Jürgen Baudewig

Functional MRI of the immediate impact of transcranial magnetic stimulation on cortical and subcortical motor circuits

Recent studies indicate that the cortical effects of transcranial magnetic stimulation (TMS) may not be localized to the site of stimulation, but spread to other distant areas. Using echo‐planar imaging with blood‐oxygenation‐level‐dependent (BOLD) contrast at 3 Tesla, we measured MRI signal changes in cortical and subcortical motor regions during high‐frequency (3.125 Hz) repetitive TMS (rTMS) of the left sensorimotor cortex (M1/S1) at intensities above and below the active motor threshold in healthy humans. The supra‐ and subthreshold nature of the TMS pulses was confirmed by simultaneous electromyographic monitoring of a hand muscle. Suprathreshold rTMS activated a network of primary and secondary cortical motor regions including M1/S1, supplementary motor area, dorsal premotor cortex, cingulate motor area, the putamen and thalamus. Subthreshold rTMS elicited no MRI‐detectable activity in the stimulated M1/S1, but otherwise led to a similar activation pattern as obtained for suprathreshold stimulation though at reduced intensity. In addition, we observed activations within the auditory system, including the transverse and superior temporal gyrus, inferior colliculus and medial geniculate nucleus. The present findings support the notion that re‐afferent feedback from evoked movements represents the dominant input to the motor system via M1 during suprathreshold stimulation. The BOLD MRI changes in motor areas distant from the site of subthreshold stimulation are likely to originate from altered synaptic transmissions due to induced excitability changes in M1/S1. They reflect the capability of rTMS to target both local and remote brain regions as tightly connected constituents of a cortical and subcortical network.

Changes in human motor cortex excitability induced by dopaminergic and anti-dopaminergic drugs

Transcranial magnetic stimulation was used to probe the acute effect of a single oral dose of various dopaminergic (levodopa, selegiline, bromocriptine) and antidopaminergic drugs (sulpiride, haloperidol) on motor cortex excitability in healthy volunteers. Motor threshold, intracortical inhibition and intracortical facilitation were tested in the abductor digiti minimi muscle. The latter two parameters were studied in a conditioning-test paired stimulus paradigm. The principal findings were an increase in intracortical inhibition by bromocriptine, and, conversely, a decrease in intracortical inhibition and an increase in intracortical facilitation by haloperidol. Effects peaked at delays consistent with the pharmacokinetics of the two drugs and were fully reversible. In conclusion, dopamine receptor agonists and antagonists can be considered inverse modulators of motor cortex excitability: the former enhance inhibition while the latter reduce it. The relation of the present findings to current models of motor excitability abnormalities in movement disorders will be discussed.

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.

Regional Modulation of BOLD MRI Responses to Human Sensorimotor Activation by Transcranial Direct Current Stimulation

Blood oxygenation level dependent (BOLD) MRI was used to monitor modulations of human sensorimotor activity by prior transcranial direct current stimulation (tDCS). Activation maps for a right hand sequential finger opposition task were obtained for six subjects before as well as 0–5 min and 15–20 min after a 5‐min period of 1 mA cathodal and, in a separate session, anodal tDCS of the left‐hemispheric motor cortex. Cathodal tDCS resulted in a global decrease of the mean number of activated pixels by 38% (P < 0.01) 0–5 min after stimulation, which reduced to 28% (P < 0.05) 15–20 min after stimulation. A region‐of‐interest analysis revealed a 57% decrease of activated pixels (P < 0.001) in the supplementary motor area, but no change in the hand area of the primary motor cortex. Anodal tDCS yielded a nonsignificant 5% increase of activated pixels with no regional differences. These findings support the view that reduced neuroaxonal excitability after cathodal tDCS causes reduced brain activity. However, rather than affecting the primary sensorimotor input of an active task, the process appears to dampen those responses that rely on cortico‐cortical connections and related processing. Magn Reson Med 45:196–201, 2001.

Subthreshold high-frequency TMS of human primary motor cortex modulates interconnected frontal motor areas as detected by interleaved fMRI-TMS

To elucidate changes in human brain activity evoked by repetitive transcranial magnetic stimulation (rTMS), sub- and suprathreshold rTMS (4 Hz, 10 s) over the left primary sensorimotor cortex (M1/S1) was interleaved with blood-oxygenation-level-dependent (BOLD) echo-planar imaging of primary and secondary motor areas. Suprathreshold rTMS over left M1/S1 caused marked increases in BOLD signal in the stimulated area and SMA-proper in seven of eight subjects. By contrast, we found no change in BOLD signal in the stimulated M1/S1, when rTMS was given at intensities that were subthreshold for inducing motor responses in the contralateral hand. However, five of eight subjects showed consistent increases in BOLD MRI signal in the SMA-proper and, to a lesser extent, in bilateral lateral premotor cortex (LPMC) during subthreshold rTMS. A decrease in BOLD MRI signal was found in contralateral (right) M1/S1 in 6/8 subjects across all conditions. No significant changes were observed in the pre-SMA. The results support the notion that BOLD MRI responses to suprathreshold rTMS over M1/S1 are dominated by neuronal activity related to reafferent processing of TMS-induced hand movements. At subthreshold intensity, a short train of high-frequency rTMS seems to predominantly modulate activity of corticocortical connections which link the stimulated area with remote frontal premotor areas.

BOLD MRI responses to repetitive TMS over human dorsal premotor cortex

Functional magnetic resonance imaging (fMRI) studies in humans have hitherto failed to demonstrate activity changes in the direct vicinity of transcranial magnetic stimulation (TMS) that cannot be attributed to re-afferent somatosensory feedback or a spread of excitation. In order to investigate the underlying activity changes at the site of stimulation as well as in remote connected regions, we applied short trains of high-intensity (110% of resting motor threshold) and low-intensity (90% of active motor threshold) repetitive TMS (rTMS; 3 Hz, 10 s duration) over the presumed location of the left dorsal premotor cortex (PMd) during fMRI. Signal increases in the direct vicinity of the stimulated PMd were observed during rTMS at 110% RMT. However, positive BOLD MRI responses were observed with rTMS at both 90% and 110% RMT in connected brain regions such as right PMd, bilateral PMv, supplementary motor area, somatosensory cortex, cingulate motor area, left posterior temporal lobe, cerebellum, and caudate nucleus. Responses were generally smaller during low-intensity rTMS. The results indicate that short trains of TMS can modify local hemodynamics in the absence of overt motor responses. In addition, premotor rTMS cannot only effectively stimulate cortico-cortical but also cortico-subcortical connections even at low stimulation intensities.

The neural basis of the egocentric and allocentric spatial frame of reference

The present study examines the functional and anatomical underpinnings of egocentric and allocentric coding of spatial coordinates. For this purpose, we set up a functional magnet resonance imaging experiment using verbal descriptions of spatial relations either with respect to the listener (egocentric) or without any body-centered relations (allocentric) to induce the two different spatial coding strategies. We aimed to identify and distinguish the neuroanatomical correlates of egocentric and allocentric spatial coding without any possible influences by visual stimulation. Results from sixteen participants show a general involvement of a bilateral fronto-parietal network associated with spatial information processing. Furthermore, the egocentric and allocentric conditions gave rise to activations in primary visual areas in both hemispheres. Moreover, data show separate neural circuits mediating different spatial coding strategies. While egocentric spatial coding mainly recruits the precuneus, allocentric coding of space activates a network comprising the right superior and inferior parietal lobe and the ventrolateral occipito-temporal cortex bilaterally. Furthermore, bilateral hippocampal involvement was observed during allocentric, but not during egocentric spatial processing. Our results demonstrate that the processing of egocentric spatial relations is mediated by medial superior-posterior areas, whereas allocentric spatial coding requires an additional involvement of right parietal cortex, the ventral visual stream and the hippocampal formation. These data suggest that a hierarchically organized processing system exists in which the egocentric spatial coding requires only a subsystem of the processing resources of the allocentric condition.

Functional MRI of cortical activations induced by transcranial magnetic stimulation (TMS)

The effects of repetitive transcranial magnetic stimulation (rTMS) on human brain activity and associated hemodynamics were investigated by blood-oxygenation-level-dependent (BOLD) MRI using echo-planar imaging at 2.0 T. Apart from bilateral activation of the auditory cortex by the audible rTMS discharges (23 bursts, 1 s duration, 10 Hz, 10–20 s interstimulus intervals), BOLD responses were restricted to cortical representations of actual finger movements performed either voluntarily or evoked by suprathreshold rTMS of the motor cortex. Neither subthreshold rTMS of the motor cortex nor suprathreshold rTMS of the lateral premotor cortex induced a detectable BOLD response. These findings suggest that neuronal depolarization as induced by rTMS modulates the spiking output of a brain area but does not automatically alter cerebral blood flow and oxygenation. The observation of BOLD MRI activations probably reflects the afferent intracortical processing of real movements.

Behavioral correlates of negative BOLD signal changes in the primary somatosensory cortex

Functional magnetic resonance imaging (fMRI) hypothesis testing based on the blood oxygenation level dependent (BOLD) contrast mechanism typically involves a search for a positive effect during a specific task relative to a control state. However, aside from positive BOLD signal changes there is converging evidence that neuronal responses within various cortical areas also induce negative BOLD signals. Although it is commonly believed that these negative BOLD signal changes reflect suppression of neuronal activity direct evidence for this assumption is sparse. Since the somatosensory system offers the opportunity to quantitatively test sensory function during concomitant activation and has been well-characterized with fMRI in the past, the aim of this study was to determine the functional significance of ipsilateral negative BOLD signal changes during unilateral sensory stimulation. For this, we measured BOLD responses in the somatosensory system during unilateral electric stimulation of the right median nerve and additionally determined the current perception threshold of the left index finger during right-sided electrical median nerve stimulation as a quantitative measure of sensory function. As expected, positive BOLD signal changes were observed in the contralateral primary and bilateral secondary somatosensory areas, whereas a decreased BOLD signal was observed in the ipsilateral primary somatosensory cortex (SI). The negative BOLD signal changes were much more spatially extensive than the representation of the hand area within the ipsilateral SI. The negative BOLD signal changes in the area of the index finger highly correlated with an increase in current perception thresholds of the contralateral, unstimulated finger, thus supporting the notion that the ipsilateral negative BOLD response reflects a functionally effective inhibition in the somatosensory system.

Voluntary pelvic floor muscle control--an fMRI study.

Storage and periodic expulsion of urine by the bladder are controlled by central pathways and organized as simple on-off switching circuits. Several reports concerning aspects of micturition control have identified distinct regions in the brainstem, like the pontine micturition center (PMC) and the periaqueductal gray (PAG), as well as the cerebellum, basal ganglia, limbic system, and cortical areas that are organized in a widespread network. The present study focused on the involvement of these specific brain regions in pelvic floor muscle control. Functional magnetic resonance imaging (fMRI) was performed at 3T in 11 healthy women with urge to void due to a filled bladder, who were instructed to either imitate voiding by releasing or to imitate interruption of voiding by contracting pelvic floor muscles. None of the subjects was able to start voiding during the experiments, presumably due to subconscious restraint resulting from the inconvenient situation. Relaxation and contraction of pelvic floor muscles induced strong and similar activation patterns including frontal cortex, sensory-motor cortex, cerebellum, and basal ganglia. Furthermore, well-localized activations in the PMC and the PAG were identified. To our knowledge, this is the first study using fMRI to demonstrate micturition-related activity in these brainstem structures. The presented approach proved to characterize the widespread central network in pelvic floor muscle control. Thus, in patients with voiding dysfunction, fMRI will be useful to elucidate the individual disturbance level.