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The cerebellum, long implicated in movement, is now recognized as a contributor to higher-order cognition. The cerebellar pathways provide key structural links between the cerebellum and cerebral regions integral to language, memory, and executive function. Here, we present a large-scale, cross-sectional diffusion MRI (dMRI) analysis investigating the relationships between cerebellar pathway microstructure and cognitive performance in over 9,000 participants spanning pre-adolescence (n>8,000 from the ABCD dataset) and young adulthood (n>900 from the HCP-YA dataset). We assessed the microstructure of five cerebellar pathways-the inferior, middle, and superior cerebellar peduncles; the parallel fibers; and input/Purkinje fibers-using three dMRI measures of fractional anisotropy, mean diffusivity, and number of streamlines. Cognitive performance was evaluated using seven NIH Toolbox assessments of language, executive function, and memory. In both datasets, we found numerous significant associations between cerebellar pathway microstructure and cognitive performance. These associations showed a strong correlation across the two datasets (r = 0.47, p < 0.0001), underscoring the reliability of cerebellar dMRI-cognition relationships in pre-adolescents and young adults. In both datasets, the strongest associations were found between the superior cerebellar peduncle and performance on language assessments, suggesting this pathway plays an important role in language function across age groups. In young adults, but not pre-adolescents, parallel fiber microstructure was linked to inhibitory control, suggesting that contributions to attentional processes may emerge or strengthen with maturation. Overall, our findings highlight the important role of cerebellar pathways in cognition and the utility of large-scale datasets for advancing our understanding of brain-cognition relationships.

Background : Individualizing transcranial direct current stimulation (tDCS) parameters can improve precision in neuropsychiatric disorders. One important decision for the clinician is the selection of an appropriate montage-conventional or high-definition (HD)-to implement dose-controlled tDCS while maintaining the patient's safety. Method : The present study simulated tDCS administration using T1-weighted brain images of 50 dementia, 25 depression patients, and 25 healthy individuals for two conventional and HD montages, targeting the regions of interest (ROIs) in the dorsal and ventral pathways that support language processing. For each tDCS configuration, the electric fields at the ROIs and the individualized dose required to achieve the desired current intensity at the target ROI across the subjects were estimated. Linear regression was performed on these parameters. Result : A significant relationship between atrophy and current dose that varies according to the disease was found. The dementia patients with significant brain atrophy required a higher personalized dosage for HD montage, as the current intensity at the target ROIs was lower and more variable than that of conventional montage. For dementia, tDCS individualization is pathway-dependent, wherein HD configuration of the dorsal route requires current dosages above the safety limit (>4 mA) for 46% of individuals. However, there was no significant difference in electrode configurations between the HD and traditional setups for depression and healthy volunteers without significant brain atrophy. Conclusions : HD-tDCS with fixed locations is limited, making conventional tDCS more effective for dose-controlled applications. In patients with atrophy, individualized adjustments based on simulations are needed due to the variable stimulation strength in the ROI.

Recent research has highlighted cerebellar involvement in cognition and several psychiatric conditions such as mood and anxiety disorders and schizophrenia. Attention-deficit/hyperactivity disorder and autism spectrum disorder have been linked to reduced cerebellar volume as well. Cerebellar alterations are frequently present after early adversity in humans and animals, but a systematic integration of results is lacking. To this end, a systematic literature search was conducted in PubMed, Web of Science, and EBSCO databases using the keywords "early adversity OR early life stress" AND "cerebellum OR cerebellar." A total of 45 publications met the inclusion criteria: 25 studies investigated human subjects and 20 reported results from animal models. Findings in healthy subjects show bilateral volume reduction and decreased functional connectivity within the cerebellum and between the cerebellum and frontal regions after adversity throughout life, especially when adversity was assessed with the Childhood Trauma Questionnaire. In clinical populations, adults demonstrate increased cerebellar volume and functional connectivity after adversity, whereas pediatric patients show reduced cerebellar volume. Animal findings reveal cerebellar alterations without necessarily co-occurring pathological behavior, highlighting alterations in stress hormone receptor levels, cell density, and neuroinflammation markers. Cerebellar alterations after early adversity are robust findings across human and animal studies and occur independent of clinical symptoms., (© 2024 The Author(s). Developmental Psychobiology published by Wiley Periodicals LLC.)

tDCS modulates the activity of the neuronal networks to induce the desired behavioural changes. Two factors determine its effectiveness- (1) whether the network being stimulated is relevant to the task, and (2) if there is a scope for improvement in behavioral performance. To explore this, both dorsal (sub-lexical) and ventral (lexical) reading networks were stimulated (20 min, 2 mA) in 25 healthy young volunteers. Participants performed two reading tasks with different levels of lexical involvement: word fragment completion tasks (WCT) and word association tasks (WAT), while event-related potentials (ERPs) were recorded simultaneously. The study used a within-subject design over three sessions, comparing various electrode montages targeting the dorsal pathway's left inferior parietal lobule or the ventral reading pathway's left middle temporal lobule, as well as sham stimulation. The impact of tDCS sessions (dorsal, ventral, & sham) and task type (WCT & WAT) on priming effects (primed vs. unprimed) of behavioral performance (accuracy and reaction times), and ERP parameters (N400 amplitudes and latencies) were statistically analyzed.It was found that tDCS modulated the performance of WAT only (a task with a lower priming effect). The failure to modulate WCT (larger priming effect) indicated that tDCS was effective for conditions with room for improvement compared to a task where performance has reached the ceiling. Ventral stimulation enhanced accuracy in the WAT condition and shortened the N400 latency of the priming effect. In contrast, dorsal stimulation delayed the priming effect reaction time in the WAT condition and enhanced the N400 amplitude. To conclude, enhancement in performance due to tDCS occurs when the network (ventral) being stimulated aligns with the cognitive demands of the task and there is a scope for improvement., (© 2024. The Author(s).)

Background: Identifying the characteristics of individuals who demonstrate response to an intervention allows us to predict who is most likely to benefit from certain interventions. Prediction is challenging in rare and heterogeneous diseases, such as primary progressive aphasia (PPA), that have varying clinical manifestations. We aimed to determine the characteristics of those who will benefit most from transcranial direct current stimulation (tDCS) of the left inferior frontal gyrus (IFG) using a novel heterogeneity and group identification analysis., Methods: We compared the predictive ability of demographic and clinical patient characteristics (e.g., PPA variant and disease progression, baseline language performance) vs. functional connectivity alone (from resting-state fMRI) in the same cohort., Results: Functional connectivity alone had the highest predictive value for outcomes, explaining 62% and 75% of tDCS effect of variance in generalization (semantic fluency) and in the trained outcome of the clinical trial (written naming), contrasted with <15% predicted by clinical characteristics, including baseline language performance. Patients with higher baseline functional connectivity between the left IFG (opercularis and triangularis), and between the middle temporal pole and posterior superior temporal gyrus, were most likely to benefit from tDCS., Conclusions: We show the importance of a baseline 7-minute functional connectivity scan in predicting tDCS outcomes, and point towards a precision medicine approach in neuromodulation studies. The study has important implications for clinical trials and practice, providing a statistical method that addresses heterogeneity in patient populations and allowing accurate prediction and enrollment of those who will most likely benefit from specific interventions.

Background: Alcohol use disorder (AUD) affects 283 million people worldwide and its prevalence is increasing. Despite the role of the cerebellum in executive control and its sensitivity to alcohol, few studies have assessed its involvement in AUD-relevant functional networks. The goal of this study is to compare resting-state functional connectivity (FC) patterns in abstinent adults with a history of AUD and controls (CTL). We hypothesized that group differences in cerebro-cerebellar FC would be present, particularly within the frontoparietal/executive control network (FPN)., Methods: Twenty-eight participants completed a resting-state functional magnetic resonance imaging (rsfMRI) study. CTL participants had no history of AUD, comorbid psychological conditions, or recent heavy drinking and/or drug use. AUD participants had a history of AUD, with sobriety for at least 30 days prior to data collection. Multivariate pattern analysis, an agnostic, whole-brain approach, was used to identify regions with significant differences in FC between groups. Seed-based analyses were then conducted to determine the directionality and extent of these FC differences. Associations between FC strength and executive function were assessed using correlations with Wisconsin Card Sorting Test (WCST) performance., Results: There were significant group differences in FC in nodes of the FPN, ventral attention network, and default mode network. Post hoc analyses predominantly identified FC differences within the cerebro-cerebellar FPN, with AUD showing significantly less FC within the FPN. In AUD, FC strength between FPN clusters identified in the multivariate pattern analysis (MVPA) analysis (Left Crus II, Right Frontal Cortex) was positively associated with performance on the WCST., Conclusions: Our results show less engagement of the FPN in individuals with AUD than in CTL. FC strength within this network was positively associated with performance on the WCST. These findings suggest that long-term heavy drinking alters cerebro-cerebellar FC, particularly within networks that are involved in executive function., (© 2023 Research Society on Alcohol.)

Recent studies increasingly highlight involvement of the cerebellum in drug craving and addiction. However, its exact role, that is, whether the cerebellum is a critical component of a brain network underlying addictive behaviour, or whether it rather is a facilitator or mediator, is still unclear. Findings concerning the newly recognized internet gaming disorder (IGD) suggest that changes in cerebellar connectivity and functioning are associated with behavioural/non-substance addiction. Here, we systematically review the literature on IGD and cerebellar involvement following the PRISMA guidelines. A total of 13 neuroimaging studies met the inclusion criteria. Studies utilized a broad range of diagnostic instruments and resulting cut-off criteria, rendering it difficult to compare findings. Results on altered cerebro-cerebellar connectivity in patients with IGD are mixed; most studies report altered or increased functional connectivity. Moreover, decreased cerebellar grey matter volume is reported. Studies have further indicated that differential activation patterns in the cerebellum may enable discrimination between healthy subjects and subjects with IGD, even allowing for prediction of treatment outcomes. Given the strong connectivity between the cerebellum and cerebral regions, the cerebellum may act as an intermediary between regions involved in craving and addiction and consequently affect symptoms of IGD. Results suggest differential involvement of the cerebellar lobes, emphasizing a need for high-resolution parcellation of the cerebellum in future studies. However, the studies included in the present review have small sample sizes and include mostly male participants. Thus, results may have limited generalizability yet highlight a crucial role of the cerebellum in IGD that needs further investigation., (© 2023 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Objectives: Generalization (or near-transfer) effects of an intervention to tasks not explicitly trained are the most desirable intervention outcomes. However, they are rarely reported and even more rarely explained. One hypothesis for generalization effects is that the tasks improved share the same brain function/computation with the intervention task. We tested this hypothesis in this study of transcranial direct current stimulation (tDCS) over the left inferior frontal gyrus (IFG) that is claimed to be involved in selective semantic retrieval of information from the temporal lobes., Materials and Methods: In this study, we examined whether tDCS over the left IFG in a group of patients with primary progressive aphasia (PPA), paired with a lexical/semantic retrieval intervention (oral and written naming), may specifically improve semantic fluency, a nontrained near-transfer task that relies on selective semantic retrieval, in patients with PPA., Results: Semantic fluency improved significantly more in the active tDCS than in the sham tDCS condition immediately after and two weeks after treatment. This improvement was marginally significant two months after treatment. We also found that the active tDCS effect was specific to tasks that require this IFG computation (selective semantic retrieval) but not to other tasks that may require different computations of the frontal lobes., Conclusions: We provided interventional evidence that the left IFG is critical for selective semantic retrieval, and tDCS over the left IFG may have a near-transfer effect on tasks that depend on the same computation, even if they are not specifically trained., Clinical Trial Registration: The Clinicaltrials.gov registration number for the study is NCT02606422., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

An increasing body of evidence points to the involvement of the cerebellum in cognition. Specifically, previous studies have shown that the superior and inferior portions of the cerebellum are involved in different verbal working memory (WM) mechanisms as part of two separate cerebro-cerebellar loops for articulatory rehearsal and phonological storage mechanisms. In comparison, our understanding of the involvement of the cerebellum in visual WM remains limited. We have previously shown that performance in verbal WM is disrupted by single-pulse transcranial magnetic stimulation (TMS) of the right superior cerebellum. The present study aimed to expand on this notion by exploring whether the inferior cerebellum is similarly involved in visual WM. Here, we used fMRI-guided, double-pulse TMS to probe the necessity of left superior and left inferior cerebellum in visual WM. We first conducted an fMRI localizer using the Sternberg visual WM task, which yielded targets in left superior and inferior cerebellum. Subsequently, TMS stimulation of these regions at the end of the encoding phase resulted in decreased accuracy in the visual WM task. Differences in the visual WM deficits caused by stimulation of superior and inferior left cerebellum raise the possibility that these regions are involved in different stages of visual WM., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Conventionally, transcranial direct current stimulation (tDCS) aims to focalize the current reaching the target region-of-interest (ROI). The focality can be quantified by the dose-target-determination-index (DTDI). Despite having a uniform tDCS setup, some individuals receive focal stimulation (high DTDI) while others show reduced focality ("non-focal"). The volume of cerebrospinal fluid (CSF), gray matter (GM), and white matter (WM) underlying each ROI govern the tDCS current distribution inside the brain, thereby regulating focality., Aim: To determine the regional volume parameters that differentiate the focal and non-focal groups., Methods: T1-weighted images of the brain from 300 age-sex matched adults were divided into three equal groups- (a) Young (20 ≤ × < 40 years), (b) Middle (40 ≤ × < 60 years), and (c) Older (60 ≤ × < 80 years). For each group, inter and intra-hemispheric montages with electrodes at (1) F3 and right supraorbital region (F3-RSO), and (2) CP5 and Cz (CP5-Cz) were simulated, targeting the left- Dorsolateral Prefrontal Cortex (DLPFC) and -Inferior Parietal Lobule (IPL), respectively. Both montages were simulated for two current doses (1 and 2 mA). For each individual head simulated for a tDCS configuration (montage and dose), the current density at each region-of-interest (ROI) and their DTDI were calculated. The individuals were categorized into two groups- (1) Focal (DTDI ≥ 0.75), and (2) Non-focal (DTDI < 0.75). The regional volume of CSF, GM, and WM of all the ROIs was determined. For each tDCS configuration and ROI, three 3-way analysis of variance was performed considering- (i) GM, (ii) WM, and (iii) CSF as the dependent variable (DV). The age group, sex, and focality group were the between-subject factors. For a given ROI, if any of the 3 DV's showed a significant main effect or interaction involving the focality group, then that ROI was classified as a "focal ROI.", Results: Regional CSF was the principal determinant of focality. For interhemispheric F3-RSO montage, interaction effect ( p < 0.05) of age and focality was observed at Left Caudate Nucleus, with the focal group exhibiting higher CSF volume. The CSF volume of focal ROI correlated positively ( r ∼ 0.16, p < 0.05) with the current density at the target ROI (DLPFC). For intrahemispheric CP5-Cz montage, a significant ( p < 0.05) main effect was observed at the left pre- and post-central gyrus, with the focal group showing lower CSF volume. The CSF volume correlated negatively ( r ∼ -0.16, p < 0.05) with current density at left IPL. The results were consistent for both current doses., Conclusion: The CSF channels the flow of tDCS current between electrodes with focal ROIs acting like reservoirs of current. The position of focal ROI in the channel determines the stimulation intensity at the target ROI. For focal stimulation in interhemispheric F3-RSO, the proximity of focal ROI reserves the current density at the target ROI (DLPFC). In contrast, for intrahemispheric montage (CP5-Cz), the far-end location of focal ROI reduces the current density at the target (IPL)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kashyap, Bhattacharjee, Bharath, Venkatasubramanian, Udupa, Bashir, Oishi, Desmond, Chen and Guan.)

The phonological loop is part of Baddeley's verbal working memory (VWM) model that stores phonological information and refreshes its contents through an articulatory process. Many studies have reported the cerebellum's involvement during VWM tasks. In the motor literature, the cerebellum is thought to support smooth and rapid movement sequences through internal models that simulate the action of motor commands, then use the error signals generating from the discrepancy between the predicted and actual sensory consequences to adjust the motor system. Here, we hypothesize that a similar monitoring and error-driven adjustment process can be extended to VWM; specifically, the cerebellum checks for discrepancies between the predicted and actual articulatory process to ensure the accuracy and fluency of articulatory rehearsal. During neuroimaging, participants rehearsed a sequence of letters in sync with the presentation of a visual pacing stimulus (#) that was terminated by the occurrence of a probe letter. Participants judged whether the probe was the correct letter in the sequence (i.e., match trial), or deviated from the sequence (i.e., mismatch trial). Detection of sequence violation was not only associated with prolonged reaction time but also an increased activation in a left executive control network. Psychophysiological interaction was used to investigate whether the cerebellum interacts with the cerebral cortex for error monitoring and adjustments. We found increased functional connectivity between the right cerebellum and the cerebral cortex during mismatch relative to match probes, indicating sequence violation resulting in greater cerebellar connectivity with areas in the cerebral cortex involved in phonological sequencing., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The observed variability in the effects of transcranial direct current stimulation (tDCS) is influenced by the amount of current reaching the targeted region-of-interest (ROI). Age and sex might affect current density at target ROI due to their impact on cortical anatomy. The present tDCS simulation study investigates the effects of cortical anatomical parameters (volumes, dimension, and torque) on simulated tDCS current density in healthy young, middle-aged, and older males and females., Methodology: Individualized head models from 240 subjects (120 males, 18-87 years of age) were used to identify the estimated current density (2 mA current intensity, 25 cm 2 electrode) from two simulated tDCS montages (CP5&#95;CZ and F3&#95;FP2) targeting the inferior parietal lobule (IPL) and middle frontal gyrus (MFG), respectively. Cortical parameters including segmented brain volumes (cerebrospinal fluid [CSF], grey and white matter), cerebral-dimensions (length/width &length/height) and brain-torque (front and back shift, petalia, and bending) were measured using the magnetic resonance images (MRIs) from each subject. The present study estimated sex differences in current density at these target ROIs mediated by these cortical parameters within each age group., Results: For both tDCS montages, females in the older age group received higher current density than their male counterparts at the target ROIs. No sex differences were observed in the middle-aged group. Males in the younger age group had a higher current density than females, only for the parietal montage. Across all age groups, CSF, and grey matter volumes significantly predicted the current intensity estimated at the target sites. In the older age group only, brain-torque was a significant mediator of the sex difference., Conclusions: Our findings demonstrate the presence of sex differences in the simulated tDCS current density, however this pattern differed across age groups and stimulation locations. Future studies should consider influence of age and sex on individual cortical anatomy and tailor tDCS stimulation parameters accordingly., Competing Interests: Declaration of competing interest The authors do not have any conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Verbal fluency (VF) is an informative cognitive task. Lesion and functional imaging studies implicate distinct cerebral areas that support letter versus semantic fluency and the understanding of neural and cognitive mechanisms underlying task performance. Most lesion studies include chronic stroke patients. People with primary progressive aphasia (PPA) provide complementary evidence for lesion-deficit associations, as different brain areas are affected in stroke versus PPA. In the present study we sought to determine imaging, clinical and demographic correlates of VF in PPA. Thirty-five patients with PPA underwent an assessment with letter and category VF tasks, evaluation of clinical features and an MRI scan for volumetric analysis. We used stepwise regression models to determine which brain areas are associated with VF performance while acknowledging the independent contribution of clinical and demographic factors. Letter fluency was predominantly associated with language severity (R 2 = 38%), and correlated with the volume of the left superior temporal regions (R 2 = 12%) and the right dorsolateral prefrontal area (R 2 = 5%). Semantic fluency was predominantly associated with dementia severity (R 2 = 47%) and correlated with the volume of the left inferior temporal gyrus (R 2 = 7%). No other variables were significantly associated with performance in the two VF tasks. We concluded that, independently of disease severity, letter fluency is significantly associated with the volume of frontal and temporal areas whereas semantic fluency is associated mainly with the volume of temporal areas. Furthermore, our findings indicated that clinical severity plays a critical role in explaining VF performance in PPA, compared to the other clinical and demographic factors.

Background: In transcranial direct current stimulation (tDCS), the injected current becomes distributed across the brain areas. The objective is to stimulate the target region of interest (ROI) while minimizing the current in non-target ROIs (the 'focality' of tDCS). For this purpose, determining the appropriate current dose for an individual is difficult. Aim: To introduce a dose-target determination index (DTDI) to quantify the focality of tDCS and examine the dose-focality relationship in three different populations. Method: Here, we extended our previous toolbox i-SATA to the MNI reference space. After a tDCS montage is simulated for a current dose, the i-SATA(MNI) computes the average (over voxels) current density for every region in the brain. DTDI is the ratio of the average current density at the target ROI to the ROI with a maximum value (the peak region). Ideally, target ROI should be the peak region, so DTDI shall range from 0 to 1. The higher the value, the better the dose. We estimated the variation of DTDI within and across individuals using T1-weighted brain images of 45 males and females distributed equally across three age groups: (a) young adults (20 ≤ x ˂ 40 years), (b) mid adults (40 ≤ x ˂ 60 years), and (c) older adults (60 ≤ x ˂ 80 years). DTDI's were evaluated for the frontal montage with electrodes at F3 and the right supraorbital for three current doses of 1 mA, 2 mA, and 3 mA, with the target ROI at the left middle frontal gyrus. Result: As the dose is incremented, DTDI may show (a) increase, (b) decrease, and (c) no change across the individuals depending on the relationship (nonlinear or linear) between the injected tDCS current and the distribution of current density in the target ROI. The nonlinearity is predominant in older adults with a decrease in focality. The decline is stronger in males. Higher current dose at older age can enhance the focality of stimulation. Conclusion: DTDI provides information on which tDCS current dose will optimize the focality of stimulation. The recommended DTDI dose should be prioritized based on the age (>40 years) and sex (especially for males) of an individual. The toolbox i-SATA(MNI) is freely available.

Several fMRI studies have shown that the superior cerebellum exhibits load-dependent activations during encoding of letters in a Sternberg verbal working memory (VWM) task. It has been hypothesized that the cerebellum regulates the acquisition of sensory data across all modalities, and thus, that VWM load activations may reflect high- vs low-load differences in sensory acquisition demands. Therefore, increased difficulty in sensory data acquisition should elicit greater activation in the cerebellum. The present fMRI study manipulated sensory acquisition in VWM by presenting visually degraded and non-degraded stimuli with high and low memory loads, thereby identifying load-dependent regions of interest in the cerebellum, and then testing if these regions showed greater activation for degraded stimuli. Results yielded partial support for the sensory acquisition hypothesis in a load-dependent region of the vermis, which showed significantly greater activation for degraded relative to non-degraded stimuli. Because eye movements did not differ for these stimulus types, and degradation-related activations were present after co-varying eye movements, this activation appears to be related to perceptual rather than oculomotor demands. In contrast to the vermis, load-sensitive regions of the cerebellar hemispheres did not show increased activation for degraded stimuli. These findings point to an overall function of association-based prediction that may underlie general cerebellar function, with perceptual prediction of stimuli from partial representations occurring in the vermis, and articulatory prediction occurring in the hemispheres.

Transcranial direct current stimulation has been shown to increase the efficiency of language therapy in chronic aphasia; however, to date, an optimal stimulation site has not been identified. We investigated whether neuromodulation of the right cerebellum can improve naming skills in chronic aphasia. Using a randomized, double-blind, sham-controlled, within-subject crossover study design, participants received anodal cerebellar stimulation ( n  = 12) or cathodal cerebellar stimulation ( n  = 12) + computerized aphasia therapy then sham + computerized aphasia therapy, or the opposite order. There was no significant effect of treatment (cerebellar stimulation versus sham) for trained naming. However, there was a significant order x treatment interaction, indicating that cerebellar stimulation was more effective than sham immediately post-treatment for participants who received cerebellar stimulation in the first phase. There was a significant effect of treatment (cerebellar stimulation versus sham) for untrained naming immediately post-treatment and the significant improvement in untrained naming was maintained at two months post-treatment. Greater gains in naming (relative to sham) were noted for participants receiving cathodal stimulation for both trained and untrained items. Thus, our study provides evidence that repetitive cerebellar transcranial direct stimulation combined with computerized aphasia treatment can improve picture naming in chronic post-stroke aphasia. These findings suggest that the right cerebellum might be an optimal stimulation site for aphasia rehabilitation and this could be an answer to handle heterogeneous participants who vary in their size and site of left hemisphere lesions., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: tDCS can modulate reading which is processed by lexical (ventral) and sub-lexical (dorsal) pathways. Previous research indicates that pathway recruitment in bilinguals depends on a script's orthographic depth and a reader's proficiency with it. The effect of tDCS on each reading pathway has not been investigated in bilinguals. We stimulated the left dorsal and ventral pathways separately in Chinese-English (C-E) bilinguals to understand whether pathway-specific modulation by tDCS is possible and, if so, how it is influenced by orthographic depth and script proficiency., Methods: A double-blind, sham-controlled, within-subject experiment was designed wherein 16 balanced bilinguals received anodal tDCS in dorsal, ventral and sham sessions. Two tDCS montages of electrode sizes 5 × 5 cm 2 with 1) anode at CP5 and cathode at CZ, and 2) anode at TP7 and cathode at nape of the neck, were applied for stimulating the dorsal and ventral pathways respectively. Bilinguals were asked to read word lists for each language before and after stimulation. RTs for accurate trials were analysed using linear mixed-effect modelling that included proficiency scores for reading English pseudo-words (PW) and Chinese pinyin., Results: For both languages, word reading RTs were faster following dorsal pathway stimulation. The dorsal stimulation effect (change in RT) was negatively correlated with pseudoword reading and pinyin proficiency. Stimulation of the ventral pathway decreased RTs only for Chinese reading., Conclusion: Dorsal and ventral reading pathways can be selectively modulated by tDCS in bilingual readers with dorsal (sub-lexical) pathway stimulation affecting reading in both scripts and ventral (lexical) pathway stimulation selectively affecting Chinese reading. Dorsal pathway tDCS effects are modulated by sub-lexical reading proficiency., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Transcranial Direct Current Stimulation (tDCS) is a technique where a weak current is passed through the electrodes placed on the scalp. The distribution of the electric current induced in the brain due to tDCS is provided by simulation toolbox like Realistic volumetric Approach based Simulator for Transcranial electric stimulation (ROAST). However, the procedure to estimate the total current density induced at the target and the intermediary region of the cortex is complex. The Systematic-Approach-for-tDCS-Analysis (SATA) was developed to overcome this problem. However, SATA is limited to standardized (MNI152) headspace only. Here we develop individual-SATA (i-SATA) to extend it to individual head., Approach: T1-weighted images of 15 subjects were taken from two Magnetic Resonance Imaging scanners of different strengths. Across the subjects, the montages were simulated in ROAST. i-SATA converts the ROAST output to Talairach space. The x, y and z coordinates of the anterior commissure (AC), posterior commissure (PC), and Mid-Sagittal (MS) points are necessary for the conversion. AC and PC are detected using the acpcdetect toolbox. We developed a method to determine the MS in the image and cross-verified its location manually using BrainSight®., Main Results: Determination of points with i-SATA is fast and accurate. The i-SATA provided estimates of the current-density induced across an individual's cortical lobes and gyri as tested on images from two different scanners., Significance: Researchers can use i-SATA for customizing tDCS-montages. With i-SATA it is also easier to compute the inter-individual variation in current-density across the target and intermediary regions of the brain. The software is publicly available.

Contingency awareness is thought to rely on an intact medial temporal lobe and also appears to be a function of age, as older subjects tend to be less aware. The current investigation used functional magnetic resonance imaging, transcranial direct current stimulation, and eyeblink classical conditioning to study brain processes related to contingency awareness as a function of age. Older adults were significantly less aware of the relationship between the tone-airpuff pairings than younger adults. Greater right parietal functional magnetic resonance imaging activation was associated with higher levels of contingency awareness for younger and older subjects. Cathodal transcranial direct current stimulation over the right parietal lobe led to lower levels of awareness in younger subjects without disrupting conditioned responses. Older adults exhibited hyperactivations in the parietal and medial temporal lobes, despite showing no conditioning deficits. These findings strongly support the idea that the parietal cortex serves as a substrate for contingency awareness and that age-related disruption of this region is sufficient to impair awareness, which may be a manifestation of some form of naturally occurring age-related neglect., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Functional MRI (fMRI) task-related analyses rely on an estimate of the brain's hemodynamic response function (HRF) to model the brain's response to events. Although changes in the HRF have been found after acute alcohol administration, the effects of heavy chronic alcohol consumption on the HRF have not been explored, and the potential benefits or pitfalls of estimating each individual's HRF on fMRI analyses of chronic alcohol use disorder (AUD) are not known., Methods: Participants with AUD and controls (CTL) received structural, functional, and vascular scans. During fMRI, participants were cued to tap their fingers, and averaged responses were extracted from the motor cortex. Curve fitting on these HRFs modeled them as a difference between 2 gamma distributions, and the temporal occurrence of the main peak and undershoot of the HRF was computed from the mean of the first and second gamma distributions, respectively., Results: ANOVA and regression analyses found that the timing of the HRF undershoot increased significantly as a function of total lifetime drinking. Although gray matter volume in the motor cortex decreased with lifetime drinking, this was not sufficient to explain undershoot timing shifts, and vascular factors measured in the motor cortex did not differ among groups. Comparison of random-effects analyses using custom-fitted and canonical HRFs for CTL and AUD groups showed better results throughout the brain for custom-fitted versus canonical HRFs for CTL subjects. For AUD subjects, the same was true except for the basal ganglia., Conclusions: These findings suggest that excessive alcohol consumption is associated with changes in the HRF undershoot. HRF changes could provide a possible biomarker for the effects of lifetime drinking on brain function. Changes in HRF topography affect fMRI activation measures, and subject-specific HRFs generally improve fMRI activation results., (© 2020 by the Research Society on Alcoholism.)

Background: Excessive alcohol consumption produces changes in the brain that often lead to cognitive impairments. One fundamental form of learning, eyeblink classical conditioning (EBC), has been widely used to study the neurobiology of learning and memory. Participants with alcohol use disorders (AUD) have consistently shown a behavioral deficit in EBC. The present functional magnetic resonance imaging (fMRI) study is the first to examine brain function during conditioning in abstinent AUD participants and healthy participants., Methods: AUD participants met DSM-IV criteria for alcohol dependence, had at least a 10-year history of heavy drinking, and were abstinent from alcohol for at least 30 days. During fMRI, participants received auditory tones that predicted the occurrence of corneal airpuffs. Anticipatory eyeblink responses to these tones were monitored during the experiment to assess learning-related changes., Results: Behavioral results indicate that AUD participants showed significant conditioning deficits and that their history of lifetime drinks corresponded to these deficits. Despite this learning impairment, AUD participants showed hyperactivation in several key cerebellar structures (including lobule VI) during conditioning. For all participants, history of lifetime drinks corresponded with their lobule VI activity., Conclusions: These findings suggest that excessive alcohol consumption is associated with abnormal cerebellar hyperactivation and conditioning impairments., (© 2020 by the Research Society on Alcoholism.)

Modulating higher cognitive functions like reading with transcranial direct current stimulation (tDCS) can be challenging as reading involves regions in the dorsal and ventral cortical areas that lie in close proximity. If the two pathways are stimulated simultaneously, the function of dorsal pathway (predominantly used for graphophonological conversion) might interfere with the function of the ventral pathway (used for semantics), and vice-versa. To achieve functional specificity in tDCS for investigating the two pathways of reading, it is important to stimulate each pathway per session such that the spread of current across the cortical areas due to the two montages has minimal overlap. The present study intends to achieve this by introducing a systematic approach for tDCS analysis. We employed the COMETS2 software to simulate 10 montage configurations (5 for each pathway) for three electrode sizes: 5 × 5, 3 × 3, and 5 × 7 cm 2 . This diversity in montage configuration is chosen since previous studies found the position and the size of anode and cathode to play an important role. The values of the magnitude of current density (MCD) obtained from the configuration were used to calculate: (i) average MCD in each cortical lobe, (ii) number of overlapping coordinates, and (iii) cortical areas with high MCD. The measures (i) and (iii) ascertained the current spread by each montage within a cortical lobe, and (ii) verified the overlap of the spread of current between a pair of montages. The analyses show that a montage using the electrode size of 5 × 5 cm 2 with the anode at CP5 and cathode at CZ, and another with anode at TP7 and cathode at nape of the neck are optimal choices for dorsal and ventral pathways, respectively. To verify, we cross-validated the results with ROAST. This systematic approach was helpful in reducing the ambiguity of montage selection prior to conducting a tDCS study.

Mounting evidence suggests that the right cerebellum contributes to verbal working memory, but the functional role of this contribution remains unclear. In an established theory of motor control, the cerebellum is thought to predict sensory consequences of movements through an internal "forward model." Here, we hypothesize a similar predictive process can generalize to cerebellar non-motor function, and that the right cerebellum plays a predictive role that is beneficial for rapidly engaging the phonological loop in verbal working memory. To test this hypothesis, double-pulse transcranial magnetic stimulation (TMS) was administered over either the right cerebellum or right occipital lobe (control site), on half the trials, to interrupt the rehearsal of a 6-letter sequence. We found that cerebellar stimulation resulted in greater errors in participants' report of the letter in the current position. Additional analyses revealed that immediately after cerebellar TMS, participants were more likely to use out of date information to predict the next letter in the sequence. This pattern of errors is consistent with TMS causing a temporary disruption of state estimation and cerebellar forward model function, leading to prediction errors in the phonological loop.

Transcranial direct current stimulation (tDCS) is an innovative technique recently shown to improve language outcomes even in neurodegenerative conditions such as primary progressive aphasia (PPA), but the underlying brain mechanisms are not known. The present study tested whether the additional language gains with repetitive tDCS (over sham) in PPA are caused by changes in functional connectivity between the stimulated area (the left inferior frontal gyrus (IFG)) and the rest of the language network. We scanned 24 PPA participants (11 female) before and after language intervention (written naming/spelling) with a resting-state fMRI sequence and compared changes before and after three weeks of tDCS or sham coupled with language therapy. We correlated changes in the language network as well as in the default mode network (DMN) with language therapy outcome measures (letter accuracy in written naming). Significant tDCS effects in functional connectivity were observed between the stimulated area and other language network areas and between the language network and the DMN. TDCS over the left IFG lowered the connectivity between the above pairs. Changes in functional connectivity correlated with improvement in language scores (letter accuracy as a proxy for written naming) evaluated before and after therapy. These results suggest that one mechanism for anodal tDCS over the left IFG in PPA is a decrease in functional connectivity (compared to sham) between the stimulated site and other posterior areas of the language network. These results are in line with similar decreases in connectivity observed after tDCS over the left IFG in aging and other neurodegenerative conditions., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Verbal working memory is one of the most studied non-motor functions with robust cerebellar involvement. While the superior cerebellum (lobule VI) has been associated with articulatory control, the inferior cerebellum (lobule VIIIa) has been linked to phonological storage. The present study was aimed to elucidate the differential roles of these regions by investigating whether the cerebellum might contribute to verbal working memory via predictions based on sequence learning/detection. 19 healthy adult subjects completed an fMRI-based Sternberg task which included repeating and novel letter sequences that were phonologically similar or dissimilar. It was hypothesized that learning a repeating sequence of study letters would reduce phonological storage demand and associated right inferior cerebellar activations and that this effect would be modulated by phonological similarity of the study letters. Specifically, while increased phonological storage demand due to high phonological similarity was expected to be reflected in increased right inferior cerebellar activations for similar relative to dissimilar study letters, the reduction in activation for repeating relative to novel sequences was expected to be more profound for phonologically similar than for dissimilar study letters, especially at higher memory load. Results confirmed the typical effects of cognitive load (5 vs. 2 study letters) and phonological similarity in several cerebellar and neocortical brain regions as well as in behavioral data (accuracy and response time). Importantly, activations in superior and inferior cerebellar regions were differentially modulated as a function of similarity and sequence novelty, indicating that particularly lobule VIIIa may contribute to verbal working memory by generating predictions of letter sequences that reduce the likelihood of phonological loop failure before stored items need to be retrieved. The present study is consistent with other investigations that support prediction, which can be based on sequence learning or detection, as an overarching cerebellar function.

Introduction: Transcranial direct current stimulation (tDCS) has been recently shown to improve language outcomes in primary progressive aphasia (PPA) but most studies are small and the influence of PPA variant is unknown., Methods: Thirty-six patients with PPA participated in a randomized, sham-controlled, double-blind, within-subject crossover design for 15 daily sessions of stimulation coupled with written naming/spelling therapy. Outcome measures were letter accuracy of treated and untreated words immediately after and at 2 weeks and 2 months posttreatment., Results: tDCS treatment was more effective than sham: gains for treated words were maintained 2 months posttreatment; gains from tDCS also generalized to untreated words and were sustained 2 months posttreatment. Different effects were obtained for each PPA variant, with no tDCS advantage for semantic variant PPA., Discussion: The study supports using tDCS as an adjunct to written language interventions in individuals with logopenic or nonfluent/agrammatic PPA seeking compensatory treatments in clinical settings.

Transcranial direct current stimulation (tDCS) is an innovative technique recently shown to improve language outcomes even in neurodegenerative conditions such as primary progressive aphasia (PPA), but the underlying brain mechanisms are not known. The present study tested whether the additional language gains with repetitive tDCS (over sham) in PPA are caused by changes in functional connectivity between the stimulated area (the left inferior frontal gyrus (IFG)) and the rest of the language network. We scanned 24 PPA participants (11 female) before and after language intervention (written naming/spelling) with a resting-state fMRI sequence and compared changes before and after three weeks of tDCS or sham coupled with language therapy. We correlated changes in the language network as well as in the default mode network (DMN) with language therapy outcome measures (letter accuracy in written naming). Significant tDCS effects in functional connectivity were observed between the stimulated area and other language network areas and between the language network and the DMN. TDCS over the left IFG lowered the connectivity between the above pairs. Changes in functional connectivity correlated with improvement in language scores (letter accuracy as a proxy for written naming) evaluated before and after therapy. These results suggest that one mechanism for anodal tDCS over the left IFG in PPA is a decrease in functional connectivity (compared to sham) between the stimulated site and other posterior areas of the language network. These results are in line with similar decreases in connectivity observed after tDCS over the left IFG in aging and other neurodegenerative conditions.

Objective: To demonstrate a correlation between anatomic regional changes in Spinocerebellar Ataxia type 6 (SCA6) patients and measures of cognitive performance on neuropsychological tests., Methods: Neurocognitive testing was conducted on 24 SCA6 and 28 control subjects. For each cognitive test, SCA6 patients were compared against the controls using Student's t-test. For the cerebellar patients, using voxel based morphometry, correlations between cerebellar gray matter volume at each voxel and performance on the neuropsychological exams were calculated using the Pearson correlation coefficient implemented in SPM8., Results: Compared to controls, SCA6 patients exhibited significantly impaired performance on the following cognitive tests: Rey-Auditory Verbal Learning Test Trial V, Controlled Oral Word Association phonemic test and semantic-verb test, Rey-Osterrieth Complex Figure copy test as well as immediate and delayed visuo-spatial memory recall test, Trail Making Test (TMT) Part A and Part B, Stroop Color Task completion time, Stroop Color-Word Task score, and Grooved Pegboard Test (GPT) Dominant and Non-Dominant Hand time. Correlations of gray matter density with cognitive test performance were determined for all SCA6 subjects. Using a p-value threshold of 0.001 and family-wise small volume error correction, significant correlations were found for GPT Non-Dominant, GPT Dominant, TMT Part A, and TMT Part B., Conclusion: Different regional patterns of cerebellar involvement were found for the motoric GPT task and the executive version of the TMT. The results for the GPT strongly indicated that the integrity of medial superior hemispheric regions was associated with motor task performance, whereas executive cognitive function was localized in distinctly different inferior regions. This is the first VBM study to differentiate cognitive and motor contributions of the cerebellum., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Prenatal alcohol exposure has been linked to a broad range of developmental deficits, with eyeblink classical conditioning (EBC) among the most sensitive endpoints. This fMRI study compared EBC-related brain activity in 47 children with fetal alcohol syndrome (FAS), partial FAS (PFAS), heavily exposed (HE) non-syndromal children, and healthy controls. All of the children had previously participated in two EBC studies conducted as part of our longitudinal study of fetal alcohol spectrum disorders. Although learning-related behavioral differences were seen in all groups during the scans, controls showed more conditioned responses (CR) than the alcohol-exposed groups. Despite lower conditioning levels relative to controls, the exposed groups exhibited extensive cerebellar activations. Specifically, children with FAS/PFAS showed increased activation of cerebellar lobule VI in session 2, while HE children showed increased activation in session 1. Continuous measures of prenatal alcohol use correlated with learning-related activations in cerebellum and frontal cortices. Only controls showed significant cerebellar activation-CR correlations in the deep nuclei and lateral lobule VI, suggesting that these key regions supporting EBC may be functionally disorganized in alcohol-exposed children. These findings are the first to characterize abnormalities in brain function associated with the behavioral conditioning deficits seen in children with prenatal alcohol exposure., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

While the cerebellum has traditionally been thought of as mainly involved in motor functions, evidence has been accumulating for cerebellar contributions also to non-motor, cognitive functions. The notion of a cerebellar internal model underlying prediction and processing of sensory events and coordination and fine-tuning of appropriate responses has put the cerebellum right at the interface of motor behavior and cognition. Along these lines, the cerebellum may critically contribute to performance monitoring, a set of cognitive and affective functions underlying adaptive behavior. This review presents and integrates evidence from recent neuroimaging and clinical studies for a cerebellar role in performance monitoring with focus on sensory prediction, error and conflict processing, response inhibition, and feedback learning. Together with evidence for involvement in articulatory monitoring during working memory, these findings suggest monitoring as the cerebellum's overarching function., Competing Interests: The authors have no conflict of interest., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

It has been argued that cerebellar activations during cognitive tasks may masquerade as cognition, while actually reflecting processes related to movement planning or motor learning. The present study investigated whether the cerebellar load effect for verbal working memory, that is, increased activations in lobule VI/Crus I and lobule VIIB/VIIIA, is related to eye movements and oculomotor processing. Fifteen participants performed an fMRI-based Sternberg verbal working memory task. Oculomotor and cognitive task demands were manipulated by using closely and widely spaced stimuli, and high and low cognitive load. Trial-based quantitative eye movement parameters were obtained from concurrent eye tracking. Conventional MRI analysis replicated the cerebellar load effect in lobules VI and VIIB/VIIIa. With quantitative eye movement parameters as regressors, analysis yielded very similar activation patterns. While load effect and eye regressor generally recruited spatially distinct neocortical and cerebellar regions, conjunction analysis showed that a small subset of prefrontal areas implicated in the load effect also responded to the eye regressor. The present results indicate that cognitive load-dependent activations in lateral superior and posteroinferior cerebellar regions in the Sternberg task are independent of eye movements occurring during stimulus encoding. This is inconsistent with the notion that cognitive load-dependent cerebellar activations merely reflect oculomotor processing., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Alcoholism is a debilitating disorder that can take a significant toll on health and professional and personal relationships. Excessive alcohol consumption can have a serious impact on both drinkers and developing fetuses, leading to long-term learning impairments. Decades of research in laboratory animals and humans have demonstrated the value of eyeblink classical conditioning (EBC) as a well-characterized model system to study the neural mechanisms underlying associative learning. Behavioral EBC studies in adults with alcohol use disorders and in children with fetal alcohol spectrum disorders report a clear learning deficit in these two patient populations, suggesting alcohol-related damage to the cerebellum and associated structures. Insight into the neural mechanisms underlying these learning impairments has largely stemmed from laboratory animal studies. In this mini-review, we present and discuss exemplary animal findings and data from patient and neuroimaging studies. An improved understanding of the neural mechanisms underlying learning deficits in EBC related to alcoholism and prenatal alcohol exposure has the potential to advance the diagnoses, treatment, and prevention of these and other pediatric and adult disorders.

Working memory (WM) involves the ability to maintain and manipulate information held in mind. Neuroimaging studies have shown that secondary motor areas activate during WM for verbal content (e.g., words or letters), in the absence of primary motor area activation. This activation pattern may reflect an inner speech mechanism supporting online phonological rehearsal. Here, we examined the causal relationship between motor system activity and WM processing by using transcranial magnetic stimulation (TMS) to manipulate motor system activity during WM rehearsal. We tested WM performance for verbalizable (words and pseudowords) and non-verbalizable (Chinese characters) visual information. We predicted that disruption of motor circuits would specifically affect WM processing of verbalizable information. We found that TMS targeting motor cortex slowed response times (RTs) on verbal WM trials with high (pseudoword) vs. low (real word) phonological load. However, non-verbal WM trials were also significantly slowed with motor TMS. WM performance was unaffected by sham stimulation or TMS over visual cortex (VC). Self-reported use of motor strategy predicted the degree of motor stimulation disruption on WM performance. These results provide evidence of the motor system's contributions to verbal and non-verbal WM processing. We speculate that the motor system supports WM by creating motor traces consistent with the type of information being rehearsed during maintenance.

Background: Transcranial magnetic stimulation (TMS) can be combined with functional magnetic resonance imaging (fMRI) to simultaneously manipulate and monitor human cortical responses. Although tremendous efforts have been directed at characterizing the impact of TMS on image acquisition, the influence of the scanner's static field on the TMS coil has received limited attention., Objective/hypothesis: The aim of this study was to characterize the influence of the scanner's static field on TMS. We hypothesized that spatial variations in the static field could account for TMS field variations in the scanner environment., Methods: Using an MRI-compatible TMS coil, we estimated TMS field strengths based on TMS-induced voltage changes measured in a search coil. We compared peak field strengths obtained with the TMS coil positioned at different locations (B0 field vs fringe field) and orientations in the static field. We also measured the scanner's static field to derive a field map to account for TMS field variations., Results: TMS field strength scaled depending on coil location and orientation with respect to the static field. Larger TMS field variations were observed in fringe field regions near the gantry as compared to regions inside the bore or further removed from the bore. The scanner's static field also exhibited the greatest spatial variations in fringe field regions near the gantry., Conclusions: The scanner's static field influences TMS fields and spatial variations in the static field correlate with TMS field variations. Coil orientation changes in the B0 field did not result in substantial TMS field variations. TMS field variations can be minimized by delivering TMS in the bore or outside of the 0-70 cm region from the bore entrance., (Copyright © 2014 Elsevier Inc. All rights reserved.)

This study characterized human cerebellar activity during eyeblink classical conditioning (EBC) in children and adults using functional magnetic resonance imaging (fMRI). During fMRI, participants were administered delay conditioning trials, in which the conditioned stimulus (a tone) precedes, overlaps, and coterminates with the unconditioned stimulus (a corneal airpuff). Behavioral eyeblink responses and brain activation were measured concurrently during two phases: pseudoconditioning, involving presentations of tone alone and airpuff alone, and conditioning, during which the tone and airpuff were paired. Although all participants demonstrated significant conditioning, the adults produced more conditioned responses (CRs) than the children. When brain activations during pseudoconditioning were subtracted from those elicited during conditioning, significant activity was distributed throughout the cerebellar cortex (Crus I-II, lateral lobules IV-IX, and vermis IV-VI) in all participants, suggesting multiple sites of associative learning-related plasticity. Despite their less optimal behavioral performance, the children showed greater responding in the pons, lateral lobules VIII, IX, and Crus I, and vermis VI, suggesting that they may require greater activation and/or the recruitment of supplementary structures to achieve successful conditioning. Correlation analyses relating brain activations to behavioral CRs showed a positive association of activity in cerebellar deep nuclei (including dentate, fastigial, and interposed nuclei) and vermis VI with CRs in the children. This is the first study to compare cerebellar cortical and deep nuclei activations in children versus adults during EBC., (Copyright © 2013 Wiley Periodicals, Inc.)

A growing interest in cerebellar function and its involvement in higher cognition have prompted much research in recent years. Cerebellar presence in a wide range of cognitive functions examined within an increasing body of neuroimaging literature has been observed. We applied a meta-analytic approach, which employed the activation likelihood estimate method, to consolidate results of cerebellar involvement accumulated in different cognitive tasks of interest and systematically identified similarities among the studies. The current analysis included 88 neuroimaging studies demonstrating cerebellar activations in higher cognitive domains involving emotion, executive function, language, music, timing and working memory. While largely consistent with a prior meta-analysis by Stoodley and Schmahmann ([2009]: Neuroimage 44:489-501), our results extended their findings to include music and timing domains to provide further insights into cerebellar involvement and elucidate its role in higher cognition. In addition, we conducted inter- and intradomain comparisons for the cognitive domains of emotion, language, and working memory. We also considered task differences within the domain of verbal working memory by conducting a comparison of the Sternberg with the n-back task, as well as an analysis of the differential components within the Sternberg task. Results showed a consistent cerebellar presence in the timing domain, providing evidence for a role in time keeping. Unique clusters identified within the domain further refine the topographic organization of the cerebellum., (Copyright © 2012 Wiley Periodicals, Inc.)

People perceive spatial form and temporal frequency through touch. Although distinct somatosensory neurons represent spatial and temporal information, these neural populations are intermixed throughout the somatosensory system. Here, we show that spatial and temporal touch can be dissociated and separately enhanced via cortical pathways that are normally associated with vision and audition. In Experiments 1 and 2, we found that anodal transcranial direct current stimulation (tDCS) applied over visual cortex, but not auditory cortex, enhances tactile perception of spatial orientation. In Experiments 3 and 4, we found that anodal tDCS over auditory cortex, but not visual cortex, enhances tactile perception of temporal frequency. This double dissociation reveals separate cortical pathways that selectively support spatial and temporal channels. These results bolster the emerging view that sensory areas process multiple modalities and suggest that supramodal domains may be more fundamental to cortical organization.

Measurement of the cerebral blood flow (CBF) with whole-brain coverage is challenging in terms of both acquisition and quantitative analysis. In order to fit arterial spin labeling-based perfusion kinetic curves, an empirical three-parameter model which characterizes the effective impulse response function (IRF) is introduced, which allows the determination of CBF, the arterial transit time (ATT) and T(1,eff). The accuracy and precision of the proposed model were compared with those of more complicated models with four or five parameters through Monte Carlo simulations. Pseudo-continuous arterial spin labeling images were acquired on a clinical 3-T scanner in 10 normal volunteers using a three-dimensional multi-shot gradient and spin echo scheme at multiple post-labeling delays to sample the kinetic curves. Voxel-wise fitting was performed using the three-parameter model and other models that contain two, four or five unknown parameters. For the two-parameter model, T(1,eff) values close to tissue and blood were assumed separately. Standard statistical analysis was conducted to compare these fitting models in various brain regions. The fitted results indicated that: (i) the estimated CBF values using the two-parameter model show appreciable dependence on the assumed T(1,eff) values; (ii) the proposed three-parameter model achieves the optimal balance between the goodness of fit and model complexity when compared among the models with explicit IRF fitting; (iii) both the two-parameter model using fixed blood T1 values for T(1,eff) and the three-parameter model provide reasonable fitting results. Using the proposed three-parameter model, the estimated CBF (46 ± 14 mL/100 g/min) and ATT (1.4 ± 0.3 s) values averaged from different brain regions are close to the literature reports; the estimated T(1,eff) values (1.9 ± 0.4 s) are higher than the tissue T1 values, possibly reflecting a contribution from the microvascular arterial blood compartment., (Copyright © 2013 John Wiley & Sons, Ltd.)

Transcranial magnetic stimulation (TMS) can be delivered during fMRI scans to evoke BOLD responses in distributed brain networks. While concurrent TMS-fMRI offers a potentially powerful tool for non-invasively investigating functional human neuroanatomy, the technique is currently limited by the lack of methods to rapidly and precisely localize targeted brain regions - a reliable procedure is necessary for validly relating stimulation targets to BOLD activation patterns, especially for cortical targets outside of motor and visual regions. Here we describe a convenient and practical method for visualizing coil position (in the scanner) and identifying the cortical location of TMS targets without requiring any calibration or any particular coil-mounting device. We quantified the precision and reliability of the target position estimates by testing the marker processing procedure on data from 9 scan sessions: Rigorous testing of the localization procedure revealed minimal variability in coil and target position estimates. We validated the marker processing procedure in concurrent TMS-fMRI experiments characterizing motor network connectivity. Together, these results indicate that our efficient method accurately and reliably identifies TMS targets in the MR scanner, which can be useful during scan sessions for optimizing coil placement and also for post-scan outlier identification. Notably, this method can be used generally to identify the position and orientation of MR-compatible hardware placed near the head in the MR scanner., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Working memory is impaired in opioid-dependent individuals, yet the neural underpinnings of working memory in this population are largely unknown. Previous studies in healthy adults have demonstrated that working memory is supported by a network of brain regions that includes a cerebro-cerebellar circuit. The cerebellum, in particular, may be important for inner speech mechanisms that assist verbal working memory. This study used functional magnetic resonance imaging to examine brain activity associated with working memory in five opioid-dependent, methadone-maintained patients and five matched, healthy controls. An item recognition task was administered in two conditions: (1) a low working memory load "match" condition in which participants determined whether target letters presented at the beginning of the trial matched a probe item, and (2) a high working memory load "manipulation" condition in which participants counted two alphabetical letters forward of each of the targets and determined whether either of these new items matched a probe item. Response times and accuracy scores were not significantly different between the groups. FMRI analyses indicated that, in association with higher working memory load ("manipulation" condition), the patient group exhibited hyperactivity in the superior and inferior cerebellum and amygdala relative to that of controls. At a more liberal statistical threshold, patients exhibited hypoactivity in the left prefrontal and medial frontal/pre-SMA regions. These results indicate that verbal working memory in opioid-dependent individuals involves a disrupted cerebro-cerebellar circuit and shed light on the neuroanatomical basis of working memory impairments in this population.

The ability to store and manipulate online information may be enhanced by an inner speech mechanism that draws upon motor brain regions. Neural correlates of this mechanism were examined using event-related functional magnetic resonance imaging (fMRI). Sixteen participants completed two conditions of a verbal working memory task. In both conditions, participants viewed one or two target letters. In the "storage" condition, these targets were held in mind across a delay. Then a probe letter was presented, and participants indicated by button press whether the probe matched the targets. In the "manipulation" condition, participants identified new targets by thinking two alphabetical letters forward of each original target (e.g., f→h). Participants subsequently indicated whether the probe matched the newly derived targets. Brain activity during the storage and manipulation conditions was examined specifically during the delay phase in order to directly compare manipulation versus storage processes. Activations that were common to both conditions, yet disproportionately greater with manipulation, were observed in the left inferior frontal cortex, premotor cortex, and anterior insula, bilaterally in the parietal lobes and superior cerebellum, and in the right inferior cerebellum. This network shares substrates with overt speech and may represent an inner speech pathway that increases activity with greater working memory demands. Additionally, an inverse correlation was observed between manipulation-related brain activity (on correct trials) and test accuracy in the left premotor cortex, anterior insula, and bilateral superior cerebellum. This inverse relationship may represent intensification of inner speech as one struggles to maintain performance levels., (© 2011 Elsevier Inc. All rights reserved.)

Speech-both overt and covert-facilitates working memory by creating and refreshing motor memory traces, allowing new information to be received and processed. Neuroimaging studies suggest a functional topography within the sub-regions of the cerebellum that subserve verbal working memory. Medial regions of the anterior cerebellum support overt speech, consistent with other forms of motor execution such as finger tapping, whereas lateral portions of the superior cerebellum support speech planning and preparation (e.g., covert speech). The inferior cerebellum is active when information is maintained across a delay, but activation appears to be independent of speech, lateralized by modality of stimulus presentation, and possibly related to phonological storage processes. Motor (dorsal) and cognitive (ventral) channels of cerebellar output nuclei can be distinguished in working memory. Clinical investigations suggest that hyper-activity of cerebellum and disrupted control of inner speech may contribute to certain psychiatric symptoms.

Normal aging has been shown to impact performance during human eyeblink classical conditioning, with older adults showing lower conditioning levels than younger adults. Previous findings showed younger adults can acquire both delay and trace conditioning concurrently, but it is not known whether older adults can learn under the same conditions. Present results indicated older adults did not produce a significantly greater number of conditioned responses during acquisition, but their ability to time eyeblink responses prior to the unconditioned stimulus was preserved. The decline in eyeblink conditioning that typically accompanies aging has been extended to concurrent presentations of delay and trace conditioning trials., ((c) 2010 APA, all rights reserved.)

Contributions of cerebro-cerebellar function to executive verbal working memory were examined using event-related functional magnetic resonance imaging (fMRI) while 16 subjects completed two versions of the Sternberg task. In both versions subjects were presented with two or six target letters during the encoding phase, which were held in memory during the maintenance phase. A single probe letter was presented during the retrieval phase. In the "match condition", subjects decided whether the probe matched the target letters. In the "executive condition", subjects created a new probe by counting two alphabetical letters forward (e.g., f-->h) and decided whether the new probe matched the target letters. Neural activity during the match and executive conditions was compared during each phase of the task. There were four main findings. First, cerebro-cerebellar activity increased as a function of executive load. Second, the dorsal cerebellar dentate co-activated with the supplementary motor area (SMA) during encoding. This likely represented the formation of an articulatory (motor) trajectory. Third, the ventral cerebellar dentate co-activated with anterior prefrontal regions Brodmann Area (BA) 9/46 and the pre-SMA during retrieval. This likely represented the manipulation of information and formation of a response. A functional dissociation between the dorsal "motor" dentate and "cognitive" ventral dentate agrees with neuroanatomical tract tracing studies that have demonstrated separate neural pathways involving each region of the dentate: the dorsal dentate projects to frontal motor areas (including the SMA), and the ventral dentate projects to frontal cognitive areas (including BA 9/46 and the pre-SMA). Finally, activity during the maintenance phase in BA 9, anterior insula, pre-SMA and ventral dentate predicted subsequent accuracy of response to the probe during the retrieval phase. This finding underscored the significant contribution of the pre-SMA/ventral dentate pathway--observed several seconds prior to any motor response to the probe--to executive verbal working memory., (Copyright (c) 2009 Elsevier Srl. All rights reserved.)

Verbal working memory (VWM) engages frontal and temporal/parietal circuits subserving the phonological loop, as well as, superior and inferior cerebellar regions which have projections from these neocortical areas. Different cerebro-cerebellar circuits may be engaged for integrating aurally- and visually-presented information for VWM. The present fMRI study investigated load (2, 4, or 6 letters) and modality (auditory and visual) dependent cerebro-cerebellar VWM activation using a Sternberg task. FMRI revealed modality-independent activations in left frontal (BA 6/9/44), insular, cingulate (BA 32), and bilateral inferior parietal/supramarginal (BA 40) regions, as well as in bilateral superior (HVI) and right inferior (HVIII) cerebellar regions. Visual presentation evoked prominent activations in right superior (HVI/CrusI) cerebellum, bilateral occipital (BA19) and left parietal (BA7/40) cortex while auditory presentation showed robust activations predominantly in bilateral temporal regions (BA21/22). In the cerebellum, we noted a visual to auditory emphasis of function progressing from superior to inferior and from lateral to medial regions. These results extend our previous findings of fMRI activation in cerebro-cerebellar networks during VWM, and demonstrate both modality dependent commonalities and differences in activations with increasing memory load.

Lack of sexual interest is the most common sexual complaint among women. However, factors affecting sexual desire in women have rarely been studied. While the role of the brain in integrating the sensory, attentional, motivational, and motor aspects of sexual response is commonly acknowledged as important, little is known about specific patterns of brain activation and sexual interest or response, particularly among women. We compared 20 females with no history of sexual dysfunction (NHSD) to 16 women with hypoactive sexual desire disorder (HSDD) in a functional magnetic resonance imaging (fMRI) study that included assessment of subjective sexual arousal, peripheral sexual response using a vaginal photoplethysmograph (VPP), as well as brain activation across three time points. Video stimuli included erotic, sports, and relaxing segments. Subjective arousal to erotic stimuli was significantly greater in NHSD participants compared with HSDD. In the erotic-sports contrast, NHSD women showed significantly greater activation in the bilateral entorhinal cortex than HSDD women. In the same contrast, HSDD females demonstrated higher activation than NHSD females in the medial frontal gyrus (Brodmann area (BA) 10), right inferior frontal gyrus (BA 47) and bilateral putamen. There were no between group differences in VPP-correlated brain activation and peripheral sexual response was not significantly associated with either subjective sexual response or brain activation patterns. Findings were consistent across the three experimental sessions. The results suggest differences between women with NHSD and HSDD in encoding arousing stimuli, retrieval of past erotic experiences, or both. The findings of greater activation in BA 10 and BA 47 among women with HSDD suggest that this group allocated significantly more attention to monitoring and/or evaluating their responses than NHSD participants, which may interfere with normal sexual response.

Classical conditioning paradigms, such as trace conditioning, in which a silent period elapses between the offset of the conditioned stimulus (CS) and the delivery of the unconditioned stimulus (US), and delay conditioning, in which the CS and US coterminate, are widely used to study the neural substrates of associative learning. However, there are significant gaps in our knowledge of the neural systems underlying conditioning in humans. For example, evidence from animal and human patient research suggests that the hippocampus plays a critical role during trace eyeblink conditioning, but there is no evidence to date in humans that the hippocampus is active during trace eyeblink conditioning or is differentially responsive to delay and trace paradigms. The present work provides a direct comparison of the neural correlates of human delay and trace eyeblink conditioning by using functional MRI. Behavioral results showed that humans can learn both delay and trace conditioning in parallel. Comparable delay and trace activation was measured in the cerebellum, whereas greater hippocampal activity was detected during trace compared with delay conditioning. These findings further support the position that the cerebellum is involved in both delay and trace eyeblink conditioning whereas the hippocampus is critical for trace eyeblink conditioning. These results also suggest that the neural circuitry supporting delay and trace eyeblink classical conditioning in humans and laboratory animals may be functionally similar.

This study was designed to investigate cerebellar lobular contributions to specific cognitive deficits observed after cerebellar tumor resection. Verbal working memory (VWM) tasks were administered to children following surgical resection of cerebellar pilocytic astrocytomas and age-matched controls. Anatomical MRI scans were used to quantify the extent of cerebellar lobular damage from each patient's resection. Patients exhibited significantly reduced digit span for auditory but not visual stimuli, relative to controls, and damage to left hemispheral lobule VIII was significantly correlated with this deficit. Patients also showed reduced effects of articulatory suppression and this was correlated with damage to the vermis and hemispheral lobule IV/V bilaterally. Phonological similarity and recency effects did not differ overall between patients and controls, but outlier patients with abnormal phonological similarity effects to either auditory or visual stimuli were found to have damage to hemispheral lobule VIII/VIIB on the left and right, respectively. We postulate that damage to left hemispheral lobule VIII may interfere with encoding of auditory stimuli into the phonological store. These data corroborate neuroimaging studies showing focal cerebellar activation during VWM paradigms, and thereby allow us to predict with greater accuracy which specific neurocognitive processes will be affected by a cerebellar tumor resection.