iPhone Targeted Content
iPad Targeted Content
Android Targeted Content
Blackberry Targeted Content
Desktop and all none targeted content
iPhone Targeted Content
THE CLINICAL CLARITY BLOG
The quality of your life
is the quality of your inhibition
FEBRUARY 23, 2017 by DR MATTHEW D. LONG
iPad Targeted Content
Android Targeted Content
THE CLINICAL CLARITY BLOG
The quality of your life
is the quality of your inhibition
FEBRUARY 23, 2017 by DR MATTHEW D. LONG
Blackberry Targeted Content
Desktop and all none targeted content
THE CLINICAL CLARITY BLOG
FEBRUARY 23, 2017 by DR MATTHEW D. LONG
When most people are asked to describe the elements of a healthy life they usually come up with phrases such as 'freedom from pain', 'energy', 'ability to move' and 'happiness'. In other words, our subjective experience of life has a lot to do with how we feel. So it might sound strange, therefore, to suggest that how good we feel has a lot to do with how well we suppress sensations.
The human nervous system is a vastly complex thing, not only in structure, but in the fascinating way it achieves such fluid control over the body under its charge. There is an unbelievable sophistication in the way it provides nuanced responses to an ever-changing environment - consistently matching our internal biology to the needs of the moment. Interestingly, the brain of an average adult human weighs about 2% of our total body weight, but it consumes around 20% of the energy we obtain from our food (1). Furthermore, a relatively large percentage of this energy demand is devoted to inhibition - the process of using interneurons as 'traffic cops' to regulate the activity of other excitatory neurons. According to Massimo Scanziani (2),
The human nervous system is a vastly complex thing, not only in structure, but in the fascinating way it achieves such fluid control over the body under its charge. There is an unbelievable sophistication in the way it provides nuanced responses to an ever-changing environment - consistently matching our internal biology to the needs of the moment. Interestingly, the brain of an average adult human weighs about 2% of our total body weight, but it consumes around 20% of the energy we obtain from our food (1). Furthermore, a relatively large percentage of this energy demand is devoted to inhibition - the process of using interneurons as 'traffic cops' to regulate the activity of other excitatory neurons. According to Massimo Scanziani (2),
"Neurons in our brain drive by pushing the brake and the accelerator at the same time. This means that there is no stimulus that you can apply that will activate purely excitatory neurons or purely inhibitory ones. There is always a tug-of-war. It's weird but very clever. It allows the brain to exert very subtle control on our response to stimuli."
These endlessly reverberating circuits allow us to think and feel and act - making us human. We inhibit our inputs and we inhibit our outputs, tempering our responses so that they are refined and appropriate (3). But sometimes, things do not work as well as nature intended, and our joy for life is undermined by a lack of inhibition.
LOSING OUR INHIBITIONS
There are many circumstances in which perfectly normal individuals will show signs of decreased inhibition. This is most readily apparent when we are stressed or fatigued - both situations in which mildly annoying tendencies become unmasked. We might express this as irritability, a twitching eyelid, a tightening shoulder muscle, a mild tremor of the hand, nausea, tinnitus, headache, or even anxiety. However, such transient symptoms are just a temporary aberration and the neurological balance tends to return to normal after a good night's sleep, or perhaps a holiday. But in some individuals a deficit in inhibition is the norm. It defines them and their neurological health. And it is often poorly understood by those charged with investigating the source of their nebulous and varied symptoms.
It is important to realise that there are a large number of common disorders that are characterised by poor inhibition. However, the boundaries between one condition and another are often blurred, making identification (and diagnosis) difficult. Indeed, science suggests that there is a 'spectrum' of neurological conditions that share many genetic and biochemical markers including migraine, fibromyalgia, irritable bowel syndrome and ADHD - to name just a few. Each of these examples demonstrate an inability to restrain brain activity within a tight set of operating limits. Of course, all of us exhibit fluctuations in the functional parameters of our body, and if we were to plot the daily rhythms of our blood pressure, body temperature, heart rate etc on a graph, we would see a constant ebb and flow of changing activity. But in a person who suffers from fibromyalgia or migraine, we might see a very different plot, with higher highs and lower lows. In other words, a much greater dynamic range.
These peaks and troughs represent periods in which normal regulation is lost and, for the individual concerned, most likely the appearance of unwanted symptoms. Furthermore, the range of possible symptoms is huge. The literature has devoted considerable space to the inhibition-related issues that can accompany such disorders, with the most obvious one being pain itself (4). To put it simply, migraineurs tend to experience more pain in general - not just headache. I have written about this previously in another article entitled, "Migraine Changes Everything - Even Back Pain" (here), but it is safe to say that migraine sufferers can be characterised as 'poor inhibitors' (5,6,7,8,9). Furthermore, this pain sensitivity is apparent during both the headache (ictal) state, and in the headache-free (interictal) period when the patient feels 'normal'. Researchers Mainero and Louapre (10) put it this way,
It is important to realise that there are a large number of common disorders that are characterised by poor inhibition. However, the boundaries between one condition and another are often blurred, making identification (and diagnosis) difficult. Indeed, science suggests that there is a 'spectrum' of neurological conditions that share many genetic and biochemical markers including migraine, fibromyalgia, irritable bowel syndrome and ADHD - to name just a few. Each of these examples demonstrate an inability to restrain brain activity within a tight set of operating limits. Of course, all of us exhibit fluctuations in the functional parameters of our body, and if we were to plot the daily rhythms of our blood pressure, body temperature, heart rate etc on a graph, we would see a constant ebb and flow of changing activity. But in a person who suffers from fibromyalgia or migraine, we might see a very different plot, with higher highs and lower lows. In other words, a much greater dynamic range.
These peaks and troughs represent periods in which normal regulation is lost and, for the individual concerned, most likely the appearance of unwanted symptoms. Furthermore, the range of possible symptoms is huge. The literature has devoted considerable space to the inhibition-related issues that can accompany such disorders, with the most obvious one being pain itself (4). To put it simply, migraineurs tend to experience more pain in general - not just headache. I have written about this previously in another article entitled, "Migraine Changes Everything - Even Back Pain" (here), but it is safe to say that migraine sufferers can be characterised as 'poor inhibitors' (5,6,7,8,9). Furthermore, this pain sensitivity is apparent during both the headache (ictal) state, and in the headache-free (interictal) period when the patient feels 'normal'. Researchers Mainero and Louapre (10) put it this way,
"A large body of evidence supports the view that migraine is also characterized by a dysfunctional central control of pain, as suggested by the observation of ictal and interictal abnormalities in subcortical brainstem and diencephalic nuclei involved in pain modulation. Such findings have led to the juxtaposition of two theories on the pathophysiology of the migraine attack: one that hypothesizes that dysfunction of brainstem nuclei and diencephalic nuclei induces abnormal interpretation of normal sensory input, causing normal sensory flow from the meninges to be interpreted as migraine pain; the other that views the brainstem more as a modulator than a generator of migraine pain, theorizing that dysfunction of inhibitory pain modulation may lead to hyperexcitability along the trigeminovascular pain pathway."
Indeed, there is considerable evidence from functional-MRI studies that migraineurs have reduced activity in their brainstem pain modulation circuitry, such as the periaqueductal gray (PAG) (11,12). The same goes for fibromyalgia, which some authors have characterised as a 'whole body migraine'. These patients also exhibit reduced intracortical inhibition (13), and a deficient descending inhibitory control of pain (14,15,16,17), while those with irritable bowel syndrome represent yet another expression of dysfunctional inhibition (18,19,20). According to López-Solà et al (21),
"In addition to pain-related changes, patients with fibromyalgia (FM) show reduced tolerance (augmented unpleasantness) to nonpainful sensory stimulation (visual, auditory, olfactory, and tactile), along with abnormal brain processing of nonpainful sensory stimuli. Our group and others have reported evidence suggesting that the brain systems involved in the primary cortical processing of nonpainful sensory signals and their integration may play an important role in FM pain. These studies suggest that pain in FM may be associated with (1) hyperexcitability of the nociceptive system, ie, increased transmission, central amplification, and/or reduced inhibitory control mechanisms and (2) reduced opponent nonnociceptive sensory processing."
An understanding that fibromyalgia is a brain-based disorder is critical to effective management. For many years it was conceived to be a rheumatological condition, and the focus of research was upon possible inflammatory and immune mechanisms. However, the advent of functional MRI and other investigatory methods has confirmed the central neurological underpinnings of fibromyalgia, and it now lies firmly on the spectrum of functional neurological disorders.
Interestingly, such individuals will continue to show heightened sensitivities when feeling at their best. For example, studies on migraineurs confirm abnormal sensory processing and reduced inhibition even between attacks (known as the interictal period) (22,23,24). Harriott et al (24) suggested that,
Interestingly, such individuals will continue to show heightened sensitivities when feeling at their best. For example, studies on migraineurs confirm abnormal sensory processing and reduced inhibition even between attacks (known as the interictal period) (22,23,24). Harriott et al (24) suggested that,
"Several studies have demonstrated that migraineurs differ in their processing and perception of unimodal and multimodal sensory inputs. During the migraine attack, migraineurs develop an enhanced perception of painful and non-painful somatosensory, visual, auditory, and olfactory sensations. Between migraine attacks, atypical sensory perception persists, with migraineurs often demonstrating low discomfort thresholds to various experimentally applied stimuli. In addition, migraine is associated with atypical integration of information from different sensory modalities presented simultaneously (i.e. multisensory integration)."
Migraineurs will often describe a host of sensitivities and symptoms that tend to be overlooked in favour of tackling the more obvious headache problem. But head pain is just the tip of the neurological iceberg, and those afflicted will be unduly sensitive to most stimuli, whether these originate from the external environment (such as light, sound, temperature), or from their internal structures (stomach, bladder, bowel, reproductive organs, musculoskeletal tissues). In each case, a failure to adequately inhibit the sensory pathways may produce an elevated awareness that the sufferer is somehow uncomfortable, or experiencing something truly unpleasant. The range of symptoms that have been linked to this inhibitory failure is indeed impressive, including; tinnitus, vulvodynia, interstitial cystitis, irritable bowel syndrome, restless leg syndrome, bruxism, photophobia, anxiety, and attention-deficit-hyperactivity disorder - to name but a few.
If we pause for a moment to reflect upon the underlying theme here, we can see that a normal, healthy human existence relies heavily upon appropriate levels of inhibition. Even our ability to think clearly will depend upon our inhibitory circuits' efficiency in shutting down any spurious stimuli that might otherwise catch our attention. This is the challenge of ADHD. Those affected by this disorder have great difficulty in sustaining attention upon a given task and inhibiting impulsivity (25,26), as well as other sensitivities to environmental and chemical stimuli (27). Of course, the widespread nature of inhibitory dysfunction might suggest that those with ADHD would also complain of other sensitivities (such as headache) - and indeed they do (28,29). This further blurs the lines between disorders and suggests that sub-optimal inhibition is common - although its expression does depend upon the genetic makeup of the individual.
For some, their challenge is to manage the rising feelings of anxiety that normally lie beneath the surface in all of us. Clearly anxiety is an important survival system, whose purpose is to increase our sensory awareness in times of threat. However, we also need an ability to adequately suppress inappropriate cognitive and autonomic responses to innocuous stimuli. Failure to do so will create a state of increased vigilance that is unjustified and unpleasant. It should be no surprise then, to find that anxiety is a frequent accompaniment to migraine and fibromyalgia (30), particularly in those individuals who also complain of photophobia.
For some, their challenge is to manage the rising feelings of anxiety that normally lie beneath the surface in all of us. Clearly anxiety is an important survival system, whose purpose is to increase our sensory awareness in times of threat. However, we also need an ability to adequately suppress inappropriate cognitive and autonomic responses to innocuous stimuli. Failure to do so will create a state of increased vigilance that is unjustified and unpleasant. It should be no surprise then, to find that anxiety is a frequent accompaniment to migraine and fibromyalgia (30), particularly in those individuals who also complain of photophobia.
SO HOW DO WE ADDRESS POOR INHIBITION?
In an interview at the University of California, San Diego School of Medicine, researcher Dr Scanziani (2) discussed the importance of the constant ratio between excitation and inhibition (known as the 'E/I ratio'),
"If this E/I balance is broken, it completely alters your perception of the world," Scanziani said. "You will be less able to adjust and adapt appropriately to the range of stimulation in a normal day without being overwhelmed or completely oblivious, and E/I imbalances may be most easily noticed in social interactions because these interactions require such nuance and subtle adjusting."
The idea that numerous and apparently-distinct disorders might share a common physiological underpinning (that is, reduced inhibition) is gaining greater acceptance in the literature. Indeed, it is quite helpful to think in these broad terms when we are challenged to make sense of a 'complex' patient's symptoms - and then come up with an effective strategy for management. So this begs the questions, why does this occur and what can we do about it?
Coppola (23) contended that,
Coppola (23) contended that,
"There is as yet no single causal explanation for this dynamic cortical dysfunction and its precise role in recurrence of migraine attacks and its possible relation with clinical features of the disease are not known. An imbalance between inhibitory and excitatory cortical mechanisms, primary or secondary to reduced cortical pre-activation levels because of an insufficient thalamocortical drive, has been considered a possible culprit."
The principal neurotransmitter involved in intracortical inhibition is GABA, and it is used to modulate or 'shape' the responsiveness of other neurons. However, other neurotransmitters such as serotonin and noradrenaline also play a role. Obviously the problem of inhibitory dysfunction is complex, but it may also present us with an opportunity. The fact that such people are highly reactive to their environment means that they may well respond to therapies that would otherwise have little effect in 'normal' individuals. For example, the average patient with migraine, fibromyalgia or anxiety will often self-select a practitioner, or a form of therapy, that some health professionals might disparagingly see as 'wishy-washy'. With no offence intended, I might suggest that aromatherapy, Bowen technique and acupuncture are often viewed in this light. Chiropractors also offer a wide range of techniques that vary in the intensity of their stimulation (Diversified, SOT, Activator etc), and each creates its own 'sensory signature'. Perhaps the reason why 'lighter' treatment modalities can be effective in poor inhibitors is that they take advantage of a fundamental flaw in their makeup - they habituate poorly.
According to Lee et al (31),
According to Lee et al (31),
"Habituation is a neurophysiological phenomenon characterized by a reduced response to repeated sensory stimulation. Neural habituation is considered protective to the organism, as it shields the brain from excessive information processing and limits energy consumption. For instance, habituation is critical for learning, in order to discriminate relevant stimuli and focus on selective properties of external stimuli. In migraine, impaired habituation to not just pain but also non-noxious sensory stimuli of various modalities (visual, auditory, olfactory, somatosensory) has been commonly reported, mainly using electrophysiological approaches."
Brighina et al (32) also stated that,
"Habituation represents the simplest form of implicit learning allowing an organism to learn the features of a new stimulus. When a new stimulus is presented, if it is irrelevant or not noxious, after a succession of exposure, the animal ignores it. Habituation can be studied in humans through evoked potential stimulation. Habituation of evoked potentials is expressed by reduced amplitude of the evoked response to repeated stimulation and is observed in normal subjects while is consistently reported to be impaired in migraine. Schoenen et al first reported that migraine patients show lack of amplitude habituation to the ongoing visual evoked potential stimulation. Impaired habituation in migraine is not confined to visual inputs, but extends to all sensory modalities. Defective habituation has been indeed described in studies of auditory potentials or somato-sensory EP and also for cognitive potentials. More recently impaired habituation has been found also in nociceptive sensory inputs by the technique of laser evoked potentials. Moreover, impaired habituation in migraine has been shown to affect also reflex activities like Blink reflex, induced either by somatosensorial or nociceptive stimulation."
Taking this into account, it may be that low-level therapeutic inputs have a chance to summate in sensitive patients, whereas more robust individuals are capable of shutting down innocuous stimulation before it can exert any real effect. As such, relatively mild forms of treatment can be effective. For example, there is considerable interest in dietary interventions or herbal supplements in the management of such patients. The herb Passion Flower (Passiflora incarnata) appears to be helpful in reducing the effects of ADHD, possibly through an ability to increase production of GABA (the principal neurotransmitter involved in cortical inhibition) (33,34). Melatonin has also shown promise in migraine (35,36,37,38,39,40), tinnitus (41) and irritable bowel syndrome management (42). Ketogenic diets have been used quite successfully in epilepsy cases, and there is some evidence that it may help temper brain responses in migraineurs. According to Di Lorenzo et al (43),
"In healthy humans, ketogenic diet (KD) is associated with a significant enhancement of intracortical inhibition as measured with transcranial magnetic stimulation. These experimental observations are of particular interest in migraine because we have previously reported that the migraineurs’ brains are characterized by an imbalance between excitation and inhibition in the sensory cortices... We hypothesize that KD works by heightening GABAergic and diminishing excitatory activities."
Possibly one of the most interesting approaches to the challenge of inhibition is the use of transcranial stimulation. This involves the application of either direct current or a magnetic field to specific areas of the brain (usually the cortex) by way of an external probe. While the actual mechanism of action is still unresolved, there is increasing evidence for its effectiveness in a growing range of disorders. These include migraine (44,45), fibromyalgia (46), anxiety, depression, chronic pain, tinnitus (47) and ADHD (48). Interestingly, a recent study on ADHD was found to alleviate many of the behavioural symptoms by targeting the trigeminal nerve (rather than the cortex directly). McGough et al (49) wrote,
"The trigeminal nerve conveys sensory inputs from the skin, muscles, and joints of the head to extensive connections in the brainstem and cortex. As with the vagus nerve, the trigeminal has connections with the locus coeruleus, reticular activating system, and nucleus tractus solitarious. These brain regions are involved in a variety of affective and cognitive functions, including selective maintenance of attention during cognitive tasks."
I find this particularly relevant to chiropractors, as the trigeminal nerve is intrinsically related to the mechanical tissues of the upper cervical spine. Furthermore, manipulation of this region most definitely qualifies as a novel form of sensory stimulation to the trigeminal system. Furthermore, Lee et al (50) found that migraineurs show "reduced habituation for an innocuous somatosensory trigeminal stimulus", suggesting that cumulative inputs may well reverberate sufficiently to trigger greater responses in the posterior insula (a key area for sensory processing in migraine). Of course, the neurological signature of a spinal manipulation differs markedly from that of an electric current applied via the skin. However, it does appear that the human nervous system will respond in beneficial fashion to many different forms of stimuli. Indeed, in the world of 'functional neurology' it is often stated that,
"Anything that we have a receptor for could be used as a treatment."
In other words, we have many different portals of entry to the human nervous system, from smell and taste, to light, or sound, or temperature, or touch or chemistry. In theory, any one of these could be harnessed to change the brain (aromatherapy, light therapy, sound therapy, massage, manipulation, pharmacology etc). Fortunately for chiropractors, it just so happens that the pathways that we typically use to exert our effects upon the neuraxis are highly influential. The large, fast, heavily-myelinated proprioceptive fibres that encode the stimuli from an adjustment have a disproportionate effect upon large areas of our somatosensory and autonomic systems, and chiropractors exploit these pathways to create change. Furthermore, it is likely that a person who has deficiencies in habituation/inhibition may be more responsive to these inputs that an otherwise 'normal' individual.
WHAT CAN SPINAL MANIPULATION DO?
In recent years there has been great interest in the effects of spinal manipulation upon the human cortex, particularly in the areas of sensorimotor integration and intracortical inhibition. As we have seen, we rely upon complex patterns of inhibitory behaviour to fine-tune the responses of our nervous system. According to Haavik and Murphy (51),
"This type of sensory filtering is the ability of an individual’s CNS to suppress or attenuate the processing of multiple afferent peripheral, mainly proprioceptive, inputs. It is thought to reflect a type of ‘‘surround-like’’ inhibition, which in healthy individuals, allows for the contrast between stimuli to remain high by suppressing the processing of input from surrounding areas. In the somatosensory system, such inhibition allows for the body to perceive stimuli as separate and process them accordingly. This filtering process has been found to be altered in individuals with neck pain, after repetitive muscular activities such as typing as well as other musculoskeletal disorders such as dystonia."
The work of Haavik and colleagues has shed significant light upon the way in which spinal manipulation can help those with such neurological disorders. Again, they state (51),
"It is therefore possible that spinal manipulation in patients with sub-clinical or more chronic neck pain is able to improve the central processing of proprioceptive information, and that this is part of the mechanism by which high-velocity, low-amplitude spinal manipulation improve function and reduce chronicity and reoccurrence in these patient populations. It is possible that the changes in cortical somatosensory processing, sensorimotor integration and motor control that have been previously documented following high-velocity, low-amplitude spinal manipulation reflect changes in central processing of proprioceptive afferent input."
It may be that a spinal adjustment works as a 'change agent' to assist the nervous system in reconfiguring its responses to future inputs (52), ensuring that our patient's neither over-react, nor under-react to our ever-changing environment. While this is clearly important in helping patients to inhibit their pain, usually via activation of the descending inhibitory pathways (53,54), we should not underestimate the benefits that this form of stimulation might have for all manner of neural integration problems.
So too, we shouldn't underestimate the impact that our words and education have on the brain's ability to self-regulate. I have written previously about the effects of patient expectation upon treatment outcomes (here) and (here), and there is good evidence that the pre-frontal cortex has a large role in analgesia (55). Van Oosterwijck et al (56) wrote the following,
So too, we shouldn't underestimate the impact that our words and education have on the brain's ability to self-regulate. I have written previously about the effects of patient expectation upon treatment outcomes (here) and (here), and there is good evidence that the pre-frontal cortex has a large role in analgesia (55). Van Oosterwijck et al (56) wrote the following,
"Could it be possible that pain physiology education is able to improve descending nociceptive processing? As descending facilitatory pathways depart from brain areas that are involved in the regulation of cognitive and emotional reactions, such as the limbic system, these cognitions and emotions can modulate the activity in the descending pathways. Negative cognitions and emotions, which can develop when patients do not understand their condition or the cause of experiencing pain, can facilitate pain through these descending pathways. Thus on theoretical basis, one can assume that altering maladaptive thoughts and cognitions could result in less top down pain facilitation and an improved descending nociceptive inhibition of the CNS, which in turn can lead to less pain and improvements in movement performance. Indeed, the current study findings can confirm this theory to certain extent. If pain physiology education can be used to improve endogenous pain inhibition, as suggested by our findings, this could be a feasible mechanism to explain previously reported improvements in pain and (pain-free) movement performance after pain physiology education."
In the end, it seems that our quality of life is intimately related to 'balance'.
Balance within the nervous system is something that chiropractors have thought about for decades, but modern neuroscience is now starting to paint for us a picture of how this equilibrium is achieved, and maintained. So next time you adjust a patient, pause for a moment and ponder the exquisite complexity that you are interacting with.
Balance within the nervous system is something that chiropractors have thought about for decades, but modern neuroscience is now starting to paint for us a picture of how this equilibrium is achieved, and maintained. So next time you adjust a patient, pause for a moment and ponder the exquisite complexity that you are interacting with.
Something to think about...
Dr Matthew D. Long
BSc (Syd), M.Chiro (Macq)
Dr Matthew D. Long
BSc (Syd), M.Chiro (Macq)
References:
1. Buzsáki, G., Kaila, K., & Raichle, M. (2007). Inhibition and brain work. Neuron, 56(5), 771–783. http://doi.org/10.1016/j.neuron.2007.11.008
2. Scanziani, M. (2014). The brain's balancing act. Researchers discover how neurons equalize between excitation and inhibition. https://www.eurekalert.org/pub_releases/2014-06/uoc--tbb061814.php
3. Isaacson, J. S., & Scanziani, M. (2011). How inhibition shapes cortical activity. Neuron, 72(2), 231–243. http://doi.org/10.1016/j.neuron.2011.09.027
4. Yoon, M.-S., Manack, A., Schramm, S., Fritsche, G., Obermann, M., Diener, H.-C., et al. (2013). Chronic migraine and chronic tension-type headache are associated with concomitant low back pain: Results of the German Headache Consortium study. Pain, 154(3), 484–492. doi:10.1016/j.pain.2012.12.010
5. Aurora, S. K., Barrodale, P., Chronicle, E. P., & Mulleners, W. M. (2005). Cortical inhibition is reduced in chronic and episodic migraine and demonstrates a spectrum of illness. Headache, 45(5), 546–552. http://doi.org/10.1111/j.1526-4610.2005.05108.x
6. Nguyen, B. N., McKendrick, A. M., & Vingrys, A. J. (2015). Abnormal inhibition-excitation imbalance in migraine. Cephalalgia, 1–10. http://doi.org/10.1177/0333102415576725
7. Siniatchkin, M., Kröner-Herwig, B., Kocabiyik, E., & Rothenberger, A. (2007). Intracortical inhibition and facilitation in migraine--a transcranial magnetic stimulation study. Headache, 47(3), 364–370. http://doi.org/10.1111/j.1526-4610.2007.00727.x
8. Vecchia, D., & Pietrobon, D. (2012). Migraine: a disorder of brain excitatory-inhibitory balance? Trends in Neurosciences, 35(8), 507–520. http://doi.org/10.1016/j.tins.2012.04.007
9. Brighina, F., Palermo, A., Panetta, M. L., Daniele, O., Aloisio, A., Cosentino, G., & Fierro, B. (2009). Reduced cerebellar inhibition in migraine with aura: a TMS study. Cerebellum (London, England), 8(3), 260–266. http://doi.org/10.1007/s12311-008-0090-4
10. Mainero, C., & Louapre, C. (2014). Migraine and inhibitory system - I can't hold it! Current Pain and Headache Reports, 18(7), 426. http://doi.org/10.1007/s11916-014-0426-3
11. Mainero, C., Boshyan, J., & Hadjikhani, N. (2011). Altered functional magnetic resonance imaging resting-state connectivity in periaqueductal gray networks in migraine. Annals of Neurology, 70(5), 838–845. http://doi.org/10.1002/ana.22537
12. Boyer, N., Dallel, R., Artola, A., & Monconduit, L. (2014). General trigeminospinal central sensitization and impaired descending pain inhibitory controls contribute to migraine progression. Pain, 155(7), 1196–1205. http://doi.org/10.1016/j.pain.2014.03.001
13. Lim, M., Roosink, M., Kim, J. S., Kim, D. J., Kim, H. W., Lee, E. B., et al. (2015). Disinhibition of the primary somatosensory cortex in patients with fibromyalgia. Pain, 156(4), 666–674. http://doi.org/10.1097/j.pain.0000000000000096
14. Mhalla, A., de Andrade, D. C., Baudic, S., Perrot, S., & Bouhassira, D. (2010). Alteration of cortical excitability in patients with fibromyalgia. Pain, 149(3), 495–500. http://doi.org/10.1016/j.pain.2010.03.009
15. Lim, M., Roosink, M., Kim, J. S., Kim, D. J., Kim, H. W., Lee, E. B., et al. (2015). Disinhibition of the primary somatosensory cortex in patients with fibromyalgia. Pain, 156(4), 666–674. http://doi.org/10.1097/j.pain.0000000000000096
16. Julien, N., Goffaux, P., Arsenault, P., & Marchand, S. (2005). Widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition. Pain, 114(1-2), 295–302. http://doi.org/10.1016/j.pain.2004.12.032
17. Jensen, K. B., Kosek, E., Petzke, F., Carville, S., Fransson, P., Marcus, H., et al. (2009). Evidence of dysfunctional pain inhibition in Fibromyalgia reflected in rACC during provoked pain. Pain, 144(1-2), 95–100. http://doi.org/10.1016/j.pain.2009.03.018
18. Chalaye, P., Goffaux, P., Bourgault, P., Lafrenaye, S., Devroede, G., Watier, A., & Marchand, S. (2012). Comparing pain modulation and autonomic responses in fibromyalgia and irritable bowel syndrome patients. The Clinical Journal of Pain, 28(6), 519–526. http://doi.org/10.1097/AJP.0b013e31823ae69e
19. Piché, M., Arsenault, M., Poitras, P., Rainville, P., & Bouin, M. (2010). Widespread hypersensitivity is related to altered pain inhibition processes in irritable bowel syndrome. Pain, 148(1), 49–58. http://doi.org/10.1016/j.pain.2009.10.005
20. King, C. D., Wong, F., Currie, T., Mauderli, A. P., Fillingim, R. B., & Riley, J. L. (2009). Deficiency in endogenous modulation of prolonged heat pain in patients with Irritable Bowel Syndrome and Temporomandibular Disorder. Pain, 143(3), 172–178. http://doi.org/10.1016/j.pain.2008.12.027
21. López-Solà, M., Woo, C.-W., Pujol, J., Deus, J., Harrison, B. J., Monfort, J., & Wager, T. D. (2017). Towards a neurophysiological signature for fibromyalgia. Pain, 158(1), 34–47. http://doi.org/10.1097/j.pain.0000000000000707
22. Coppola, G., Di Renzo, A., Tinelli, E., Lepre, C., Di Lorenzo, C., Di Lorenzo, G., et al. (2016). Thalamo-cortical network activity between migraine attacks: Insights from MRI-based microstructural and functional resting-state network correlation analysis. J Headache Pain, 17(1), 65–9. http://doi.org/10.1186/s10194-016-0693-y
23. Coppola, G., Bracaglia, M., Di Lenola, D., Iacovelli, E., Di Lorenzo, C., Serrao, M., et al. (2015). Lateral inhibition in the somatosensory cortex during and between migraine without aura attacks: Correlations with thalamocortical activity and clinical features. Cephalalgia, 1–11. http://doi.org/10.1177/0333102415610873
24. Harriott, A. M., & Schwedt, T. J. (2014). Migraine is associated with altered processing of sensory stimuli. Current Pain and Headache Reports, 18(11), 458. http://doi.org/10.1007/s11916-014-0458-8
25. Gilbert, D. L., Isaacs, K. M., Augusta, M., Macneil, L. K., & Mostofsky, S. H. (2011). Motor cortex inhibition: a marker of ADHD behavior and motor development in children. Neurology, 76(7), 615–621. http://doi.org/10.1212/WNL.0b013e31820c2ebd
26. Shaw, P., Lalonde, F., Lepage, C., Rabin, C., Eckstrand, K., Sharp, W., et al. (2009). Development of cortical asymmetry in typically developing children and its disruption in attention-deficit/hyperactivity disorder. Archives of General Psychiatry, 66(8), 888–896. http://doi.org/10.1001/archgenpsychiatry.2009.103
27. Lorenzen, A., Scholz-Hehn, D., Wiesner, C. D., Wolff, S., Bergmann, T. O., van Eimeren, T., et al. (2016). Chemosensory processing in children with attention-deficit/hyperactivity disorder. Journal of Psychiatric Research, 76, 121–127. http://doi.org/10.1016/j.jpsychires.2016.02.007
28. Parisi, P., Verrotti, A., Paolino, M. C., Ferretti, A., Raucci, U., Moavero, R., et al. (2014). Headache and attention deficit and hyperactivity disorder in children: Common condition with complex relation and disabling consequences. Epilepsy & Behavior, 32, 72–75. http://doi.org/10.1016/j.yebeh.2013.12.028
29. Paolino, M. C., Ferretti, A., Villa, M. P., & Parisi, P. (2015). Headache and ADHD in Pediatric Age: Possible Physiopathological Links. Current Pain and Headache Reports, 19(7), 25–7. http://doi.org/10.1007/s11916-015-0494-z
30. Llop, S. M., Frandsen, J. E., Digre, K. B., Katz, B. J., Crum, A. V., Zhang, C., & Warner, J. E. A. (2016). Increased prevalence of depression and anxiety in patients with migraine and interictal photophobia. J Headache Pain, 17(1), 3838–7. http://doi.org/10.1186/s10194-016-0629-6
31. Lee, J., Lin, R. L., Garcia, R. G., Kim, J., Kim, H., Loggia, M. L., et al. (2016). Reduced insula habituation associated with amplification of trigeminal brainstem input in migraine. Cephalalgia. http://doi.org/10.1177/0333102416665223
32. Brighina, F., Palermo, A., & Fierro, B. (2009). Cortical inhibition and habituation to evoked potentials: relevance for pathophysiology of migraine. The Journal of Headache and Pain, 10(2), 77–84. http://doi.org/10.1007/s10194-008-0095-x
33. Akhondzadeh, S., Mohammadi, M. R., & Momeni, F. (2005). Passiflora incarnata in the treatment of attention-deficit hyperactivity disorder in children and adolescents. Therapy, 2(4), 609–614. http://doi.org/10.1586/14750708.2.4.609
34. Anheyer, D., Lauche, R., Schumann, D., Dobos, G., & Cramer, H. (2017). Herbal medicines in children with attention deficit hyperactivity disorder (ADHD): A systematic review. Complementary Therapies in Medicine, 30, 14–23. http://doi.org/10.1016/j.ctim.2016.11.004
35. le Grand, S. M., Patumraj, S., Phansuwan-Pujito, P., & Srikiatkhachorn, A. (2006). Melatonin inhibits cortical spreading depression-evoked trigeminal nociception. Neuroreport, 17(16), 1709–1713. http://doi.org/10.1097/WNR.0b013e3280101207
36. Gelfand, A. A., & Goadsby, P. J. (2016). The Role of Melatonin in the Treatment of Primary Headache Disorders. Headache, 56(8), 1257–1266. http://doi.org/10.1111/head.12862
37. Peres, M. F. P. (2011). Melatonin for migraine prevention. Current Pain and Headache Reports, 15(5), 334–335. http://doi.org/10.1007/s11916-011-0219-x
38. Miano, S., Parisi, P., Pelliccia, A., Luchetti, A., Paolino, M. C., & Villa, M. P. (2008). Melatonin to prevent migraine or tension-type headache in children. Neurological Sciences, 29(4), 285–287. http://doi.org/10.1007/s10072-008-0983-5
39. Peres, M. F. P., Masruha, M. R., Zukerman, E., Moreira-Filho, C. A., & Cavalheiro, E. A. (2006). Potential therapeutic use of melatonin in migraine and other headache disorders. Expert Opinion on Investigational Drugs, 15(4), 367–375. http://doi.org/10.1517/13543784.15.4.367
40. Peres, M. F. P., Zukerman, E., da Cunha Tanuri, F., Moreira, F. R., & Cipolla-Neto, J. (2004). Melatonin, 3 mg, is effective for migraine prevention. Neurology, 63(4), 757
41. Merrick, L., Youssef, D., Tanner, M., & Peiris, A. N. (2014). Does melatonin have therapeutic use in tinnitus? Southern Medical Journal, 107(6), 362–366. http://doi.org/10.14423/01.SMJ.0000450714.38550.d4
42. Lu, W. Z., Gwee, K. A., Moochhalla, S., & Ho, K. Y. (2005). Melatonin improves bowel symptoms in female patients with irritable bowel syndrome: a double-blind placebo-controlled study. Alimentary Pharmacology and Therapeutics, 22(10), 927–934. http://doi.org/10.1111/j.1365-2036.2005.02673.x
43. Di Lorenzo, C., Coppola, G., Bracaglia, M., Di Lenola, D., Evangelista, M., Sirianni, G., et al. (2016). Cortical functional correlates of responsiveness to short-lasting preventive intervention with ketogenic diet in migraine: a multimodal evoked potentials study. J Headache Pain, 17(1), 493–10. http://doi.org/10.1186/s10194-016-0650-9
44. Brighina, F., Piazza, A., Vitello, G., Aloisio, A., Palermo, A., Daniele, O., & Fierro, B. (2004). rTMS of the prefrontal cortex in the treatment of chronic migraine: a pilot study. Journal of the Neurological Sciences, 227(1), 67–71. http://doi.org/10.1016/j.jns.2004.08.008
45. Kalita, J., Bhoi, S. K., & Misra, U. K. (2016). Effect of high rate rTMS on somatosensory evoked potential in migraine. Cephalalgia. http://doi.org/10.1177/0333102416675619
46. Fagerlund, A. J., Hansen, O. A., & Aslaksen, P. M. (2015). Transcranial direct current stimulation as a treatment for patients with fibromyalgia: a randomized controlled trial. Pain, 156(1), 62–71. http://doi.org/10.1016/j.pain.0000000000000006
47. Kuo MF, Paulus W, Nitsche MA (2014). Therapeutic effects of non-invasive brain stimulation with direct currents (tDCS) in neuropsychiatric diseases. Neuroimage 85(Pt 3):948–960. doi:10.1016/j.neuroimage.2013.05.117
48. Soff, C., Sotnikova, A., Christiansen, H., Becker, K., & Siniatchkin, M. (2017). Transcranial direct current stimulation improves clinical symptoms in adolescents with attention deficit hyperactivity disorder. Journal of Neural Transmission, 124(1), 133–144. http://doi.org/10.1007/s00702-016-1646-y
49. McGough, J. J., Loo, S. K., Sturm, A., Cowen, J., Leuchter, A. F., & Cook, I. A. (2015). An eight-week, open-trial, pilot feasibility study of trigeminal nerve stimulation in youth with attention-deficit/hyperactivity disorder. Brain Stimulation, 8(2), 299–304. http://doi.org/10.1016/j.brs.2014.11.013
50. Lee, J., Lin, R. L., Garcia, R. G., Kim, J., Kim, H., Loggia, M. L., et al. (2016). Reduced insula habituation associated with amplification of trigeminal brainstem input in migraine. Cephalalgia. http://doi.org/10.1177/0333102416665223
51. Haavik, H., & Murphy, B. (2012). The role of spinal manipulation in addressing disordered sensorimotor integration and altered motor control. Journal of Electromyography and Kinesiology, 22(5), 768–776. http://doi.org/10.1016/j.jelekin.2012.02.012
52. Gay, C. W., Robinson, M. E., George, S. Z., Perlstein, W. M., & Bishop, M. D. (2014). Immediate changes after manual therapy in resting-state functional connectivity as measured by functional magnetic resonance imaging in participants with induced low back pain. Journal of Manipulative and Physiological Therapeutics, 37(9), 614–627. http://doi.org/10.1016/j.jmpt.2014.09.001
53. Aguirrebeña, I. L., Newham, D., & Critchley, D. J. (2016). Mechanism of Action of Spinal Mobilizations. Spine, 41(2), 159–172. http://doi.org/10.1097/BRS.0000000000001151
54. Savva, C., Giakas, G., & Efstathiou, M. (2014). The role of the descending inhibitory pain mechanism in musculoskeletal pain following high-velocity, low amplitude thrust manipulation. A review of the literature. Journal of Back and Musculoskeletal Rehabilitation. http://doi.org/10.3233/BMR-140472
55. Krummenacher, P., Candia, V., Folkers, G., Schedlowski, M., & Schönbächler, G. (2010). Prefrontal cortex modulates placebo analgesia. Pain, 148(3), 368–374. http://doi.org/10.1016/j.pain.2009.09.033
56. Van Oosterwijck, J., Meeus, M., Paul, L., De Schryver, M., Pascal, A., Lambrecht, L., & Nijs, J. (2013). Pain Physiology Education Improves Health Status and Endogenous Pain Inhibition in Fibromyalgia: A Double-Blind Randomized Controlled Trial. The Clinical Journal of Pain. http://doi.org/10.1097/AJP.0b013e31827c7a7d
1. Buzsáki, G., Kaila, K., & Raichle, M. (2007). Inhibition and brain work. Neuron, 56(5), 771–783. http://doi.org/10.1016/j.neuron.2007.11.008
2. Scanziani, M. (2014). The brain's balancing act. Researchers discover how neurons equalize between excitation and inhibition. https://www.eurekalert.org/pub_releases/2014-06/uoc--tbb061814.php
3. Isaacson, J. S., & Scanziani, M. (2011). How inhibition shapes cortical activity. Neuron, 72(2), 231–243. http://doi.org/10.1016/j.neuron.2011.09.027
4. Yoon, M.-S., Manack, A., Schramm, S., Fritsche, G., Obermann, M., Diener, H.-C., et al. (2013). Chronic migraine and chronic tension-type headache are associated with concomitant low back pain: Results of the German Headache Consortium study. Pain, 154(3), 484–492. doi:10.1016/j.pain.2012.12.010
5. Aurora, S. K., Barrodale, P., Chronicle, E. P., & Mulleners, W. M. (2005). Cortical inhibition is reduced in chronic and episodic migraine and demonstrates a spectrum of illness. Headache, 45(5), 546–552. http://doi.org/10.1111/j.1526-4610.2005.05108.x
6. Nguyen, B. N., McKendrick, A. M., & Vingrys, A. J. (2015). Abnormal inhibition-excitation imbalance in migraine. Cephalalgia, 1–10. http://doi.org/10.1177/0333102415576725
7. Siniatchkin, M., Kröner-Herwig, B., Kocabiyik, E., & Rothenberger, A. (2007). Intracortical inhibition and facilitation in migraine--a transcranial magnetic stimulation study. Headache, 47(3), 364–370. http://doi.org/10.1111/j.1526-4610.2007.00727.x
8. Vecchia, D., & Pietrobon, D. (2012). Migraine: a disorder of brain excitatory-inhibitory balance? Trends in Neurosciences, 35(8), 507–520. http://doi.org/10.1016/j.tins.2012.04.007
9. Brighina, F., Palermo, A., Panetta, M. L., Daniele, O., Aloisio, A., Cosentino, G., & Fierro, B. (2009). Reduced cerebellar inhibition in migraine with aura: a TMS study. Cerebellum (London, England), 8(3), 260–266. http://doi.org/10.1007/s12311-008-0090-4
10. Mainero, C., & Louapre, C. (2014). Migraine and inhibitory system - I can't hold it! Current Pain and Headache Reports, 18(7), 426. http://doi.org/10.1007/s11916-014-0426-3
11. Mainero, C., Boshyan, J., & Hadjikhani, N. (2011). Altered functional magnetic resonance imaging resting-state connectivity in periaqueductal gray networks in migraine. Annals of Neurology, 70(5), 838–845. http://doi.org/10.1002/ana.22537
12. Boyer, N., Dallel, R., Artola, A., & Monconduit, L. (2014). General trigeminospinal central sensitization and impaired descending pain inhibitory controls contribute to migraine progression. Pain, 155(7), 1196–1205. http://doi.org/10.1016/j.pain.2014.03.001
13. Lim, M., Roosink, M., Kim, J. S., Kim, D. J., Kim, H. W., Lee, E. B., et al. (2015). Disinhibition of the primary somatosensory cortex in patients with fibromyalgia. Pain, 156(4), 666–674. http://doi.org/10.1097/j.pain.0000000000000096
14. Mhalla, A., de Andrade, D. C., Baudic, S., Perrot, S., & Bouhassira, D. (2010). Alteration of cortical excitability in patients with fibromyalgia. Pain, 149(3), 495–500. http://doi.org/10.1016/j.pain.2010.03.009
15. Lim, M., Roosink, M., Kim, J. S., Kim, D. J., Kim, H. W., Lee, E. B., et al. (2015). Disinhibition of the primary somatosensory cortex in patients with fibromyalgia. Pain, 156(4), 666–674. http://doi.org/10.1097/j.pain.0000000000000096
16. Julien, N., Goffaux, P., Arsenault, P., & Marchand, S. (2005). Widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition. Pain, 114(1-2), 295–302. http://doi.org/10.1016/j.pain.2004.12.032
17. Jensen, K. B., Kosek, E., Petzke, F., Carville, S., Fransson, P., Marcus, H., et al. (2009). Evidence of dysfunctional pain inhibition in Fibromyalgia reflected in rACC during provoked pain. Pain, 144(1-2), 95–100. http://doi.org/10.1016/j.pain.2009.03.018
18. Chalaye, P., Goffaux, P., Bourgault, P., Lafrenaye, S., Devroede, G., Watier, A., & Marchand, S. (2012). Comparing pain modulation and autonomic responses in fibromyalgia and irritable bowel syndrome patients. The Clinical Journal of Pain, 28(6), 519–526. http://doi.org/10.1097/AJP.0b013e31823ae69e
19. Piché, M., Arsenault, M., Poitras, P., Rainville, P., & Bouin, M. (2010). Widespread hypersensitivity is related to altered pain inhibition processes in irritable bowel syndrome. Pain, 148(1), 49–58. http://doi.org/10.1016/j.pain.2009.10.005
20. King, C. D., Wong, F., Currie, T., Mauderli, A. P., Fillingim, R. B., & Riley, J. L. (2009). Deficiency in endogenous modulation of prolonged heat pain in patients with Irritable Bowel Syndrome and Temporomandibular Disorder. Pain, 143(3), 172–178. http://doi.org/10.1016/j.pain.2008.12.027
21. López-Solà, M., Woo, C.-W., Pujol, J., Deus, J., Harrison, B. J., Monfort, J., & Wager, T. D. (2017). Towards a neurophysiological signature for fibromyalgia. Pain, 158(1), 34–47. http://doi.org/10.1097/j.pain.0000000000000707
22. Coppola, G., Di Renzo, A., Tinelli, E., Lepre, C., Di Lorenzo, C., Di Lorenzo, G., et al. (2016). Thalamo-cortical network activity between migraine attacks: Insights from MRI-based microstructural and functional resting-state network correlation analysis. J Headache Pain, 17(1), 65–9. http://doi.org/10.1186/s10194-016-0693-y
23. Coppola, G., Bracaglia, M., Di Lenola, D., Iacovelli, E., Di Lorenzo, C., Serrao, M., et al. (2015). Lateral inhibition in the somatosensory cortex during and between migraine without aura attacks: Correlations with thalamocortical activity and clinical features. Cephalalgia, 1–11. http://doi.org/10.1177/0333102415610873
24. Harriott, A. M., & Schwedt, T. J. (2014). Migraine is associated with altered processing of sensory stimuli. Current Pain and Headache Reports, 18(11), 458. http://doi.org/10.1007/s11916-014-0458-8
25. Gilbert, D. L., Isaacs, K. M., Augusta, M., Macneil, L. K., & Mostofsky, S. H. (2011). Motor cortex inhibition: a marker of ADHD behavior and motor development in children. Neurology, 76(7), 615–621. http://doi.org/10.1212/WNL.0b013e31820c2ebd
26. Shaw, P., Lalonde, F., Lepage, C., Rabin, C., Eckstrand, K., Sharp, W., et al. (2009). Development of cortical asymmetry in typically developing children and its disruption in attention-deficit/hyperactivity disorder. Archives of General Psychiatry, 66(8), 888–896. http://doi.org/10.1001/archgenpsychiatry.2009.103
27. Lorenzen, A., Scholz-Hehn, D., Wiesner, C. D., Wolff, S., Bergmann, T. O., van Eimeren, T., et al. (2016). Chemosensory processing in children with attention-deficit/hyperactivity disorder. Journal of Psychiatric Research, 76, 121–127. http://doi.org/10.1016/j.jpsychires.2016.02.007
28. Parisi, P., Verrotti, A., Paolino, M. C., Ferretti, A., Raucci, U., Moavero, R., et al. (2014). Headache and attention deficit and hyperactivity disorder in children: Common condition with complex relation and disabling consequences. Epilepsy & Behavior, 32, 72–75. http://doi.org/10.1016/j.yebeh.2013.12.028
29. Paolino, M. C., Ferretti, A., Villa, M. P., & Parisi, P. (2015). Headache and ADHD in Pediatric Age: Possible Physiopathological Links. Current Pain and Headache Reports, 19(7), 25–7. http://doi.org/10.1007/s11916-015-0494-z
30. Llop, S. M., Frandsen, J. E., Digre, K. B., Katz, B. J., Crum, A. V., Zhang, C., & Warner, J. E. A. (2016). Increased prevalence of depression and anxiety in patients with migraine and interictal photophobia. J Headache Pain, 17(1), 3838–7. http://doi.org/10.1186/s10194-016-0629-6
31. Lee, J., Lin, R. L., Garcia, R. G., Kim, J., Kim, H., Loggia, M. L., et al. (2016). Reduced insula habituation associated with amplification of trigeminal brainstem input in migraine. Cephalalgia. http://doi.org/10.1177/0333102416665223
32. Brighina, F., Palermo, A., & Fierro, B. (2009). Cortical inhibition and habituation to evoked potentials: relevance for pathophysiology of migraine. The Journal of Headache and Pain, 10(2), 77–84. http://doi.org/10.1007/s10194-008-0095-x
33. Akhondzadeh, S., Mohammadi, M. R., & Momeni, F. (2005). Passiflora incarnata in the treatment of attention-deficit hyperactivity disorder in children and adolescents. Therapy, 2(4), 609–614. http://doi.org/10.1586/14750708.2.4.609
34. Anheyer, D., Lauche, R., Schumann, D., Dobos, G., & Cramer, H. (2017). Herbal medicines in children with attention deficit hyperactivity disorder (ADHD): A systematic review. Complementary Therapies in Medicine, 30, 14–23. http://doi.org/10.1016/j.ctim.2016.11.004
35. le Grand, S. M., Patumraj, S., Phansuwan-Pujito, P., & Srikiatkhachorn, A. (2006). Melatonin inhibits cortical spreading depression-evoked trigeminal nociception. Neuroreport, 17(16), 1709–1713. http://doi.org/10.1097/WNR.0b013e3280101207
36. Gelfand, A. A., & Goadsby, P. J. (2016). The Role of Melatonin in the Treatment of Primary Headache Disorders. Headache, 56(8), 1257–1266. http://doi.org/10.1111/head.12862
37. Peres, M. F. P. (2011). Melatonin for migraine prevention. Current Pain and Headache Reports, 15(5), 334–335. http://doi.org/10.1007/s11916-011-0219-x
38. Miano, S., Parisi, P., Pelliccia, A., Luchetti, A., Paolino, M. C., & Villa, M. P. (2008). Melatonin to prevent migraine or tension-type headache in children. Neurological Sciences, 29(4), 285–287. http://doi.org/10.1007/s10072-008-0983-5
39. Peres, M. F. P., Masruha, M. R., Zukerman, E., Moreira-Filho, C. A., & Cavalheiro, E. A. (2006). Potential therapeutic use of melatonin in migraine and other headache disorders. Expert Opinion on Investigational Drugs, 15(4), 367–375. http://doi.org/10.1517/13543784.15.4.367
40. Peres, M. F. P., Zukerman, E., da Cunha Tanuri, F., Moreira, F. R., & Cipolla-Neto, J. (2004). Melatonin, 3 mg, is effective for migraine prevention. Neurology, 63(4), 757
41. Merrick, L., Youssef, D., Tanner, M., & Peiris, A. N. (2014). Does melatonin have therapeutic use in tinnitus? Southern Medical Journal, 107(6), 362–366. http://doi.org/10.14423/01.SMJ.0000450714.38550.d4
42. Lu, W. Z., Gwee, K. A., Moochhalla, S., & Ho, K. Y. (2005). Melatonin improves bowel symptoms in female patients with irritable bowel syndrome: a double-blind placebo-controlled study. Alimentary Pharmacology and Therapeutics, 22(10), 927–934. http://doi.org/10.1111/j.1365-2036.2005.02673.x
43. Di Lorenzo, C., Coppola, G., Bracaglia, M., Di Lenola, D., Evangelista, M., Sirianni, G., et al. (2016). Cortical functional correlates of responsiveness to short-lasting preventive intervention with ketogenic diet in migraine: a multimodal evoked potentials study. J Headache Pain, 17(1), 493–10. http://doi.org/10.1186/s10194-016-0650-9
44. Brighina, F., Piazza, A., Vitello, G., Aloisio, A., Palermo, A., Daniele, O., & Fierro, B. (2004). rTMS of the prefrontal cortex in the treatment of chronic migraine: a pilot study. Journal of the Neurological Sciences, 227(1), 67–71. http://doi.org/10.1016/j.jns.2004.08.008
45. Kalita, J., Bhoi, S. K., & Misra, U. K. (2016). Effect of high rate rTMS on somatosensory evoked potential in migraine. Cephalalgia. http://doi.org/10.1177/0333102416675619
46. Fagerlund, A. J., Hansen, O. A., & Aslaksen, P. M. (2015). Transcranial direct current stimulation as a treatment for patients with fibromyalgia: a randomized controlled trial. Pain, 156(1), 62–71. http://doi.org/10.1016/j.pain.0000000000000006
47. Kuo MF, Paulus W, Nitsche MA (2014). Therapeutic effects of non-invasive brain stimulation with direct currents (tDCS) in neuropsychiatric diseases. Neuroimage 85(Pt 3):948–960. doi:10.1016/j.neuroimage.2013.05.117
48. Soff, C., Sotnikova, A., Christiansen, H., Becker, K., & Siniatchkin, M. (2017). Transcranial direct current stimulation improves clinical symptoms in adolescents with attention deficit hyperactivity disorder. Journal of Neural Transmission, 124(1), 133–144. http://doi.org/10.1007/s00702-016-1646-y
49. McGough, J. J., Loo, S. K., Sturm, A., Cowen, J., Leuchter, A. F., & Cook, I. A. (2015). An eight-week, open-trial, pilot feasibility study of trigeminal nerve stimulation in youth with attention-deficit/hyperactivity disorder. Brain Stimulation, 8(2), 299–304. http://doi.org/10.1016/j.brs.2014.11.013
50. Lee, J., Lin, R. L., Garcia, R. G., Kim, J., Kim, H., Loggia, M. L., et al. (2016). Reduced insula habituation associated with amplification of trigeminal brainstem input in migraine. Cephalalgia. http://doi.org/10.1177/0333102416665223
51. Haavik, H., & Murphy, B. (2012). The role of spinal manipulation in addressing disordered sensorimotor integration and altered motor control. Journal of Electromyography and Kinesiology, 22(5), 768–776. http://doi.org/10.1016/j.jelekin.2012.02.012
52. Gay, C. W., Robinson, M. E., George, S. Z., Perlstein, W. M., & Bishop, M. D. (2014). Immediate changes after manual therapy in resting-state functional connectivity as measured by functional magnetic resonance imaging in participants with induced low back pain. Journal of Manipulative and Physiological Therapeutics, 37(9), 614–627. http://doi.org/10.1016/j.jmpt.2014.09.001
53. Aguirrebeña, I. L., Newham, D., & Critchley, D. J. (2016). Mechanism of Action of Spinal Mobilizations. Spine, 41(2), 159–172. http://doi.org/10.1097/BRS.0000000000001151
54. Savva, C., Giakas, G., & Efstathiou, M. (2014). The role of the descending inhibitory pain mechanism in musculoskeletal pain following high-velocity, low amplitude thrust manipulation. A review of the literature. Journal of Back and Musculoskeletal Rehabilitation. http://doi.org/10.3233/BMR-140472
55. Krummenacher, P., Candia, V., Folkers, G., Schedlowski, M., & Schönbächler, G. (2010). Prefrontal cortex modulates placebo analgesia. Pain, 148(3), 368–374. http://doi.org/10.1016/j.pain.2009.09.033
56. Van Oosterwijck, J., Meeus, M., Paul, L., De Schryver, M., Pascal, A., Lambrecht, L., & Nijs, J. (2013). Pain Physiology Education Improves Health Status and Endogenous Pain Inhibition in Fibromyalgia: A Double-Blind Randomized Controlled Trial. The Clinical Journal of Pain. http://doi.org/10.1097/AJP.0b013e31827c7a7d