Differences in scalp-to-cortex tissues across age groups, sexes and brain regions: Implications for neuroimaging and brain stimulation techniques.

Aging affects the scalp-to-cortex distance (SCD) and the comprising tissues. This is crucial for noninvasive neuroimaging and brain stimulation modalities as they rely on traversing from the scalp to the cortex or vice versa. The specific relationship between aging and these tissues has not been comprehensively investigated. We conducted a study on 250 younger and older adults to examine age-related differences in SCD and its constituent tissues. We identified region-specific differences in tissue thicknesses related to age and sex. Older adults exhibit larger SCD in the frontocentral regions compared to younger adults. Men exhibit greater SCD in the inferior scalp regions, while women show similar-to-greater SCD values in regions closer to the vertex compared to men. Younger adults and men have thicker soft tissue layers, whereas women and older adults exhibit thicker compact bone layers. CSF is considerably thicker in older adults, particularly in men. These findings emphasize the need to consider age, sex, and regional differences when interpreting SCD and its implications for noninvasive neuroimaging and brain stimulation.

Outcome measures for electric field modeling in tES and TMS: A systematic review and large-scale modeling study.

BACKGROUND: Electric field (E-field) modeling is a potent tool to estimate the amount of transcranial magnetic and electrical stimulation (TMS and tES, respectively) that reaches the cortex and to address the variable behavioral effects observed in the field. However, outcome measures used to quantify E-fields vary considerably and a thorough comparison is missing. OBJECTIVES: This two-part study aimed to examine the different outcome measures used to report on tES and TMS induced E-fields, including volume- and surface-level gray matter, region of interest (ROI), whole brain, geometrical, structural, and percentile-based approaches. The study aimed to guide future research in informed selection of appropriate outcome measures. METHODS: Three electronic databases were searched for tES and/or TMS studies quantifying E-fields. The identified outcome measures were compared across volume- and surface-level E-field data in ten tES and TMS modalities targeting two common targets in 100 healthy individuals. RESULTS: In the systematic review, we extracted 308 outcome measures from 202 studies that adopted either a gray matter volume-level (n = 197) or surface-level (n = 111) approach. Volume-level results focused on E-field magnitude, while surface-level data encompassed E-field magnitude (n = 64) and normal/tangential E-field components (n = 47). E-fields were extracted in ROIs, such as brain structures and shapes (spheres, hexahedra and cylinders), or the whole brain. Percentiles or mean values were mostly used to quantify E-fields. Our modeling study, which involved 1,000 E-field models and > 1,000,000 extracted E-field values, revealed that different outcome measures yielded distinct E-field values, analyzed different brain regions, and did not always exhibit strong correlations in the same within-subject E-field model. CONCLUSIONS: Outcome measure selection significantly impacts the locations and intensities of extracted E-field data in both tES and TMS E-field models. The suitability of different outcome measures depends on the target region, TMS/tES modality, individual anatomy, the analyzed E-field component and the research question. To enhance the quality, rigor, and reproducibility in the E-field modeling domain, we suggest standard reporting practices across studies and provide four recommendations.

From scalp to cortex, the whole isn't greater than the sum of its parts: introducing GetTissueThickness (GTT) to assess age and sex differences in tissue thicknesses.

Noninvasive techniques to record and stimulate the brain rely on passing through the tissues in between the scalp and cortex. Currently, there is no method to obtain detailed information about these scalp-to-cortex distance (SCD) tissues. We introduce GetTissueThickness (GTT), an open-source, automated approach to quantify SCD, and unveil how tissue thicknesses differ across age groups, sexes and brain regions (n = 250). We show that men have larger SCD in lower scalp regions and women have similar-to-larger SCD in regions closer to the vertex, with aging resulting in increased SCD in fronto-central regions. Soft tissue thickness varies by sex and age, with thicker layers and greater age-related decreases in men. Compact and spongy bone thickness also differ across sexes and age groups, with thicker compact bone in women in both age groups and an age-related thickening. Older men generally have the thickest cerebrospinal fluid layer and younger women and men having similar cerebrospinal fluid layers. Aging mostly results in grey matter thinning. Concerning SCD, the whole isn't greater than the sum of its parts. GTT enables rapid quantification of the SCD tissues. The distinctive sensitivity of noninvasive recording and stimulation modalities to different tissues underscores the relevance of GTT.

Midfrontal Theta and Cognitive Control During Interlimb Coordination Across the Adult Lifespan.

Interlimb coordination is required for adequate execution of most daily life activities. Yet, aging negatively affects interlimb coordination, impacting the quality of life in older people. Therefore, disentangling the underlying age-related neural mechanisms is of utmost importance. Here, we investigated neurophysiological processes of an interlimb reaction time task, including both simple and complex coordination modes. Midfrontal theta power, measured using electroencephalography (EEG), was analyzed as a marker for cognitive control. In total, 82 healthy adults participated, with 27 younger, 26 middle-aged, and 29 older adults. On a behavioral level, reaction time increased across the adult lifespan, and error rate was higher in older adults. Notably, aging disproportionately affected reaction times in the complex coordination modes, with larger reaction time increases from simple to complex movements than in younger adults, starting already at middle age. On the neurophysiological level, EEG showed that only younger adults had significantly increased levels of midfrontal theta power during complex relative to simple coordination modes, while no significant differences were found between simple and complex movements in middle-aged and older adults. The absence of this theta power upregulation with regard to movement complexity with increasing age might reflect a premature saturation of the available mental resources.

A Systematic Review and Large-Scale tES and TMS Electric Field Modeling Study Reveals How Outcome Measure Selection Alters Results in a Person- and Montage-Specific Manner.

Background: Electric field (E-field) modeling is a potent tool to examine the cortical effects of transcranial magnetic and electrical stimulation (TMS and tES, respectively) and to address the high variability in efficacy observed in the literature. However, outcome measures used to report E-field magnitude vary considerably and have not yet been compared in detail. Objectives: The goal of this two-part study, encompassing a systematic review and modeling experiment, was to provide an overview of the different outcome measures used to report the magnitude of tES and TMS E-fields, and to conduct a direct comparison of these measures across different stimulation montages. Methods: Three electronic databases were searched for tES and/or TMS studies reporting E-field magnitude. We extracted and discussed outcome measures in studies meeting the inclusion criteria. Additionally, outcome measures were compared via models of four common tES and two TMS modalities in 100 healthy younger adults. Results: In the systematic review, we included 118 studies using 151 outcome measures related to E-field magnitude. Structural and spherical regions of interest (ROI) analyses and percentile-based whole-brain analyses were used most often. In the modeling analyses, we found that there was an average of only 6% overlap between ROI and percentile-based whole-brain analyses in the investigated volumes within the same person. The overlap between ROI and whole-brain percentiles was montage- and person-specific, with more focal montages such as 4Ã-1 and APPS-tES, and figure-of-eight TMS showing up to 73%, 60%, and 52% overlap between ROI and percentile approaches respectively. However, even in these cases, 27% or more of the analyzed volume still differed between outcome measures in every analyses. Conclusions: The choice of outcome measures meaningfully alters the interpretation of tES and TMS E-field models. Well-considered outcome measure selection is imperative for accurate interpretation of results, valid between-study comparisons, and depends on stimulation focality and study goals. We formulated four recommendations to increase the quality and rigor of E-field modeling outcome measures. With these data and recommendations, we hope to guide future studies towards informed outcome measure selection, and improve the comparability of studies.

Age-related changes in midfrontal theta activity during steering control: A driving simulator study.

Motor control, a ubiquitous part of driving, requires increased cognitive controlled processing in older adults relative to younger adults. However, the influence of aging on motor-related neural mechanisms in the context of driving has rarely been studied. The present study aimed to identify age-related changes in cognitive control and attention allocation during a simulated steering task, using electroencephalography. Midfrontal theta, a marker for cognitive control, and posterior alpha power, a marker for attention allocation, were measured in a total of 26 young, 25 middle-aged, and 28 older adults. By adapting driving speed, the difficulty level of this steering task was individualized for each participant. Results show age-related changes in midfrontal theta power, but not in posterior alpha power, despite similar steering accuracy across age groups. Specifically, only younger and, to a lesser extent, middle-aged adults exhibited increased theta power while driving through more demanding curved segments relative to straight segments. In contrast, theta power upregulation was absent in older adults, suggesting a saturation of cognitive resources while driving, possibly due to a limitation in resource capacity, or less automatic motor-related neural processing.

Dual-site TMS as a tool to probe effective interactions within the motor network: a review.

Dual-site transcranial magnetic stimulation (ds-TMS) is well suited to investigate the causal effect of distant brain regions on the primary motor cortex, both at rest and during motor performance and learning. However, given the broad set of stimulation parameters, clarity about which parameters are most effective for identifying particular interactions is lacking. Here, evidence describing inter- and intra-hemispheric interactions during rest and in the context of motor tasks is reviewed. Our aims are threefold: (1) provide a detailed overview of ds-TMS literature regarding inter- and intra-hemispheric connectivity; (2) describe the applicability and contributions of these interactions to motor control, and; (3) discuss the practical implications and future directions. Of the 3659 studies screened, 109 were included and discussed. Overall, there is remarkable variability in the experimental context for assessing ds-TMS interactions, as well as in the use and reporting of stimulation parameters, hindering a quantitative comparison of results across studies. Further studies examining ds-TMS interactions in a systematic manner, and in which all critical parameters are carefully reported, are needed.

Aging and Complexity Effects on Hemisphere-Dependent Movement-Related Beta Desynchronization during Bimanual Motor Planning and Execution.

With aging comes degradation of bimanual movement performance. A hallmark feature of bimanual movements is movement-related beta desynchronization (MRBD), an attenuation in the amplitude of beta oscillations associated with sensorimotor activation. Here, we investigated MRBD in 39 healthy adults (20 younger and 19 older adults) in frontal, central, and parietal regions across both hemispheres, during the planning and execution of a bimanual tracking task. Task accuracy decreased with age and during more difficult conditions when both hands had to move at different relative speeds. MRBD was mostly situated in the central region, and increased in older versus younger adults during movement execution but not planning. Irrespective of age, motor planning and execution were associated with increased MRBD in the left and right hemispheres, respectively. Notably, right central MRBD during motor planning was associated with bimanual task performance, particularly in older adults. Specifically, persons who demonstrated high MRBD during motor planning performed better on the bimanual tracking task. Our results highlight the importance of lateralized MRBD during motor planning, thereby shining new light on previous research and providing a promising avenue for future interventions.

Age and Interlimb Coordination Complexity Modulate Oscillatory Spectral Dynamics and Large-scale Functional Connectivity.

Interlimb coordination deteriorates as a result of aging. Due to its ubiquity in daily life, a greater understanding of the underlying neurophysiological changes is required. Here, we combined electroencephalography time-frequency spectral power and functional connectivity analyses to provide a comprehensive overview of the neural dynamics underlying the age-related deterioration of interlimb coordination involving all four limbs. Theta, alpha and beta oscillations in the frontal, central and parietal regions were analyzed in twenty younger (18-30 years) and nineteen older adults (65-78 years) during a complex interlimb reaction time task. Reaction time was significantly higher in older adults across all conditions, and the discrepancy between both age groups was largest in the most complex movement condition. Older adults demonstrated enhanced beta event-related desynchronization (i.e., the attenuation of beta power), which further increased along with task complexity and was positively linked to behavioral performance. Theta functional connectivity between frontal, central and parietal regions generally increased with movement complexity, irrespective of age group. In general, frontoparietal alpha band functional connectivity tended to be reduced in older versus younger adults, although these contrasts did not survive multiple comparison corrections. Overall, spectral results suggest that enhanced beta desynchronization in older adults reflects a successful compensatory mechanism to cope with increased difficulty during complex interlimb coordination. Functional connectivity results suggest that theta and alpha band connectivity are prone to respectively task- and age-related modulations. Future work could target these spectral and functional connectivity dynamics through noninvasive brain stimulation to potentially improve interlimb coordination in older adults.

Cerebellar Activation During Simple and Complex Bimanual Coordination: an Activation Likelihood Estimation (ALE) Meta-analysis.

Bimanual coordination is an important part of everyday life and recruits a large neural network, including the cerebellum. The specific role of the cerebellum in bimanual coordination has not yet been studied in depth, although several studies indicate a differential role of the anterior and posterior cerebellum depending on the complexity of the coordination. An activation likelihood estimation (ALE) meta-analysis was used combining the data of several functional MRI studies involving bimanual coordination tasks with varying complexities to unravel the involvement of the different areas of the cerebellum in simple and complex bimanual coordination. This study confirms the general bimanual network as found by Puttemans et al. (Puttemans et al. in J Neurosci 25:4270-4278, 2005) and highlights the differences between preferred in-phase (simultaneous movements of homologous muscle groups) and anti-phase movement conditions (alternating movements of homologous muscle groups), and more complex, non-preferred bimanual movements (e.g., out-of-phase movements). Our results show a differential role for the anterior and posterior vermis in bimanual coordination, with a role for the anterior vermis in anti-phase and complex bimanual coordination, and an exclusive role for the posterior vermis in complex bimanual movements. In addition, the way complexity was manipulated also seems to play a role in the involvement of the anterior and posterior vermis. We hypothesize that the anterior vermis is involved in sequential/spatial control, while the posterior vermis is involved in temporal control of (bimanual) coordination, though other factors such as (visual) feedback and continuity of the movement also seem to have an impact. More studies are needed to unravel the specific role of the cerebellar vermis in bimanual coordination.

Neurophysiological modulations in the (pre)motor-motor network underlying age-related increases in reaction time and the role of GABA levels - a bimodal TMS-MRS study.

It has been argued that age-related changes in the neurochemical and neurophysiological properties of the GABAergic system may underlie increases in reaction time (RT) in older adults. However, the role of GABA levels within the sensorimotor cortices (SMC) in mediating interhemispheric interactions (IHi) during the processing stage of a fast motor response, as well as how both properties explain interindividual differences in RT, are not yet fully understood. In this study, edited magnetic resonance spectroscopy (MRS) was combined with dual-site transcranial magnetic stimulation (dsTMS) for probing GABA+ levels in bilateral SMC and task-related neurophysiological modulations in corticospinal excitability (CSE), and primary motor cortex (M1)-M1 and dorsal premotor cortex (PMd)-M1 IHi, respectively. Both CSE and IHi were assessed during the preparatory and premotor period of a delayed choice RT task. Data were collected from 25 young (aged 18-33 years) and 28 older (aged 60-74 years) healthy adults. Our results demonstrated that older as compared to younger adults exhibited a reduced bilateral CSE suppression, as well as a reduced magnitude of long latency M1-M1 and PMd-M1 disinhibition during the preparatory period, irrespective of the direction of the IHi. Importantly, in older adults, the GABA+ levels in bilateral SMC partially accounted for task-related neurophysiological modulations as well as individual differences in RT. In contrast, in young adults, neither task-related neurophysiological modulations, nor individual differences in RT were associated with SMC GABA+ levels. In conclusion, this study contributes to a comprehensive initial understanding of how age-related differences in neurochemical properties and neurophysiological processes are related to increases in RT.

The effects of transcranial direct current stimulation on upper-limb function post-stroke: A meta-analysis of multiple-session studies.

OBJECTIVE: To systematically review how patient characteristics and/or transcranial direct current stimulation (tDCS) parameters influence tDCS effectiveness in respect to upper limb function post-stroke. METHODS: Three electronic databases were searched for sham-controlled randomised trials using the Fugl-Meyer Assessment for upper extremity as outcome measure. A meta-analysis and nine subgroup-analyses were performed to identify which tDCS parameters yielded the greatest impact on upper limb function recovery in stroke patients. RESULTS: Eighteen high-quality studies (507 patients) were included. tDCS applied in a chronic stage yields greater results than tDCS applied in a (sub)acute stage. Additionally, patients with low baseline upper limb impairments seem to benefit more from tDCS than those with high baseline impairments. Regarding tDCS configuration, all stimulation types led to a significant improvement, but only tDCS applied during therapy, and not before therapy, yielded significant results. A positive dose-response relationship was identified for current/charge density and stimulation duration, but not for number of sessions. CONCLUSION: Our results demonstrate that tDCS improves upper limb function post-stroke. However, its effectiveness depends on numerous factors. Especially chronic stroke patients improved, which is promising as they are typically least amenable to recovery. SIGNIFICANCE: The current work highlights the importance of several patient-related and protocol-related factors regarding tDCS effectiveness.

Unravelling Ipsilateral Interactions Between Left Dorsal Premotor and Primary Motor Cortex: A Proof of Concept Study.

Few studies have identified the intrahemispheric functional connectivity between the ipsilateral dorsal premotor cortex (PMd) and the primary motor hand area (M1hand) due to technical limitations. In this proof-of-concept study, a novel neuronavigated dsTMS set-up was employed, combining stimulation over left PMd and left M1hand using the edge of a butterfly coil and a small cooled-coil. This arrangement was warranted because coil (over)heating and inter coil distance are limiting factors when investigating connectivity between stimulation targets in close proximity and over a longer duration. The proposed set-up was designed to deal with these limitations. Specifically, the effect of four dual-site transcranial magnetic stimulation (dsTMS) protocols on twenty-eight right-handed participants (12 males) was evaluated. These protocols differed in stimulus order, interstimulus interval and current direction induced in PMd. A structural scan with electric (E-)field modeling was obtained from seven participants prior to dsTMS, demonstrating that PMd and M1hand were effectively stimulated. Results indicate that one protocol, in which a latero-medial current was induced in PMd 2.8 ms prior to stimulation over M1hand, induced a sex-mediated effect. In males, significant inhibition of motor-evoked potentials was identified, whereas females demonstrated a facilitatory effect that did not survive correction for multiple comparisons. E-field simulations revealed that the E-field induced by the coil targeting PMd was maximal in PMd, with weaker E-field strengths extending to regions beyond PMd. Summarizing, the current dsTMS set-up enabled stimulating at an inter-target distance of 35 mm without any indications of coil-overheating.

Dissociating the causal role of left and right dorsal premotor cortices in planning and executing bimanual movements - A neuro-navigated rTMS study.

BACKGROUND: The dorsal premotor cortex (PMd) is a key region in bimanual coordination. However, causal evidence linking PMd functionality during motor planning and execution to movement quality is lacking. OBJECTIVE: We investigated how left (PMdL) and right PMd (PMdR) are causally involved in planning and executing bimanual movements, using short-train repetitive transcranial magnetic stimulation (rTMS). Additionally, we explored to what extent the observed rTMS-induced modulation of performance could be explained by rTMS-induced modulation of PMd-M1 interhemispheric interactions (IHI). METHODS: Twenty healthy adults (mean age ± SD = 22.85 ± 3.73 years) participated in two sessions, in which either PMdL or PMdR was targeted with rTMS (10 Hz) in a pseudo-randomized design. PMd functionality was transiently modulated during the planning or execution of a complex bimanual task, whereby the participant was asked to track a moving dot by controlling two dials. The effect of rTMS on several performance measures was investigated. Concurrently, rTMS-induced modulation of PMd-M1 IHI was measured using a dual-coil paradigm, and associated with the rTMS-induced performance modulation. RESULTS: rTMS over PMdL during planning increased bilateral hand movement speed (p = 0.03), thereby improving movement accuracy (p = 0.02). In contrast, rTMS over PMdR during both planning and execution induced deterioration of movement stability (p = 0.04). rTMS-induced modulation of PMd-M1 IHI during planning did not predict rTMS-induced performance modulation. CONCLUSION: The current findings support the growing evidence on PMdL dominance during motor planning, as PMdL was crucially involved in planning the speed of each hand, subserving bimanual coordination accuracy. Moreover, the current results suggest that PMdR fulfills a role in continuous adjustment processes of movement.

Transcranial direct current stimulation and attention skills in burnout patients: a randomized blinded sham-controlled pilot study.

Background: Burnout is characterized by deficiencies in attention and several components of the working memory, of which the lingering effects of impaired attention and executive functions are the most frustrating. We hypothesized that anodal transcranial direct current stimulation (atDCS) over the left dorsolateral prefrontal cortex (DLPFC) can improve the executive control of attention and possibly several other components of working memory in patients with burnout. Methods: This was a randomized double-blind sham-controlled pilot study with two groups. Patients with burnout received three weeks of daily sessions (15 sessions in total) of atDCS or sham stimulation in addition to three weekly sessions of standard behavioral therapy. The primary outcome measure was attention and the central executive of the working memory. Secondary, the effect of atDCS was measured on other components of working memory, on burnout and depression scores, and on quality of life (QoL). Results: We enrolled and randomly assigned 16 patients to a sham or real stimulation group, 15 (7 sham, 8 real) were included in the analysis. atDCS had a significant impact on attention. Post-hoc comparisons also revealed a trend towards more improvement after real tDCS for inhibition and shifting, updating and control, and encoding. Both groups improved on burnout and depression scores. Conclusion: These data provide preliminary evidence for the value of atDCS over the left DLPFC in rehabilitating attention deficits, and possibly also central executive and encoding deficits, in burnout. However, the current study has some limitations, including the sample size and heterogeneous patient population. More elaborate studies are needed to elucidate the specific impact of atDCS over the left DLPFC on burnout. Trial registration: ISRCTN.com ( ISRCTN94275121) 17/11/19.

Age-related differences of motor cortex plasticity in adults: A transcranial direct current stimulation study.

BACKGROUND: Cognitive, and motor performance are reduced in aging, especially with respect to acquisition of new knowledge, which is associated with a neural plasticity decline. Animal models show a reduction of long-term potentiation, but not long-term depression, in higher age. Findings in humans are more heterogeneous, with some studies showing respective deficits, but others not, or mixed results, for plasticity induced by non-invasive brain stimulation. One reason for these heterogeneous results might be the inclusion of different age ranges in these studies. In addition, a systematic detailed comparison of the age-dependency of neural plasticity in humans is lacking so far. OBJECTIVE: We aimed to explore age-dependent plasticity alterations in adults systematically by discerning between younger and older participants in our study. METHODS: We recruited three different age groups (Young: 18-30, Pre-Elderly: 50-65, and Elderly: 66-80 years). Anodal, cathodal, or sham transcranial direct current stimulation (tDCS) was applied over the primary motor cortex with 1 mA for 15 min to induce neuroplasticity. Cortical excitability was monitored by single-pulse transcranial magnetic stimulation as an index of plasticity. RESULTS: For anodal tDCS, the results show a significant excitability enhancement, as compared to sham stimulation, for both, Young and the Pre-Elderly groups, while no LTP-like plasticity was obtained in the Elderly group by the applied stimulation protocol. Cathodal tDCS induced significant excitability-diminishing plasticity in all age groups. CONCLUSION: Our study provides further insight in age-related differences of plasticity in healthy humans, which are similar to those obtained in animal models. The decline of LTP-like plasticity in higher age could contribute to cognitive deficits observed in aging.

Induced Suppression of the Left Dorsolateral Prefrontal Cortex Favorably Changes Interhemispheric Communication During Bimanual Coordination in Older Adults-A Neuronavigated rTMS Study.

Recent transcranial magnetic stimulation (TMS) research indicated that the ability of the dorsolateral prefrontal cortex (DLPFC) to disinhibit the contralateral primary motor cortex (M1) during motor preparation is an important predictor for bimanual motor performance in both young and older healthy adults. However, this DLPFC-M1 disinhibition is reduced in older adults. Here, we transiently suppressed left DLPFC using repetitive TMS (rTMS) during a cyclical bimanual task and investigated the effect of left DLPFC suppression: (1) on the projection from left DLPFC to the contralateral M1; and (2) on motor performance in 21 young (mean age ± SD = 21.57 ± 1.83) and 20 older (mean age ± SD = 69.05 ± 4.48) healthy adults. As predicted, without rTMS, older adults showed compromised DLPFC-M1 disinhibition as compared to younger adults and less preparatory DLPFC-M1 disinhibition was related to less accurate performance, irrespective of age. Notably, rTMS-induced DLPFC suppression restored DLPFC-M1 disinhibition in older adults and improved performance accuracy right after the local suppression in both age groups. However, the rTMS-induced gain in disinhibition was not correlated with the gain in performance. In sum, this novel rTMS approach advanced our mechanistic understanding of how left DLPFC regulates right M1 and allowed us to establish the causal role of left DLPFC in bimanual coordination.