The vascular locked-in and locked-in-plus syndrome: A retrospective case series.

The locked-in syndrome (LiS) is defined as the loss of most voluntary muscle movements with preserved cognitive abilities due to a ventral pontine lesion. However, some patients may also have severe impairment of consciousness [locked-in plus syndrome (LiPS)]. Here we aimed to explore structural differences between LiS and LiPS patients of vascular aetiology, focusing on lesion patterns and locations to better delineate the clinical spectrum of LiS and LiPS. In this retrospective case series study, we report nine patients (two women), ages 29-74 years (median 50) with LiS and LiPS who were diagnosed between 2007 and 2021. Clinical parameters, MRI findings including the lesioned structures, and a shape feature calculation are presented for every patient. The lesioned structures were determined by a senior neuroradiologist. Two of nine patients had fully retained consciousness (LiS) and seven showed various degrees of impaired consciousness (LiPS). Lesions of LiS patients are round and confined to the pons, whereas lesions of LiPS patients are more elongated and reach neighbouring areas such as the mesencephalon, thalamus or ascending reticular activating system. Lesions involving the mesencephalon and the thalamus are strong indicators of LiPS, whereas for lesions restricted to the pons, the dorsal extension and the associated damage to the ascending reticular activating system are crucial to differentiate LiS from LiPS. Recognizing LiPS using clinical and radiological findings is important as these patients may need different therapies and care and, most importantly, should not be mistaken as unresponsive wakefulness syndrome.

Locked-in syndrome revisited.

The locked-in syndrome (LiS) is characterized by quadriplegia with preserved vertical eye and eyelid movements and retained cognitive abilities. Subcategorization, aetiologies and the anatomical foundation of LiS are discussed. The damage of different structures in the pons, mesencephalon and thalamus are attributed to symptoms of classical, complete and incomplete LiS and the locked-in plus syndrome, which is characterized by additional impairments of consciousness, making the clinical distinction to other chronic disorders of consciousness at times difficult. Other differential diagnoses are cognitive motor dissociation (CMD) and akinetic mutism. Treatment options are reviewed and an early, interdisciplinary and aggressive approach, including the provision of psychological support and coping strategies is favoured. The establishment of communication is a main goal of rehabilitation. Finally, the quality of life of LiS patients and ethical implications are considered. While patients with LiS report a high quality of life and well-being, medical professionals and caregivers have largely pessimistic perceptions. The negative view on life with LiS must be overthought and the autonomy and dignity of LiS patients prioritized. Knowledge has to be disseminated, diagnostics accelerated and technical support system development promoted. More well-designed research but also more awareness of the needs of LiS patients and their perception as individual persons is needed to enable a life with LiS that is worth living.

Narrative Review: Quantitative EEG in Disorders of Consciousness.

In this narrative review, we focus on the role of quantitative EEG technology in the diagnosis and prognosis of patients with unresponsive wakefulness syndrome and minimally conscious state. This paper is divided into two main parts, i.e., diagnosis and prognosis, each consisting of three subsections, namely, (i) resting-state EEG, including spectral power, functional connectivity, dynamic functional connectivity, graph theory, microstates and nonlinear measurements, (ii) sleep patterns, including rapid eye movement (REM) sleep, slow-wave sleep and sleep spindles and (iii) evoked potentials, including the P300, mismatch negativity, the N100, the N400 late positive component and others. Finally, we summarize our findings and conclude that QEEG is a useful tool when it comes to defining the diagnosis and prognosis of DOC patients.

Combining SPECT and Quantitative EEG Analysis for the Automated Differential Diagnosis of Disorders with Amnestic Symptoms.

Single photon emission computed tomography (SPECT) and Electroencephalography (EEG) have become established tools in routine diagnostics of dementia. We aimed to increase the diagnostic power by combining quantitative markers from SPECT and EEG for differential diagnosis of disorders with amnestic symptoms. We hypothesize that the combination of SPECT with measures of interaction (connectivity) in the EEG yields higher diagnostic accuracy than the single modalities. We examined 39 patients with Alzheimer's dementia (AD), 69 patients with depressive cognitive impairment (DCI), 71 patients with amnestic mild cognitive impairment (aMCI), and 41 patients with amnestic subjective cognitive complaints (aSCC). We calculated 14 measures of interaction from a standard clinical EEG-recording and derived graph-theoretic network measures. From regional brain perfusion measured by 99mTc-hexamethyl-propylene-aminoxime (HMPAO)-SPECT in 46 regions, we calculated relative cerebral perfusion in these patients. Patient groups were classified pairwise with a linear support vector machine. Classification was conducted separately for each biomarker, and then again for each EEG- biomarker combined with SPECT. Combination of SPECT with EEG-biomarkers outperformed single use of SPECT or EEG when classifying aSCC vs. AD (90%), aMCI vs. AD (70%), and AD vs. DCI (100%), while a selection of EEG measures performed best when classifying aSCC vs. aMCI (82%) and aMCI vs. DCI (90%). Only the contrast between aSCC and DCI did not result in above-chance classification accuracy (60%). In general, accuracies were higher when measures of interaction (i.e., connectivity measures) were applied directly than when graph-theoretical measures were derived. We suggest that quantitative analysis of EEG and machine-learning techniques can support differentiating AD, aMCI, aSCC, and DCC, especially when being combined with imaging methods such as SPECT. Quantitative analysis of EEG connectivity could become an integral part for early differential diagnosis of cognitive impairment.

Cortical afferent inhibition reflects cognitive impairment in obstructive sleep apnea syndrome: a TMS study.

OBJECTIVES: Patients with obstructive sleep apnea syndrome (OSAS) show neurocognitive impairment, but the exact mechanisms that cause cognitive dysfunctions remain unknown. The cholinergic system is known to play a key role in all attentional processes and cognitive functions. A transcranial magnetic stimulation (TMS) protocol may give direct information about the function of some cholinergic circuits in the human brain; this technique relies on short latency afferent inhibition (SAI) of the motor cortex. The objective of this exploratory study was to test the hypothesis that impaired cognitive performances in OSAS patients are associated with a dysfunction of the cholinergic system, as assessed by SAI. METHODS: We applied SAI technique in a group of 13 patients with OSAS and compared the data with those from a group of 13 age-matched healthy subjects. All the patients underwent a sleep study, an extensive neuropsychological evaluation, and TMS examination. RESULTS: Mean SAI was significantly reduced in our OSAS patients when compared with controls. The neuropsychological evaluation showed impairments in most cognitive areas in the OSAS patients. SAI values were strongly correlated with the neuropsychological test scores. CONCLUSIONS: These findings suggest that the cognitive deficits in OSAS may be, at least in part, secondary to alterations in cholinergic neurotransmission, presumably caused by nocturnal hypoxemia. TMS studies may shed light on the pathophysiological mechanisms of the cognitive disturbances in OSAS patients.

Abnormal short-latency synaptic plasticity in the motor cortex of subjects with Becker muscular dystrophy: a rTMS study.

We used repetitive transcranial magnetic stimulation (rTMS) to further investigate motor cortex excitability in 13 patients with Becker muscular dystrophy (BMD), six of them with slight mental retardation. RTMS delivered at 5Hz frequency and suprathreshold intensity progressively increases the size of motor evoked potentials (MEPs) in healthy subjects; the rTMS-induced facilitation of MEPs was significantly reduced in the BMD patients mentally retarded or classified as borderline when compared with age-matched control subjects and the BMD patients with normal intelligence. The increase in the duration of the cortical silent period was similar in both patient groups and controls. These findings suggest an altered cortical short-term synaptic plasticity in glutamate-dependent excitatory circuits within the motor cortex in BMD patients with intellectual disabilities. RTMS studies may shed new light on the physiological mechanisms of cortical involvement in dystrophinopathies.

Impaired consciousness is linked to changes in effective connectivity of the posterior cingulate cortex within the default mode network.

The intrinsic connectivity of the default mode network has been associated with the level of consciousness in patients with severe brain injury. Especially medial parietal regions are considered to be highly involved in impaired consciousness. To better understand what aspect of this intrinsic architecture is linked to consciousness, we applied spectral dynamic causal modeling to assess effective connectivity within the default mode network in patients with disorders of consciousness. We included 12 controls, 12 patients in minimally conscious state and 13 in vegetative state in this study. For each subject, we first defined the four key regions of the default mode network employing a subject-specific independent component analysis approach. The resulting regions were then included as nodes in a spectral dynamic causal modeling analysis in order to assess how the causal interactions across these regions as well as the characteristics of neuronal fluctuations change with the level of consciousness. The resulting pattern of interaction in controls identified the posterior cingulate cortex as the main driven hub with positive afferent but negative efferent connections. In patients, this pattern appears to be disrupted. Moreover, the vegetative state patients exhibit significantly reduced self-inhibition and increased oscillations in the posterior cingulate cortex compared to minimally conscious state and controls. Finally, the degree of self-inhibition and strength of oscillation in this region is correlated with the level of consciousness. These findings indicate that the equilibrium between excitatory connectivity towards posterior cingulate cortex and its feedback projections is a key aspect of the relationship between alterations in consciousness after severe brain injury and the intrinsic functional architecture of the default mode network. This impairment might be principally due to the disruption of the mechanisms underlying self-inhibition and neuronal oscillations in the posterior cingulate cortex.

Neural repetition suppression: evidence for perceptual expectation in object-selective regions.

It is an established finding that neuronal activity is decreased for repeated stimuli. Recent studies revealed that repetition suppression (RS) effects are altered by manipulating the probability with which stimuli are repeated. RS for faces is more pronounced when the probability of repetition is high than when it is low. This response pattern is interpreted with reference to the predictive coding (PC) account, which assumes that RS is influenced by top-down expectations. Recent findings challenge the generality of PC accounts of RS by showing repetition probability does not modulate RS for other visual stimuli than faces. However, a number of findings on visual processing are in line with PC. Thus, the influence of repetition probability on RS effects during object processing requires careful reinvestigations. In the present fMRI study, object pictures were presented in a high (75%) or low (25%) repetition probability context. We found increased RS in the high-probability context compared to the low-probability context in the left lateral occipital complex (LOC). The dorsal-caudal and the ventral-anterior subdivisions of the LOC revealed similar neuronal responses. These results indicate that repetition probability effects can be found for other visual objects than faces and provide evidence in favor of the PC account.

Altered network properties of the fronto-parietal network and the thalamus in impaired consciousness.

Recovery of consciousness has been associated with connectivity in the frontal cortex and parietal regions modulated by the thalamus. To examine this model and to relate alterations to deficits in cognitive functioning and conscious processing, we investigated topological network properties in patients with chronic disorders of consciousness recovered from coma. Resting state fMRI data of 34 patients with unresponsive wakefulness syndrome and 25 in minimally conscious state were compared to 28 healthy controls. We investigated global and local network characteristics. Additionally, behavioral measures were correlated with the local metrics of 28 regions within the fronto-parietal network and the thalamus. In chronic disorders of consciousness, modularity at the global level was reduced suggesting a disturbance in the optimal balance between segregation and integration. Moreover, network properties were altered in several regions which are associated with conscious processing (particularly, in medial parietal, and frontal regions, as well as in the thalamus). Between minimally conscious and unconscious patients the local efficiency of medial parietal regions differed. Alterations in the thalamus were particularly evident in non-conscious patients. Most of the regions affected in patients with impaired consciousness belong to the so-called 'rich club' of highly interconnected central nodes. Disturbances in their topological characteristics have severe impact on information integration and are reflected in deficits in cognitive functioning probably leading to a total breakdown of consciousness.

Connectivity biomarkers can differentiate patients with different levels of consciousness.

OBJECTIVE: In the present study, we searched for resting-EEG biomarkers that distinguish different levels of consciousness on a single subject level with an accuracy that is significantly above chance. METHODS: We assessed 44 biomarkers extracted from the resting EEG with respect to their discriminative value between groups of minimally conscious (MCS, N=22) patients, vegetative state patients (VS, N=27), and - for a proof of concept - healthy participants (N=23). We applied classification with support vector machines. RESULTS: Partial coherence, directed transfer function, and generalized partial directed coherence yielded accuracies that were significantly above chance for the group distinction of MCS vs. VS (.88, .80, and .78, respectively), as well as healthy participants vs. MCS (.96, .87, and .93, respectively) and VS (.98, .84, and .96, respectively) patients. CONCLUSIONS: The concept of connectivity is crucial for determining the level of consciousness, supporting the view that assessing brain networks in the resting state is the golden way to examine brain functions such as consciousness. SIGNIFICANCE: The present results directly show that it is possible to distinguish patients with different levels of consciousness on the basis of resting-state EEG.

Comparison of EEG-features and classification methods for motor imagery in patients with disorders of consciousness.

Current research aims at identifying voluntary brain activation in patients who are behaviorally diagnosed as being unconscious, but are able to perform commands by modulating their brain activity patterns. This involves machine learning techniques and feature extraction methods such as applied in brain computer interfaces. In this study, we try to answer the question if features/classification methods which show advantages in healthy participants are also accurate when applied to data of patients with disorders of consciousness. A sample of healthy participants (N = 22), patients in a minimally conscious state (MCS; N = 5), and with unresponsive wakefulness syndrome (UWS; N = 9) was examined with a motor imagery task which involved imagery of moving both hands and an instruction to hold both hands firm. We extracted a set of 20 features from the electroencephalogram and used linear discriminant analysis, k-nearest neighbor classification, and support vector machines (SVM) as classification methods. In healthy participants, the best classification accuracies were seen with coherences (mean = .79; range = .53-.94) and power spectra (mean = .69; range = .40-.85). The coherence patterns in healthy participants did not match the expectation of central modulated [Formula: see text]-rhythm. Instead, coherence involved mainly frontal regions. In healthy participants, the best classification tool was SVM. Five patients had at least one feature-classifier outcome with p[Formula: see text]0.05 (none of which were coherence or power spectra), though none remained significant after false-discovery rate correction for multiple comparisons. The present work suggests the use of coherences in patients with disorders of consciousness because they show high reliability among healthy subjects and patient groups. However, feature extraction and classification is a challenging task in unresponsive patients because there is no ground truth to validate the results.

EEG-response consistency across subjects in an active oddball task.

The active oddball paradigm is a candidate task for voluntary brain activation. Previous research has focused on group effects, and has largely overlooked the potential problem of interindividual differences. Interindividual variance causes problems with the interpretation of group-level results. In this study we want to demonstrate the degree of consistency in the active oddball task across subjects, in order to answer the question of whether this task is able to reliably detect conscious target processing in unresponsive patients. We asked 18 subjects to count rare targets and to ignore frequent standards and rare distractors in an auditory active oddball task. Event-related-potentials (ERPs) and time-frequency data were analyzed with permutation-t-tests on a single subject level. We plotted the group-average ERPs and time-frequency data, and evaluated the numbers of subjects showing significant differences between targets and distractors in certain time-ranges. The distinction between targets/distractors and standards was found to be significant in the time-range of the P300 in all participants. In contrast, significant differences between targets and distractors in the time-range of the P3a/b were found in 8 subjects, only. By including effects in the N1 and in a late negative component there remained 2 subjects who did not show a distinction between targets and distractors in the ERP. While time-frequency data showed prominent effects for target/distractor vs. standard, significant differences between targets and distractors were found in 2 subjects, only. The results suggest that time-frequency- and ERP-analysis of the active oddball task may not be sensitive enough to detect voluntary brain activation in unresponsive patients. In addition, we found that time-frequency analysis was even less informative than ERPs about the subject's task performance. Despite suggesting the use of more sensitive paradigms and/or analysis techniques, the present results give further evidence that electroencephalographic research should rely more strongly on single-subject analysis because interpretations of group-effects may be misleading.

Self-related processing and deactivation of cortical midline regions in disorders of consciousness.

Self-related stimuli activate anterior parts of cortical midline regions, which normally show task-induced deactivation. Deactivation in medial posterior and frontal regions is associated with the ability to focus attention on the demands of the task, and therefore, with consciousness. Studies investigating patients with impaired consciousness, that is, patients in minimally conscious state and patients with unresponsive wakefulness syndrome (formerly vegetative state), demonstrate that these patients show responses to self-related content in the anterior cingulate cortex. However, it remains unclear if these responses are an indication for conscious processing of stimuli or are due to automatic processing. To shed further light on this issue, we investigated responses of cortical midline regions to the own and another name in 27 patients with a disorder of consciousness and compared them to task-induced deactivation. While almost all of the control subjects responding to the own name demonstrated higher activation due to the self-related content in anterior midline regions and additional deactivation, none of the responding patients did so. Differences between groups showed a similar pattern of findings. Despite the relation between behavioral responsiveness in patients and activation in response to the own name, the findings of this study do not provide evidence for a direct association of activation in anterior midline regions and conscious processing. The deficits in processing of self-referential content in anterior midline regions may rather be due to general impairments in cognitive processing and not particularly linked to impaired consciousness.

Functional brain reorganization after spinal cord injury: systematic review of animal and human studies.

Plastic changes of neural circuits occur after spinal cord injury (SCI) at various level of the central nervous system. In this review we will focus on delineating the pathophysiological mechanisms of the brain plasticity changes following SCI, based on the existing neuroimaging and neurophysiological evidence in experimental models and humans. In animal experiments, reorganization of the sensory topography as well as of the topographical map of primary motor and premotor cortices have been reported in several studies. Brain imaging revealed that cortical representation in response to spared forelimb stimulation early enlarges and invades adjacent sensory-deprived hind limb territory. Electrophysiological studies demonstrated that the deafferentation due to SCI can immediately change the state of large cortical networks within 1h, and that these changes play a critical role in the functional reorganization after SCI. In humans neuroimaging also showed shifts of functional motor and sensory cortical representations that relate to the severity of SCI. In patients with cervical SCI, cortical forearm motor representations, as assessed by means of transcranial magnetic stimulation, may reorganize towards the intrinsic hand motor representation to maximize output to muscles of the impaired forearm. Excessive or aberrant reorganisation of cerebral cortex may also have pathological consequences, such as phantom sensations or neuropathic pain. Integrated neuroimaging and neurophysiological approaches may also lead to the development of new therapeutic strategies, which have the potential of enhancing sensorimotor recovery in patients with SCI.

Functional evaluation of central cholinergic circuits in patients with Parkinson's disease and REM sleep behavior disorder: a TMS study.

Central cholinergic dysfunction has been reported in patients with Parkinson's disease (PD) and hallucinations by evaluating short latency afferent inhibition (SAI), a transcranial magnetic stimulation protocol which gives the possibility to test an inhibitory cholinergic circuit in the human brain. REM sleep behavior disorder (RBD) was also found to be associated with cognitive impairment in PD patients. The objective of the study was to assess the cholinergic function, as measured by SAI, in PD patients with RBD (PD-RBD) and PD patients without RBD (PD-nRBD). We applied the SAI technique in 10 PD-RBD patients, in 13 PD-nRBD patients and in 15 age-matched normal controls. All PD patients and control subjects also underwent a comprehensive battery of neuropsychological tests. Mean SAI was significantly reduced in PD-RBD patients when compared with PD-nRBD patients and controls. Neuropsychological examination showed mild cognitive impairment in 9 out of the 10 PD-RBD patients, and in 5 out of the 13 PD-nRBD. SAI values correlated positively with neuropsychological tests measuring episodic verbal memory, executive functions, visuoconstructional and visuoperceptual abilities. Similar to that previously reported in the idiopathic form of RBD, SAI abnormalities suggest a cholinergic dysfunction in PD patients who develop cognitive impairment, and present findings indicate that RBD is an important determinant of MCI in PD.

Real movement vs. motor imagery in healthy subjects.

Motor imagery tasks are well established procedures in brain computer interfaces, but are also used in the assessment of patients with disorders of consciousness. For testing awareness in unresponsive patients it is necessary to know the natural variance of brain responses to motor imagery in healthy subjects. We examined 22 healthy subjects using EEG in three conditions: movement of both hands, imagery of the same movement, and an instruction to hold both hands still. Single-subject non-parametric statistics were applied to the fast-Fourier transformed data. Most effects were found in the α- and ß-frequency ranges over central electrodes, that is, in the µ-rhythm. We found significant power changes in 18 subjects during movement and in 11 subjects during motor imagery. In 8 subjects these changes were consistent over both conditions. The significant power changes during movement were a decrease of µ-rhythm. There were 2 subjects with an increase and 9 subjects with a decrease of µ-rhythm during imagery. α and ß are the most responsive frequency ranges, but there is a minor number of subjects who show a synchronization instead of the more common desynchronization during motor imagery. A (de)synchronization of µ-rhythm can be considered to be a normal response.

Non-invasive brain stimulation in the functional evaluation of alcohol effects and in the treatment of alcohol craving: a review.

Acute and chronic consumption of alcohol have direct effects on central nervous system by altering predominantly gamma-aminobutyric acidergic and glutamatergic neurotransmission. Abnormalities in these neurotransmitter systems can be demonstrated by changes in cortical excitability parameters assessed with transcranial magnetic stimulation (TMS). Furthermore, integrated approaches utilizing TMS combined with electroencephalography (EEG) enable the evaluation of the focal effects of alcohol on the human cortex, providing useful information, different from that obtained using other functional brain imaging modalities. Alcohol was found to modulate EEG responses evoked by motor-cortex TMS, predominantly at the right prefrontal cortex, indicating that ethanol alters the functional connectivity between motor and prefrontal areas. Alcohol decreases amplitudes of EEG responses of anterior parts of the cortex after left prefrontal TMS, suggesting a decrease of prefrontal cortical excitability. High-frequency repetitive TMS (rTMS) revealed significant changes in short-term plasticity of the primary motor cortex after acute ethanol intake and in patients with chronic alcohol abuse. TMS findings also support the recently emerged theory that abnormal function of glutamate receptors plays a relevant role in the development of alcohol dependence and manifestation of the alcohol withdrawal syndrome. Finally, initial studies provide evidence that non-invasive brain stimulation techniques (rTMS and transcranial direct current stimulation) might represent a potential therapeutic tool to reduce alcohol craving. Future studies with larger sample size evaluating the clinical effects of these neuromodulatory approaches are required to confirm and extend the preliminary findings.

Cortical afferent inhibition is reduced in patients with idiopathic REM sleep behavior disorder and cognitive impairment: a TMS study.

OBJECTIVES: Impaired cognitive profile and electroencephalography (EEG) slowing have been reported in patients with REM sleep behavior disorder (RBD), but the neurobiological significance of these findings remains unknown. The cholinergic system is known to play a key role in all attentional processes and cognitive functions. A transcranial magnetic stimulation (TMS) protocol may give direct information about the function of some cholinergic circuits in the human brain; this technique relies on short latency afferent inhibition (SAI) of the motor cortex. The objective of this study was to test the hypothesis that cognitive performance and cortical activation in RBD patients are associated with a dysfunction of the cholinergic system. METHODS: We applied the SAI technique in a group of 10 patients with idiopathic RBD (iRBD) and compared the data with those from a group of 15 age-matched healthy subjects. All the iRBD patients and the control subjects also underwent an extensive neuropsychological evaluation. RESULTS: Mean SAI was significantly reduced in patients with iRBD when compared with controls. Neuropsychological examination showed mild cognitive impairment in six out of the 10 iRBD patients. SAI values correlated strongly with tests measuring episodic verbal memory and executive functions. CONCLUSIONS: These results support the hypothesis of cholinergic dysfunction in some patients with iRBD who develop cognitive impairment. Our findings raise the possibility that the presence of SAI abnormalities may indicate increased risk of cognitive impairment in patients diagnosed with iRBD.

Modulation of motor cortex excitability by different levels of whole-hand afferent electrical stimulation.

OBJECTIVE: In a previous transcranial magnetic stimulation (TMS) study we demonstrated that suprathreshold mesh-glove (MG) whole-hand stimulation elicits lasting changes in motor cortical excitability. Currently, there is no consensus with regard to the optimal parameters for the induction of sensorimotor cortical plasticity using peripheral electrical stimulation. Thus, in the present study we explore the modulatory effects of MG stimulation at different stimulus intensities and different frequencies in order to identify an optimal stimulation protocol. METHODS: MG stimulation was performed on 12 healthy subjects in separate sessions at different stimulation levels: sub-sensory at 50 Hz, sensory at 50 Hz and motor at 2 Hz. To verify if stimulation at lower frequencies is less effective, an additional experiment at sensory level with 2 Hz was performed. TMS was used to assess motor threshold (MT), motor evoked potentials (MEPs) recruitment curve (RC), short latency intracortical inhibition (SICI) and intracortical facilitation (ICF) to paired-pulse TMS at baseline (T0), immediately after (T1) and 1h (T2) after 30 min of MG stimulation. F-wave studies were performed to assess spinal motoneuron excitability. RESULTS: MG stimulation at sub-sensory/50 Hz and sensory/2 Hz level determines no significant cortical excitability changes; at sensory/50 Hz level and at motor/2 Hz level we found decreased MT, increased MEP RC as well as reduced SICI and increased ICF at T1 and T2. CONCLUSIONS: MG stimulation at sensory/50 Hz and motor/2 Hz level induces similar long-lasting modulatory effects on motor cortical excitability. Both the strength of the corticospinal projections and the intracortical networks are influenced to the same extend. SIGNIFICANCE: The study provides further evidence that stimulation intensity and frequency can independently modulate motor cortical plasticity. The selection of optimal stimulation parameters has potentially important implications for the neurorehabilitation of patients after brain damage (e.g. stroke, traumatic brain injury) with hand motor deficits.