Deep brain stimulation in the central nucleus of the amygdala decreases ‘wanting’ and ‘liking’ of food rewards

We investigated the potential of deep brain stimulation (DBS) in the central nucleus of the amygdala (CeA) in rats to modulate functional reward mechanisms. The CeA is the major output of the amygdala with direct connections to the hypothalamus and gustatory brainstem, and indirect connections with the nucleus accumbens. Further, the CeA has been shown to be involved in learning, emotional integration, reward processing, and regulation of feeding. We hypothesized that DBS, which is used to treat movement disorders and other brain dysfunctions, might block reward motivation. In rats performing a lever‐pressing task to obtain sugar pellet rewards, we stimulated the CeA and control structures, and compared stimulation parameters. During CeA stimulation, animals stopped working for rewards and rejected freely available rewards. Taste reactivity testing during DBS exposed aversive reactions to normally liked sucrose tastes and even more aversive taste reactions to normally disliked quinine tastes. Interestingly, given the opportunity, animals implanted in the CeA would self‐stimulate with 500 ms trains of stimulation at the same frequency and current parameters as continuous stimulation that would stop reward acquisition. Neural recordings during DBS showed that CeA neurons were still active and uncovered inhibitory‐excitatory patterns after each stimulus pulse indicating possible entrainment of the neural firing with DBS. In summary, DBS modulation of CeA may effectively usurp normal neural activity patterns to create an ‘information lesion’ that not only decreased motivational ‘wanting’ of food rewards, but also blocked ‘liking’ of rewards.     

Case reports: headache caused by a spinal cord stimulator in the upper cervical spine

We report persistent headaches developing in a patient subsequent to the placement of a spinal cord stimulator in the upper cervical spine. These persistent headaches responded to dihydroergotamine and sumatriptan. Headaches ceased upon repositioning of the stimulator lower in the cervical spine. We postulate an effect of the device on the trigeminovascular system via the nucleus caudalis trigeminalis and/or spinal trigeminal tract.     

Recent developments in colorectal cancer screening and prevention

Colorectal cancer is a significant contributor to morbidity and mortality in the United States. Studies published in the early 1990s, showing that screening for colorectal cancer can reduce colorectal cancer-related mortality, led many organizations to recommend screening in asymptomatic, average-risk adults older than 50 years. Since then, however, national screening rates remain low. Several important studies published over the past four years have refined our understanding of existing screening tools and explored novel means of screening and prevention. The most important new developments, which are reviewed in this article, include the following: Additional trial results support the effectiveness of fecal occult blood testing in reducing the incidence of, and mortality from, colorectal cancer. New studies document the sensitivity of fecal occult blood testing, sigmoidoscopy, and double-contrast barium enema compared with colonoscopy. Cost-effectiveness models show that screening by any of several methods is cost-effective compared to no screening. Randomized trials show that calcium is effective but fiber is not effective in preventing reoccurrence of adenomatous polyps. Preliminary data suggest that nonsteroidal anti-inflammatory drugs may prevent adenomatous polyps and that DNA stool tests and virtual colonoscopy may show promise as screening tools. This new information provides further support for efforts to increase the use of colorectal cancer screening and prevention services in adults older than 50 years.     

Pharmacokinetics and pharmacodynamics of an antisense phosphorothioate oligonucleotide targeting Fas mRNA in mice

ISIS 22023 is a modified phosphorothioate antisense oligonucleotide targeting murine Fas mRNA. Treatment of mice with ISIS 22023 reduced Fas expression in liver in a concentration-dependent and sequence-specific manner, which completely protected mice from fulminant death induced by agonistic Fas antibody. In this study, we characterized the relationships in mice between total dose administered, dose to the target organ, and ultimately, the intracellular concentration within target cell types to the pharmacologic activity of ISIS 22023. After subcutaneous injection, ISIS 22023 distributed to the liver rapidly and remained in the liver with the t(1/2) ranging from 11 to 19 days, depending on dose. There were apparent differences in patterns of uptake and elimination in different types of liver cells. Oligonucleotide appeared within hepatocytes rapidly, whereas the peak concentrations in Kupffer cells were delayed until 2 days after dose administration. Hepatocytes cleared oligonucleotide the most rapidly, whereas Kupffer cells appeared to retain oligonucleotide longer. The reduction of Fas mRNA levels (pharmacodynamic response) paralleled the increase of oligonucleotide concentration in mouse liver with maximum mRNA reduction of 90% at 2 days after a single 50 mg/kg subcutaneous administration. Moreover, the pharmacodynamics of ISIS 22023 correlated better with the pharmacokinetics in hepatocytes, supporting the concept that the presence of oligonucleotide in target cells results in reductions in mRNA and, ultimately, pharmacologic activity. These results provide a comprehensive understanding of the kinetics of an antisense drug at the site of action and demonstrate that the reductions in mRNA induced by this antisense oligonucleotide correlate with its concentrations in cell targets.