Michael L. Oshinsky

A neural circuit for circadian regulation of arousal

An unknown aspect of behavioral state regulation is how the circadian oscillator of the suprachiasmatic nucleus (SCN) regulates sleep and waking. In this report, we describe the necessary elements for a circuit that provides circadian regulation of arousal. Trans-synaptic retrograde tracing revealed a prominent indirect projection from the SCN to the noradrenergic nucleus locus coeruleus (LC), a brain arousal system. Double-labeling experiments revealed several possible links between the SCN and the LC, including the dorsomedial (DMH) and paraventricular hypothalamic nuclei (PVN), as well as medial and ventrolateral pre-optic areas. Lesion studies confirmed that the DMH is a substantial relay in this circuit. Next, neurophysiology experiments revealed circadian variations in LC impulse activity. Lesions of the DMH eliminated these circadian changes in LC activity, confirming the functionality of the SCN–DMH–LC circuit. These results reveal mechanisms for regulation of circadian and sleep–waking functions.

Hyperacute directional hearing in a microscale auditory system.

The physics of sound propagation imposes fundamental constraints on sound localization: for a given frequency, the smaller the receiver, the smaller the available cues. Thus, the creation of nanoscale acoustic microphones with directional sensitivity is very difficult. The fly Ormia ochracea possesses an unusual ‘ear’ that largely overcomes these physical constraints; attempts to exploit principles derived from O. ochracea for improved hearing aids are now in progress. Here we report that O. ochracea can behaviourally localize a salient sound source with a precision equal to that of humans. Despite its small size and minuscule interaural cues, the fly localizes sound sources to within 2° azimuth. As the flys eardrums are less than 0.5 mm apart, localization cues are around 50 ns. Directional information is represented in the auditory system by the relative timing of receptor responses in the two ears. Low-jitter, phasic receptor responses are pooled to achieve hyperacute timecoding. These results demonstrate that nanoscale/microscale directional microphones patterned after O. ochracea have the potential for highly accurate directional sensitivity, independent of their size. Notably, in the fly itself this performance is dependent on a newly discovered set of specific coding strategies employed by the nervous system.

Episodic dural stimulation in awake rats : A model for recurrent headache

Objectives.—To model, in rats, the development of chronic trigeminal nociceptive hypersensitivity seen in patients with recurrent headache.

Open label trial of coenzyme Q10 as a migraine preventive

The objective was to assess the efficacy of coenzyme Q10 as a preventive treatment for migraine headaches. Thirty-two patients (26 women, 6 men) with a history of episodic migraine with or without aura were treated with coenzyme Q10 at a dose of 150 mg per day. Thirty-one of 32 patients completed the study; 61.3% of patients had a greater than 50% reduction in number of days with migraine headache. The average number of days with migraine during the baseline period was 7.34 and this decreased to 2.95 after 3 months of therapy, which was a statistically significant response (P < 0.0001). Mean reduction in migraine frequency after 1 month of treatment was 13.1% and this increased to 55.3% by the end of 3 months. Mean migraine attack frequency was 4.85 during the baseline period and this decreased to 2.81 attacks by the end of the study period, which was a statistically significant response (P < 0.001). There were no side-effects noted with coenzyme Q10. From this open label investigation coenzyme Q10 appears to be a good migraine preventive. Placebo-controlled trials are now necessary to determine the true efficacy of coenzyme Q10 in migraine prevention.

Neurochemistry of Trigeminal Activation in an Animal Model of Migraine

Research techniques such as electrophysiology, cFos protein expression, and other measurements of neuronal activation provide insights into the pathophysiology of pain processing in migraine, but they do not indicate the specific neurotransmitter systems involved. This paper summarizes data from microdialysis experiments in which changes in the neurochemistry of the trigeminal nucleus caudalis (TNC) were monitored during dural stimulation. Microdialysis allows the measurement of extracellular concentrations of neurotransmitters in a small area of the brain, in vivo, by means of a probe equipped with a semipermeable membrane. Microdialysis enables direct measurement of changes in extracellular concentrations of neurotransmitters in the intact animal over time in response to dural inflammation. Following the activation of the dural nociceptors, changes in the extracellular amino acid neurotransmitters in the deep lamina of the TNC were tracked. A 5‐minute application of inflammatory soup when compared with saline to the dura of rats induced a transient decrease in extracellular glutamate in the TNC at approximately 30 minutes postapplication. This short‐lived decrease was followed by a continuous increase in extracellular glutamate to a level of approximately 3 times the baseline value at 3 hours after application of the inflammatory soup. The time course of this increase in extracellular glutamate correlated with changes in sensory thresholds on the face of the rat from electrophysiological recordings of secondary sensory neurons in the TNC. No significant differences between the inflammatory soup and saline conditions were observed for extracellular concentrations of aspartate (an excitatory amino acid) or the inhibitory neurotransmitters gamma‐aminobutyric acid or glutamine. Results of these experiments support an integral role for glutamate in central sensitization of neurons in the TNC, and suggest an important contribution of glutamate to allodynia and hyperalgia in this animal model of migraine.

Noninvasive vagus nerve stimulation as treatment for trigeminal allodynia.

Summary The reduction of glutamate is identified as the mechanism of action of noninvasive vagus nerve stimulation for the treatment of trigeminal allodynia. ABSTRACT Implanted vagus nerve stimulation (VNS) has been used to treat seizures and depression. In this study, we explored the mechanism of action of noninvasive vagus nerve stimulation (nVNS) for the treatment of trigeminal allodynia. Rats were repeatedly infused with inflammatory mediators directly onto the dura, which led to chronic trigeminal allodynia. Administration of nVNS for 2 minutes decreased periorbital sensitivity in rats with periorbital trigeminal allodynia for up to 3.5 hours after stimulation. Using microdialysis, we quantified levels of extracellular neurotransmitters in the trigeminal nucleus caudalis (TNC). Allodynic rats showed a 7.7 ± 0.9‐fold increase in extracellular glutamate in the TNC after i.p. administration of the chemical headache trigger glyceryl trinitrate (GTN; 0.1 mg/kg). Allodynic rats that received nVNS had only a 2.3 ± 0.4‐fold increase in extracellular glutamate after GTN, similar to the response in control naive rats. When nVNS was delayed until 120 minutes after GTN treatment, the high levels of glutamate in the TNC were reversed after nVNS. The nVNS stimulation parameters used in this study did not produce significant changes in blood pressure or heart rate. These data suggest that nVNS may be used to treat trigeminal allodynia.

Consecutive Transcranial Magnetic Stimulation: Phosphene Thresholds in Migraineurs and Controls

Objective.—To characterize the temporal course of transcranial magnetic stimulation‐induced phosphene thresholds in subjects with migraine and in controls.

Spontaneous Trigeminal Allodynia in Rats: A Model of Primary Headache

Animal models are essential for studying the pathophysiology of headache disorders and as a screening tool for new therapies. Most animal models modify a normal animal in an attempt to mimic migraine symptoms. They require manipulation to activate the trigeminal nerve or dural nociceptors. At best, they are models of secondary headache. No existing model can address the fundamental question: How is a primary headache spontaneously initiated? In the process of obtaining baseline periorbital von Frey thresholds in a wild‐type Sprague‐Dawley rat, we discovered a rat with spontaneous episodic trigeminal allodynia (manifested by episodically changing periorbital pain threshold). Subsequent mating showed that the trait is inherited. Animals with spontaneous trigeminal allodynia allow us to study the pathophysiology of primary recurrent headache disorders. To validate this as a model for migraine, we tested the effects of clinically proven acute and preventive migraine treatments on spontaneous changes in rat periorbital sensitivity. Sumatriptan, ketorolac, and dihydroergotamine temporarily reversed the low periorbital pain thresholds. Thirty days of chronic valproic acid treatment prevented spontaneous changes in trigeminal allodynia. After discontinuation, the rats returned to their baseline of spontaneous episodic threshold changes. We also tested the effects of known chemical human migraine triggers. On days when the rats did not have allodynia and showed normal periorbital von Frey thresholds, glycerol trinitrate and calcitonin gene related peptide induced significant decreases in the periorbital pain threshold. This model can be used as a predictive model for drug development and for studies of putative biomarkers for headache diagnosis and treatment.

Nociceptive Neuropeptide Increases and Periorbital Allodynia in a Model of Traumatic Brain Injury

Objective.— This study tests the hypothesis that injury to the somatosensory cortex is associated with periorbital allodynia and increases in nociceptive neuropeptides in the brainstem in a mouse model of controlled cortical impact (CCI) injury.

Remitting form of hemicrania continua with seasonal pattern

Hemicrania continua is a primary headache syndrome characterized by a continuous, unilateral headache that is completely responsive to indomethacin. Hemicrania continua exists in continuous and remitting forms. Ten cases of the remitting form have been reported, none of which have had a seasonal pattern. We report a patient with remitting hemicrania continua with a clear seasonal predilection.