Deep brain stimulation in Alzheimer's disease.

Benefits from symptomatic and etiologic treatments in Alzheimer's Disease (AD), the most frequent dementia, are still insufficient. During the last decade, several studies showed that electrical stimulation of memory circuits could enhance memory in humans without memory impairment. First, improvement of verbal recollection was reported after deep brain stimulation (DBS) of the fornix in the hypothalamus in a patient treated for morbid obesity. Several studies in epileptic patients explored by deep electrodes reported that visuo-spatial memorization was facilitated by electrical stimulation of the entorhinal cortex or theta burst stimulation of the fornix. Recent studies suggested that DBS could be useful to modulate memory circuits in patients with cognitive decline. Phase I and II studies (about 50 patients) showed that chronic fornix DBS was safe and could achieved to stabilize or slow the memory decline of some patients with mild to moderate AD, especially older ones with less severe and/or advanced disease. DBS of the cholinergic nucleus of Meynert also has been explored in phase I studies in AD and Parkinson-related dementia. Growing experimental data suggest several mechanisms of action: restoration of hippocampal theta rhythms, enhanced long term potentiation, increase of hippocampal neurogenesis, neuroprotection by release of neurotrophic factors, diffuse reactivation of hypoactive neocortical associative regions. However, DBS in AD is still investigational and numerous issues remain to be solved before envisaging its use in clinical practice, including optimal anatomical DBS target, stimulation modalities (continuous, intermittent, theta-bursts, closed loop stimulation), best candidate patients, relevant targeted symptoms, ethical considerations.

Managing cluster headache with sphenopalatine ganglion stimulation: a review.

Cluster headache (CH) is a primary headache and considered as one of the worst pains known to man. The sphenopalatine ganglion (SPG) plays a pivotal role in cranial autonomic symptoms associated with pain. Lesioning procedures involving the SPG and experimental acute SPG stimulation have shown some degree of efficacy with regard to CH. A neuromodulation device, chronically implanted in the pterygopalatine fossa, has been specifically designed for acute on-demand SPG stimulation. In a pilot placebo-controlled study in 28 patients suffering from refractory chronic CH, alleviation of pain was achieved in 67.1% of full stimulation-treated attacks compared to 7% of sham stimulation-treated attacks (p<0.0001). Long-term results (24 months; 33 patients) confirmed the efficacy of SPG stimulation as an abortive treatment for CH attacks. Moreover, 35% of the patients observed a >50% reduction in attack frequency, suggesting that repeated use of SPG stimulation might act as a CH-preventive treatment. Globally, 61% of the patients were acute responders, frequency responders, or both, and 39% did not respond to SPG stimulation. The safety of SPG microstimulator implantation procedure was evaluated in a cohort of 99 patients; facial sensory disturbances were observed in 67% of the patients (46% of them being transient), transient allodynia in 3%, and infection in 5%. SPG stimulation appears as a promising innovative, efficient, and safe therapeutic solution for patients suffering from severe CH. It has shown its efficacy in aborting CH attacks compared to placebo stimulation, suggesting that it is particularly adapted for CH patients who are not sufficiently improved by abortive treatments such as sumatriptan and oxygen. However, further studies comparing SPG stimulation with standard abortive and/or preventive CH treatments will be necessary to define more precisely its place within the management of severe chronic and/or episodic CH.

Dural and pial pain-sensitive structures in humans: new inputs from awake craniotomies.

Our knowledge on intracranial pain-sensitive structures in humans comes essentially from observations during neurosurgical procedures performed in awake patients. It is currently accepted that intracranial pain-sensitive structures are limited to the dura mater and its feeding vessels and that small cerebral vessels and pia mater are insensitive to pain, which is inconsistent with some neurosurgical observations during awake craniotomy procedures. We prospectively collected observations of painful events evoked by mechanical stimulation (touching, stretching, pressure, or aspiration) of intracranial structures during awake craniotomies, routinely performed for intraoperative functional mapping to tailor brain tumour resection in the eloquent area. Intraoperatively, data concerning the locations of pain-sensitive structures were drawn by the surgeon on a template and their corresponding referred pain was indicated by the patient by drawing a cross on a diagram representing the head. Ninety-three painful events were observed and collected in 53 different patients (mean age 41.2 years, 25 males) operated on awake craniotomy for left (44 cases) or right (nine cases) supra-tentorial tumour resection in eloquent areas. On average, 1.8 painful events were observed per patient (range 1-5). All the painful events were referred ipsilaterally to the stimulus. In all cases, the evoked pain was sharp, intense and brief, stopped immediately after termination of the causing action, and did not interfere with the continuation of the surgery. In 30 events, pain was induced by stimulation of the dura mater of the skull base (23 events) or of the falx (seven events) and was referred predominantly in the V1 territory and in the temporal region. In 61 cases, pain was elicited by mechanical stimulation of the pia mater or small cerebral vessels of the temporal (19 events), frontal (25 events), parietal (four events) lobes and/or the peri-sylvian region, including the insular lobe (13 events), and referred in the V1 territory. In this observational study, we confirmed that dura of the skull base and dura of the falx cerebri are sensitive to pain and that their mechanical stimulation induced pain mainly referred in the sensory territories of the V1 and V3 divisions of the trigeminal nerve. Unlike earlier studies, we observed that the pia and the small cerebral vessels were also pain-sensitive, as their mechanical stimulation induced pain referred mainly in the V1 territory. These observations suggest that small pial cerebral vessels may also be involved in the pathophysiology of primary and secondary headaches.awy005media15756834882001.

beta-N-methylamino-L-alanine induced in vivo retinal cell death.

Controversial debates still remain around the nature of the etiologic agent responsible for Amyotrophic lateral sclerosis/Parkinson dementia complex (ALS/PDC) whose incidence is unusually high among the population of the pacific island of Guam. It has been hypothesized that the neurotoxin beta-N-methylamino-L-alanine (L-BMAA) produced by cyanobacteria in the roots of Cycas Circinalis seeds might trigger ALS/PDC. Frequently observed in patients with ALS/PDC, retinopathy is one of the clinical features of the disease. The effect of the L-BMAA on cell viability was examined in vivo by measuring the electrophysiological activity of the mouse retinal neurons by electroretinography recordings. Intra-ocular injections of L-BMAA selectively reduced the b-wave amplitude, without affecting neither the a-wave amplitude nor the a- and b-latencies. The cell death of retinal cells was evidenced by histology on retina sections, caspase 3 activation, incorporation of propidium iodide and production of reactive oxygen species. Co-injection with the specific NMDA antagonist, MK-801, significantly protected the retinal neurons from L-BMAA/NMDA-induced apoptosis. We provide evidence that L-BMAA induced neuronal cell death in vivo supporting a direct causal link between L-BMAA and neuronal damages.