms. Acquisition, extinction, recall and reinstatement of differential conditioned fear responses (CS+ > CS-), however, were not significantly different between the groups. There were no significant group by stimulus type interactions. The finding of largely preserved associative fear learning in very preterm-born young adults was unexpected and needs to be confirmed in future studies.

Changes in Brain Activation Patterns During Working Memory Tasks in People With Post-COVID Condition and Persistent Neuropsychiatric Symptoms.

BACKGROUND AND OBJECTIVES: Post-COVID condition (PCC) is common and often involves neuropsychiatric symptoms. This study aimed to use blood oxygenation level-dependent fMRI (BOLD-fMRI) to assess whether participants with PCC had abnormal brain activation during working memory (WM) and whether the abnormal brain activation could predict cognitive performance, motor function, or psychiatric symptoms. METHODS: The participants with PCC had documented coronavirus disease 2019 (COVID-19) at least 6 weeks before enrollment. Healthy control participants had no prior history of COVID-19 and negative tests for severe acute respiratory syndrome coronavirus 2. Participants were assessed using 3 NIH Toolbox (NIHTB) batteries for Cognition (NIHTB-CB), Emotion (NIHTB-EB), and Motor function (NIHTB-MB) and selected tests from the Patient-Reported Outcomes Measurement Information System (PROMIS). Each had BOLD-fMRI at 3T, during WM (N-back) tasks with increasing attentional/WM load. RESULTS: One hundred sixty-nine participants were screened; 50 fulfilled the study criteria and had complete and usable data sets for this cross-sectional cohort study. Twenty-nine participants with PCC were diagnosed with COVID-19 242 ± 156 days earlier; they had similar ages (42 ± 12 vs 41 ± 12 years), gender proportion (65% vs 57%), racial/ethnic distribution, handedness, education, and socioeconomic status, as the 21 uninfected healthy controls. Despite the high prevalence of memory (79%) and concentration (93%) complaints, the PCC group had similar performance on the NIHTB-CB as the controls. However, participants with PCC had greater brain activation than the controls across the network (false discovery rate-corrected p = 0.003, Tmax = 4.17), with greater activation in the right superior frontal gyrus (p = 0.009, Cohen d = 0.81, 95% CI 0.15-1.46) but lesser deactivation in the default mode regions (p = 0.001, d = 1.03, 95% CI 0.61-1.99). Compared with controls, participants with PCC also had poorer dexterity and endurance on the NIHTB-MB, higher T scores for negative affect and perceived stress, but lower T scores for psychological well-being on the NIHTB-EB, as well as more pain symptoms and poorer mental and physical health on measures from the PROMIS. Greater brain activation predicted poorer scores on measures that were abnormal on the NIHTB-EB. DISCUSSION: Participants with PCC and neuropsychiatric symptoms demonstrated compensatory neural processes with greater usage of alternate brain regions, and reorganized networks, to maintain normal performance during WM tasks. BOLD-fMRI was sensitive for detecting brain abnormalities that correlated with various quantitative neuropsychiatric symptoms.

Associations between socioeconomic gradients and racial disparities in preadolescent brain outcomes.

BACKGROUND: The aim of this study was to determine the extent to which socioeconomic characteristics of the home and neighborhood are associated with racial inequalities in brain outcomes. METHODS: We performed a cross-sectional analysis of the baseline dataset (v.2.0.1) from the Adolescent Brain and Cognitive Development (ABCD) Study. Cognitive performance was assessed using the National Institutes of Health Toolbox (NIH-TB) cognitive battery. Standard socioeconomic indicators of the family and neighborhood were derived from census-related statistics. Cortical morphometric measures included MRI-derived thickness, area, and volume. RESULTS: 9638 children were included. Each NIH-TB cognitive measure was negatively associated with household and neighborhood socioeconomic characteristics. Differences in cognitive scores between Black or Hispanic children and other racial groups were mitigated by higher household income. Most children from lowest-income families or residents in impoverished neighborhoods were Black or Hispanic. These disparities were associated with racial differences in NIH-TB measures and mediated by smaller cortical brain volumes. CONCLUSIONS: Neighborhood socioeconomic characteristics are associated with racial differences in preadolescent brain outcomes and mitigated by greater household income. Household income mediates racial differences more strongly than neighborhood-level socioeconomic indicators in brain outcomes. Highlighting these socioeconomic risks may direct focused policy-based interventions such as allocation of community resources to ensure equitable brain outcomes in children. IMPACT: Neighborhood socioeconomic characteristics are associated with racial differences in preadolescent brain outcomes and mitigated by greater household income. Household income mediates racial differences more strongly than neighborhood-level socioeconomic indicators in brain outcomes. Highlighting these disparities related to socioeconomic risks may direct focused policy-based interventions such as allocation of community resources to ensure equitable brain outcomes in children.

Absence of modulatory effects of 6Hz cerebellar transcranial alternating current stimulation on fear learning in men.

Fear is a vital defense mechanism to potential threats, which is influenced by the cerebellum. While the cerebellum's role in acquiring fear responses is well understood, limited knowledge exists about its involvement in fear extinction. In this study, we investigated the effects of cerebellar theta band transcranial alternating current stimulation (ctACS) administered during fear extinction training, based on previous evidence from animal studies suggesting a role of cerebellar theta oscillations in associative memory formation. To this end, thirty-seven healthy right-handed male participants were recruited for a two-day differential fear renewal paradigm. On day 1, they underwent acquisition training in context A followed by extinction training in context B. On day 2, recall was tested in contexts A and B. One group of participants received ctACS in the theta band (6 Hz) during extinction training. The other group received sham ctACS. Although both groups demonstrated the ability to recall previously learned fear and distinguish between low and high threat stimuli, no significant differences were observed between the ctACS and sham groups, indicating that ctACS at this theta frequency range did not impact extinction and recall of previously acquired fear in this study. Nevertheless, using ctACS could still be useful in future research, including brain imaging studies, to better understand how the cerebellum is involved in fear and extinction processes.

CerebNet: A fast and reliable deep-learning pipeline for detailed cerebellum sub-segmentation.

Quantifying the volume of the cerebellum and its lobes is of profound interest in various neurodegenerative and acquired diseases. Especially for the most common spinocerebellar ataxias (SCA), for which the first antisense oligonculeotide-base gene silencing trial has recently started, there is an urgent need for quantitative, sensitive imaging markers at pre-symptomatic stages for stratification and treatment assessment. This work introduces CerebNet, a fully automated, extensively validated, deep learning method for the lobular segmentation of the cerebellum, including the separation of gray and white matter. For training, validation, and testing, T1-weighted images from 30 participants were manually annotated into cerebellar lobules and vermal sub-segments, as well as cerebellar white matter. CerebNet combines FastSurferCNN, a UNet-based 2.5D segmentation network, with extensive data augmentation, e.g. realistic non-linear deformations to increase the anatomical variety, eliminating additional preprocessing steps, such as spatial normalization or bias field correction. CerebNet demonstrates a high accuracy (on average 0.87 Dice and 1.742mm Robust Hausdorff Distance across all structures) outperforming state-of-the-art approaches. Furthermore, it shows high test-retest reliability (average ICC >0.97 on OASIS and Kirby) as well as high sensitivity to disease effects, including the pre-ataxic stage of spinocerebellar ataxia type 3 (SCA3). CerebNet is compatible with FreeSurfer and FastSurfer and can analyze a 3D volume within seconds on a consumer GPU in an end-to-end fashion, thus providing an efficient and validated solution for assessing cerebellum sub-structure volumes. We make CerebNet available as source-code (https://github.com/Deep-MI/FastSurfer).

Cerebellum and Emotion Memory.

Fear is an important emotion for survival, and the cerebellum has been found to contribute not only to innate affective and defensive behavior, but also to learned fear responses. Acquisition and retention of fear conditioned bradycardia and freezing have been shown to depend on the integrity of the cerebellar vermis in rodents. There is a considerable number of brain imaging studies, which observe activation of the human cerebellum in fear conditioning paradigms. Different to what one may expect based on the initial cerebellar lesion studies, activations related to the learned prediction of threat go well beyond the vermis, and are most prominent in the lateral cerebellum. Different parts of the cerebellum likely contribute to learning of autonomic, motor, emotional and cognitive responses involved in classical fear conditioning. The neural operation which is performed in the various parts of the cerebellum is frequently assumed to be the same. One hypothesis is that the cerebellum acts as, or is part of, a predictive device. More recent findings will be discussed that the cerebellum may not only be involved in the processing of sensory prediction errors, but also in the processing of reward and reward prediction errors, which may play a central role in emotions and emotional learning. Current knowledge about the intrinsic learning mechanisms underlying fear memory in the cerebellum, and its connections with subcortical and cortical fear circuitry will be presented. The chapter will conclude with a discussion on how disordered cerebellar fear learning may contribute to affective disorders.

Temporal dynamics of fMRI signal changes during conditioned interoceptive pain-related fear and safety acquisition and extinction.

Associative learning and memory mechanisms drive interoceptive signaling along the gut-brain axis, thus shaping affective-emotional reactions and behavior. Specifically, learning to predict potentially harmful, visceral pain is assumed to succeed within very few trials. However, the temporal dynamics of cerebellar and cerebral fMRI signal changes underlying early acquisition and extinction of learned fear signals and the concomitant evolvement of safety learning remain incompletely understood. 3 T fMRI data of healthy individuals from three studies were uniformly processed across the whole brain and the cerebellum. All studies employed differential delay conditioning (N = 94) with one visual cue (CS+) being repeatedly paired with visceral pain as unconditioned stimulus (US) while a second cue remained unpaired (CS-). During subsequent extinction (N = 51), all CS were presented without US. Behavioral results revealed increased CS+-aversiveness and CS--pleasantness after conditioning and diminished valence ratings for both CS following extinction. During early acquisition, the CS- induced linearly increasing neural activation in the insula, midcingulate cortex, hippocampus, precuneus as well as cerebral and cerebellar somatomotor regions. The comparison between acquisition and extinction phases yielded a CS--induced linear increase in the posterior cingulate cortex and precuneus during early acquisition, while there was no evidence for linear fMRI signal changes for the CS+ during acquisition and for both CS during extinction. Based on theoretical accounts of discrimination and temporal difference learning, these results suggest a gradual evolvement of learned safety cues that engage emotional arousal, memory, and cortical modulatory networks. As safety signals are presumably more difficult to learn and to discriminate from learned threat cues, the underlying temporal dynamics may reflect enhanced salience and prediction processing as well as increasing demands for attentional resources and the integration of multisensory information. Maladaptive responses to learned safety signals are a clinically relevant phenotype in multiple conditions, including chronic visceral pain, and can be exceptionally resistant to modification or extinction. Through sustained hypervigilance, safety seeking constitutes one key component in pain and stress-related avoidance behavior, calling for future studies targeting the mechanisms of safety learning and extinction to advance current cognitive-behavioral treatment approaches.

Subcutaneous and visceral fat assessment by DXA and MRI in older adults and children.

OBJECTIVE: Given the importance of body fat distribution in chronic disease development, feasible methods to assess body fat are essential. This study compared dual-energy x-ray absorptiometry (DXA) in measuring visceral and subcutaneous adipose tissue (VAT and SAT) with magnetic resonance imaging (MRI). METHODS: VAT and SAT were assessed using similar DXA and MRI protocols among 1,795 elderly participants of the Adiposity Phenotype Study (APS) and 309 children/adolescents in Shape Up! Kids (SKids). Spearman correlations, Bland-Altman plots, and coefficients of determination (R2 ) assessed agreement between DXA and MRI measures. RESULTS: DXA overestimated SAT values in APS (315 vs. 229 cm2 ) and SKids (212 vs. 161 cm2 ), whereas DXA underestimated VAT measures (141 vs. 167 cm2 ) in adults only. The correlations between DXA and MRI values were stronger for SAT than VAT (APS: r = 0.92 vs. 0.88; SKids: 0.90 vs. 0.74). Bland-Altman plots confirmed better agreement for SAT than VAT despite differences by sex, ethnicity, and weight status with respective R2 values for SAT and VAT of 0.88 and 0.84 (APS) and 0.81 and 0.69 (SKids). CONCLUSION: These findings indicate that SAT by DXA reflects MRI measures in children and older adults, whereas agreement for VAT is weaker for individuals with low VAT levels.

Body Fat Distribution, Glucose Metabolism, and Diabetes Status Among Older Adults: The Multiethnic Cohort Adiposity Phenotype Study.

BACKGROUND: As the proportion of visceral (VAT) to subcutaneous adipose tissue (SAT) may contribute to type 2 diabetes (T2D) development, we examined this relation in a cross-sectional design within the Multiethnic Cohort that includes Japanese Americans known to have high VAT. The aim was to understand how ectopic fat accumulation differs by glycemic status across ethnic groups with disparate rates of obesity, T2D, and propensity to accumulate VAT. METHODS: In 2013-2016, 1,746 participants aged 69.2 (standard deviation, 2.7) years from five ethnic groups completed questionnaires, blood collections, and whole-body dual X-ray absorptiometry and abdominal magnetic resonance imaging scans. Participants with self-reported T2D and/or medication were classified as T2D, those with fasting glucose >125 and 100-125 mg/dL as undiagnosed cases (UT2D) and prediabetes (PT2D), respectively. Using linear regression, we estimated adjusted means of adiposity measures by T2D status. RESULTS: Overall, 315 (18%) participants were classified as T2D, 158 (9%) as UT2D, 518 (30%) as PT2D, and 755 (43%) as normoglycemic (NG), with significant ethnic differences (P < 0.0001). In fully adjusted models, VAT, VAT/SAT, and percent liver fat increased significantly from NG, PT2D, UT2D, to T2D (P < 0.001). Across ethnic groups, the VAT/SAT ratio was lowest for NG participants and highest for T2D cases. Positive trends were observed in all groups except African Americans, with highest VAT/SAT in Japanese Americans. CONCLUSION: These findings indicate that VAT plays an important role in T2D etiology, in particular among Japanese Americans with high levels of ectopic adipose tissue, which drives the development of T2D to a greater degree than in other ethnic groups.

Motor training-related brain reorganization in patients with cerebellar degeneration.

Cerebellar degeneration progressively impairs motor function. Recent research showed that cerebellar patients can improve motor performance with practice, but the optimal feedback type (visual, proprioceptive, verbal) for such learning and the underlying neuroplastic changes are unknown. Here, patients with cerebellar degeneration (N = 40) and age- and sex-matched healthy controls (N = 40) practiced single-joint, goal-directed forearm movements for 5 days. Cerebellar patients improved performance during visuomotor practice, but a training focusing on either proprioceptive feedback, or explicit verbal feedback and instruction did not show additional benefits. Voxel-based morphometry revealed that after training gray matter volume (GMV) was increased prominently in the visual association cortices of controls, whereas cerebellar patients exhibited GMV increase predominantly in premotor cortex. The premotor cortex as a recipient of cerebellar efferents appears to be an important hub in compensatory remodeling following damage of the cerebro-cerebellar motor system.

Resection of cerebellar tumours causes widespread and functionally relevant white matter impairments.

Several diffusion tensor imaging studies reveal that white matter (WM) lesions are common in children suffering from benign cerebellar tumours who are treated with surgery only. The clinical implications of WM alterations that occur as a direct consequence of cerebellar disease have not been thoroughly studied. Here, we analysed structural and diffusion imaging data from cerebellar patients with chronic surgical lesions after resection for benign cerebellar tumours. We aimed to elucidate the impact of focal lesions of the cerebellum on WM integrity across the entire brain, and to investigate whether WM deficits were associated with behavioural impairment in three different motor tasks. Lesion symptom mapping analysis suggested that lesions in critical cerebellar regions were related to deficits in savings during an eyeblink conditioning task, as well as to deficits in motor action timing. Diffusion imaging analysis of cerebellar WM indicated that better behavioural performance was associated with higher fractional anisotropy (FA) in the superior cerebellar peduncle, cerebellum's main outflow path. Moreover, voxel-wise analysis revealed a global pattern of WM deficits in patients within many cerebral WM tracts critical for motor and non-motor function. Finally, we observed a positive correlation between FA and savings within cerebello-thalamo-cortical pathways in patients but not in controls, showing that saving effects partly depend on extracerebellar areas, and may be recruited for compensation. These results confirm that the cerebellum has extended connections with many cerebral areas involved in motor/cognitive functions, and the observed WM changes likely contribute to long-term clinical deficits of posterior fossa tumour survivors.

Microstructural brain abnormalities in HIV+ individuals with or without chronic marijuana use.

OBJECTIVE: Cognitive deficits and microstructural brain abnormalities are well documented in HIV-positive individuals (HIV+). This study evaluated whether chronic marijuana (MJ) use contributes to additional cognitive deficits or brain microstructural abnormalities that may reflect neuroinflammation or neuronal injury in HIV+. METHOD: Using a 2 × 2 design, 44 HIV+ participants [23 minimal/no MJ users (HIV+), 21 chronic active MJ users (HIV + MJ)] were compared to 46 seronegative participants [24 minimal/no MJ users (SN) and 22 chronic MJ users (SN + MJ)] on neuropsychological performance (7 cognitive domains) and diffusion tensor imaging metrics, using an automated atlas to assess fractional anisotropy (FA), axial (AD), radial (RD), and mean (MD) diffusivities, in 18 cortical and 4 subcortical brain regions. RESULTS: Compared to SN and regardless of MJ use, the HIV+ group had lower FA and higher diffusivities in multiple white matter and subcortical structures (p < 0.001-0.050), as well as poorer cognition in Fluency (p = 0.039), Attention/Working Memory (p = 0.009), Learning (p = 0.014), and Memory (p = 0.028). Regardless of HIV serostatus, MJ users had lower AD in uncinate fasciculus (p = 0.024) but similar cognition as nonusers. HIV serostatus and MJ use showed an interactive effect on mean diffusivity in the right globus pallidus but not on cognitive function. Furthermore, lower FA in left anterior internal capsule predicted poorer Fluency across all participants and worse Attention/Working Memory in all except SN subjects, while higher diffusivities in several white matter tracts also predicted lower cognitive domain Z-scores. Lastly, MJ users with or without HIV infection showed greater than normal age-dependent FA declines in superior longitudinal fasciculus, external capsule, and globus pallidus. CONCLUSIONS: Our findings suggest that, except in the globus pallidus, chronic MJ use had no additional negative influence on brain microstructure or neurocognitive deficits in HIV+ individuals. However, lower AD in the uncinate fasciculus of MJ users suggests axonal loss in this white matter tract that connects to cannabinoid receptor rich brain regions that are involved in verbal memory and emotion. Furthermore, the greater than normal age-dependent FA declines in the white matter tracts and globus pallidus in MJ users suggest that older chronic MJ users may eventually have lesser neuronal integrity in these brain regions.

Developmental score of the infant brain: characterizing diffusion MRI in term- and preterm-born infants.

Large-scale longitudinal neuroimaging studies of the infant brain allow us to map the spatiotemporal development of the brain in its early phase. While the postmenstrual age (PMA) is commonly used as a time index to analyze longitudinal MRI data, the nonlinear relationship between PMA and MRI data imposes challenges for downstream analyses. We propose a mathematical model that provides a Developmental Score (DevS) as a data-driven time index to characterize the brain development based on MRI features. 319 diffusion tensor imaging (DTI) datasets were collected from 87 term-born and 66 preterm-born infants at multiple visits, which were automatically segmented based on the JHU neonatal atlas. The mean diffusivity (MD) and fractional anisotropy (FA) in 126 brain parcels were used in the model to derive DevS. We demonstrate that transforming the time index from PMA to DevS improves the linearity of the longitudinal changes in MD and FA in both gray and white matter structures. More importantly, regional developmental differences in DTI metrics between preterm- and term-born infants were identified more clearly using DevS, e.g. 79 structures showed significantly different regression patterns in MD between preterm- and term-born infants, compared to only 27 structures that showed group differences using PMA as the index. Therefore, the DevS model facilitates linear analyses of DTI metrics in the infant brain, and provides a useful tool to characterize altered brain development due to preterm-birth.

Extinction of cognitive associations is preserved in patients with cerebellar disease.

In the present study extinction and renewal of cognitive associations were assessed in two experiments in participants with focal and degenerative cerebellar disease. Using a predictive learning task, participants had to learn by trial and error the relationships between food items and the occurrence of stomach trouble in a hypothetical patient. In the first experiment, focus was on renewal effects. Participants with chronic cerebellar stroke (n = 14; mean age 50.9 ± 12 years), participants with degenerative cerebellar disease (n = 16; mean age 58 ± 12 years), age-, sex-, and education matched controls (n = 20; mean age 53.7 ± 10.8 years) and young controls (n = 19; mean age 23.2 ± 2.7 years) were tested. Acquisition and extinction of food-stomach trouble associations took part in two different contexts (represented by restaurants). In a subsequent test phase, food stimuli were presented in both contexts and no feedback was given. This allowed testing for renewal of the initially acquired associations in the acquisition context. Acquisition and extinction learning were not significantly different between groups. Significant renewal effects were present in young controls only. In the second experiment, focus was on extinction. To control for age effects, 19 young participants with chronic surgical lesions of the cerebellum (mean age 25.6 ± 6.1 years), and 24 age-, sex- and education-matched healthy controls were tested. Acquisition and extinction of food-stomach trouble associations took part in the same context. In the extinction phase, the relationship with stomach trouble was reversed in some of the food items. Acquisition and extinction learning were not significantly different between groups. The main finding of the present study was preserved extinction of learned cognitive associations in participants with chronic cerebellar disease. Findings agree with previous observations in the literature that cognitive abnormalities are frequently absent or weak in adults with cerebellar disease. This does not exclude a contribution of the cerebellum to extinction of learned associations. For example, findings may be different in more challenging cognitive tasks, and in participants with acute cerebellar disease with no time for compensation.

Long-term effects of cerebellar anodal transcranial direct current stimulation (tDCS) on the acquisition and extinction of conditioned eyeblink responses.

Cerebellar transcranial direct current stimulation (tDCS) has been reported to enhance the acquisition of conditioned eyeblink responses (CR), a form of associative motor learning. The aim of the present study was to determine possible long-term effects of cerebellar tDCS on the acquisition and extinction of CRs. Delay eyeblink conditioning was performed in 40 young and healthy human participants. On day 1, 100 paired CS (conditioned stimulus)-US (unconditioned stimulus) trials were applied. During the first 50 paired CS-US trials, 20 participants received anodal cerebellar tDCS, and 20 participants received sham stimulation. On days 2, 8 and 29, 50 paired CS-US trials were applied, followed by 30 CS-only extinction trials on day 29. CR acquisition was not significantly different between anodal and sham groups. During extinction, CR incidences were significantly reduced in the anodal group compared to sham, indicating reduced retention. In the anodal group, learning related increase of CR magnitude tended to be reduced, and timing of CRs tended to be delayed. The present data do not confirm previous findings of enhanced acquisition of CRs induced by anodal cerebellar tDCS. Rather, the present findings suggest a detrimental effect of anodal cerebellar tDCS on CR retention and possibly CR performance.