Sham tDCS: A hidden source of variability? Reflections for further blinded, controlled trials.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique increasingly used to modulate neural activity in the living brain. In order to establish the neurophysiological, cognitive or clinical effects of tDCS, most studies compare the effects of active tDCS to those observed with a sham tDCS intervention. In most cases, sham tDCS consists in delivering an active stimulation for a few seconds to mimic the sensations observed with active tDCS and keep participants blind to the intervention. However, to date, sham-controlled tDCS studies yield inconsistent results, which might arise in part from sham inconsistencies. Indeed, a multiplicity of sham stimulation protocols is being used in the tDCS research field and might have different biological effects beyond the intended transient sensations. Here, we seek to enlighten the scientific community to this possible confounding factor in order to increase reproducibility of neurophysiological, cognitive and clinical tDCS studies.

A comparison of language mapping by preoperative navigated transcranial magnetic stimulation and direct cortical stimulation during awake surgery.

BACKGROUND: Navigated transcranial magnetic stimulation (nTMS) is increasingly used in presurgical brain mapping. Preoperative nTMS results correlate well with direct cortical stimulation (DCS) data in the identification of the primary motor cortex. Repetitive nTMS can also be used for mapping of speech-sensitive cortical areas. OBJECTIVE: The current cohort study compares the safety and effectiveness of preoperative nTMS with DCS mapping during awake surgery for the identification of language areas in patients with left-sided cerebral lesions. METHODS: Twenty patients with tumors in or close to left-sided language eloquent regions were examined by repetitive nTMS before surgery. During awake surgery, language-eloquent cortex was identified by DCS. nTMS results were compared for accuracy and reliability with regard to DCS by projecting both results into the cortical parcellation system. RESULTS: Presurgical nTMS maps showed an overall sensitivity of 90.2%, specificity of 23.8%, positive predictive value of 35.6%, and negative predictive value of 83.9% compared with DCS. For the anatomic Broca's area, the corresponding values were a sensitivity of 100%, specificity of 13.0%, positive predictive value of 56.5%, and negative predictive value of 100%, respectively. CONCLUSION: Good overall correlation between repetitive nTMS and DCS was observed, particularly with regard to negatively mapped regions. Noninvasive inhibition mapping with nTMS is evolving as a valuable tool for preoperative mapping of language areas. Yet its low specificity in posterior language areas in the current study necessitates further research to refine the methodology.

A novel approach for documenting naming errors induced by navigated transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) is widely used both in basic research and in clinical practice. TMS has been utilized in studies of functional organization of speech in healthy volunteers. Navigated TMS (nTMS) allows preoperative mapping of the motor cortex for surgical planning. Recording behavioral responses to nTMS in the speech-related cortical network in a manner that allows off-line review of performance might increase utility of nTMS both for scientific and clinical purposes, e.g., for a careful preoperative planning. Four subjects participated in the study. The subjects named pictures of objects presented every 2-3s on a computer screen. One-second trains of 5 pulses were applied by nTMS 300ms after the presentation of pictures. The nTMS and stimulus presentation screens were cloned. A commercial digital camera was utilized to record the subject's performance and the screen clones. Delays between presentation, audio and video signals were eliminated by carefully tested combination of displays and camera. An experienced neuropsychologist studied the videos and classified the errors evoked by nTMS during the object naming. Complete anomias, semantic, phonological and performance errors were observed during nTMS of left fronto-parieto-temporal cortical regions. Several errors were detected only in the video classification. nTMS combined with synchronized video recording provides an accurate monitoring tool of behavioral TMS experiments. This experimental setup can be particularly useful for high-quality cognitive paradigms and for clinical purposes.

Preoperative functional mapping for rolandic brain tumor surgery: comparison of navigated transcranial magnetic stimulation to direct cortical stimulation.

BACKGROUND: Transcranial magnetic stimulation (TMS) is the only noninvasive method for presurgical stimulation mapping of cortical function. Recent technical advancements have significantly increased the focality and usability of the method. OBJECTIVE: To compare the accuracy of a 3-dimensional magnetic resonance imaging-navigated TMS system (nTMS) with the gold standard of direct cortical stimulation (DCS). METHODS: The primary motor areas of 20 patients with rolandic tumors were mapped preoperatively with nTMS at 110% of the individual resting motor threshold. Intraoperative DCS was available from 17 patients. The stimulus locations eliciting the largest electromyographic response in the target muscles ("hotspots") were determined for both methods. RESULTS: The nTMS and DCS hotspots were located on the same gyrus in all cases. The mean ± SEM distance between the nTMS and DCS hotspots was 7.83 ± 1.18 mm for the abductor pollicis brevis (APB) muscle (n = 15) and 7.07 ± 0.88 mm for the tibialis anterior muscle (n = 8). When a low number of DCS stimulations was performed, the distance between the nTMS and DCS hotspots increased substantially (r = -0.86 for APB). After the exclusion of the cases with < 15 DCS APB responses, the mean ± SEM distance between the hotspots was only 4.70 ± 1.09 mm for APB (n = 8). CONCLUSION: Peritumoral mapping of the motor cortex by nTMS agreed well with the gold standard of DCS. Thus, nTMS is a reliable tool for preoperative mapping of motor function.

Facilitation of tactile working memory by top-down suppression from prefrontal to primary somatosensory cortex during sensory interference.

Tactile working memory (WM) is improved by increasing top-down suppression of interfering sensory processing in S1 via a link from the middle frontal gyrus (MFG) to S1. Here we studied in healthy subjects whether the efficacy of top-down suppression varies with submodality of sensory interference. Navigated stimulation of the MFG-S1 link significantly improved tactile WM performance when accompanied by tactile but not visual interference of memory maintenance.

Cognitive and motor loops of the human cerebro-cerebellar system.

We applied fMRI and diffusion-weighted MRI to study the segregation of cognitive and motor functions in the human cerebro-cerebellar system. Our fMRI results show that a load increase in a nonverbal auditory working memory task is associated with enhanced brain activity in the parietal, dorsal premotor, and lateral prefrontal cortices and in lobules VII-VIII of the posterior cerebellum, whereas a sensory-motor control task activated the motor/somatosensory, medial prefrontal, and posterior cingulate cortices and lobules V/VI of the anterior cerebellum. The load-dependent activity in the crus I/II had a specific relationship with cognitive performance: This activity correlated negatively with load-dependent increase in RTs. This correlation between brain activity and RTs was not observed in the sensory-motor task in the activated cerebellar regions. Furthermore, probabilistic tractography analysis of the diffusion-weighted MRI data suggests that the tracts between the cerebral and the cerebellar areas exhibiting cognitive load-dependent and sensory-motor activity are mainly projected via separated pontine (feed-forward tracts) and thalamic (feedback tracts) nuclei. The tractography results also indicate that the crus I/II in the posterior cerebellum is linked with the lateral prefrontal areas activated by cognitive load increase, whereas the anterior cerebellar lobe is not. The current results support the view that cognitive and motor functions are segregated in the cerebellum. On the basis of these results and theories of the function of the cerebellum, we suggest that the posterior cerebellar activity during a demanding cognitive task is involved with optimization of the response speed.

Increasing top-down suppression from prefrontal cortex facilitates tactile working memory.

Navigated transcranial magnetic stimulation (TMS) combined with diffusion-weighted magnetic resonance imaging (DW-MRI) and tractography allows investigating functional anatomy of the human brain with high precision. Here we demonstrate that working memory (WM) processing of tactile temporal information is facilitated by delivering a single TMS pulse to the middle frontal gyrus (MFG) during memory maintenance. Facilitation was obtained only with a TMS pulse applied to a location of the MFG with anatomical connectivity to the primary somatosensory cortex (S1). TMS improved tactile WM also when distractive tactile stimuli interfered with memory maintenance. Moreover, TMS to the same MFG site attenuated somatosensory evoked responses (SEPs). The results suggest that the TMS-induced memory improvement is explained by increased top-down suppression of interfering sensory processing in S1 via the MFG-S1 link. These results demonstrate an anatomical and functional network that is involved in maintenance of tactile temporal WM.

Major depressive disorder and white matter abnormalities: a diffusion tensor imaging study with tract-based spatial statistics.

BACKGROUND: A few diffusion tensor imaging (DTI) studies have shown abnormalities in areas of white matter tracts involved in mood regulation in geriatric depressive patients, using a region-of-interest technique. A voxel-based morphometry DTI study of young depressive patients reported similar results. In this study, we explored the structure of the white matter of the whole brain with DTI in middle-aged major depressive disorder (MDD) patients, using novel tract-based spatial statistics. METHODS: Sixteen MDD patients and 20 controls underwent DTI. An automated tract-based spatial method (TBSS) was used to analyze the scans. RESULTS: Compared with controls, the MDD patients showed a trend for lower values of fractional anisotropy (FA) in the left sagittal stratum, and suggestive decreased FA in the right cingulate cortex and posterior body of corpus callosum. Regressing out the duration and severity of disorder in the model did not change the finding in the sagittal stratum, but dissipated the decrease of FA in latter regions. LIMITATIONS: Possibly by reason of a relatively small study sample for a TBSS, the results are suggestive, and should be replicated in further studies. CONCLUSIONS: A novel observer-independent DTI method showed decreased FA in the middle-aged MDD patients in white matter regions that have previously connected to the emotional regulation. Lower FA might imply underlying structural abnormalities that contribute to the dysfunction detected in the limbic-cortical network of depressive patients.

Distracters impair and create working memory-related neuronal activity in the prefrontal cortex.

The prefrontal cortex (PFC) has a central role in working memory (WM). Resistance to distraction is considered a fundamental feature of WM and PFC neuronal activity. However, although unexpected stimuli often disrupt our work, little is known about the underlying neuronal mechanisms involved. In the present study, we investigated whether irregularly presented distracters disrupt WM task performance and underlying neuronal activity. We recorded single neuron activity in the PFC of 2 monkeys performing WM tasks and investigated effects of auditory and visual distracters on WM performance and neuronal activity. Distracters impaired memory task performance and affected PFC neuronal activity. Distraction that was of the same sensory modality as the memorandum was more likely to impair WM performance and interfere with memory-related neuronal activity than information that was of a different sensory modality. The study also shows that neurons not involved in memory processing in less demanding conditions may become engaged in WM processing in more demanding conditions. The study demonstrates that WM performance and underlying neuronal activity are vulnerable to irregular distracters and suggests that the PFC has mechanisms that help to compensate for disruptive effects of external distracters.

Navigated transcranial magnetic stimulation of the primary somatosensory cortex impairs perceptual processing of tactile temporal discrimination.

Previous studies indicate that transcranial magnetic stimulation (TMS) with biphasic pulses applied approximately over the primary somatosensory cortex (S1) suppresses performance in vibrotactile temporal discrimination tasks; these previous results, however, do not allow separating perceptual influence from memory or decision-making. Moreover, earlier studies using external landmarks for directing biphasic TMS pulses to the cortex do not reveal whether the changes in vibrotactile task performance were due to action on S1 or an adjacent area. In the present study, we determined whether the S1 area representing a cutaneous test site is critical for perceptual processing of tactile temporal discrimination. Electrical test pulses were applied to the thenar skin of the hand and the subjects attempted to discriminate single from twin pulses. During discrimination task, monophasic TMS pulses or sham TMS pulses were directed anatomically accurately to the S1 area representing the thenar using magnetic resonance image-guided navigation. The subject's capacity to temporal discrimination was impaired with a decrease in the delay between the TMS pulse and the cutaneous test pulse from 50 to 0 ms. The result indicates that S1 area representing a cutaneous test site is involved in perceptual processing of tactile temporal discrimination.

Effects of an NMDA-receptor antagonist MK-801 on an MMN-like response recorded in anesthetized rats.

In the human brain, auditory sensory memory has been extensively studied using a well-defined component of event-related potential named the mismatch negativity (MMN). The MMN is generated in the auditory and frontal cortices in response to deviant stimuli. In monkeys, cortical N-methyl-d-aspartate (NMDA) receptors have a central role in the generation of the MMN. MMN-like responses have also been recorded in other animals, including rats. The present study aimed at determining whether the MMN-like response in rats depends on an intact NMDA-receptor system. We recorded auditory evoked responses during an oddball paradigm epidurally in anesthetized rats that had received intraperitoneal injections of saline or an NMDA-receptor antagonist MK-801. An MMN-like response was recorded in the oddball paradigm in saline-treated rats. Further, this response was dose-dependently blocked by MK-801. These results suggest that the MMN-like response in rats depends on an intact NMDA-receptor system.

Adaptation of neuromagnetic N1 without shifts in dipolar orientation.

306-channel magnetoencephalography, coregistered with high-resolution volumetric magnetic resonance imaging, was used with 10 healthy participants to test if repetition adapts subsequent processing of sounds in a sequence and whether this adaptation influenced the orientation of the dipolar sources in the auditory cortex. Auditory N1m responses to 1 kHz pure tones were indexed by clusters of sensors situated bilaterally over the temporal lobes. N1m was augmented in amplitude at an interstimulus interval of 16 s relative to 1 s. This neuromagnetic amplitude augment occurred in dipoles in the vicinity of the auditory cortex, without significant shifts in the dipolar orientation. Recent repetition thus adapts auditory cortical neurons, in a manner subject to recovery after a period of silence.

Significance of tissue anisotropy in optical tomography of the infant brain.

We study the effect of tissue anisotropy in optical tomography of neonates. A Monte Carlo method capable of modeling photon migration in an arbitrary 3D tissue model with spatially varying optical properties and tissue anisotropy is used for simulating measurements of neonates. Anatomical and diffusion tensor magnetic resonance imaging of neonates are used for creating the anatomical models. We find that tissue anisotropy affects the measured signal and the pattern of sensitivity in optical measurements.

Affine registration of diffusion tensor MR images.

We present a new algorithm for affine registration of diffusion tensor magnetic resonance (DT-MR) images. The method is based on a new formulation of a point-wise tensor similarity measure, which weights directional and magnitude information differently depending on the type of diffusion. The method is compared to a reference method, which uses normalized mutual information (NMI), calculated either from a fractional anisotropy (FA) map or a T2-weighted MR image. The registration methods are applied to real and simulated DT-MR images. Visual assessment is done for real data and for simulated data, registration accuracy is defined. The results show that the proposed method outperforms the reference method.

Modeling anisotropic light propagation in a realistic model of the human head.

A Monte Carlo model capable of describing photon migration in arbitrary three-dimensional geometry with spatially varying optical properties and tissue anisotropy is presented. We use the model to explore the effects of anisotropy for optical measurements of the human head. An anisotropic diffusion equation that corresponds to our Monte Carlo model is derived, and a comparison between the Monte Carlo model and the diffusion equation solution with finite elements is given.

Characterizing diffusion tensor imaging data with directional entropy.

We describe the use of directional entropy (DE) in the directional analysis of diffusion tensor imaging (DTI) data. The directional entropy is a measure of disorder in a directional distribution. It could provide a relatively simple, yet meaningful measure about the brain white matter integrity, complementary to the traditional measures used, such as mean diffusivity or indices of diffusion anisotropy. The challenge of the DTI is to produce measures that would be easily comparable across subject and patient populations. We studied directional distributions and entropy with simulations and measured DTI data. Directional entropy could serve as an additional measure to characterize developmental or pathological states in brain.