The effect of evening light on circadian-related outcomes: A systematic review.

Bright light exposure at night can help workers adapt to their shift schedules, but there has been relatively little research on evening light. We conducted a systematic review of studies that manipulated light exposure in the evening (broadly defined as 16:00-22:00) before real or simulated night shifts. Across the five eligible studies, evening light produced phase delays in melatonin, body temperature, and sleep propensity; it also improved sleep quality, sleep duration, memory, and work performance. There were mixed effects for mood, no changes in sleepiness, and no negative effects. The confidence in these results ranged from moderate for physiological markers of circadian phase delays to very low for mood. Future studies should compare the relative effectiveness and safety of evening versus night-time light exposure. Overall, the benefits of evening light for shift workers are tentative yet promising.

Ictal and interictal brain activation in episodic migraine: Neural basis for extent of allodynia.

In some patients, migraine attacks are associated with symptoms of allodynia which can be localized (cephalic) or generalized (extracephalic). Using functional neuroimaging and cutaneous thermal stimulation, we aimed to investigate the differences in brain activation of patients with episodic migraine (n = 19) based on their allodynic status defined by changes between ictal and interictal pain tolerance threshold for each subject at the time of imaging. In this prospective imaging study, differences were found in brain activity between the ictal and interictal visits in the brainstem/pons, thalamus, insula, cerebellum and cingulate cortex. Significant differences were also observed in the pattern of activation along the trigeminal pathway to noxious heat stimuli in no allodynia vs. generalized allodynia in the thalamus and the trigeminal nucleus but there were no activation differences in the trigeminal ganglion. The functional magnetic resonance imaging (fMRI) findings provide direct evidence for the view that in migraine patients who are allodynic during the ictal phase of their attacks, the spinal trigeminal nucleus and posterior thalamus become hyper-responsive (sensitized)-to the extent that they mediate cephalic and extracephalic allodynia, respectively. In addition, descending analgesic systems seem as "switched off" in generalized allodynia.

Shifting brain circuits in pain chronicity.

The evaluation of brain changes to a specific pain condition in pediatric and adult patients allows for insights into potential mechanisms of pain chronicity and possibly long-term brain changes. Here we focused on the primary somatosensory system (SS) involved in pain processing, namely the ventroposterolateral thalamus (VPL) and the primary somatosensory cortex (SI). We evaluated, using MRI, three specific processes: (a) somatotopy of changes in the SS for different pain origins (viz., foot vs. arm); (b) differences in acute (ankle sprain versus complex regional pain syndrome-CRPS); and (c) differences of the effects of CRPS on SS in pediatric versus adult patients. In all cases, age- and sex-matched individuals were used as controls. Our results suggest a shift in concurrent gray matter density (GMD) and resting functional connectivity strengths (rFC) across pediatric and adult CRPS with (a) differential patterns of GMD (VPL) and rFC (SI) on SS in pediatric vs. adult patterns that are consistent with upper and lower limb somatotopical organization; and (b) widespread GMD alterations in pediatric CRPS from sensory, emotional and descending modulatory processes to more confined sensory-emotional changes in adult CRPS and rFC patterns from sensory-sensory alterations in pediatric populations to a sensory-emotional change in adult populations. These results support the idea that pediatric and adult CRPS are differentially represented and may reflect underlying differences in pain chronification across age groups that may contribute to the well-known differences between child and adult pain vulnerability and resilience.

Neural mechanism for hypothalamic-mediated autonomic responses to light during migraine.

Migraineurs avoid light because it intensifies their headache. However, this is not the only reason for their aversion to light. Studying migraineurs and control subjects, we found that lights triggered more changes in autonomic functions and negative emotions during, rather than in the absence of, migraine or in control subjects, and that the association between light and positive emotions was stronger in control subjects than migraineurs. Seeking to define a neuroanatomical substrate for these findings, we showed that, in rats, axons of retinal ganglion cells converge on hypothalamic neurons that project directly to nuclei in the brainstem and spinal cord that regulate parasympathetic and sympathetic functions and contain dopamine, histamine, orexin, melanin-concentrating hormone, oxytocin, and vasopressin. Although the rat studies define frameworks for conceptualizing how light triggers the symptoms described by patients, the human studies suggest that the aversive nature of light is more complex than its association with headache intensification.

Neuropeptides and Neurotransmitters That Modulate Thalamo-Cortical Pathways Relevant to Migraine Headache.

Dynamic thalamic regulation of sensory signals allows the cortex to adjust better to rapidly changing behavioral, physiological, and environmental demands. To fulfill this role, thalamic neurons must themselves be subjected to constantly changing modulatory inputs that originate in multiple neurochemical pathways involved in autonomic, affective, and cognitive functions. This review defines a chemical framework for thinking about the complexity of factors that modulate the response properties of relay trigeminovascular thalamic neurons. Following the presentation of scientific evidence for monosynaptic connections between thalamic trigeminovascular neurons and axons containing glutamate, GABA, dopamine, noradrenaline, serotonin, histamine, orexin, and melanin-concentrating hormone, this review synthesizes a large body of data to propose that the transmission of headache-related nociceptive signals from the thalamus to the cortex is modulated by potentially opposing forces and that the so-called 'decision' of which system (neuropeptide/neurotransmitter) will dominate the firing of a trigeminovascular thalamic neuron at any given time is determined by the constantly changing physiological (sleep, wakefulness, food intake, body temperature, heart rate, blood pressure), behavioral (addiction, isolation), cognitive (attention, learning, memory use), and affective (stress, anxiety, depression, anger) adjustment needed to keep homeostasis.

Increased Amplitude of Thalamocortical Low-Frequency Oscillations in Patients with Migraine.

UNLABELLED: For many years, neurobiological theories have emphasized the importance of neuronal oscillations in the emergence of brain function. At the same time, clinical studies have shown that disturbances or irregularities in brain rhythms may relate to various common neurological conditions, including migraine. Increasing evidence suggests that the CNS plays a fundamental role in the predisposition to develop different forms of headache. Here, we present human imaging data that strongly support the presence of abnormal low-frequency oscillations (LFOs) in thalamocortical networks of patients in the interictal phase of migraine. Our results show that the main source of arrhythmic activity was localized to the higher-order thalamic relays of the medial dorsal nucleus. In addition, spontaneous LFOs in the thalamus were selectively associated with the headache attack frequency, meaning that the varying amplitude of dysrhythmia could predispose patients to recurrent attacks. Rhythmic cortical feedback to the thalamus is a major factor in the amplification of thalamocortical oscillations, making it a strong candidate for influencing neuronal excitability. We further speculate that the intrinsic dynamics of thalamocortical network oscillations are crucial for early sensory processing and therefore could underlie important pathophysiological processes involved in multisensory integration. SIGNIFICANCE STATEMENT: In many cases, migraine attacks are thought to begin centrally. A major obstacle to studying intrinsic brain activity has been the identification of the precise anatomical structures and functional networks that are involved in migraine. Here, we present imaging data that strongly support the presence of abnormal low-frequency oscillations in thalamocortical networks of patients in the interictal phase of migraine. This arrhythmic activity was localized to the higher-order thalamic relays of the medial dorsal nucleus and was selectively associated with headache attack frequency. Rhythmic cortical feedback to the thalamus is a major factor in the amplification of thalamocortical oscillations, making it a strong candidate for influencing neuronal excitability and higher-level processes involved in multisensory integration.

Migraine photophobia originating in cone-driven retinal pathways.

Migraine headache is uniquely exacerbated by light. Using psychophysical assessments in patients with normal eyesight we found that green light exacerbates migraine headache significantly less than white, blue, amber or red lights. To delineate mechanisms, we used electroretinography and visual evoked potential recording in patients, and multi-unit recording of dura- and light-sensitive thalamic neurons in rats to show that green activates cone-driven retinal pathways to a lesser extent than white, blue and red; that thalamic neurons are most responsive to blue and least responsive to green; and that cortical responses to green are significantly smaller than those generated by blue, amber and red lights. These findings suggest that patients' experience with colour and migraine photophobia could originate in cone-driven retinal pathways, fine-tuned in relay thalamic neurons outside the main visual pathway, and preserved by the cortex. Additionally, the findings provide substrate for the soothing effects of green light.

Neurochemical pathways that converge on thalamic trigeminovascular neurons: potential substrate for modulation of migraine by sleep, food intake, stress and anxiety.

Dynamic thalamic regulation of sensory signals allows the cortex to adjust better to rapidly changing behavioral, physiological and environmental demands. To fulfill this role, thalamic neurons must themselves be subjected to constantly changing modulatory inputs that originate in multiple neurochemical pathways involved in autonomic, affective and cognitive functions. Our overall goal is to define an anatomical framework for conceptualizing how a 'decision' is made on whether a trigeminovascular thalamic neuron fires, for how long, and at what frequency. To begin answering this question, we determine which neuropeptides/neurotransmitters are in a position to modulate thalamic trigeminovascular neurons. Using a combination of in-vivo single-unit recording, juxtacellular labeling with tetramethylrhodamine dextran (TMR) and in-vitro immunohistochemistry, we found that thalamic trigeminovascular neurons were surrounded by high density of axons containing biomarkers of glutamate, GABA, dopamine and serotonin; moderate density of axons containing noradrenaline and histamine; low density of axons containing orexin and melanin concentrating hormone (MCH); but not axons containing CGRP, serotonin 1D receptor, oxytocin or vasopressin. In the context of migraine, the findings suggest that the transmission of headache-related nociceptive signals from the thalamus to the cortex may be modulated by opposing forces (i.e., facilitatory, inhibitory) that are governed by continuous adjustments needed to keep physiological, behavioral, cognitive and emotional homeostasis.

Lost but making progress--Where will new analgesic drugs come from?

There is a critical need for effective new pharmacotherapies for pain. The paucity of new drugs successfully reaching the clinic calls for a reassessment of current analgesic drug discovery approaches. Many points early in the discovery process present significant hurdles, making it critical to exploit advances in pain neurobiology to increase the probability of success. In this review, we highlight approaches that are being pursued vigorously by the pain community for drug discovery, including innovative preclinical pain models, insights from genetics, mechanistic phenotyping of pain patients, development of biomarkers, and emerging insights into chronic pain as a disorder of both the periphery and the brain. Collaborative efforts between pharmaceutical, academic, and public entities to advance research in these areas promise to de-risk potential targets, stimulate investment, and speed evaluation and development of better pain therapies.

Altered hypothalamic functional connectivity with autonomic circuits and the locus coeruleus in migraine.

The hypothalamus has been implicated in migraine based on the manifestation of autonomic symptoms with the disease, as well as neuroimaging evidence of hypothalamic activation during attacks. Our objective was to determine functional connectivity (FC) changes between the hypothalamus and the rest of the brain in migraine patients vs. control subjects. This study uses fMRI (functional magnetic resonance imaging) to acquire resting state scans in 12 interictal migraine patients and 12 healthy matched controls. Hypothalamic connectivity seeds were anatomically defined based on high-resolution structural scans, and FC was assessed in the resting state scans. Migraine patients had increased hypothalamic FC with a number of brain regions involved in regulation of autonomic functions, including the locus coeruleus, caudate, parahippocampal gyrus, cerebellum, and the temporal pole. Stronger functional connections between the hypothalamus and brain areas that regulate sympathetic and parasympathetic functions may explain some of the hypothalamic-mediated autonomic symptoms that accompany or precede migraine attacks.

Thalamic sensitization transforms localized pain into widespread allodynia.

OBJECTIVE: Focal somatic pain can evolve into widespread hypersensitivity to nonpainful and painful skin stimuli (allodynia and hyperalgesia, respectively). We hypothesized that transformation of headache into whole-body allodynia/hyperalgesia during a migraine attack is mediated by sensitization of thalamic neurons that process converging sensory impulses from the cranial meninges and extracephalic skin. METHODS: Extracephalic allodynia was assessed using single unit recording of thalamic trigeminovascular neurons in rats and contrast analysis of blood oxygenation level-dependent (BOLD) signals registered in functional magnetic resonance imaging (fMRI) scans of patients exhibiting extracephalic allodynia. RESULTS: Sensory neurons in the rat posterior thalamus that were activated and sensitized by chemical stimulation of the cranial dura exhibited long-lasting hyperexcitability to innocuous (brush, pressure) and noxious (pinch, heat) stimulation of the paws. Innocuous, extracephalic skin stimuli that did not produce neuronal firing at baseline (eg, brush) became as effective as noxious stimuli (eg, pinch) in eliciting large bouts of neuronal firing after sensitization was established. In migraine patients, fMRI assessment of BOLD signals showed that brush and heat stimulation at the skin of the dorsum of the hand produced larger BOLD responses in the posterior thalamus of subjects undergoing a migraine attack with extracephalic allodynia than the corresponding responses registered when the same patients were free of migraine and allodynia. INTERPRETATION: We propose that the spreading of multimodal allodynia and hyperalgesia beyond the locus of migraine headache is mediated by sensitized thalamic neurons that process nociceptive information from the cranial meninges together with sensory information from the skin of the scalp, face, body, and limbs.

Using NMR approaches to drive the search for new CNS therapeutics.

The use of MRI-based imaging in drug development has received increased interest recently because of the difficulties associated with the development of CNS pharmacotherapies. While not yet routine, there have been significant advances in imaging that allow this technology to be used for evaluating disease state and drug effects. For disease states, both single and longitudinal studies of non-invasive measures may be obtained to provide a read-out of disease processes and, potentially, to predict the disease state and its evolution. In addition, imaging has enabled the development of improved preclinical disease models based on changes in brain circuitry. Pharmacological MRI, the imaging-based evaluation of drug effects, includes measures of direct effects on the brain, as well as the effects of chronic dosing on brain changes and neurochemical changes associated with these brain effects using magnetic resonance spectroscopy. Thus, imaging may become an integrated process in drug development, during both the preclinical and clinical stages. However, validation, the implementation of good clinical practices and regulatory acceptance are hurdles that remain to be overcome.

A role for fMRI in optimizing CNS drug development.

Drug development today needs to balance agility, speed and risk in defining the probability of success for molecules, mechanisms and therapeutic concepts. New techniques in functional magnetic resonance imaging (fMRI) promise to be part of a sequence that could transform drug development for disorders of the central nervous system (CNS) by examining brain systems and their functional activation dynamically. The brain is complex and multiple transmitters and intersecting brain circuits are implicated in many CNS disorders. CNS therapeutics are designed against specific CNS targets, many of which are unprecedented. The challenge is to reveal the functional consequences of these interactions to assess therapeutic potential. fMRI can help optimize CNS drug discovery by providing a key metric that can increase confidence in early decision-making, thereby improving success rates and reducing risk, development times and costs of drug development.

Neural circuitry underlying pain modulation: expectation, hypnosis, placebo.

The ability to predict the likelihood of an aversive event is an important adaptive capacity. Certainty and uncertainty regarding pain cause different adaptive behavior, emotional states, attentional focus, and perceptual changes. Recent functional neuroimaging studies indicate that certain and uncertain expectation are mediated by different neural pathways-the former having been associated with activity in the rostral anterior cingulate cortex and posterior cerebellum, the latter with activation changes in the ventromedial prefrontal cortex, mid-cingulate cortex and hippocampus. Expectation plays an important role not only in its modulation of acute and chronic pain, but also in other disorders which are characterized by certain expectation (specific phobias) or uncertain expectation (generalized anxiety disorder) of aversive events.

Somatotopic activation in the human trigeminal pain pathway.

Functional magnetic resonance imaging was used to image pain-associated activity in three levels of the neuraxis: the medullary dorsal horn, thalamus, and primary somatosensory cortex. In nine subjects, noxious thermal stimuli (46 degrees C) were applied to the facial skin at sites within the three divisions of the trigeminal nerve (V1, V2, and V3) and also to the ipsilateral thumb. Anatomical and functional data were acquired to capture activation across the spinothalamocortical pathway in each individual. Significant activation was observed in the ipsilateral spinal trigeminal nucleus within the medulla and lower pons in response to at least one of the three facial stimuli in all applicable data sets. Activation from the three facial stimulation sites exhibited a somatotopic organization along the longitudinal (rostrocaudal) axis of the brain stem that was consistent with the classically described "onion skin" pattern of sensory deficits observed in patients after trigeminal tractotomy. In the thalamus, activation was observed in the contralateral side involving the ventroposteromedial and dorsomedial nuclei after stimulation of the face and in the ventroposterolateral and dorsomedial nuclei after stimulation of the thumb. Activation in the primary somatosensory cortex displayed a laminar sequence that resembled the trigeminal nucleus, with V2 more rostral, V1 caudal, and V3 medial, abutting the region of cortical activation observed for the thumb. These results represent the first simultaneous imaging of pain-associated activation at three levels of the neuraxis in individual subjects. This approach will be useful for exploring central correlates of plasticity in models of experimental and clinical pain.