Methods for analysis of brain connectivity: An IFCN-sponsored review.

The goal of this paper is to examine existing methods to study the "Human Brain Connectome" with a specific focus on the neurophysiological ones. In recent years, a new approach has been developed to evaluate the anatomical and functional organization of the human brain: the aim of this promising multimodality effort is to identify and classify neuronal networks with a number of neurobiologically meaningful and easily computable measures to create its connectome. By defining anatomical and functional connections of brain regions on the same map through an integrated approach, comprising both modern neurophysiological and neuroimaging (i.e. flow/metabolic) brain-mapping techniques, network analysis becomes a powerful tool for exploring structural-functional connectivity mechanisms and for revealing etiological relationships that link connectivity abnormalities to neuropsychiatric disorders. Following a recent IFCN-endorsed meeting, a panel of international experts was selected to produce this current state-of-art document, which covers the available knowledge on anatomical and functional connectivity, including the most commonly used structural and functional MRI, EEG, MEG and non-invasive brain stimulation techniques and measures of local and global brain connectivity.

Bilateral changes in excitability of sensorimotor cortices during unilateral movement: combined electroencephalographic and transcranial magnetic stimulation study.

It remains unclear what neuronal mechanisms in humans are reflected in the activation of the ipsilateral hemisphere during the performance of unilateral movements. To address this question we combined transcranial magnetic stimulation (TMS), electroencephalography (EEG), and electromyographic (EMG) recordings of motor evoked potentials (MEPs). Compared with previous TMS studies, where changes in excitability might be related to both cortical and spinal mechanisms, our setup allowed a more direct evaluation of the cortical processes related to the performance of unilateral movements. EEG responses showed that the unilateral motor reactions were associated with the bilateral increase in the excitability of sensorimotor cortices. However, this increase was smaller in the ipsilateral hemisphere most likely due to the fact that the excitation in ipsilateral hemisphere coincided with additional inhibitory processes related to the suppression of mirror movements. This explanation was further corroborated by showing that only contralateral changes in cortical excitability led to the increase in the amplitude of peripheral MEPs, while neuronal activation in the ipsilateral hemisphere was not associated with the changes in the muscle responses. These results suggest that the increased excitability in the ipsilateral hemisphere was uncoupled from the modulation of the cortico-spinal output. Moreover, we show that the background neuronal activity during unilateral movements was different in the ipsi- and contralateral hemisphere. This difference most likely reflects inter-hemispheric balance between the excitation and inhibition which is required for the optimal performance of the unilateral movement.

Prefrontal transcranial magnetic stimulation produces intensity-dependent EEG responses in humans.

The reactivity of the prefrontal cortex (PFC) was studied by measuring electroencephalographic (EEG) responses to transcranial magnetic stimulation (TMS) with different stimulus intensities. Focal TMS at intensities of 60%, 80%, 100%, and 120% of the motor threshold was delivered to the left middle frontal gyrus identified individually from magnetic resonance images (MRI) in seven healthy subjects. EEG was simultaneously recorded with 60 scalp electrodes. Stimulation evoked clear responses at all intensities. Left prefrontal TMS evoked an averaged EEG response consisting of five deflections at 27 +/- 3 ms (peak I), 39 +/- 3 ms (II), 52 +/- 7 ms (III), 105 +/- 14 ms (IV), and 193 +/- 15 ms (V) at the Fz/FCz electrodes. The slope of the almost linear dependence of the overall response on stimulus intensity varied with latency. Potential distributions were relatively similar for the four intensities, suggesting that the same cortical structures may be activated. Intensity dependence function to TMS may be an indicator of cortical activation in humans.

EEG minimum-norm estimation compared with MEG dipole fitting in the localization of somatosensory sources at S1.

OBJECTIVE: Dipole models, which are frequently used in attempts to solve the electromagnetic inverse problem, require explicit a priori assumptions about the cerebral current sources. This is not the case for solutions based on minimum-norm estimates. In the present study, we evaluated the spatial accuracy of the L2 minimum-norm estimate (MNE) in realistic noise conditions by assessing its ability to localize sources of evoked responses at the primary somatosensory cortex (SI). METHODS: Multichannel somatosensory evoked potentials (SEPs) and magnetic fields (SEFs) were recorded in 5 subjects while stimulating the median and ulnar nerves at the left wrist. A Tikhonov-regularized L2-MNE, constructed on a spherical surface from the SEP signals, was compared with an equivalent current dipole (ECD) solution obtained from the SEFs. RESULTS: Primarily tangential current sources accounted for both SEP and SEF distributions at around 20 ms (N20/N20m) and 70 ms (P70/P70m), which deflections were chosen for comparative analysis. The distances between the locations of the maximum current densities obtained from MNE and the locations of ECDs were on the average 12-13 mm for both deflections and nerves stimulated. In accordance with the somatotopical order of SI, both the MNE and ECD tended to localize median nerve activation more laterally than ulnar nerve activation for the N20/N20m deflection. Simulation experiments further indicated that, with a proper estimate of the source depth and with a good fit of the head model, the MNE can reach a mean accuracy of 5 mm in 0.2-microV root-mean-square noise. CONCLUSIONS: When compared with previously reported localizations based on dipole modelling of SEPs, it appears that equally accurate localization of S1 can be obtained with the MNE. SIGNIFICANCE: MNE can be used to verify parametric source modelling results. Having a relatively good localization accuracy and requiring minimal assumptions, the MNE may be useful for the localization of poorly known activity distributions and for tracking activity changes between brain areas as a function of time.

Mismatch negativity indexes auditory temporal resolution: evidence from event-related potential (ERP) and event-related field (ERF) recordings.

This study examined auditory temporal resolution as indexed by gap detection using the mismatch negativity (MMN) component of the auditory event-related potential (ERP) and its magnetic counterpart (MMNm). ERPs were recorded in 10 subjects who were presented with auditory stimuli. These stimuli were presented in sequences of repetitive continuous 'standard' sinusoidal tones interspersed with infrequently occurring 'deviant' stimuli that differed from standards only in that they contained a silent gap midway in the stimulus. The gap size varied in separate stimulus blocks and was either 3, 5 or 7 ms. The stimuli were presented monaurally either to the left or the right ear. In a separate session, event-related magnetic fields (ERFs) were recorded from eight subjects using a similar paradigm but with gap sizes of 3, 7 or 11 ms and with binaural stimulation. Both ERP and ERF recordings showed that the smallest gap size (3 ms) did not elicit as large or reliable MMN or MMNm as did the larger ones. There were no differences in the laterality of the MMN as might be predicted on the basis of previous behavioural studies, but this result is likely a reflection of differences in task requirements. Nonetheless, the findings suggest that MMN and MMNm successfully index auditory temporal resolution thresholds, as measures that are independent of attention.

Evidence for dissociation of spatial and nonspatial auditory information processing.

Several lines of evidence suggest that visual information processing is segregated into the ventral "what" and dorsal "where" pathways. But the question whether information processing in the auditory system is also parceled to spatial and nonspatial domains remains open. In the present study, we performed simultaneous EEG and MEG recordings during auditory location and pitch delayed matching-to-sample tasks to find out whether working memory processing of the auditory stimulus attribute affects the transient components of the evoked potentials. In both tasks, identical blocks of tone stimuli of one of two frequencies were presented in one of two locations; the only difference between the tasks was the instruction to attend either to the frequency or to the location. In the match condition, the N1 latency was shorter and the N1m amplitude larger in the location task compared to the pitch task. Furthermore, the right-hemisphere generator of N1m elicited in the match condition of the location task was situated significantly medially to the N1m generator in the match condition of the pitch task. Latency and amplitude task-related differences in the N1/N1m components as well as the source location differences indicate at least partial segregation of neuronal mechanisms involved in working memory processing of spatial and nonspatial auditory information.

Brain activity index of distractibility in normal school-age children.

Children's attention is easily diverted from a current activity to a new event in the environment. This was indexed in school-age children by diminished performance speed and accuracy in a visual discrimination task caused by task-irrelevant novel sounds. Event-related brain potentials (ERPs) elicited by these distracting sounds showed a prominent positive deflection that was generated by brain processes associated with involuntary switching of attention to novel sounds. Recordings of the magnetoencephalographic (MEG) counterpart of this brain activity revealed a major bilateral generator source in the superior temporal cortex. However, ERP scalp distributions indicated also overlapping brain activity generated in other brain areas involved in involuntary attention switching. Moreover, differences in ERP amplitudes and in their correlations with the reaction times between younger (7-10 years) and older (11-13 years) children indicated developmental changes in attentional brain functions.

Superior formation of cortical memory traces for melodic patterns in musicians.

The human central auditory system has a remarkable ability to establish memory traces for invariant features in the acoustic environment despite continual acoustic variations in the sounds heard. By recording the memory-related mismatch negativity (MMN) component of the auditory electric and magnetic brain responses as well as behavioral performance, we investigated how subjects learn to discriminate changes in a melodic pattern presented at several frequency levels. In addition, we explored whether musical expertise facilitates this learning. Our data show that especially musicians who perform music primarily without a score learn easily to detect contour changes in a melodic pattern presented at variable frequency levels. After learning, their auditory cortex detects these changes even when their attention is directed away from the sounds. The present results thus show that, after perceptual learning during attentive listening has taken place, changes in a highly complex auditory pattern can be detected automatically by the human auditory cortex and, further, that this process is facilitated by musical expertise.

No evidence for dependence of early cortical auditory processing on dopamine D(2)-receptor modulation: a whole-head magnetoencephalographic study.

Magnetoencephalography (MEG) was used to determine the effect of neuroleptic challenge on brain responses in healthy subjects. In a double-blind, randomized, placebo-controlled, cross-over design study, the dopamine D(2) receptor antagonist haloperidol (2 mg) was given orally to 12 healthy volunteers. The middle-latency auditory evoked magnetic fields (MAEF) were recorded 3 h after administration of haloperidol or placebo with a whole-head 122-channel MEG. Haloperidol did not significantly affect MAEF responses. The dipole moments and source locations of the responses were not significantly influenced by haloperidol. These results suggest that dopamine D(2) receptors are not involved in the early phases of auditory cortical processing.

Transcranial magnetic stimulation as a tool for cognitive studies.

Transcranial Magnetic Stimulation (TMS) is a tool for the non-invasive stimulation of the human brain. It allows the activation of arbitrary sites of the superficial cortex and, combined with other brain-imaging techniques such as EEG, PET, and fMRI, it can be used to evaluate cortical excitability and connectivity. This is of major importance in, for example, the study of cognitive processes such as language, learning, memory and self-representation, which are thought to be represented in multiple brain areas. The mechanisms of action of TMS are known on a basic level, but its effect on the activation state of brain tissue is still poorly understood. Clinical applications of TMS have also been proposed and guidelines for its safe use drafted.

Memory traces for words as revealed by the mismatch negativity.

Brain responses to the same spoken syllable completing a Finnish word or a pseudo-word were studied. Native Finnish-speaking subjects were instructed to ignore the sound stimuli and watch a silent movie while the mismatch negativity (MMN), an automatic index of experience-dependent auditory memory traces, was recorded. The MMN to each syllable was larger when it completed a word than when it completed a pseudo-word. This enhancement, reaching its maximum amplitude at about 150 ms after the word's recognition point, did not occur in foreign subjects who did not know any Finnish. These results provide the first demonstration of the presence of memory traces for individual spoken words in the human brain. Using whole-head magnetoencephalography, the major intracranial source of this word-related MMN was found in the left superior temporal lobe.

Interhemispheric phase synchrony and amplitude correlation of spontaneous beta oscillations in human subjects: a magnetoencephalographic study.

Interhemispheric phase synchrony and amplitude correlation of beta oscillations were studied with MEG in a resting condition. The left and right hemisphere beta oscillations exhibited phase-locking with a phase-lag near zero degrees. The index of synchronization was strongest when these oscillations had large amplitude. Functionally, we interpret the phase synchrony on the basis of bilaterality of movement organization. A positive interhemispheric correlation was also found for the amplitude of spontaneous beta oscillations over long time intervals (> 1 s). The low-frequency correlation of spontaneous rhythmic activity may be the source of the low-frequency correlations of the hemodynamic responses in homologous areas that have been reported previously and have been interpreted as functional connectivity between these areas.

Visual attention to words of native versus later acquired languages: a magnetoencephalographic study in humans.

We recorded evoked magnetic fields while short words were visually presented in different languages with an oddball paradigm. The task was to count how many words were in a target language when most of the words were in another language and there were also non-target deviants in a third language. When native words (Finnish) were targets, they evoked a selection response at the latency of 300-600 ms. However, when the task was to count non-native words among native standards, in addition to the targets, also the non-target foreign words evoked the selection response. These results may reflect differences in the selection process for native versus non-native words brought about by different proficiency levels of the languages.

Ethanol modulates cortical activity: direct evidence with combined TMS and EEG.

The motor cortex of 10 healthy subjects was stimulated by transcranial magnetic stimulation (TMS) before and after ethanol challenge (0.8 g/kg resulting in blood concentration of 0.77 +/- 0.14 ml/liter). The electrical brain activity resulting from the brief electromagnetic pulse was recorded with high-resolution electroencephalography (EEG) and located using inversion algorithms. Focal magnetic pulses to the left motor cortex were delivered with a figure-of-eight coil at the random interstimulus interval of 1.5-2.5 s. The stimulation intensity was adjusted to the motor threshold of abductor digiti minimi. Two conditions before and after ethanol ingestion (30 min) were applied: (1) real TMS, with the coil pressed against the scalp; and (2) control condition, with the coil separated from the scalp by a 2-cm-thick piece of plastic. A separate EMG control recording of one subject during TMS was made with two bipolar platinum needle electrodes inserted to the left temporal muscle. In each condition, 120 pulses were delivered. The EEG was recorded from 60 scalp electrodes. A peak in the EEG signals was observed at 43 ms after the TMS pulse in the real-TMS condition but not in the control condition or in the control scalp EMG. Potential maps before and after ethanol ingestion were significantly different from each other (P = 0.01), but no differences were found in the control condition. Ethanol changed the TMS-evoked potentials over right frontal and left parietal areas, the underlying effect appearing to be largest in the right prefrontal area. Our findings suggest that ethanol may have changed the functional connectivity between prefrontal and motor cortices. This new noninvasive method provides direct evidence about the modulation of cortical connectivity after ethanol challenge.

Preserved stimulus deviance detection in Alzheimer's disease.

Aging attenuates automatic auditory discrimination to duration change, whereas frequency change detection is relatively unimpaired in aging and in Alzheimer's disease (AD). Here we studied with a whole-head magnetometer whether cortical auditory discrimination to duration change as shown by magnetic mismatch negativity (MMNm) response is impaired in AD. Twenty AD patients with mild to moderate cognitive impairment and 18 age-matched healthy subjects were monaurally presented a sequence of frequent standard tones embedded with occasional deviants with shorter duration. MMNm was significantly delayed in the left hemisphere ipsilaterally to the ear stimulated in the patient group, whereas the MMNm amplitudes over both hemispheres were quite similar in both groups. This suggests that although MMNm is delayed in the left hemisphere, the automatic discrimination to duration change in the auditory cortex is not attenuated in the early stages of AD.

Scopolamine reduces the P35m and P60m deflections of the human somatosensory evoked magnetic fields.

Acetylcholine (ACh) is a potent neuromodulator in the brain with multiple, complex effects on neuronal function, most of which are mediated by muscarinic receptors. Generally, the most significant effect is excitation of pyramidal neurones and facilitation of responses to afferent stimulation. Much of the information on the ACh effects comes from studies utilizing in vitro or anesthetized in vivo preparations, while fewer data are available from awake animals or humans. We studied human somatosensory evoked magnetic fields (SEFs), which reflect summated postsynaptic currents in pyramidal neurones in area 3b, and in the opercular somatosensory cortex, when cholinergic transmission was modulated either by a central (scopolamine, 0.3 mg, i.v.) or peripheral (glycopyrrolate, 0.2 mg, i.v.) muscarinic antagonist. A randomized, double-blind, cross-over design was employed. SEFs were elicited by right median nerve stimulation at the wrist with constant-current pulses above motor threshold. The first excitatory cortical response from area 3b (N20m) was not affected by the central muscarinic blockade, while later P35m and P60m deflections were significantly reduced. The responses from the opercular somatosensory cortex showed some tendency toward reduction, but no significant alterations. The results show that somatosensory cortical processing can be modulated by muscarinic transmission at a relatively early stage. Relative membrane hyperpolarization of pyramidal neurons due to scopolamine (caused by blocking an ACh-induced tonic depolarization) is discussed as a possible mechanism underlying the observed effects.

Magnetoencephalographic (MEG) localization of the auditory N400m: effects of stimulus duration.

The effects of stimulus duration on the elicitation and equivalent current dipole (ECD) localization of the auditory N400(m) were studied in two subject groups, either familiar or unfamiliar with Finnish language, using a sentence-processing paradigm with incongruent ending words of either short or long duration. Long-duration words elicited a broad response at around 400 ms, the generator location(s) of which could not be reliably determined using ECD estimation. In contrast, short-duration words elicited a sharp, strong-amplitude response at about 400 ms latency and it's source location could be reliably determined as being in the vicinity of auditory cortex. Subjects unfamiliar with the Finnish language elicited no response at the 400 ms range. Thus, the use of short-duration words appears to be an important prerequisite for the elicitation and localization of N400m. The differential amplitude behaviour of the N400m between the two subject groups further suggests that comprehension of the semantic content of the speech message is also required.

Long-range temporal correlations and scaling behavior in human brain oscillations.

The human brain spontaneously generates neural oscillations with a large variability in frequency, amplitude, duration, and recurrence. Little, however, is known about the long-term spatiotemporal structure of the complex patterns of ongoing activity. A central unresolved issue is whether fluctuations in oscillatory activity reflect a memory of the dynamics of the system for more than a few seconds. We investigated the temporal correlations of network oscillations in the normal human brain at time scales ranging from a few seconds to several minutes. Ongoing activity during eyes-open and eyes-closed conditions was recorded with simultaneous magnetoencephalography and electroencephalography. Here we show that amplitude fluctuations of 10 and 20 Hz oscillations are correlated over thousands of oscillation cycles. Our analyses also indicated that these amplitude fluctuations obey power-law scaling behavior. The scaling exponents were highly invariant across subjects. We propose that the large variability, the long-range correlations, and the power-law scaling behavior of spontaneous oscillations find a unifying explanation within the theory of self-organized criticality, which offers a general mechanism for the emergence of correlations and complex dynamics in stochastic multiunit systems. The demonstrated scaling laws pose novel quantitative constraints on computational models of network oscillations. We argue that critical-state dynamics of spontaneous oscillations may lend neural networks capable of quick reorganization during processing demands.

EEG responses to combined somatosensory and transcranial magnetic stimulation.

OBJECTIVES: To investigate a possible interaction between sensory processing and transcranial magnetic stimulation (TMS), an experimental set-up permitting multichannel EEG measurements was used. METHODS: A somatosensory stimulus was delivered to the right wrist, while single-pulse TMS was applied to the contralateral somatosensory cortex, either concurrent with the somatosensory stimulus or 10 ms after it. A control condition served to mimic the sound of TMS without actually resulting in brain stimulation. RESULTS: An enhancement of the P25 component of the somatosensory-evoked potential (SEP) was consistently observed for TMS concurrent with somatosensory stimulus. The effect was topographically specific to the EEG recording sites below the TMS coil, i.e. above the somatosensory cortex contralateral to the stimulated peripheral nerve. CONCLUSIONS: The results can be interpreted (1) as an indication of local interaction between the somatosensory-evoked cortical activity and TMS-evoked activity or (2) as support of a relationship between the background EEG and the evoked potential (EP), this relationship being 'disrupted' by TMS.

Discrimination of speech and of complex nonspeech sounds of different temporal structure in the left and right cerebral hemispheres.

The key question in understanding the nature of speech perception is whether the human brain has unique speech-specific mechanisms or treats all sounds equally. We assessed possible differences between the processing of speech and complex nonspeech sounds in the two cerebral hemispheres by measuring the magnetic equivalent of the mismatch negativity, the brain's automatic change-detection response, which was elicited by speech sounds and by similarly complex nonspeech sounds with either fast or slow acoustic transitions. Our results suggest that the right hemisphere is predominant in the perception of slow acoustic transitions, whereas neither hemisphere clearly dominates the discrimination of nonspeech sounds with fast acoustic transitions. In contrast, the perception of speech stimuli with similarly rapid acoustic transitions was dominated by the left hemisphere, which may be explained by the presence of acoustic templates (long-term memory traces) for speech sounds formed in this hemisphere.