Fibromyalgia in Pregnancy: Neuro-Endocrine Fluctuations Provide Insight into Pathophysiology and Neuromodulation Treatment.

Fibromyalgia (FM) is a chronic pain disorder with unclear pathophysiological mechanisms, which leads to challenges in patient management. In addition to pain, the disorder presents with a broad range of symptoms, such as sleep disruption, chronic fatigue, brain fog, depression, muscle stiffness, and migraine. FM has a considerable female prevalence, and it has been shown that symptoms are influenced by the menstrual cycle and periods of significant hormonal and immunological changes. There is increasing evidence that females with FM experience an aggravation of symptoms in pregnancy, particularly during the third trimester and after childbirth. In this perspective paper, we focus on the neuro-endocrine interactions that occur between progesterone, allopregnanolone, and cortisol during pregnancy, and propose that they align with our previously proposed model of FM pathogenesis based on GABAergic "weakening" in a thalamocortical neural loop system. Based on our hypothesis, we introduce the possibility of utilizing transcranial direct current stimulation (tDCS) as a non-invasive treatment potentially capable of exerting sex-specific effects on FM patients.

Deep brain stimulation in the bed nucleus of the stria terminalis: A symptom provocation study in patients with obsessive-compulsive disorder.

BACKGROUND: Deep brain stimulation (DBS) is an emerging therapy for treatment-resistant obsessive-compulsive disorder (OCD), and several targets for electrode implantation and contact selection have been proposed, including the bed nucleus of the stria terminalis (BST). Selecting the active electrode contacts (patients typically have four to choose from in each hemisphere), and thus the main locus of stimulation, can be a taxing process. Here, we investigated whether contact selection based purely on their neuroanatomical position in the BST is a worthwhile approach. For the first time, we also compared the effects of uni- versus bilateral BST stimulation. METHODS: Nine OCD patients currently receiving DBS participated in a double-blind, randomized symptom provocation study to compare no versus BST stimulation. Primary outcomes were anxiety and mood ratings in response to disorder-relevant trigger images, as well as ratings of obsessions, compulsions, tendency to avoid and overall wellbeing. Furthermore, we asked whether patients preferred the electrode contacts in the BST over their regular stimulation contacts as a new treatment setting after the end of the task. RESULTS: We found no statistically significant group differences between the four conditions (no, left, right and bilateral BST stimulation). Exploratory analyses, as well as follow-up data, did indicate that (bilateral) bipolar stimulation in the BST was beneficial for some patients, particularly for those who had achieved unsatisfactory effects through the typical contact selection procedure. CONCLUSIONS: Despite its limitations, this study suggests that selection of stimulation contacts in the BST is a viable option for DBS in treatment-resistant OCD patients.

Determination of Current Flow Induced by Transcutaneous Electrical Nerve Stimulation for the Treatment of Migraine: Potential for Optimization.

Introduction: Transcutaneous electrical nerve stimulation (TENS) for migraine involves the application of pulsatile stimulation through electrodes placed on the forehead to target the underlying trigeminal nerves. It is a simple, safe modality and has secured clinical approval in several markets including the European Union and the United States. Despite nearing almost 7 years of use (postclinical approval), the exact mechanism of action is not fully known. Guided by the need to stimulate the trigeminal nerves bilaterally, electrode dimensions are simply required to extend enough to cover the underlying nerves. The goal of this study is to examine induced current flow [magnitude and spatial distribution of electric field (EF)] and another driver of stimulation [activating function (AF)] due to TENS therapy for migraine for the first time. We further consider the effect of changing the electrode dimension and shape and propose a design modification to deliver optimal flow. Methods: We developed the first ultra-high-resolution finite element (FE) model of TENS for migraine incorporating the target supratrochlear (ST) and the supraorbital (SO) nerves. We first simulated the clinically approved V-shaped geometry. We then considered three additional designs: extended V-shaped, idealized pill-shaped, and finally an extended V-shaped but with greater contact spacing (extended V-shaped +CS). Results: Our findings revealed that the clinically approved electrode design delivered substantially higher mean current flow to the ST nerve in comparison with the SO nerves (Medial: 53% and Lateral: 194%). Consideration of an extended design (~10 mm longer and ~ 4 mm shorter) and a pill-like design had negligible impact on the induced current flow pattern. The extended V-shaped +CS montage delivered relatively comparable current flow to each of the three target nerves. The EF induced in the ST nerve was 49 and 141% higher in the Medial and Lateral SO nerve, respectively. When considering maximum induced values, the delivery of comparable stimulation was further apparent. Given the existing electrode design's established efficacy, our results imply that preferential targeting of the ST nerve is related to the mechanism of action. Additionally, if comparable targeting of all three nerves continues to hold promise, the extended V-shaped +CS montage presents an optimized configuration to explore in clinical studies.

Case Report: Initial Evidence of Safety and Efficacy of High Definition-Transcranial Direct Current Stimulation in a Patient With Neuropathic Pain and Implanted Spinal Cord Stimulator.

Neuropathic pain (NP), often treatment-refractory, is one of the most debilitating conditions contributing to suffering and disability worldwide. Recently, non-invasive neuromodulation techniques, particularly repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have emerged as potential therapeutic alternatives due to their ability to alter cortical excitability of neural circuits. However, the magnetic field induced in rTMS may be unsafe for patients with an implanted electrode in the head or neck area while tDCS poses no theoretical risk of injury to these patients. High definition (HD)-tDCS is a novel, more focal technique of tDCS and may be safer to the patient compared to the more diffuse stimulation of conventional tDCS. To our knowledge, no study has ever demonstrated the safety and/or feasibility of HD-tDCS in patients with spinal cord stimulation (SCS) devices using computational modeling of induced electrical fields. Furthermore, this study highlights the potential use of (HD-)tDCS as predictive tool for a positive response in chronic epidural motor cortex stimulation (MCS), especially in patients with an implanted device not suitable for rTMS. In a 54-year-old woman with an implanted spinal cord stimulation (SCS) system for another pain syndrome, HD-tDCS was initiated for refractory post-surgical inferior alveolar nerve neuropathy. She was submitted to 7 days of anodal HD-tDCS over the left motor cortex at 1.5 mA for 30 min. A notable decrease in pain perception was observed, lasting for approximately 5-6 h (Numeric Rating Score decreased from 8 to 4.34). No adverse events were reported. The stimulation parameters and clinical efficacy of the SCS system remained unchanged. Additionally, computational analysis indicated no meaningful alteration of current flow when considering a model with a SCS implant with respect to a model without implant. Regarding the positive therapeutic effect of HD-tDCS, the patient was selected for an epidural MCS trial and subsequent implantation, which showed short-term pain relief of 50-75%. Although one case does not demonstrate efficacy, tolerability, or safety to the novel intervention, it paves the way for better diagnosis and treatment for patients who are otherwise excluded from other non-invasive neuromodulation techniques, such as rTMS. A positive tDCS effect could be a potential biomarker for positive epidural MCS response in patients with an implanted stimulation device non-compatible with rTMS.

Neurophysiological Effects of Trait Empathy in Music Listening.

The social cognitive basis of music processing has long been noted, and recent research has shown that trait empathy is linked to musical preferences and listening style. Does empathy modulate neural responses to musical sounds? We designed two functional magnetic resonance imaging (fMRI) experiments to address this question. In Experiment 1, subjects listened to brief isolated musical timbres while being scanned. In Experiment 2, subjects listened to excerpts of music in four conditions (familiar liked (FL)/disliked and unfamiliar liked (UL)/disliked). For both types of musical stimuli, emotional and cognitive forms of trait empathy modulated activity in sensorimotor and cognitive areas: in the first experiment, empathy was primarily correlated with activity in supplementary motor area (SMA), inferior frontal gyrus (IFG) and insula; in Experiment 2, empathy was mainly correlated with activity in prefrontal, temporo-parietal and reward areas. Taken together, these findings reveal the interactions between bottom-up and top-down mechanisms of empathy in response to musical sounds, in line with recent findings from other cognitive domains.

EEG to Primary Rewards: Predictive Utility and Malleability by Brain Stimulation.

Theta burst stimulation (TBS) is thought to affect reward processing mechanisms, which may increase and decrease reward sensitivity. To test the ability of TBS to modulate response to strong primary rewards, participants hypersensitive to primary rewards were recruited. Twenty men and women with at least two opposite-sex, sexual partners in the last year received two forms of TBS. Stimulations were randomized to avoid order effects and separated by 2 hours to reduce carryover. The two TBS forms have been demonstrated to inhibit (continuous) or excite (intermittent) the left dorsolateral prefrontal cortex using different pulse patterns, which links to brain areas associated with reward conditioning. After each TBS, participants completed tasks assessing their reward responsiveness to monetary and sexual rewards. Electroencephalography (EEG) was recorded. They also reported their number of orgasms in the weekend following stimulation. This signal was malleable by TBS, where excitatory TBS resulted in lower EEG alpha relative to inhibitory TBS to primary rewards. EEG responses to sexual rewards in the lab (following both forms of TBS) predicted the number of orgasms experienced over the forthcoming weekend. TBS may be useful in modifying hypersensitivity or hyposensitivity to primary rewards that predict sexual behaviors. Since TBS altered the anticipation of a sexual reward, TBS may offer a novel treatment for sexual desire problems.

Psychophysical and rTMS Evidence for the Presence of Motion Opponency in Human V5.

BACKGROUND: Motion sensitive cells within macaque V5, but not V1, exhibit motion opponency whereby their firing is suppressed by motion in their anti-preferred direction. fMRI studies indicate the presence of motion opponent mechanisms in human V5. OBJECTIVE/HYPOTHESIS: We tested two hypotheses. 1) Performance of a motion discrimination task would be poorer when stimuli were constructed from pairs of dots that moved in counter-phase vs. in-phase, because counter-phase dots would activate motion opponent mechanisms in V5. 2) Offline 1 Hz rTMS of V5 would impair discrimination performance for in-phase stimuli but not counter-phase stimuli, and the opposite effect would be found for rTMS of V1. METHODS: Stimuli were constructed from 100 dot pairs. Paired dots moved along a fixed motion axis either in counter-phase (motion opponent stimulus) or in-phase (non-opponent motion stimulus). Motion axis orientation discrimination thresholds were measured for each stimulus. Blocks of 300 trials were then presented at 85% correct threshold and discrimination accuracy was measured before and after 1 Hz offline rTMS of either V1 or V5. Subjects were 8 healthy adults. RESULTS: Discrimination thresholds were significantly larger (worse) for counter-phase than in-phase stimuli (p = 0.02). V5 rTMS mildly impaired discrimination accuracy for the in-phase dot stimuli (p = 0.02) but not the counter-phase dot stimuli. The opposite effect occurred for V1 rTMS (p = 0.05). CONCLUSIONS: Opponent motion mechanisms are present within human V5 and activation of these mechanisms impairs motion discrimination. In addition, perception of the motion axis within opponent motion stimuli involves processing within V1.

Double-Blind Sham-Controlled Crossover Trial of Repetitive Transcranial Magnetic Stimulation for Mal de Debarquement Syndrome.

OBJECTIVE: To determine whether the chronic rocking dizziness that occurs in Mal de Debarquement Syndrome (MdDS) can be suppressed with repetitive transcranial magnetic stimulation (rTMS) beyond the treatment period. METHODS: We performed a prospective randomized double-blind sham controlled crossover trial of 5-days of rTMS utilizing high frequency (10 Hz) stimulation over the left dorsolateral prefrontal cortex (DLPFC). RESULTS: Eight right-handed women (44.5 [SD 7.0] yr) with classical motion-triggered MdDS (mean duration 42.1 [SD 13.2] mo) participated. Group level mixed effects repeated measures analysis of variance (ANOVA) showed improvement in our primary outcome measure, the Dizziness Handicap Inventory (DHI) at Post TMS Weeks 1, 3, and 4 (p < 0.05) and a trend at Week 2 (p = 0.089) after Real rTMS. On the Hospital Anxiety and Depression Scale (HADS), improvements started at Post TMS Week 2 for the Anxiety subscore and Post TMS Week 3 for the Depression subscore after Real rTMS only (p < 0.05). There were no group level improvements on the MdDS Balance Rating Scale (MBRS) after Real rTMS though there were three participants who improved on an individual level. There were no significant group level changes after Sham stimulation on any measure. CONCLUSION: Our study provides evidence that the dizziness, mood and anxiety symptoms of MdDS can be improved with 10 Hz rTMS over left DLPFC beyond the treatment period in selected individuals. rTMS may be a useful adjunctive treatment for the management of chronic rocking dizziness in individuals with MdDS but treatment durations longer than 5 days or maintenance treatment are likely needed for sustained symptom suppression.

Neuromodulation of group prejudice and religious belief.

People cleave to ideological convictions with greater intensity in the aftermath of threat. The posterior medial frontal cortex (pMFC) plays a key role in both detecting discrepancies between desired and current conditions and adjusting subsequent behavior to resolve such conflicts. Building on prior literature examining the role of the pMFC in shifts in relatively low-level decision processes, we demonstrate that the pMFC mediates adjustments in adherence to political and religious ideologies. We presented participants with a reminder of death and a critique of their in-group ostensibly written by a member of an out-group, then experimentally decreased both avowed belief in God and out-group derogation by downregulating pMFC activity via transcranial magnetic stimulation. The results provide the first evidence that group prejudice and religious belief are susceptible to targeted neuromodulation, and point to a shared cognitive mechanism underlying concrete and abstract decision processes. We discuss the implications of these findings for further research characterizing the cognitive and affective mechanisms at play.

Early semantic and phonological effects on temporal- and muscle-specific motor resonance.

Previous studies using functional magnetic resonance imaging and transcranial magnetic stimulation (TMS) explored the relationships between linguistic processing and motor resonance, i.e. the activation of the motor system while perceiving others performing an action. These studies have mainly investigated a specific linguistic domain, i.e. semantics, whereas phonology has been largely neglected. Here we used single-pulse TMS to compare the effects of semantic and phonological processing with motor resonance effects. We applied TMS to the primary motor hand area while subjects observed object-oriented actions and performed semantic and phonological tasks related to the observed action. Motor evoked potentials were recorded in two hand muscles, one of them more involved in the execution of the observed actions than the other one, at three different timepoints (0, 200 and 400 ms after stimulus onset). The results demonstrated increased corticospinal excitability that was muscle-specific (i.e. restricted to the hand muscle involved in the observed action), hemisphere-specific (left), and time-specific (400 ms after stimulus onset). The results suggest an additive effect of independent semantic and phonological processing on motor resonance. The novel phonological effect reported here expands the links between language and the motor system and is consistent with a theory of shared control for hand and mouth. Furthermore, the timing of the semantic effect suggests that motor activation during semantic processing is not an 'epiphenomenon' but rather is essential to the construction of meaning.

Neuroimaging of nonmotor features of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms that respond to dopaminergic therapy. However, there is increasing interest in nonmotor PD features such as hyposmia, sleep disorders, dementia, depression, and psychoses. We review neuroimaging studies in nonmotor symptoms of PD and the use of dopaminergic imaging to support screening of nonmotor symptoms for early PD. Neuroimaging data document nonmotor pathophysiologic involvement of systems beyond the nigrostriatal dopaminergic pathway. These neuroimaging studies support a broader view of PD with early involvement in time and wider involvement of monoamine and cortical systems that may provide targets for novel therapies for nonmotor symptoms.

Noninvasive brain stimulation for Parkinson's disease and dystonia.

Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are promising noninvasive cortical stimulation methods for adjunctive treatment of movement disorders. They avoid surgical risks and provide theoretical advantages of specific neural circuit neuromodulation. Neuromodulatory effects depend on extrinsic stimulation factors (cortical target, frequency, intensity, duration, number of sessions), intrinsic patient factors (disease process, individual variability and symptoms, state of medication treatment), and outcome measures. Most studies to date have shown beneficial effects of rTMS or tDCS on clinical symptoms in Parkinson's disease (PD) and support the notion of spatial specificity to the effects on motor and nonmotor symptoms. Stimulation parameters have varied widely, however, and some studies are poorly controlled. Studies of rTMS or tDCS in dystonia have provided abundant data on physiology, but few on clinical effects. Multiple mechanisms likely contribute to the clinical effects of rTMS and tDCS in movement disorders, including normalization of cortical excitability, rebalancing of distributed neural network activity, and induction of dopamine release. It remains unclear how to individually adjust rTMS or tDCS factors for the most beneficial effects on symptoms of PD or dystonia. Nonetheless, the noninvasive nature, minimal side effects, positive effects in preliminary clinical studies, and increasing evidence for rational mechanisms make rTMS and tDCS attractive for ongoing investigation.

Correlation between motor and phosphene thresholds: a transcranial magnetic stimulation study.

Transcranial magnetic stimulation (TMS) has become a common tool for the brain mapping of a wide variety of cognitive functions. Because TMS over cortical regions of interest other than motor cortex often does not produce easily observable effects, the ability to calibrate TMS intensity for stimulation over nonmotor regions can be problematic. Previous studies reported no correlation between motor thresholds (MT) over the motor cortex and phosphene thresholds (PT) over the visual cortex. However, different thresholding methods, lighting, and eye-closure conditions were used to determine MT and PT. We investigated the correlation between resting MT (rMT), active MT (aMT), and PT in 27 dark-adapted healthy volunteers. All thresholds were measured with eyes-open in the dark and determined by gradually reducing stimulation intensity downward. All subjects had aMT and rMT; 21 subjects had measurable PT. rMT was 70.4% +/- 9.8% (mean +/- SD of maximum stimulator output); aMT was 61.1% +/- 7.9%; PT was 82.2% +/- 10.1%. A significant positive correlation was found between aMT and PT (r = 0.53; P = 0.014) with a trend toward correlation between rMT and PT (r = 0.43; P = 0.052). Our results suggest that sensitivity to TMS over visual and motor cortices may be correlated under similar thresholding procedures. They also provide a rationale for the use of easily obtained aMT to calibrate TMS intensities in brain mapping studies that employ TMS in cortical regions besides motor cortex.

The essential role of premotor cortex in speech perception.

Besides the involvement of superior temporal regions in processing complex speech sounds, evidence suggests that the motor system might also play a role [1-4]. This suggests that the hearer might perceive speech by simulating the articulatory gestures of the speaker [5, 6]. It is still an open question whether this simulation process is necessary for speech perception. We applied repetitive transcranial magnetic stimulation to the premotor cortex to disrupt subjects' ability to perform a phonetic discrimination task. Subjects were impaired in discriminating stop consonants in noise but were unaffected in a control task that was matched in difficulty, task structure, and response characteristics. These results show that the disruption of human premotor cortex impairs speech perception, thus demonstrating an essential role of premotor cortices in perceptual processes.

Attractiveness of natural faces compared to computer constructed perfectly symmetrical faces.

Attractiveness of natural faces was compared to perfectly symmetrical faces constructed on the computer from digitized photographs, in order to assess the role of left-right symmetry in beauty assessment. Three different groups of participants viewed separate series of sequentially presented faces (natural faces, left-left, and right-right) and provided attractiveness ratings on a 5-point Likert scale. The results revealed statistically significant lower ratings for the computer constructed left-left and right-right compared to the natural faces. The discussion is in the context of a biological trend away from perfect symmetry in primates consequent to adaptive evolutionary alteration favoring functional asymmetry in the brain, perception, and face.