TMS-EEG Biomarkers of Amnestic Mild Cognitive Impairment Due to Alzheimer's Disease: A Proof-of-Concept Six Years Prospective Study.

Background: Early and affordable identification of subjects with amnestic mild cognitive impairment (aMCI) who will convert to Alzheimer's disease (AD) is a major scientific challenge. Objective: To investigate the neurophysiological hallmarks of sensorimotor cortex function in aMCI under the hypothesis that some may represent the plastic rearrangements induced by neurodegeneration, hence predictors of future conversion to AD. We sought to determine (1) whether the sensorimotor network shows peculiar alterations in patients with aMCI and (2) if sensorimotor network alterations predict long-term disease progression at the individual level. Methods: We studied several transcranial magnetic stimulation (TMS)-electroencephalogram (EEG) parameters of the sensorimotor cortex in a group of patients with aMCI and followed them for 6 years. We then identified aMCI who clinically converted to AD [prodromal to AD-MCI (pAD-MCI)] and those who remained cognitively stable [non-prodromal to AD-MCI (npAD-MCI)]. Results: Patients with aMCI showed reduced motor cortex (M1) excitability and disrupted EEG synchronization [decreased intertrial coherence (ITC)] in alpha, beta and gamma frequency bands compared to the control subjects. The degree of alteration in M1 excitability and alpha ITC was comparable between pAD-MCI and npAD-MCI. Importantly, beta and gamma ITC impairment in the stimulated M1 was greater in pAD-MCI than npAD-MCI. Furthermore, an additional parameter related to the waveform shape of scalp signals, reflecting time-specific alterations in global TMS-induced activity [stability of the dipolar activity (sDA)], discriminated npAD-MCI from MCI who will convert to AD. Discussion: The above mentioned specific cortical changes, reflecting deficit of synchronization within the cortico-basal ganglia-thalamo-cortical loop in aMCI, may reflect the pathological processes underlying AD. These changes could be tested in larger cohorts as neurophysiological biomarkers of AD.

Age-related changes of cortical excitability and connectivity in healthy humans: non-invasive evaluation of sensorimotor network by means of TMS-EEG.

The sensorimotor cortical system undergoes structural and functional changes across its lifespan. Some of these changes are physiological and parallel the normal aging process, while others might represent pathophysiological mechanisms underlying neurodegenerative disorders. In the last years, the study of possible age-related modifications in brain sensorimotor functional characteristics has been the focus of several research projects. Here we have used the transcranial magnetic stimulation (TMS)-electroencephalography (EEG) navigated co-registration to investigate the influence of physiological aging on the excitability and connectivity of the human sensorimotor cortical system. To this end, we compared the TMS-evoked EEG potentials (TEPs) collected after stimulating the dominant primary motor cortex (M1) in healthy young subjects (mean age 24.5years) with those collected in healthy older adults (mean age 67.6years). We have shown that, after stimulation of the left motor cortex, TEPs are significantly affected by physiological aging. This phenomenon has a clear spatio-temporal specificity and we speculate that normal aging per se leads to some changes in the excitability of specific cortical neural assemblies whereas other alterations could reflect compensatory mechanisms to such changes.

Age related differences in functional synchronization of EEG activity as evaluated by means of TMS-EEG coregistrations.

It was recently demonstrated that the characteristics of EEG rhythms preceding a transcranial magnetic stimulation (TMS) of the motor cortex (M1) influence the motor-evoked potential (MEP) amplitude with a peculiar pattern, thus reflecting the M1 functional state. As physiological aging is related to a decrease in motor performance and changes in excitability and connectivity strength within cerebral sensorimotor circuits, we aimed to explore whether aging affects EEG-MEP interactions. Using MRI-navigated TMS and multichannel EEG, we compared the EEG-MEP interactions observed in healthy aged subjects with those observed in young volunteers. We divided the MEPs amplitude into two different subgroups consisting of "high" and "low" MEPs, based on the 50th percentile of their amplitude distribution. Then we analysed the characteristics of the pre-stimulus EEG from M1 and correlated areas separately for the "high" and "low" MEPs, comparing the two conditions. In both young and old subjects, significantly larger MEPs were evoked when the stimulated M1 was coupled in the beta-2 band with the homolateral prefrontal cortex. Conversely, only in young participants was the MEP size modulated when the M1 and homolateral parieto-occipital cortices were coupled in the delta band. The elderly didn't show this kind of pattern. Importantly, this coupling was significantly higher in elderly brains than in young brains, both for high and low MEPs. Our results suggest an age-related significant influence of time-varying coupling of spatially patterned EEG rhythms on motor cortex excitability in response to TMS.

Development of cortical motor circuits between childhood and adulthood: A navigated TMS-HdEEG study.

Motor functions improve during childhood and adolescence, but little is still known about the development of cortical motor circuits during early life. To elucidate the neurophysiological hallmarks of motor cortex development, we investigated the differences in motor cortical excitability and connectivity between healthy children, adolescents, and adults by means of navigated suprathreshold motor cortex transcranial magnetic stimulation (TMS) combined with high-density electroencephalography (EEG). We demonstrated that with development, the excitability of the motor system increases, the TMS-evoked EEG waveform increases in complexity, the magnitude of induced activation decreases, and signal spreading increases. Furthermore, the phase of the oscillatory response to TMS becomes less consistent with age. These changes parallel an improvement in manual dexterity and may reflect developmental changes in functional connectivity. Hum Brain Mapp 38:2599-2615, 2017. © 2017 Wiley Periodicals, Inc.

Sensorimotor cortex excitability and connectivity in Alzheimer's disease: A TMS-EEG Co-registration study.

Several studies have shown that, in spite of the fact that motor symptoms manifest late in the course of Alzheimer's disease (AD), neuropathological progression in the motor cortex parallels that in other brain areas generally considered more specific targets of the neurodegenerative process. It has been suggested that motor cortex excitability is enhanced in AD from the early stages, and that this is related to disease's severity and progression. To investigate the neurophysiological hallmarks of motor cortex functionality in early AD we combined transcranial magnetic stimulation (TMS) with electroencephalography (EEG). We demonstrated that in mild AD the sensorimotor system is hyperexcitable, despite the lack of clinically evident motor manifestations. This phenomenon causes a stronger response to stimulation in a specific time window, possibly due to locally acting reinforcing circuits, while network activity and connectivity is reduced. These changes could be interpreted as a compensatory mechanism allowing for the preservation of sensorimotor programming and execution over a long period of time, regardless of the disease's progression. Hum Brain Mapp 37:2083-2096, 2016. © 2016 Wiley Periodicals, Inc.

Neurophysiological features of motor cortex excitability and plasticity in Subcortical Ischemic Vascular Dementia: a TMS mapping study.

OBJECTIVE: To evaluate neurophysiological features of M1 excitability and plasticity in Subcortical Ischemic Vascular Dementia (SIVD), by means of a TMS mapping study. METHODS: Seven SIVD and nine AD patients, along with nine control subjects were tested. The M1 excitability was studied by resting thresholds, area and volume of active cortical sites for forearm and hand's examined muscles. For M1 plasticity, coordinates of the hot-spot and the center of gravity (CoG) were evaluated. The correlation between the degree of hyperexcitability and the amount of M1 plastic rearrangement was also calculated. RESULTS: Multivariate analysis of excitability measures demonstrated similarly enhanced cortical excitability in AD and SIVD patients with respect to controls. SIVD patients showed a medial and frontal shift of CoG from the hot-spot, not statistically different from that observed in AD. A significant direct correlation was seen between parameters related to cortical excitability and those related to cortical plasticity. CONCLUSIONS: The results suggest the existence of common compensatory mechanisms in different kind of dementing diseases supporting the idea that cortical hyperexcitability can promote cortical plasticity. SIGNIFICANCE: This study characterizes neurophysiological features of motor cortex excitability and plasticity in SIVD, providing new insights on the correlation between cortical excitability and plasticity.

Unilateral cortical hyperexcitability in congenital hydrocephalus: a TMS study.

INTRODUCTION: Changes in cortical excitability are considered to play an important role in promoting brain plasticity both in healthy people and in neurological diseases. Hydrocephalus is a brain development disorder related to an excessive accumulation of cerebrospinal fluid (CSF) in the ventricular system. The functional relevance of cortical structural changes described in this disease is largely unexplored in human. We investigated cortical excitability using multimodal transcranial magnetic stimulation (TMS) in a case of congenital hydrocephalus with almost no neurological signs. METHODS: A caucasian 40 years old, ambidextrous and multilingual woman affected by occult spina bifida and congenital symmetrical hydrocephalous underwent a TMS study. The intracortical and interhemispheric paired pulse paradigms were used, together with the mapping technique. RESULTS: No significant differences were found in the resting motor thresholds between the two hemispheres. Instead, the intracortical excitability curves were statistically different between the two hemispheres (with short intracortical inhibition (SICI) being strongly reduced and intracortical facilitation (ICF) enhanced in the right one), and the interhemispheric curves showed a general hyper-excitability on the right hemisphere (when conditioned by the left one) and a general hypo-excitability in the left hemisphere (when conditioned by the right one). It is noteworthy that an asymmetric right hemisphere (RH) change of excitability was observed by means of mapping technique. CONCLUSION: We hypothesize that in this ambidextrous subject, the observed RH hyper-excitability could represent a mechanism of plasticity to preserve functionality of specific brain areas possibly devoted to some special skills, such as multilingualism.

Disorders of consciousness and electrophysiological treatment strategies: a review of the literature and new perspectives.

The last years have witnessed a significant increase in our understanding of brain functions in survivors of severe brain injuries with disorders of consciousness (DOC). Despite there is currently no effective standardized treatment for DOC patients, in the past decade many potential pharmacological as well as non-pharmacological therapies have been proposed. A promising and increasingly growing field of non-pharmacological therapeutic trials has been supported by the application of electrophysiological techniques. This article reviews the most relevant studies in the literature in order to provide the reader with a clear picture of the current available neurophysiological instruments that could be used to treat DOC patients. We will hereinafter briefly discuss the basic principles of deep brain stimulation (DBS), repetitive transcranial magnetic stimulation (rTMS), spinal cord stimulation (SCS) and peripheral nerve stimulation (MNS) that are the main techniques now used by researchers as a treatment and we will explain the rationale of these therapies. Then, we will outline the more relevant studies regarding their application in DOC patients. Finally, due to the fact that only a moderate amount of individual or clinically-dependent approaches are available, we conclude that more standardized studies are necessary to address the role of electrophysiological treatment strategies in DOC as well as to further elucidate their therapeutic effects and define optimal stimulation parameters. Undoubtedly, at present the multidimensional approach is the most interesting.

Time-varying coupling of EEG oscillations predicts excitability fluctuations in the primary motor cortex as reflected by motor evoked potentials amplitude: an EEG-TMS study.

PURPOSE: Motor evoked potentials (MEPs) elicited by a train of consecutive, individual transcranial magnetic stimuli demonstrate fluctuations in amplitude with respect to time when recorded from a relaxed muscle. The influence of time-varying, instantaneous modifications of the electroencephalography (EEG) properties immediately preceding the transcranial magnetic stimulation (TMS) has rarely been explored. The aim of this study was to investigate the influence of the pre-TMS motor cortex and related areas EEG profile on time variants of the MEPs amplitude. METHOD: MRI-navigated TMS and multichannel TMS-compatible EEG devices were used. For each experimental subject, post-hoc analysis of the MEPs amplitude that was based on the 50th percentile of the MEPs amplitude distribution provided two subgroups corresponding to "high" (large amplitude) and "low" (small amplitude). The pre-stimulus EEG characteristics (coherence and spectral profile) from the motor cortex and related areas were analyzed separately for the "high" and "low" MEPs and were then compared. RESULTS: On the stimulated hemisphere, EEG coupling was observed more often in the high compared to the low MEP trials. Moreover, a paradigmatic pattern in which TMS was able to lead to significantly larger MEPs was found when the EEG of the stimulated motor cortex was coupled in the beta 2 band with the ipsilateral prefrontal cortex and in the delta band with the bilateral centro-parietal-occipital cortices. CONCLUSION: This data provide evidence for a statistically significant influence of time-varying and spatially patterned synchronization of EEG rhythms in determining cortical excitability, namely motor cortex excitability in response to TMS.

Human brain cortical correlates of short-latency afferent inhibition: a combined EEG-TMS study.

When linking in time electrical stimulation of the peripheral nerve with transcranial magnetic stimulation (TMS), the excitability of the motor cortex can be modulated to evoke clear inhibition, as reflected by the amplitude decrement in the motor-evoked potentials (MEPs). This specific property, designated short-latency afferent inhibition (SAI), occurs when the nerve-TMS interstimulus interval (ISI) is approximately 25 ms and is considered to be a corticothalamic phenomenon. The aim of the present study was to use the electroencephalographic (EEG) responses to navigated-TMS coregistration to better characterize the neuronal circuits underlying SAI. The present experimental set included magnetic resonance imaging (MRI)-navigated TMS and 60-channel TMS-compatible EEG devices. TMS-evoked EEG responses and MEPs were analyzed in eight healthy volunteers; ISIs between median nerve and cortical stimulation were determined relative to the latency of the individual N20 component of the somatosensory-evoked potential (SEP) obtained after stimulation of the median nerve. ISIs from the latency of the N20 plus 3 ms and N20 plus 10 ms were investigated. In all experimental conditions, TMS-evoked EEG responses were characterized by a sequence of negative deflections peaking at approximately 7, 44, and 100 ms alternating with positive peaks at approximately 30, 60, and 180 ms post-TMS. Moreover, ISI N20+3 ms modulated both EEG-evoked activity and MEPs. In particular, it inhibited MEP amplitudes, attenuated cortical P60 and N100 responses, and induced motor cortex beta rhythm selective decrement of phase locking. The findings of the present experiment suggest the cortical origin of SAI that could result from the cortico-cortical activation of GABAergic-mediated inhibition onto the corticospinal neurons modulated by cholinergic activation able to reducing intralaminar inhibition and promoting intracolumnar inhibition.

Motor cortex excitability in Alzheimer's disease: a transcranial magnetic stimulation follow-up study.

Transient cognitive and behavioral stabilization of patients with Alzheimer's disease (AD) is the main goal of acetylcholinesterase inhibitor (AChEI) therapy. Response to treatment is variable and it is usually assessed clinically via neuropsychological scales. Functional neuroimaging could ideally permit the objective evaluation of the topographic correlates of therapy on brain functioning, but is expensive and little available on a large scale. On the other hand, neurophysiological methods such as transcranial magnetic stimulation (TMS) could offer an alternative, low-cost and risk free tool of assessing response to treatment in AD. Previous TMS studies have demonstrated hyperexcitability and asymptomatic motor cortex reorganization in the early stages of AD in patients with normal motor function. The aim of this study was to compare motor cortex functionality in 10 AD patients before and after long-term AchEIs therapy in order to monitor potential drug-related changes in cortical excitability and organization. Examined parameters of motor cortex physiology were found to be unchanged in patients with stabilized cognitive performance during the therapy. TMS, along with clinical, neuropsychological, and neuroimaging data, could be an inexpensive measure of biological progression in AD and it might supplement traditional methods to assess the effects of therapy.

Human brain connectivity during single and paired pulse transcranial magnetic stimulation.

OBJECTIVE: Intracortical inhibition (SICI) and facilitation (ICF) in the human motor cortex can be measured using a paired pulse transcranial magnetic stimulation (ppTMS) protocol. Recently, a technical device has been introduced, which allows recording electroencephalographic (EEG) responses to TMS of a given scalp site. The latency, amplitude and scalp topography of such responses are considered a reflection of cortico-cortical connectivity and functional state. The aim of the present study is to better characterize the neuronal circuits underlying motor cortex connectivity as well as the mechanisms regulating its balance between inhibition and facilitation by means of EEG navigated-ppTMS coregistration. METHODS: Sub-threshold and supra-threshold single and ppTMS of the left primary motor cortex were carried out during a multi-channel EEG recording on 8 healthy volunteers; the between-pulse intervals used in the paired pulse trials were 3 (for SICI) and 11 ms (for ICF). Motor evoked potentials (MEPs) from the opposite hand were simultaneously recorded. RESULTS: Single and ppTMS induced EEG responses characterized by a sequence of negative deflections peaking at approximately 7, 18, 44, 100 and 280 ms alternated with positive peaks at approximately 13, 30, 60 and 190 ms post-TMS. Moreover, ppTMS modulated both EEG evoked activity and MEPs. Amplitude variability of EEG responses was correlated with - and therefore might partially explain - amplitude variability of MEPs. INTERPRETATION: EEG-ppTMS is a promising tool to better characterize the neuronal circuits underlying cortical effective connectivity as well as the mechanisms regulating the balance between inhibition and facilitation within the human cortices and the corticospinal pathway.