Fast Intracortical Sensory-Motor Integration: A Window Into the Pathophysiology of Parkinson’s Disease

Parkinson’s Disease (PD) is a prototypical basal ganglia disorder. Nigrostriatal dopaminergic denervation leads to progressive dysfunction of the cortico-basal ganglia-thalamo-cortical sensorimotor loops, causing the classical motor symptoms. Although the basal ganglia do not receive direct sensory input, they are important for sensorimotor integration. Therefore, the basal ganglia dysfunction in PD may profoundly affect sensory-motor interaction in the cortex. Cortical sensorimotor integration can be probed with transcranial magnetic stimulation (TMS) using a well-established conditioning-test paradigm, called short-latency afferent inhibition (SAI). SAI probes the fast-inhibitory effect of a conditioning peripheral electrical stimulus on the motor response evoked by a TMS test pulse given to the contralateral primary motor cortex (M1). Since SAI occurs at latencies that match the peaks of early cortical somatosensory potentials, the cortical circuitry generating SAI may play an important role in rapid online adjustments of cortical motor output to changes in somatosensory inputs. Here we review the existing studies that have used SAI to examine how PD affects fast cortical sensory-motor integration. Studies of SAI in PD have yielded variable results, showing reduced, normal or even enhanced levels of SAI. This variability may be attributed to the fact that the strength of SAI is influenced by several factors, such as differences in dopaminergic treatment or the clinical phenotype of PD. Inter-individual differences in the expression of SAI has been shown to scale with individual motor impairment as revealed by UPDRS motor score and thus, may reflect the magnitude of dopaminergic neurodegeneration. The magnitude of SAI has also been linked to cognitive dysfunction, and it has been suggested that SAI also reflects cholinergic denervation at the cortical level. Together, the results indicate that SAI is a useful marker of disease-related alterations in fast cortical sensory-motor integration driven by subcortical changes in the dopaminergic and cholinergic system. Since a multitude of neurobiological factors contribute to the magnitude of inhibition, any mechanistic interpretation of SAI changes in PD needs to consider the group characteristics in terms of phenotypical spectrum, disease stage, and medication

Can Transcranial Electrical Stimulation Localize Brain Function?

Transcranial electrical stimulation (TES) uses constant (TDCS) or alternating currents (TACS) to modulate brain activity. Most TES studies apply low-intensity currents through scalp electrodes (≤2 mA) using bipolar electrode arrangements, producing weak electrical fields in the brain (<1 V/m). Low-intensity TES has been employed in humans to induce changes in task performance during or after stimulation. In analogy to focal transcranial magnetic stimulation, TES-induced behavioral effects have often been taken as evidence for a causal involvement of the brain region underlying one of the two stimulation electrodes, often referred to as the active electrode. Here, we critically review the utility of bipolar low-intensity TES to localize human brain function. We summarize physiological substrates that constitute peripheral targets for TES and may mediate subliminal or overtly perceived peripheral stimulation during TES. We argue that peripheral co-stimulation may contribute to the behavioral effects of TES and should be controlled for by “sham” TES. We discuss biophysical properties of TES, which need to be considered, if one wishes to make realistic assumptions about which brain regions were preferentially targeted by TES. Using results from electric field calculations, we evaluate the validity of different strategies that have been used for selective spatial targeting. Finally, we comment on the challenge of adjusting the dose of TES considering dose–response relationships between the weak tissue currents and the physiological effects in targeted cortical areas. These considerations call for caution when attributing behavioral effects during or after low-intensity TES studies to a specific brain region and may facilitate the selection of best practices for future TES studies

Bifrontal transcranial direct current stimulation slows reaction time in a working memory task

BACKGROUND: Weak transcortical direct current stimulation (tDCS) applied to the cortex can shift the membrane potential of superficial neurons thereby modulating cortical excitability and activity. Here we test the possibility of modifying ongoing activity associated with working memory by tDCS. The concept of working memory applies to a system that is capable of transiently storing and manipulating information, as an integral part of the human memory system. We applied anodal and cathodal transcranial direct current (tDCS) stimulation (260 μA) bilaterally at fronto-cortical electrode sites on the scalp over 15 min repeatedly (15 sec-on/15 sec-off) as well as sham-tDCS while subjects performed a modified Sternberg task. RESULTS: Reaction time linearly increased with increasing set size. The slope of this increase was closely comparable for real and sham stimulation indicating that our real stimulation did not effect time required for memory scanning. However, reaction time was slowed during both anodal and cathodal stimulation as compared to placebo (p < 0.05) indicating that real stimulation hampered neuronal processing related to response selection and preparation. CONCLUSION: Intermittent tDCS over lateral prefrontal cortex during a working memory task impairs central nervous processing related to response selection and preparation. We conclude that this decrease in performance by our protocol of intermittent stimulation results from an interference mainly with the temporal dynamics of cortical processing as indexed by event-related sustained and oscillatory EEG activity such as theta

Aberrant neural signatures of decision-making:Pathological gamblers display cortico-striatal hypersensitivity to extreme gambles

AbstractPathological gambling is an addictive disorder characterized by an irresistible urge to gamble despite severe consequences. One of the hallmarks of pathological gambling is maladaptive and highly risky decision-making, which has been linked to dysregulation of reward-related brain regions such as the ventral striatum. However, previous studies have produced contradictory results regarding the implication of this network, revealing either hypo- or hypersensitivity to monetary gains and losses. One possible explanation is that the gambling brain might be misrepresenting the benefits and costs when weighting the potential outcomes, and not the gains and losses per se. To address this issue, we investigated whether pathological gambling is associated with abnormal brain activity during decisions that weight the utility of possible gains against possible losses. Pathological gamblers and healthy human subjects underwent functional magnetic resonance imaging while they accepted or rejected mixed gain/loss gambles with fifty–fifty chances of winning or losing. Contrary to healthy individuals, gamblers showed a U-shaped response profile reflecting hypersensitivity to the most appetitive and most aversive bets in an executive cortico-striatal network including the dorsolateral prefrontal cortex and caudate nucleus. This network is concerned with the evaluation of action–outcome contingencies, monitoring recent actions and anticipating their consequences. The dysregulation of this specific network, especially for extreme bets with large potentials consequences, offers a novel understanding of the neural basis of pathological gambling in terms of deficient associations between gambling actions and their financial impact

Human In-vivo Brain MR Current Density Imaging (MRCDI) based on Steady-state Free Precession Free Induction Decay (SSFP-FID)

MRCDI is a novel technique for non-invasive measurement of weak currents in the human head, which is important in several neuroscience applications. Here, we present reliable in-vivo MRCDI measurements in the human brain based on SSFP-FID, yielding an unprecedented accuracy. We demonstrate the destructive influences of stray magnetic fields caused by the current passing through feeding cables, and propose a correction method. Also, we show inter-individual differences in MRCDI measurements for two different current profiles, and compare the measurements with simulations based on individualized head models. The simulations of the current-induced magnetic fields show good agreement with in-vivo brain measurements