The pathophysiology of migraine: insights from functional neuroimaging

Over the last 20 years, functional neuroimaging has led to major advances in the understanding of the pathophysiology of migraine. The migraine aura is characterized by the occurrence of an hypoperfusion of moderate intensity which is peculiar by its initial appearance in the posterior cortex and its anterior spread at a speed of about 2 to 3mm per minute, congruent with the migrainous march of neurologic deficit and reminiscent of the phenomenon of cortical spreading depression described in the laboratory animal after various neuronal aggressions. The hypoperfusion is followed by a phase of long-lasting hyperperfusion temporally dissociated from the headache, which seems rather to result from vasodilatation and inflammation of the extra-cerebral large vessels. Although this sequence of hypoperfusion followed by hyperperfusion would be consistent with an ischemic process, there is presently no formal argument in favour of such a process being operational in migraine aura. It is however possible that migrainous subjects are genetically susceptible to the development of some unknown process at the borderline between spreading depression and classic ischemia. In migraine without aura, the data indicate only rare and mild changes in brain perfusion, although there also exist isolated observations of pauci-symptomatic spreading bilateral hypoperfusion. Physiologic imaging has also documented the occurrence during migraine without aura of a dorsal mesencephalic activation in the vicinity of the raphé and the locus coeruleus, independent of the pain itself and which might represent the long sought-after "migraine generator". It remains unknown if this phenomenon is also present in migraine with aura. The main prevalent hypotheses attempting a synthesis of all the available data are briefly presented in the conclusion.     

New insights into migraine: application of functional and structural imaging

PURPOSE OF REVIEW: Functional neuroimaging in headache patients has revolutionized our understanding of these syndromes. Further insights into the pathophysiology of headache syndromes have been provided by innovative neuroimaging analysis using structural data. This review highlights the recent advances made in studying migraine using neuroimaging techniques. RECENT FINDINGS: Several independent studies have reinforced the crucial role for the brainstem in acute and probably also chronic migraine. Recently described structural abnormalities in the visual network of motion-processing areas could account for, or be caused by, the cortical hyperexcitability observed in migraineurs. Although data from morphometric studies are heterogeneous, a recent study suggests an increased density of brainstem structures and decreased grey matter in pain-transmitting areas in migraine patients. SUMMARY: Given the rapid advances in functional neuroimaging, in particular newer techniques such as voxel-based morphometry and magnetic resonance spectrometry, functional imaging continues to play a significant role and opens new avenues in targeting the neural substrates in individual primary headache syndromes.     

New insights into migraine pathophysiology

PURPOSE OF REVIEW: This article will review new and exciting developments in migraine research, with particular emphasis on mutations associated with familial hemiplegic migraine and the role of cortical spreading depression in its pathophysiology and treatment. RECENT FINDINGS: The recent discovery of multiple point mutations in familial hemiplegic migraine has led to the suggestion that migraine and its variants may be due to a paroxysmal disturbance in ion-translocating mechanisms. Mutations associated with familial hemiplegic migraine render the brain more susceptible to prolonged cortical spreading depression caused by either excessive synaptic glutamate release or decreased removal of glutamate and potassium from the synaptic cleft, or persistent sodium influx. Suppression of cortical spreading depression has become an interesting target for preventive migraine treatment. Prolonged treatment with beta-blockers, valproate, topiramate, methysergide or amitriptyline reduced the number of potassium-evoked cortical spreading depressions and elevated the electrical stimulation threshold for the induction of cortical spreading depression in rats. Recent imaging studies in patients suffering from migraine without aura also point to the presence of silent cortical spreading depression as an underlying mechanism. Repeated waves of cortical spreading depression may have deleterious effects on brain function, and perhaps cause silent ischaemic lesions in vulnerable brain regions such as the cerebellum in susceptible individuals. SUMMARY: This review emphasizes several neurobiological aspects of migraine that reveal paroxysmal disturbances in neuronal and vascular function, that in turn reflect disturbances in the maintenance of ionic gradients.     

The neural bases of prosopagnosia and pure alexia: recent insights from functional neuroimaging

PURPOSE OF REVIEW: To discuss whether recent functional neuroimaging results can account for clinical phenomenology in visual associative agnosias. RECENT FINDINGS: Functional neuroimaging studies in healthy human subjects have identified only two regions of ventral occipitotemporal cortex that invariantly respond to individual faces and visual words, respectively. The signature of face identity coding in the fusiform neural response was shown to be missing in a patient with prosopagnosia. Another case study established that a surgical lesion close to the region sensitive to visual words can result in pure alexia. SUMMARY: Evidence is increasing that functional specialization for processing face identity and visual word forms is restricted to two specialized sensory modules in the occipitotemporal cortex. A structural or functional lesion to face-sensitive and word-sensitive regions in the ventral occipitotemporal cortex can provide the most parsimonious account for the clinical syndromes of prosopagnosia and agnosic alexia. This review suggests that functional specialization should be considered in terms of whether exclusively one brain region (instead of many) underpins a defined function and not as whether this brain region underpins exclusively one cognitive function. Such functional specialization seems to exist for at least two higher-order visual perceptual functions, face and word identification.     

New insights help define the pathophysiology of bipolar affective disorder: neuroimaging and neuropathology findings

Bipolar affective disorder (BD) is a severe mental illness, characterized by episodes of mania and depression. With the development of Magnetic Resonance Imaging (MRI), neuroimaging methods are now allowing investigation of the neurocircuitry involved in this disorder. This in turn has aided further neuropathological exploration of the brain. Structural MRI and Magnetic Resonance Spectroscopy studies suggest that brain abnormalities in BD are mostly regional, as global measures (cerebral, white and gray matter and ventricular volumes) do not seem to be affected in the majority of patients. The prefrontal and anterior cingulate cortices, and amygdalae are consistently implicated in BD, whilst the evidence for hippocampal involvement is less convincing. Functional studies have found that the activity of the dorsal prefrontal cortex and the anterior cingulate are closely associated with mood symptoms. Activity in the ventral and orbital prefrontal cortex appears reduced both during episodes and in remission. In contrast, amygdala activity shows a persistent increase. We suggest that abnormal interaction between the amygdala and the ventral/orbitofrontal cortex may be a central feature of the pathophysiology of BD.     

The retrosplenial cortex and emotion: new insights from functional neuroimaging of the human brain.

Little is known about the function of the retrosplenial cortex and until recently, there was no evidence that it had any involvement in emotional processes. Surprisingly, recent functional neuroimaging studies show that the retrosplenial cortex is consistently activated by emotionally salient words. A review of the functional neuroimaging literature reveals a previously overlooked pattern of observations: the retrosplenial cortex is the cortical region most consistently activated by emotionally salient stimuli. Evidence that this region is also involved in episodic memory suggests that it might have a role in the interaction between emotion and episodic memory. Recognition that the retrosplenial cortex has a prominent role in the processing of emotionally salient stimuli invites further studies to define its specific functions and its interactions with other emotion-related brain regions.     

Chemobrain: A systematic review of structural and functional neuroimaging studies

Nowadays, chemotherapy-induced cognitive impairment or ‘chemobrain’ is a well-established clinical syndrome, consisting of moderate to subtle cognitive changes across various domains, especially working memory, executive function and episodic verbal memory that persist only in a subgroup of long-term cancer survivors. In recent years, several studies using neuroimaging techniques have reported structural and functional neural changes associated with chemotherapy. This review provides an overview of the relevant advances that neuroimaging techniques have added to the understanding of the underlying mechanisms of chemotherapy-induced cognitive impairment. In summary, our review showed: (i) a pre-treatment (prior to chemotherapy) widespread decrease in white matter (WM) volume as well as an increased level of activation of the frontoparietal attentional network of cancer patients compared to controls; (ii) an early diffuse decrease of gray matter (GM) and WM volume together with a decrease of the overactivation in frontal regions in chemotherapy-treated patients compared to controls and (iii) a long-term persisting decrease in GM and WM volumes together with a predominantly frontal cortex hypoactivation in only a subgroup of chemotherapy-treated patients.     

Vestibular migraine: objective diagnostic criteria

Classification of migraine or vertigo based only on clinical symptoms is rather difficult, especially in the postacute stage. The use of diagnostic instrumentation greatly aids clinicians in offereing objective measures of patient physiology. In migraine and vertigo, the “gold standard” objective measure has not been fully defined thereby hindering a criteria for vestibular migraine. This study proposes the use of two seperate modalities; infrared videonystagraphy for vertigo and electric pain thresholds for migraine to quantify patient complaints. While these instruments offer to document patient pathophsyiology, simple clinical procedures are presented to provoke the dizzyness of vertigo and the allodynia of migraine in patients being evaluted allowing clinicians larger diagnostic and therapeutic options Received: 28 November 2002 / Accepted: 30 January 2003 Correspondence to: J. O. Di Duro     

Attentional orienting and response inhibition: insights from spatial-temporal neuroimaging

Attentional orienting and response inhibition have largely been studied separately. Each has yielded important findings, but controversy remains concerning whether they share any neurocognitive processes. These conflicting findings may originate from two issues: (1) at the cognitive level, attentional orienting and response inhibition are typically studied in isolation; and (2) at the technological level, a single neuroimaging method is typically used to study these processes. This article reviews recent achievements in both spatial and temporal neuroimaging, emphasizing the relationship between attentional orienting and response inhibition. We suggest that coordinated engagement, both top-down and bottom-up, serves as a common neural mechanism underlying these two cognitive processes. In addition, the right ventrolateral prefrontal cortex may play a major role in their harmonious operation.     

New insights into attention-deficit/hyperactivity disorder using structural neuroimaging

This article reviews recent advances in structural neuroimaging in attention-deficit/hyperactivity disorder (ADHD). Observational studies have found treatment with psychostimulants to be associated more closely with dimensions of some brain structures in typically developing children than in those found in treatment-naïve children with ADHD. Novel analytic approaches allow for greater precision in the definition of brain regions that are most compromised in ADHD, with meta-analyses highlighting compromise of the basal ganglia. Cortical changes, particularly in the lateral prefrontal and parietal cortex, are also commonly reported, but with less consensus on the exact location of structural change. Anomalies in the shape of subcortical structures, specifically of the basal ganglia, hippocampus, and amygdala, implicate frontostriatal loops and the limbic system in the disorder. Finally, longitudinal data suggest that ADHD in childhood may be characterized by a delay in cortical maturation and that different clinical outcomes may be associated with different developmental trajectories in adolescence and beyond.     

Vestibular hypersensitivity to sound (Tullio phenomenon): structural and functional assessment

OBJECTIVES: To establish the role of high-resolution CT imaging and tests of vestibulocollic reflexes in diagnosing and understanding the pathogenesis of the Tullio phenomenon. BACKGROUND: The Tullio phenomenon is a syndrome in which acoustic stimulation produces symptoms and signs of vestibular activation. It has previously been associated with an abnormally low threshold for click-evoked vestibulocollic responses and also with dehiscence of the roof of the anterior (superior) semicircular canal on high-resolution CT scans of the temporal bones. METHODS: High-resolution CT scans of the temporal bones and vestibulocollic responses in sternocleidomastoid to both clicks and transmastoid galvanic stimulation (3 mA/2 msec) were studied in four patients with the Tullio phenomenon (one bilateral). RESULTS: Click-evoked thresholds were low for all affected ears (four at 65 dB nHL, one at 55 dB nHL) and normal (>70 dB nHL) for the three unaffected ears. In contrast, galvanic-evoked vestibulocollic responses were symmetric and of normal size in all patients. The bony roof of the anterior (superior) semicircular canal was thin, possibly absent, on CT of all affected ears and also in two out of three unaffected ears. CONCLUSIONS: The normal galvanic vestibulocollic responses indicate that sound sensitivity in patients with the Tullio phenomenon is likely to occur distal to the vestibular nerve, probably at the level of the receptors. Both click hypersensitivity and dehiscence of the anterior (superior) semicircular canal are associated with the Tullio phenomenon but as the CT scan abnormality can occur in clinically unaffected ears, click testing is important for specific diagnosis. Abnormal sound sensitivity, as demonstrated by click responses, confirms that the radiologic abnormality is function significant.     

Diagnosis and pathophysiology of migraine

Over the past 10 years there has been an explosion of knowledge about headache, particularly migraine. Fueled by new, highly effective therapeutic agents, vast resources have been invested in improving diagnostic accuracy and attempting to understand the mechanisms by which this symptom is generated. Public awareness has increased as has that of the medical community. Tools are now available to help diagnose particular types of headache and measure/monitor disability. Numerous pathophysiologic changes have been studied which may in turn increase the therapeutic armamentarium. With approximately 10% of the public suffering from migraine and with most of these cases remaining undiagnosed, it is likely that this segment of the healthcare market will continue to expand in the future.     

Spontaneous brain activity abnormalities in migraine: A meta‐analysis of functional neuroimaging

Neuroimaging studies have demonstrated that migraine is accompanied by spontaneous brain activity alterations in specific regions. However, these findings are inconsistent, thus hindering our understanding of the potential neuropathology. Hence, we performed a quantitative whole‐brain meta‐analysis of relevant resting‐state functional imaging studies to identify brain regions consistently involved in migraine. A systematic search of studies that investigated the differences in spontaneous brain activity patterns between migraineurs and healthy controls up to April 2022 was conducted. We then performed a whole‐brain voxel‐wise meta‐analysis using the anisotropic effect size version of seed‐based d mapping software. Complementary analyses including jackknife sensitivity analysis, heterogeneity test, publication bias test, subgroup analysis, and meta‐regression analysis were conducted as well. In total, 24 studies that reported 31 datasets were finally eligible for our meta‐analysis, including 748 patients and 690 controls. In contrast to healthy controls, migraineurs demonstrated consistent and robust decreased spontaneous brain activity in the angular gyrus, visual cortex, and cerebellum, while increased activity in the caudate, thalamus, pons, and prefrontal cortex. Results were robust and highly replicable in the following jackknife sensitivity analysis and subgroup analysis. Meta‐regression analyses revealed that a higher visual analog scale score in the patient sample was associated with increased spontaneous brain activity in the left thalamus. These findings provided not only a comprehensive overview of spontaneous brain activity patterns impairments, but also useful insights into the pathophysiology of dysfunction in migraine.     

The hallucinating brain: a review of structural and functional neuroimaging studies of hallucinations

Hallucinations remains one of the most intriguing phenomena in psychopathology. In the past two decades the advent of neuroimaging techniques have allowed researchers to investigate what is happening in the brain of those who experience hallucinations. In this article we review both structural and functional neuroimaging studies of patients with auditory and visual hallucinations as well as a small number of studies that have assessed cognitive processes associated with hallucinations in healthy volunteers. The current literature suggests that in addition to secondary (and occasionally primary) sensory cortices, dysfunction in prefrontal premotor, cingulate, subcortical and cerebellar regions also seem to contribute to hallucinatory experiences. Based on the findings of these studies we tentatively propose a neurocognitive model in which both bottom-up and top-down processes interact to produce these erroneous percepts. Finally, directions for future work are discussed.     

Structural neuroimaging in schizophrenia: from methods to insights to treatments

Historically, Kraepelin speculated that dementia praecox resulted from damage to the cerebral cortex, most notably the frontal and temporal cortices. It is only recently, however, that tools have been available to test this hypothesis. Now, more than a century later, we know that schizophrenia is a brain disorder. This knowledge comes from critical advances in imaging technology--including computerized axial tomography, magnetic resonance imaging, and diffusion imaging--all of which provide an unprecedented view of neuroanatomical structures, in vivo. Here, we review evidence for structural neuroimaging abnormalities, beginning with evidence for focal brain abnormalities, primarily in gray matter, and proceeding to the quest to identify abnormalities in brain systems and circuits by focusing on damage to white matter connections in the brain. We then review future prospects that need to be explored and pursued in order to translate our current knowledge into an understanding of the neurobiology of schizophrenia, which can then be translated into novel treatments.