Exploring the Therapeutic Potential of Quadripulse rTMS over the Visual Cortex: A Proof-of-Concept Study in Healthy Volunteers and Chronic Migraine Patients with Medication Overuse Headache.

In chronic migraine with medication overuse (CM-MOH), sensitization of visual cortices is reflected by (i) increased amplitude of stimulus-evoked responses and (ii) habituation deficit during repetitive stimulation. Both abnormalities might be mitigated by inhibitory transcranial neurostimulation. Here, we tested an inhibitory quadripulse repetitive transcranial magnetic stimulation (rTMS-QPI) protocol to decrease durably visual cortex excitability in healthy subjects (HS) and explored its therapeutic potential in CM-MOH patients. Pattern-reversal visual evoked potentials (VEP) were used as biomarkers of effect and recorded before (T1), immediately after (T2), and 3 h after stimulation (T3). In HS, rTMS-QPI durably decreased the VEP 1st block amplitude (p < 0.05) and its habituation (p < 0.05). These changes were more pronounced for the P1N2 component that was modified already at T2 up to T3, while for N1P1 they were significant only at T3. An excitatory stimulation protocol (rTMS-QPE) tended to have an opposite effect, restricted to P1N2. In 12 CM-MOH patients, during a four-week treatment (2 sessions/week), rTMS-QPI significantly reduced monthly headache days (p < 0.01). In patients reversing from CM-MOH to episodic migraine (n = 6), VEP habituation significantly improved after treatment (p = 0.005). rTMS-QPI durably decreases visual cortex responsivity in healthy subjects. In a proof-of-concept study of CM-MOH patients, rTMS-QPI also has beneficial clinical and electrophysiological effects, but sham-controlled trials are needed.

Visually induced analgesia during face or limb stimulation in healthy and migraine subjects.

BACKGROUND: Visually induced analgesia (VIA) defines a phenomenon in which viewing one's own body part during its painful stimulation decreases the perception of pain. VIA occurs during direct vision of the stimulated body part and also when seeing it reflected in a mirror. To the best of our knowledge, VIA has not been studied in the trigeminal area, where it could be relevant for the control of headache. SUBJECTS AND METHODS: We used heat stimuli (53°C) to induce pain in the right forehead or wrist in 11 healthy subjects (HSs) and 14 female migraine without aura (MO) patients between attacks. The subjects rated pain on a visual analog scale (VAS) and underwent contact heat-evoked potential (CHEP) recordings (five sequential blocks of four responses) with or without observation of their face/wrist in a mirror. RESULTS: During wrist stimulation, amplitude of the first block of P1-P2 components of CHEPs decreased compared to that in the control recording when HSs were seeing their wrist reflected in the mirror (p = 0.036; Z = 2.08); however, this was not found in MO patients. In the latter, the VAS pain score increased viewing the reflected wrist (p = 0.049; Z = 1.96). Seeing their forehead reflected in the mirror induced a significant increase in N2 latency of CHEPs in HSs, as well as an amplitude reduction in the first block of P1-P2 components of CHEPs both in HSs (p = 0.007; Z = 2.69) and MO patients (p = 0.035; Z = 2.10). Visualizing the body part did not modify habituation of CHEP amplitudes over the five blocks of averaged responses, neither during wrist nor during forehead stimulation. CONCLUSION: This study adds to the available knowledge on VIA and demonstrates this phenomenon for painful stimuli in the trigeminal area, as long as CHEPs are used as indices of central pain processing. In migraine patients during interictal periods, VIA assessed with CHEPs is within normal limits in the face but absent at the wrist, possibly reflecting dysfunctioning of extracephalic pain control.

Intrinsic brain networks normalize with treatment in pediatric complex regional pain syndrome.

Pediatric complex regional pain syndrome (P-CRPS) offers a unique model of chronic neuropathic pain as it either resolves spontaneously or through therapeutic interventions in most patients. Here we evaluated brain changes in well-characterized children and adolescents with P-CRPS by measuring resting state networks before and following a brief (median = 3 weeks) but intensive physical and psychological treatment program, and compared them to matched healthy controls. Differences in intrinsic brain networks were observed in P-CRPS compared to controls before treatment (disease state) with the most prominent differences in the fronto-parietal, salience, default mode, central executive, and sensorimotor networks. Following treatment, behavioral measures demonstrated a reduction of symptoms and improvement of physical state (pain levels and motor functioning). Correlation of network connectivities with spontaneous pain measures pre- and post-treatment indicated concomitant reductions in connectivity in salience, central executive, default mode and sensorimotor networks (treatment effects). These results suggest a rapid alteration in global brain networks with treatment and provide a venue to assess brain changes in CRPS pre- and post-treatment, and to evaluate therapeutic effects.

Effects of visual cortex activation on the nociceptive blink reflex in healthy subjects.

Bright light can cause excessive visual discomfort, referred to as photophobia. The precise mechanisms linking luminance to the trigeminal nociceptive system supposed to mediate this discomfort are not known. To address this issue in healthy human subjects we modulated differentially visual cortex activity by repetitive transcranial magnetic stimulation (rTMS) or flash light stimulation, and studied the effect on supraorbital pain thresholds and the nociceptive-specific blink reflex (nBR). Low frequency rTMS that inhibits the underlying cortex, significantly decreased pain thresholds, increased the 1st nBR block ipsi- and contralaterally and potentiated habituation contralaterally. After high frequency or sham rTMS over the visual cortex, and rMS over the right greater occipital nerve we found no significant change. By contrast, excitatory flash light stimulation increased pain thresholds, decreased the 1st nBR block of ipsi- and contralaterally and increased habituation contralaterally. Our data demonstrate in healthy subjects a functional relation between the visual cortex and the trigeminal nociceptive system, as assessed by the nociceptive blink reflex. The results argue in favour of a top-down inhibitory pathway from the visual areas to trigemino-cervical nociceptors. We postulate that in normal conditions this visuo-trigeminal inhibitory pathway may avoid disturbance of vision by too frequent blinking and that hypoactivity of the visual cortex for pathological reasons may promote headache and photophobia.

Habenula functional resting-state connectivity in pediatric CRPS.

The habenula (Hb) is a small brain structure located in the posterior end of the medial dorsal thalamus and through medial (MHb) and lateral (LHb) Hb connections, it acts as a conduit of information between forebrain and brainstem structures. The role of the Hb in pain processing is well documented in animals and recently also in acute experimental pain in humans. However, its function remains unknown in chronic pain disorders. Here, we investigated Hb resting-state functional connectivity (rsFC) in patients with complex regional pain syndrome (CRPS) compared with healthy controls. Twelve pediatric patients with unilateral lower-extremity CRPS (9 females; 10-17 yr) and 12 age- and sex-matched healthy controls provided informed consent to participate in the study. In healthy controls, Hb functional connections largely overlapped with previously described anatomical connections in cortical, subcortical, and brainstem structures. Compared with controls, patients exhibited an overall Hb rsFC reduction with the rest of the brain and, specifically, with the anterior midcingulate cortex, dorsolateral prefrontal cortex, supplementary motor cortex, primary motor cortex, and premotor cortex. Our results suggest that Hb rsFC parallels anatomical Hb connections in the healthy state and that overall Hb rsFC is reduced in patients, particularly connections with forebrain areas. Patients' decreased Hb rsFC to brain regions implicated in motor, affective, cognitive, and pain inhibitory/modulatory processes may contribute to their symptomatology.

Safety and patients' satisfaction of transcutaneous supraorbital neurostimulation (tSNS) with the Cefaly® device in headache treatment: a survey of 2,313 headache sufferers in the general population.

BACKGROUND: Transcutaneous supraorbital nerve stimulation (tSNS) with the Cefaly® device was recently found superior to sham stimulation for episodic migraine prevention in a randomized trial. Its safety and efficiency in larger cohorts of headache sufferers in the general population remain to be determined.The objective of this study was to assess the satisfaction with the Cefaly® device in 2,313 headache sufferers who rented the device for a 40-day trial period via Internet. METHODS: Only subjects using specific anti-migraine drugs, and thus most likely suffering from migraine, were included in the survey. Adverse events (AEs) and willingness to continue tSNS were monitored via phone interviews after the trial period. A built-in software allowed monitoring the total duration of use and hence compliance in subjects who returned the device to the manufacturer after the trial period. RESULTS: After a testing period of 58.2 days on average, 46.6% of the 2,313 renters were not satisfied and returned the device, but the compliance check showed that they used it only for 48.6% of the recommended time. The remaining 54.4% of subjects were satisfied with the tSNS treatment and willing to purchase the device. Ninety-nine subjects out of the 2,313 (4.3%) reported one or more AEs, but none of them was serious. The most frequent AEs were local pain/intolerance to paresthesia (47 subjects, i.e. 2.03%), arousal changes (mostly sleepiness/fatigue, sometimes insomnia, 19 subjects, i.e. 0.82%), headache after the stimulation (12 subjects, i.e. 0.52%). A transient local skin allergy was seen in 2 subjects, i.e. 0.09%. CONCLUSIONS: This survey of 2,313 headache sufferers in the general population confirms that tSNS with is a safe and well-tolerated treatment for migraine headaches that provides satisfaction to a majority of patients who tested it for 40 days. Only 4.3% of subjects reported AEs, all of them were minor and fully reversible.

Pearls and pitfalls: electrophysiology for primary headaches.

BACKGROUND: Primary headaches are functional neurological diseases characterized by a dynamic cyclic pattern over time (ictal/pre-/interictal). Electrophysiological recordings can non-invasively assess the activity of an underlying nervous structure or measure its response to various stimuli, and are therefore particularly appropriate for the study of primary headaches. Their interest, however, is chiefly pathophysiological, as interindividual, and to some extent intraindividual, variations preclude their use as diagnostic tools. AIM OF THE WORK: This article will review the most important findings of electrophysiological studies in primary headache pathophysiology, especially migraine on which numerous studies have been published. RESULTS: In migraine, the most reproducible hallmark is the interictal lack of neuronal habituation to the repetition of various types of sensory stimulations. The mechanism subtending this phenomenon remains uncertain, but it could be the consequence of a thalamocortical dysrythmia that results in a reduced cortical preactivation level. In tension-type headache as well as in cluster headache, there seems to be an impairment of central pain-controlling mechanisms but the studies are scarce and their outcomes are contradictory. The discrepancies between studies might be as a result of methodological differences as well as patients' dissimilarities, which are also discussed. CONCLUSIONS AND PERSPECTIVES: Electrophysiology is complementary to functional neuroimaging and will undoubtedly remain an important tool in headache research. One of its upcoming applications is to help select neurostimulation techniques and protocols that correct best the functional abnormalities detectable in certain headache disorders.

Transcranial Direct Current Stimulation (tDCS) of the visual cortex: a proof-of-concept study based on interictal electrophysiological abnormalities in migraine.

BACKGROUND: Preventive pharmacotherapy for migraine is not satisfactory because of the low efficacy/tolerability ratio of many available drugs. Novel and more efficient preventive strategies are therefore warranted. Abnormal excitability of cortical areas appears to play a pivotal role in migraine pathophysiology. Transcranial direct current stimulation (tDCS) is a non-invasive and safe technique that is able to durably modulate the activity of the underlying cerebral cortex, and is being tested in various medical indications. The results of small open studies using tDCS in migraine prophylaxis are conflicting, possibly because the optimal stimulation settings and the brain targets were not well chosen. We have previously shown that the cerebral cortex, especially the visual cortex, is hyperresponsive in migraine patients between attacks and provided evidence from evoked potential studies that this is due to a decreased cortical preactivation level. If one accepts this concept, anodal tDCS over the visual cortex may have therapeutic potentials in migraine prevention, as it is able to increase neuronal firing. OBJECTIVE: To study the effects of anodal tDCS on visual cortex activity in healthy volunteers (HV) and episodic migraine without aura patients (MoA), and its potentials for migraine prevention. METHODS: We recorded pattern-reversal visual evoked potentials (VEP) before and after a 15-min session of anodal tDCS over the visual cortex in 11 HV and 13 MoA interictally. Then 10 MoA patients reporting at least 4 attacks/month subsequently participated in a therapeutic study, and received 2 similar sessions of tDCS per week for 8 weeks as migraine preventive therapy. RESULTS: In HV as well as in MoA, anodal tDCS transiently increased habituation of the VEP N1P1 component. VEP amplitudes were not modified by tDCS. Preventive treatment with anodal tDCS turned out to be beneficial in MoA: migraine attack frequency, migraine days, attack duration and acute medication intake significantly decreased during the treatment period compared to pre-treatment baseline (all p < 0.05), and this benefit persisted on average 4.8 weeks after the end of tDCS. CONCLUSIONS: Anodal tDCS over the visual cortex is thus able to increase habituation to repetitive visual stimuli in healthy volunteers and in episodic migraineurs, who on average lack habituation interictally. Moreover, 2 weekly sessions of anodal tDCS had a significant preventive anti- migraine effect, proofing the concept that the low preactivation level of the visual cortex in migraine patients can be corrected by an activating neurostimulation. The therapeutic results indicate that a larger sham-controlled trial using the same tDCS protocol is worthwhile.

A preliminary study of sex differences in brain activation during a spatial navigation task in healthy adults.

The hippocampus plays a significant role in spatial memory processing, with sex differences being prominent on various spatial tasks. This study examined sex differences in healthy adults, using functional magnetic resonance imaging (fMRI) in areas implicated in spatial processing during navigation of a virtual analogue of the Morris water-maze. There were three conditions: learning, hidden, and visible control. There were no significant differences in performance measures. However, sex differences were found in regional brain activation during learning in the right hippocampus, right parahippocampal gyrus, and the cingulate cortex. During the hidden condition, the hippocampus, parahippocampal gyrus, and cingulate cortex were activated in both men and women. Additional brain areas involved in spatial processing may be recruited in women when learning information about the environment, by utilizing external cues (landmarks) more than do men, contributing to the observed sex differences in brain activation.

Supraorbital transcutaneous neurostimulation has sedative effects in healthy subjects.

BACKGROUND: Transcutaneous neurostimulation (TNS) at extracephalic sites is a well known treatment of pain. Thanks to recent technical progress, the Cefaly® device now also allows supraorbital TNS. During observational clinical studies, several patients reported decreased vigilance or even sleepiness during a session of supraorbital TNS. We decided therefore to explore in more detail the potential sedative effect of supraorbital TNS, using standardized psychophysical tests in healthy volunteers. METHODS: We performed a double-blind cross-over sham-controlled study on 30 healthy subjects. They underwent a series of 4 vigilance tests (Psychomotor Vigilance Task, Critical Flicker Fusion Frequency, Fatigue Visual Numeric Scale, d2 test). Each subject was tested under 4 different experimental conditions: without the neurostimulation device, with sham supraorbital TNS, with low frequency supraorbital TNS and with high frequency supraorbital TNS. RESULTS: As judged by the results of three tests (Psychomotor Vigilance Task, Critical Flicker Fusion Frequency, Fatigue Visual Numeric Scale) there was a statistically significant (p < 0.001) decrease in vigilance and attention during high frequency TNS, while there were no changes during the other experimental conditions. Similarly, performance on the d2 test was impaired during high frequency TNS, but this change was not statistically significant. CONCLUSION: Supraorbital high frequency TNS applied with the Cefaly® device decreases vigilance in healthy volunteers. Additional studies are needed to determine the duration of this effect, the underlying mechanisms and the possible relation with the stimulation parameters. Meanwhile, this effect opens interesting perspectives for the treatment of hyperarousal states and, possibly, insomnia.

Changes in visual-evoked potential habituation induced by hyperventilation in migraine.

Hyperventilation is often associated with stress, an established trigger factor for migraine. Between attacks, migraine is associated with a deficit in habituation to visual-evoked potentials (VEP) that worsens just before the attack. Hyperventilation slows electroencephalographic (EEG) activity and decreases the functional response in the occipital cortex during visual stimulation. The neural mechanisms underlying deficient-evoked potential habituation in migraineurs remain unclear. To find out whether hyperventilation alters VEP habituation, we recorded VEPs before and after experimentally induced hyperventilation lasting 3 min in 18 healthy subjects and 18 migraine patients between attacks. We measured VEP P100 amplitudes in six sequential blocks of 100 sweeps and habituation as the change in amplitude over the six blocks. In healthy subjects, hyperventilation decreased VEP amplitude in block 1 and abolished the normal VEP habituation. In migraine patients, hyperventilation further decreased the already low block 1 amplitude and worsened the interictal habituation deficit. Hyperventilation worsens the habituation deficit in migraineurs possibly by increasing dysrhythmia in the brainstem-thalamo-cortical network.

The pain imaging revolution: advancing pain into the 21st century.

The great advances in brain imaging techniques over the last few decades have determined a shift in our understanding of chronic pain conditions and opened the door for new opportunities to develop better diagnoses and perhaps better drug treatments. Neuroimaging has helped shape the concept of chronic pain from a disease affecting mainly the somatosensory system, to a condition in which emotional, cognitive, and modulatory areas of the brain are affected, in addition to degenerative processes. All these contribute to the development and maintenance of pain symptoms and comorbid features, including alterations in anxiety, depression, and cognitive processes. In this article the authors review the current understanding of the brain changes in chronic pain and the developments made possible by the use of various brain imaging techniques. They also discuss the possible applications of brain imaging to developing a "pain phenotype" that could aid in diagnostic and treatment choices of chronic pain conditions.

Abnormal cortical responses to somatosensory stimulation in medication-overuse headache.

BACKGROUND: Medication-overuse headache (MOH) is a frequent, disabling disorder. Despite a controversial pathophysiology convincing evidence attributes a pivotal role to central sensitization. Most patients with MOH initially have episodic migraine without aura (MOA) characterized interictally by an absent amplitude decrease in cortical evoked potentials to repetitive stimuli (habituation deficit), despite a normal initial amplitude (lack of sensitization). Whether central sensitization alters this electrophysiological profile is unknown. We therefore sought differences in somatosensory evoked potential (SEP) sensitization and habituation in patients with MOH and episodic MOA. METHODS: We recorded median-nerve SEPs (3 blocks of 100 sweeps) in 29 patients with MOH, 64 with MOA and 42 controls. Episodic migraineurs were studied during and between attacks. We measured N20-P25 amplitudes from 3 blocks of 100 sweeps, and assessed sensitization from block 1 amplitude, and habituation from amplitude changes between the 3 sequential blocks. RESULTS: In episodic migraineurs, interictal SEP amplitudes were normal in block 1, but thereafter failed to habituate. Ictal SEP amplitudes increased in block 1, then habituated normally. Patients with MOH had larger-amplitude block 1 SEPs than controls, and also lacked SEP habituation. SEP amplitudes were smaller in triptan overusers than in patients overusing nonsteroidal anti-inflammatory drugs (NSAIDs) or both medications combined, lowest in patients with the longest migraine history, and highest in those with the longest-lasting headache chronification. CONCLUSIONS: In patients with MOH, especially those overusing NSAIDs, the somatosensory cortex becomes increasingly sensitized. Sensory sensitization might add to the behavioral sensitization that favors compulsive drug intake, and may reflect drug-induced changes in central serotoninergic transmission.

Pain: Do ACE inhibitors exacerbate complex regional pain syndrome?

Complex regional pain syndrome is a chronic condition arising mainly after tissue injury and involves both inflammatory and neurogenic factors. Use of angiotensin-converting-enzyme inhibitors has been associated with an increased risk of developing the chronic pain condition, which suggests possible roles for substance P and bradykinin in the underlying pathogenic process.

Challenges of functional imaging research of pain in children.

Functional imaging has revolutionized the neurosciences. In the pain field it has dramatically altered our understanding of how the brain undergoes significant functional, anatomical and chemical changes in patients with chronic pain. However, most studies have been performed in adults. Because functional imaging is non-invasive and can be performed in awake individuals, applications in children have become more prevalent, but only recently in the pain field. Measures of changes in the brains of children have important implications in understanding neural plasticity in response to acute and chronic pain in the developing brain. Such findings may have implications for treatments in children affected by chronic pain and provide novel insights into chronic pain syndromes in adults. In this review we summarize this potential and discuss specific concerns related to the imaging of pain in children.

Does the dorsal hippocampus process navigational routes or behavioral context? A single-unit analysis.

In humans the hippocampus plays a role in both episodic memory and spatial navigation. Similar findings have been shown in other animals including monkeys and rats. The relationship between the processing of episodic and spatial related inputs within the hippocampus remains a puzzle. One approach to understanding how the hippocampus processes information is to examine how hippocampal cell activity corresponds to environmental experience. Hippocampal pyramidal cells can alter their spatial tuning (re-map) in response to changes in task demands. The degree to which this re-mapping is related to contextual/episodic information or to changes in spatial navigation/trajectories is unclear. The current study was designed to examine cell activity under two conditions that differed in contextual information without alterations in the goal-directed trajectories taken by the animals. Adult and aged rats were trained to do an alternation task on a fixed pathway [J. A. Oler et al. (2005)Neuroscience, 131, 1-12]. The animals ran this pathway during either 'safe' or 'unsafe' (a tone indicating a shock region) trials, with hesitation during 'unsafe' trials providing a clear behavioral measure of discrimination between these two conditions. Relatively few place cells displayed re-mapping between the two conditions. We propose that the principle source of re-mapping in the dorsal hippocampus is changes in the animal's trajectories rather than behavioral context. Possible reasons why so few cells responded to the change in context are discussed.

Activation of the medial septum reverses age-related hippocampal encoding deficits: a place field analysis.

When a rat runs through a familiar environment, the hippocampus retrieves a previously stored spatial representation of the environment. When the environment is modified a new representation is seen, presumably corresponding to the hippocampus encoding the new information. The medial septum is hypothesized to modulate whether the hippocampus engages in retrieval or encoding. The cholinergic agonist carbachol was infused into the medial septum, and hippocampal CA1 place cells were recorded in freely moving rats. In a familiar environment, septal activation impaired the retrieval of a previously stored hippocampal place cell representation regardless of age. When the environment was changed, medial septal activation impaired the encoding process in young, but facilitated the encoding of the new information in aged rats. Moreover, the improved encoding was evident during a subsequent exposure to the modified environment 24 h later. The findings support the role the septum plays in modulating hippocampal retrieval/encoding states. Furthermore, our data indicate a mechanism of age-related cognitive impairment.

Functional magnetic resonance in psychiatry.

Neuroimaging is a powerful tool for the study of the neurobiological changes in psychiatric disorders. Functional magnetic resonance imaging (MRI) is a noninvasive method that assesses cortical activation by measuring changes in the local concentration of deoxyhemoglobin, which is paramagnetic and therefore can be detected using MRI. This method has been referred to as blood oxygen level-dependent imaging. This article discusses the application of functional MRI techniques, with emphasis on blood oxygen level-dependent imaging, to the study of psychiatric diseases. The first part of the article provides an overview of the contribution of functional MRI research to the current understanding of mood disorders, schizophrenia, and substance abuse. The last part reviews recent advances and highlights future directions for the use of the functional MRI technique for psychiatric research.

Mood disorders.

Despite the prevalence of the mood disorders, the underlying neuropathology is still poorly understood. This article describes abnormalities in brain activation that have been reported in neuroimaging studies of patients with depression and bipolar illness. Functional changes have been identified in regions important for neural networks underlying emotional processing, including frontal, subcortical, and limbic regions. The interpretation of neuroimaging studies in mood disorders is limited by potential confounding factors including medication effects, duration of illness, comorbidity, and gender.

Intramaze cue utilization in the water maze: effects of sex and estrous cycle in rats.

Rats can use a wide spectrum of intra- and extramaze information while navigating through the environment. The current study examined the relative contribution of an intramaze cue with regard to its proximity to the goal. Three experiments were conducted and the impact of intramaze cue removal or rotation on water maze search was examined. In males, the effect of the intramaze cue declined monotonically in relation to the proximity of the cue to the goal. A more complex relationship between cue location and utilization was found in estrous and proestrus females. Estrous females showed a strong effect of the cue only when it was near the goal, ignoring it when it was situated further away. Conversely proestrus females were affected by the cue under all conditions. It is concluded that previous reports of behavioral differences may stem from the fact that proestrus females are affected by and attend to a wider range of stimuli, while estrous females are more affected by salient stimuli.