Neuroprotection of Low-Frequency Repetitive Transcranial Magnetic Stimulation after Ischemic Stroke in Rats.

OBJECTIVE: Stroke is a leading cause of human death and disability. Effective early treatments with reasonable therapeutic windows remain critically important to improve the outcomes of stroke. Transcranial magnetic stimulation (TMS) is an established noninvasive technique that has been applied clinically and in animal research for multiple brain disorders, but few studies have examined acute neuroprotection against ischemic stroke. The present investigation tested the novel approach of low-frequency repetitive TMS (rTMS) as an acute treatment after ischemic stroke. METHODS: Adult male rats received focal ischemic surgery through occlusion of the right middle cerebral artery for 60 minutes. The rats received either rTMS or sham treatment with 1.5-, 3-, 4-, or 7-hour delay after the onset of stroke. Low-frequency and low-intensity rTMS was applied to the rat brain for two 30-minute episodes separated by a 1-hour interval. RESULTS: Three days after stroke, compared to stroke controls, rats receiving rTMS treatment with a 1.5-hour delay showed a 35% reduction of infarct volume. Protective effects were also seen with 3- or 4-hour-delayed treatments by rTMS, shown as reduced infarct volume and cell death. rTMS treatment upregulated the antiapoptotic factor Bcl-2 and downregulated the proapoptotic caspase-3 cleavage, expressions of Bax and matrix metallopeptidase-9. In sensorimotor functional assessments 3 to 21 days after stroke, rats receiving rTMS treatment with a 1.5- or 3-hour delay showed significantly better performance compared to stroke controls. INTERPRETATION: These results support the inference that low-frequency rTMS may be feasible as a neuroprotective acute treatment after ischemic stroke. ANN NEUROL 2023;93:336-347.

Open surgery or laser interstitial thermal therapy for low-grade epilepsy-associated tumors of the temporal lobe: A single-institution consecutive series.

Outcomes of treating low-grade epilepsy-associated tumors (LEATs) in the temporal lobe with MRI-guided laser interstitial thermal therapy (MRgLITT) remain poorly characterized. This study aimed to compare the safety and effectiveness of treating temporal lobe LEATs with MRgLITT versus open resection in a consecutive single-institution series. We reviewed all adult patients with epilepsy that underwent surgery for temporal lobe LEATs at our institution between 2002 and 2019, during which time we switched from open surgery to MRgLITT. Surgical outcome was categorized by Engel classification at >12mo follow-up and Kaplan-Meir analysis of seizure freedom. We recorded hospital length of stay, adverse events, and available neuropsychological results. Of 14 total patients, 7 underwent 9 open resections, 6 patients underwent MRgLITT alone, and 1 patient underwent an open resection followed by MRgLITT. Baseline group demographics differed and were notable for preoperative duration of epilepsy of 9.0 years (range 1-36) for open resection versus 14.0 years (range 2-34) for MRgLITT. Median length of stay was one day shorter for MRgLITT compared to open resection (p=<.0001). There were no major adverse events in the series, but there were fewer minor adverse events following MRgLITT. At 12mo follow-up, 50% (5/10) of patients undergoing open resection and 57% (4/7) of patients undergoing MRgLITT were free of disabling seizures (Engel I). When comparing patients who underwent similar procedures in the dominant temporal lobe, patients undergoing MRgLITT had fewer and milder material-specific neuropsychological declines than patients undergoing open resections. In this small series, MRgLITT was comparably safe and effective relative to open resection of temporal lobe LEATs.

Oscillatory activity in neocortical networks during tactile discrimination near the limit of spatial acuity.

Oscillatory interactions within functionally specialized but distributed brain regions are believed to be central to perceptual and cognitive functions. Here, using human scalp electroencephalography (EEG) recordings combined with source reconstruction techniques, we study how oscillatory activity functionally organizes different neocortical regions during a tactile discrimination task near the limit of spatial acuity. While undergoing EEG recordings, blindfolded participants felt a linear three-dot array presented electromechanically, under computer control, and reported whether the central dot was offset to the left or right. The average brain response differed significantly for trials with correct and incorrect perceptual responses in the timeframe approximately between 130 and 175ms. During trials with correct responses, source-level peak activity appeared in the left primary somatosensory cortex (SI) at around 45ms, in the right lateral occipital complex (LOC) at 130ms, in the right posterior intraparietal sulcus (pIPS) at 160ms, and finally in the left dorsolateral prefrontal cortex (dlPFC) at 175ms. Spectral interdependency analysis of activity in these nodes showed two distinct distributed networks, a dominantly feedforward network in the beta band (12-30Hz) that included all four nodes and a recurrent network in the gamma band (30-100Hz) that linked SI, pIPS and dlPFC. Measures of network activity in both bands were correlated with the accuracy of task performance. These findings suggest that beta and gamma band oscillatory networks coordinate activity between neocortical regions mediating sensory and cognitive processing to arrive at tactile perceptual decisions.

Application of high-frequency Granger causality to analysis of epileptic seizures and surgical decision making.

OBJECTIVE: In recent decades intracranial EEG (iEEG) recordings using increasing numbers of electrodes, higher sampling rates, and a variety of visual and quantitative analyses have indicated the presence of widespread, high frequency ictal and preictal oscillations (HFOs) associated with regions of seizure onset. Seizure freedom has been correlated with removal of brain regions generating pathologic HFOs. However, quantitative analysis of preictal HFOs has seldom been applied to the clinical problem of planning the surgical resection. We performed Granger causality (GC) analysis of iEEG recordings to analyze features of preictal seizure networks and to aid in surgical decision making. METHODS: Ten retrospective and two prospective patients were chosen on the basis of individually stereotyped seizure patterns by visual criteria. Prospective patients were selected, additionally, for failure of those criteria to resolve apparent multilobar ictal onsets. iEEG was recorded at 500 or 1,000 Hz, using up to 128 surface and depth electrodes. Preictal and early ictal GC from individual electrodes was characterized by the strength of causal outflow, spatial distribution, and hierarchical causal relationships. RESULTS: In all patients we found significant, widespread preictal GC network activity at peak frequencies from 80 to 250 Hz, beginning 2-42 s before visible electrographic onset. In the two prospective patients, GC source/sink comparisons supported the exclusion of early ictal regions that were not the dominant causal sources, and contributed to planning of more limited surgical resections. Both patients have a class 1 outcome at 1 year. SIGNIFICANCE: GC analysis of iEEG has the potential to increase understanding of preictal network activity, and to help improve surgical outcomes in cases of otherwise ambiguous iEEG onset.

A Stable EEG Epilepsy Network Spans From Infraslow to Ripple and From Interictal to Ictus.

PURPOSE: To characterize the epilepsy network as reflected in intracranial electroencephalography (iEEG) across the full spectrum of iEEG frequencies and different phases of epilepsy, using a single, conceptually straightforward mathematical measure. METHODS: The authors applied the spectral Granger causality techniques to intracranial electroencephalography recordings and computed contact-by-contact inward, outward, and total causal flow across frequencies and seizure phases in a selected group of three patients with well-defined, nonlesional seizure foci and prolonged responses to invasive procedures. One seizure and one interictal sample were analyzed per subject. RESULTS: A prominent intracranial electroencephalography network was identified by Granger causality at both high and low frequencies. This network persists during the preictal and interictal phases of epilepsy and closely matches the visible seizure onset. The causal inflow network corresponded to seizure onset electrode contacts in 8 of 12 conditions, including ripple, infraslow, preictal, and interictal phases of epilepsy. Its most striking feature is the consistent dominance of causal inflow rather than outflow in the vicinity of the seizure onset zone. CONCLUSIONS: Findings of this study indicate that a stable intracranial electroencephalography epilepsy network persists, and it can be characterized by a single Granger causality measure from infraslow to ripple frequencies and from the interictal to the immediate preictal phases of epilepsy.

Reduced Interference and Serial Dependency Effects for Naming in Older but Not Younger Adults after 1 Hz rTMS of Right Pars Triangularis.

1 Hz repetitive transcranial magnetic stimulation (rTMS) was used to decrease excitability of right pars triangularis (R PTr) to determine whether increased R PTr activity during picture naming in older adults hampers word finding. We hypothesized that decreasing R PTr excitability would reduce interference with word finding, facilitating faster picture naming. 15 older and 16 younger adults received two rTMS sessions. In one, speech onset latencies for picture naming were measured after both sham and active R PTr stimulation. In the other session, sham and active stimulation of a control region, right pars opercularis (R POp), were administered before picture naming. Order of active vs. sham stimulation within session was counterbalanced. Younger adults showed no significant effects of stimulation. In older adults, a trend indicated that participants named pictures more quickly after active than sham R PTr stimulation. However, older adults also showed longer responses during R PTr than R POp sham stimulation. When order of active vs. sham stimulation was modeled, older adults receiving active stimulation first had significantly faster responding after active than sham R PTr stimulation and significantly faster responding after R PTr than R POp stimulation, consistent with experimental hypotheses. However, older adults receiving sham stimulation first showed no significant differences between conditions. Findings are best understood, based on previous studies, when the interaction between the excitatory effects of picture naming and the inhibitory effects of 1 Hz rTMS on R PTr is considered. Implications regarding right frontal activity in older adults and for design of future experiments are discussed.

Accelerated repetitive transcranial magnetic stimulation for treatment-resistant depression.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has shown safety and efficacy for treatment-resistant depression, but requires daily treatment for 4-6 weeks. Accelerated TMS, with all treatments delivered over a few days, would have significant advantages in terms of access and patient acceptance. METHODS: Open-label accelerated TMS (aTMS), consisting of 15 rTMS sessions administered over 2 days, was tested in 14 depressed patients not responding to at least one antidepressant medication. Effects on depression, anxiety, and cognition were assessed the day following treatment, then after 3 and 6 weeks. RESULTS: No seizure activity was observed and only one patient had a serious adverse event (increased suicidal ideation). Two patients failed to complete a full course of aTMS treatments, and 36% did not complete all study visits. Depression and anxiety significantly decreased following aTMS treatments and improvements persisted 3 and 6 weeks later. Response rates immediately following treatment and at 3 and 6 weeks were 43, 36, and 36%, respectively. Remission rates at the same timepoints were 29, 36, and 29%. CONCLUSIONS: Accelerated TMS demonstrated an excellent safety profile with efficacy comparable to that achieved in daily rTMS in other trials. Limitations primarily include open-label treatment and a small sample size.

Prolonged neurophysiologic effects of levetiracetam after oral administration in humans.

PURPOSE: To determine whether neurophysiological effects of levetiracetam (LEV) outlast its serum half-life of approximately 7 h. Demonstration of prolonged effects would help to explain the efficacy of LEV at conventional dosing intervals that are longer than the serum half-life. METHODS: Following an oral dose of LEV 3 g in 12 normal volunteers, we compared transcranial magnetic stimulation (TMS) measures of motor threshold (MT) and recruitment with LEV serum levels and subjective ratings of toxicity over 48 h. Subjects used a two-dimensional visual-analog scale to estimate the time course of any side effects. RESULTS: LEV serum levels and subjective toxicity both peaked around 1 h after oral administration. MT elevation was delayed in comparison to peak serum levels and subjective toxicity. MT was maximally elevated at 6-9 h, and recruitment maximally reduced at 0.6-9 h. Changes in both measures had recovered by approximately 50% at 24 h. Despite the time difference between toxicity and TMS changes, toxicity estimates correlated with the maximum increase in MT. CONCLUSION: There is a substantial time lag between LEV serum levels and TMS measures of neuronal effects, and a similar temporal dissociation between subjective toxicity and maximum TMS change. The time course of neurophysiological effects, as measured by TMS, may help to explain the sustained clinical efficacy of LEV despite a short peripheral half-life.

Enhanced Brain Network Activity in Complex Movement Rhythms: A Simultaneous Functional Magnetic Resonance Imaging and Electroencephalography Study.

Generating movement rhythms is known to involve a network of distributed brain regions associated with motor planning, control, execution, and perception of timing for the repertoire of motor actions. What brain areas are bound in the network and how the network activity is modulated by rhythmic complexity have not been completely explored. To contribute to answering these questions, we designed a study in which nine healthy participants performed simple to complex rhythmic finger movement tasks while undergoing simultaneous functional magnetic resonance imaging and electroencephalography (fMRI-EEG) recordings of their brain activity during the tasks and rest. From fMRI blood oxygenation-level-dependent (BOLD) measurements, we found that the complexity of rhythms was associated with brain activations in the primary motor cortex (PMC), supplementary motor area (SMA), and cerebellum (Cb), and with network interactions from these cortical regions to the cerebellum. The spectral analysis of single-trial EEG source waveforms at the cortical regions further showed that there were bidirectional interactions between PMC and SMA, and the complexity of rhythms was associated with power spectra and Granger causality spectra in the beta (13-30 Hz) frequency band, not in the alpha (8-12 Hz) and gamma (30-58 Hz) bands. These results provide us new insights into the mechanisms for movement rhythm complexity.

An open study of repetitive transcranial magnetic stimulation in treatment-resistant depression with Parkinson's disease.

OBJECTIVE: Major depression is a common concomitant of chronic central nervous system disorders, notably Parkinson's disease (PD). Repetitive transcranial magnetic stimulation (rTMS) has been investigated as a potential treatment for depression in PD and for the movement disorder of PD, but comprehensive testing in multiple areas of performance has seldom been carried out within a single study. We studied the effect of left dorsolateral prefrontal rTMS on several different functional domains. METHODS: Fourteen PD patients with treatment-resistant depression entered an open, 10-day inpatient study of 10-Hz rTMS, undergoing extensive psychiatric, neuropsychological, and motor testing from baseline to 6 weeks after treatment. Motor testing included a defined "off" state. RESULTS: rTMS was well tolerated. Highly significant improvement in depression scores was seen 3 days and 3-6 weeks after treatment. Improvement was also found in anxiety, movement scores (especially in the off state), and some neuropsychological measures. We found no evidence of increased risk from rTMS in this population. CONCLUSIONS: Further controlled trials of rTMS in PD appear worthwhile, and should include a defined "off" state. SIGNIFICANCE: TMS may be beneficial for depressed PD patients in multiple functional domains.

Neuroimaging somatosensory perception and masking.

The specific cortical and subcortical regions involved in conscious perception and masking are uncertain. This study sought to identify brain areas involved in conscious perception of somatosensory stimuli during a masking task using functional magnetic resonance (fMRI) to contrast perceived vs. non-perceived targets. Electrical trains were delivered to the right index finger for targets and to the left index finger for masks. Target intensities were adjusted to compensate for threshold drift. Sham target trials were given in ~10% of the trials, and target stimuli without masks were delivered in one of the five runs (68 trials/run). When healthy dextral adult volunteers (n=15) perceived right hand targets, greater left- than right-cerebral activations were seen with similar patterns across the parietal cortex, thalamus, insula, claustrum, and midbrain. When targets were not perceived, left/right cerebral activations were similar overall. Directly comparing perceived vs. non-perceived stimuli with similar intensities in the masking task revealed predominate activations contralateral to masks. In contrast, activations were greater contralateral to perceived targets if no masks were given or if masks were given but target stimulus intensities were greater for perceived than non-perceived targets. The novel aspects of this study include: 1) imaging of cortical and subcortical activations in healthy humans related to somatosensory perception during a masking task, 2) activations in the human thalamus and midbrain related to perception of stimuli compared to matched non-perceived stimuli, and 3) similar left/right cerebral activation patterns across cortical, thalamic and midbrain structures suggesting interactions across all three levels during conscious perception in humans.

Infraslow Electroencephalographic and Dynamic Resting State Network Activity.

A number of studies have linked the blood oxygenation level dependent (BOLD) signal to electroencephalographic (EEG) signals in traditional frequency bands (δ, θ, α, ß, and γ), but the relationship between BOLD and its direct frequency correlates in the infraslow band (<1 Hz) has been little studied. Previously, work in rodents showed that infraslow local field potentials play a role in functional connectivity, particularly in the dynamic organization of large-scale networks. To examine the relationship between infraslow activity and network dynamics in humans, direct current (DC) EEG and resting state magnetic resonance imaging data were acquired simultaneously. The DC EEG signals were correlated with the BOLD signal in patterns that resembled resting state networks. Subsequent dynamic analysis showed that the correlation between DC EEG and the BOLD signal varied substantially over time, even within individual subjects. The variation in DC EEG appears to reflect the time-varying contribution of different resting state networks. Furthermore, some of the patterns of DC EEG and BOLD correlation are consistent with previous work demonstrating quasiperiodic spatiotemporal patterns of large-scale network activity in resting state. These findings demonstrate that infraslow electrical activity is linked to BOLD fluctuations in humans and that it may provide a basis for large-scale organization comparable to that observed in animal studies.

Digital EEG: trouble in paradise?

Digital EEG embodies enormous technological advances, but also presents new problems that users have not previously encountered and are still learning to deal with. Digital recording and display can produce unique artifacts, data distortion, and risks to data integrity. If used incautiously, digital displays may obscure important activity.

Aliasing in the visual EEG: a potential pitfall of video display technology.

Computerized clinical electroencephalographic (EEG) systems are now widely used, with interpretation performed solely on video monitors. The possibility of artifacts from aliasing of EEG data on a computer screen has received little attention. We describe and illustrate several examples. Photographs of the video display were used. Three cases are shown. Two had escaped initial review and one led to transient changes in patient management. Aliasing artifacts are seen frequently with computerized EEG systems; some may be misinterpreted as EEG activity. Even compliance with current guidelines may not prevent all such artifacts.

Modeling the effects of electrical conductivity of the head on the induced electric field in the brain during magnetic stimulation.

OBJECTIVE: The objective of this document is to quantify the effect of changing conductivity within the brain in transcranial magnetic stimulation. METHODS: Extreme examples of white and grey matter distributions as well as cerebral spinal fluid are analyzed with numerical boundary element methods to show that the induced E fields for these various distributions vary little from the homogeneous case. RESULTS: Models representative of the brain that demarcate regions of white matter and grey matter add an unnecessary level of complexity to the design and analysis of magnetic stimulators. The induced E field varies little between a precise model with exact placement of white and grey matter from that of its homogeneous counterpart. The E field will increase in white matter, and decrease in grey, but the variation is small. The contour integral of the E field around a closed path is dictated by the flux change through that contour. DISCUSSION: The maximum value of the variation of the electric field between a fully homogeneous medium, and one filled with different conductivity media is 1/2 the conductivity ratio of the media involved. Neuronal stimulation is more likely at the interface between dissimilar mediums, the greatest being between white matter and cerebral spinal fluid. The interface location where no normal electric field exists will witness a localized electric field 51% greater than the homogeneous E field on the white matter side of that interface. White-grey matter interfaces will have a maximum localized increase in the E field 22.9% greater than the homogeneous case. CONCLUSIONS: Variations in neural intracellular potential during a magnetic stimulation pulse will be small among patients. The most efficient modeling will follow by assuming the medium homogeneous, and noting that perturbations from this result will exist.

Natural rhythm: evidence for occult 40 Hz gamma oscillation in resting motor cortex.

Fast gamma oscillations, often at 40 Hz, have been demonstrated throughout the brain including the thalamus, auditory, visual and motor cortices. The function of gamma rhythms is elusive, but several authors have hypothesized that they contribute to the "binding" of diverse information into a single coherent percept, and to the synchronization of movement. In skeletal muscle a "Piper rhythm" around 40 Hz is commonly observed during maximal voluntary contraction, and has been shown to correlate with activity of similar frequency in a limited area of contralateral motor cortex. Gamma rhythms are detected primarily during complex cortical activity, and are seldom recorded at rest or coherently over wide areas. Here we use bihemispheric transcranial magnetic stimulation (TMS) to study time-dependent correlations between evoked motor potentials from non-homologous muscles in opposite limbs of normal volunteers. The results suggest the presence of an occult, synchronous 40 Hz rhythm across broad areas of resting motor cortex in both hemispheres.

Asymmetries of prefrontal cortex in human episodic memory: effects of transcranial magnetic stimulation on learning abstract patterns.

Functional neuroimaging suggests asymmetries of memory encoding and retrieval in the prefrontal lobes, but different hypotheses have been presented concerning the nature of prefrontal hemispheric specialization. We studied an associative memory task involving pairs of Kanji (Chinese) pictographs and unfamiliar abstract patterns. Subjects were ten Japanese adults fluent in Kanji, so only the abstract patterns represented novel material. During encoding, transcranial magnetic stimulation (TMS) was applied over the left and right dorsolateral prefrontal cortex (DLPFC). A significant (P<0.05) reduction in subsequent recall of new associations was seen only with TMS over the right DLPFC. This result suggests that the right DLPFC contributes to encoding of visual-object associations, and is consistent with a material-specific rather than a process-specific model of mnemonic function in DLPFC.

Iron-core coils for transcranial magnetic stimulation.

Transcranial magnetic stimulation requires a great deal of power, which mandates bulky power supplies and produces rapid coil heating. The authors describe the construction, modeling, and testing of an iron-core TMS coil that reduces power requirements and heat generation substantially, while improving the penetration of the magnetic field. Experimental measurements and numeric boundary element analysis show that the iron-core stimulation coil induces much stronger electrical fields, allows greater charge recovery, and generates less heat than air-core counterparts when excited on a constant-energy basis. These advantages are magnified in constant-effect comparisons. Examples are given in which the iron-core coil allows more effective operation in research and clinical applications.

Assessing low-frequency repetitive transcranial magnetic stimulation with functional magnetic resonance imaging: a case series.

BACKGROUND AND PURPOSE: This case series assesses the effects of five consecutive days of low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) with and without a 6-Hz primer. Although this paper studies able-bodied individuals, similar rTMS protocols are used to facilitate motor recovery in patients with hemiplegia following stroke. However, the cortical mechanisms associated with repeated daily doses of rTMS are not completely understood. CASE DESCRIPTION: Four right-handed healthy volunteers (two men, aged 20-50 years) participated in a double-blind case series of primed and unprimed rTMS. Functional magnetic resonance imaging was used to compare task-related haemodynamics during a simple motor task and resting-state cortical connectivity. Understanding the mechanisms of repeated rTMS sessions may serve as a precursor to development of rTMS paradigms involving motor cortex stimulation in patients with a range of neurologic dysfunction. OUTCOMES: Following five consecutive days of rTMS, all subjects had reduced task-related haemodynamics. Resting-state brain connectivity between motor regions was reduced only after primed rTMS. DISCUSSION: This is the first study to indicate that resting-state brain connectivity can distinguish the effect of primed and unprimed rTMS to a greater extent than task-related haemodynamics. Furthermore, priming may inhibit the connectivity between the area of the cortex underlying the rTMS site and remote brain regions. SIGNIFICANCE: These findings benefit rTMS rehabilitation studies by examining haemodynamics on repeated days of stimulation and incorporating resting-state brain connectivity analysis to further understand underlying neural mechanisms. Furthermore, this work encourages the utilization of resting connectivity in future rTMS studies.

Localizing epileptic seizure onsets with Granger causality.

Accurate localization of the epileptic seizure onset zones (SOZs) is crucial for successful surgery, which usually depends on the information obtained from intracranial electroencephalography (IEEG) recordings. The visual criteria and univariate methods of analyzing IEEG recordings have not always produced clarity on the SOZs for resection and ultimate seizure freedom for patients. Here, to contribute to improving the localization of the SOZs and to understanding the mechanism of seizure propagation over the brain, we applied spectral interdependency methods to IEEG time series recorded from patients during seizures. We found that the high-frequency (>80 Hz) Granger causality (GC) occurs before the onset of any visible ictal activity and causal relationships involve the recording electrodes where clinically identifiable seizures later develop. These results suggest that high-frequency oscillatory network activities precede and underlie epileptic seizures, and that GC spectral measures derived from IEEG can assist in precise delineation of seizure onset times and SOZs.