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Med Hypotheses. Author manuscript; available in PMC 2009 Jan 1.
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The Minicolumnopathy of Autism: a Link between Migraine and Gastrointestinal Symptoms

Manuel F. Casanova, MD*
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Abstract

Gastrointestinal symptoms are common medical problems among autistic patients. A leaky gut and viruses have been proposed as possible culprits but evidence for these etiological agents remains elusive. In this article we put forward an alternate etiology: abdominal migraines. Recent postmortem studies in autism indicate the presence of a minicolumnopathy and its relationship to both serotonergic abnormalities and a hyperexcitable cortex. These features of phenomenology are also observed in miganeurs. A putative relationship between autism and migraine is further suggested by similarities in clinical histories and laboratory evidence. Some commonalities include the presence of neuroinflammation, sensory overstimulation (e.g., flickering of fluorescent lights), “food allergies”, benefits from similar diets, and the role of nitric oxide. Abdominal migraine therefore stands as a falsifiable hypothesis with added importance accrued to potential therapeutic interventions.

Keywords: autism, migraine, minicolumns, gastrointestinal symptoms, serotonin, glutamate

“The brain should not be thought of as a hierarchy of organized autonomous structures, each delivering its output to the next level in a linear function, but as a set of complex interacting networks that are in a state of dynamic equilibrium with the brain’s environment. Migraine…can be considered as one result of an upset in this environment.” [1].

Autism is a condition defined by abnormalities in socialization, language, communication, range of interests, and motor behaviors. The CDC reported that 1 in 152 8-year-olds in 14 states surveyed have an Autism Spectrum Disorders [2]. Multiple studies have associated autism to a variety of genetic disorders or syndromes, e.g., Fragile X [3, 4], Down [5], Fetal Rubella, Fetal Valproate [6], and Moebius (congenital facial diplegia) [7]. Medical problems commonly raised by children with autism include sleep disturbances, feeding problems, and gastrointestinal complaints. In order to facilitate treatment and address possible etiologic factors these medical concerns have become topics of recent research.

Recent postmortem studies indicate the presence of minicolumnar disturbances in autism [7-9]. To the extent that autism is a minicolumnopathy, core features of the condition should be explained in terms of pathophysiologcal mechanisms involving this cortical module. A useful pathological construct, when considered in lieu of prevailing paradigms (e.g., loss of Purkinje cells, diminished size of limbic neurons), should provide additional or novel information having functional implications for affected patients (incremental validity). In this regard we consider the explanatory power of a putative minicolumnopathy as applied to the gastrointestinal symptoms commonly reported by autistic patients. It is our contention that in autism a minicolumnopathy provides for both a hyperexcitable cortex and a serotonergic imbalance that manifests itself early in life as abdominal migraines. Indeed, short autobiographical accounts and anecdotal evidence from the medical literature suggests that autistic individuals have an increased prevalence of migraines [10].

Autism as a Minicolumnopathy

The cause of autism remains unknown but the presence of seizures and derangement in multiple higher order cognitive functions suggests a cortical lesion. Although the findings may be argued, neuroimaging and neuropathological studies indicate a dysplastic process that manifests itself occasionally as gross cortical malformations, lamination abnormalities, aberrant positioning of cells, and underdeveloped neurons [3, 7, 11]. The concurrence of autism spectrum disorders with brainstem dysplastic processes and disruptions of early morphogenetic areas (e.g., limb fields) suggests that the underlying mechanism takes its toll during embryonic development. A time frame of susceptibility has been calculated based on the fact that brief exposures to thalidomide in pregnant women are linked to an increased occurrence of limb teratogenesis, Moebius syndrome, and autism [12]. The geneses of these side effects encompass the 20th through 36th day of gestation [13].

Recent postmortem studies suggest that autism is the result of a minicolumnar disturbance [8]. Minicolumns are a primary motif of structural organization within the isocortex [14]. Their presence antedates other architectural elements of brain parcellation, e.g., synapsis, lamination, gyrification. It is believed that the cortex is autonomously patterned after germinal cells divide symmetrically (E<40 days in primates) to form a protomap (Gk., prōtos; first in time) of the cortex within the ventricular zone [15]. Later on during development the germinal cells divide asymmetrically (E= 40-120 days in primates) and define the total number of pyramidal cells within the minicolumns. Areal identity stems from afferent innervation to the cortex (protocortex) [16]. According to the thalidomide model (see above) the time frame that defines the total number of minicolumns (symmetrical divisions, E<40 days) coincides with the window of susceptibility for autism.

Arguably, thalamic innervation binds minicolumns into larger constructs (macrocolumns) with feature extraction properties [17-19]. Minicolumns, groups of minicolumns, macrocolumns and networks of macrocolumns offer different echelons within the human brain whose interconnectivity provides for the emergence of higher cognitive properties [14]. As compared to controls minicolumns in autism are smaller and therefore increased in total numbers per linear length of cortical field surveyed [8]. In these smaller minicolumns the peripheral neuropil space appears affected more than the core cellular compartment. The peripheral neuropil space provides the conduit for the inhibitory pericolumnar surround which accounts for spatial contrast during a stimulus evoked afferent drive [20]. Abnormalities in the vertical flow of pericolumnar inhibition provides for amplification of signals and thus explains, in part, the seizures observed in some autistic patients [14].

A recent postmortem study using an independent sample has expanded the original findings of a minicolumnopathy in autism by describing a reduction in somatic and nucleolar size of constituent neurons [9]. The pathological changes preferentially affect heteromodal areas of the isocortex with relative preservation of primary or idiotypic regions [21]. The resultant circuitry is biased so as to emphasize short corticocortical connections at the expense of longer ones, e.g. commisural projections [9].

Serotonin and Cortical Modularity

The anatomical basis of the macrocolumn is defined, in part, by the balance of activity between glutamate and serotonin (5HT) neurotransmission [22, 23]. Levels of serotonin modulate the density of α-amino-3-hydroxy-5-methylisoxazole-4- propionic acid (AMPA) receptor subtypes [24]. Increased levels of serotonin (facilitated release or decreased reuptake) have an anticonvulsant effect [25, 26]. This mechanism of action helps explain the link between epilepsy and depression [26].

Neural network models clarify the relationship between the clinical symptoms of autism, serotonergic abnormalities and narrowed neural columns [27]. These models also indicate an association between narrowed neural columns and deficiencies in nitric oxide [27]. The conclusions from these constructs are supported by a florescent literature on nitric oxide and serotonin interactions. This includes the formation of dimmers and nitro- and nitroso-serotonin, all of which are inactive at modulatory 5HT sites [28, 29].

Prenatal exposure to alcohol, selective serotonin reuptake inhibitors, and excess serotonin (monoamine oxidase inhibitors [MAO-A] and MAO-A knockout mice) deleteriously affect the postnatal development of cortical barrel formation [23, 30]. The effects appear to be mediated by the transient expression of functional serotonin transporter in the axons of thalamocortical fibers. Knock-out mice for the serotonin transporter show a complete lack of macrocolumnar structures (barrels) despite no visible alterations in either the density of synapses or the length of synaptic contacts in layer IV [31]. Serotonergic projections to the marginal zone make synaptic contacts with Cajal-Retzius cells. Disturbing the normal development of these connections lowers reelin levels and alters columnar development [32]. Some of these early effects of serotonin on cortical modularity may unfold during protracted periods of time as sub-compartmentalization of macrocolumnar organization is a process that occurs gradually during the postnatal period [33].

Serotonin and Cortical Hyperexcitability

Autism

It has been hypothesized that in the presence of normal-sized thalamocortical terminal fields the smaller minicolumns observed in autism provide for an overabundance of these modules within any given macrocolumn [8]. The resultant excess of minicolumns would require an increase of inhibitory tone (e.g. serotonin, see above) to balance the physiology of the cortex. In effect, alterations in the capacity of the brain to synthesize serotonin have been reported in autistic children using positron emission tomography [34]. Peripheral serotonergic biomarkers exhibit abnormalities similar to those reported in the brain, e.g., platelet serotonin is increased in approximately one third of autistic patients [35-39]. After controlling for racial and pubertal effects autistic patients have a 25% mean increase in blood serotonin levels [40]. The increased whole blood serotonin is found not only in autistic patients but also in first degree relatives [37, 41]. Platelet serotonin is exogenously derived and taken within cells by an active transport mechanism. In autism multiple lines of evidence suggest that platelets are not exposed to increased concentrations of serotonin but, rather, seem to mishandle this chemical [42].

Some of the behavioral symptoms of autism, specifically the repetitive behaviors, are strongly related to serotonergic (5HT) dysfunction [43]. It has also been reported that Sumitriptan, a 5-HT1d receptor agonist and an antimigraine medication, improved symptoms of autism and migraine in patients who suffered from both disorders [43]. Although Sumitriptan is primarily a 5-HT1d receptor agonist it may also bind to other subtypes of 5HT receptors [44]. Double blind studies of serotonin reuptake inhibitors, clomipramine [45], and fluvoxamine [46] as well as open label studies of fluoxetine [47] and sertraline [48], have documented efficacy in treating various symptoms of autism. Depletion of 5HT precursor tryptophan, have been shown to induce a worsening of autistic symptoms in some but not all patients [49].

We have already discussed how serotonergic abnormalities appear related to epilepsy [25, 26]. It is thus unsurprising that approximately one third of patients with autism suffer from seizures by the time that they reach puberty [7]. The percentage may be higher when considering epileptiform EEG activity regardless of seizure activity [50]. It has been hypothesized that early serotonergic disturbances alter the development of cortical thalamocortical innervation and underlies the pathophysiology of epilepsy in autism [51]. Cortical hyperexcitability and serotonergic abnormalities are therefore well established and interrelated features of autistic phenomenology.

Migraine

The large majority of the body’s serotonin is found in the enterochromaffin cells of the gut. Serotonin is released from the gut to the bloodstream but serum levels are kept low by uptake into platelets [1]. In migraineurs there is a deficit in uptake kinetic of serotonin by platelets that accounts for abnormal levels of this chemical. During the headache phase there is a fall in blood levels of serotonin and an increase in its metabolites in both plasma and urine [1].

Modern pharmacological interventions for migraine started with subcutaneous ergotamine, a powerful alkaloid vasoconstrictor. Later on serotonin, a potent vasoconstrictor, was shown to be released from platelets during migraine attacks. Current management of migraine includes serotonergic agonists during acute episodes and the use of serotonergic antagonists and anticonvulsants as migraine prophylactics [1, 52, 53]. A therapeutic response to anticonvulsant therapy has been noted in case reports and series of children with abdominal migraine and epileptiform discharges [54, 55].

A hyperexcitable cortex and increased serotonin are characteristic of migraine [56]. Epileptiform activity, including spike and wave patterns, has been reported in patients during migraine attacks [57]. It has been argued that the visual discomfort and illusions of migraineurs are a manifestation of their hyperexcitable cortex. Although results have been inconsistent there appears to be a reduced threshold for the induction of visual auras by transcranial magnetic stimulation and reduced latencies and increased amplitude responses to evoked potentials [58]. The mechanism underlying cortical hyperexcitability in migraine is unknown but may be related to increased levels of cerebrospinal glutamate and reduced brain levels of Mg2+ [59, 60].

Clinical History

Autism

It is well established that autistic individuals sometimes respond in an unusual manner to sensory stimuli. The hum of a vacuum cleaner or the school bell’s ringing can hurt their ears and provide for pathological anxiety. Temple Grandin [61] describes a lady who could not tolerate a baby’s crying, even when she was wearing both earplugs and earmuffs. She also describes from self-experience stiffening up and pulling away when people hugged her. The needs to desensitize, relax, and tolerate touch led Temple Grandin [61] to build a pressure machine. The fact that such experiences tend to generalize among autistic subjects have led other researchers to implement treatments such as auditory and sensory integration therapies.

Sensory processing abnormalities are correlated with higher levels of repetitive and stereotypical behaviors. From a behaviorist standpoint some autistic symptoms represent an avoidance reaction to overstimulation [62]. This reasoning has important implications for treatment. Indeed, occasional autistic tantrums are best handled by diminishing all sources of stimulation; e.g., going into a room and closing all windows, turning off the light, etc. Visual overload is a common phenomenon in autism, especially troublesome is the flickering of fluorescent lights. Transitional prism lenses modify distortions of ambient vision. Their use has also been shown to diminish behavioral problems in a double-blind crossover study of autistic patients [63]. Many of these patients are photosensitive and experience some benefit from wearing photoreactive lenses [64, 65].

Autistic patients similar to migraineurs react strongly to smells and have peculiarities in terms of food intake. Furthermore migraine-like equivalents have been described in young children with autism, e.g. abdominal pain. Some investigators speak about a gastroenteritis of autism [66] due to the high incidence (approximately 19%) of gastrointestinal problems in this population [67]. Esophagitis and duodenitis were described in almost two thirds of the symptomatic children brought for endoscopy. Findings of lymphoid nodular hyperplasia from biopsied specimens of autistic children have been controversial as several of the coauthors from the original study by Wakefield and associates (1998)[68] have retracted their conclusions and renounced the findings [69]. Lymphoid nodular hyperplasia has been found in conditions other than autism, including allergies [70]. At least two series of nonautistic children having colonoscopy for gastrointestinal symptoms have reported lymphoid nodular hyperplasia in 46 out of 140 and in 53 out of 74 cases [66, 71]. Treatment includes special diets restricting casein and gluten intake [62]. At least two studies using large samples have reported some benefits from this dietary intervention [72, 73]

The underlying pathology of autism is unknown. Recent findings suggest the presence of a minicolumnopathy which could explain many of the signs and symptoms of this condition [9, 74]. However, it is sometimes difficult to distinguish primary lesions from secondary features of pathology especially when secondary aspects of pathology are more easily visualized than less conspicuous core features. One example may be the presence of astrocytosis in postmortem brain tissue of autistic individuals when compared to computer generated measures of minicolumnar morphometry [75].

Inflammation is a response to cell injury that involves, among other things, a vascular component. Thus far there has been no evidence of inflammatory changes in either brain or CSF of patients with autism (e.g., cell counts, protein electrophoresis). Recent work by Vargas and associates (2005) [76]has shown that brains of autistic patients have an increased number of astrocytes and microglia in the absence of a vascular component or cellular transmigration. This innate, noninflammatory response of the brain appears to be chronic in nature as suggested by a cytokine profile that includes both inflammatory and anti-inflammatory agents. Similarly, the cytokine profile suggests that involved glia cells appear to be activated. Otherwise, except for increased cell numbers, there is no evidence of glia activation by light microscopy, e.g., astrocytes do not acquire a characteristic gemistocytic appearance nor microglia participate in neurophagia, nodule formation or transform into foam cells. In this regard the pathology is different from other immune mediated disorders of the central nervous system (e.g. Alzheimer’s disease, epilepsy, multiple sclerosis) but similar to that reported for migraine (see below).

Migraine

Migraine is a condition entirely diagnosed by clinical history [1]. Diagnostic criteria were provided by the International Headache Society in a series of definitions last revised in 2004 (ICH-2). The inclusion of a “probable migraine” classification within ICH-2 attests to borderline cases where clinical suspicion supercedes the lack of diagnostic criteria. In effect, headache is the most prominent feature of migraine but the underlying pathophysoilogical mechanisms often cause other systemic manifestations without necessitating a cephalea. The term “migraine equivalent or variant” is used in these cases where transient organ system dysfunction occurs in some individuals with migraine or familial predisposition to the same [77]. Symptoms include discrete paroxysmal attacks of dizziness/vertigo, abdominal pains, bloating, vomiting (bilious attacks), and diarrhea. These paroxysmal attacks occur in a setting of phonophobia/photophobia and other autonomic symptoms such as pallor and flushing. Symptoms are usually seen in children and young adults with a mean age of onset of 7 years, reaching a peak at age 10 years and thereafter falling rapidly [78]. During attacks patients usually retreat to isolation, choosing to stay in a dark room, remain undisturbed, and avoid their normal activities and human contact.

Abdominal migraine is episodic with recovery between attacks. The differential diagnosis includes episodic abdominal conditions such as biliary disease, partial bowel obstruction and irritable bowel syndrome [79]. Oliver Sacks (1985) [80] has stated that with migraine equivalents “…indeed there is probably no field in medicine so strewn with the debris of misdiagnosis and mistreatment, and of well-intentioned but wholly mistaken medical and surgical interventions” (pages 49 and 50). Least to say the misdiagnosis of migraine equivalents is a common occurrence brought upon by multiple referrals through varied medical specialties.

Foods are usual triggers for abdominal migraine, common culprits include cow’s milk, chocolate, cheese, wheat products, rye, and baked beans [81]. Intolerance to a wide range of foods has led some investigators to suggest that migraine is a food allergy [82] In a study of 88 children with severe frequent migraine, 93% recovered with an oligoantigenic diet [82]. The study included a challenge phase where provoking foods were introduced one by one causing recurrence of abdominal symptoms. A successful diet requires a wide spectrum diet as the sole exclusion of foods high in tyramine, such as cheese and chocolate provided recovery in only 5% of patients. The same appeared to be true upon the sole avoidance of food colorings and preservatives.

Migraine headaches can be triggered by flickering lights, sounds, dietary factors, and odors. Early writers believed that migraine was caused by toxins connected to abdominal disorders [83, 84]. More recently, researchers believe that migraine is generated by normal brain structures in response to abnormal physiological reactions in what has been called a wave of “spreading depression.” Small trauma, toxins, excitatory amino acids, electrical stimuli and nitric oxide donors when applied to the cortex cause a short-lived positive wave of neural excitation followed by a prolonged phase of neural depression and a dramatic failure of brain ion homeostasis [85]. The wave spreads from its origin in all outward directions at a rate of 3 to 5 mm/min. The spread occurs without regards to anatomical boundaries or vascular territories and appears to be mediated by K+ homeostasis. Numerous neuroprotective mechanisms counter the spreading wave of depression including increases in the levels of tumor necrosis factor, interleukin 1, and clustering (a protein produced by neurons and activated astrocytes) [86]. Perfusates of sites of migraine headaches possess inflammatory activity proportional to the intensity of the pain [87]. Repeated episodes of cortical spreading depression lead to activation of astrocytes and consequent increased immunocytochemical staining of glial fibrillary acidic protein (GFAP) [88]. The prominent response of innate elements of the brain to the spread of depression and activation of the trigeminovascular system has led some researchers to label migraine as a neuroinflammatory condition [89].

Conclusions

This article espouses the hypothesis that the gastrointestinal complaints of autistic patients are a migraine equivalent. Both autism and migraine are defined by serotonergic abnormalities and a hyperexcitable cortex. Other commonalities exist in regards to clinical history and laboratory findings making the hypothesis empirically meaningful. Difficulties in establishing a relationship stem from the fact that diagnostic criteria for migraine rely exclusively on a good history. Autistic patients have deficits in language development which makes it difficult for them to communicating symptoms. However, electrophysiological methods may bypass history and provide for outcome measures making the hypothesis falsifiable. In this regards methods such as transcranial magnetic stimulation (TMS) may simultaneously provide for outcome measures of cortical hyperexcitability and provide for potential interventions [90].

The discovery of hyperserotonemia in 1961 by Schain and Freedman gave rise to a putative intervention with a drug that causes the long term depletion of serotonin: fenfluramine. After some promising results [91], the drug showed great variability of effects and no improvements in large clinical trials. Ultimately the drug was withdrawn from the US market after reports of some serious side effects that included heart valve disease, pulmonary hypertension and cardiac fibrosis. It is thus important to cautiously consider any conclusions before translating findings into clinical trials, e.g. serotonergic drugs and nitric oxide synthase inhibitors. According to the mechanisms presented in this article these attempts would be directed towards secondary aspects of pathology and not the core features of the condition (minicolumnopathy). Such attempts provide an opportunity for symptomatic treatment but otherwise remain far removed from providing a cure.

Acknowledgments

This work was supported by grant funding from the National Alliance for Autism Research (NAAR) (MFC), and NIH grant numbers MH62654 and MH69991.

Footnotes

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