Recent progress in migraine pathophysiology: role of cortical spreading depression and magnetic resonance imaging

Migraine is characterised by debilitating pain, which affects the quality of life in affected patients in both the western and the eastern worlds. The purpose of this article is to give a detailed outline of the pathophysiology of migraine pain, which is one of the most confounding pathologies among pain disorders in clinical conditions. We critically evaluate the scientific basis of various theories concerning migraine pathophysiology, and draw insights from brain imaging approaches that have unraveled the prevalence of cortical spreading depression (CSD) in migraine. The findings supporting the role of CSD as a physiological substrate in clinical pain are discussed. We also give an exhaustive overview of brain imaging approaches that have been employed to solve the genesis of migraine pain, and its possible links to the brainstem, the neocortex, genetic endophenotypes, and pathogenetic factors (such as dopaminergic hypersensitivity). Furthermore, a roadmap is proposed to provide a better understanding of pain pathophysiology in migraine, to enable the development of strategies using leads from brain imaging studies for the identification of early biomarkers, efficient prognosis, and treatment planning, which eventually may help in alleviating some of the devastating impact of pain morbidity in patients afflicted with migraine.     

Diagnostic test utilization in evaluation for resective epilepsy surgery in children

Epilepsy surgery is highly successful in achieving seizure freedom in carefully selected children with drug‐resistant focal epilepsy. Advances in technology have aided presurgical evaluation and increased the number of possible candidates. Many of the tests employed are resource intense, and in specific cases they may be unhelpful or have adverse effects. Some standardization of the evaluation process is thus considered timely. Given the lack of class 1 or 2 evidence defining the relative utility of each test in specific clinicopathologic cohorts, a set of expert recommendations was attempted using consensus among members of the Pediatric Epilepsy Surgery Task Force of the International League Against Epilepsy (ILAE) Commissions of Pediatrics and Diagnostics These recommendations aim to limit fringe over or underutilization of use while retaining substantial flexibility in the use of various tests, in keeping with most standard practices at established pediatric epilepsy centers. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .     

Subthreshold delta‐frequency resonance in thalamic reticular neurons

The thalamic reticular nucleus (nRt) is an assembly of GABAergic projection neurons that participate in the generation of brain rhythms during synchronous sleep and absence epilepsy. NRt cells receive inhibitory and excitatory synaptic inputs, and are endowed with an intricate set of intrinsic conductances. However, little is known about how intrinsic and synaptic properties interact to generate rhythmic discharges in these neurons. In order to better understand this interaction, I studied the subthreshold responses of nRt cells to time‐varying inputs. Patch‐clamp recordings were performed in acute slices of rat thalamus (postnatal days 12–21). Sinusoidal current waveforms of linearly changing frequencies were injected into the soma, and the resulting voltage oscillations were recorded. At the resting membrane potential, the impedance profile showed a characteristic resonance at 1.7 Hz. The relative strength of the resonance was 1.2, and increased with membrane hyperpolarization. Small suprathreshold current injections led to preferred spike generation at the resonance frequency. Bath application of ZD7288 or Cs⁺, inhibitors of the hyperpolarization‐activated cation current (I_h), transformed the resonance into low‐pass behaviour, whereas the T‐channel blockers mibefradil and Ni²⁺ decreased the strength of the resonance. It is concluded that nRt cells have an I_h‐mediated intrinsic frequency preference in the subthreshold voltage range that favours action potential generation in the delta‐frequency band.     

Changes in orexinergic immunoreactivity of the piglet hypothalamus and pons after exposure to chronic postnatal nicotine and intermittent hypercapnic hypoxia

We recently showed that orexin expression in sudden infant death syndrome (SIDS) infants was reduced by 21% in the hypothalamus and by 40–50% in the pons as compared with controls. Orexin maintains wakefulness/sleeping states, arousal, and rapid eye movement sleep, abnormalities of which have been reported in SIDS. This study examined the effects of two prominent risk factors for SIDS, intermittent hypercapnic hypoxia (IHH) (prone‐sleeping) and chronic nicotine exposure (cigarette‐smoking), on orexin A (OxA) and orexin B (OxB) expression in piglets. Piglets were randomly assigned to five groups: saline control (n = 7), air control (n = 7), nicotine [2 mg/kg per day (14 days)] (n = 7), IHH (6 min of 7% O₂/8% CO₂ alternating with 6‐min periods of breathing air, for four cycles) (n = 7), and the combination of nicotine and IHH (N + IHH) (n = 7). OxA/OxB expression was quantified in the central tuberal hypothalamus [dorsal medial hypothalamus (DMH), perifornical area (PeF), and lateral hypothalamus], and the dorsal raphe, locus coeruleus of the pons. Nicotine and N + IHH exposures significantly increased: (i) orexin expression in the hypothalamus and pons; and (ii) the total number of neurons in the DMH and PeF. IHH decreased orexin expression in the hypothalamus and pons without changing neuronal numbers. Linear relationships existed between the percentage of orexin‐positive neurons and the area of pontine orexin immunoreactivity of control and exposure piglets. These results demonstrate that postnatal nicotine exposure increases the proportion of orexin‐positive neurons in the hypothalamus and fibre expression in the pons, and that IHH exposure does not prevent the nicotine‐induced increase. Thus, although both nicotine and IHH are risk factors for SIDS, it appears they have opposing effects on OxA and OxB expression, with the IHH exposure closely mimicking what we recently found in SIDS.     

Brivaracetam does not modulate ionotropic channels activated by glutamate, γ‐aminobutyric acid,and glycine in hippocampal neurons

Brivaracetam (BRV) is a selective, high‐affinity ligand for synaptic vesicle protein 2A (SV2A), recently approved as adjunctive treatment for drug‐refractory partial‐onset seizures in adults. BRV binds SV2A with higher affinity than levetiracetam (LEV), and was shown to have a differential interaction with SV2A. Because LEV was reported to interact with multiple excitatory and inhibitory ligand‐gated ion channels and that may impact its pharmacological profile, we were interested in determining whether BRV directly modulates inhibitory and excitatory ionotropic receptors in central neurons. Voltage‐clamp experiments were performed in primary cultures of mouse hippocampal neurons. At a supratherapeutic concentration of 100 μm , BRV was devoid of any direct effect on currents gated by γ‐aminobutyric acidergic type A, glycine, kainate, N‐methyl‐d ‐aspartate, and α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid. Similarly to LEV, BRV reveals a potent ability to oppose the action of negative modulators on the inhibitory receptors. In conclusion, these results show that BRV contrasts with LEV by not displaying any direct action on inhibitory or excitatory postsynaptic ligand‐gated receptors at therapeutic concentrations and thereby support BRV's role as a selective SV2A ligand. These findings add further evidence to the validity of SV2A as a relevant antiepileptic drug target and emphasize the potential for exploring further presynaptic mechanisms as a novel approach to antiepileptic drug discovery.     

Downregulation of cannabinoid receptor 1 from neuropeptide Y interneurons in the basal ganglia of patients with Huntington's disease and mouse models

Cannabinoid receptor 1 (CB₁ receptor) controls several neuronal functions, including neurotransmitter release, synaptic plasticity, gene expression and neuronal viability. Downregulation of CB₁ expression in the basal ganglia of patients with Huntington's disease (HD) and animal models represents one of the earliest molecular events induced by mutant huntingtin (mHtt). This early disruption of neuronal CB₁ signaling is thought to contribute to HD symptoms and neurodegeneration. Here we determined whether CB₁ downregulation measured in patients with HD and mouse models was ubiquitous or restricted to specific striatal neuronal subpopulations. Using unbiased semi‐quantitative immunohistochemistry, we confirmed previous studies showing that CB₁ expression is downregulated in medium spiny neurons of the indirect pathway, and found that CB₁ is also downregulated in neuropeptide Y (NPY)/neuronal nitric oxide synthase (nNOS)‐expressing interneurons while remaining unchanged in parvalbumin‐ and calretinin‐expressing interneurons. CB₁ downregulation in striatal NPY/nNOS‐expressing interneurons occurs in R6/2 mice, Hdh^Q150/Q150 mice and the caudate nucleus of patients with HD. In R6/2 mice, CB₁ downregulation in NPY/nNOS‐expressing interneurons correlates with diffuse expression of mHtt in the soma. This downregulation also occludes the ability of cannabinoid agonists to activate the pro‐survival signaling molecule cAMP response element‐binding protein in NPY/nNOS‐expressing interneurons. Loss of CB₁ signaling in NPY/nNOS‐expressing interneurons could contribute to the impairment of basal ganglia functions linked to HD.     

Altered motor plasticity in an acute relapse of multiple sclerosis

In relapsing‐remitting MS (RRMS), the symptoms of a clinical relapse subside over time. Neuroplasticity is believed to play an important compensatory role. In this study, we assessed excitability‐decreasing plasticity during an acute relapse of MS and 12 weeks afterwards. Motor plasticity was examined in 19 patients with clinically isolated syndrome or RRMS during a steroid‐treated relapse (t1) and 12 weeks afterwards (t2) using paired‐associative stimulation (PAS10). This method combines repetitive electric nerve stimulation with transcranial magnetic stimulation of the contralateral motor cortex to model long‐term synaptic depression in the human cortex. Additionally, 19 age‐matched healthy controls were assessed. Motor‐evoked potentials of the abductor pollicis brevis muscle were recorded before and after intervention. Clinical disability was assessed by the multiple sclerosis functional composite and the subscore of the nine‐hole peg test taken as a measure of hand function. The effect of PAS10 was significantly different between controls and patients; at t1, but not at t2, baseline‐normalized postinterventional amplitudes were significantly higher in patients (106 [IQR 98–137] % post10–15 and 111 [IQR 88–133] % post20–25) compared to controls (92 [IQR 85–111] % and 90 [IQR 75–102] %). Additional exploratory analysis indicated a potentially excitability‐enhancing effect of PAS10 in patients as opposed to controls. Significant clinical improvement between t1 and t2 was not correlated with PAS10 effects. Our results indicate an alteration of PAS10‐induced synaptic plasticity during relapse, presumably reflecting a polarity shift due to metaplastic processes within the motor cortex. Further studies will need to elucidate the functional significance of such changes for the clinical course of MS.