Lessons learned from an fMRI-guided rTMS study on performance in a numerical Stroop task.

The Stroop task is a well-established tool to investigate the influence of competing visual categories on decision making. Neuroimaging as well as rTMS studies have demonstrated the involvement of parietal structures, particularly the intraparietal sulcus (IPS), in this task. Given its reliability, the numerical Stroop task was used to compare the effects of different TMS targeting approaches by Sack and colleagues (Sack AT 2009), who elegantly demonstrated the superiority of individualized fMRI targeting. We performed the present study to test whether fMRI-guided rTMS effects on numerical Stroop task performance could still be observed while using more advanced techniques that have emerged in the last decade (e.g., electrical sham, robotic coil holder system, etc.). To do so we used a traditional reaction time analysis and we performed, post-hoc, a more advanced comprehensive drift diffusion modeling approach. Fifteen participants performed the numerical Stroop task while active or sham 10 Hz rTMS was applied over the region of the right intraparietal sulcus (IPS) showing the strongest functional activation in the Incongruent > Congruent contrast. This target was determined based on individualized fMRI data collected during a separate session. Contrary to our assumption, the classical reaction time analysis did not show any superiority of active rTMS over sham, probably due to confounds such as potential cumulative rTMS effects, and the effect of practice. However, the modeling approach revealed a robust effect of rTMS on the drift rate variable, suggesting differential processing of congruent and incongruent properties in perceptual decision-making, and more generally, illustrating that more advanced computational analysis of performance can elucidate the effects of rTMS on the brain where simpler methods may not.

Consensus Paper: Cerebellum and Ageing.

Given the key roles of the cerebellum in motor, cognitive, and affective operations and given the decline of brain functions with aging, cerebellar circuitry is attracting the attention of the scientific community. The cerebellum plays a key role in timing aspects of both motor and cognitive operations, including for complex tasks such as spatial navigation. Anatomically, the cerebellum is connected with the basal ganglia via disynaptic loops, and it receives inputs from nearly every region in the cerebral cortex. The current leading hypothesis is that the cerebellum builds internal models and facilitates automatic behaviors through multiple interactions with the cerebral cortex, basal ganglia and spinal cord. The cerebellum undergoes structural and functional changes with aging, being involved in mobility frailty and related cognitive impairment as observed in the physio-cognitive decline syndrome (PCDS) affecting older, functionally-preserved adults who show slowness and/or weakness. Reductions in cerebellar volume accompany aging and are at least correlated with cognitive decline. There is a strongly negative correlation between cerebellar volume and age in cross-sectional studies, often mirrored by a reduced performance in motor tasks. Still, predictive motor timing scores remain stable over various age groups despite marked cerebellar atrophy. The cerebello-frontal network could play a significant role in processing speed and impaired cerebellar function due to aging might be compensated by increasing frontal activity to optimize processing speed in the elderly. For cognitive operations, decreased functional connectivity of the default mode network (DMN) is correlated with lower performances. Neuroimaging studies highlight that the cerebellum might be involved in the cognitive decline occurring in Alzheimer's disease (AD), independently of contributions of the cerebral cortex. Grey matter volume loss in AD is distinct from that seen in normal aging, occurring initially in cerebellar posterior lobe regions, and is associated with neuronal, synaptic and beta-amyloid neuropathology. Regarding depression, structural imaging studies have identified a relationship between depressive symptoms and cerebellar gray matter volume. In particular, major depressive disorder (MDD) and higher depressive symptom burden are associated with smaller gray matter volumes in the total cerebellum as well as the posterior cerebellum, vermis, and posterior Crus I. From the genetic/epigenetic standpoint, prominent DNA methylation changes in the cerebellum with aging are both in the form of hypo- and hyper-methylation, and the presumably increased/decreased expression of certain genes might impact on motor coordination. Training influences motor skills and lifelong practice might contribute to structural maintenance of the cerebellum in old age, reducing loss of grey matter volume and therefore contributing to the maintenance of cerebellar reserve. Non-invasive cerebellar stimulation techniques are increasingly being applied to enhance cerebellar functions related to motor, cognitive, and affective operations. They might enhance cerebellar reserve in the elderly. In conclusion, macroscopic and microscopic changes occur in the cerebellum during the lifespan, with changes in structural and functional connectivity with both the cerebral cortex and basal ganglia. With the aging of the population and the impact of aging on quality of life, the panel of experts considers that there is a huge need to clarify how the effects of aging on the cerebellar circuitry modify specific motor, cognitive, and affective operations both in normal subjects and in brain disorders such as AD or MDD, with the goal of preventing symptoms or improving the motor, cognitive, and affective symptoms.

Feasibility of Cerebellar Transcranial Direct Current Stimulation to Facilitate Goal-Directed Weight Shifting in Chronic Post-Stroke Hemiplegics.

Neurological disorder such as stroke can adversely affect one's weight-bearing symmetry leading to dysfunctional postural control. Recovery after stroke is facilitated through functionally-relevant neuroplastic modulation. Functionally-relevant cerebellum coordinates voluntary movements. Specifically, the dentate nuclei and lower limb representations (lobules VII-IX) of the cerebellum are involved in error-correction, crucial for postural control. It is postulated that cerebellar transcranial direct current stimulation (ctDCS) of the dentate nuclei and lobules VII-IX can modulate postural control in chronic stroke survivors. The objectives of this work were to (1) present a refined Virtual Reality (VR)-based balance training platform (VBaT) that can measure Center of Pressure (CoP) and (2) carry out a study to understand the implication of ctDCS stimulating the dentate nuclei (PhaseD) and lobules VII-IX (PhaseL) on the postural control of chronic stroke patients when they interacted with VBaT. Also, we investigated whether hemiplegic patients (with intact cerebellum) having Basal Ganglia (BG) infarction had any differential abilities to correct postural sway from those with no BG infarction (while shifting weight to the Affected side). Results of a single-session single-blind crossover study on randomized PhaseD and PhaseL stimulation (with an intermediate resting state bipolar bilateral ctDCS) on 12 chronic hemiplegic patients on separate days indicated differentiated findings (post stimulation) on CoP-related indices. We observed an incremental effect on one's postural control during PhaseD and inhibitory effect on the dentate nuclei during PhaseL. Clustering analysis showed that those with BG infarction demonstrated poor postural control and deficit in error correction ability irrespective of the ctDCS Phase.

Feasibility of combining functional near-infrared spectroscopy with electroencephalography to identify chronic stroke responders to cerebellar transcranial direct current stimulation-a computational modeling and portable neuroimaging methodological study.

Feasibility of portable neuroimaging of cerebellar transcranial direct current stimulation (ctDCS) effects on the cerebral cortex has not been investigated vis-à-vis cerebellar lobular electric field strength. We studied functional near-infrared spectroscopy (fNIRS) in conjunction with electroencephalography (EEG) to measure changes in the brain activation at the prefrontal cortex (PFC) and the sensorimotor cortex (SMC) following ctDCS as well as virtual reality-based balance training (VBaT) before and after ctDCS treatment in 12 hemiparetic chronic stroke survivors. We performed general linear modeling (GLM) that putatively associated the lobular electric field strength with the changes in the fNIRS-EEG measures at the ipsilesional and contra-lesional PFC and SMC. Here, fNIRS-EEG measures were found in the latent space from canonical correlation analysis (CCA) between the changes in total hemoglobin (tHb) concentrations (0.01-0.07Hz and 0.07-0.13Hz bands) and log10-transformed EEG bandpower within 1-45 Hz where significant (Wilks' lambda>0.95) canonical correlations were found only for the 0.07-0.13-Hz band. Also, the first principal component (97.5% variance accounted for) of the mean lobular electric field strength was a good predictor of the latent variables of oxy-hemoglobin (O2Hb) concentrations and log10-transformed EEG bandpower. GLM also provided insights into non-responders to ctDCS who also performed poorly in the VBaT due to ideomotor apraxia. Future studies should investigate fNIRS-EEG joint-imaging in a larger cohort to identify non-responders based on GLM fitting to the fNIRS-EEG data.

Investigating the feasibility of cerebellar transcranial direct current stimulation to facilitate post-stroke overground gait performance in chronic stroke: a partial least-squares regression approach.

BACKGROUND: Investigation of lobule-specific electric field effects of cerebellar transcranial direct current stimulation (ctDCS) on overground gait performance has not been performed, so this study aimed to investigate the feasibility of two lobule-specific bilateral ctDCS montages to facilitate overground walking in chronic stroke. METHODS: Ten chronic post-stroke male subjects participated in this repeated-measure single-blind crossover study, where we evaluated the single-session effects of two bilateral ctDCS montages that applied 2 mA via 3.14 cm2 disc electrodes for 15 min targeting (a) dentate nuclei (also, anterior and posterior lobes), and (b) lower-limb representations (lobules VIIb-IX). A two-sided Wilcoxon rank-sum test was performed at a 5% significance level on the percent normalized change measures in the overground gait performance. Partial least squares regression (PLSR) analysis was performed on the quantitative gait parameters as response variables to the mean lobular electric field strength as the predictors. Clinical assessments were performed with the Ten-Meter walk test (TMWT), Timed Up & Go (TUG), and the Berg Balance Scale based on minimal clinically important differences (MCID). RESULTS: The ctDCS montage specific effect was found significant using a two-sided Wilcoxon rank-sum test at a 5% significance level for 'Step Time Affected Leg' (p = 0.0257) and '%Stance Time Unaffected Leg' (p = 0.0376). The changes in the quantitative gait parameters were found to be correlated to the mean electric field strength in the lobules based on PLSR analysis (R2 statistic = 0.6574). Here, the mean electric field strength at the cerebellar lobules, Vermis VIIIb, Ipsi-lesional IX, Vermis IX, Ipsi-lesional X, had the most loading and were positively related to the 'Step Time Affected Leg' and '%Stance Time Unaffected Leg,' and negatively related to the '%Swing Time Unaffected Leg,' '%Single Support Time Affected Leg.' Clinical assessments found similar improvement in the TMWT (MCID: 0.10 m/s), TUG (MCID: 8 s), and BBS score (MCID: 12.5 points) for both the ctDCS montages. CONCLUSION: Our feasibility study found an association between the lobular mean electric field strength and the changes in the quantitative gait parameters following a single ctDCS session in chronic stroke. Both the ctDCS montages improved the clinical outcome measures that should be investigated with a larger sample size for clinical validation. TRIAL REGISTRATION: Being retrospectively registered.

Deep Cerebellar Transcranial Direct Current Stimulation of the Dentate Nucleus to Facilitate Standing Balance in Chronic Stroke Survivors-A Pilot Study.

OBJECTIVE: Cerebrovascular accidents are the second leading cause of death and the third leading cause of disability worldwide. We hypothesized that cerebellar transcranial direct current stimulation (ctDCS) of the dentate nuclei and the lower-limb representations in the cerebellum can improve functional reach during standing balance in chronic (>6 months' post-stroke) stroke survivors. MATERIALS AND METHODS: Magnetic resonance imaging (MRI) based subject-specific electric field was computed across a convenience sample of 10 male chronic (>6 months) stroke survivors and one healthy MRI template to find an optimal bipolar bilateral ctDCS montage to target dentate nuclei and lower-limb representations (lobules VII-IX). Then, in a repeated-measure crossover study on a subset of 5 stroke survivors, we compared 15minutes of 2mA ctDCS based on the effects on successful functional reach (%) during standing balance task. Three-way ANOVA investigated the factors of interest- brain regions, montages, stroke participants, and their interactions. RESULTS: "One-size-fits-all" bipolar ctDCS montage for the clinical study was found to be PO9h-PO10h for dentate nuclei and Exx7-Exx8 for lobules VII-IX with the contralesional anode. PO9h-PO10h ctDCS performed significantly (alpha = 0.05) better in facilitating successful functional reach (%) when compared to Exx7-Exx8 ctDCS. Furthermore, a linear relationship between successful functional reach (%) and electric field strength was found where PO9h-PO10h montage resulted in a significantly (alpha = 0.05) higher electric field strength when compared to Exx7-Exx8 montage for the same 2mA current. CONCLUSION: We presented a rational neuroimaging based approach to optimize deep ctDCS of the dentate nuclei and lower limb representations in the cerebellum for post-stroke balance rehabilitation. However, this promising pilot study was limited by "one-size-fits-all" bipolar ctDCS montage as well as a small sample size.

Lobule-Specific Dosage Considerations for Cerebellar Transcranial Direct Current Stimulation During Healthy Aging: A Computational Modeling Study Using Age-Specific Magnetic Resonance Imaging Templates.

OBJECTIVE: Aging is associated with a decline in cognitive and motor performances, which are a part of geriatric syndromes. Since aging is associated with morphological changes in the cerebellum and cerebellar morphology is a good predictor of cognitive and motor performances, so the study of cerebellar role in age-related decline in performance is necessary. Cerebellar transcranial direct current stimulation (ctDCS) has been proposed to study and facilitate the cerebellar function. However, lobule-specific dosing has not been investigated in healthy aging. This is important because the same electrode montage across different individuals for ctDCS (called the "one-size-fits-all" approach) can lead to inter-individual differences in the lobule-specific dosing of the electric field (EF). These differences can be due to the inter-individual variability and age-related changes in the cerebellar structure. To investigate such lobule-specific dosing differences in healthy aging, we modeled the lobular EF distribution across groups of 18 to 89 years for a commonly used "one-size-fits-all" ctDCS montage. MATERIALS AND METHODS: A fully automated open-source pipeline performed age-group specific computational modeling of EF using 18 age-appropriate human brain magnetic resonance imaging (MRI) templates. The 18 age-appropriate human brain MRI templates were obtained from a database found online at https://jerlab.sc.edu/projects/neurodevelopmental-mri-database/. We extracted the EF magnitude (called EF strength) across the 28 cerebellar lobules based on a spatially unbiased cerebellar atlas. We investigated the aging effects on various measures of specificity including the ratio of the mean lobular EF at the lobules beneath the active electrode (ipsilateral [right] lobules VIIIa, VIIIb, IX) divided by the mean EF across both the targeted (ipsi) and the contralateral (contra) cerebellar hemisphere. RESULTS: Two-way ANOVA showed that the lobules as well as the age group (and their interaction term) had a significant effect (p < 0.01) on the EF strength. Specifically, EF strength increased significantly at the neighboring cerebellar lobules (e.g., ipsilateral [right] lobules VIIb, Crus I and Crus II) of the targeted cerebellar hemisphere at an old age (70-74, 75-79, and 85-89 years) that reduced the specificity of ctDCS at the ipsilateral (right) lobules VIIIa, VIIIb, IX beneath the active electrode. We also found that the maximum EF strength in the cerebellar hemispheres decreased with an increase in the volume of the cerebrospinal fluid (CSF) and a decrease in the cerebellar volume with aging in a linear manner. DISCUSSION: We found that cerebellar shrinkage and increasing thickness of the highly conductive CSF during healthy aging can lead to the dispersion of the current away from the lobules underlying the active electrode. We concluded that an individualized ctDCS approach for dosimetry is critical when ctDCS is used as an adjuvant treatment for active aging to address age-related lobule-specific cerebellar geriatric syndromes effectively. Future work is necessary to investigate age-related effects of lobule-specific ctDCS on the large-scale cognitive and motor networks using functional neuroimaging that is expected due to the cerebellum's extensive reciprocal connectivity with the cerebral cortex.

A computational pipeline to find lobule-specific electric field distribution during non-invasive cerebellar stimulation.

OBJECTIVE: Cerebellar Transcranial direct current stimulation (ctDCS) of cerebellar lobules is challenging due to the complexity of the cerebellar structure. Therefore, we present a freely available computational pipeline to determine the subject-specific lobule-specific electric field distribution during ctDCS. METHODS: The computational pipeline isolates subject-specific cerebellar lobules based on a spatially unbiased atlas template (SUIT) for the cerebellum, and then calculates the lobule-specific electric field distribution during ctDCS. The computational pipeline was tested using Colin27 Average Brain. The 5 cm × 5 cm anode was placed 3 cm lateral to inion, and the same sized cathode was placed on the contralateral supra-orbital area (called Manto montage) and buccinators muscle (called Celnik montage). A published 4x1 HD-ctDCS electrode montage was also implemented for a comparison using analysis of variance. RESULTS: The electric field strength of both the Celnik and the Manto montages affected the lobules Crus II, VIIb, VIII, and IX of the targeted cerebellar hemispheres while Manto montage had a more bilateral effect. The HD-ctDCS montage primarily affected the lobules Crus I, Crus II, VIIb of the targeted cerebellar hemisphere. DISCUSSION: Our freely available subject-specific computational modeling pipeline can be used to analyze lobulespecific electric field distribution to select an optimal ctDCS electrode montage.

Effects of cerebellar transcranial direct current stimulation on cerebellar-brain inhibition in humans: A systematic evaluation.

BACKGROUND: Cerebellar transcranial direct current stimulation (ctDCS) is increasingly used to modulate cerebellar excitability and plasticity in healthy subjects and various patient populations. ctDCS parameters are poorly standardized, and its physiology remains little understood. Our aim was to compare the physiological effects of three different non-target electrode positions (buccinator muscle, supraorbital region, deltoid muscle). METHODS: In the first experiment, physiological after-effects of ctDCS were compared based on cerebellar-brain inhibition (CBI) in a group of 15 healthy right-handed participants. In the second experiment, CBI after-effects of ctDCS were assessed using different transcranial magnetic stimulation (TMS) intensities in 14 participants (CBI recruitment curve). The electric field distribution was calculated for each of the electrode montages based on a single anatomically accurate head model. RESULTS: Anodal and cathodal ctDCS polarities significantly decreased cerebellar-brain inhibition (CBI) with no substantial differences between the montages. Lower cerebellar TMS intensities resulted in decreased CBI following cathodal and increased CBI after anodal ctDCS. Computational modeling revealed minor differences in the electric field distribution between non-target electrode positions based on the effect size. CONCLUSION: Our results show that the non-target electrode position has no significant impact on modeling results and physiological ctDCS after-effects. The recruitment of the cerebellar-M1 connection, however, varied depending on ctDCS polarity and cerebellar transcranial magnetic stimulation intensity, possibly due to diverse effects on different cell populations in the cerebellar cortex. This may be one of the reasons why ctDCS effects on functional measures are difficult to predict.

Cerebellar Lobules Optimal Stimulation (CLOS): A Computational Pipeline to Optimize Cerebellar Lobule-Specific Electric Field Distribution.

OBJECTIVE: Cerebellar transcranial direct current stimulation (ctDCS) is challenging due to the complexity of the cerebellar structure which is reflected by the well-known variability in ctDCS effects. Therefore, our objective is to present a freely available computational modeling pipeline for cerebellar lobules' optimal stimulation (CLOS). METHODS: CLOS can optimize lobule-specific electric field distribution following finite element analysis (FEA) using freely available computational modeling pipelines. We modeled published ctDCS montages with 5 cm × 5 cm anode placed 3 cm lateral to inion, and the same sized cathode was placed on the: (1) contralateral supra-orbital area (called Manto montage), and (2) buccinators muscle (called Celnik montage). Also, a published (3) 4×1 HD-ctDCS electrode montage was modeled. We also investigated the effects of the subject-specific head model versus Colin 27 average head model on lobule-specific electric field distribution. Three-way analysis of variance (ANOVA) was used to determine the effects of lobules, montage, and head model on the electric field distribution. The differences in lobule-specific electric field distribution across different freely available computational pipelines were also evaluated using subject-specific head model. We also presented an application of our computational pipeline to optimize a ctDCS electrode montage to deliver peak electric field at the cerebellar lobules VII-IX related to ankle function. RESULTS: Eta-squared effect size after three-way ANOVA for electric field strength was 0.05 for lobule, 0.00 for montage, 0.04 for the head model, 0.01 for lobule∗montage interaction, 0.01 for lobule∗ head model interaction, and 0.00 for montage∗head model interaction. The electric field strength of both the Celnik and the Manto montages affected the lobules Crus I/II, VIIb, VIII, and IX of the targeted cerebellar hemisphere where Manto montage had a spillover to the contralateral cerebellar hemisphere. The 4×1 HD-ctDCS montage primarily affected the lobules Crus I/II of the targeted cerebellar hemisphere. All three published ctDCS montages were found to be not optimal for ankle function (lobules VII-IX), so we presented a novel HD-ctDCS electrode montage. DISCUSSION: Our freely available CLOS pipeline can be leveraged to optimize electromagnetic stimulation to target cerebellar lobules related to different cognitive and motor functions.

Transcranial Direct Current Stimulation of the Leg Motor Area - is it partly somatosensory?

Non-invasive brain stimulation such as transcranial direct current stimulation (tDCS) involves passing low currents through the brain and is a promising tool for the modulation of cortical excitability. We computationally investigated the effects of the size of the anode in the conventional montage (contralateral supraorbital cathode) using finite element analysis (FEA) for the targeted leg area of the motor cortex where tDCS is challenging due to the depth and orientation of the leg motor area in the inter-hemispheric fissure. We used FEA to develop two anode sizes (same cathode size) with the same current density but different electric field magnitude at the targeted leg area of the motor cortex. Then, we evaluated the effects of the two anode sizes via neurophysiological testing on twelve healthy subjects, seven males and five females (age: 21-36 years, all right-leg dominant). Here, conventional anodal tDCS electrode montage for the leg area of the motor cortex used a large-anode (5cmx7cm, current strength 2mA) which was compared based on transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEP) with a small-anode (3.5cmx1cm at 0.2mA) montage of the same current density at the skin-electrode interface and identical contralateral supraorbital cathode placement. Small-anode decreased the electric field magnitude by almost one-tenth but still got a similar statistically significant $(\mathrm {P}<0.05)$ increase in the cortical excitability (MEP) at the targeted leg motor area when compared to sham tDCS. Since the electric field magnitude was similar at the scalp (skin-electrode interface) level but differed significantly at the leg motor area in the inter-hemispheric fissure, so a possible contribution of scalp sensory nerve responses to electrocutaneous stimulation is proposed.

Effects of Cathode Location and the Size of Anode on Anodal Transcranial Direct Current Stimulation Over the Leg Motor Area in Healthy Humans.

Objective: Non-invasive brain stimulation such as transcranial direct current stimulation (tDCS) involves passing low currents through the brain and is a promising tool for the modulation of cortical excitability. In this study, we investigated the effects of cathode location and the size of anode for anodal tDCS of the right-leg area of the motor cortex, which is challenging due to its depth and orientation in the inter-hemispheric fissure. Methods: We first computationally investigated the effects of cathode location and the size of the anode to find the best montage for specificity of stimulation effects for the targeted leg motor area using finite element analysis (FEA). We then compared the best electrode montage found from FEA with the conventional montage (contralateral supraorbital cathode) via neurophysiological testing of both, the targeted as well as the contralateral leg motor area. Results: The conventional anodal tDCS electrode montage for leg motor cortex stimulation using a large-anode (5 cm × 7 cm, current strength 2 mA) affected the contralateral side more strongly in both the FEA and the neurophysiological testing when compared to other electrode montages. A small-anode (3.5 cm × 1 cm at 0.2 mA) with the same current density at the electrode surface and identical contralateral supraorbital cathode placement improved specificity. The best cathode location for the small-anode in terms of specificity for anodal tDCS of the right-leg motor area was T7 (10-10 EEG system). Conclusion: A small-anode (3.5 cm × 1 cm) with the same current density at the electrode surface as a large-anode (5 cm × 7 cm) resulted in similar cortical excitability alterations of the targeted leg motor cortex respresentation. In relation to the other stimulation conditions, the small-anode montage with the cathode positioned at T7 resulted in the best specificity.