Human cortical excitability increases with time awake.

Prolonged wakefulness is associated not only with obvious changes in the way we feel and perform but also with well-known clinical effects, such as increased susceptibility to seizures, to hallucinations, and relief of depressive symptoms. These clinical effects suggest that prolonged wakefulness may be associated with significant changes in the state of cortical circuits. While recent animal experiments have reported a progressive increase of cortical excitability with time awake, no conclusive evidence could be gathered in humans. In this study, we combine transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to monitor cortical excitability in healthy individuals as a function of time awake. We observed that the excitability of the human frontal cortex, measured as the immediate (0-20 ms) EEG reaction to TMS, progressively increases with time awake, from morning to evening and after one night of total sleep deprivation, and that it decreases after recovery sleep. By continuously monitoring vigilance, we also found that this modulation in cortical responsiveness is tonic and not attributable to transient fluctuations of the level of arousal. The present results provide noninvasive electrophysiological evidence that wakefulness is associated with a steady increase in the excitability of human cortical circuits that is rebalanced during sleep.

Projecting out muscle artifacts from TMS-evoked EEG.

Transcranial magnetic stimulation combined with electroencephalography is a powerful tool for probing cortical excitability and connectivity; we can perturb one brain area and study the reactions at the stimulated and interconnected sites. When stimulating areas near cranial muscles, their activation produces a large artifact in the electroencephalographic signal, lasting tens of milliseconds and masking the early brain signals. We present an artifact removal method based on projecting out the topographic patterns of the muscle activity. Although the brain and muscle components overlap both temporally and spectrally, the fact that muscle activity is present also at frequencies higher than 100 Hz, while brain signal is mostly restricted to frequencies lower than that, allows us to study the high-frequency muscle activity without brain contribution. We determined the muscle activity topographies from data highpass-filtered at a 100-Hz cutoff frequency using principal component analysis. Projecting out the topographies of the principal components which explain most of the variance of the high-frequency data reduces not only the high-frequency activity but also the low-frequency muscle contribution, because the topography produced by a muscle source can be expected to be the same regardless of the frequency. The method greatly reduced the muscle artifact evoked by stimulation of Broca's area, while a significant brain signal contribution remained. Improvement in the signal-to-artifact ratio, defined as the relative amplitudes of brain signals peaking after 50 ms and the first artifact deflection, was of the order of 10-100 depending on the number of projections. The presented artifact removal method enables one to study the cortical state when stimulating areas near the cranial muscles.

Some considerations about the biological appearance of pacing stimuli in visuomotor finger-tapping tasks.

Sensorimotor synchronization is a crucial function for human daily activities, which relies on the ability of predicting external events. Synchronization performance, as assessed in finger-tapping (FT) tasks, is characterized by an anticipation tendency, as the tap generally precedes the pacing event. This synchronization error (SE) depends on many factors, in particular on the features of the pacing stimulus. Interest is growing in the facilitation effect that action observation has on motor execution. So far, neuroimaging and neurophysiology studies of motor priming via action observation have mainly employed tasks requiring single action instances. The impact of action observation on motor synchronization to periodic stimuli has not yet been tested; to this aim, a synchronization FT task may be an eligible probing task. The purpose of this study was to characterize a biological pacer at the behavioral level and provide information for those interested in studying the brain processes of continuous observation/execution coupling in timed actions using FT tasks. We evaluated the influence of the biological appearance of a pacer (a tapping finger) on SE, when compared to an abstract, kinematically equivalent pacer (a tilting hinged bar) and a more standard stimulus (a pulsating dot). We showed that the continuous visual display of a biological pacer yields comparable results to the abstract pacer, and a more robust performance and larger anticipations than a traditional pulsating stimulus.

Correlation between the Cogstate computerized measure and WAIS-IV among birth cohort mothers.

OBJECTIVE: Large studies, with limited resources call for cost-effective cognitive assessment methods. Computerized tests offer viable alternatives but more data are needed on their functioning. Our aim was to evaluate the overlap between a computerized neuropsychological test battery and a traditional test of general intelligence (IQ). METHOD: Cognitive functioning was assessed in birth cohort mothers (n = 80) with two widely used methods: Cogstate, computerized test battery, and WAIS-IV, a traditional IQ test. Correlational analyses were conducted. RESULTS: We found weak-to-moderate correlations between the measures, except for verbal comprehension. The indices of overall performance showed more consistent correlations than Subtests. DISCUSSION: The overall correlations were in accordance with earlier studies. Cogstate is relatively independent of verbal comprehension abilities. The choice of the cognitive assessment method should be strongly guided by the research question. More studies are needed to evaluate the applicability of the Cogstate Composite Score in cognitive screening.

The Frequency-Dependent Neuronal Length Constant in Transcranial Magnetic Stimulation.

BACKGROUND: The behavior of the dendritic or axonal membrane voltage due to transcranial magnetic stimulation (TMS) is often modeled with the one-dimensional cable equation. For the cable equation, a length constant λ0 is defined; λ0 describes the axial decay of the membrane voltage in the case of constant applied electric field. In TMS, however, the induced electric field waveform is typically a segment of a sinusoidal wave, with characteristic frequencies of the order of several kHz. OBJECTIVE: To show that the high frequency content of the stimulation pulse causes deviations in the spatial profile of the membrane voltage as compared to the steady state. METHODS: We derive the cable equation in complex form utilizing the complex frequency-dependent representation of the membrane conductivity. In addition, we define an effective length constant λeff, which governs the spatial decay of the membrane voltage. We model the behavior of a dendrite in an applied electric field oscillating at 3.9 kHz with the complex cable equation and by solving the traditional cable equation numerically. RESULTS: The effective length constant decreases as a function of frequency. For a model dendrite or axon, for which λ0 = 1.5 mm, the effective length constant at 3.9 kHz is decreased by a factor 10 to 0.13 mm. CONCLUSION: The frequency dependency of the neuronal length constant has to be taken into account when predicting the spatial behavior of the membrane voltage as a response to TMS.

Transformation of diffuse beta-amyloid precursor protein and beta-amyloid deposits to plaques in the thalamus after transient occlusion of the middle cerebral artery in rats.

BACKGROUND AND PURPOSE: The present study examined the long-term presence of beta-amyloid precursor protein (APP) and beta-amyloid (Abeta) accumulation in the rat thalamus after focal cerebral ischemia. METHODS: Male Wistar rats were subjected to transient middle cerebral artery occlusion (MCAO) for 2 hours. Sensorimotor outcome was assessed using a tapered/ledged beam-walking task after operation. The distribution of APP and Abeta was examined immunohistochemically at 1 week, 1 month, and 9 months after MCAO. RESULTS: MCAO caused a long-lasting deficit in forelimb and hind limb function assessed using the beam-walking test. Histologic examination revealed a transient increase in APP and Abeta staining in axons in the corpus callosum and in neurons at the border of the ischemic region. APP and Abeta deposits persisted in the thalamic nuclei (ventroposterior lateral and ventroposterior medial nuclei), eventually leading to dense plaque-like deposits by the end of the 9-month follow-up. The deposits were surrounded by an astroglial scar. The deposits were positive for Abeta and N-terminal APP, but not for C-terminal APP. Antibodies against the C-terminal of Abeta, ie, Abeta42 and Abeta40, showed a preferential staining for Abeta42. Congo red or thioflavine S did not stain the deposits. CONCLUSIONS: The present results demonstrated the persistent presence and aggregation of APP and Abeta, or their fragments, to dense plaque-like deposits in the ventroposterior lateral and ventroposterior medial nuclei of rats subjected to focal cerebral ischemia.

The effect of stimulus parameters on TMS-EEG muscle artifacts.

BACKGROUND: When transcranial magnetic stimulation (TMS) is delivered close to the lateral aspects of the head, large-amplitude (~10-1000 µV) biphasic electroencephalographic (EEG) deflections, peaking at around 4-10 and 8-20 ms, appear. OBJECTIVE: To characterize the spatiotemporal features of these artifacts, to quantify the effect of stimulus parameters on them, and thus, to study the feasibility of different measurement procedures to decrease the artifacts online. Furthermore, to show that these deflections, when measured with a sample-and-hold system, mainly result from excitation of cranial muscles. METHODS: Three subjects received TMS to 16 sites over the left hemisphere. TMS-compatible EEG was recorded simultaneously. Four other subjects received TMS to M1 with different coil rotation and tilt angles and stimulation intensities. We also stimulated a conductive phantom and recorded simultaneous EEG to exclude the possibility of residual electromagnetic artifacts. RESULTS: The artifacts were largest when the stimulator was placed above cranial muscles, whereas stimulation of relatively central sites far from the muscles produced muscle artifact-free data. The laterally situated EEG channels were most severely contaminated. The artifacts were significantly reduced when reducing the intensity or when tilting or rotating the coil so that coil wings moved further away from the temporal muscle, while brain responses remained visible. Stimulation of the phantom did not produce such large-amplitude biphasic artifacts. CONCLUSION: Altering the stimulation parameters can reduce the described artifact, while brain responses can still be recorded. The early, laterally appearing, large biphasic TMS-evoked EEG deflections recorded with a sample-and-hold system are caused by cranial muscle activation.

Effect of task-related extracerebral circulation on diffuse optical tomography: experimental data and simulations on the forehead.

The effect of task-related extracerebral circulatory changes on diffuse optical tomography (DOT) of brain activation was evaluated using experimental data from 14 healthy human subjects and computer simulations. Total hemoglobin responses to weekday-recitation, verbal-fluency, and hand-motor tasks were measured with a high-density optode grid placed on the forehead. The tasks caused varying levels of mental and physical stress, eliciting extracerebral circulatory changes that the reconstruction algorithm was unable to fully distinguish from cerebral hemodynamic changes, resulting in artifacts in the brain activation images. Crosstalk between intra- and extracranial layers was confirmed by the simulations. The extracerebral effects were attenuated by superficial signal regression and depended to some extent on the heart rate, thus allowing identification of hemodynamic changes related to brain activation during the verbal-fluency task. During the hand-motor task, the extracerebral component was stronger, making the separation less clear. DOT provides a tool for distinguishing extracerebral components from signals of cerebral origin. Especially in the case of strong task-related extracerebral circulatory changes, however, sophisticated reconstruction methods are needed to eliminate crosstalk artifacts.

Uncovering neural independent components from highly artifactual TMS-evoked EEG data.

Transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG) is a powerful tool for studying cortical excitability and connectivity. To enhance the EEG interpretation, independent component analysis (ICA) has been used to separate the data into independent components (ICs). However, TMS can evoke large artifacts in EEG, which may greatly distort the ICA separation. The removal of such artifactual EEG from the data is a difficult task. In this paper we study how badly the large artifacts distort the ICA separation, and whether the distortions could be avoided without removing the artifacts. We first show that, in the ICA separation, the time courses of the ICs are not affected by the large artifacts, but their topographies could be greatly distorted. Next, we show how this distortion can be circumvented. We introduce a novel technique of suppression, by which the EEG data are modified so that the ICA separation of the suppressed data becomes reliable. The suppression, instead of removing the artifactual EEG, rescales all the data to about the same magnitude as the neural EEG. For the suppressed data, ICA returns the original time courses, but instead of the original topographies, it returns modified ones, which can be used, e.g., for the source localization. We present three suppression methods based on principal component analysis, wavelet analysis, and whitening of the data matrix, respectively. We test the methods with numerical simulations. The results show that the suppression improves the source localization.

Magnetic-stimulation-related physiological artifacts in hemodynamic near-infrared spectroscopy signals.

Hemodynamic responses evoked by transcranial magnetic stimulation (TMS) can be measured with near-infrared spectroscopy (NIRS). This study demonstrates that cerebral neuronal activity is not their sole contributor. We compared bilateral NIRS responses following brain stimulation to those from the shoulders evoked by shoulder stimulation and contrasted them with changes in circulatory parameters. The left primary motor cortex of ten subjects was stimulated with 8-s repetitive TMS trains at 0.5, 1, and 2 Hz at an intensity of 75% of the resting motor threshold. Hemoglobin concentration changes were measured with NIRS on the stimulated and contralateral hemispheres. The photoplethysmograph (PPG) amplitude and heart rate were recorded as well. The left shoulder of ten other subjects was stimulated with the same protocol while the hemoglobin concentration changes in both shoulders were measured. In addition to PPG amplitude and heart rate, the pulse transit time was recorded. The brain stimulation reduced the total hemoglobin concentration (HbT) on the stimulated and contralateral hemispheres. The shoulder stimulation reduced HbT on the stimulated shoulder but increased it contralaterally. The waveforms of the HbT responses on the stimulated hemisphere and shoulder correlated strongly with each other (r = 0.65-0.87). All circulatory parameters were also affected. The results suggest that the TMS-evoked NIRS signal includes components that do not result directly from cerebral neuronal activity. These components arise from local effects of TMS on the vasculature. Also global circulatory effects due to arousal may affect the responses. Thus, studies involving TMS-evoked NIRS responses should be carefully controlled for physiological artifacts and effective artifact removal methods are needed to draw inferences about TMS-evoked brain activity.

The functional role of the ventral premotor cortex in a visually paced finger tapping task: a TMS study.

The accurate control of timed actions is a fundamental aspect of our daily activities. Repetitive movements can be either self-paced or synchronized with an external stimulus. Finger tapping (FT) is a suitable task to study the mechanisms of motor timing in both conditions. The neuronal network supporting motor timing in FT tasks comprises the lateral cerebellum, the lateral and mesial premotor areas as well as parietal sites. It has been suggested that lateral premotor cortices (PMC) are involved in time representation and sensorimotor transformations needed for synchronization. Most studies have focused on the dorsal aspect of PMC (dPMC) whereas the ventral PMC (vPMC) function has been poorly investigated. Here we used an online transcranial magnetic stimulation (TMS) protocol to probe the role of vPMC in an FT task, as compared to a functionally relevant site (dPMC) and an unrelated one. According to the synchronization-continuation paradigm, subjects had to synchronize their tapping to a periodic continuous visual stimulus, and then continue without the external pacer. Two different visual pacers were used: a tapping finger and a hinged tilting bar. We show that TMS reduced the synchronization error when delivered to the vPMC. This effect was larger when the more abstract hinged tilting bar was used as a pacer instead of the finger. No effects were observed in the continuation phase. We hereby offer the first online-TMS evidence of the involvement of vPMC in visually cued FT tasks.

Removal of large muscle artifacts from transcranial magnetic stimulation-evoked EEG by independent component analysis.

We present two techniques utilizing independent component analysis (ICA) to remove large muscle artifacts from transcranial magnetic stimulation (TMS)-evoked EEG signals. The first one is a novel semi-automatic technique, called enhanced deflation method (EDM). EDM is a modification of the deflation mode of the FastICA algorithm; with an enhanced independent component search, EDM is an effective tool for removing the large, spiky muscle artifacts. The second technique, called manual method (MaM) makes use of the symmetric mode of FastICA and the artifactual components are visually selected by the user. In order to evaluate the success of the artifact removal methods, four different quality parameters, based on curve comparison and frequency analysis, were studied. The dorsal premotor cortex (dPMC) and Broca's area (BA) were stimulated with TMS. Both methods removed the very large muscle artifacts recorded after stimulation of these brain areas. However, EDM was more stable, less subjective, and thus also faster to use than MaM. Until now, examining lateral areas of the cortex with TMS-EEG has been restricted because of strong muscle artifacts. The methods described here can remove those muscle artifacts, allowing one to study lateral areas of the human brain, e.g., BA, with TMS-EEG.

EEG oscillations and magnetically evoked motor potentials reflect motor system excitability in overlapping neuronal populations.

OBJECTIVE: To understand the relationship between neuronal excitability reflected by transcranial magnetic stimulation (TMS) evoked motor potentials (MEPs) and spontaneous oscillation amplitude and phase. METHODS: We combined spontaneous EEG measurement with motor cortex TMS and recorded MEP amplitudes from abductor digiti minimi (ADM). RESULTS: Midrange-beta oscillations over the stimulated left motor cortex were, on average, weaker before large- than small-amplitude MEPs. The phase of occipital midrange-beta oscillations was related to the MEP amplitudes. CONCLUSIONS: The present results support the view that MEP and Rolandic beta oscillation amplitudes are associated with motor cortical excitability. However, oscillations seen in EEG reflect the excitability of a large population of cortical neurons, and MEP amplitude is affected also by spinal excitability and action potential desynchronization. Thus, MEP and EEG oscillation amplitudes are not strongly correlated. In addition, even during rest, motor system excitability appears to be related to activity in occipital areas at frequency ranges associated with visuomotor processing. SIGNIFICANCE: The ability of spontaneous oscillations and MEPs to inform us about cortical excitability is clarified. For example, it is suggested that oscillatory activity at non-motor sites might be related to motor system excitability at rest.

The relationship between peripheral and early cortical activation induced by transcranial magnetic stimulation.

The purpose of this study was to assess the relationship between peripheral muscle responses (motor evoked potentials, MEP) evoked by transcranial magnetic stimulation (TMS) and the early components of the TMS-evoked EEG response, both of which reflect cortical excitability. Left primary motor cortex of five healthy volunteers was stimulated with 100% of the motor threshold. The relationship between MEP amplitudes and the peak-to-peak amplitudes of the N15-P30 complex of the evoked EEG signal was determined at the single-trial level. MEP and N15-P30 amplitudes were significantly correlated in all five subjects. The results support the view that the amount of direct activation of neurons in M1 evoked by TMS affects both subsequent cortical activation and the activation of the target muscle. Cortical excitability is altered in some neuronal disorders and modulated locally during various tasks. It could thus be used as a marker of the state of health in many cases and as a method to study brain function. The present results improve our understanding of the early components of the TMS-evoked EEG signal, which reflect cortical excitability, and may thus have widespread use in clinical and scientific studies.

Screening of genetic and expression alterations of SRC1 gene in prostate cancer.

BACKGROUND: Genetic alterations of the SRC1 gene have not been thoroughly studied in prostate cancer. MATERIALS AND METHODS: Five prostate cancer cell lines and 32 xenografts were screened for mutations and gene copy number alterations. Subsequently, frequencies of detected sequence variations were further analyzed in 44 clinical prostate cancers, 6 benign prostate hyperplasias, and 48 normal controls. Finally, the protein expression of SRC1 in 254 clinical prostate tumors was investigated. RESULTS: Three non-recurrent sequence variations, and one single nucleotide polymorphism in the coding region of SRC1, as well as one case of SRC1 gene amplification were found. The protein expression of SRC1 was higher in androgen ablation resistant than untreated prostate carcinomas, but the difference was not statistically significant (P = 0.0796). CONCLUSIONS: Genetic alterations of SRC1 are rare in prostate cancer. The nuclear protein accumulation of SRC1 seems to be mildly increased in androgen ablation resistant prostate cancers. .

Learning difficulties, social intelligence, and self-concept: connections to bully-victim problems.

Learning skills, social intelligence, and self-concept were related to each other and to bully-victim problems among fifth-grade children (79 boys and 62 girls, aged 11-12 years). In addition to exploring connections between single variables, a person-oriented approach was applied in order to analyze children's value patterns with respect to learning skills, self-concept, and social intelligence, and how these value patterns are related to bully-victim problems. Social intelligence was found to be positively correlated with learning skills, but negatively related to victimization. Bullying was positively correlated with self-concept scores. However, this was true only of boys. According to cross-tabulations, there were significantly more bullies among children with learning difficulties (LD) than would have been expected by chance. Victimization, on the other hand, was not related to LD. LD children's proposed victim status was in some degree supported by cluster analysis: a group of LD children emerged, who not only scored high on bullying, but also tended to be victimized by others. In addition, two groups of bullies appeared: one whose members could be interpreted as socially unskilled and another as socially skilled. This finding is in line with recent theoretical reasoning, which calls into question the idea of bullies as a unified group, lacking in social skills.