The connectivity index: an effective metric for grading epileptogenicity

OBJECTIVEThe aim of this study was to investigate the performance of a metric of functional connectivity to classify and grade the excitability of brain regions based on evoked potentials in response to single-pulse electrical stimulation (SPES).METHODSPatients who underwent 1-Hz frequency stimulation at prospectively selected contacts between 2003 and 2014 at the Yale Comprehensive Epilepsy Center were included. The stimulated contacts were classified as the seizure onset zone (SOZ), highly irritative zone (possibly epileptogenic irritative zone [IZp]), and control contacts not involved in the epileptic activity. Response contacts were classified as SOZ, active interictal irritative zone (IZ), quiet, or other. The normalized number of responses was defined as the number of contacts with any evoked responses divided by the total number of recorded contacts, and the normalized distance is the ratio of the average distance between the site of stimulation and sites of evoked responses to the average distances between the site of stimulation and all other recording contacts. A new metric that the authors labeled the connectivity index (CI) is defined as the product of the 2 values.RESULTSA total of 57 stimulation sessions in 22 patients were analyzed. The CI of the SOZ was higher than for control contacts (median CI of 0.74 vs 0.16, p = 0.0002). The evoked responses after stimulation of SOZ were seen at further distances compared to control (median normalized distance 0.96 vs 0.62, p = 0.0005). It was 1.8 times more likely that a response would be recorded at the SOZ than in nonepileptic contacts after stimulation of a control site. Habitual seizures were triggered in 27% of patients and 35% of SOZ contacts (median stimulation intensity 4 mA) but in none of the control or IZp contacts. Non-SOZ contacts in multifocal or poor surgical outcome cases had a higher CI than non-SOZ contacts in patients with localizable onsets (median CI of 0.5 vs 0.12, p = 0.04). There was a correlation between the stimulation current intensity and the normalized number of evoked responses (r = + 0.49, p = 0.01) but not with distance (r = + 0.1, p = 0.64).CONCLUSIONSThe authors found enhanced connectivity when stimulating the SOZ compared to stimulating control contacts; responses were more distant as well. Habitual auras and seizures provoked by SPES were highly predictive of brain sites involved in seizure generation.

Deep Brain Stimulation for Disabling “Outflow” Tremors

“Outflow” tremors, sometimes referred to in the literature by a variety of terms (outflow, rubral, midbrain, Holmes), are frequently associated with significant disability and are notoriously unresponsive or only partially responsive to medical treatment. Deep brain stimulation (DBS) has been successfully used in patients with outflow tremors; however, long-term outcomes are not well-documented because large case series are hard to assemble. This chapter describes a patient with disabling outflow tremors secondary to multiple sclerosis, treated with unilateral thalamic DBS, who achieved excellent tremor control with initial programming but shortly afterward developed rebound tremor. Intensive programming involved alternating the site of stimulation by using different combinations of contacts; this was a successful strategy for maintaining a clinically significant reduction in tremor. Disease progression, worsening of tremor, habituation, and loss of efficacy are known problems with some tremors, and their management can be challenging. The pathophysiology of worsening tremor after DBS is discussed in the chapter, as are potential programming strategies to manage this problem.

TMS alters multivoxel patterns in the absence of overall activity changes

Transcranial magnetic stimulation (TMS) has become one of the major tools for establishing the causal role of specific brain regions in perceptual, motor, and cognitive processes. Nevertheless, a persistent limitation of the technique is the lack of clarity regarding its precise effects on neural activity. Here, we examined the effects of TMS intensity and frequency on concurrently recorded blood-oxygen level-dependent (BOLD) signals at the site of stimulation. In two experiments, we delivered TMS to the dorsolateral prefrontal cortex in human subjects of both sexes. In Experiment 1, we delivered a series of pulses at high (100% of motor threshold) or low (50% of motor threshold) intensity, whereas in Experiment 2, we always used high intensity but delivered stimulation at four different frequencies (5, 8.33, 12.5, and 25 Hz). We found that the TMS intensity and frequency could be reliably decoded using multivariate analysis techniques even though TMS had no effect on overall BOLD activity at the site of stimulation in either experiment. These results provide important insight into the mechanisms through which TMS influences neural activity.SignificanceTranscranial magnetic stimulation (TMS) is a promising tool for the treatment of a number of neuropsychiatric disorders. However, its effectiveness is still impeded by an incomplete understanding of its neural effects. One fundamental unresolved issue is whether TMS leads to local changes in overall neural activity in the absence of a task. Here we performed two experiments where TMS was delivered inside an MRI scanner while brain activity was continuously monitored. We found converging evidence for the notion that TMS affects the pattern of local activity changes but does not lead to an overall increase in activity. These results help clarify the mechanisms of how TMS affects local neural activity.

The effects of repetitive transcranial magnetic stimulation in older adults with mild cognitive impairment: a protocol for a randomized, controlled three-arm trial

Background Mild Cognitive Impairment (MCI) carries a high risk of progression to Alzheimer’s disease (AD) dementia. Previous clinical trials testing whether cholinesterase inhibitors can slow the rate of progression from MCI to AD dementia have yielded disappointing results. However, recent studies of the effects of repetitive transcranial magnetic stimulation (rTMS) in AD have demonstrated improvements in cognitive function. Because few rTMS trials have been conducted in MCI, we designed a trial to test the short-term efficacy of rTMS in MCI. Yet, in both MCI and AD, we know little about what site of stimulation would be ideal for improving cognitive function. Therefore, two cortical sites will be investigated in this trial: (1) the dorsolateral prefrontal cortex (DLPFC), which has been well studied for treatment of major depressive disorder; and (2) the lateral parietal cortex (LPC), a novel site with connectivity to AD-relevant limbic regions. Methods/design In this single-site trial, we plan to enroll 99 participants with single or multi-domain amnestic MCI. We will randomize participants to one of three groups: (1) Active DLPFC rTMS; (2) Active LPC rTMS; and (3) Sham rTMS (evenly split between DLPFC and LPC locations). After completing 20 bilateral rTMS treatment sessions, participants will be followed for 6 months to test short-term efficacy and track durability of effects. The primary efficacy measure is the California Verbal Learning Test-II (CVLT-II), assessed 1 week after intervention. Secondary analyses will examine effects of rTMS on other cognitive measures, symptoms of depression, and brain function with respect to the site of stimulation. Finally, selected biomarkers will be analyzed to explore predictors of response and mechanisms of action. Discussion The primary aim of this trial is to test the short-term efficacy of rTMS in MCI. Additionally, the project will provide information on the durability of cognitive effects and potentially distinct effects of stimulating DLPFC versus LPC regions. Future efforts would be directed toward better understanding therapeutic mechanisms and optimizing rTMS for treatment of MCI. Ultimately, if rTMS can be utilized to slow the rate of progression to AD dementia, this will be a significant advancement in the field. Trial registration Clinical Trials NCT03331796. Registered 6 November 2017, https://clinicaltrials.gov/ct2/show/NCT03331796. All items from the World Health Organization Trial Registration Data Set are listed in Appendix A. Protocol version This report is based on version 1, approved by the DSMB on 30 November, 2017 and amended on 14 August, 2018 and 19 September, 2019.

The Connectivity Index: An Effective Metric for Grading Epileptogenicity

ObjectiveTo investigate the performance of a metric of functional connectivity to classify and grade the excitability of brain regions based on evoked potentials to single pulse electrical stimulation (SPES).MethodsPatients who received 1-Hz frequency stimulation between 2003 and 2014 at Yale at prospectively selected contacts were included. The stimulated contacts were classified as seizure onset zone (SOZ), highly irritative zone (IZp) or control. Response contacts were classified as seizure onset zone (SOZ), active interictal (IZp), quiet or other. The normalized number of responses was defined as the number of contacts with any evoked responses divided by the total number of recorded contacts, and the normalized distance is the ratio of the average distance between the site of stimulation and sites of evoked responses to the average distances between the site of stimulation and all other recording contacts. A new metric we labeled the connectivity index (CI) is defined as the product of the two values.Results57 stimulation-sessions in 22-patients were analyzed. The connectivity index (CI) of the SOZ was higher than control (median CI of 0.74 vs. 0.16, p = 0.0002). The evoked responses after stimulation of SOZ were seen at further distance compared to control (median normalized distance 0.96 vs. 0.62, p = 0.0005). It was 1.8 times more likely to record a response at SOZ than in non-epileptic contacts after stimulation of a control site. Habitual seizures were triggered in 27% of patients and 35 % of SOZ contacts (median stimulation intensity 4 mA) but in none of the control or IZp contacts. Non-SOZ contacts in multifocal or poor surgical outcome cases had a higher CI than non-SOZ contacts in those with localizable onsets (medians CI of 0.5 vs. 0.12, p = 0.04). There was a correlation between the stimulation current intensity and the normalized number of evoked responses (r = + 0.49, p 0.01) but not with distance (r = + 0.1, p 0.64)ConclusionsWe found enhanced connectivity when stimulating the SOZ compared to stimulating control contacts; responses were more distant as well. Habitual auras and seizures provoked by SPES were highly predictive of brain sites involved in seizure generation.

Microstimulation in a spiking neural network model of the midbrain superior colliculus

The midbrain superior colliculus (SC) generates a rapid saccadic eye movement to a sensory stimulus by recruiting a population of cells in its topographically organized motor map. Supra-threshold electrical microstimulation in the SC reveals that the site of stimulation produces a normometric saccade vector with little effect of the stimulation parameters. Moreover, electrically evoked saccades (E-saccades) have kinematic properties that strongly resemble natural, visual-evoked saccades (V-saccades). These findings support models in which the saccade vector is determined by a center-of-gravity computation of activated neurons, while its trajectory and kinematics arise from downstream feedback circuits in the brainstem. Recent single-unit recordings, however, have indicated that the SC population also specifies instantaneous kinematics. These results support an alternative model, in which the desired saccade trajectory, including its kinematics, follows from instantaneous summation of movement effects of all SC spike trains. But how to reconcile this model with microstimulation results? Although it is thought that microstimulation activates a large population of SC neurons, the mechanism through which it arises is unknown. We developed a spiking neural network model of the SC, in which microstimulation directly activates a relatively small set of neurons around the electrode tip, which subsequently sets up a large population response through lateral synaptic interactions. We show that through this mechanism the population drives an E-saccade with near-normal kinematics that are largely independent of the stimulation parameters. Only at very low stimulus intensities the network recruits a population with low firing rates, resulting in abnormally slow saccades.Author SummaryThe midbrain Superior Colliculus (SC) contains a topographically organized map for rapid goal-directed gaze shifts, in which the location of the active population determines size and direction of the eye-movement vector, and the neural firing rates specify the eye-movement kinematics. Electrical microstimulation in this map produces eye movements that correspond to the site of stimulation with normal kinematics. We here explain how intrinsic lateral interactions within the SC network of spiking neurons sets up the population activity profile in response to local microstimulation to explain these results.

Transcranial magnetic stimulation (TMS) safety: a practical guide for psychiatrists

Objectives: Repetitive transcranial magnetic stimulation (rTMS) is increasingly being utilised as a treatment option for depression, and with this comes a need for a practical review of safety issues intended for clinicians. This article provides an overview of the current literature regarding safety issues with rTMS for depression, and provides recommendations for clinical practice. Conclusions: Overall, rTMS is a well-tolerated treatment with common side effects (such as headache or local pain at the site of stimulation) being mild. Severe adverse effects, such as seizures, hearing impairment or mania, are uncommon. Certain populations, including adolescents, pregnant women, older adults and those with metal/electronic implants, require special consideration when prescribing and monitoring treatment courses. With adequate assessment and monitoring processes, rTMS can be administered safely in a large proportion of depressed patients.