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.

Magnetoencephalography in studies of human cognitive brain function.

Magnetoencephalography provides a new dimension to the functional imaging of the brain. The cerebral magnetic fields recorded noninvasively enable the accurate determination of locations of cerebral activity with an uncompromized time resolution. The first whole-scalp sensor arrays have just recently come into operation, and significant advances are to be expected in both neurophysiological and cognitive studies, as well as in clinical practice. However, although the accuracy of locating isolated sources of brain activity has improved, identification of multiple simultaneous sources can still be a problem. Therefore, attempts are being made to combine magnetoencephalography with other brain-imaging methods to improve spatial localization of multiple sources and, simultaneously, to achieve a more complete characterization of different aspects of brain activity during cognitive processing. Owing to its good time resolution and considerably better spatial accuracy than that provided by EEG, magnetoencephalography holds great promise as a tool for revealing information-processing sequences of the human brain.

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.

Face-specific responses from the human inferior occipito-temporal cortex.

Whole-head neuromagnetic responses were recorded from seven subjects to pictures of faces and to various control stimuli. Four subjects displayed signals specific to faces. The combination of functional information from magnetoencephalography and anatomical data from magnetic resonance images suggests that the face-specific activity was generated in the inferior occipitotemporal cortex. All four subjects showed the face-specific response in the right hemisphere, one of them also in the left. Our results, together with recent position emission tomography and lesion studies, suggest a right-hemisphere preponderance of face processing in the inferior occipitotemporal cortex.

Seeing faces activates three separate areas outside the occipital visual cortex in man.

We have examined magnetic cortical responses of 15 healthy humans to 46 different pictures of faces. At least three areas outside the occipital visual cortex appeared to be involved in processing this input, 105-560 ms after the stimulus onset. The first active area was near the occipitotemporal junction, the second in the inferior parietal lobe, and the third in the middle temporal lobe. The source in the inferior parietal lobe was also activated by other simple and complex visual stimuli.

Reversal of cerebral asymmetry in schizophrenia measured with magnetoencephalography.

It has been suggested that schizophrenic patients fail to develop left-hemisphere dominance because of an early disturbance in neuronal development. This hypothesis has been supported by some post-mortem. CT and magnetic resonance imaging (MRI) studies, while other in-vivo studies have given contradicting results. We used 122-channel whole-head magnetoencephalography and MRI to locate the sources of auditory evoked responses in 19 schizophrenic patients and in 20 healthy controls. Auditory evoked responses were detected in all subjects. The left-right hemisphere asymmetry of cerebral sources for auditory evoked responses was markedly dispersed among patients when compared with controls. The source locations for left auditory cortex were clearly anterior with respect to the right hemisphere in 32% of the patients, while the corresponding prevalence of this abnormal asymmetry was 0% in controls (p = 0.008. Fisher's exact test). The reversed asymmetry appeared to be associated with a shorter anterior-posterior distance between the auditory cortex and the anterior tip of the temporal lobe in the left side when compared with the right side. The reversed asymmetry was associated with higher PANSS general psychopathological score, and especially with higher guilt feelings and motor retardation scores. The large 2.5-fold standard deviation in the inter-hemispheric anterior posterior difference in the location of the auditory cortex among patients (p 0.001 for the difference in the magnitude of variance between controls and patients) clearly reflects the dispersion of the left right asymmetry into both direction, and three of the patients with 'normal asymmetry' had a greater left-right asymmetry than any of the controls. Markedly greater reversal of hemispheric asymmetry among patients implies that regulation of the development of brain asymmetry is disturbed among schizophrenic patients. Abnormality in the cerebral asymmetry may be a crucial factor in the development of schizophrenic disorder in a substantial proportion of patients. The results suggest that the reversed asymmetry is associated with the higher severity of general psychopathological symptoms.

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.

Characterizing the local oscillatory content of spontaneous cortical activity during mental imagery.

We report on the determination of detailed spectra for simultaneously active sources of spontaneous neuronal activity in humans directly from data recorded with a whole-scalp 122-channel magnetometer array. Subjects rested with eyes open and performed two contrasting mental imagery tasks: the imagination of the self-performance of a motor activity and the silent generation of a chain of words. A novel analysis technique, frequency-domain signal-space projection (FDSSP) was utilized to determine the temporal and spectral characteristics of spontaneous brain activity at specific cortical sites. Although intersubject differences were significant, spectra for individual subjects contained task-dependent features which were reproducible over successive 20-s epochs. This result supports the concept of multiple sources of spontaneous cortical activity and suggests that detailed spectra of localized oscillatory activity obtained non-invasively with magnetoencephalographic arrays may provide a useful characterization of cortical involvement in mental imagery.

Auditory stimuli activate parietal brain regions: a whole-head MEG study.

Previous studies using magnetoencephalographic (MEG) recordings have revealed neuronal populations responding to discrete auditory stimuli in the supratemporal cortex of the human brain. We used the novel whole-head magnetometer (Neuromag-122) to determine whether regions outside the auditory cortex are activated by auditory stimulation as well. In the present study we report evidence for activation of the parietal cortex of the human brain in response to auditory stimuli.

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.

Auditory cortex evoked magnetic fields and lateralization of speech processing.

Potential use of different auditory evoked brain responses for determining cerebral lateralization of speech function was evaluated. Cortical magnetic fields elicited by plosive syllables or complex non-speech sounds analogous to them were recorded with 122-channel magnetometer. We estimated parameters of magnetic P1, N1 and P2 responses to both stimuli in the two hemispheres and found no hemispheric asymmetry for any of the responses. No correlation between the right-ear advantage, determined with dichotic listening test, and any of asymmetry indexes, calculated for the speech-elicited responses, was observed. These results suggest that P1, N1 and P2 responses to speech signals do not indicate lateralization of speech function in the brain. The results are discussed in relation to previous studies suggesting that the mismatch negativity (MMN) seems to be the only early auditory cortex response sensitive to the lateralization of speech function.

Noise affects speech-signal processing differently in the cerebral hemispheres.

This study explored the effects of acoustic noise on the cerebral asymmetry of speech perception. We measured magnetic fields of the brain elicited by consonant-vowel syllables in silence and white noise. Background noise affected brain responses to these stimuli differently in the left and right auditory cortices. Its depressive effect on cortical responses was found mainly in the left hemisphere, whereas the right hemisphere was unaffected or exhibited increased activity in noise. Locations of the P1, N1, and P2 activity sources in noise were different from those in silence in the right but not in the left hemisphere. These results suggest an increased right hemisphere role in speech sound processing in noisy conditions, involving the recruitment of additional right auditory cortex structures.

Temporal span of human echoic memory and mismatch negativity: revisited.

The stimulus onset asynchrony (SOA)-related decrease in mismatch negativity (MMN) amplitude has been used to infer a putative auditory sensory memory duration of 4-10 s. However, both increased standard-to-standard (SSA) and standard-to-deviant (SDA) gaps could contribute to the effect. Fourteen subjects were presented with standard and deviant tones with short (0.35 s) and long (3.5 s) SOAs. In addition, the SSA and SDA were separately manipulated to test the relative contributions of slower rate of standard tone presentation and longer SDA gap to the SOA-related decrease in MMN amplitude. The MMN amplitude decreased with long SOA by 61%. Increases in SSA and SDA resulted in intermediate 47% and 31% decreases, these manipulations explaining 67% of the long SOA effect (p<0.001). Consequently, echoic memory length cannot be directly inferred from an MMN-SOA dependency function.

Human cortical responses evoked by dichotically presented tones of different frequencies.

Behavioral and patient studies have suggested that during dichotic listening the ipsilateral auditory pathways are strongly inhibited, so that each hemisphere is treats the sound coming to the contralateral ear. We analysed the auditory N100m neuromagnetic evoked response following passive listening of dichotic tones of different frequencies. We found that the N100m in each hemisphere depended on both ipsilateral and contralateral stimuli, revealing no strong inhibition of ipsilateral pathways. The N100m increased with the interaural frequency disparity and was reduced as both ears received identical stimuli. The results can be explained by the existence of a frequency-dependent excitatory/inhibitory organization of the auditory cortex, as has been described in the cat. We suggest that the N100m might also reflect automatic processes involved in multiple-stream perception.

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.

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.

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.

Alzheimer's disease affects parallel processing between the auditory cortices.

Auditory evoked magnetic fields (AEFs) were recorded from 11 patients with Alzheimer's disease (AD) and 11 age-matched controls using the 122-channel whole-head magnetometer. Auditory stimuli were monaurally presented with interstimulus intervals (ISI) of 0.5 and 2.5 s in different blocks. The peak latencies of P50m and N100m responses were significantly longer in AD patients than in controls over the ipsilateral but not over the contralateral auditory cortex with respect to the ear stimulated. This finding suggests that parallel auditory processing is impaired between the auditory cortices in AD patients. The present MEG measurement might provide an objective index to evaluate auditory dysfunction in AD.

Significance of the second somatosensory cortex in sensorimotor integration: enhancement of sensory responses during finger movements.

The functional significance of the second somatosensory cortex (SII) is poorly understood. However, lesion and cortical stimulation studies indicate that SII may be involved in sensory aspects of tactile learning and in movement control. In the present study, we explored a possible role of SII in sensorimotor integration in humans using a multichannel magnetometer. Somatosensory evoked fields (SEFs) from SII to electrical stimulation of left and right median nerves were recorded in six healthy volunteers during rest and in different test conditions. Continuous cutaneous stimulation of the right hand or face reduced the SEFs to both left and right median nerve stimulation. Right-sided finger movements increased the SEFs to right, but not left, median nerve stimulation. The responses were equally enhanced by simple finger flexion movement and by a complex finger sequence. The suppression of SEFs by competing cutaneous inputs from different areas of the body indicates that the neurones underlying the responses receive inputs from large, bilateral receptive fields. The enhancement of sensory reactions to signals from the actively moving limb but not to those from the opposite limb indicates a spatial tuning of the SII neurones to behaviourally relevant input channels, also suggesting that SII is important for the integration of sensory information to motor programmes.