Tag Archives: neurology

MIGRAINE AND DEPRESSION: It’s All The Same Brain – Gale Scott * Migraine May Permanently Change Brain Structure – American Academy of Neurology * Migraine: Multiple Processes, Complex Pathophysiology – Rami Burstein, Rodrigo Noseda, and David Borsook.

The symptoms that accompany migraine suggest that multiple neuronal systems function abnormally. Neuroimaging studies show that brain networks, brain morphology, and brain chemistry are altered in episodic and chronic migraineurs. As a consequence of the disease itself or its genetic underpinnings, the migraine brain is altered structurally and functionally.

Migraine tends to run in families and as such is considered a genetic disorder. Genetic predisposition to migraine resides in multiple susceptible gene variants, many of which encode proteins that participate in the regulation of glutamate neurotransmission and proper formation of synaptic plasticity.

Migraine is a leading cause of suicide, an indisputable proof of the severity of the distress that the disease may inflict on the individual. 40% of migraine patients are also depressed.

Migraine and Depression: It’s All The Same Brain

Gale Scott

When a patient suffers from both migraines and depression or other psychiatric comorbidities, physicians have to treat both. It’s a common situation, since 40% of migraine patients are also depressed. Anxiety is even more prevalent in these patients. An estimated 50% of migraine patients are anxious whether with generalized anxiety, phobias, panic attacks. or other forms of anxiety, said Mia Minen, MD Director of Headache Services at NYU Langoni Medical Center.

Health care costs in treating these co-morbid patients are 1.5 times higher than for migraine patients without accompanying psychiatric disorders.

But sorting out whether one problem is causing the other is not always easy, she said in a recent interview at NYU Langone. “it’s really interesting, which came first,” she said, “We really don’t know.”

There may be a bidirectional relationship with depression. Anxiety may precede migraines, then depression may follow.

Fortunately, she said, the question of which problem came first doesn’t really matter that much.

“It’s all one brain, one organ, and some of the same neurotransmitters are implicated in both disorders.” Serotonin is affected in migraine just as it is in depression and anxiety, she said. Dopamine and norepinephrine are also related both to migraines and psychiatric comorbidities.

“So it’s really one organ that’s controlling all these things,” Minen said.

The first step in treatment is having patients keep a headache diary to track the intensity and frequency and what they take when they feel it coming on.

For a mild migraine that might be ibuprofen or another over-the-counter pain killer.

If the migraine is moderately severe there are 7 migraine-specifuc medications that are effective, she said. There are oral, nasal, and injectable forms of triptans a family of tryptamine-based drugs. “We sometimes tell patients to combine the triptan with Naprosyn,” she said.

If triptans are contraindicated because the patient has other health problems, there are still more pharmaceutical options.

Those include some classes of beta blockers, antiseizure medications, and tricyclic antidepressants at low doses.

The drug regimen may vary with the particular comorbidity. For instance, for migraines with anxiety, venlafaxine might work. If patients have sleep disturbances, amitriptyline might be effective. “Lack of sleep is also a trigger for migraine,” she noted.

The toughest co-morbidity to treat in patients with migraine is finding a regimen that works for patients who are taking a lot of psychiatric medications, like SSRIs and antipsychotics.

For older patients with migraines plus cardiovascular disease, drug choices are also limited.

Botox injections seem promising, but Minen is cautious. “It’s a great treatment for patients with chronic migraines but they have to have failed 2 or 3 medications before they qualify for Botox.” Treatment involves 31 injections over the forehead, the back of the head and the neck. Relief lasts about 3 months, she said.

In addition to pharmaceutical treatment, there are cognitive behavior approaches that can work, like biofeedback and progressive muscle relaxation therapy.

Opioids are not the treatment of choice, she said. They have not been shown to be effective, Minen said and reduce the body’s ability to respond to triptans.

“For chronic migraine, studies don’t show opioids enable patients to return to work; there is no objective study showing they work,” and their uses raises other problems. Patients used to taking opioids who go to an emergency room and request them may find themselves suspected of drugseeking behavior. “It’s hard for doctors and patients,” she said, when patients ask for opioids “It puts doctors in a predicament.”

New drugs are on the horizon, she said. “Calcitonin gene related peptide antagonists look good,” and unlike triptans are not contraindicated for people at risk of strokes or heart attacks.

For now, said Minen, treating migraine and comorbidities “is more an art than a science,” she said, “But a large majority of patients do get better.”

Migraine May Permanently Change Brain Structure

American Academy of Neurology

Migraine may have longlasting effects on the brain’s structure, according to a study published in the August 28, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“Traditionally, migraine has been considered a benign disorder without long-term consequences for the brain,” said study author Messoud Ashina, MD, PhD, with the University of Copenhagen in Denmark. “Our review and meta-analysis study suggests that the disorder may permanently alter brain structure in multiple ways.”

The study found that migraine raised the risk of brain lesions, white matter abnormalities and altered brain volume compared to people without the disorder. The association was even stronger in those with migraine with aura.

Migraine with aura
A common type of migraine featuring additional neurological symptoms. Aura is a term used to describe a neurological symptom of migraine, most commonly visual disturbances.
People who experience ‘migraine with aura’ will have many or all the symptoms of a ‘migraine without aura‘ and additional neurological symptoms which develop over a 5 to 20 minute period and last less than an hour.
Visual disturbances can include: blind spots in the field of eyesight, coloured spots, sparkles or stars, flashing lights before the eyes, tunnel vision, zig zag lines, temporary blindness.
Other symptoms include: numbness or tingling, pins and needles in the arms and legs, weakness on one side of the body, dizziness, a feeling of spinning (vertigo).
Speech and hearing can be affected and some people have reported memory changes, feelings of fear and confusion and, more rarely, partial paralysis or fainting.
These neurological symptoms usually happen before a headache, which could be mild, or no headache may follow.

For the meta-analysis, researchers reviewed six population-based studies and 13 clinic-based studies to see whether people who experienced migraine or migraine with aura had an increased risk of brain lesions, silent abnormalities or brain volume changes on MRI brain scans compared to those without the conditions.

The results showed that migraine with aura increased the risk of white matter brain lesions by 68 percent and migraine with no aura increased the risk by 34 percent, compared to those without migraine. The risk for infarct-like abnormalities increased by 44 percent for those without aura. Brain volume changes were more common in people with migraine and migraine with aura than those with no migraines.

“Migraine affects about 10 to 15 percent of the general population and can cause a substantial personal, occupational and social burden,” said Ashina. “We hope that through more study, we can clarify the association of brain structure changes to attack frequency and length of the disease. We also want to find out how these lesions may influence brain function.”

The study was supported by the Lundbeck Foundation and the Novo Nordisk Foundation.

To learn more about migraine, please visit American Academy of Neurology.

Migraine: Multiple Processes, Complex Pathophysiology

Rami Burstein (1,3), Rodrigo Noseda (1,3) and David Borsook (2,3)
1 – Department of Anesthesia, Critical Care, and Pain Medicine, Beth Israel Deaconess Medical Center, Boston
2 – Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children’s Hospital
3 – Harvard Medical School

Migraine is a common, multifactorial, disabling, recurrent, hereditary neurovascular headache disorder. It usually strikes sufferers a few times per year in childhood and then progresses to a few times per week in adulthood, particularly in females. Attacks often begin with warning signs (prodromes) and aura (transient focal neurological symptoms) whose origin is thought to involve the hypothalamus, brainstem, and cortex.

Once the headache develops, it typically throbs, intensifies with an increase in intracranial pressure, and presents itself in association with nausea, vomiting, and abnormal sensitivity to light, noise, and smell. It can also be accompanied by abnormal skin sensitivity (anodynia) and muscle tenderness.

Collectively, the symptoms that accompany migraine from the prodromal stage through the headache phase suggest that multiple neuronal systems function abnormally.

As a consequence of the disease itself or its genetic underpinnings, the migraine brain is altered structurally and functionally. These molecular, anatomical, and functional abnormalities provide a neuronal substrate for an extreme sensitivity to fluctuations in homeostasis, a decreased ability to adapt, and the recurrence of headache.

Homeostasis is the state of steady internal conditions maintained by living things.

Advances in understanding the genetic predisposition to migraine, and the discovery of multiple susceptible gene variants (many of which encode proteins that participate in the regulation of glutamate neurotransmission and proper formation of synaptic plasticity) define the most compelling hypothesis for the generalized neuronal hyperexcitability and the anatomical alterations seen in the migraine brain.

Regarding the headache pain itself, attempts to understand its unique qualities point to activation of the trigeminovascular pathway as a prerequisite for explaining why the pain is restricted to the head, often affecting the periorhital area and the eye, and intensities when intracranial pressure increases.


Migraine is a recurrent headache disorder affecting 15% of the population during the formative and most productive periods of their lives, between the ages of 22 and 55 years. It frequently starts in childhood, particularly around puberty, and affects women more than men.

It tends to run in families and as such is considered a genetic disorder.

In some cases, the headache begins with no warning signs and ends with sleep. In other cases, the headache may be preceded by a prodromal phase that includes fatigue; euphoria; depression; irritability; food cravings; constipation; neck stiffness; increased yawning; and/or abnormal sensitivity to light, sound, and smell and an aura phase that includes a variety of focal cortically mediated neurological symptoms that appear just before and/or during the headache phase. Symptoms of migraine aura develop gradually, feature exeitatory and inhibitory phases, and resolve completely. Positive (gain of function) and negative (loss of function) symptoms may present as scintillating lights and scotomas when affecting the visual cortex; paresthesia, and numbness of the face and hands when affecting the somatosensory cortex; tremor and unilateral muscle weakness when affecting the motor cortex or basal ganglia; and difficulty saying words (aphasia) when affecting the speech area.

The pursuant headache is commonly unilateral, pulsating, aggravated by routine physical activity, and can last a few hours to a few days (Headache Classification Committee of the International Headache Society, 2013). As the headache progresses, it may be accompanied by a variety of autonomic symptoms (nausea, vomiting, nasallsinus congestion, rhinorrhea, lacrimation, ptosis, yawning, frequent urination, and diarrhea), affective symptoms (depression and irritability), cognitive symptoms (attention deficit, difficulty finding words, transient amnesia, and reduced ability to navigate in familiar environments), and sensory symptoms (photophobia, phonophobia, osmophobia, muscle tenderness, and cutaneous allodynia).

The extent of these diverse symptoms suggests that migraine is more than a headache. It is now viewed as a complex neurological disorder that affects multiple cortical, subcortical, and brainstem areas that regulate autonomic, affective, cognitive, and sensory functions. As such, it is evident that the migraine brain differs from the non-migraine brain and that an effort to unravel the pathophysiology of migraine must expand beyond the simplistic view that there are “migraine generator” areas.

In studying migraine pathophysiology, we must consider how different neural networks interact with each other to allow migraine to commence with stressors such as insufficient sleep, skipping meals, stressful or post stressful periods, hormonal fluctuations, alcohol, certain foods, flickering lights, noise, or certain scents, and why migraine attacks are sometimes initiated by these triggers and sometimes not.

We must tackle the enigma of how attacks are resolved on their own or just weaken and become bearable by sleep, relaxation, food, and/or darkness. We must explore the mechanisms by which the frequency of episodic migraine increases over time (from monthly to weekly to daily), and why progression from episodic to chronic migraine is uncommon.

Disease mechanisms

In many cases, migraine attacks are likely to begin centrally, in brain areas capable of generating the classical neurological symptoms of prodromes and aura, whereas the headache phase begins with consequential activation of meningeal nociceptors at the origin of the trigeminovascular system.

A nociceptor is a sensory neuron that responds to damaging or potentially damaging stimuli by sending “possible threat” signals to the spinal cord and the brain. If the brain perceives the threat as credible, it creates the sensation of pain to direct attention to the body part, so the threat can hopefully be mitigated; this process is called nociception.

The meninges are the three membranes that envelop the brain and spinal cord. In mammals, the meninges are the dura mater, the arachnoid mater, and the pia mater. Cerebrospinal fluid is located in the subarachnoid space between the arachnoid mater and the pia mater. The primary function of the meninges is to protect the central nervous system.

While some clues about how the occurrence of aura can activate nociceptors in the meninges exist, nothing is known about the mechanisms by which common prodromes initiate the headache phase or what sequence of events they trigger that results in activation of the meningeal nociceptors. A mechanistic search for a common denominator in migraine symptomatology and characteristics points heavily toward a genetic predisposition to generalized neuronal hyperexcitability. Mounting evidence for alterations in brain structure and function that are secondary to the repetitive state of headache can explain the progression of disease.


In the context of migraine, prodromes are symptoms that precede the headache by several hours. Examination of symptoms that are most commonly described by patients point to the potential involvement of the hypothalamus (fatigue, depression, irritability, food cravings, and yawning), brainstem (muscle tenderness and neck stiffness), cortex (abnormal sensitivity to light, sound, and smell), and limbic system (depression and anhedonia) in the prodromal phase of a migraine attack. Given that symptoms such as fatigue, yawning, food craving, and transient mood changes occur naturally in all humans, it is critical that we understand how their occurrence triggers a headache; whether the routine occurrence of these symptoms in migraineurs (i.e., when no headache develops) differs mechanistically from their occurrence before the onset of migraine; and why yawning, food craving, and fatigue do not trigger a migraine in healthy subjects.

Recently, much attention has been given to the hypothalamus because it plays a key role in many aspects of human circadian rhythms (wake sleep cycle, body temperature, food intake, and hormonal fluctuations) and in the continuous effort to maintain homeostasis. Because the migraine brain is extremely sensitive to deviations from homeostasis, it seems reasonable that hypothalamie neurons that regulate homeostasis and circadian cycles are at the origin of some of the migraine prodromes.

Unraveling the mechanisms by which hypothalamic and brainstem neurons can trigger a headache is central to our ability to develop therapies that can intercept the headache during the prodromal phase (i.e., before the headache begins. The ongoing effort to answer this question focuses on two very different possibilities (Fig. 1). The first suggests that hypothalamic neurons that respond to changes in physiological and emotional homeostasis can activate meningeal nociceptors by altering the balance between parasympathetic and sympathetic tone in the meninges toward the predominance of parasympathetic tone. Support for such a proposal is based on the following: (1) hypothalamic neurons are in a position to regulate the firing of preganglionic parasympathetic neurons in the superior salivatory nucleus (SSN) and sympathetic preganglionic neurons in the spinal intermediolateral nucleus. (2) the SSN can stimulate the release of acetylcholine, vasoactive intestinal peptide, and nitric oxide from meningeal terminals of postganglionic parasympathetic neurons in the Spheno palatine ganglion (SPG), leading to dilation of intracranial blood vessels, plasma protein extravasation, and local release of inflammatory molecules capable of activating pial and dural branches of meningeal nociceptors; (3) meningeal blood vessels are densely innervated by para sympathetic fibers. (4) activation of SSN neurons can modulate the activity of central trigeminovascular neurons in the spinal trigeminal nucleus. (5) activation of meningeal nociceptors appears to depend partially on enhanced activity in the SPG. (6) enhanced cranial parasympathetic tone during migraine is evident by lacrimation and nasal congestion, and, finally, (7) blockade of the sphenopalatine ganglion provides partial or complete relief of migraine pain.

The second proposal suggests that hypothalamic and brainstem neurons that regulate responses to deviation from physiological and emotional homeostasis can lower the threshold for the transmission of nociceptive trigeminovascular signals from the thalamus to the cortex, a critical step in establishing the headache experience. This proposal is based on understanding how the thalamus selects, amplifies, and prioritizes information it eventually transfers to the cortex, and how hypothalamic and brainstem nuclei regulate relay thalamocortical neurons. It is constructed from recent evidence that relay trigeminothalamic neurons in sensory thalamie nuclei receive direct input from hypothalamic neurons that contain dopamine, histamine, orexin, and melanin concentrating hormone (MCH), and brainstem neurons that contain noradrenaline and serotonin. In principle, each of these neuropeptides/neurotransmitters can shift the activity of thalamic neurons from burst to tonic mode if it is excitatory (dopamine, and high concentration of serotonin, noradrenaline, histamine, orexin, and from tonic to burst mode if it is inhibitory (MCH and low concentration of serotonin). The opposing factors that regulate the firing of relay trigeminovascular thalamic neurons provide an anatomical foundation for explaining why prodromes give rise to some migraine attacks but not to others, and why external (e.g., exposure to strong perfume) and internal conditions (e.g., skipping a meal and feeling hungry, sleeping too little and being tired, or simple stress) trigger migraine attacks so inconsistently.

In the context of migraine, the convergence of these hypothalamic and brainstem neurons on thalamic trigeminovascular neuruns can establish high and low set points for the allostatic load of the migraine brain. The allostatic load, defined as the amount of brain activity required to appropriately manage the level of emotional or physiological stress at any given time, can explain why external and internal conditions only trigger headache some of the times, when they coincide with the right circadian phase of cyclic rhythmicity of brainstem, and hypothalamic and thalamic neurons that preserve homeostasis.

Cortical spreading depression

Clinical and preclinical studies suggest that migraine aura is caused by cortical spreading depression (CSD), a slowly propagating wave of depolarization/excitation followed by hyperpolarization/inhibition in cortical neurons and glia. While specific processes that initiate CSD in humans are not known, mechanisms that invoke inflammatory molecules as a result of emotional or physiological stress, such as lack of sleep, may play a role. In the cortex, the initial membrane depolarization is associated with a large efflux of potassium; influx of sodium and calcium; release of glutamate, ATP, and hydrogen ions; neuronal swelling ; upregulation of genes involved in inflammatory processing; and a host of changes in cortical perfusion and enzymatic activity that include opening of the megachannel Panxl, activation of caspase-1, and a breakdown of the blood brain barrier.

Outside the brain, caspase-1 activation can initiate inflammation by releasing high mobility group protein B1 and interleukin-1 into the CSF, which then activates nuclear factor KB in astrocytes, with the consequential release of cyclooxygenase-2 and inducible nitric oxide swithase (iNOS) into the subarach noid space. The introduction into the meninges of these proinflammatory molecules, as well as calcitonin gene related peptide (CGRP) and nitric oxide, may be the link between aura and headache because the meninges are densely innervated by pain fibers whose activation distinguishes headaches of intracranial origin (e.g., migraine, meningitis, and subaraeh noid bleeds) from headaches of extracranial origin (e.g., tension type headache, cervicogenic headache, or headaches caused by mild trauma to the cranium).

Anatomy and physiology of the trigeminovascular pathway: from activation to sensitization

Anatomical description

The trigeminovascular pathway conveys nociceptive information from the meninges to the brain. The pathway originates in trigeminal ganglion neurons whose peripheral axons reach the pia, dura, and large cerebral arteries, and whose central axons reach the nociceptive dorsal horn laminae of the SpV. In the SpV, the nociceptors converge on neurons that receive additional input from the periorbital skin and pericranial muscles. The ascending axonal projections of trigeminovascular SpV neurons transmit monosynaptic nocieeptive signals to (1) brainstem nuclei, such as the ventro lateral periaqueductal gray, reticular for mation, superior salivatory, parabrachial, cuneiform, and the nucleus of the solitary tract; (2) hypothalamic nuclei, such as the anterior, lateral, perifornical, dorsome dial, suprachiasmatic, and supraoptic; and (3) basal ganglia nuclei, such as the caudate putamen, globus pallidus, and sub stantia innominata. These projections maybe critical for the initiation of nausea, vomiting, yawning, lacrimation, urination, loss of appetite, fatigue, anxiety, irritability, and depression by the headache itself.

Additional projections of trigeminovascular SpV neurons are found in the thalamic ventral posteromedial (VPM), posterior (PO), and parafascicular nuclei. Relay trigeminovascular thalamic neurons that project to the somatosensory, insular, motor, parietal association, retrosplenial, auditory, visual, and olfactory cortices are in a position to construct the specific nature of migraine pain (i.e., location, intensity, and quality) and many of the cortically mediated symptoms that distinguish between migraine headache and other pains. These include transient symptoms of motor clumsiness, difficulty focusing, amnesia, allodynia, phonophobia, photophobia, and osmophobia. Figure 2A illustrates the complexity of the trigeminovascular pathway.


Studies in animals show that CSD initiates delayed activation (Fig. 2D, 2B,C) and immediate activation (Fig. 2D) of peripheral and central trigeminovascular neurons in a fashion that resembles the classic delay and occasional immediate onset of headache after aura, and that systemic administration of the M type potassium channel opener KCNQ2/3 can prevent the CSD induced activation of the nociceptors.

These findings support the notion that the onset of the headache phase of migraine with aura coincides with the activation of meningeal nociceptors at the peripheral origin of the trigeminovascular pathway. Whereas the vascular, cellular, and molecular events involved in the activation of meningeal nocieeptors by CSD are not well under stood, a large body of data suggests that transient constriction and dilatation of pial arteries and the development of dural plasma protein extravasation, neurogenic inflammation, platelet aggregation, and mast cell degranulation, many of which may be driven by CSD dependent peripheral CGRP release, can introduce to the meninges proinflammatory molecules, such as histamine, bradykinin, serotonin, and prostaglandins (prostaglandin E2), and a high level of hydrogen ions thus altering the molecular environment in which meningeal nociceptors exist.


When activated in the altered molecular environment described above, peripheral trigeminovascular neurons become sensitized (their response threshold decreases and their response magnitude increases) and begin to respond to dura stimuli to which they showed minimal or no response at base line. When central trigeminovascular neurons in laminae I and V of SpV (Fig. 2F) and in the thalamic PO/VPM nuclei (Fig. 2G) become sensitized, their spontaneous activity increases, their receptive fields expand, and they begin to respond to innocuous mechanical and thermal stimulation of cephalic and extracephalic skin areas as if it were noxious. The human correlates of the electrophysiological measures of neuronal sensitization in animal studies are evident in contrast analysis of BOLD signals registered in MRI scans of the human trigeminal ganglion (Fig. 2H), spinal trigeminal nucleus (Fig. 2I), and the thalamus (Fig. 2J), all measured during migraine attacks.

The clinical manifestation of peripheral sensitization during migraine, which takes roughly 10 mins to develop, includes the perception of throbbing headache and the transient intensiflcation of headache while bending over or coughing, activities that momentarily increase intracranial pressure.

The clinical manifestation of sensitization of central trigeminovascular neurons in the SpV, which takes 30-60 min to develop and 120 min to reach full extent, include the development of cephalic allodynia signs such as scalp and muscle tenderness and hypersensitivity to touch. These signs are often recognized in patients reporting that they avoid wearing glasses, earrings, hats, or any other object that come in contact with the facial skin during migraine.

The clinical manifestation of thalamic sensitization during migraine, which takes 2-4 h to develop, also includes extracephalic allodynia signs that cause patients to remove tight clothing and jewelry, and avoid being touched, massaged, or hugged.

Evidence that triptans, 5HT agonists that disrupt communications between peripheral and central trigeminovascular neurons in the dorsal horn, are more effective in aborting migraine when administered early (i.e., before the development of central sensitization and allodynia) rather than late (i.e., after the development of allodynia) provides further support for the notion that meningeal nociceptors drive the initial phase of the headache. Further support for this concept was provided recently by studies showing that humanized monoclonal antihodies against CGRP, molecules that are too big to penetrate the bloodbrain barrier and act centrally (according to the companies that developed them), are effective in preventing migraine. Along this line, it was also reported that drugs that act on central trigeminovascular neurons, e.g., dihydroergotamine (DHE), are equally effective in reversing an already developed central sensitization a possible explanation for DHE effectiveness in aborting migraine after the failure of therapy with triptans.

Genetics and the hyperexcitable brain

Family history points to a genetic predisposition to migraine. A genetic association with migraine was first observed and defined in patients with familial hemiplegic migraine (FHM).

The three genes identified with FHM encode proteins that regulate glutamate availability in the synapse. FHM1 (CACNAIA) encodes the pore-forming a1 subunit of the P/Q type calcium channel; FHM2 (ATP1A2) encodes the 112 subunit of the Na+/K+ ATPase pump; and the FHM3 (SCNIA) encodes the a1 sub unit of the neuronal voltage gated Nav1.1 channel.

Collectively, these genes regulate transmitter release, glial ability to clear (reuptake) glutamate from the synapse, and the generation of action potentials.

Since these early findings, large genome wide association studies have identified 13 susceptibility gene variants for migraine with and without aura, three of which regulate glutaminergic neurotransmission (MTDH/AEG-1 downregulates glutamate transporter, LPRI modulates synaptic transmission through the NMDA receptor, and MEF-2D regulates the glutamatergic excitatory synapse), and two of which regulate synaptic development and plasticity (ASTN2 is involved in the structural development of cortical layers, and FHI5 regulates cAMP sensitive CREB proteins involved msynaptic plasticity).

These findings provide the most plausible explanation for the “generalized” neuronal hyperexcitability of the migraine brain.

In the context of migraine, increased activity in glutamalergic systems can lead to excessive occupation of the NMDA receptor, which in turn may amplify and reinforce pain transmission, and the development of allodynia and central sensitization. Network wise, wide spread neuronal hyperexcitability may also be driven by thalamocortical dysrhythmia, defective modulatory brainstem circuits that regulate excitability at multiple levels along the neuraxis; and inherently improper regulation/habituation of cortical, thalamic, and brainstem functions by limbic structures, such as the hypothalamus, amygdala, nucleus accumbens, caudate, putamen, and globus pallidus. Given that 2 of the 13 susceptibility genes regulate synaptic development and plasticity, it is reasonable to speculate that some of the networks mentioned above may not be properly wired to set a normal level of habituation throughout the brain, thus explaining the multi factorial nature of migraine. Along this line, it is also tempting to propose that at least some of the structural alterations seen in the migraine brain may be inherited and, as such, may be the “cause” of migraine, rather than being secondary to (i.e., being caused by) the repeated headache attacks. But this concept awaits evidence.

Structural and functional brain alterations

Brain alterations can be categorized into the following two processes: (1) alteration in brain function and (2) alterations in brain structure (Fig. 3). Functionally, a variety of imaging techniques used to measure relative activation in different brain areas in migraineurs (vs control subjects) revealed enhanced activation in the periaqueductal gray; red nucleus and substantia nigra; hypothalamus; posterior thalamus; cerebellum, insula, cingulate and prefrontal cortices, anterior temporal pole, and the hippocampus; and decreased activation in the somatosensory cortex, nucleus cuneiformis, caudate, putamen, and pallidum. All of these activity changes occurred in response to nonrepetitive stimuli, and in the cingulate and prefrontal cortex they occurred in response to repetitive stimuli.

Collectively, these studies support the concept that the migraine brain lacks the ability to habituate itself and consequently becomes hyperexcitable. It is a matter of debate, however, if such changes are unique to migraine headache. Evidence for nearly identical activation patterns in other pain conditions, such as lower back pain, neuropathic pain, Hbromyalgia, irritable bowel syndrome, and cardiac pain, raises the possibility that differences between somatic pain and migraine pain are not due to differences in central pain processing.

Anatomically, voxel based morphometry and diffusion sensor imaging studies in migraine patients (vs control subjects) have revealed thickening of the somatosensory cortex; increased gray matter density in the caudate; and gray matter volume loss in the superior temporal gyms, inferior frontal gyms, precentral gyms, anterior cingulate cortex, amygdala, parietal operculum, middle and inferior frontal gyrus, inferior frontal gyrus, and bilateral insula.

Changes in cortical and subcortical structures may also depend on the frequency of migraine attacks for a number of cortical and subcortical regions. As discussed above, it is unclear whether such changes are genetically predetermined or simply a result of the repetitive exposure to pain/stress. Favoring the latter are studies showing that similar gray matter changes occurring in patients experiencing other chronic pain conditions are reversible and that the magnitude of these changes can be correlated with the duration of disease.

Further complicating our ability to determine how the migraine brain differs from the brain of a patient experiencing other chronic pain conditions are anatomical findings showing decreased gray matter density in the prefrontal cortex, thalamus, posterior insula, secondary somatosensory cortex, precentral and posteentral gyms, hippocampus, and temporal pole of chronic back pain patients; anterior insula and orbitofrontal cortex of complex regional pain syndrome patients; and the insula, midanterior cingulate cortex, hippocampus and inferior temporal coxtex in osteoarthritis pa tients with chronic back pain.

Whereas some of the brain alterations seen in migraineurs depend on the sex of the patient, little can he said about the role played by the sex of patients who experience other pain conditions.

Treatments in development

Migraine therapy has two goals: to terminate acute attacks; and to prevent the next attack from happening. The latter can potentially prevent the progression from episodic to chronic state. Regarding the effort to terminate acute attacks, migraine represents one of the few pain conditions for which a specific drug (i.e., triptan) has been developed based on understanding the mechanisms of the disease. In contrast, the effort to prevent migraine from happening is likely to face a much larger challenge given that migraine can originate in an unknown number of brain areas (see above), and is associated with generalized functional and structural brain abnormalities.

A number of treatments that attract attention are briefly reviewed below.

Medications The most exciting drug currently under development is humanized monoclonal antibodies against CGRP. The development of these monoclonal antibodies are directed at both CGRP and its receptors. The concept is based on CGRP localization in the trigeminal ganglion and its relevance to migaine patho-physiology. In recent phase II randomized placebo-controlled trials, the neutralizing humanized monoclonal antibodies against CGRP administered by injection for the prevention of episodic migraine, showed promising results. Remarkably, a single injection may prevent or significantly reduce migraine attacks for 3 months.

Given our growing understanding of the importance of prodromes (likely representing abnormal sensitivity to the fluctuation in hypothalamically regulated homeostasis) and aura (likely representing the inherited conical hyperexcitability) in the pathophysiology of migraine, drugs that target ghrelin, leptin, and orexin receptors may be considered for therapeutic development which is based on their ability to restore proper hypothalamic control of stress, hyperphagia, adiposity, and sleep. All may be critical in reducing allostatic load and, consequently, in initiating the next migraine attack.

Brain modification

Neuroimaging studies showing that brain networks, brain morphology, and brain chemistry are altered in episodic and chronic migraineurs justify attempts to develop therapies that widely modify brain networks and their functions. Transcranial magnetic stimulation, which is thought to modify cortical hyperexcitability, is one such approach. Another approach for generalized brain modification is cognitive behavioral therapy.


Migraine is a common and undertreated disease. For those who suffer, it is a major cause of disability, including missing work or school, and it frequently has associated comorbidities such as anxiety and depression. To put this in context, it is a leading cause of suicide, an indisputable proof of the severity of the distress that the disease may inflict on the individual.

There is currently no objective diagnosis or treatment that is universally effective in aborting or preventing attacks. As an intermittent disorder, migraine represents a neurological condition wherein systems that continuously evaluate errors (error detection) frequently fail, thus adding to the allostatic load of the disease.

Given the enormous burden to society, there is an urgent imperative to focus on better understanding the neurobiology of the disease to enable the discovery of novel treatment approaches.

LOOKING BACK FROM DEATH ROW. A Gunman’s Regret – R. Douglas Fields * Study: Violent aggression predicted by multiple pre-adult environmental hits – Molecular Psychiatry.

Alternative Title: Adverse Childhood Experiences cause Epigenetic changes in the developing young Brain, leading to mental illness, depression, anger management issues, violent crime, incarceration and a multi generational vicious cycle of hopelessness and despair.

With only 5 percent of the world’s population, the United States has 25 percent of the world’s prison population. Why?

This study is the first to provide sound evidence, based on 6 separate cohorts, of a disease independent relationship between accumulation of multifaceted pre-adult environmental hits and violent aggression.

The name “correctional facility” is accurate from society’s perspective, but it is a delusional euphemism from the perspective of most inmates. According to the National Institute of Justice, three quarters of prisoners will be rearrested within five years of their release.

We lock up 7.16 out of 1,000 people in the United States, the highest rate of incarceration in the world.

The explosion of senseless mass violence in places that were once society’s most cherished communal places, schools, concert stadiums, public transportation and even houses of worship, is ripping apart the social fabric of American life.

The roots of violence at the level of brain biology need to be understood so that violence can be prevented.

Researchers have found a high incidence of genetic factors that increase impulsivity and anger in the violent prison population, and also an increased incidence of neurological abnormalities detectable with brain imaging. Studies of twins show that heredity accounts for over 60 percent of the risk for aggression.

The perpetrators of violent crime are almost always male. Humans have evolved through the survival-of-the-fittest struggle in the wild, evolved brain and bodily attributes that equip and predispose them to engage in aggression to provide and protect. This biological drive in males for aggression still exists in modern civilization.

Changes in society and in traditional male roles must be accompanied by new approaches to channel male aggression positively.

This can be reached by a path guided by neuroscience. Males have this biology of aggression for a reason, but it must be adapted to our current environment.

A new study finds that exposure to certain adverse events in early life, while the brain is undergoing maturation, greatly multiplies the odds of being institutionalized as an adult for violent aggression. They include poverty, social rejection from peer groups, cannabis and alcohol abuse, living in an urban environment, traumatic brain injury, immigration, conflict and violence in the home, and physical or sexual abuse.

. . . Scientific American

Molecular Psychiatry: Study

Violent aggression predicted by multiple pre-adult environmental hits.

Early exposure to negative environmental impact shapes individual behavior and potentially contributes to any mental disease. We reported previously that accumulated environmental risk markedly decreases age at schizophrenia onset. Follow up of matched extreme group individuals unexpectedly revealed that high risk subjects had 5 times greater probability of forensic hospitalization.

In line with longstanding sociological theories, we hypothesized that risk accumulation before adulthood induces violent aggression and criminal conduct, independent of mental illness. We determined in 6 independent cohorts (4 schizophrenia and 2 general population samples) pre adult risk exposure, comprising urbanicity, migration, physical and sexual abuse as primary, and cannabis or alcohol as secondary hits. All single hits by themselves were marginally associated with higher violent aggression.

Most strikingly, however, their accumulation strongly predicted violent aggression. An epigenome wide association scan to detect differential methylation of blood-derived DNA of selected extreme group individuals yielded overall negative results. Conversely. detemination in peripheral blood mononuclear cells of histone deacetylasel mRNA as ‘umbrella mediator’ of epigenetic processes revealed an increase in the high risk group, suggesting lasting epigenetic alterations.

Together, we provide sound evidence of a disease independent unfortunate relationship between well defined pre adult environmental hits and violent aggression, calling for more efficient prevention.


Early exposure to external risk factors like childhood maltreatment, sexual abuse or head trauma, but also living in urban environment or migration from other countries and cultures, have long been known or suspected to exert adverse effects on individual development and socioeconomic functioning. Moreover, these environmental risk factors seem to contribute to abnormal behavior and to severity and onset of mental illness, even though different risk factors may have different impact, dependent on the particular neuropsychiatric disease in focus. On top of these ‘primary factors‘ that are rather inevitable for the affected, ‘secondary’, avoidable risks add to the negative individual and societal outcome, namely cannabis and alcohol abuse.

Adverse experiences in adulthood, like exposure to violence, traumatic brain injury, or substance intoxication, can act as single triggers to increase the short term risk of violence in mentally ill individuals as much as in control subjects.

However, comprehensive studies, including large numbers of individuals and replication cohorts, on pre-adult accumulation of environmental risk factors and their long term consequences on human behavior do not exist.

In a recent report we showed that accumulation of environmental risks leads to a nearly 10 year earlier schizophrenia onset, demonstrating the substantial impact of the environment on mental disease, which by far outlasted any common genetic effects. To search for epigenetic signatures in blood of carefully matched extreme group subjects of this previous study we had to re-contact them. This reconnect led to the unforeseen observation that high risk subjects had 5 times higher probability to be hospitalized in forensic units compared to low risk subjects.

This finding stimulated the present work: Having the longstanding concepts of sociologists and criminologists in mind, we hypothesized that early accumulation of environmenml risk factors would lead to increased violent aggression and social rule-breaking in affected individuals, independent of any mental illness. To test this hypothesis, we explored environmental risk before the age of 18 years in 4 schizophrenia samples of me GRAS (Göttingen Research Association for Schizophrenia) data collection. Likewise, risk factors were assessed as available in 2 general population samples.

In all cohorts, accumulation of pre-adult environmental hits was highly significantly associated with lifetime conviction for violent acts or high psychopathy and aggression hostility scores as proxies of violent aggression and rule breaking.

As a first small hint of epigenetic alterations in our high risk subjects, histone deacelylasel (HDACI) mRNA was found increased in peripheral blood mono nuclear cells (PBMC).

Fig. 1 Multiple environmental hits before adulthood predict violent aggression in mentally ill subjects as well as in the general population. Results from 6 independent samples.

a – Distribution of forensic hospitalization in the discovery sample (see results) suggested a substantial impact of environmental risk accumulation on violent aggression, a finding replicated in the remaining GRAS sample (GRAS I males and females minus extreme group subjects of the discovery sample). Note the ‘stair pattem’ upon stepwise increase in risk factors; stacked charts illustrate risk factor composition in the respective groups (including all risk factors of each individual in the respective risk group), Each color represents a panicular risk (same legend for dg and jk); b – Brief presentation of the violent aggression severity score, VASS, ranging from no documented aggression to lethal consequences of violent aggression with relative weight given to severity of aggression and number of registered re occurrences. c – Highly significant intercorrelation of violent aggression measures used in the present paper. d – Application of VASS to risk accumulation in the discovery sample; Kmskal Wallis H test (two sided). e-g – Schizophrenia replication cohorts 1: ‘stair pattem‘ of aggression proxy in risk accumulation groups: all 12 test (one sided). h – Comparative presentation of subjects (%) with violent aggression in risk accumulation groups across schizophrenia cohorts. i – Comparative presentation of subjects (%) with violent aggression before (pre morbid, ‘early’) or after schizophrenia onset (‘late‘) vs. individuals without evidence of aggression (‘no’) in risk accumulation groups of the discovery sample. j-k – General population replication cohorts IV and V: ‘stair pattern‘ of aggression proxies, LSRP secondary psy chopathy score (j) and aggression hostility factor of ZKFQ 50 CC (k) in risk accumulation groups; Kruskal Wallis 1 test (one sided). l – HDACI mRNA levels in PBMC of male extreme group subjects as available for analysis; Student‘s t test (one sided).


The present work was initiated based on the observation in a schizophrenia cohort that accumulation of environmental risk factors before adulthood promotes the likelihood of later forensic hospitalization, interpreted as indicator of violent aggression. This interpretation and the effect of risk accumulation were consolidated using direct scoring of aggression over lifetime or, as aggression proxies, forensic hospitalization and conviction for battery, sexual assault, manslaughter or murder. or respective psychopathology measures in 4 independent schizophrenia cohorts and 2 general population samples. Importantly, our data support the concept of a disease independent development of violent aggression in subjects exposed to multiple pre adult environmental risk factors.

Whereas a vast amount of literature on single environmental risk factors reports consequences for abnormal behavior and mental illness, publications on pre-adult risk accumulation are scarce and mostly based on closely interrelated social/familial risk factors. Also, risk and consequence are often not clearly defined. Studies including larger, comprehensively characterized datasets and replication samples do not exist.

The present work is the first to provide sound evidence, based on 6 separate cohorts, of a disease independent relationship between accumulation of multifaceted pre-adult environmental hits and violent aggression.

The overall societal damage is enormous, and we note that mentally ill individuals who re-enter the community from prison are even more at risk for unemployment, homelessness, and criminal recidivism. These results should encourage better precautionary measures, including intensified research on protective factors which is still underrepresented.

In the psychosociological literature, the so called externalizing behavior in childhood includes hostile and aggressive physical behavior toward others, impulsivity, hyperactivity, and noncompliance with limit setting. The respective risk factors are all highly plausible, yet often theoretical, and derived from 4 broad domains: child risk factors (e.g., adverse temperament, genetic and gender risk), sociocultural risks (e.g., poverty, stressful life events), parenting and caregiving (e.g., confiict and violence at home, physical abuse), and children’s peer experiences (e.g., instable relationships, social rejection). A full model of the development of conduct problems has been suggested to include at least these 4 domains.

The risk factors analyzed in the present study are perhaps somewhat clearer defined but partially related to and overlapping across these domains. Urbanicity, migration, cannabis and alcohol reflect sociocultural input but also peer experience, and physical or sexual abuse belong to the parenting/caregiver aspect.

Certainly, there are many more, still undiscovered risk and numerous protective factors, potentially explaining why ‘only’ 40-50% of high risk individuals in our schizophrenia samples fulfill criteria of violent aggression.

We note that this study does not include genetic data analysis or correction for any genetic impact. The genetic influence on aggression, however, may be of considerable relevance for the individual, even though highly heterogeneous as for essentially all behavioral traits. Heritability of aggression, estimated from twin studies, reaches >60%. In fact, 50% of individuals with violent aggression upon pre-adult risk accumulation in the present study means another 50% without detectable aggression. This consistent finding across samples likely indicates that genetic predisposition is prerequisite for whichever behavioral consequence. Individuals without genetic predisposition and/or with more protective factors (genetic and environmental) may not react with violent aggression to accumulated environmental risk.

Importantly, the obvious gender effect may be a matter of degree rather than of pattern. In fact, the etiology of externalizing behavior problems is similar for girls and boys, as is the consequence of risk accumulation in the present study for males and females.

The risk factors of the sociological domains seem to be stable predictors over time, to some degree interchangeable, pointing to many pathways leading to the same outcome (principle of equifinality). The interchangeability is highly interesting also with respect to potential biological mechanisms. It appears that any of the here investigated hits alone, independent of its kind, can be compensated for but that higher risk load increases the probability of violent aggression.

Also for that reason, we are weighing risk factors equally in the present study. This could theoretically create some bias. However, to be able to estimate the true effect size of each specific factor separately on violent aggression and subsequently weigh all factors in a more proper way, much larger samples sizes would be needed that are presently not available anywhere in the world.

In contrast to the marginal influence of genome wide association data on mental disease in GRAS, the accumulated environmental impact on development of violent aggression is huge, reflected by odds ratios of >10. When striking at a vulnerable time of brain development, namely around/before puberty, the environmental input may ‘non specifically’ affect any predisposed individual. The hypothetical biological mechanisms underlying this accumulation effect in humans may range from alterations in neuroendocrine and neurotransmitter systems, neuronal/ synaptic plasticity and neurogenesis to changes in the adaptive immune system and interference with developmental myelination, affecting brain connectivity and network function.

Our approach to detect methylation changes in blood using an epigenome wide association scan was unsuccessful despite matched extreme group comparison, likely due to the small sample size, and perhaps the etiological/pathogenetic complexity of accumulated risks. Changes in brain, not accessible here for analysis, can certainly not be excluded. Interestingly, however, HDAC1 mRNA levels in PBMC of male extreme group subjects were increased in the high risk compared to the low risk group. This finding confirms peripheral HDAC1 mRNA levels as a more robust readout of epigenetic alterations in relatively small sample sizes, as compared to specific methylation sites in epigenome wide association scans or even in candidate genes. To gain further mechanistic insight and thereby develop in addition to prevention measures novel individualized treatment concepts, animal studies modeling risk accumulation seem unavoidable.

To conclude, this study should motivate sociopolitical actions, aiming at identifying individuals at risk and improving precautionary measures. Effective violence prevention strategies start early and include family focused and school based programs. Additional risk factors, interchangeable in their long term consequences, like urbanicity, migration, and substance abuse, should be increasingly considered. Health care providers are essential for all of these prevention concepts. More research on protective factors and resilience should be launched. Animal studies need to be supported that model risk accumulation for mechanistic insight into brain alterations leading to aggression, and for developing new treatment approaches, also those targeting reversal of epigenetic alterations. As a novel concept, scientific efforts on ‘phenaryptyping of the environment’, should be promoted to achieve more fundamental risk estimation and more effective prevention in the future.


Read the complete study here: Violent aggression predicted by multiple pre-adult environmental hits