Tremor Relief and Structural Integrity after MRI-guided Focused US Thalamotomy in Tremor Disorders.

Background MRI-guided focused US thalamotomy of ventral intermediate nucleus of the thalamus is a treatment for tremor disorders. Purpose To evaluate white matter integrity before and after thalamotomy and its correlation with clinical outcome. Materials and Methods Participants with essential tremor (ET) or Parkinson disease (PD) undergoing thalamotomy were prospectively recruited between March 2016 and October 2018. Tremor and quality of life were assessed before, 1 month after, and 6 months after thalamotomy. Participants underwent T1-weighted, T2-weighted fluid-attenuated image recovery, and diffusion-tensor MRI before and 1 day, 7-10 days, 1-3 months, and 6 months or longer after treatment. Diffusivity and fiber tractography measures were calculated. Repeated measures analysis of variance with post hoc paired t test and Skillings-Mack test with post hoc Wilcoxon signed-rank test were used for normally and nonnormally distributed data, respectively, and Bonferroni method corrected for multiple comparisons. Results Twenty-two study participants with ET (mean age, 72 years ± 6 [standard deviation]; 14 men), 17 participants with PD (mean age, 65 years ± 8; 13 men), and a replication set of 17 participants with ET (mean age, 73 years ± 6; 10 men) were evaluated. Long-term damage was found in the ablated core (mean fractional anisotropy [FA] at baseline, 0.41 ± 0.10, and at ≥6 months, 0.23 ± 0.09; P < .001) and thalamus to red nucleus tract (mean number of tracts at baseline, 1663, and at ≥6 months, 1070; P = .003). Negative correlation was observed between motor thalamus FA 1 day after ablation and tremor improvement (ET: R = -0.52 [P = .03]; PD: R = -0.61 [P = .003]). Better tremor relief in ET was associated with lower fractional anisotropy before treatment (R = -0.5; P = .02). Conclusion MRI-guided focused US thalamotomy resulted in short- and long-term white-matter changes. Diffusion-tensor imaging provided evidence for long-term damage in the ablation core and in the thalamus and red nucleus tract, and a correlation between preablation fractional anisotropy in the motor thalamus and clinical outcome. © RSNA, 2020 Online supplemental material is available for this article.

[EFFECT OF GENDER ON OUTCOME OF TREATMENT FOR TREMOR WITH MRI GUIDED FOCUSED ULTRASOUND].

INTRODUCTION: Thalamotomy is an effective treatment for medication-resistant tremor. MRI-guided focused ultrasound (MRgFUS) has been shown to be an effective and safe treatment for alleviating tremor. OBJECTIVES: We examined whether there is a gender difference in the efficacy and safety of thalamotomy using MRgFUS. METHODS: Seventy patients with moderate to severe medication-resistant tremor were treated with MRgFUS at Rambam Medical Center. Thermal ablation with ultrasound waves was carried out in the MRI suite while real-time monitoring of treatment efficacy and adverse events were recorded. A comparison was made between outcomes in men and women. RESULTS: Seventy patients, 47 men and 23 women with essential tremor, Parkinson's disease, paraneoplastic syndrome, and multiple system atrophy were treated. Both men and women reported the disappearance of tremor after MRgFUS with the exception of one patient with a paraneoplastic syndrome. In all patients, there was a significant decrease in the tremor scores (p <0.001), with no gender difference, and all patients reported a significant improvement in quality of life (p<0.001) regardless of gender. In ten patients, 8 men and 2 women, the tremor returned, but was bothersome in only 4, all men. This gender difference was not statistically significant. Transient adverse events were observed in the same frequency in men and women. The most common adverse event was transient gait instability and ataxia. CONCLUSIONS: In this series of patients, MRgFUS was an effective and safe treatment for both sexes with no significant difference in efficacy or adverse events.

Sex dimorphism in a mediatory role of the posterior midcingulate cortex in the association between anxiety and pain sensitivity.

Behavioral studies found greater pain sensitivity in females that vanishes fully or partially when controlling for the emotional state. Furthermore, pain-related brain activation hints at the role of limbic structures in sex differences in pain processing. We aimed to investigate the role of pain-related limbic structures in mediating the relation between subjects' affective state (i.e., anxiety) and pain. Contact heat-evoked potentials (CHEPs) were recorded in 26 healthy subjects (13 males) simultaneously with innocuous (42 °C) baseline and target noxious (52 °C) series of stimuli administered to the left non-dominant volar forearm. The N2 and P2 components were analyzed, and their generators' activity was estimated using standardized low-resolution brain electromagnetic tomography. Thereafter, structural equation modeling (SEM) was applied separately for females and males, examining the mediatory role of the CHEPs' limbic structures generators [posterior midcingulate cortex (pMCC), insula, amygdala, and hippocampus] in the anxiety-pain sensitivity association. Females exhibited greater P2 amplitudes that were highly associated with larger pMCC activity (r = 0.910, p < 0.001). This correlation was also evident in males, though with less strength (r = 0.578, p = 0.039). Moreover, the P2 amplitudes were associated both in females (r = 0.645, p = 0.017) and males (r = 0.608, p = 0.028) with the activity of the amygdala\hippocampus\insula. SEM revealed that the relationship between state anxiety and pain ratings was only in females fully mediated via the effect of the pMCC on the P2 amplitude. These findings suggest that sexual dimorphism in anxiety-related brain activity may explain the differences found in CHEPs and the sex-related association between anxiety and pain.

Focused Ultrasound Thalamotomy for Tremor Relief in Atypical Parkisnsonism.

Background: Magnetic resonance imaging (MRI)-guided focused ultrasound (FUS) VIM-thalamotomy has established efficacy and safety in tremor relief in patients with essential tremor and Parkinson's disease. The efficacy and safety in patients with atypical parkinsonism have not been reported. Objective: To report on the efficacy and safety of FUS VIM-thalamotomy in 8 patients with parkinsonism, multiple system atrophy-Parkinsonian type (MSA-P) (n = 5), and dementia with Lewy bodies (DLB) (n = 3). Methods: Tremor was assessed in the treated hemibody using the Clinical Rating Scale for Tremor (CRST). The motor Unified MSA Rating Scale (UMSAR) was used in the MSA-P and motor sections of the Unified Parkinson's Disease Rating Scale (UPDRS-III) in DLB patients. Cognition was measured using the Montreal Cognitive Assessment (MoCA). Results: In MSA-P and DLB patients, there was immediate tremor relief. CRST scores measured on the treated side improved compared to baseline. During the follow-up of up to 1 year tremor reduction persisted. The change in CRST scores at different time points did not reach statistical significance, probably due to the small sample size. Adverse events were transient and resolved within a year. Conclusions: In our experience, FUS VIM-thalamotomy was effective in patients with MSA-P and DLB. Larger, controlled studies are needed to verify our preliminary observations.

Real-time change detection of steady-state evoked potentials.

Steady-state evoked potentials (SSEP) are the electrical activity recorded from the scalp in response to high-rate sensory stimulation. SSEP consist of a constituent frequency component matching the stimulation rate, whose amplitude and phase remain constant with time and are sensitive to functional changes in the stimulated sensory system. Monitoring SSEP during neurosurgical procedures allows identification of an emerging impairment early enough before the damage becomes permanent. In routine practice, SSEP are extracted by averaging of the EEG recordings, allowing detection of neurological changes within approximately a minute. As an alternative to the relatively slow-responding empirical averaging, we present an algorithm that detects changes in the SSEP within seconds. Our system alerts when changes in the SSEP are detected by applying a two-step Generalized Likelihood Ratio Test (GLRT) on the unaveraged EEG recordings. This approach outperforms conventional detection and provides the monitor with a statistical measure of the likelihood that a change occurred, thus enhancing its sensitivity and reliability. The system's performance is analyzed using Monte Carlo simulations and tested on real EEG data recorded under coma.

Connectivity between perisylvian and bilateral basal temporal cortices.

Language processing requires the orchestrated action of different neuronal populations, and some studies suggest that the role of the basal temporal (BT) cortex in language processing is bilaterally distributed. Our aim was to demonstrate connectivity between perisylvian cortex and both BT areas. We recorded corticocortical evoked potentials (CCEPs) in 8 patients with subdural electrodes implanted for surgical evaluation of intractable epilepsy. Four patients had subdural grids over dominant perisylvian and BT areas, and 4 had electrode strips over both BT areas and left posterior superior temporal gyrus (LPSTG). After electrocortical mapping, patients with grids had 1-Hz stimulation of language areas. Patients with strips did not undergo mapping but had 1-Hz stimulation of the LPSTG. Posterior language area stimulation elicited CCEPs in ipsilateral BT cortex in 3/4 patients with left hemispheric grids. CCEPs were recorded in bilateral BT cortices in 3/4 patients with strips upon stimulation of the LPSTG, and in the LPSTG in the fourth patient upon stimulation of either BT area. This is the first in vivo demonstration of connectivity between LPSTG and both BT cortices. The role of BT cortex in language processing may be bilaterally distributed and related to linking visual information with phonological representations stored in the LPSTG.

Focused Ultrasound Thalamotomy in Tremor Dominant Parkinson's Disease: Long-Term Results.

BACKGROUND: MRI-guided focused ultrasound (FUS) has established short-term efficacy in tremor relief. OBJECTIVE: We report our long-term experience of treating tremor with unilateral FUS unilateral VIM-thalamotomy in tremor dominant Parkinson's disease (TDPD) patients. METHODS: We report outcome of FUS thalamotomy in TDPD patients with 1-5 years of follow-up. OUTCOMES: tremor reduction assessed with Clinical Rating Scale for Tremor (CRST) and Unified Parkinson's Disease Rating Scale (UPDRS part III) overall and in the treated hemibody and safety. RESULTS: Twenty-six TDPD patients completed 1-5 years of follow-up (median follow-up 36 months, range 12-60 months). Median age was 60 years (range 46-79), with median disease duration of 6 years (range 2-16). Immediately, treatment resulted in 100%improvement in tremor in the treated arm in 23 patients and 90%improvement in 3 patients. In 15 patients with leg tremor, 2 patients with chin tremor and 1 patient with head tremor, tremor was significantly improved. Up to 5 years, median CRST score, median UPDRS score, overall and in treated hemibody, decreased significantly as compared with baseline (p < 0.0001). In 2 patients tremor returned completely and in 8 patients there was partial return of tremor. Adverse events were mild and resolved within 3 months. At baseline 4 patients were not receiving any medication vs. 3 at last follow-up and 15 were not taking levodopa vs.9 at last follow-up. CONCLUSION: Unilateral FUS VIM-thalamotomy in TDPD patients was effective and safe and provided long-term tremor relief in most patients. FUS thalamotomy for tremor may delay initiation of levodopa treatment.

Clinical Effects of Repetitive Transcranial Magnetic Stimulation of the Motor Cortex Are Associated With Changes in Resting-State Functional Connectivity in Patients With Fibromyalgia Syndrome.

In this double-blinded, sham-controlled, counterbalanced, and crossover study, we investigated the potential neuroplasticity underlying pain relief and daily function improvements following repetitive transcranial magnetic stimulation of the motor cortex (M1-rTMS) in fibromyalgia syndrome (FMS) patients. Specifically, we used magnetic resonance imaging (MRI) to examine changes in brain structural and resting-state functional connectivity (rsFC) that correlated with improvements in FMS symptomology following M1-rTMS. Twenty-seven women with FMS underwent real and sham treatment series, each consisting of 10 daily treatments of 10Hz M1-rTMS over 2 weeks, with a washout period in between. Before and after each series, participants underwent anatomical and resting-state functional MRI scans and questionnaire assessments of FMS-related clinical pain and functional and psychological burdens. The expected reductions in FMS-related symptomology following M1-rTMS occurred with the real treatment only and correlated with rsFC changes in brain areas associated with pain processing and modulation. Specifically, between the ventromedial prefrontal cortex and the M1 (t = -5.54, corrected P = .002), the amygdala and the posterior insula (t = 5.81, corrected P = .044), and the anterior and posterior insula (t = 6.01, corrected P = .029). Neither treatment significantly changed brain structure. Therefore, we provide the first evidence of an association between the acute clinical effects of M1-rTMS in FMS and functional alterations of brain areas that have a significant role in the experience of chronic pain. Structural changes could potentially occur over a more extended treatment period. PERSPECTIVE: We show that the neurophysiological mechanism of the improvement in fibromyalgia symptoms following active, but not sham, rTMS applied to M1 involves changes in resting-state functional connectivity in sensory, affective and cognitive pain processing brain areas, thus substantiating the essence of fibromyalgia syndrome as a treatable brain-based disorder.

Resting-state functional connectivity predicts motor cortex stimulation-dependent pain relief in fibromyalgia syndrome patients.

MRI-based resting-state functional connectivity (rsFC) has been shown to predict response to pharmacological and non-pharmacological treatments for chronic pain, but not yet for motor cortex transcranial magnetic stimulation (M1-rTMS). Twenty-seven fibromyalgia syndrome (FMS) patients participated in this double-blind, crossover, and sham-controlled study. Ten daily treatments of 10 Hz M1-rTMS were given over 2 weeks. Before treatment series, patients underwent resting-state fMRI and clinical pain evaluation. Significant pain reduction occurred following active, but not sham, M1-rTMS. The following rsFC patterns predicted reductions in clinical pain intensity after the active treatment: weaker rsFC of the default-mode network with the middle frontal gyrus (r = 0.76, p < 0.001), the executive control network with the rostro-medial prefrontal cortex (r = 0.80, p < 0.001), the thalamus with the middle frontal gyrus (r = 0.82, p < 0.001), and the pregenual anterior cingulate cortex with the inferior parietal lobule (r = 0.79, p < 0.001); and stronger rsFC of the anterior insula with the angular gyrus (r = - 0.81, p < 0.001). The above regions process the attentional and emotional aspects of pain intensity; serve as components of the resting-state networks; are modulated by rTMS; and are altered in FMS. Therefore, we suggest that in FMS, the weaker pre-existing interplay between pain-related brain regions and networks, the larger the pain relief resulting from M1-rTMS.

New US device versus imaging US to assess tumor-in-brain.

BACKGROUND: Applying ultrasonic imaging system during surgery requires the poring of saline, performing the measurement, and acquiring data from its display-which requires time and is highly "performer dependent," i.e., the measure is of a subjective nature. A new ultrasonic device was recently developed that overcomes most of these drawbacks and was successfully applied during tumor-in-brain neurosurgeries. The purpose of this study was to compare the two types of US devices and demonstrate their properties. METHODS: The study was performed in the following stages: (i) an ex vivo experiment, where slices of the muscle and brain of a young porcine were laid one on top the other. Thicknesses and border depths were measured and compared, using the two types of US instruments. (ii) During human clinical neurosurgeries, tumor depth was compared by measuring it with both devices. (iii) Following the success of stages (i) and (ii), using solely the new US device, the tumor thickness was monitored while its resection.Correlation, Pearson's coefficient, average, mean, and standard deviation were applied for statistical tests. RESULTS: A high correlation was obtained for the distances of tissue borders and for their respective thicknesses. Applying these ultrasonic devices during neurosurgeries, tumor depths were monitored with high similarity (87%), which was also obtained by Pearson's correlation coefficient (0.44). The new US device, thanks to its small footprint, its remote measurement, and the capability of monitoring intraoperatively and in real-time, provides the approach to tumor's border before its complete resection. CONCLUSIONS: The new US device provides better accuracy than an ultrasonic imaging system; its data is objective; it enables to control the residual tumor thickness during its resection, and it is especially useful in restricted areas. These features were found of great help during a tumor-in-brain surgery and especially in the final stages of tumor's resection.

Motor corticospinal excitability: a novel facet of pain modulation?

INTRODUCTION: Increase in excitability of the primary motor cortex (M1) is associated with pain inhibition by analgesics, which is, in turn, associated with the psychophysical antinociceptive pain modulation profile. However, the relationship between neurophysiological M1 excitability and psychophysical pain modulation has not yet been explored. OBJECTIVES: We aim to study these relationships in healthy subjects. METHODS: Forty-one young healthy subjects (22 women) underwent a wide battery of psychophysical testing that included conditioned pain modulation (CPM) and pain temporal summation, and a transcranial magnetic stimulation neurophysiological assessment of the motor corticospinal excitability, including resting motor threshold, motor-evoked potentials (MEPs), and cortical silent period. RESULTS: Increased motor corticospinal excitability in 2 parameters was associated with more efficient CPM: (1) higher MEP amplitude (r = -0.574; P _Bonferroni = 0.02) and (2) longer MEP duration (r = -0.543; P _Bonferroni = 0.02). The latter also correlated with the lower temporal summation magnitude (r = -0.421; P = 0.007); however, on multiplicity adjustment, significance was lost. CONCLUSIONS: Increased corticospinal excitability of the primary motor cortex is associated with more efficient inhibitory pain modulation as assessed by CPM, in healthy subjects. Motor-evoked potential amplitude and duration may be considered as an additional, objective and easy to measure parameter to allow for better individual assessment of pain modulation profile.

Magnetic resonance-guided focused ultrasound thalamotomy for essential tremor: a 5-year single-center experience.

OBJECTIVE: The authors report their experience in treating patients suffering from medication-resistant essential tremor (ET) with MR-guided focused ultrasound (MRgFUS) thalamotomy over a 5-year period. METHODS: Forty-four ET patients treated with unilateral MRgFUS ventral intermediate nucleus (VIM) thalamotomy were assessed using the Clinical Rating Scale for Tremor (CRST) score and the Quality of Life in Essential Tremor Questionnaire (QUEST) over a 5-year span. RESULTS: Tremor was significantly improved immediately following MRgFUS in all patients and ceased completely in 24 patients. CRST scores in the treated hand at baseline (median 19; range 7-32, 44 patients) improved by a median of 16 at 1 month (44 patients; p < 0.0001), 17 at 6 months (31 patients; p < 0.0001), 15 at 1 year (24 patients; p < 0.0001), 18 at 2 years (15 patients; p < 0.0001), 19 at 3 years, (10 patients; p < 0.0001), 21 at 4 years (6 patients; p < 0.01), and 23 at 5 years (2 patients, significance not tested). Return of tremor that impacted activities of daily living was reported in 5 patients (11%). QUEST scores showed significant improvement, with median change of 35 points (p < 0.0001; 44 patients) at 1 month, 33 (p < 0.0001; 31 patients) at 6 months, 27 (p < 0.0001; 24 patients) at 1 year, 26 (p < 0.001; 15 patients) at 2 years, 25 (p < 0.001; 10 patients) at 3 years, 33 (p < 0.001; 6 patients) at 4 years, and 28 (significance not tested, 2 patients) at 5 years. Adverse events after the procedure were reversible in all but 5 patients (11%). CONCLUSIONS: MRgFUS thalamotomy for ET is an effective and safe procedure that provides long-term tremor relief and improvement in quality of life even in patients with medication-resistant disabling tremor. Additional studies with a larger group of patients is needed to substantiate these favorable results.

High-frequency gamma activity (80-150Hz) is increased in human cortex during selective attention.

OBJECTIVE: To study the role of gamma oscillations (>30Hz) in selective attention using subdural electrocorticography (ECoG) in humans. METHODS: We recorded ECoG in human subjects implanted with subdural electrodes for epilepsy surgery. Sequences of auditory tones and tactile vibrations of 800 ms duration were presented asynchronously, and subjects were asked to selectively attend to one of the two stimulus modalities in order to detect an amplitude increase at 400 ms in some of the stimuli. RESULTS: Event-related ECoG gamma activity was greater over auditory cortex when subjects attended auditory stimuli and was greater over somatosensory cortex when subjects attended vibrotactile stimuli. Furthermore, gamma activity was also observed over prefrontal cortex when stimuli appeared in either modality, but only when they were attended. Attentional modulation of gamma power began approximately 400 ms after stimulus onset, consistent with the temporal demands on attention. The increase in gamma activity was greatest at frequencies between 80 and 150 Hz, in the so-called high-gamma frequency range. CONCLUSIONS: There appears to be a strong link between activity in the high-gamma range (80-150 Hz) and selective attention. SIGNIFICANCE: Selective attention is correlated with increased activity in a frequency range that is significantly higher than what has been reported previously using EEG recordings.

Magnetic resonance-guided focused ultrasound thalamotomy for tremor: a report of 30 Parkinson's disease and essential tremor cases.

OBJECTIVE Thalamotomy of the ventral intermediate nucleus (VIM) is effective in alleviating medication-resistant tremor in patients with essential tremor (ET) and Parkinson's disease (PD). MR-guided focused ultrasound (MRgFUS) is an innovative technology that enables noninvasive thalamotomy via thermal ablation. METHODS Patients with severe medication-resistant tremor underwent unilateral VIM thalamotomy using MRgFUS. Effects on tremor were evaluated using the Clinical Rating Scale for Tremor (CRST) in patients with ET and by the motor part of the Unified Parkinson's Disease Rating Scale (UPDRS) in patients with PD and ET-PD (defined as patients with ET who developed PD many years later). Quality of life in ET was measured by the Quality of Life in Essential Tremor (QUEST) questionnaire and in PD by the PD Questionnaire (PDQ-39). RESULTS Thirty patients underwent MRgFUS, including 18 with ET, 9 with PD, and 3 with ET-PD. The mean age of the study population was 68.9 ± 8.3 years (range 46-87 years) with a mean disease duration of 12.1 ± 8.9 years (range 2-30 years). MRgFUS created a lesion at the planned target in all patients, resulting in cessation of tremor in the treated hand immediately following treatment. At 1 month posttreatment, the mean CRST score of the patients with ET decreased from 40.7 ± 11.6 to 9.3 ± 7.1 (p < 0.001) and was 8.2 ± 5.0 six months after treatment (p < 0.001, compared with baseline). Average QUEST scores decreased from 44.8 ± 12.9 to 13.1 ± 13.2 (p < 0.001) and was 12.3 ± 7.2 six months after treatment (p < 0.001). In patients with PD, the mean score of the motor part of the UPDRS decreased from 24.9 ± 8.0 to 16.4 ± 11.1 (p = 0.042) at 1 month and was 13.4 ± 9.2 six months after treatment (p = 0.009, compared with baseline). The mean PDQ-39 score decreased from 38.6 ± 16.8 to 26.1 ± 7.2 (p = 0.036) and was 20.6 ± 8.8 six months after treatment (p = 0.008). During follow-up of 6-24 months (mean 11.5 ± 7.2 months, median 12.0 months), tremor reappeared in 6 of the patients (2 with ET, 2 with PD, and 2 with ET-PD), to a lesser degree than before the procedure in 5. Adverse events that transiently occurred during sonication included headache (n = 11), short-lasting vertigo (n = 14) and dizziness (n = 4), nausea (n = 3), burning scalp sensation (n = 3), vomiting (n = 2) and lip paresthesia (n = 2). Adverse events that lasted after the procedure included gait ataxia (n = 5), unsteady feeling (n = 4), taste disturbances (n = 4), asthenia (n = 4), and hand ataxia (n = 3). No adverse event lasted beyond 3 months. Patients underwent on average 21.0 ± 6.9 sonications (range 14-45 sonications) with an average maximal sonication time of 16.0 ± 3.0 seconds (range 13-24 seconds). The mean maximal energy reached was 12,500 ± 4274 J (range 5850-23,040 J) with a mean maximal temperature of 56.5° ± 2.2°C (range 55°-60°C). CONCLUSIONS MRgFUS VIM thalamotomy to relieve medication-resistant tremor was safe and effective in patients with ET, PD, and ET-PD. Current results emphasize the superior adverse events profile of MRgFUS over other surgical approaches for treating tremor with similar efficacy. Large randomized studies are needed to assess prolonged efficacy and safety.

The Role of the Anesthesiologist during Magnetic Resonance-Guided Focused Ultrasound Thalamotomy for Tremor: A Single-Center Experience.

Ablative incisionless neurosurgery has become possible through advances in focused ultrasound and magnetic resonance imaging (MRI). The great advantage of MRI-guided focused ultrasound (MRgFUS) is that the ablation is performed through an intact skull without surgery. Here, we review the new modality of MRgFUS for treating tremor and enlighten the role of the anesthesiologist in the unique procedural setting of the MRI suite. During the MRgFUS process, the patients should be awake and are required to cooperate with the medical staff to allow assessment of tremor reduction and potential occurrence of adverse effects. In addition, the patient's head is immobilized inside the MRI tunnel for hours. This combination presents major challenges for the attending anesthesiologist, who is required to try to prevent pain and nausea and when present, to treat these symptoms. Anxiety, vertigo, and vomiting may occur during treatment and require urgent treatment. Here, we review the literature available on anesthetic management during the procedure and our own experience and provide recommendations based on our collected knowledge.

Can a single pulse transcranial magnetic stimulation targeted to the motor cortex interrupt pain processing?

The modulatory role of the primary motor cortex (M1), reflected by an inhibitory effect of M1-stimulation on clinical pain, motivated us to deepen our understanding of M1's role in pain modulation. We used Transcranial Magnetic Stimulation (TMS)-induced virtual lesion (VL) to interrupt with M1 activity during noxious heat pain. We hypothesized that TMS-VL will effect experimental pain ratings. Three VL protocols were applied consisting of single-pulse TMS to transiently interfere with right M1 activity: (1) VLM1- TMS applied to 11 subjects, 20 msec before the individual's first pain-related M1 peak activation, as determined by source analysis (sLORETA), (2) VL-50 (N = 16; TMS applied 50 ms prior to noxious stimulus onset), and (3) VL+150 (N = 16; TMS applied 150 ms after noxious stimulus onset). Each protocol included 3 conditions ('pain-alone', ' TMS-VL', and 'SHAM-VL'), each consisted of 30 noxious heat stimuli. Pain ratings were compared, in each protocol, for TMS-VL vs. SHAM-VL and vs. pain-alone conditions. Repeated measures analysis of variance, corrected for multiple comparisons revealed no significant differences in the pain ratings between the different conditions within each protocol. Therefore, our results from this exploratory study suggest that a single pulse TMS-induced VL that is targeted to M1 failed to interrupt experimental pain processing in the specific three stimulation timing examined here.

MRI-Guided Focused Ultrasound in Parkinson's Disease: A Review.

MRI-guided focused ultrasound is a new technology that enables intracranial ablation. Since lesioning ameliorates some of the symptoms of PD, this technology is being explored as a possible treatment for medication resistant symptoms in PD patients. The purpose of this paper is to review the clinical use and treatment outcomes of PD patients treated to date with this technology.

Bi-phasic activation of the primary motor cortex by pain and its relation to pain-evoked potentials - an exploratory study.

The primary motor cortex (M1) is a known target for brain stimulation aimed at pain alleviation in chronic pain patients, yet the mechanisms through which analgesia occurs, and the exact pain-motor interrelations are not fully understood. We used noxious contact heat evoked potentials (CHEPs) and cortical source analysis to further explore the relevance of M1 in pain processing. Twenty-four healthy young females received brief noxious heat stimuli to their left non-dominant volar forearm, simultaneously with CHEPs recordings. Thereafter, the pain-evoked activity of M1 and a control area in the occipital cortex (OC) was analyzed and estimated using sLORETA (standardized low-resolution brain electromagnetic tomography). This analysis revealed two phases of M1 pain-evoked activation (phase 1: the peak at 261.5±25.7ms; phase 2: the peak at 381.3±28.3ms). Canonical correlations revealed that M1, but not the OC, was the main factor contributing to the relation with the CHEPs components. In detail, the activity magnitude of M1 first and second phases was related to the N2 and P2 amplitude, respectively. The latency of the second phase was associated with both N2 and P2 latencies. In relation to pain, the latency of M1's first activity phase was positively correlated with pain ratings, suggesting pain interference to synchronized activity in M1. Our results confirm the established relevance of the primary motor cortex to pain processing.

High-frequency gamma oscillations and human brain mapping with electrocorticography.

Invasive EEG recordings with depth and/or subdural electrodes are occasionally necessary for the surgical management of patients with epilepsy refractory to medications. In addition to their vital clinical utility, electrocorticographic (ECoG) recordings provide an unprecedented opportunity to study the electrophysiological correlates of functional brain activation in greater detail than non-invasive recordings. The proximity of ECoG electrodes to the cortical sources of EEG activity enhances their spatial resolution, as well as their sensitivity and signal-to-noise ratio, particularly for high-frequency EEG activity. ECoG recordings have, therefore, been used to study the event-related dynamics of brain oscillations in a variety of frequency ranges, and in a variety of functional-neuroanatomic systems, including somatosensory and somatomotor systems, visual and auditory perceptual systems, and cortical networks responsible for language. These ECoG studies have confirmed and extended the original non-invasive observations of ERD/ERS phenomena in lower frequencies, and have discovered novel event-related responses in gamma frequencies higher than those previously observed in non-invasive recordings. In particular, broadband event-related gamma responses greater than 60 Hz, extending up to approximately 200 Hz, have been observed in a variety of functional brain systems. The observation of these "high gamma" responses requires a recording system with an adequate sampling rate and dynamic range (we use 1000 Hz at 16-bit A/D resolution) and is facilitated by event-related time-frequency analyses of the recorded signals. The functional response properties of high-gamma activity are distinct from those of ERD/ERS phenomena in lower frequencies. In particular, the timing and spatial localization of high-gamma ERS often appear to be more specific to the putative timing and localization of functional brain activation than alpha or beta ERD/ERS. These findings are consistent with the proposed role of synchronized gamma oscillations in models of neural computation, which have in turn been inspired by observations of gamma activity in animal preparations, albeit at somewhat lower frequencies. Although ECoG recordings cannot directly measure the synchronization of action potentials among assemblies of neurons, they may demonstrate event-related interactions between gamma oscillations in macroscopic local field potentials (LFP) generated by different large-scale populations of neurons engaged by the same functional task. Indeed, preliminary studies suggest that such interactions do occur in gamma frequencies, including high-gamma frequencies, at latencies consistent with the timing of task performance. The neuronal mechanisms underlying high-gamma activity and its unique response properties in humans are still largely unknown, but their investigation through invasive methods is expected to facilitate and expand their potential clinical and research applications, including functional brain mapping, brain-computer interfaces, and neurophysiological studies of human cognition.

Electrocorticographic high gamma activity versus electrical cortical stimulation mapping of naming.

Subdural electrocorticographic (ECoG) recordings in patients undergoing epilepsy surgery have shown that functional activation is associated with event-related broadband gamma activity in a higher frequency range (>70 Hz) than previously studied in human scalp EEG. To investigate the utility of this high gamma activity (HGA) for mapping language cortex, we compared its neuroanatomical distribution with functional maps derived from electrical cortical stimulation (ECS), which remains the gold standard for predicting functional impairment after surgery for epilepsy, tumours or vascular malformations. Thirteen patients had undergone subdural electrode implantation for the surgical management of intractable epilepsy. Subdural ECoG signals were recorded while each patient verbally named sequentially presented line drawings of objects, and estimates of event-related HGA (80-100 Hz) were made at each recording site. Routine clinical ECS mapping used a subset of the same naming stimuli at each cortical site. If ECS disrupted mouth-related motor function, i.e. if it affected the mouth, lips or tongue, naming could not be tested with ECS at the same cortical site. Because naming during ECoG involved these muscles of articulation, the sensitivity and specificity of ECoG HGA were estimated relative to both ECS-induced impairments of naming and ECS disruption of mouth-related motor function. When these estimates were made separately for 12 electrode sites per patient (the average number with significant HGA), the specificity of ECoG HGA with respect to ECS was 78% for naming and 81% for mouth-related motor function, and equivalent sensitivities were 38% and 46%, respectively. When ECS maps of naming and mouth-related motor function were combined, the specificity and sensitivity of ECoG HGA with respect to ECS were 84% and 43%, respectively. This study indicates that event-related ECoG HGA during confrontation naming predicts ECS interference with naming and mouth-related motor function with good specificity but relatively low sensitivity. Its favourable specificity suggests that ECoG HGA can be used to construct a preliminary functional map that may help identify cortical sites of lower priority for ECS mapping. Passive recordings of ECoG gamma activity may be done simultaneously at all electrode sites without the risk of after-discharges associated with ECS mapping, which must be done sequentially at pairs of electrodes. We discuss the relative merits of these two functional mapping techniques.