Seppo Kähkönen

Consensus paper: Combining transcranial stimulation with neuroimaging

In the last decade, combined transcranial magnetic stimulation (TMS)-neuroimaging studies have greatly stimulated research in the field of TMS and neuroimaging. Here, we review how TMS can be combined with various neuroimaging techniques to investigate human brain function. When applied during neuroimaging (online approach), TMS can be used to test how focal cortex stimulation acutely modifies the activity and connectivity in the stimulated neuronal circuits. TMS and neuroimaging can also be separated in time (offline approach). A conditioning session of repetitive TMS (rTMS) may be used to induce rapid reorganization in functional brain networks. The temporospatial patterns of TMS-induced reorganization can be subsequently mapped by using neuroimaging methods. Alternatively, neuroimaging may be performed first to localize brain areas that are involved in a given task. The temporospatial information obtained by neuroimaging can be used to define the optimal site and time point of stimulation in a subsequent experiment in which TMS is used to probe the functional contribution of the stimulated area to a specific task. In this review, we first address some general methodologic issues that need to be taken into account when using TMS in the context of neuroimaging. We then discuss the use of specific brain mapping techniques in conjunction with TMS. We emphasize that the various neuroimaging techniques offer complementary information and have different methodologic strengths and weaknesses.

The effect of stimulus intensity on brain responses evoked by transcranial magnetic stimulation

To better understand the neuronal effects of transcranial magnetic stimulation (TMS), we studied how the TMS‐evoked brain responses depend on stimulation intensity. We measured electroencephalographic (EEG) responses to motor‐cortex TMS, estimated the intensity dependence of the overall brain response, and compared it to a theoretical model for the intensity dependence of the TMS‐evoked neuronal activity. Left and right motor cortices of seven volunteers were stimulated at intensities of 60, 80, 100, and 120% of the motor threshold (MT). A figure‐of‐eight coil (diameter of each loop 4 cm) was used for focal stimulation. EEG was recorded with 60 scalp electrodes. The intensity of 60% of MT was sufficient to produce a distinct global mean field amplitude (GMFA) waveform in all subjects. The GMFA, reflecting the overall brain response, was composed of four peaks, appearing at 15 ± 5 msec (Peak I), 44 ± 10 msec (II), 102 ± 18 msec (III), and 185 ± 13 msec (IV). The peak amplitudes depended nonlinearly on intensity. This nonlinearity was most pronounced for Peaks I and II, whose amplitudes appeared to sample the initial part of the sigmoid‐shaped curve modeling the strength of TMS‐evoked neuronal activity. Although the response amplitude increased with stimulus intensity, scalp distributions of the potential were relatively similar for the four intensities. The results imply that TMS is able to evoke measurable brain activity at low stimulus intensities, probably significantly below 60% of MT. The shape of the response‐stimulus intensity curve may be an indicator of the activation state of the brain. Hum. Brain Mapp. 21:154–164, 2004.

Functional connectivity in the brain--is it an elusive concept?

Even though functional brain connectivity is an influential concept in modern cognitive neuroscience, it is a very controversial notion. This is why further theoretical and methodological clarification are needed to help define precisely what is meant by functional connectivity and to help frame-associated issues. In this review we present the neurophysiological concept of functional connectivity, which utilizes in a plausible manner the notion of neural assemblies, as well as local and large-scale levels of description. Here functional connectivity is the mechanism for the coordination of activity between different neural assemblies in order to achieve a complex cognitive task or perceptual process. Our theoretical and empirical findings offer new insights into possible implications of the concept of functional connectivity for cognitive neuroscience.

Breakdown of Long-Range Temporal Correlations in Theta Oscillations in Patients with Major Depressive Disorder

Neuroimaging has revealed robust large-scale patterns of high neuronal activity in the human brain in the classical eyes-closed wakeful rest condition, pointing to the presence of a baseline of sustained endogenous processing in the absence of stimulus-driven neuronal activity. This baseline state has been shown to differ in major depressive disorder. More recently, several studies have documented that despite having a complex temporal structure, baseline oscillatory activity is characterized by persistent autocorrelations for tens of seconds that are highly replicable within and across subjects. The functional significance of these long-range temporal correlations has remained unknown. We recorded neuromagnetic activity in patients with a major depressive disorder and in healthy control subjects during eyes-closed wakeful rest and quantified the long-range temporal correlations in the amplitude fluctuations of different frequency bands. We found that temporal correlations in the theta-frequency band (3-7 Hz) were almost absent in the 5-100 s time range in the patients but prominent in the control subjects. The magnitude of temporal correlations over the left temporocentral region predicted the severity of depression in the patients. These data indicate that long-range temporal correlations in theta oscillations are a salient characteristic of the healthy human brain and may have diagnostic potential in psychiatric disorders. We propose a link between the abnormal temporal structure of theta oscillations in the depressive patients and the systems-level impairments of limbic-cortical networks that have been identified in recent anatomical and functional studies of patients with major depressive disorder.

Modulation of electroencephalographic responses to transcranial magnetic stimulation: evidence for changes in cortical excitability related to movement.

Transcranial magnetic stimulation (TMS) and multichannel electroencephalography (EEG) were used for the investigation of cortical excitability preceding voluntary movement in human subjects. The study showed the practical value of the combined TMS–EEG approach in differentiating between cortical and spinal‐cord mechanisms, which is difficult with conventional electromyographic measures alone. TMS induced a pronounced negativity (N100) lasting for 150–200 ms, with the amplitude maximum in the stimulated hemisphere. When TMS was applied just before the onset of the visually triggered movement, N100 was markedly attenuated, although motor evoked potentials (MEPs) became larger. We suggest that the N100 component represents an inhibitory response following TMS. This interpretation is in agreement with intracellular recordings in animals, paired‐pulse TMS studies and experiments showing increased premovement excitability on the basis of MEPs. N100 was not affected only by the subsequent movement, but also by the switching from rest to the motor‐task condition, which caused a slight attenuation of the N100 component; no changes, however, were found in the amplitude of MEPs, suggesting that modified excitability did not affect the output of the corticospinal pyramidal cells. By contrast to MEPs, N100 was modulated also by the presentation of the visual stimulus alone, i.e. when no movement was required. This attenuation suggests that even in a rest condition visual stimuli have an access to the sensorimotor regions of the cortex, most probably through ascending arousal brain systems.

Impaired Functional Connectivity at EEG Alpha and Theta Frequency Bands in Major Depression

Recent reports on functional brain imaging in major depression have lead to an assumption that observed psychopathology might be related to an altered brain functional connectivity. Our hypothesis was that an increase in brain functional connectivity occurs in major depression. As a measure of functional connectivity, the electroencephalogram (EEG) structural synchrony approach was used in 12 medication‐free depressive outpatients and 10 control subjects. Differences in the number and strength of structurally synchronized EEG patterns were compared between groups. In depressive patients the number and strength of short cortex functional connections were significantly larger for the left than for the right hemisphere, while the number and strength of long functional connections were significantly larger for the right than for the left hemisphere. Some of the functional connections were positively correlated with the severity of depression, thus being predictive. These were short‐range anterior, posterior, and left hemisphere functional connections for the alpha frequency band and short‐range anterior functional connections for the theta frequency band. The topology of the most representative functional connections among all patients with major depression indicated that the right anterior and left posterior brain parts may discriminate depressive patients from healthy controls. The obtained data support our hypothesis that there is an increase in brain functional connectivity in major depression. This finding was interpreted within the semantic framework, where different specialization of left (monosemantic context) and right (polysemantic context) hemispheres is functionally insufficient in patients with depression. Hum Brain Mapp, 2007.

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.

Ethanol modulates cortical activity: Direct evidence with combined TMS and EEG

Abstract 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.

Artifact correction and source analysis of early electroencephalographic responses evoked by transcranial magnetic stimulation over primary motor cortex.

Analyzing the brain responses to transcranial magnetic stimulation (TMS) using electroencephalography (EEG) is a promising method for the assessment of functional cortical connectivity and excitability of areas accessible to this stimulation. However, until now it has been difficult to analyze the EEG responses during the several tens of milliseconds immediately following the stimulus due to TMS-induced artifacts. In the present study we show that by combining a specially adapted recording system with software artifact correction it is possible to remove a major part of the artifact and analyze the cortical responses as early as 10 ms after TMS. We used this methodology to examine responses of left and right primary motor cortex (M1) to TMS at different intensities. Based on the artifact-corrected data we propose a model for the cortical activation following M1 stimulation. The model revealed the same basic response sequence for both hemispheres. A large part of the response could be accounted for by two sources: a source close to the stimulation site (peaking approximately 15 ms after the stimulus) and a midline frontal source ipsilateral to the stimulus (peaking approximately 25 ms). In addition the model suggests responses in ipsilateral temporo-parietal junction areas (approximately 35 ms) and ipsilateral (approximately 30 ms) and middle (approximately 50 ms) cerebellum. Statistical analysis revealed significant dependence on stimulation intensity for the ipsilateral midline frontal source. The methodology developed in the present study paves the way for the detailed study of early responses to TMS in a wide variety of brain areas.

Alcohol Reduces Prefrontal Cortical Excitability in Humans: A Combined TMS and EEG Study

The effects of alcohol (0.8 g/kg) on the prefrontal cortex were studied in nine healthy subjects using the technique of transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG). A total of 120 magnetic pulses were delivered with a figure-of-eight coil to the left prefrontal cortex at the rate of 0.4–0.7 Hz. The EEG was recorded simultaneously with 60 scalp electrodes (41 electrodes were used for analysis); the TMS-evoked activation was estimated by the area under the global mean field amplitude (GMFA) time curve. TMS caused changes in EEG activity lasting up to 270 ms poststimulus. Alcohol decreased GMFA at 30–270 ms poststimulus (713±303 vs 478±142 μV ms; p=0.007). Alcohol-induced differences were most pronounced at anterior electrodes. These results suggest that alcohol reduces the excitability in the prefrontal cortex.