EEG Changes in Migraine-Can EEG Help to Monitor Attack Susceptibility?

Migraine is a highly prevalent brain condition with paroxysmal changes in brain excitability believed to contribute to the initiation of an attack. The attacks and their unpredictability have a major impact on the lives of patients. Clinical management is hampered by a lack of reliable predictors for upcoming attacks, which may help in understanding pathophysiological mechanisms to identify new treatment targets that may be positioned between the acute and preventive possibilities that are currently available. So far, a large range of studies using conventional hospital-based EEG recordings have provided contradictory results, with indications of both cortical hyper- as well as hypo-excitability. These heterogeneous findings may largely be because most studies were cross-sectional in design, providing only a snapshot in time of a patient's brain state without capturing day-to-day fluctuations. The scope of this narrative review is to (i) reflect on current knowledge on EEG changes in the context of migraine, the attack cycle, and underlying pathophysiology; (ii) consider the effects of migraine treatment on EEG features; (iii) outline challenges and opportunities in using EEG for monitoring attack susceptibility; and (iv) discuss future applications of EEG in home-based settings.

System identification: a feasible, reliable and valid way to quantify upper limb motor impairments.

BACKGROUND: Upper limb impairments in a hemiparetic arm are clinically quantified by well-established clinical scales, known to suffer poor validity, reliability, and sensitivity. Alternatively, robotics can assess motor impairments by characterizing joint dynamics through system identification. In this study, we establish the merits of quantifying abnormal synergy, spasticity, and changes in joint viscoelasticity using system identification, evaluating (1) feasibility and quality of parametric estimates, (2) test-retest reliability, (3) differences between healthy controls and patients with upper limb impairments, and (4) construct validity. METHODS: Forty-five healthy controls, twenty-nine stroke patients, and twenty cerebral palsy patients participated. Participants were seated with the affected arm immobilized in the Shoulder-Elbow-Perturbator (SEP). The SEP is a one-degree-of-freedom perturbator that enables applying torque perturbations to the elbow while providing varying amounts of weight support to the human arm. Participants performed either a 'do not intervene' or a resist task. Elbow joint admittance was quantified and used to extract elbow viscosity and stiffness. Fifty-four of the participants performed two sessions to establish the test-retest reliability of the parameters. Construct validity was assessed by correlating system identification parameters to parameters extracted using a SEP protocol that objectifies current clinical scales (Re-Arm protocol). RESULTS: Feasibility was confirmed by all participants successfully completing the study protocol within ~ 25 min without reporting pain or burden. The parametric estimates were good with a variance-accounted-for of ~ 80%. A fair to excellent test-retest reliability was found ([Formula: see text]) for patients, except for elbow stiffness with full weight support ([Formula: see text]). Compared to healthy controls, patients had a higher elbow viscosity and stiffness during the 'do not intervene' task and lower viscosity and stiffness during the resist task. Construct validity was confirmed by a significant (all [Formula: see text]) but weak to moderate ([Formula: see text]) correlation with parameters from the Re-Arm protocol. CONCLUSIONS: This work demonstrates that system identification is feasible and reliable for quantifying upper limb motor impairments. Validity was confirmed by differences between patients and controls and correlations with other measurements, but further work is required to optimize the experimental protocol and establish clinical value.

Bi-sinusoidal light stimulation reveals an enhanced response power and reduced phase coherence at the visual cortex in migraine.

Introduction: Migraine is associated with enhanced visual sensitivity during and outside attacks. Processing of visual information is a highly non-linear process involving complex interactions across (sub)cortical networks. In this exploratory study, we combined electroencephalography with bi-sinusoidal light stimulation to assess non-linear features of visual processing in participants with migraine. Methods: Twenty participants with migraine (10 with aura, 10 without aura) and ten non-headache controls were measured (outside attacks). Participants received bi-sinusoidal 13 + 23 Hz red light visual stimulation. Electroencephalography spectral power and multi-spectral phase coherence were compared between groups at the driving stimulation frequencies together with multiples and combinations of these frequencies (harmonic and intermodulation frequencies) caused by non-linearities. Results: Only at the driving frequency of 13 Hz higher spectral power was found in migraine with aura participants compared with those with migraine without aura and controls. Differences in phase coherence were present for 2nd, 4th, and 5th-order non-linearities in those with migraine (migraine with and without aura) compared with controls. Bi-sinusoidal light stimulation revealed evident non-linearities in the brain's electroencephalography response up to the 5th order with reduced phase coherence for higher order interactions in interictal participants with migraine. Discussion: Insight into interictal non-linear visual processing may help understand brain dynamics underlying migraine attack susceptibility. Future research is needed to determine the clinical value of the results.

An Efficient Dual-Hierarchy t-SNE Minimization.

t-distributed Stochastic Neighbour Embedding (t-SNE) has become a standard for exploratory data analysis, as it is capable of revealing clusters even in complex data while requiring minimal user input. While its run-time complexity limited it to small datasets in the past, recent efforts improved upon the expensive similarity computations and the previously quadratic minimization. Nevertheless, t-SNE still has high runtime and memory costs when operating on millions of points. We present a novel method for executing the t-SNE minimization. While our method overall retains a linear runtime complexity, we obtain a significant performance increase in the most expensive part of the minimization. We achieve a significant improvement without a noticeable decrease in accuracy even when targeting a 3D embedding. Our method constructs a pair of spatial hierarchies over the embedding, which are simultaneously traversed to approximate many N-body interactions at once. We demonstrate an efficient GPGPU implementation and evaluate its performance against state-of-the-art methods on a variety of datasets.

The Cortical Response Evoked by Robotic Wrist Perturbations Reflects Level of Proprioceptive Impairment After Stroke.

Background: Proprioception is important for regaining motor function in the paretic upper extremity after stroke. However, clinical assessments of proprioception are subjective and require verbal responses from the patient to applied proprioceptive stimuli. Cortical responses evoked by robotic wrist perturbations and measured by electroencephalography (EEG) may be an objective method to support current clinical assessments of proprioception. Objective: To establish whether evoked cortical responses reflect proprioceptive deficits as assessed by clinical scales and whether they predict upper extremity motor function at 26 weeks after stroke. Methods: Thirty-one patients with stroke were included. In week 1, 3, 5, 12, and 26 after stroke, the upper extremity sections of the Erasmus modified Nottingham Sensory Assessment (EmNSA-UE) and the Fugl-Meyer Motor Assessment (FM-UE) and the EEG responses (64 channels) to robotic wrist perturbations were measured. The extent to which proprioceptive input was conveyed to the affected hemisphere was estimated by the signal-to-noise ratio (SNR) of the evoked response. The relationships between SNR and EmNSA-UE as well as SNR and time after stroke were investigated using linear regression. Receiver-operating-characteristic curves were used to compare the predictive values of SNR and EmNSA-UE for predicting whether patients regained some selective motor control (FM-UE > 22) or whether they could only move their paretic upper extremity within basic limb synergies (FM-UE ≤ 22) at 26 weeks after stroke. Results: Patients (N = 7) with impaired proprioception (EmNSA-UE proprioception score < 8) had significantly smaller SNR than patients with unimpaired proprioception (N = 24) [EmNSA-UE proprioception score = 8, t(29) = 2.36, p = 0.03]. No significant effect of time after stroke on SNR was observed. Furthermore, there was no significant difference in the predictive value between EmNSA-UE and SNR for predicting motor function at 26 weeks after stroke. Conclusion: The SNR of the evoked cortical response does not significantly change as a function of time after stroke and differs between patients with clinically assessed impaired and unimpaired proprioception, suggesting that SNR reflects persistent damage to proprioceptive pathways. A similar predictive value with respect to EmNSA-UE suggests that SNR may be used as an objective predictor next to clinical sensory assessments for predicting motor function at 26 weeks after stroke.

Enhanced pre-ictal cortical responsivity in migraine patients assessed by visual chirp stimulation.

BACKGROUND: Migraine is associated with altered sensory processing and cortical responsivity that may contribute to susceptibility to attacks by changing brain network excitability dynamics. To gain better insight into cortical responsivity changes in migraine we subjected patients to a short series of light inputs over a broad frequency range ("chirp" stimulation), designed to uncover dynamic features of visual cortex responsivity. METHODS: EEG responses to visual chirp stimulation (10-40 Hz) were measured in controls (n = 24) and patients with migraine with aura (n = 19) or migraine without aura (n = 20). Average EEG responses were assessed at (i) all EEG frequencies between 5 and 125 Hz, (ii) stimulation frequencies, and (iii) harmonic frequencies. We compared average responses in a low (10-18 Hz), medium (19-26 Hz) and high (27-40 Hz) frequency band. RESULTS: Responses to chirp stimulation were similar in controls and migraine subtypes. Eight measurements (n = 3 migraine with aura; n = 5 without aura) were assigned as "pre-ictal", based on reported headache within 48 hours after investigation. Pre-ictally, an increased harmonic response to 22-32 Hz stimulation (beta band) was observed (p = 0.001), compared to interictal state measurements. CONCLUSIONS: We found chirp responses to be enhanced in the 48 hours prior to migraine headache onset. Visual chirp stimulation proved a simple and reliable technique with potential to detect changes in cortical responsivity associated with the onset of migraine attacks.

Interindividual Variability in Use-Dependent Plasticity Following Visuomotor Learning: The Effect of Handedness and Muscle Trained.

Motor learning has been linked with increases in corticospinal excitability (CSE). However, the robustness of this link is unclear. In this study, changes in CSE associated with learning a visuomotor tracking task were mapped using transcranial magnetic stimulation (TMS). TMS maps were obtained before and after training with the first dorsal interosseous (FDI) of the dominant and nondominant hand, and for a distal (FDI) and proximal (biceps brachii) muscle. Tracking performance improved following 20 min of visuomotor training, while map area was unaffected. Large individual differences were observed with 18%-36% of the participants revealing an increase in TMS map area. This result highlights the complex relationship between motor learning and use-dependent plasticity of the motor cortex.

False positives associated with responder/non-responder analyses based on motor evoked potentials.

BACKGROUND: A trend in the non-invasive brain stimulation literature is to assess the outcome of an intervention using a responder analysis whereby participants are di- or trichotomised in order that they may be classified as either responders or non-responders. OBJECTIVE: Examine the extent of the Type I error in motor evoked potential (MEP) data subjected to responder analyses. METHODS: Seven sets of 30 MEPs were recorded from the first dorsal interosseous muscle in 52 healthy volunteers. Four classification techniques were used to classify the participants as responders or non-responders: (1) the two-step cluster analysis, (2) dichotomised thresholding, (3) relative method and (4) baseline variance method. RESULTS: Despite the lack of any intervention, a significant number of participants were classified as responders (21-71%). CONCLUSION: This study highlights the very large Type I error associated with dichotomising continuous variables such as the TMS MEP.

StimTrack: An open-source software for manual transcranial magnetic stimulation coil positioning.

BACKGROUND: During Transcranial Magnetic Stimulation (TMS) experiments researchers often use a neuronavigation system to precisely and accurately maintain coil position and orientation. NEW METHOD: This study aimed to develop and validate an open-source software for TMS coil navigation. StimTrack uses an optical tracker and an intuitive user interface to facilitate the maintenance of position and orientation of any type of coil within and between sessions. Additionally, online access to navigation data is provided, hereby adding e.g. the ability to start or stop the magnetic stimulator depending on the distance to target or the variation of the orientation angles. RESULTS: StimTrack allows repeatable repositioning of the coil within 0.7mm for translation and <1° for rotation. Stimulus-response (SR) curves obtained from 19 healthy volunteers were used to demonstrate that StimTrack can be effectively used in a typical experiment. An excellent intra and inter-session reliability (ICC >0.9) was obtained on all parameters computed on SR curves acquired using StimTrack. COMPARISON WITH EXISTING METHOD: StimTrack showed a target accuracy similar to that of a commercial neuronavigation system (BrainSight, Rogue Research Inc.). Indeed, small differences both in position (∼0.2mm) and orientation (<1°) were found between the systems. These differences are negligible given the human error involved in landmarks registration. CONCLUSIONS: StimTrack, available as supplementary material, is found to be a good alternative for commercial neuronavigation systems facilitating assessment changes in corticospinal excitability using TMS. StimTrack allows researchers to tailor its functionality to their specific needs, providing added value that benefits experimental procedures and improves data quality.

Intra and inter-session reliability of rapid Transcranial Magnetic Stimulation stimulus-response curves of tibialis anterior muscle in healthy older adults.

OBJECTIVE: The clinical use of Transcranial Magnetic Stimulation (TMS) as a technique to assess corticospinal excitability is limited by the time for data acquisition and the measurement variability. This study aimed at evaluating the reliability of Stimulus-Response (SR) curves acquired with a recently proposed rapid protocol on tibialis anterior muscle of healthy older adults. METHODS: Twenty-four neurologically-intact adults (age:55-75 years) were recruited for this test-retest study. During each session, six SR curves, 3 at rest and 3 during isometric muscle contractions at 5% of maximum voluntary contraction (MVC), were acquired. Motor Evoked Potentials (MEPs) were normalized to the maximum peripherally evoked response; the coil position and orientation were monitored with an optical tracking system. Intra- and inter-session reliability of motor threshold (MT), area under the curve (AURC), MEPmax, stimulation intensity at which the MEP is mid-way between MEPmax and MEPmin (I50), slope in I50, MEP latency, and silent period (SP) were assessed in terms of Standard Error of Measurement (SEM), relative SEM, Minimum Detectable Change (MDC), and Intraclass Correlation Coefficient (ICC). RESULTS: The relative SEM was ≤10% for MT, I50, latency and SP both at rest and 5%MVC, while it ranged between 11% and 37% for AURC, MEPmax, and slope. MDC values were overall quite large; e.g., MT required a change of 12%MSO at rest and 10%MSO at 5%MVC to be considered a real change. Inter-sessions ICC were >0.6 for all measures but slope at rest and MEPmax and latency at 5%MVC. CONCLUSIONS: Measures derived from SR curves acquired in <4 minutes are affected by similar measurement errors to those found with long-lasting protocols, suggesting that the rapid method is at least as reliable as the traditional methods. As specifically designed to include older adults, this study provides normative data for future studies involving older neurological patients (e.g. stroke survivors).

The TMS Motor Map Does Not Change Following a Single Session of Mirror Training Either with Or without Motor Imagery.

Both motor imagery and mirror training have been used in motor rehabilitation settings to promote skill learning and plasticity. As motor imagery and mirror training are suggested to be closely linked, it was hypothesized that mirror training augmented by motor imagery would increase corticospinal excitability (CSE) significantly compared to mirror training alone. Forty-four participants were split over two experimental groups. Each participant visited the laboratory once to receive either mirror training alone or mirror training augmented with layered stimulus response training (LSRT), a type of motor imagery training. Participants performed 16 min of mirror training, making repetitive grasping movements paced by a metronome. Transcranial magnetic stimulation (TMS) mapping was performed before and after the mirror training to test for changes in CSE of the untrained hand. Self-reports suggested that the imagery training was effective in helping the participant to perform the mirror training task as instructed. Nonetheless, neither training type resulted in a significant change of TMS map area, nor was there an interaction between the groups. The results from the study revealed no effect of a single session of 16 min of either mirror training or mirror training enhanced by imagery on TMS map area. Despite the negative result of the present experiment, this does not suggest that either motor imagery or mirror training might be ineffective as a rehabilitation therapy. Further study is required to allow disentangling the role of imagery and action observation in mirror training so that mirror training can be further tailored to the individual according to their abilities.

Nonlinear Coupling between Cortical Oscillations and Muscle Activity during Isotonic Wrist Flexion.

Coupling between cortical oscillations and muscle activity facilitates neuronal communication during motor control. The linear part of this coupling, known as corticomuscular coherence, has received substantial attention, even though neuronal communication underlying motor control has been demonstrated to be highly nonlinear. A full assessment of corticomuscular coupling, including the nonlinear part, is essential to understand the neuronal communication within the sensorimotor system. In this study, we applied the recently developed n:m coherence method to assess nonlinear corticomuscular coupling during isotonic wrist flexion. The n:m coherence is a generalized metric for quantifying nonlinear cross-frequency coupling as well as linear iso-frequency coupling. By using independent component analysis (ICA) and equivalent current dipole source localization, we identify four sensorimotor related brain areas based on the locations of the dipoles, i.e., the contralateral primary sensorimotor areas, supplementary motor area (SMA), prefrontal area (PFA) and posterior parietal cortex (PPC). For all these areas, linear coupling between electroencephalogram (EEG) and electromyogram (EMG) is present with peaks in the beta band (15-35 Hz), while nonlinear coupling is detected with both integer (1:2, 1:3, 1:4) and non-integer (2:3) harmonics. Significant differences between brain areas is shown in linear coupling with stronger coherence for the primary sensorimotor areas and motor association cortices (SMA, PFA) compared to the sensory association area (PPC); but not for the nonlinear coupling. Moreover, the detected nonlinear coupling is similar to previously reported nonlinear coupling of cortical activity to somatosensory stimuli. We suggest that the descending motor pathways mainly contribute to linear corticomuscular coupling, while nonlinear coupling likely originates from sensory feedback.

The TMS Map Scales with Increased Stimulation Intensity and Muscle Activation.

One way to study cortical organisation, or its reorganisation, is to use transcranial magnetic stimulation (TMS) to construct a map of corticospinal excitability. TMS maps are reported to be acquired with a wide variety of stimulation intensities and levels of muscle activation. Whilst MEPs are known to increase both with stimulation intensity and muscle activation, it remains to be established what the effect of these factors is on the map's centre of gravity (COG), area, volume and shape. Therefore, the objective of this study was to systematically examine the effect of stimulation intensity and muscle activation on these four key map outcome measures. In a first experiment, maps were acquired with a stimulation intensity of 110, 120 and 130% of resting threshold. In a second experiment, maps were acquired at rest and at 5, 10, 20 and 40% of maximum voluntary contraction. Map area and map volume increased with both stimulation intensity (P < 0.01) and muscle activation (P < 0.01). Neither the COG nor the map shape changed with either stimulation intensity or muscle activation (P > 0.09 in all cases). This result indicates the map simply scales with stimulation intensity and muscle activation.

TMS brain mapping in less than two minutes.

BACKGROUND: Transcranial magnetic stimulation (TMS) corticospinal excitability maps are a valuable tool to study plasticity in the corticospinal tract. Traditionally, data acquisition for a single map is time consuming, limiting the method's applicability when excitability changes quickly, such as during motor learning, and in clinical investigations where assessment time is a limiting factor. OBJECTIVE: To reduce the time needed to create a reliable map by 1) investigating the minimum interstimulus interval (ISI) at which stimuli may be delivered, and 2) investigating the minimum number of stimuli required to create a map. METHOD: Frameless stereotaxy was used to monitor coil position as the coil was moved pseudorandomly within a 6 × 6 cm square. Maps were acquired using 1-4 s ISIs in 12 participants. The minimum number of stimuli was determined by randomly extracting data and comparing the resulting map to the original data set. To confirm validity, the pseudorandom walk method was compared against a traditional mapping method. RESULTS: Reliable maps could be created with 63 stimuli recorded with a 1 s ISI. Maps created acquiring data using the pseudorandom walk method were not significantly different from maps acquired following the traditional method. CONCLUSIONS: To account for inter-participant variability, outliers, coil positioning errors and, most importantly, participant comfort during data acquisition, we recommend creating a map with 80 stimuli and a 1.5 s ISI. This makes it possible to acquire TMS maps in 2 min, making mapping a more feasible tool to study short- and long-term changes in cortical organization.

Rapid acquisition of the transcranial magnetic stimulation stimulus response curve.

BACKGROUND: Transcranial magnetic stimulation is frequently used to construct stimulus response (SR) curves in studies of motor learning and rehabilitation. A drawback of the established method is the time required for data acquisition, which is frequently greater than a participant's ability to maintain attention. The technique is therefore difficult to use in the clinical setting. OBJECTIVE: To reduce the time of curve acquisition by determining the minimum acquisition time and number of stimuli required to acquire an SR curve. METHODS: SR curves were acquired from first dorsal interosseous (FDI) and abductor digiti minimi (ADM) at 6 interstimulus intervals (ISI) between 1.4 and 4 s in 12 participants. To determine if low-frequency rTMS might affect the SR curve, MEP amplitudes were monitored before and after 3 min of 1 Hz rTMS delivered at 120% of resting motor threshold in 12 participants. Finally, SR curves were acquired from FDI, ADM and Biceps Brachii (BB) in 12 participants, and the minimum number of stimuli was calculated using a sequential MEP elimination process. RESULTS: There were no significant differences between curves acquired with 1.4 s ISI and any other ISI. Low frequency rTMS did not significantly depress MEP amplitude (P = 0.87). On average, 61 ± 18 (FDI), 60 ± 16 (ADM) and 59 ± 16 (BB) MEPs were needed to construct a representative SR curve. CONCLUSIONS: This study demonstrates that reliable SR curves may be acquired in less than 2 min. At this rate, SR curves become a clinically feasible method for assessing corticospinal excitability in research and rehabilitation settings.

Spinal inhibition of descending command to soleus motoneurons is removed prior to dorsiflexion.

It has recently been demonstrated that soleus motor-evoked potentials (MEPs) are facilitated prior to the onset of dorsiflexion. The purpose of this study was to examine if this could be explained by removal of spinal inhibition of the descending command to soleus motoneurons. To test this, we investigated how afferent inputs from the tibialis anterior muscle modulate the corticospinal activation of soleus spinal motoneurons at rest, during static contraction and prior to movement. MEPs activated by transcranial magnetic stimulation (TMS) and Hoffmann reflexes (H-reflexes), activated by electrical stimulation of the posterior tibial nerve (PTN), were conditioned by prior stimulation of the common peroneal nerve (CPN) at a variety of conditioning-test (CT) intervals. MEPs in the precontracted soleus muscle were inhibited when the TMS pulse was preceded by CPN stimulation with a CT interval of 35 ms, and they were facilitated for CT intervals of 50-55 ms. A similar inhibition of the soleus H-reflex was not observed. To investigate which descending pathways might be responsible for the afferent-evoked inhibition and facilitation, we examined the effect of CPN stimulation on short-latency facilitation (SLF) and long-latency facilitation (LLF) of the soleus H-reflex induced by a subthreshold TMS pulse at different CT intervals. SLF is known to reflect the excitability of the fastest conducting, corticomotoneuronal cells whereas LLF is believed to be caused by more indirect descending pathways. At CT intervals of 40-45 ms, the LLF was significantly more inhibited compared to the SLF when taking the effect on the H-reflex into account. Finally, we investigated how the CPN-induced inhibition and facilitation of the soleus MEP were modulated prior to dorsiflexion. Whereas the late facilitation (CT interval: 55 ms) was similar prior to dorsiflexion and at rest, no inhibition could be evoked at the earlier latency (CT interval: 35 ms) prior to onset of dorsiflexion. The observation that the CPN-induced inhibition of soleus MEPs disappears prior to onset of dorsiflexion may explain why soleus MEPs are facilitated prior to onset of dorsiflexion contraction. A possible mechanism involves the removal of inhibition of the descending command to the motoneurons at a spinal interneuronal level because the inhibition was seen in LLF and not in SLF, and the MEP inhibition was not observed in the H-reflex. The data illustrate that spinal interneuronal pathways modify descending commands to human spinal motoneurons and influence the size of MEPs elicited by TMS.