Alexander T. Sack

Optimizing functional accuracy of tms in cognitive studies: A comparison of methods

Transcranial magnetic stimulation (TMS) is a tool for inducing transient disruptions of neural activity noninvasively in conscious human volunteers. In recent years, the investigative domain of TMS has expanded and now encompasses causal structure–function relationships across the whole gamut of cognitive functions and associated cortical brain regions. Consequently, the importance of how to determine the target stimulation site has increased and a number of alternative methods have emerged. Comparison across studies is precluded because different studies necessarily use different tasks, sites, TMS conditions, and have different goals. Here, therefore, we systematically compare four commonly used TMS coil positioning approaches by using them to induce behavioral change in a single cognitive study. Specifically, we investigated the behavioral impact of right parietal TMS during a number comparison task, while basing TMS localization either on (i) individual fMRI-guided TMS neuronavigation, (ii) individual MRI-guided TMS neuronavigation, (iii) group functional Talairach coordinates, or (iv) 10–20 EEG position P4. We quantified the exact behavioral effects induced by TMS using each approach, calculated the standardized experimental effect sizes, and conducted a statistical power analysis in order to calculate the optimal sample size required to reveal statistical significance. Our findings revealed a systematic difference between the four approaches, with the individual fMRI-guided TMS neuronavigation yielding the strongest and the P4 stimulation approach yielding the smallest behavioral effect size. Accordingly, power analyses revealed that although in the fMRI-guided neuronavigation approach five participants were sufficient to reveal a significant behavioral effect, the number of necessary participants increased to n = 9 when employing MRI-guided neuronavigation, to n = 13 in case of TMS based on group Talairach coordinates, and to n = 47 when applying TMS over P4. We discuss these graded effect size differences in light of the revealed interindividual variances in the actual target stimulation site within and between approaches.

Tracking the Mind's Image in the Brain I: Time-Resolved fMRI during Visuospatial Mental Imagery

Mental imagery, the generation and manipulation of mental representations in the absence of sensory stimulation, is a core element of numerous cognitive processes. We investigate the cortical mechanisms underlying imagery and spatial analysis in the visual domain using event-related functional magnetic resonance imaging during the mental clock task. The time-resolved analysis of cortical activation from auditory perception to motor response reveals a sequential activation of the left and right posterior parietal cortex, suggesting that these regions perform distinct functions in this imagery task. This is confirmed by a trial-by-trial analysis of correlations between reaction time and onset, width, and amplitude of the hemodynamic response. These findings pose neurophysiological constraints on cognitive models of mental imagery.

Functional imaging of visuospatial processing in Alzheimer's disease

Alzheimers disease (AD) is known to cause a variety of disturbances of higher visual functions that are closely related to the neuropathological changes. Visual association areas are more affected than primary visual cortex. Additionally, there is evidence from neuropsychological and imaging studies during rest or passive visual stimulation that the occipitotemporal pathway is less affected than the parietal pathway. Our goal was to investigate functional activation patterns during active visuospatial processing in AD patients and the impact of local cerebral atrophy on the strength of functional activation. Fourteen AD patients and fourteen age-matched controls were measured with functional magnetic resonance imaging (fMRI) while they performed an angle discrimination task. Both groups revealed overlapping networks engaged in angle discrimination including the superior parietal lobule (SPL), frontal and occipitotemporal (OTC) cortical regions, primary visual cortex, basal ganglia, and thalamus. The most pronounced differences between the two groups were found in the SPL (more activity in controls) and OTC (more activity in patients). The differences in functional activation between the AD patients and controls were partly explained by the differences in individual SPL atrophy. These results indicate that parietal dysfunction in mild to moderate AD is compensated by recruitment of the ventral visual pathway. We furthermore suggest that local cerebral atrophy should be considered as a covariate in functional imaging studies of neurodegenerative disorders.

Virtual dyscalculia induced by parietal-lobe TMS impairs automatic magnitude processing

People suffering from developmental dyscalculia encounter difficulties in automatically accessing numerical magnitudes [1-3]. For example, when instructed to attend to the physical size of a number while ignoring its numerical value, dyscalculic subjects, unlike healthy participants, fail to process the irrelevant dimension automatically and subsequently show a smaller size-congruity effect (difference in reaction time between incongruent [e.g., a physically large 2 and a physically small 4] and congruent [e.g., a physically small 2 and a physically large 4] conditions), and no facilitation (neutral [e.g., a physically small 2 and a physically large 2] versus congruent) [3]. Previous imaging studies determined the intraparietal sulcus (IPS) as a central area for numerical processing [4-11]. A few studies tried to identify the brain dysfunction underlying developmental dyscalculia but yielded mixed results regarding the involvement of the left [12] or the right [13] IPS. Here we applied fMRI-guided TMS neuronavigation to disrupt left- or right-IPS activation clusters in order to induce dyscalculic-like behavioral deficits in healthy volunteers. Automatic magnitude processing was impaired only during disruption of right-IPS activity. When using the identical paradigm with dyscalculic participants, we reproduced a result pattern similar to that obtained with nondyscalculic volunteers during right-IPS disruption. These findings provide direct evidence for the functional role of right IPS in automatic magnitude processing.

Combining transcranial magnetic stimulation and functional imaging in cognitive brain research: possibilities and limitations.

Transcranial magnetic stimulation (TMS) is a widely used tool for the non-invasive study of basic neurophysiological processes and the relationship between brain and behavior. We review the physical and physiological background of TMS and discuss the large body of perceptual and cognitive studies, mainly in the visual domain, that have been performed with TMS in the past 15 years. We compare TMS with other neurophysiological and neuropsychological research tools and propose that TMS, compared with the classical neuropsychological lesion studies, can make its own unique contribution. As the main focus of this review, we describe the different approaches of combining TMS with functional neuroimaging techniques. We also discuss important shortcomings of TMS, especially the limited knowledge concerning its physiological effects, which often make the interpretation of TMS results ambiguous. We conclude with a critical analysis of the resulting conceptual and methodological limitations that the investigation of functional brain-behavior relationships still has to face. We argue that while some of the methodological limitations of TMS applied alone can be overcome by combination with functional neuroimaging, others will persist until its physical and physiological effects can be controlled.

Parietal cortex and spatial cognition

The parietal cortex consists of several prominent anatomical regions in the posterior part of the human brain. Although very heterogeneous stimuli and tasks activate parietal brain regions, a large body of empirical evidence points to a particular role of the posterior parietal cortex in spatial cognition. This article aims at providing a comprised overview regarding the existing evidence on the functional architecture of posterior parietal cortex and its relation to spatial cognition abilities. The article summarizes and systematically compares evidence from lesion, human functional brain imaging, and human functional brain interference studies, providing the whole range from early neuropsychological insights to latest state-of-the-art multimodal functional imaging and multivariate brain connectivity approaches. As for this latter type of evidence, the article outlines in more detail how our group has recently applied: (i) combined TMS & fMRI, (ii) data-driven multivariate fMRI, and (iii) effective brain connectivity analyses in order to functionally segregate the specific contribution of various parietal sub-regions for particular spatial sub-functions. Based on these recent findings, it is proposed that we are now at the verge of applying these new analytical frameworks in human functional brain imaging in order to functionally fractionate brain regions which are conventionally modelled as functional units, e.g. areas within the posterior parietal cortex, into distinct subdivisions with different functional contributions.

The temporal characteristics of motion processing in hMT/V5+: combining fMRI and neuronavigated TMS

Functional imaging has demonstrated the specific involvement of the human middle-temporal complex (hMT/V5+) during processing of moving stimuli. Some studies applied transcranial magnetic stimulation (TMS) to investigate the causal relevance of hMT/V5+ for motion perception. Although the studies used similar visual stimuli and TMS parameters, the critical time point of functionally relevant hMT/V5+ activity differed by 100 ms and more. The present study aimed to elucidate further the temporal characteristics of motion processing in hMT/V5+ by investigating all critical time windows currently debated in the literature. In contrast to previous studies, we used TMS neuronavigation based on individual fMRI results of five participants to target hMT/V5+, applying single-pulse TMS at 24 different time windows (-50 till +200 ms relative to stimulus onset). We revealed that TMS significantly impaired motion perception when applied over hMT/V5+ at 40 to 30 ms before as well as 130 to 150 ms after onset of the moving stimuli. While the late effective time window conforms to results from previous experiments, we did not find evidence for an early time window around 0 ms that has been reported in other studies. Our neuronavigation approach enabled us to quantify the interindividual variance in the exact location of hMT/V5+ and the respective TMS target position on the skull of the participants. Considering that shifting the TMS coil position only by a few millimeters can already lead to a complete loss of TMS effects, our study clearly demonstrates the utility of neuronavigated TMS when investigating specific neuronal effects as in the case of motion processing.

Functional activation imaging in aging and dementia

With life expectancy increasing continuously, the effects of neurodegeneration on brain function are a topic of ever increasing importance. Thus there is a need for tools and models that probe both the functional consequences of neurodegenerative processes and compensatory mechanisms that might occur. As neurodegenerative burden and compensatory mechanisms may change over time, these tools will ideally be applied multiple times over the lifespan. Specifically, in order to elucidate whether brain-activation patterns in Alzheimers disease (AD) and in healthy aging follow general rules in the context of degeneration and compensation, it is necessary to compare functional brain-activation patterns during different states of neurodegeneration. This article integrates the findings of functional activation studies at different stages of neurodegeneration: in healthy aging, in subjects at high risk of developing dementia, in subjects with mild cognitive impairment (MCI), and in patients suffering from AD. We review existing theoretical models that aim to explain the underlying mechanisms of functional activation changes in aging and dementia, and we propose an integrative account, which allows for different neural response patterns depending on the amount of neuronal damage and the recruitment of compensatory pathways.

The Brain's Intention to Imitate: The Neurobiology of Intentional versus Automatic Imitation

Whenever we observe a movement of a conspecific, our mirror neuron system becomes activated, urging us to imitate the observed movement. However, because such automatic imitation is not always appropriate, an inhibitive component keeping us from imitating everything we see seems crucial for an effective social behavior. This becomes evident from neuropsychological conditions like echopraxia, in which this suppression is absent. Here, we unraveled the neurodynamics underlying this proposed inhibition of automatic imitation by measuring and manipulating brain activity during the execution of a stimulus-response compatibility paradigm. Within the identified connectivity network, right middle/inferior frontal cortex sends neural input concerning general response inhibition to right premotor cortex, which is involved in automatic imitation. Subsequently, the fully prepared imitative response is sent to left opercular cortex that functions as a final gating mechanism for intentional imitation. We propose an informed neurocognitive model of inhibition of automatic imitation, suggesting a functional dissociation between automatic and intentional imitation.

Alpha-Band Rhythms in Visual Task Performance: Phase-Locking by Rhythmic Sensory Stimulation

Oscillations are an important aspect of neuronal activity. Interestingly, oscillatory patterns are also observed in behaviour, such as in visual performance measures after the presentation of a brief sensory event in the visual or another modality. These oscillations in visual performance cycle at the typical frequencies of brain rhythms, suggesting that perception may be closely linked to brain oscillations. We here investigated this link for a prominent rhythm of the visual system (the alpha-rhythm, 8–12 Hz) by applying rhythmic visual stimulation at alpha-frequency (10.6 Hz), known to lead to a resonance response in visual areas, and testing its effects on subsequent visual target discrimination. Our data show that rhythmic visual stimulation at 10.6 Hz: 1) has specific behavioral consequences, relative to stimulation at control frequencies (3.9 Hz, 7.1 Hz, 14.2 Hz), and 2) leads to alpha-band oscillations in visual performance measures, that 3) correlate in precise frequency across individuals with resting alpha-rhythms recorded over parieto-occipital areas. The most parsimonious explanation for these three findings is entrainment (phase-locking) of ongoing perceptually relevant alpha-band brain oscillations by rhythmic sensory events. These findings are in line with occipital alpha-oscillations underlying periodicity in visual performance, and suggest that rhythmic stimulation at frequencies of intrinsic brain-rhythms can be used to reveal influences of these rhythms on task performance to study their functional roles.