At present, resilience refers to a highly heterogeneous concept with ill‐defined determinants, mechanisms, and outcomes. This call for action argues for the need to define resilience as a ...person‐centered multidimensional metric, informed by a dynamic lifespan perspective and combining observational and interventional experimental studies to identify specific neural markers and correlated behavioral measures. The coronavirus disease 2019 (COVID‐19) pandemic highlights the urgent need of such an effort with the ultimate goal of defining a new vital sign, an individual index of resilience, as a life‐long metric with the capacity to predict an individual's risk for disability in the face of a stressor, insult, injury, or disease. ANN NEUROL 2021;90:336–349
Human cognitive abilities and behavior are linked to functional coupling of many brain regions organized in distinct networks. Gaining insights on the role those networks' dynamics play in cognition ...and pathology requires their selective, reliable, and reversible manipulation. Here we document the possibility to manipulate the interplay between two brain networks in a controlled manner, by means of a Transcranial Magnetic Stimulation (TMS) protocol inducing spike timing dependent plasticity (STDP). Pairs of TMS pulses at specific inter-stimulus intervals, repeatedly delivered over two negatively correlated nodes of the default mode network (DMN) and the task-positive network (TPN) defined on the basis of individual functional magnetic resonance imaging (fMRI) data, induced a modulation of network-to-network connectivity, even reversing correlation from negative to slightly positive in 30% of cases. Results also suggest a baseline-dependent effect, with a greater connectivity modulation observed in participants with weaker between-networks connectivity strength right before TMS. Finally, modulation of task-evoked fMRI activity patterns during a sustained attention task was also observed after stimulation, with a faster or slower switch between rest and task blocks according to the timing of TMS pulses. The present findings promote paired associative TMS as a promising technique for controlled manipulation of fMRI connectivity dynamics in humans, as well as the causal investigation of brain-behavior relations.
Objective
This study aimed to assess whether non‐invasive brain stimulation with transcranial alternating current stimulation at gamma‐frequency (γ‐tACS) applied over the precuneus can improve ...episodic memory and modulate cholinergic transmission by modulating cerebral rhythms in early Alzheimer's disease (AD).
Methods
In this randomized, double‐blind, sham controlled, crossover study, 60 AD patients underwent a clinical and neurophysiological evaluation including assessment of episodic memory and cholinergic transmission pre and post 60 minutes treatment with γ‐tACS targeting the precuneus or sham tACS. In a subset of 10 patients, EEG analysis and individualized modelling of electric field distribution were carried out. Predictors to γ‐tACS efficacy were evaluated.
Results
We observed a significant improvement in the Rey Auditory Verbal Learning (RAVL) test immediate recall (p < 0.001) and delayed recall scores (p < 0.001) after γ‐tACS but not after sham tACS. Face‐name associations scores improved with γ‐tACS (p < 0.001) but not after sham tACS. Short latency afferent inhibition, an indirect measure of cholinergic transmission, increased only after γ‐tACS (p < 0.001). ApoE genotype and baseline cognitive impairment were the best predictors of response to γ‐tACS. Clinical improvement correlated with the increase in gamma frequencies in posterior regions and with the amount of predicted electric field distribution in the precuneus.
Interpretation
Precuneus γ‐tACS, able to increase γ‐power activity on the posterior brain regions, showed a significant improvement of episodic memory performances, along with restoration of intracortical excitability measures of cholinergic transmission. Response to γ‐tACS was dependent on genetic factors and disease stage. ANN NEUROL 2022;92:322–334
Objective
To examine the association of the plasma neuroaxonal injury markers neurofilament light (NfL), total tau, glial fibrillary acid protein, and ubiquitin carboxyl‐terminal hydrolase L1 with ...delirium, delirium severity, and cognitive performance.
Methods
Delirium case–no delirium control (n = 108) pairs were matched by age, sex, surgery type, cognition, and vascular comorbidities. Biomarkers were measured in plasma collected preoperatively (PREOP), and 2 days (POD2) and 30 days postoperatively (PO1MO) using Simoa technology (Quanterix, Lexington, MA). The Confusion Assessment Method (CAM) and CAM‐S (Severity) were used to measure delirium and delirium severity, respectively. Cognitive function was measured with General Cognitive Performance (GCP) scores.
Results
Delirium cases had higher NfL on POD2 and PO1MO (median matched pair difference = 16.2pg/ml and 13.6pg/ml, respectively; p < 0.05). Patients with PREOP and POD2 NfL in the highest quartile (Q4) had increased risk for incident delirium (adjusted odds ratio OR = 3.7 95% confidence interval (CI) = 1.1–12.6 and 4.6 95% CI = 1.2–18.2, respectively) and experienced more severe delirium, with sum CAM‐S scores 7.8 points (95% CI = 1.6–14.0) and 9.3 points higher (95% CI = 3.2–15.5). At PO1MO, delirium cases had continued high NfL (adjusted OR = 9.7, 95% CI = 2.3–41.4), and those with Q4 NfL values showed a −2.3 point decline in GCP score (−2.3 points, 95% CI = −4.7 to −0.9).
Interpretation
Patients with the highest PREOP or POD2 NfL levels were more likely to develop delirium. Elevated NfL at PO1MO was associated with delirium and greater cognitive decline. These findings suggest NfL may be useful as a predictive biomarker for delirium risk and long‐term cognitive decline, and once confirmed would provide pathophysiological evidence for neuroaxonal injury following delirium. ANN NEUROL 2020;88:984–994
Objective
American‐style football (ASF) has gained attention because of possible links between repetitive head injury and neurodegenerative diseases. Although postmortem pathologic changes consistent ...with chronic traumatic encephalopathy (CTE) have been reported in ASF players, there are currently no established premortem diagnostic criteria for CTE. Nevertheless, presented with symptoms of cognitive impairment, clinicians treating former players may be inclined to suggest CTE without a thorough exploration of comorbid factors that demonstrate similar clinical phenotypes to putative CTE.
Methods
A survey of 3,913 former ASF players aged 24 to 89 was conducted for those who responded by March 2019.
Results
Despite being a postmortem diagnosis, 108 players (2.8%) self‐reported clinician‐diagnosed CTE. The percentage of players under age 60 years reporting a CTE diagnosis was 2.3% versus 3.7% in participants age 60 or older. Comorbidities in participants self‐reporting CTE were significantly more common, including sleep apnea, hypercholesterolemia, obesity, indicators of past or current depression, hypertension, prescription pain medication use, heart conditions, and low testosterone when compared to non‐CTE respondents. Patterns of reporting for obesity, hypertension, heart conditions, or hypercholesterolemia differed between older and younger participants. Cognitive impairment symptoms were significantly higher in participants self‐reporting CTE.
Interpretation
Some former professional football players have been clinically diagnosed with CTE, a postmortem condition. Comorbidities that can affect cognition were associated with CTE diagnoses in both older and younger players. Although underlying neuropathology cannot be ruled out, treatable conditions should be explored in former athletes demonstrating CTE‐linked clinical phenotypes or symptoms as a means of improving cognitive health in these patients. ANN NEUROL 2020 ANN NEUROL 2020;88:106–112
In neurology, as in all branches of medicine, symptoms of disease and the resulting burden of illness and disability are not simply the consequence of the injury, inflammation or dysfunction of a ...given organ; they also reflect the consequences of the nervous system's attempt to adapt to the insult. This plastic response includes compensatory changes that prove adaptive for the individual, as well as changes that contribute to functional disability and are, therefore, maladaptive. In this context, brain stimulation techniques tailored to modulate individual plastic changes associated with neurological diseases might enhance clinical benefits and minimize adverse effects. In this Review, we discuss the use of two noninvasive brain stimulation techniques--repetitive transcranial magnetic stimulation and transcranial direct current stimulation--to modulate activity in the targeted cortex or in a dysfunctional network, to restore an adaptive equilibrium in a disrupted network for best behavioral outcome, and to suppress plastic changes for functional advantage. We review randomized controlled studies, in focal epilepsy, Parkinson's disease, recovery from stroke, and chronic pain, to illustrate these principles, and we present evidence for the clinical effects of these two techniques.
Dynamics within and between functional resting‐state networks have a crucial role in determining both healthy and pathological brain functioning in humans. The possibility to noninvasively interact ...and selectively modulate the activity of networks would open to relevant applications in neuroscience. Here we tested a novel approach for multichannel, network‐targeted transcranial direct current stimulation (net‐tDCS), optimized to increase excitability of the sensorimotor network (SMN) while inducing cathodal inhibitory modulation over prefrontal and parietal brain regions negatively correlated with the SMN. Using an MRI‐compatible multichannel transcranial electrical stimulation (tES) device, 20 healthy participants underwent real and sham tDCS while at rest in the MRI scanner. Changes in functional connectivity (FC) during and after stimulation were evaluated, looking at the intrinsic FC of the SMN and the strength of the negative connectivity between SMN and the rest of the brain. Standard, bifocal tDCS targeting left motor cortex (electrode ~C3) and right frontopolar (~Fp2) regions was tested as a control condition in a separate sample of healthy subjects to investigate network specificity of multichannel stimulation effects. Net‐tDCS induced greater FC increase over the SMN compared to bifocal tDCS, during and after stimulation. Moreover, exploratory analysis of the impact of net‐tDCS on negatively correlated networks showed an increase in the negative connectivity between SMN and prefrontal/parietal areas targeted by cathodal stimulation both during and after real net‐tDCS. Results suggest preliminary evidence of the possibility of manipulating distributed network connectivity patterns through net‐tDCS, with potential relevance for the development of cognitive enhancement and therapeutic tES solutions.
Based on physiological data, biophysical modeling allows the optimization of tDCS montages for stimulation of brain networks. The efficacy of network‐targeted electrical stimulation is shown by the increase of spontaneous activity in the targeted network, as well as the modulation of its interplay with negatively correlated brain networks.
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