Paired-pulse navigated TMS is more effective than single-pulse navigated TMS for mapping upper extremity muscles in brain tumor patients

ObjectiveSingle-pulse navigated transcranial magnetic stimulation (sp-nTMS) is used for presurgical motor mapping in patients with motor-eloquent lesions. However, recently introduced paired-pulse nTMS (pp-nTMS) with biphasic pulses could improve motor mapping.MethodsThirty-four patients (mean age: 56.0 ± 12.7 years, 53.0% high-grade glioma) with motor-eloquent lesions underwent motor mapping of upper extremity representations and nTMS-based tractography of the corticospinal tract (CST) by both sp-nTMS and pp-nTMS with biphasic pulses for the tumor-affected hemisphere before resection.ResultsIn three patients (8.8%), conventional sp-nTMS did not provide motor-positive points, in contrast to pp-nTMS that was capable of generating motor maps in all patients. Good concordance between pp-nTMS and sp-nTMS in the spatial location of motor hotspots and center of gravity (CoG) as well as for CST tracking was observed, with pp-nTMS leading to similar motor map volumes (585.0 ± 667.8 vs. 586.8 ± 204.2 mm³, p = 0.9889) with considerably lower resting motor thresholds (35.0 ± 8.8 vs. 32.8 ± 7.6% of stimulator output, p = 0.0004).ConclusionsPp-nTMS with biphasic pulses may provide motor maps even in highly demanding cases with tumor-affected motor structures or edema, using lower stimulation intensity compared to sp-nTMS.SignificancePp-nTMS with biphasic pulses could replace standardly used sp-nTMS for motor mapping and may be safer due to lower stimulation intensity.     

Visualization of the electrical activity of the cauda equina using a magnetospinography system in healthy subjects

ObjectiveTo establish a method to measure cauda equina action fields (CEAFs) and visualize the electrical activities of the cauda equina in a broadly aged group of healthy adults.MethodsUsing a 124-channel magnetospinography (MSG) system with superconducting interference devices, the CEAFs of 43 healthy volunteers (22–64 years of age) were measured after stimulation of the peroneal nerve at the knee. Reconstructed currents were obtained from the CEAFs and superimposed on the X-ray image. Conduction velocities were also calculated from the waveform of the reconstructed currents.ResultsThe reconstructed currents were successfully visualized. They flowed into the L5/S1 foramen about 8.25–8.95 ms after the stimulation and propagated cranially along the spinal canal. In 32 subjects (74%), the conduction velocities of the reconstructed currents in the cauda equina could be calculated from the peak latency at the L2–L5 level.ConclusionsMSG visualized the electrical activity of the cauda equina after peroneal nerve stimulation in healthy adults. In addition, the conduction velocities of the reconstructed currents in the cauda equina could be calculated, despite previously being difficult to measure.SignificanceMSG has the potential to be a novel and noninvasive functional examination for lumbar spinal disease.     

Age-related changes in late synaptic inputs to corticospinal neurons and their functional significance: A paired-pulse TMS study

BackgroundRecent work suggests that the function of intracortical interneurons activated by transcranial magnetic stimulation (TMS) is modified in older adults, with the circuits generating short-interval intracortical facilitation (SICF) at longer intervals appearing to be particularly affected.ObjectiveTo use SICF to quantify age-related changes in the excitability and recruitment of late synaptic inputs to corticospinal neurons, and investigate if changes within these circuits contribute to altered motor performance in older adults.MethodsSICF was recorded with 3 different conditioning intensities in 23 young (23.0 ± 4.2 years) and 21 older (67.1 ± 1.1 years) adults. These measures were performed with conventional (posterior-anterior, PA) and reverse (anterior-posterior, AP) current directions using interstimulus intervals targeting late synaptic inputs to corticospinal neurons (3.5–5.3 ms).ResultsPeak SICF recorded with a PA current (SICF_PA) was reduced in older adults (P < 0.0001), and occurred at a longer latency (P < 0.05). Furthermore, there was reduced recruitment of SICF_PA in older adults (P < 0.0001), but this did not interact with the age-related shift in SICF_PA (P = 0.2). In addition, reduced performance on the Purdue pegboard was predicted by increased SICF_PA (P < 0.04) occurring at longer latencies (P < 0.04) in old but not young adults. For SICF recorded with an AP current (SICF_AP), facilitation was again reduced at longer latencies in older adults (P < 0.0001), but recruitment was not different between groups (P = 0.7) and was unrelated to motor function.ConclusionThese results suggest that there are age-related changes in late synaptic inputs to corticospinal neurons and that these changes influence fine motor performance.     

Improvement of brain function after surgery in infants with posterior quadrant cortical dysplasia

ObjectiveTo reveal whether neurodevelopmental outcome of infants after epilepsy surgery can be quantitatively assessed by electroencephalography (EEG) functional connectivity analysis.MethodsWe enrolled 13 infants with posterior quadrant dysplasia aged <2 years who were treated using posterior quadrantectomy and 21 age-matched infants. EEG was performed both before and one year after surgery. Developmental quotient (DQ) was assessed both before and 3 years after surgery. The phase lag index (PLI) of three different pairs of electrodes in the nonsurgical hemisphere, i.e., the anterior short distance (ASD), posterior short distance (PSD), and long distance (LD) pairs, were calculated as indices of brain connectivity. The relationship between the PLI and DQ was evaluated.ResultsOverall, 77% infants experienced seizure freedom after surgery. The beta- and gamma- range PLI of PSD pairs increased preoperatively. All these pairs normalized postoperatively. Simple linear regression analysis revealed a significant relationship between the postoperative DQ and the postoperative beta-band PLI of ASD pairs.ConclusionPreoperative abnormal hyper-connectivity was normalized to the control level after surgery. The postoperative hyperconnectivity was associated with long-term neurodevelopmental improvement.SignificancePLI quantifies neurodevelopmental improvements after posterior quadrantectomy.     

SICI during changing brain states: Differences in methodology can lead to different conclusions

BackgroundShort-latency intracortical inhibition (SICI) is extensively used to probe GABAergic inhibitory mechanisms in M1. Task-related changes in SICI are presumed to reflect changes in the central excitability of GABAergic pathways. Usually, the level of SICI is evaluated using a single intensity of conditioning stimulus so that inhibition can be compared in different brain states.ObjectiveHere, we show that this approach may sometimes be inadequate since distinct conclusions can be drawn if a different CS intensity is used.MethodsWe measured SICI using a range of CS intensities at rest and during a warned simple reaction time task.ConclusionsOur results show that SICI changes that occurred during the task could be either larger or smaller than at rest depending on the intensity of the CS. These findings indicate that careful interpretation of results are needed when a single intensity of CS is used to measure task-related physiological changes.     

Comparison of clinical outcomes with left unilateral and sequential bilateral Transcranial Magnetic Stimulation (TMS) treatment of major depressive disorder in a large patient registry

BackgroundIt has been suggested that sequential bilateral (SBL) TMS, combining high frequency, left dorsolateral prefrontal cortex (DLPFC) stimulation and low frequency, right DLPFC stimulation, is more effective than unilateral TMS.ObjectiveTo contrast treatment outcomes of left unilateral (LUL) and SBL protocols.MethodsRegistry data were collected at 111 practice sites. Of 10,099 patients, 3,871 comprised a modified intent-to-treat (mITT) sample, defined as a primary MDD diagnosis, age ≥18, and PHQ-9 completion before TMS and at least one PHQ-9 assessment after baseline. The mITT sample received high frequency (10 Hz) LUL TMS exclusively (N = 3,327) or SBL TMS in at least 90% of sessions (N = 544). Completers (N = 3,049) were responders or had received ≥20 sessions and had an end of acute treatment PHQ-9 assessment. To control for site effects, a Matched sample (N = 653) included Completers at sites that used both protocols. To control for selection bias, the SBL group was also compared to a Restricted LUL group, drawn from sites where no patient switched to SBL after substantial exposure to LUL TMS. Secondary analyses were conducted on CGI-S ratings.ResultsThe LUL group had superior outcomes compared to the SBL group for multiple PHQ-9 and CGI-S continuous and categorical measures in the mITT, Completer and Matched samples, including in the specified primary analyses. However, outcome differences were not observed when comparing the Restricted LUL and SBL groups. Within SBL protocols, the LUL-RUL order had superior outcomes compared to the RUL-LUL order in all CGI-S, but not PHQ-9, measures.ConclusionsWhile limited by the naturalistic design, there was no evidence that SBL TMS was superior to LUL TMS. The sequential order of RUL TMS followed by LUL TMS may have reduced efficacy compared to LUL TMS followed by RUL TMS.     

A theoretical framework for the site-specific and frequency-dependent neuronal effects of deep brain stimulation

BackgroundDeep brain stimulation is an established therapy for several neurological disorders; however, its effects on neuronal activity vary across brain regions and depend on stimulation settings. Understanding these variable responses can aid in the development of physiologically-informed stimulation paradigms in existing or prospective indications.ObjectiveProvide experimental and computational insights into the brain-region-specific and frequency-dependent effects of extracellular stimulation on neuronal activity.MethodsIn patients with movement disorders, single-neuron recordings were acquired from the subthalamic nucleus, substantia nigra pars reticulata, ventral intermediate nucleus, or reticular thalamus during microstimulation across various frequencies (1–100 Hz) to assess single-pulse and frequency-response functions. Moreover, a biophysically-realistic computational framework was developed which generated postsynaptic responses under the assumption that electrical stimuli simultaneously activated all convergent presynaptic inputs to stimulation target neurons. The framework took into consideration the relative distributions of excitatory/inhibitory afferent inputs to model site-specific responses, which were in turn embedded within a model of short-term synaptic plasticity to account for stimulation frequency-dependence.ResultsWe demonstrated microstimulation-evoked excitatory neuronal responses in thalamic structures (which have predominantly excitatory inputs) and inhibitory responses in basal ganglia structures (predominantly inhibitory inputs); however, higher stimulation frequencies led to a loss of site-specificity and convergence towards neuronal suppression. The model confirmed that site-specific responses could be simulated by accounting for local neuroanatomical/microcircuit properties, while suppression of neuronal activity during high-frequency stimulation was mediated by short-term synaptic depression.ConclusionsBrain-region-specific and frequency-dependant neuronal responses could be simulated by considering neuroanatomical (local microcircuitry) and neurophysiological (short-term plasticity) properties.     

A multimodal approach using TMS and EEG reveals neurophysiological changes in Parkinson's disease

IntroductionAlterations in large scale neural networks leading to neurophysiological changes have been described in Parkinson's disease (PD). The combination of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) has been suggested as a promising tool to identify and quantify neurophysiological mechanisms. The aim of this study was to investigate specific changes in electrical brain activity in response to stimulation of four brain areas in patients with PD.Methods21 healthy controls and 32 patients with PD underwent a combined TMS-EEG assessment that included stimulation of four brain areas: left M1, right M1, left dorso-lateral prefrontal cortex (DLPFC), and right DLPFC. Six measures were calculated to characterize the TMS evoked potentials (TEP) using EEG: (1) wave form adherence (WFA), (2) late phase deflection (LPD), (3) early phase deflection (EPD), (4) short-term plasticity (STP), (5) inter-trial adherence, and (6) connectivity between right and left M1 and DLPFC. A Linear mixed-model was used to compare these measures between groups and areas stimulated.ResultsPatients with PD showed lower WFA (p = 0.052), lower EPD (p = 0.009), lower inter-trial adherence (p < 0.001), and lower connectivity between homologs areas (p = 0.050), compared to healthy controls. LPD and STP measures were not different between the groups. In addition, lower inter-trial adherence correlated with longer disease duration (r = −0.355, p = 0.050).ConclusionsOur findings provide evidence to various alterations in neurophysiological measures in patients with PD. The higher cortical excitability along with increased variability and lower widespread of the evoked potentials in PD can elucidate different aspects related to the pathophysiology of the disease.     

Relationship between high-frequency activity in the cortical sensory and the motor hand areas,and their myelin content

BackgroundThe human primary sensory (S1) and primary motor (M1) hand areas feature high-frequency neuronal responses. Electrical nerve stimulation evokes high-frequency oscillations (HFO) at around 650 Hz in the contralateral S1. Likewise, transcranial magnetic stimulation (TMS) of M1 can evoke a series of descending volleys in the corticospinal pathway that can be detected non-invasively with a paired-pulse TMS protocol, called short interval intracortical facilitation (SICF). SICF features several peaks of facilitation of motor evoked potentials in contralateral hand muscles, which are separated by inter-peak intervals resembling HFO rhythmicity.HypothesisIn this study, we tested the hypothesis that the individual expressions of HFO and SICF are tightly related to each other and to the regional myelin content in the sensorimotor cortex.MethodsIn 24 healthy volunteers, we recorded HFO and SICF, and, in a subgroup of 20 participants, we mapped the cortical myelin content using the ratio between the T1- and T2-weighted MRI signal as read-out.ResultsThe individual frequencies and magnitudes of HFO and SICF curves were tightly correlated: the intervals between the first and second peak of cortical HFO and SICF showed a positive linear relationship (r = 0.703, p < 0.001), while their amplitudes were inversely related (r = ?0.613, p = 0.001). The rhythmicity, but not the magnitude of the high-frequency responses, was related to the cortical myelin content: the higher the cortical myelin content, the shorter the inter-peak intervals of HFO and SICF.ConclusionThe results confirm a tight functional relationship between high-frequency responses in S1 (i.e., HFO) and M1 (i.e., as measured with SICF). They also establish a link between the degree of regional cortical myelination and the expression of high-frequency responses in the human sensorimotor cortex, giving further the opportunity to infer their generators.     

Development of cortical folds in the human brain: An attempt to review biological hypotheses,early neuroimaging investigations and functional correlates

The folding of the human brain mostly takes place in utero, making it challenging to study. After a few pioneer studies looking into it in post-mortem foetal specimen, modern approaches based on neuroimaging have allowed the community to investigate the folding process in vivo, its normal progression, its early disturbances, and its relationship to later functional outcomes. In this review article, we aimed to first give an overview of the current hypotheses on the mechanisms governing cortical folding. After describing the methodological difficulties raised by its study in fetuses, neonates and infants with magnetic resonance imaging (MRI), we reported our current understanding of sulcal pattern emergence in the developing brain. We then highlighted the functional relevance of early sulcal development, through recent insights about hemispheric asymmetries and early factors influencing this dynamic such as prematurity. Finally, we outlined how longitudinal studies have started to relate early folding markers and the child’s sensorimotor and cognitive outcome. Through this review, we hope to raise awareness on the potential of studying early sulcal patterns both from a fundamental and clinical perspective, as a window into early neurodevelopment and plasticity in relation to growth in utero and postnatal environment of the child.     

Restoration of functional network state towards more physiological condition as the correlate of clinical effects of pallidal deep brain stimulation in dystonia

BackgroundDeep brain stimulation of the internal globus pallidus (GPi DBS) is an invasive therapeutic modality intended to retune abnormal central nervous system patterns and relieve the patient of dystonic or other motor symptoms.ObjectivesThe aim of the presented research was to determine the neuroanatomical signature of GPi DBS modulation and its association with the clinical outcome.MethodsThis open-label fixed-order study with cross-sectional validation against healthy controls analysed the resting-state functional MRI activity changes induced by GPi DBS in 18 dystonia patients of heterogeneous aetiology, focusing on both global (full brain) and local connectivity (local signal homogeneity).ResultsCompared to the switched-off state, the activation of GPi DBS led to the restoration of global subcortical connectivity patterns (in both putamina, diencephalon and brainstem) towards those of healthy controls, with positive direct correlation over large-scale cortico-basal ganglia-thalamo-cortical and cerebellar networks with the clinical improvement. Nonetheless, on average, GPi DBS also seemed to bring local connectivity both in the cortical and subcortical regions farther away from the state detected in healthy controls. Interestingly, its correlation with clinical outcome showed that in better DBS responders, local connectivity defied this effect and approached healthy controls.ConclusionsAll in all, the extent of restoration of both these main metrics of interest towards the levels found in healthy controls clearly correlated with the clinical improvement, indicating that the restoration of network state towards more physiological condition may be a precondition for successful GPi DBS outcome in dystonia.     

Training in the practice of noninvasive brain stimulation: Recommendations from an IFCN committee

As the field of noninvasive brain stimulation (NIBS) expands, there is a growing need for comprehensive guidelines on training practitioners in the safe and effective administration of NIBS techniques in their various research and clinical applications. This article provides recommendations on the structure and content of this training. Three different types of practitioners are considered (Technicians, Clinicians, and Scientists), to attempt to cover the range of education and responsibilities of practitioners in NIBS from the laboratory to the clinic. Basic or core competencies and more advanced knowledge and skills are discussed, and recommendations offered regarding didactic and practical curricular components. We encourage individual licensing and governing bodies to implement these guidelines.     

Bidirectional and state-dependent modulation of brain activity by transcranial focused ultrasound in non-human primates

Transcranial focused ultrasound (FUS) stimulation under MRI guidance, coupled with functional MRI (fMRI) monitoring of effects, offers a precise, noninvasive technology to dissect functional brain circuits and to modulate altered brain functional networks in neurological and psychiatric disorders. Here we show that ultrasound at moderate intensities modulated neural activity bi-directionally. Concurrent sonication of somatosensory areas 3a/3b with 250 kHz FUS suppressed the fMRI signals produced there by peripheral tactile stimulation, while at the same time eliciting fMRI activation at inter-connected, off-target brain regions. Direct FUS stimulation of the cortex resulted in different degrees of BOLD signal changes across all five off-target regions, indicating that its modulatory effects on active and resting neurons differed. This is the first demonstration of the dual suppressive and excitative modulations of FUS on a specific functional circuit and of ability of concurrent FUS and MRI to evaluate causal interactions between functional circuits with neuron-class selectivity.     

Association of cortical spreading depression and seizures in patients with medically intractable epilepsy

ObjectiveMonitoring of the ultra-low frequency potentials, particularly cortical spreading depression (CSD), is excluded in epilepsy monitoring due to technical barriers imposed by the scalp ultra-low frequency electroencephalogram (EEG). As a result, clinical studies of CSD have been limited to invasive EEG. Therefore, the occurrence of CSD and its interaction with epileptiform field potentials (EFP) require investigation in epilepsy monitoring.MethodsUsing a novel AC/DC-EEG approach, the occurrence of DC potentials in patients with intractable epilepsy presenting different symptoms of aura was investigated during long-term video-EEG monitoring.ResultsVarious forms of slow potentials, including simultaneous negative direct current (DC) potentials and prolonged EFP, propagated negative DC potentials, and non-propagated single negative DC potentials were recorded from the scalp of the epileptic patients. The propagated and single negative DC potentials preceded the prolonged EFP with a time lag and seizure appeared at the final shoulder of some instances of the propagated negative DC potentials. The slow potential deflections had a high amplitude and prolonged duration and propagated slowly through the brain. The high-frequency EEG was suppressed in the vicinity of the negative DC potential propagations.ConclusionsThe study is the first to report the recording of the propagated and single negative DC potentials with EFP at the scalp of patients with intractable epilepsy. The negative DC potentials preceded the prolonged EFP and may trigger seizures. The propagated and single negative DC potentials may be considered as CSD.SignificanceRecordings of CSD may serve as diagnostic and prognostic monitoring tools in epilepsy.     

Meta-analysis of brain structural changes after electroconvulsive therapy in depression

BackgroundIncreases in the volume of the amygdala and hippocampus after electroconvulsive therapy (ECT) are among the most robust effects known to the brain-imaging field. Recent advances in the segmentation of substructures of these regions allow for novel insights on the relationship between brain structure and clinical outcomes of ECT.ObjectiveWe aimed to provide a comprehensive synthesis of evidence available on changes in brain structure after ECT, including recently published data on hippocampal subfields.MethodsA meta-analysis of published studies was carried out using random-effects models of standardized mean change of regional brain volumes measured with longitudinal magnetic resonance imaging of depressive patients before and after a series of ECT.ResultsData from 21 studies (543 depressed patients) were analysed, including 6 studies (118 patients) on hippocampal subfields. Meta-analyses could be carried out for seven brain regions for which data from at least three published studies was available. We observed increases in left and right hippocampi, amygdalae, cornua ammonis (CA) 1, CA 2/3, dentate gyri (DG) and subicula with standardized mean change scores ranging between 0.34 and 1.15. The model did not reveal significant volume increases in the caudate. Meta-regression indicated a negative relationship between the reported increases in the DG and relative symptom improvement (−0.27 (SE: 0.09) per 10%).ConclusionsECT is accompanied by significant volume increases in the bilateral hippocampus and amygdala that are not associated with treatment outcome. Among hippocampal subfields, the most robust volume increases after ECT were measured in the dentate gyrus. The indicated negative correlation of this effect with antidepressant efficacy warrants replication in data of individual patients.     

LTP-like cortical plasticity predicts conversion to dementia in patients with memory impairment

BackgroundNew diagnostic criteria consider Alzheimer’s disease (AD) as a clinico-biological entity identifiable in vivo on the presence of specific patterns of CSF biomarkers.ObjectiveHere we used transcranial magnetic stimulation to investigate the mechanisms of cortical plasticity and sensory-motor integration in patients with hippocampal-type memory impairment admitted for the first time in the memory clinic stratified according to CSF biomarkers profile.MethodsSeventy-three patients were recruited and divided in three groups according to the new diagnostic criteria: 1) Mild Cognitive Impaired (MCI) patients (n = 21); Prodromal AD (PROAD) patients (n = 24); AD with manifest dementia (ADD) patients (n = 28). At time of recruitment all patients underwent CSF sampling for diagnostic purposes. Repetitive and paired-pulse transcranial magnetic stimulation protocols were performed to investigate LTP-like and LTD-like cortical plasticity, short intracortical inhibition (SICI) and short afferent inhibition (SAI). Patients were the followed up during three years to monitor the clinical progression or the conversion to dementia.ResultsMCI patients showed a moderate but significant impairment of LTP-like cortical plasticity, while ADD and PROAD groups showed a more severe loss of LTP-like cortical plasticity. No differences were observed for LTD-like cortical plasticity, SICI and SAI protocols. Kaplan-Meyer analyses showed that PROAD and MCI patients converting to dementia had weaker LTP-like plasticity at time of first evaluation.ConclusionLTP-like cortical plasticity could be a novel biomarker to predict the clinical progression to dementia in patients with memory impairment at prodromal stages of AD identifiable with the new diagnostic criteria based on CSF biomarkers.