Local and Transient Changes of Sleep Spindle Density During Series of Prefrontal Repetitive Transcranial Magnetic Stimulation in Patients With a Major Depressive Episode

The neuromodulatory effects of brain stimulation therapies notably involving repetitive transcranial magnetic stimulation (rTMS) on nocturnal sleep, which is critically disturbed in major depression and other neuropsychiatric disorders, remain largely undetermined. We have previously reported in major depression patients that prefrontal rTMS sessions enhanced their slow wave activity (SWA) power, but not their sigma power which is related to sleep spindle activity, for electrodes located nearby the stimulation site. In the present study, we focused on measuring the spindle density to investigate cumulative effects of prefrontal rTMS sessions on the sleep spindle activity. Fourteen male inpatients diagnosed with medication-resistant unipolar or bipolar depression were recruited and subjected to 10 daily rTMS sessions targeting the left dorsolateral prefrontal cortex (DLPFC). All-night polysomnography (PSG) data was acquired at four time points: Adaptation, Baseline, Post-1 (follow-up after the fifth rTMS session), and Post-2 (follow-up after the tenth rTMS session). Clinical and cognitive evaluations were longitudinally performed at Baseline, Post-1, and Post-2 time points to explore associations with the spindle density changes. The PSG data from 12 of 14 patients was analyzed to identify sleep spindles across the sleep stages II–IV at four electrode sites: F3 (frontal spindle near the stimulation site), F4 (contralateral homologous frontal region), P3 (parietal spindle in the hemisphere ipsilateral to the stimulation site), and P4 (contralateral parietal region). Statistical analysis by two-way ANOVA revealed that spindle density at F3 increased at Post-1 but decreased at Post-2 time points. Moreover, the local and transient increase of spindle density at F3 was associated with the previously reported SWA power increase at F3, possibly reflecting a shared mechanism of thalamocortical synchronization locally enhanced by diurnal prefrontal rTMS sessions. Clinical and cognitive correlations were not observed in this dataset. These findings suggest that diurnal rTMS sessions transiently modulate nocturnal sleep spindle activity at the stimulation site, although clinical and cognitive effects of the local changes warrant further investigation.

Impact of stimulation location relative to grey and white matter on single pulse electrical stimulation responses in the human brain

Background: Electrical neuromodulation is an increasingly common therapy for a wide variety of neuropsychiatric diseases. Unfortunately, therapeutic efficacy is inconsistent, possibly a result of our limited understanding of the mechanisms and the massive stimulation parameter space. Objective/Hypothesis: To better understand the role different parameters play in inducing a response, we systematically examined single pulse-induced cortico-cortico evoked potentials (CCEP) as a function of stimulation amplitude, duration and location in the brain and relative to grey and white matter. Methods: We measured voltage peak amplitudes and area under the curve of intracranially recorded stimulation responses as a function of distance from the stimulation site, pulse width, current injected, location relative to grey and white matter, and brain region stimulated (N=52, n=719 stimulation sites). Results: Increasing stimulation pulse width increased response values near the stimulation location. Increasing stimulation amplitude (current) increased responses nonlinearly. Locally (<15 mm from the stimulation site), stimulation closer to the grey matter-white matter boundary induced larger responses. In contrast, for distant sites (>15 mm), white matter stimulation consistently produced larger responses than stimulation in or near grey matter. These relationships were different between cingulate, lateral prefrontal, and lateral temporal cortical stimulation. Conclusion: These results demonstrate the importance of location and stimulation parameters in inducing a specific output and indicate that a stronger local response may require stimulation in the grey-white boundary while stimulation in the white matter may be needed for network activation, suggesting that stimulation location can be tailored for a specific outcome, key to informed neuromodulatory therapy.

Cognitive Enhancement of Repetitive Transcranial Magnetic Stimulation in Patients With Mild Cognitive Impairment and Early Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation technique, has been considered as a potentially effective treatment for the cognitive impairment in patients with mild cognitive impairment (MCI) and Alzheimer’s Disease (AD). However, the effectiveness of this therapy is still under debate due to the variety of rTMS parameters and individual differences including distinctive stages of AD in the previous studies. The current meta-analysis is aiming to assess the cognitive enhancement of rTMS treatment on patients of MCI and early AD. Three datasets (PubMed, Web of Science and CKNI) were searched with relative terms and finally twelve studies with 438 participants (231 in the rTMS group and 207 in the control group) in thirteen randomized, double-blind and controlled trials were included. Random effects analysis revealed that rTMS stimulation significantly introduced cognitive benefits in patients of MCI and early AD compared with the control group (mean effect size, 1.17; 95% CI, 0.76 - 1.57). Most settings of rTMS parameters (frequency, session number, stimulation site number) significantly enhanced global cognitive function, and the results revealed that protocols with 10 Hz repetition frequency and DLPFC as the stimulation site for 20 sessions can already be able to produce cognitive improvement. The cognitive enhancement of rTMS could last for one month after the end of treatment and patients with MCI were likely to benefit more from the rTMS stimulation. Our meta-analysis added important evidence to the cognitive enhancement of rTMS in patients with MCI and early AD and discussed potential underlying mechanisms about the effect induced by rTMS.

A pilot study verifying the effectiveness of high-frequency repetitive transcranial magnetic stimulation in combination with intensive speech-language-hearing therapy in patients with chronic aphasia

BACKGROUND: A lot of research on the effectiveness of repetitive transcranial magnetic stimulation (rTMS) in patients with aphasia in the chronic stage deals with low-frequency stimulation, and reports on high-frequency stimulation (HF-rTMS) are scarce. OBJECTIVE: The purpose of this study was to evaluate retrospectively the effectiveness of high-frequency rTMS in combination with intensive speech-language-hearing therapy (ST) following the identification of the stimulation site using functional magnetic resonance imaging (fMRI) before, after the procedure and at 3 months in patients with aphasia in the chronic stage. METHODS: 20 patients with aphasia in the chronic stage who met the eligibility criteria for rTMS therapy and who underwent HF-rTMS for the first time were included in the present study. All patients received fMRI before hospitalization, and the stimulation site was decided accordingly. RESULTS: There was a significant improvement in all patients, rTMS to the left hemisphere, fluent and non-fluent groups by the evaluation of pre- and post- treatment by hospitalization. All groups had a significant improvement in total Standard Language Test of Aphasia score at 3 months when compared with the time of hospitalization. CONCLUSIONS: The current study indicates that HF-rTMS in combination with intensive ST is an effective therapeutic approach for patients with aphasia in the chronic stage.

A Structured ICA-based Process for Removing Auditory Evoked Potentials Reveals TMS-evoked Potentials and TMS-modulated Oscillations

Background: Transcranial magnetic stimulation (TMS)-evoked potentials (TEPs), recorded using electroencephalography (EEG), reflect a combination of TMS-induced cortical activity and multi-sensory responses to TMS. The auditory evoked potential (AEP) is a high-amplitude sensory potential—evoked by the “click” sound produced by every TMS pulse—that can dominate the TEP and obscure observation of other neural components. The AEP is peripherally evoked and therefore should not be stimulation site specificObjectives/Methods: We address the problem of disentangling the peripherally evoked AEP of the TEP from components evoked by cortical stimulation and ask whether removal of AEP enables more accurate isolation of TEP. We hypothesized that isolation of the AEP using Independent Components Analysis (ICA) would reveal features that are stimulation site specific and unique individual features. In order to improve the effectiveness of ICA for removal of AEP from the TEP, and thus more clearly separate the transcranial-evoked and non-specific TMS-modulated potentials, we merged sham and active TMS datasets representing multiple stimulation conditions, removed the resulting AEP component, and evaluated performance across different sham protocols and clinical populations using reduction in Global and Local Mean Field Potentials (GMFA/LMFA) and cosine similarity analysis.Results: We show that removing AEPs significantly reduced GMFA and LMFA in the post-stimulation TEP (14 to 400 ms), driven by time windows consistent with the N100 and P200 temporal characteristics of AEPs. Cosine similarity analysis supports that removing AEPs reduces TEP similarity between subjects and reduces TEP similarity between stimulation conditions. Similarity is reduced most in a mid-latency window consistent with the N100 time-course, but nevertheless remains high in this time window. Residual TEP in this window has a time-course and topography unique from AEPs, which follow-up analyses suggest could be a modulation in the alpha band that is not stimulation site specific but is unique to individual subject.Conclusion(s): We show, using two datasets and two implementations of sham, evidence in cortical topography, TEP time-course, GMFA/LMFA and cosine similarity analyses that this procedure is effective and conservative in removing the AEP from TEP, and thereby reveals better defined TMS-evoked activity. We show TEP remaining in early, mid and late latencies. The early response is site and subject specific. Later responses are consistent with TMS-modulated alpha activity that is not site specific but is unique to the individual. TEP remaining after removal of AEP is unique and can provide insight into TMS-evoked potentials and other modulated oscillatory dynamics.

The Effect of Non-Invasive Brain Stimulation (NIBS) on Executive Functioning, Attention and Memory in Rehabilitation Patients with Traumatic Brain Injury: A Systematic Review

In recent years, the potential of non-invasive brain stimulation (NIBS) for therapeutic effects on cognitive functions has been explored for populations with traumatic brain injury (TBI). However, there is no systematic NIBS review of TBI cognitive impairment with a focus on stimulation sites and stimulation parameters. The purpose of this study was to conduct a systematic review examining the effectiveness and safety of NIBS for cognitive impairment after a TBI. This study was prospectively registered with the PROSPERO database of systematic reviews (CRD42020183298). All English articles from the following databases were searched from inception up to 31 December 2020: Pubmed/MEDLINE, Scopus, CINAHL, Embase, PsycINFO and CENTRAL. Randomized and prospective controlled trials, including cross-over studies, were included for analysis. Studies with at least five individuals with TBI, whereby at least five sessions of NIBS were provided and used standardized neuropsychological measurement of cognition, were included. A total of five studies met eligibility criteria. Two studies used repetitive transcranial magnetic stimulation (rTMS) and three studies used transcranial direct current stimulation (tDCS). The pooled sample size was 44 individuals for rTMS and 91 for tDCS. Three of five studies combined cognitive training or additional therapy (computer assisted) with NIBS. Regarding rTMS, target symptoms included attention (n = 2), memory (n = 1), and executive function (n = 2); only one study showing significant improvement compared than control group with respect to attention. In tDCS studies, target symptoms included cognition (n = 2), attention (n = 3), memory (n = 3), working memory (WM) (n = 3), and executive function (n = 1); two of three studies showed significant improvement compared to the control group with respect to attention and memory. The evidence for NIBS effectiveness in rehabilitation of cognitive function in TBI is still in its infancy, more studies are needed. In all studies, dorsolateral prefrontal cortex (DLPFC) was selected as the stimulation site, along with the stimulation pattern promoting the activation of the left DLPFC. In some studies, there was a significant improvement compared to the control group, but neither rTMS nor tDCS had sufficient evidence of effectiveness. To the establishment of evidence we need the evaluation of brain activity at the stimulation site and related areas using neuroimaging on how NIBS acts on the neural network.

Single-Pulse TMS to the Temporo-Occipital and Dorsolateral Prefrontal Cortex Evokes Lateralized Long Latency EEG Responses at the Stimulation Site

IntroductionTranscranial magnetic stimulation (TMS)–evoked potentials (TEPs) allow for probing cortical functions in health and pathology. However, there is uncertainty whether long-latency TMS-evoked potentials reflect functioning of the targeted cortical area. It has been suggested that components such as the TMS-evoked N100 are stereotypical and related to nonspecific sensory processes rather than transcranial effects of the changing magnetic field. In contrast, TEPs that vary according to the targeted brain region and are systematically lateralized toward the stimulated hemisphere can be considered to reflect activity in the stimulated brain region resulting from transcranial electromagnetic induction.MethodsTMS with concurrent 64-channel electroencephalography (EEG) was sequentially performed in homologous areas of both hemispheres. One sample of healthy adults received TMS to the dorsolateral prefrontal cortex; another sample received TMS to the temporo-occipital cortex. We analyzed late negative TEP deflections corresponding to the N100 component in motor cortex stimulation.ResultsTEP topography varied according to the stimulation target site. Long-latency negative TEP deflections were systematically lateralized (higher in ipsilateral compared to contralateral electrodes) in electrodes over the stimulated brain region. A calculation that removes evoked components that are not systematically lateralized relative to the stimulated hemisphere revealed negative maxima located around the respective target sites.ConclusionTEPs contain long-latency negative components that are lateralized toward the stimulated hemisphere and have their topographic maxima at the respective stimulation sites. They can be differentiated from co-occurring components that are invariable across different stimulation sites (probably reflecting coactivation of peripheral sensory afferences) according to their spatiotemporal patterns. Lateralized long-latency TEP components located at the stimulation site likely reflect activity evoked in the targeted cortex region by direct transcranial effects and are therefore suitable for assessing cortical functions.

Local Differences in Cortical Excitability – A Systematic Mapping Study of the TMS-Evoked N100 Component

Transcranial magnetic stimulation (TMS) with simultaneous electroencephalography applied to the primary motor cortex provides two parameters for cortical excitability: motor evoked potentials (MEPs) and TMS-evoked potentials (TEPs). This study aimed to evaluate the effects of systematic coil shifts on both the TEP N100 component and MEPs in addition to the relationship between both parameters. In 12 healthy adults, the center of a standardized grid was fixed above the hot spot of the target muscle of the left primary motor cortex. Twelve additional positions were arranged in a quadratic grid with positions between 5 and 10 mm from the hot spot. At each of the 13 positions, TMS single pulses were applied. The topographical maximum of the resulting N100 was located ipsilateral and slightly posterior to the stimulation site. A source analysis revealed an equivalent dipole localized more deeply than standard motor cortex coordinates that could not be explained by a single seeded primary motor cortex dipole. The N100 topography might not only reflect primary motor cortex activation, but also sum activation of the surrounding cortex. N100 amplitude and latency decreased significantly during stimulation anterior-medial to the hot spot although MEP amplitudes were smaller at all other stimulation sites. Therefore, N100 amplitudes might be suitable for detecting differences in local cortical excitability. The N100 topography, with its maximum located posterior to the stimulation site, possibly depends on both anatomical characteristics of the stimulated cortex and differences in local excitability of surrounding cortical areas. The less excitable anterior cortex might contribute to a more posterior maximum. There was no correlation between N100 and MEP amplitudes, but a single-trial analysis revealed a trend toward larger N100 amplitudes in trials with larger MEPs. Thus, functionally efficient cortical excitation might increase the probability of higher N100 amplitudes, but TEPs are also generated in the absence of MEPs.