K. C. Brennan

Shedding Light on Photophobia

Photophobia is a common yet debilitating symptom seen in many ophthalmic and neurologic disorders. Despite its prevalence, it is poorly understood and difficult to treat. However, the past few years have seen significant advances in our understanding of this symptom. We review the clinical characteristics and disorders associated with photophobia, discuss the anatomy and physiology of this phenomenon, and conclude with a practical approach to diagnosis and treatment.

Casein Kinase Iδ Mutations in Familial Migraine and Advanced Sleep Phase

Mutations in casein kinase Iδ that are associated with migraine in patients cause changes in enzymatic function, pain behavior, cortical excitability, and astrocyte signaling in mice. The Pain of Sleep If you have experienced the excruciating pain of a migraine, chances are that some of your relatives have too. Despite this clear heritability, the genes that transfer this disease from generation to generation are known for only a few specialized types of migraine. While studying families with a sleep disorder called familial advanced sleep phase syndrome, Brennan et al. may have found another one of these genes. They discovered that mutations in a gene (casein kinase Iδ) that cause the sleep problems also seemed to cause migraine. In two families, everyone who carried the sleep-disrupting casein kinase Iδ mutation (each family had a slightly different mutation) also suffered from migraines, although there were several members who had migraines but not the mutation or the sleep disorder. To see whether the casein kinase mutation might really be contributing to migraine, the authors took their experiments in vitro and into mice. In a test of whether the two mutations affected casein kinase Iδ enzyme activity, the authors found that neither mutated form of casein kinase Iδ was able to properly phosphorylate its substrate. But does this weakened enzyme activity cause headaches? To see, the authors generated mice carrying mutated casein kinase Iδ. Because migraine is a pain syndrome, patients’ reports of their pain are important for characterizing the disease. Although mice cannot tell us if they hurt, the authors found some mouse phenotypes that suggest they are experiencing a migraine-like disorder: When treated with nitroglycerin (a migraine trigger), the mice were more sensitive to pain, just as humans are. The mice also more easily exhibited cortical spreading depression (a wave of ionic disturbance thought to be similar to migraine aura), and their arteries were abnormally dilated during the spreading depression—both phenomena similar to those seen during migraine in humans. The suggestive segregation of the casein kinase mutations in migraine patients and the ability of the same mutations to produce migraine-like phenomena in mice together make a strong case that casein kinase mutations can contribute to migraine, adding another gene to the small list associated with this debilitating headache syndrome. Migraine is a common disabling disorder with a significant genetic component, characterized by severe headache and often accompanied by nausea, vomiting, and light sensitivity. We identified two families, each with a distinct missense mutation in the gene encoding casein kinase Iδ (CKIδ), in which the mutation cosegregated with both the presence of migraine and advanced sleep phase. The resulting alterations (T44A and H46R) occurred in the conserved catalytic domain of CKIδ, where they caused reduced enzyme activity. Mice engineered to carry the CKIδ-T44A allele were more sensitive to pain after treatment with the migraine trigger nitroglycerin. CKIδ-T44A mice also exhibited a reduced threshold for cortical spreading depression (believed to be the physiological analog of migraine aura) and greater arterial dilation during cortical spreading depression. Astrocytes from CKIδ-T44A mice showed increased spontaneous and evoked calcium signaling. These genetic, cellular, physiological, and behavioral analyses suggest that decreases in CKIδ activity can contribute to the pathogenesis of migraine.

Sumatriptan alleviates nitroglycerin-induced mechanical and thermal allodynia in mice

The association between the clinical use of nitroglycerin (NTG) and headache has led to the examination of NTG as a model trigger for migraine and related headache disorders, both in humans and laboratory animals. In this study in mice, we hypothesized that NTG could trigger behavioural and physiological responses that resemble a common manifestation of migraine in humans. We report that animals exhibit a dose-dependent and prolonged NTG-induced thermal and mechanical allodynia, starting 30–60 min after intraperitoneal injection of NTG at 5–10 mg/kg. NTG administration also induced Fos expression, an anatomical marker of neuronal activity in neurons of the trigeminal nucleus caudalis and cervical spinal cord dorsal horn, suggesting that enhanced nociceptive processing within the spinal cord contributes to the increased nociceptive behaviour. Moreover, sumatriptan, a drug with relative specificity for migraine, alleviated the NTG-induced allodynia. We also tested whether NTG reduces the threshold for cortical spreading depression (CSD), an event considered to be the physiological substrate of the migraine aura. We found that the threshold of CSD was unaffected by NTG, suggesting that NTG stimulates migraine mechanisms that are independent of the regulation of cortical excitability.

Is essential tremor predominantly a kinetic or a postural tremor? A clinical and electrophysiological study.

Both postural and kinetic tremors may occur in essential tremor (ET), however the relative contribution of each is not clear. ET has been variably defined with respect to kinetic and postural tremors. To examine the relative severity of postural and kinetic tremors in ET, 50 ET cases from a clinic and 55 from a community underwent a videotaped tremor examination. Kinetic and postural tremors were rated using a validated clinical rating scale (score range, 0–3). Thirty‐one cases also underwent accelerometry to precisely quantify tremor amplitude. In clinic cases, the mean postural tremor rating was 1.25 (S.D., 0.89). The mean kinetic tremor rating was 52% higher (1.90; S.D., 0.57; P < 0.001). The community cases had similar characteristics. Sixty percent of the 105 cases had postural tremor ratings scoring 0 or 1 (no tremor or low amplitude, intermittent tremor). In clinic cases, the mean amplitude of postural tremor during tremor analysis was 0.51 mm (S.D., 0.66 mm), and the mean amplitude of kinetic tremor was 2.91 mm (S.D., 2.11 mm; P < 0.01). Similar values were obtained for community cases. These quantitative data suggest that kinetic tremor is more severe than postural tremor in ET. The majority of cases had mild or absent postural tremor. Despite this, ET is defined only as a postural tremor in many studies. Our data argue for a more consistent inclusion of kinetic tremor in diagnostic criteria for ET.

Reduced threshold for cortical spreading depression in female mice

The prevalence of migraine is much greater in female than male individuals. Cortical spreading depression (CSD) is thought to be a fundamental mechanism of migraine, and CSD in rodents is used as a model for migraine. We used optical intrinsic signal imaging and electrophysiological techniques to investigate CSD in C57Bl/6 mice. Using two different methods for induction of CSD, we found that female mice had a significantly reduced threshold for induction of CSD compared with male mice. These results suggest an increased cortical excitability in female mice that may be independent of the estrous cycle. Ann Neurol 2007

Biphasic direct current shift, haemoglobin desaturation and neurovascular uncoupling in cortical spreading depression.

Cortical spreading depression is a propagating wave of depolarization that plays important roles in migraine, stroke, subarachnoid haemorrhage and brain injury. Cortical spreading depression is associated with profound vascular changes that may be a significant factor in the clinical response to cortical spreading depression events. We used a combination of optical intrinsic signal imaging, electro-physiology, potassium sensitive electrodes and spectroscopy to investigate neurovascular changes associated with cortical spreading depression in the mouse. We identified two distinct phases of altered neurovascular function, one during the propagating cortical spreading depression wave and a second much longer phase after passage of the wave. The direct current shift associated with the cortical spreading depression wave was accompanied by marked arterial constriction and desaturation of cortical haemoglobin. After recovery from the initial cortical spreading depression wave, we observed a second phase of prolonged, negative direct current shift, arterial constriction and haemoglobin desaturation, lasting at least an hour. Persistent disruption of neurovascular coupling was demonstrated by a loss of coherence between electro-physiological activity and perfusion. Extracellular potassium concentration increased during the cortical spreading depression wave, but recovered and remained at baseline after passage of the wave, consistent with different mechanisms underlying the first and second phases of neurovascular dysfunction. These findings indicate that cortical spreading depression is associated with a multiphasic alteration in neurovascular function, including a novel second direct current shift accompanied by arterial constriction and decrease in tissue oxygen supply, that is temporally and mechanistically distinct from the initial propagated cortical spreading depression wave. Vascular/metabolic uncoupling with cortical spreading depression may have important clinical consequences, and the different phases of dysfunction may represent separate therapeutic targets in the disorders where cortical spreading depression occurs.

The continuum of spreading depolarizations in acute cortical lesion development: Examining Leão's legacy.

A modern understanding of how cerebral cortical lesions develop after acute brain injury is based on Aristides Leão’s historic discoveries of spreading depression and asphyxial/anoxic depolarization. Treated as separate entities for decades, we now appreciate that these events define a continuum of spreading mass depolarizations, a concept that is central to understanding their pathologic effects. Within minutes of acute severe ischemia, the onset of persistent depolarization triggers the breakdown of ion homeostasis and development of cytotoxic edema. These persistent changes are diagnosed as diffusion restriction in magnetic resonance imaging and define the ischemic core. In delayed lesion growth, transient spreading depolarizations arise spontaneously in the ischemic penumbra and induce further persistent depolarization and excitotoxic damage, progressively expanding the ischemic core. The causal role of these waves in lesion development has been proven by real-time monitoring of electrophysiology, blood flow, and cytotoxic edema. The spreading depolarization continuum further applies to other models of acute cortical lesions, suggesting that it is a universal principle of cortical lesion development. These pathophysiologic concepts establish a working hypothesis for translation to human disease, where complex patterns of depolarizations are observed in acute brain injury and appear to mediate and signal ongoing secondary damage.

An update on the blood vessel in migraine.

Purpose of reviewThe cranial blood vessel is considered an integral player in the pathophysiology of migraine, but its perceived role has been subject to much discussion and controversy over the years. We will discuss the evolution in our scientific understanding of cranial blood vessels (primarily arteries) in migraine. Recent findingsRecent developments have clarified the role of cranial blood vessels in the trigemino-vascular system and in cortical spreading depression. An underlying theme is the intimate relation between vascular activity and neural function, and we will emphasize the various roles of the blood vessel that go beyond delivering blood. We conclude that migraine cannot be understood, either from a research or clinical point of view, without an understanding of the vascular derangements that accompany it. SummaryMigraine is accompanied by significant derangements in vascular function that may represent important targets for investigation and treatment.

Memantine Enhances Recovery From Stroke

Background and Purpose— Stroke treatment is constrained by limited treatment windows and the clinical inefficacy of agents that showed preclinical promise. Yet animal and clinical data suggest considerable poststroke plasticity, which could allow treatment with recovery-modulating agents. Memantine is a well-tolerated N-methyl-D-aspartate glutamate receptor antagonist in common use for Alzheimer disease. Methods— Memantine, 30 mg/kg per day, or vehicle, was delivered chronically in drinking water beginning >2 hours after photothrombotic stroke. Results— Although there was no difference in infarct size, behavior, or optical intrinsic signal maps in the first 7 days after stroke, mice treated chronically with memantine showed significant improvements in motor control, measured by cylinder test and grid-walking performance, compared with vehicle-treated animals. Optical intrinsic signal revealed an increased area of forepaw sensory maps at 28 days after stroke. There was decreased reactive astrogliosis and increased vascular density around the infarcted cortex. Peri-infarct Western blots revealed increased brain-derived neurotrophic factor and phosphorylated-tropomyosin–related kinase-B receptor expression. Conclusions— Our results suggest that memantine improves stroke outcomes in an apparently non-neuroprotective manner involving increased brain-derived neurotrophic factor signaling, reduced reactive astrogliosis, and improved vascularization, associated with improved recovery of sensory and motor cortical function. The clinical availability and tolerability of memantine make it an attractive candidate for clinical translation.

Multimodal Examination of Structural and Functional Remapping in the Mouse Photothrombotic Stroke Model

Recent studies show a limited capacity for neural repair after stroke, which includes remapping of sensorimotor functions and sprouting of new connections. However, physiologic and connectional plasticity of sensory maps during long-term functional recovery in the mouse have not been determined. Using a photothrombotic stroke model, we targeted the motor cortex, which we show results in lasting behavioral deficits on the grid-walking and in the cylinder tasks out to 8 weeks after stroke. Mice recovered performance in a skilled reaching task, showing no deficit from week 2 after stroke. Long-term optical intrinsic signal imaging revealed functional reorganization of sensory cortical maps for both forelimb and hindlimb, with more diffuse sensory physiologic maps. There was a small but significant increase in motor neuron projections within the areas of functional cortical reorganization as assessed using the neuroanatomic tracer biotinylated dextran amine. These findings show that the sensorimotor cortex undergoes remapping of cortical functions and axonal sprouting within the same regions during recovery after stroke. This suggests a linked structural and physiologic plasticity underlying recovery. Combined long-term structural and functional mapping after stroke in the mouse is practical and provides a rich data set for mechanistic analysis of stroke recovery.