Regional Precuneus Cortical Hyperexcitability in Alzheimer's Disease Patients.

OBJECTIVE: Neuronal excitation/inhibition (E/I) imbalance is a potential cause of neuronal network malfunctioning in Alzheimer's disease (AD), contributing to cognitive dysfunction. Here, we used a novel approach combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to probe cortical excitability in different brain areas known to be directly involved in AD pathology. METHODS: We performed TMS-EEG recordings targeting the left dorsolateral prefrontal cortex (l-DLPFC), the left posterior parietal cortex (l-PPC), and the precuneus (PC) in a large sample of patients with mild-to-moderate AD (n = 65) that were compared with a group of age-matched healthy controls (n = 21). RESULTS: We found that patients with AD are characterized by a regional cortical hyperexcitability in the PC and, to some extent, in the frontal lobe, as measured by TMS-evoked potentials. Notably, cortical excitability assessed over the l-PPC was comparable between the 2 groups. Furthermore, we found that the individual level of PC excitability was associated with the level of cognitive impairment, as measured with Mini-Mental State Examination, and with corticospinal fluid levels of Aß42 . INTERPRETATION: Our data provide novel evidence that precuneus cortical hyperexcitability is a key feature of synaptic dysfunction in patients with AD. The current results point to the combined approach of TMS and EEG as a novel promising technique to measure hyperexcitability in patients with AD. This index could represent a useful biomarker to stage disease severity and evaluate response to novel therapies. ANN NEUROL 2023;93:371-383.

Harnessing Placebo Effects for the Treatment of Functional Cognitive Disorder: A Feasibility Pilot Study.

OBJECTIVE: Limited research has directly investigated whether and how placebo effects can be harnessed for the treatment of functional neurological disorder (FND), despite a long-standing and controversial history of interest in this area. METHODS: A small exploratory study was conducted with adults with a cognitive subtype of FND recruited from a single cognitive neurology center in the United States. Participants were given the expectation of receiving cranial stimulation that could benefit their memory symptoms; however, the intervention was sham transcranial magnetic stimulation (placebo). Outcomes included measures of short-term memory testing, subjective memory rating, and state anxiety before and after stimulation. After the study, the true objective and rationale for investigating placebo effects were explained in a scripted debriefing session. Acceptability of the study design and qualitative feedback were collected. Institutional ethics approval and signed consent were obtained. RESULTS: Three patients (female, N=2; male, N=1; average age=57 years) were recruited. Outcome data were analyzed descriptively at the patient level. Trends of improvement in subjective memory rating, but not objective cognitive test scores, and decreases in state anxiety were observed. After the debriefing session, all patients found the study design to be acceptable (ratings of 70%, 90%, and 100%), and two of the three patients believed that withholding mechanistic information about the intervention was needed to leverage placebo effects as treatment. CONCLUSIONS: In the first study to prospectively investigate the feasibility of harnessing placebo effects for the treatment of FND, promising preliminary findings were obtained, and methods and resources for use in larger future studies are offered.

Cortico-cortical paired associative stimulation (ccPAS) over premotor-motor areas affects local circuitries in the human motor cortex via Hebbian plasticity.

Transcranial magnetic stimulation (TMS) studies have shown that cortico-cortical paired associative stimulation (ccPAS) can strengthen connectivity between the ventral premotor cortex (PMv) and the primary motor cortex (M1) by modulating convergent input over M1 via Hebbian spike-timing-dependent plasticity (STDP). However, whether ccPAS locally affects M1 activity remains unclear. We tested 60 right-handed young healthy humans in two studies, using a combination of dual coil TMS and ccPAS over the left PMv and M1 to probe and manipulate PMv-to-M1 connectivity, and single- and paired-pulse TMS to assess neural activity within M1. We provide convergent evidence that ccPAS, relying on repeated activations of excitatory PMv-to-M1 connections, acts locally over M1. During ccPAS, motor-evoked potentials (MEPs) induced by paired PMv-M1 stimulation gradually increased. Following ccPAS, the threshold for inducing MEPs of different amplitudes decreased, and the input-output curve (IO) slope increased, highlighting increased M1 corticospinal excitability. Moreover, ccPAS reduced the magnitude of short-interval intracortical inhibition (SICI), reflecting suppression of GABA-ergic interneuronal mechanisms within M1, without affecting intracortical facilitation (ICF). These changes were specific to ccPAS Hebbian strengthening of PMv-to-M1 connectivity, as no modulations were observed when reversing the order of the PMv-M1 stimulation during a control ccPAS protocol. These findings expand prior ccPAS research that focused on the malleability of cortico-cortical connectivity at the network-level, and highlight local changes in the area of convergent activation (i.e., M1) during plasticity induction. These findings provide new mechanistic insights into the physiological basis of ccPAS that are relevant for protocol optimization.

In vivo phase-dependent enhancement and suppression of human brain oscillations by transcranial alternating current stimulation (tACS).

Transcranial alternating current stimulation (tACS) can influence perception and behavior, with recent evidence also highlighting its potential impact in clinical settings, but its underlying mechanisms are poorly understood. Behavioral and indirect physiological evidence indicates that phase-dependent constructive and destructive interference between the applied electric field and brain oscillations at the stimulation frequency may play an important role, but in vivo validation during stimulation was unfeasible because stimulation artifacts impede single-trial assessment of brain oscillations during tACS. Here, we attenuated stimulation artifacts to provide evidence for phase-dependent enhancement and suppression of visually evoked steady state responses (SSR) during amplitude-modulated tACS (AM-tACS). We found that AM-tACS enhanced and suppressed SSR by 5.77 ± 2.95%, while it enhanced and suppressed corresponding visual perception by 7.99 ± 5.15%. While not designed to investigate the underlying mechanisms of this effect, our study suggests feasibility and superiority of phase-locked (closed-loop) AM-tACS over conventional (open-loop) AM-tACS to purposefully enhance or suppress brain oscillations at specific frequencies.

A physical neural mass model framework for the analysis of oscillatory generators from laminar electrophysiological recordings.

Cortical function emerges from the interactions of multi-scale networks that may be studied at a high level using neural mass models (NMM) that represent the mean activity of large numbers of neurons. Here, we provide first a new framework called laminar NMM, or LaNMM for short, where we combine conduction physics with NMMs to simulate electrophysiological measurements. Then, we employ this framework to infer the location of oscillatory generators from laminar-resolved data collected from the prefrontal cortex in the macaque monkey. We define a minimal model capable of generating coupled slow and fast oscillations, and we optimize LaNMM-specific parameters to fit multi-contact recordings. We rank the candidate models using an optimization function that evaluates the match between the functional connectivity (FC) of the model and data, where FC is defined by the covariance between bipolar voltage measurements at different cortical depths. The family of best solutions reproduces the FC of the observed electrophysiology by selecting locations of pyramidal cells and their synapses that result in the generation of fast activity at superficial layers and slow activity across most depths, in line with recent literature proposals. In closing, we discuss how this hybrid modeling framework can be more generally used to infer cortical circuitry.

Decreased Frontal Gamma Activity in Alzheimer Disease Patients.

OBJECTIVE: In Alzheimer disease (AD) animal models, synaptic dysfunction has recently been linked to a disorder of high-frequency neuronal activity. In patients, a clear relation between AD and oscillatory activity remains elusive. Here, we attempt to shed light on this relation by using a novel approach combining transcranial magnetic stimulation and electroencephalography (TMS-EEG) to probe oscillatory activity in specific hubs of the frontoparietal network in a sample of 60 mild-to-moderate AD patients. METHODS: Sixty mild-to-moderate AD patients and 21 age-matched healthy volunteers (HVs) underwent 3 TMS-EEG sessions to assess cortical oscillations over the left dorsolateral prefrontal cortex, the precuneus, and the left posterior parietal cortex. To investigate the relations between oscillatory activity, cortical plasticity, and cognitive decline, AD patients underwent a TMS-based neurophysiological characterization and a cognitive evaluation at baseline. The latter was repeated after 24 weeks to monitor clinical evolution. RESULTS: AD patients showed a significant reduction of frontal gamma activity as compared to age-matched HVs. In addition, AD patients with a more prominent decrease of frontal gamma activity showed a stronger impairment of long-term potentiation-like plasticity and a more pronounced cognitive decline at subsequent follow-up evaluation at 24 weeks. INTERPRETATION: Our data provide novel evidence that frontal lobe gamma activity is dampened in AD patients. The current results point to the TMS-EEG approach as a promising technique to measure individual frontal gamma activity in patients with AD. This index could represent a useful biomarker to predict disease progression and to evaluate response to novel pharmacological therapies. ANN NEUROL 2022;92:464-475.

Placebo effects and neuromodulation for depression: a meta-analysis and evaluation of shared mechanisms.

There is growing evidence that placebo effects can meaningfully modulate the brain. However, there has been little consideration of whether these changes may overlap with regions/circuits targeted by depression treatments and what the implications of this overlap would be on measuring efficacy in placebo-controlled clinical trials. In this systematic review and meta-analysis, we searched PubMed/Medline and Google Scholar for functional MRI and PET neuroimaging studies of placebo effects. Studies recruiting both healthy subjects and patient populations were included. Neuroimaging coordinates were extracted and included for Activation Likelihood Estimation (ALE) meta-analysis. We then searched for interventional studies of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) for depression and extracted target coordinates for comparative spatial analysis with the placebo effects maps. Of 1169 articles identified, 34 neuroimaging studies of placebo effects were included. There were three significant clusters of activation: left dorsolateral prefrontal cortex (DLPFC) (x = -41, y = 16, z = 34), left sub-genual anterior cingulate cortex (sgACC)/ventral striatum (x = -8, y = 18, z = -15) and the right rostral anterior cingulate cortex (rACC) (x = 4, y = 42, z = 10). There were two significant deactivation clusters: right basal ganglia (x = 20, y = 2, z = 7) and right dorsal anterior cingulate cortex (dACC) (x = 1, y = -5, z = 45). TMS and DBS targets for depression treatment overlapped with the left DLPFC cluster and sgACC cluster, respectively. Our findings identify a common set of brain regions implicated in placebo effects across healthy individuals and patient populations, and provide evidence that these regions overlap with depression treatment targets. We model the statistical impacts of this overlap and demonstrate critical implications on measurements of clinical trial efficacy for this field.

Precuneus magnetic stimulation for Alzheimer's disease: a randomized, sham-controlled trial.

Repetitive transcranial magnetic stimulation (rTMS) is emerging as a non-invasive therapeutic strategy in the battle against Alzheimer's disease. Alzheimer's disease patients primarily show alterations of the default mode network for which the precuneus is a key node. Here, we hypothesized that targeting the precuneus with TMS represents a promising strategy to slow down cognitive and functional decline in Alzheimer's disease patients. We performed a randomized, double-blind, sham-controlled, phase 2, 24-week trial to determine the safety and efficacy of precuneus stimulation in patients with mild-to-moderate Alzheimer's disease. Fifty Alzheimer's disease patients were randomly assigned in a 1:1 ratio to either receive precuneus or sham rTMS (mean age 73.7 years; 52% female). The trial included a 24-week treatment, with a 2-week intensive course in which rTMS (or sham) was applied daily five times per week, followed by a 22-week maintenance phase in which stimulation was applied once weekly. The Clinical Dementia Rating Scale-Sum of Boxes was selected as the primary outcome measure, in which post-treatment scores were compared to baseline. Secondary outcomes included score changes in the Alzheimer's Disease Assessment Scale-Cognitive Subscale, Mini-Mental State Examination and Alzheimer's Disease Cooperative Study-Activities of Daily Living scale. Moreover, single-pulse TMS in combination with EEG was used to assess neurophysiological changes in precuneus cortical excitability and oscillatory activity. Our findings show that patients that received precuneus repetitive magnetic stimulation presented a stable performance of the Clinical Dementia Rating Scale-Sum of Boxes score, whereas patients treated with sham showed a worsening of their score. Compared with the sham stimulation, patients in the precuneus stimulation group also showed also significantly better performances for the secondary outcome measures, including the Alzheimer's Disease Assessment Scale-Cognitive Subscale, Mini-Mental State Examination and Alzheimer's Disease Cooperative Study-Activities of Daily Living scale. Neurophysiological results showed that precuneus cortical excitability remained unchanged after 24 weeks in the precuneus stimulation group, whereas it was significantly reduced in the sham group. Finally, we found an enhancement of local gamma oscillations in the group treated with precuneus stimulation but not in patients treated with sham. We conclude that 24 weeks of precuneus rTMS may slow down cognitive and functional decline in Alzheimer's disease. Repetitive TMS targeting the default mode network could represent a novel therapeutic approach in Alzheimer's disease patients.

Individualized perturbation of the human connectome reveals reproducible biomarkers of network dynamics relevant to cognition.

Large-scale brain networks are often described using resting-state functional magnetic resonance imaging (fMRI). However, the blood oxygenation level-dependent (BOLD) signal provides an indirect measure of neuronal firing and reflects slow-evolving hemodynamic activity that fails to capture the faster timescale of normal physiological function. Here we used fMRI-guided transcranial magnetic stimulation (TMS) and simultaneous electroencephalography (EEG) to characterize individual brain dynamics within discrete brain networks at high temporal resolution. TMS was used to induce controlled perturbations to individually defined nodes of the default mode network (DMN) and the dorsal attention network (DAN). Source-level EEG propagation patterns were network-specific and highly reproducible across sessions 1 month apart. Additionally, individual differences in high-order cognitive abilities were significantly correlated with the specificity of TMS propagation patterns across DAN and DMN, but not with resting-state EEG dynamics. Findings illustrate the potential of TMS-EEG perturbation-based biomarkers to characterize network-level individual brain dynamics at high temporal resolution, and potentially provide further insight on their behavioral significance.

Phase-dependent local brain states determine the impact of image-guided transcranial magnetic stimulation on motor network electroencephalographic synchronization.

Recent studies have synchronized transcranial magnetic stimulation (TMS) application with pre-defined brain oscillatory phases showing how brain response to perturbation depends on the brain state. However, none have investigated whether phase-dependent TMS can possibly modulate connectivity with homologous distant brain regions belonging to the same network. In the framework of network-targeted TMS, we investigated whether stimulation delivered at a specific phase of ongoing brain oscillations might favour stronger cortico-cortical (c-c) synchronization of distant network nodes connected to the stimulation target. Neuronavigated TMS pulses were delivered over the primary motor cortex (M1) during ongoing electroencephalography recording in 24 healthy individuals over two repeated sessions 1 month apart. Stimulation effects were analysed considering whether the TMS pulse was delivered at the time of a positive (peak) or negative (trough) phase of µ-frequency oscillation, which determines c-c synchrony within homologous areas of the sensorimotor network. Diffusion weighted imaging was used to study c-c connectivity within the sensorimotor network and identify contralateral regions connected with the stimulation spot. Depending on when during the µ-activity the TMS-pulse was applied (peak or trough), its impact on inter-hemispheric network synchrony varied significantly. Higher M1-M1 phase-lock synchronization after the TMS-pulse (0-200 ms) in the µ-frequency band was found for trough compared to peak stimulation trials in both study visits. Phase-dependent TMS delivery might be crucial not only to amplify local effects but also to increase the magnitude and reliability of the response to the external perturbation, with implications for interventions aimed at engaging more distributed functional brain networks. KEY POINTS: Synchronized transcranial magnetic stimulation (TMS) pulses with pre-defined brain oscillatory phases allow evaluation of the impact of brain states on TMS effects. TMS pulses over M1 at the negative peak of the µ-frequency band induce higher phase-lock synchronization with interconnected contralateral homologous regions. Cortico-cortical synchronization changes are linearly predicted by the fibre density and cross-section of the white matter tract that connects the two brain regions. Phase-dependent TMS delivery might be crucial not only to amplify local effects but also to increase the magnitude and reliability of within-network synchronization.

Effect of group-based vs individualized stimulation site selection on reliability of network-targeted TMS.

BACKGROUND: Transcranial magnetic stimulation (TMS) is a widely used technique for the noninvasive assessment and manipulation of brain activity and behavior. Although extensively used for research and clinical purposes, recent studies have questioned the reliability of TMS findings because of the high inter-individual variability that has been observed. OBJECTIVE: In this study, we compared the efficacy and reliability of different targeting scenarios on the TMS-evoked response. METHODS: 24 subjects underwent a single pulse stimulation protocol over two parietal nodes belonging to the Dorsal Attention (DAN) and Default Mode (DMN) Networks respectively. Across visits, the stimulated target for both networks was chosen either based on group-derived networks' maps or personalized network topography based on individual anatomy and functional profile. All stimulation visits were conducted twice, one month apart, during concomitant electroencephalography recording. RESULTS: At the network level, we did not observe significant differences in the TMS-evoked response between targeting conditions. However, reliable patterns of activity were observed- for both networks tested- following the individualized targeting approach. When the same analyses were carried out at the electrode space level, evidence of reliable patterns was observed following the individualized stimulation of the DAN, but not of the DMN. CONCLUSIONS: Our findings suggest that individualization of stimulation sites might ensure reliability of the evoked TMS-response across visits. Furthermore, individualized stimulation sites appear to be of foremost importance in highly variable, high order task-positive networks, such as the DAN.

Neural correlates of N-back task performance and proposal for corresponding neuromodulation targets in psychiatric and neurodevelopmental disorders.

AIM: Working memory (WM) deficit represents the most common cognitive impairment in psychiatric and neurodevelopmental disorders, making the identification of its neural substrates a crucial step towards the conceptualization of restorative interventions. We present a meta-analysis focusing on neural activations associated with the most commonly used task to measure WM, the N-back task, in patients with schizophrenia, depressive disorder, bipolar disorder, and attention-deficit/hyperactivity disorder. Showing qualitative similarities and differences in WM processing between patients and healthy controls, we propose possible targets for cognitive enhancement approaches. METHODS: Selected studies, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, were analyzed through the activation likelihood estimate statistical framework, with subsequent generation of disorder-specific N-back activation maps. RESULTS: Despite similar WM deficits shared across all disorders, results highlighted different brain activation patterns for each disorder compared with healthy controls. In general, results showed brain activity in frontal, parietal, subcortical, and cerebellar regions; however, reduced engagement of specific nodes of the fronto-parietal network emerged in patients compared with healthy controls. In particular, neither bipolar nor depressive disorders showed detectable activations in the dorsolateral prefrontal cortices, while their parietal activation patterns were lateralized to the left and right hemispheres, respectively. On the other hand, patients with attention-deficit/hyperactivity disorder showed a lack of activation in the left parietal lobe, whereas patients with schizophrenia showed lower activity over the left prefrontal cortex. CONCLUSION: These results, together with biophysical modeling, were then used to discuss the design of future disorder-specific cognitive enhancement interventions based on noninvasive brain stimulation.

Local and Distributed fMRI Changes Induced by 40 Hz Gamma tACS of the Bilateral Dorsolateral Prefrontal Cortex: A Pilot Study.

Over the past few years, the possibility of modulating fast brain oscillatory activity in the gamma (γ) band through transcranial alternating current stimulation (tACS) has been discussed in the context of both cognitive enhancement and therapeutic scenarios. However, the effects of tACS targeting regions outside the motor cortex, as well as its spatial specificity, are still unclear. Here, we present a concurrent tACS-fMRI block design study to characterize the impact of 40 Hz tACS applied over the left and right dorsolateral prefrontal cortex (DLPFC) in healthy subjects. Results suggest an increase in blood oxygenation level-dependent (BOLD) activity in the targeted bilateral DLPFCs, as well as in surrounding brain areas affected by stimulation according to biophysical modeling, i.e., the premotor cortex and anterior cingulate cortex (ACC). However, off-target effects were also observed, primarily involving the visual cortices, with further effects on the supplementary motor areas (SMA), left subgenual cingulate, and right superior temporal gyrus. The specificity of 40 Hz tACS over bilateral DLPFC and the possibility for network-level effects should be considered in future studies, especially in the context of recently promoted gamma-induction therapeutic protocols for neurodegenerative disorders.

Network-level macroscale structural connectivity predicts propagation of transcranial magnetic stimulation.

Information processing in the brain is mediated by structural white matter pathways and is highly dependent on topological brain properties. Here we combined transcranial magnetic stimulation (TMS) with high-density electroencephalography (EEG) and Diffusion Weighted Imaging (DWI), specifically looking at macroscale connectivity to understand whether regional, network-level or whole-brain structural properties are more responsible for stimulus propagation. Neuronavigated TMS pulses were delivered over two individually defined nodes of the default mode (DMN) and dorsal attention (DAN) networks in a group of healthy subjects, with test-retest reliability assessed 1-month apart. TMS-evoked activity was predicted by the modularity and structural integrity of the stimulated network rather than the targeted region(s) or the whole-brain connectivity, suggesting network-level structural connectivity as more relevant than local and global brain properties in shaping TMS signal propagation. The importance of network structural connectome was unveiled only by evoked activity, but not resting-state data. Future clinicals interventions might enhance target engagement by adopting DWI-guided, network-focused TMS.

Heritability of brain resilience to perturbation in humans.

Resilience is the capacity of complex systems to persist in the face of external perturbations and retain their functional properties and performance. In the present study, we investigated how individual variations in brain resilience, which might influence response to stress, aging and disease, are influenced by genetics and/or the environment, with potential implications for the implementation of resilience-boosting interventions. Resilience estimates were derived from in silico lesioning of either brain regions or functional connections constituting the connectome of healthy individuals belonging to two different large and unique datasets of twins, specifically: 463 individual twins from the Human Connectome Project and 453 individual twins from the Colorado Longitudinal Twin Study. As has been reported previously, moderate heritability was found for several topological indexes of brain efficiency and modularity. Importantly, evidence of heritability was found for resilience measures based on removal of brain connections rather than specific single regions, suggesting that genetic influences on resilience are preferentially directed toward region-to-region communication rather than local brain activity. Specifically, the strongest genetic influence was observed for moderately weak, long-range connections between a specific subset of functional brain networks: the Default Mode, Visual and Sensorimotor networks. These findings may help identify a link between brain resilience and network-level alterations observed in neurological and psychiatric diseases, as well as inform future studies investigating brain shielding interventions against physiological and pathological perturbations.

Overlapping and dissociable brain activations for fluid intelligence and executive functions.

Cognitive enhancement interventions aimed at boosting human fluid intelligence (gf) have targeted executive functions (EFs), such as updating, inhibition, and switching, in the context of transfer-inducing cognitive training. However, even though the link between EFs and gf has been demonstrated at the psychometric level, their neurofunctional overlap has not been quantitatively investigated. Identifying whether and how EFs and gf might share neural activation patterns could provide important insights into the overall hierarchical organization of human higher-order cognition, as well as suggest specific targets for interventions aimed at maximizing cognitive transfer. We present the results of a quantitative meta-analysis of the available fMRI and PET literature on EFs and gf in humans, showing the similarity between gf and (i) the overall global EF network, as well as (ii) specific maps for updating, switching, and inhibition. Results highlight a higher degree of similarity between gf and updating (80% overlap) compared with gf and inhibition (34%), and gf and switching (17%). Moreover, three brain regions activated for both gf and each of the three EFs also were identified, located in the left middle frontal gyrus, left inferior parietal lobule, and anterior cingulate cortex. Finally, resting-state functional connectivity analysis on two independent fMRI datasets showed the preferential behavioural correlation and anatomical overlap between updating and gf. These findings confirm a close link between gf and EFs, with implications for brain stimulation and cognitive training interventions.

Mindfulness-based stress reduction training modulates striatal and cerebellar connectivity.

Mindfulness is a meditation practice frequently associated with changes in subjective evaluation of cognitive and sensorial experience, as well as with modifications of brain activity and morphometry. Aside from the anatomical localization of functional changes induced by mindfulness practice, little is known about changes in functional and effective functional magnetic resonance imaging (fMRI) connectivity. Here we performed a connectivity fMRI analysis in a group of healthy individuals participating in an 8-week mindfulness-based stress reduction (MBSR) training program. Data from both a "mind-wandering" and a "meditation" state were acquired before and after the MBSR course. Results highlighted decreased local connectivity after training in the right anterior putamen and insula during spontaneous mind-wandering and the right cerebellum during the meditative state. A further effective connectivity analysis revealed (a) decreased modulation by the anterior cingulate cortex over the anterior portion of the putamen, and (b) a change in left and right posterior putamen excitatory input and inhibitory output with the cerebellum, respectively. Results suggest a rearrangement of dorsal striatum functional and effective connectivity in response to mindfulness practice, with changes in cortico-subcortical-cerebellar modulatory dynamics. Findings might be relevant for the understanding of widely documented mindfulness behavioral effects, especially those related to pain perception.

Realistic modeling of mesoscopic ephaptic coupling in the human brain.

Several decades of research suggest that weak electric fields may influence neural processing, including those induced by neuronal activity and proposed as a substrate for a potential new cellular communication system, i.e., ephaptic transmission. Here we aim to model mesoscopic ephaptic activity in the human brain and explore its trajectory during aging by characterizing the electric field generated by cortical dipoles using realistic finite element modeling. Extrapolating from electrophysiological measurements, we first observe that modeled endogenous field magnitudes are comparable to those in measurements of weak but functionally relevant self-generated fields and to those produced by noninvasive transcranial brain stimulation, and therefore possibly able to modulate neuronal activity. Then, to evaluate the role of these fields in the human cortex in large MRI databases, we adapt an interaction approximation that considers the relative orientation of neuron and field to estimate the membrane potential perturbation in pyramidal cells. We use this approximation to define a simplified metric (EMOD1) that weights dipole coupling as a function of distance and relative orientation between emitter and receiver and evaluate it in a sample of 401 realistic human brain models from healthy subjects aged 16-83. Results reveal that ephaptic coupling, in the simplified mesoscopic modeling approach used here, significantly decreases with age, with higher involvement of sensorimotor regions and medial brain structures. This study suggests that by providing the means for fast and direct interaction between neurons, ephaptic modulation may contribute to the complexity of human function for cognition and behavior, and its modification across the lifespan and in response to pathology.

Differential Contribution of Cortical Thickness, Surface Area, and Gyrification to Fluid and Crystallized Intelligence.

Human intelligence can be broadly subdivided into fluid (gf) and crystallized (gc) intelligence, each tapping into distinct cognitive abilities. Although neuroanatomical correlates of intelligence have been previously studied, differential contribution of cortical morphologies to gf and gc has not been fully delineated. Here, we tried to disentangle the contribution of cortical thickness, cortical surface area, and cortical gyrification to gf and gc in a large sample of healthy young subjects (n = 740, Human Connectome Project) with high-resolution MRIs, followed by replication in a separate data set with distinct cognitive measures indexing gf and gc. We found that while gyrification in distributed cortical regions had positive association with both gf and gc, surface area and thickness showed more regional associations. Specifically, higher performance in gf was associated with cortical expansion in regions related to working memory, attention, and visuo-spatial processing, while gc was associated with thinner cortex as well as higher cortical surface area in language-related networks. We discuss the results in a framework where "horizontal" cortical expansion enables higher resource allocation, computational capacity, and functional specificity relevant to gf and gc, while lower cortical thickness possibly reflects cortical pruning facilitating "vertical" intracolumnar efficiency in knowledge-based tasks relevant mostly to gc.

Light aerobic exercise modulates executive function and cortical excitability.

Single bouts of aerobic exercise can modulate cortical excitability and executive cognitive function, but less is known about the effect of light-intensity exercise, an intensity of exercise more achievable for certain clinical populations. Fourteen healthy adults (aged 22 to 30) completed the following study procedures twice (≥7 days apart) before and after 30 min of either light aerobic exercise (cycling) or seated rest: neurocognitive battery (multitasking performance, inhibitory control and spatial working memory), paired-pulse TMS measures of cortical excitability. Significant improvements in response times during multitasking performance and increases in intracortical facilitation (ICF) were seen following light aerobic exercise. Light aerobic exercise can modulate cortical excitability and some executive function tasks. Populations with deficits in multitasking ability may benefit from this intervention.