Marine Vernet

Characterizing Brain Cortical Plasticity and Network Dynamics Across the Age-Span in Health and Disease with TMS-EEG and TMS-fMRI

Brain plasticity can be conceptualized as nature’s invention to overcome limitations of the genome and adapt to a rapidly changing environment. As such, plasticity is an intrinsic property of the brain across the lifespan. However, mechanisms of plasticity may vary with age. The combination of transcranial magnetic stimulation (TMS) with electroencephalography (EEG) or functional magnetic resonance imaging (fMRI) enables clinicians and researchers to directly study local and network cortical plasticity, in humans in vivo, and characterize their changes across the age-span. Parallel, translational studies in animals can provide mechanistic insights. Here, we argue that, for each individual, the efficiency of neuronal plasticity declines throughout the age-span and may do so more or less prominently depending on variable ‘starting-points’ and different ‘slopes of change’ defined by genetic, biological, and environmental factors. Furthermore, aberrant, excessive, insufficient, or mistimed plasticity may represent the proximal pathogenic cause of neurodevelopmental and neurodegenerative disorders such as autism spectrum disorders or Alzheimer’s disease.

Changes in Cortical Plasticity Across the Lifespan

Deterioration of motor and cognitive performance with advancing age is well documented, but its cause remains unknown. Animal studies dating back to the late 1970s reveal that age-associated neurocognitive changes are linked to age-dependent changes in synaptic plasticity, including alterations of long-term potentiation and depression (LTP and LTD). Non-invasive brain stimulation techniques enable measurement of LTP- and LTD-like mechanisms of plasticity, in vivo, in humans, and may thus provide valuable insights. We examined the effects of a 40-s train of continuous theta-burst stimulation (cTBS) to the motor cortex (600 stimuli, three pulses at 50 Hz applied at a frequency of 5 Hz) on cortico-spinal excitability as measured by the motor evoked potentials (MEPs) induced by single-pulse transcranial magnetic stimulation before and after cTBS in the contralateral first dorsal interosseus muscle. Thirty-six healthy individuals aged 19–81 years old were studied in two sites (Boston, USA and Barcelona, Spain). The findings did not differ across study sites. We found that advancing age is negatively correlated with the duration of the effect of cTBS (r = −0.367; p = 0.028) and the overall amount of corticomotor suppression induced by cTBS (r = −0.478; p = 0.003), and positively correlated with the maximal suppression of amplitude on motor evoked responses in the target muscle (r = 0.420; p = 0.011). We performed magnetic resonance imaging (MRI)-based individual morphometric analysis in a subset of subjects to demonstrate that these findings are not explained by age-related brain atrophy or differences in scalp-to-brain distance that could have affected the TBS effects. Our findings provide empirical evidence that the mechanisms of cortical plasticity area are altered with aging and their efficiency decreases across the human lifespan. This may critically contribute to motor and possibly cognitive decline.

Reproducibility of the effects of theta burst stimulation on motor cortical plasticity in healthy participants

OBJECTIVE Theta-burst stimulation (TBS) is a repetitive transcranial magnetic stimulation (TMS) protocol, capable of enhancing or suppressing the amplitude of contralateral motor-evoked potentials (MEP) for several minutes after stimulation over the primary motor cortex. Continuous TBS (cTBS) produces a long-term depression (LTD)-like reduction of cortical excitability. The purpose of this study was to assess the test-retest reproducibility of the effects of cTBS and to investigate which neurophysiologic markers of cTBS-induced plasticity are most reproducible. METHODS In ten healthy participants we evaluated in two different sessions the effects of cTBS (using AP-PA current direction, opposite to most commercial rTMS stimulators) on MEPs induced by single-pulse suprathreshold TMS (using AP-PA or PA current direction) over left motor cortex in the first dorsal interosseus (FDI) muscle. RESULTS Results demonstrate that the marker of cTBS induced-plasticity with highest within-subject reproducibility is the modulation of corticospinal excitability measured 5min after cTBS. CONCLUSION Overall the effects of cTBS modulation show limited test-retest reproducibility and some measures of the cTBS effects are more reproducible than others. SIGNIFICANCE Studies comparing cTBS effects in healthy subjects and patients need to proceed with care. Further characterization of the effects of TBS and identification of the best metrics warrant future studies.

Insights on the neural basis of motor plasticity induced by theta burst stimulation from TMS-EEG

Transcranial magnetic stimulation (TMS) is a useful tool to induce and measure plasticity in the human brain. However, the cortical effects are generally indirectly evaluated with motor‐evoked potentials (MEPs) reflective of modulation of cortico‐spinal excitability. In this study, we aim to provide direct measures of cortical plasticity by combining TMS with electroencephalography (EEG). Continuous theta‐burst stimulation (cTBS) was applied over the primary motor cortex (M1) of young healthy adults, and we measured modulation of (i) MEPs, (ii) TMS‐induced EEG evoked potentials (TEPs), (iii) TMS‐induced EEG synchronization and (iv) eyes‐closed resting EEG. Our results show the expected cTBS‐induced decrease in MEP size, which we found to be paralleled by a modulation of a combination of TEPs. Furthermore, we found that cTBS increased the power in the theta band of eyes‐closed resting EEG, whereas it decreased single‐pulse TMS‐induced power in the theta and alpha bands. In addition, cTBS decreased the power in the beta band of eyes‐closed resting EEG, whereas it increased single‐pulse TMS‐induced power in the beta band. We suggest that cTBS acts by modulating the phase alignment between already active oscillators; it synchronizes low‐frequency (theta and/or alpha) oscillators and desynchronizes high‐frequency (beta) oscillators. These results provide novel insight into the cortical effects of cTBS and could be useful for exploring cTBS‐induced plasticity outside of the motor cortex.

Differential effects of motor cortical excitability and plasticity in young and old individuals: a Transcranial Magnetic Stimulation (TMS) study

Aging is associated with changes in the motor system that, over time, can lead to functional impairments and contribute negatively to the ability to recover after brain damage. Unfortunately, there are still many questions surrounding the physiological mechanisms underlying these impairments. We examined cortico-spinal excitability and plasticity in a young cohort (age range: 19–31) and an elderly cohort (age range: 47–73) of healthy right-handed individuals using navigated transcranial magnetic stimulation (nTMS). Subjects were evaluated with a combination of physiological [motor evoked potentials (MEPs), motor threshold (MT), intracortical inhibition (ICI), intracortical facilitation (ICF), and silent period (SP)] and behavioral [reaction time (RT), pinch force, 9 hole peg task (HPT)] measures at baseline and following one session of low-frequency (1 Hz) navigated repetitive TMS (rTMS) to the right (non-dominant) hemisphere. In the young cohort, the inhibitory effect of 1 Hz rTMS was significantly in the right hemisphere and a significant facilitatory effect was noted in the unstimulated hemisphere. Conversely, in the elderly cohort, we report only a trend toward a facilitatory effect in the unstimulated hemisphere, suggesting reduced cortical plasticity and interhemispheric communication. To this effect, we show that significant differences in hemispheric cortico-spinal excitability were present in the elderly cohort at baseline, with significantly reduced cortico-spinal excitability in the right hemisphere as compared to the left hemisphere. A correlation analysis revealed no significant relationship between cortical thickness of the selected region of interest (ROI) and MEPs in either young or old subjects prior to and following rTMS. When combined with our preliminary results, further research into this topic could lead to the development of neurophysiological markers pertinent to the diagnosis, prognosis, and treatment of neurological diseases characterized by monohemispheric damage and lateralized motor deficits.

Changes in cortical plasticity after mild traumatic brain injury

PURPOSE Even after a mild traumatic brain injury (TBI) symptoms may be long lasting and never resolve completely. The neurophysiologic substrate for such lasting deficits remains unclear. There is a lack of objective measures of early brain abnormalities following mild TBI, which could shed light on the genesis of these lasting impairments. METHODS Here we report findings in a previously healthy man tested 2 and 6 weeks after a well-documented concussion. Findings were compared with 12 control subjects. All subjects underwent brain magnetic resonance imaging (MRI) and diffusion-tensor imaging (DTI). Testing included neuropsychological evaluation and physiological assessment with TMS and EEG, excitatory/inhibitory balance and brain plasticity. RESULTS While the MRI, DTI and neuropsychological evaluations showed no abnormalities, neurophysiologic tests revealed subclinical abnormalities in our patient: (1) Significantly higher intracortical facilitation than the control group at both time points; (2) Intracortical inhibition presumably mediated by GABAB receptors was absent at week 2, but returned to normal value at week 6; (3) Abnormal mechanisms of plasticity at week 2, that normalize at week 6. CONCLUSIONS These findings demonstrate a transient alteration of brain cortical physiology following concussion independent of anatomical findings and neuropsychological function. This case study suggests that TMS measures may serve as sensitive biomarkers of physiologic brain abnormalities after concussion.

Characterizing and Modulating Brain Circuitry through Transcranial Magnetic Stimulation Combined with Electroencephalography

The concurrent combination of transcranial magnetic stimulation (TMS) with electroencephalography (TMS-EEG) is a powerful technology for characterizing and modulating brain networks across developmental, behavioral, and disease states. Given the global initiatives in mapping the human brain, recognition of the utility of this technique is growing across neuroscience disciplines. Importantly, TMS-EEG offers translational biomarkers that can be applied in health and disease, across the lifespan, and in humans and animals, bridging the gap between animal models and human studies. However, to utilize the full potential of TMS-EEG methodology, standardization of TMS-EEG study protocols is needed. In this article, we review the principles of TMS-EEG methodology, factors impacting TMS-EEG outcome measures, and the techniques for preventing and correcting artifacts in TMS-EEG data. To promote the standardization of this technique, we provide comprehensive guides for designing TMS-EEG studies and conducting TMS-EEG experiments. We conclude by reviewing the application of TMS-EEG in basic, cognitive and clinical neurosciences, and evaluate the potential of this emerging technology in brain research.

Theta burst stimulation to characterize changes in brain plasticity following mild traumatic brain injury: a proof-of-principle study

PURPOSE Recent studies investigating the effects of mild traumatic brain injury (mTBI) suggest the presence of unbalanced excitatory and inhibitory mechanisms within primary motor cortex (M1). Whether these abnormalities are associated with impaired synaptic plasticity remains unknown. METHODS The effects of continuous theta burst stimulation (cTBS) on transcranial magnetic stimulation-induced motor evoked potentials (MEPs) were assessed on average two weeks and six weeks following mTBI in five individuals. RESULTS The procedure was well-tolerated by all participants. Continuous TBS failed to induce a significant reduction of MEP amplitudes two weeks after the injury, but response to cTBS normalized six weeks following injury, as a majority of patients became asymptomatic. CONCLUSIONS These preliminary results suggest that cTBS can be used to assess M1 synaptic plasticity in subacute phase following mTBI and may provide insights into neurobiological substrates of symptoms and consequences of mTBI.

Enhanced motor function and its neurophysiological correlates after navigated low-frequency repetitive transcranial magnetic stimulation over the contralesional motor cortex in stroke

BACKGROUND The net effect of altered interhemispheric interactions between homologous motor cortical areas after unilateral stroke has been previously reported to contribute to residual hemiparesis. Using this framework, we hypothesized that navigated 1 Hz repetitive transcranial magnetic stimulation (rTMS) over the contralesional hemisphere would induce a stronger physiological and behavioural response in patients with residual motor deficit than in healthy subjects, because an imbalance in interhemispheric excitability may underlie motor dysfunction. METHODS Navigated rTMS was conducted in 8 chronic stroke patients (67.50±13.77 years) and in 8 comparable normal subjects (57.38±9.61 years). We evaluated motor function (Finger tapping, Nine Hole Peg test, Strength Index and Reaction Time) as well as the excitatory and inhibitory function (resting motor threshold, motor evoked potential amplitude, intra-cortical inhibition and facilitation, and silent period) of the stimulated and non-stimulated motor cortex before and after navigated rTMS. RESULTS rTMS induced an increase in excitability in the ipsilesional (non-stimulated) motor cortex and led to improved performance in the finger tapping task and pinch force task. These physiological and behavioral effects were more prominent (or robust) in the group of stroke patients than in the control group. CONCLUSION Navigated low-frequency rTMS involving precise and consistent targeting of the contralesional hemisphere in stroke patients enhanced the cortical excitability of the ipsilesional hemisphere and the motor response of the hemiparetic hand.

Electroencephalography During Transcranial Magnetic Stimulation: Current Modus Operandi

Transcranial magnetic stimulation (TMS) is a widely used research and clinical device that has the potential to modulate and interact with brain activity. However, its mechanisms of action, whether used to explore brain functions in healthy participants or to induce meaningful therapeutic effects in patients, are still not fully understood. One method allowing bridging the gap between TMS administration and its behavioral consequences is the simultaneous recording of brain activity with electroencephalography (EEG). Unfortunately, the acquisition and interpretation of EEG data during TMS is still not straightforward because of the contamination of the EEG by artifacts, despite the introduction of several TMS-compatible EEG systems. This chapter is providing a step-by-step guide to online TMS-EEG experimentation, from the selection of appropriate material, to conducting the experiment and later data analysis. We first review the multiple possible sources of EEG contaminations related to a TMS discharge (of electromagnetic, mechanical, and physiological origin). We then examine various methods that have been proposed in the literature to minimize these artifacts or isolate them from genuine neuronal responses to TMS. We finally survey insights in cognitive and clinical neurosciences that have been gained from the TMS-EEG combination between its introduction in 1997 (first TMS-compatible EEG systems) up to 2011.