No abstract

Cortical thickness is a more reliable measure of atrophy than volume due to the low variability in the cytoarchitectural structure of the grey matter. However, this more desirable measure of disease-related alterations is not fully evaluated in early dementia. The study presented here is the first to report the spatial patterns of cortical thickness in the pre-clinical stages of Alzheimer's disease, namely mild cognitive impairment (MCI). Cortical thickness measurements for 34 healthy elderly, 62 MCI and 42 Alzheimer's disease subjects were made using fully automated magnetic resonance imaging-based analysis techniques in order to determine the pattern of cortical thinning as a function of disease progression. The thickness of the cortex decreased significantly when the healthy elderly brains were compared to those with MCI, mainly in the medial temporal lobe region and in some regions of the frontal and the parietal cortices. With the progression of disease from MCI to Alzheimer's disease, a general thinning of the entire cortex with significant extension into the lateral temporal lobe was found. In all cases, the results were more pronounced in the left hemisphere. In conclusion, we have shown that there is a specific pattern in the thinning of the cortical ribbon which is in agreement with the previous histological reports. These novel findings support the notion of increased isocortical involvement with the progression of disease.

Vagus nerve stimulation (VNS) is an antiepileptic treatment, which has recently shown promise as an antidepressant. Yet, its antidepressant mechanisms of action are unknown. Serotonergic [5-hydroxytryptamine (5-HT, serotonin)] and noradrenergic [norepinephrine (NE)] systems are involved in the pathophysiology of depression and in the mechanisms of action of antidepressants. The present study analyzes 5-HT and NE neuronal firing rates in their brainstem nuclei: the dorsal raphe nucleus (DRN) and locus coeruleus (LC), respectively. The basal firing rates in the DRN and LC were significantly increased after long-term treatments with VNS. After short-term VNS treatments, firing rates were significantly higher for LC (at 1 h and 3 days). As changes in their firing rate may have been due to altered autoreceptor sensitivities, the responses of autoreceptors to the acute administration of their respective agonists were assessed. However, no significant difference was seen in the DRN. No significant differences in dose response curves for 5-HT 1A somatodendritic and ␣ 2 -adrenergic autoreceptors were noticed between long-term VNS and controls. VNS appears to have a novel mechanism of antidepressant action, enabling its effectiveness in treatment-resistant depression. LC firing rates significantly increase earlier than the DRN basal firing. As the LC has an excitatory influence on DRN, it is possible that the increased DRN firing rate is secondary to an initial increased LC firing rate from VNS.The vagus nerve (cranial nerve 10) is generally thought of as a group of efferent parasympathetic fibers regulating autonomic functions. However, this nerve consists of 80% afferent fibers (Foley and DuBois, 1937) from the head, neck, and body, leading up toward the cerebrum. These afferent fibers were targeted for therapeutic use by stimulation in medically and surgically intractable epilepsy, with several patients reporting a large decrease in seizure frequency (reviewed in .In addition to decreasing seizure frequency, an improvement in mood was witnessed in patients with vagus nerve stimulation (VNS), even in those with little or no change in seizure frequency (Harden et al., 2000). Clinical studies with VNS in treatment-resistant depression have generated positive results, with 3-month treatments inducing a 31% response rate and a 15% remission rate, based on Hamilton Rating Scales for Depression scores. Response and remission rates increased further with longer VNS treatments (Nahas et al., 2005). Recently, Krahl et al. (2004) showed that VNS significantly reduced immobility in rats with the forced-swim test, an animal model used to predict antidepressant treatments efficacy. The immobility levels of VNS-treated animals were similar to those of animals treated with desipramine and electroconvulsive therapy (ECT), two antidepressant treatments. VNS therapy is now approved for treatment-resistant depression in the European Union, the United States, and Canada, but its mechanisms of action in depression are unknown.