Continuous theta burst stimulation over the supplementary motor area in refractory obsessive-compulsive disorder treatment: A randomized sham-controlled trial.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a complex disorder with 40 to 60 % of patients resistant to treatment. Theta burst transcranial magnetic stimulation (TBS) is a promising new technique that has been shown to induce potent and long lasting effects on cortical excitability. The present study evaluated for the first time therapeutic efficacy and tolerability of continuous TBS (cTBS) over the supplementary motor area (SMA) in treatment resistant OCD patients using a double blind, sham-controlled design. METHODS: Thirty treatment resistant OCD outpatients were randomized to receive either active cTBS or sham cTBS for 6 weeks (5 sessions per week). Each treatment session consisted of 600 stimuli at an intensity of 70% of resting motor threshold. Patients were evaluated at baseline, at the end of treatment (week 6), and follow-up (week 12). Response to treatment was defined as at least 25% decrease on the Yale-Brown Obsessive Compulsive Scale. RESULTS: There was no significant difference between active and sham cTBS groups in treatment efficacy. Responder rates were not different between the two groups at week 6 (cTBS 28% versus sham 36%; p = 0.686) and week 12 (cTBS 28% versus sham 36%; p = 0.686). Depressive and anxious symptoms improvements were similar in the two groups. CONCLUSION: This study is the first controlled trial using cTBS in treatment resistant OCD patients. The use of cTBS over the SMA is safe but not sufficient to improve OCD symptoms. Further studies are needed to identify the optimal parameters to be used in OCD patients.

Imipramine, in part through tumor necrosis factor alpha inhibition, prevents cognitive decline and beta-amyloid accumulation in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD), the most common form of dementia in the older people, is a multifactoral pathology, characterized by cognitive deficits, increase in cerebral deposition of the beta-amyloid (Abeta) peptide, neurofibrillary tangles, and neurodegeneration. Studies currently support a central role of neuroinflammation, through production of proinflammatory cytokines including excess tumor necrosis factor alpha (TNF-alpha) in the pathogenesis of AD, especially in Abeta-induced cognitive deficits. Imipramine, a tricyclic antidepressant, has potent anti-inflammatory and neuroprotective effects. This study investigates the effect of imipramine on alterations of long-term and short-term memories, TNF-alpha expression, and amyloid precursor protein (APP) processing induced by intracerebroventricular injection of Abeta25-35 in mice. Mice were treated with imipramine (10 mg/kg i.p. once a day for 13 days) from the day after the Abeta25-35 injection. Memory function was evaluated in the water-maze (days 10-14) and Y-maze (day 9) tests. TNF-alpha levels and APP processing were examined in the frontal cortex and the hippocampus (day 14). Imipramine significantly prevented memory deficits caused by Abeta25-35 in the water-maze and Y-maze tests, and inhibited the TNF-alpha increase in the frontal cortex. Moreover, imipramine decreased the elevated levels of Abeta both in frontal cortex and hippocampus with different modulations of APP and C-terminal fragments of APP. So, imipramine prevents memory impairment through its intrinsic property to inhibit TNF-alpha and Abeta accumulation and may represent a potential candidate for AD treatment.

Activated double-stranded RNA-dependent protein kinase and neuronal death in models of Alzheimer's disease.

Neuronal death is a pathological hallmark of Alzheimer's disease. We have shown previously that phosphorylated double-stranded RNA-dependent protein kinase is present in degenerating hippocampal neurons and in senile plaques of Alzheimer's disease brains and that genetically down-regulating double-stranded RNA-dependent protein kinase activity protects against in vitro beta-amyloid peptide neurotoxicity. In this report, we showed that two double-stranded RNA-dependent protein kinase blockers attenuate, in human neuroblastoma cells, beta-amyloid peptide toxicity evaluated by caspase 3 assessment. In addition, we have used the newly engineered APP(SL)/presenilin 1 knock-in transgenic mice, which display a severe neuronal loss in hippocampal regions, to analyze the activation of double-stranded RNA-dependent protein kinase. Western blots revealed the increased levels of activated double-stranded RNA-dependent protein kinase and the inhibition of eukaryotic initiation factor 2 alpha activity in the brains of these double transgenic mice. Phosphorylated RNA-dependent protein kinase-like endoplasmic reticulum-resident kinase was also increased in the brains of these mice. The levels of activated double-stranded RNA-dependent protein kinase were also increased in the brains of patients with Alzheimer's disease. At 3, 6 and 12 months, hippocampal neurons display double stranded RNA-dependent protein kinase labelings in both the nucleus and the cytoplasm. Confocal microscopy showed that almost constantly activated double-stranded RNA-dependent protein kinase co-localized with DNA strand breaks in apoptotic nuclei of CA1 hippocampal neurons. Taken together these results demonstrate that double-stranded RNA-dependent protein kinase is associated with neurodegeneration in APP(SL)/presenilin 1 knock-in mice and could represent a new therapeutic target for neuroprotection.