Baseline functional connectivity predicts who will benefit from neuromodulation: evidence from primary progressive aphasia.

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.

Disrupted executive cerebro-cerebellar functional connectivity in alcohol use disorder.

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.

The role of the cerebellum in internet gaming disorder-A systematic review.

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.

Specificity in Generalization Effects of Transcranial Direct Current Stimulation Over the Left Inferior Frontal Gyrus in Primary Progressive Aphasia.

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.

Cerebellar Transcranial Magnetic Stimulation (TMS) Impairs Visual Working Memory.

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.

Variation of cerebrospinal fluid in specific regions regulates focality in transcranial direct current stimulation.

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).

Cerebro-Cerebellar Response to Sequence Violation in a Cognitive Task: an fMRI Study.

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.

Sex difference in tDCS current mediated by changes in cortical anatomy: A study across young, middle and older adults.

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 cm2 electrode) from two simulated tDCS montages (CP5_CZ and F3_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.

Focality-Oriented Selection of Current Dose for Transcranial Direct Current Stimulation.

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.

Sensory acquisition functions of the cerebellum in verbal working memory.

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.

Neural Correlates of Letter and Semantic Fluency in Primary Progressive Aphasia.

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 (R2 = 38%), and correlated with the volume of the left superior temporal regions (R2 = 12%) and the right dorsolateral prefrontal area (R2 = 5%). Semantic fluency was predominantly associated with dementia severity (R2 = 47%) and correlated with the volume of the left inferior temporal gyrus (R2 = 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.

Cerebellar neuromodulation improves naming in post-stroke aphasia.

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.

Reading proficiency influences the effects of transcranial direct current stimulation: Evidence from selective modulation of dorsal and ventral pathways of reading in bilinguals.

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 cm2 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.

i-SATA: A MATLAB based toolbox to estimate current density generated by transcranial direct current stimulation in an individual brain.

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, aging, and the parietal lobe.

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.

Changes in Hemodynamic Response Function Resulting From Chronic Alcohol Consumption.

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.

Neural Substrates Underlying Eyeblink Classical Conditioning in Adults With Alcohol Use Disorders.

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.

Simulation Analyses of tDCS Montages for the Investigation of Dorsal and Ventral Pathways.

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 cm2. 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 cm2 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.

Disruption of Cerebellar Prediction in Verbal Working Memory.

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.

"The effect of tDCS on functional connectivity in primary progressive aphasia" NeuroImage: Clinical, volume 19 (2018), pages 703-715.

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.