Gamma knife capsulotomy for intractable OCD: Neuroimage analysis of lesion size, location, and clinical response.

Obsessive-compulsive disorder (OCD) affects 2-3% of the population. One-third of patients are poorly responsive to conventional therapies, and for a subgroup, gamma knife capsulotomy (GKC) is an option. We examined lesion characteristics in patients previously treated with GKC through well-established programs in Providence, RI (Butler Hospital/Rhode Island Hospital/Alpert Medical School of Brown University) and São Paulo, Brazil (University of São Paolo). Lesions were traced on T1 images from 26 patients who had received GKC targeting the ventral half of the anterior limb of the internal capsule (ALIC), and the masks were transformed into MNI space. Voxel-wise lesion-symptom mapping was performed to assess the influence of lesion location on Y-BOCS ratings. General linear models were built to compare the relationship between lesion size/location along different axes of the ALIC and above or below-average change in Y-BOCS ratings. Sixty-nine percent of this sample were full responders (≥35% improvement in OCD). Lesion occurrence anywhere within the targeted region was associated with clinical improvement, but modeling results demonstrated that lesions occurring posteriorly (closer to the anterior commissure) and dorsally (closer to the mid-ALIC) were associated with the greatest Y-BOCS reduction. No association was found between Y-BOCS reduction and overall lesion volume. GKC remains an effective treatment for refractory OCD. Our data suggest that continuing to target the bottom half of the ALIC in the coronal plane is likely to provide the dorsal-ventral height required to achieve optimal outcomes, as it will cover the white matter pathways relevant to change. Further analysis of individual variability will be essential for improving targeting and clinical outcomes, and potentially further reducing the lesion size necessary for beneficial outcomes.

Task-specific neural activity in the primate prefrontal cortex.

Real-world behavior is typically more complicated than a one-to-one mapping between a stimulus and response; the same stimulus can lead to different behaviors depending on the situation, or the same behavior may be cued by different stimuli. In such cases, knowledge of the formal demands of the task at hand is required. We found that in monkeys trained to alternate between three tasks, the activity of many neurons in the prefrontal cortex was task dependent. This included changes in overall firing rate, in firing-rate profiles (shape of responses over time), and in stimulus and response selectivity. These findings support the hypothesis that a major prefrontal function is the acquisition and implementation of task context and the "rules" used to guide behavior.

Attenuation of NMDA receptor activity and neurotoxicity by nitroxyl anion, NO-.

Recent evidence indicates that the NO-related species, nitroxyl anion (NO), is produced in physiological systems by several redox metal-containing proteins, including hemoglobin, nitric oxide synthase (NOS), superoxide dismutase, and S-nitrosothiols (SNOs), which have recently been identified in brain. However, the chemical biology of NO- remains largely unknown. Here, we show that NO- -unlike NO*, but reminiscent of NO+ transfer (or S-nitrosylation)- -reacts mainly with Cys-399 in the NR2A subunit of the N-methyl-D-aspartate (NMDA) receptor to curtail excessive Ca2+ influx and thus provide neuroprotection from excitotoxic insults. This effect of NO- closely resembles that of NOS, which also downregulates NMDA receptor activity under similar conditions in culture.

Memory fields of neurons in the primate prefrontal cortex.

Many prefrontal (PF) neurons convey information about both an object's identity (what) and its location (where). To explore how they represent conjunctions of what and where, we explored the receptive fields of their mnemonic activity (i.e., their "memory fields") by requiring monkeys to remember both an object and its location at many positions throughout a wide portion of central vision. Many PF neurons conveyed object information and had highly localized memory fields that emphasized the contralateral, but not necessarily foveal, visual field. These results indicate that PF neurons can simultaneously convey precise location and object information and thus may play a role in constructing a unified representation of a visual scene.

Selective representation of relevant information by neurons in the primate prefrontal cortex.

The severe limitation of the capacity of working memory, the ability to store temporarily and manipulate information, necessitates mechanisms that restrict access to it. Here we report tests to discover whether the activity of neurons in the prefrontal (PF) cortex, the putative neural correlate of working memory, might reflect these mechanisms and preferentially represent behaviourally relevant information. Monkeys performed a 'delayed-matching-to-sample' task with an array of three objects. Only one of the objects in the array was relevant for task performance and the monkeys needed to find that object (the target) and remember its location. For many PF neurons, activity to physically identical arrays varied with the target location; the location of the non-target objects had little or no influence on activity. Information about the target location was present in activity as early as 140ms after array onset. Also, information about which object was the target was reflected in the sustained activity of many PF neurons. These results suggest that the prefrontal cortex is involved in selecting and maintaining behaviourally relevant information.

Neural activity in the primate prefrontal cortex during associative learning.

The prefrontal (PF) cortex has been implicated in the remarkable ability of primates to form and rearrange arbitrary associations rapidly. This ability was studied in two monkeys, using a task that required them to learn to make specific saccades in response to particular cues and then repeatedly reverse these responses. We found that the activity of individual PF neurons represented both the cues and the associated responses, perhaps providing a neural substrate for their association. Furthermore, during learning, neural activity conveyed the direction of the animals' impending responses progressively earlier within each successive trial. The final level of activity just before the response, however, was unaffected by learning. These results suggest a role for the PF cortex in learning arbitrary cue-response associations, an ability critical for complex behavior.

Concentric orientation summation in human form vision.

Psychophysical data demonstrate that orientation information in concentric, random-dot Glass patterns is summed linearly to extract a global form percept. Surprisingly, no such global pooling was found for Glass patterns with parallel structure. A simple neural model explains these results and agrees with recent V4 single unit physiology. As V4 provides the major input to IT, global concentric units may play an important role in analyzing complex images such as faces. In support of this possibility, deficits in the perception of concentric Glass patterns have recently been linked to prosopagnosia.

Excretion and tissue distribution of selenium following treatment of male F344 rats with benzylselenocyanate or sodium selenite.

Benzylselenocyanate (BSC), a synthetic organoselenium compound less toxic than sodium selenite (Na2SeO3), has been demonstrated to inhibit the development of neoplasia in several experimental animal models. We examined the excretion and tissue distribution of total Se after acute administration of BSC compared to Na2SeO3. Male F344 rats were treated po with approximately one-tenth of the LD50 values, our estimate of highest non-toxic dose. The doses administered were 9.85 mg/kg in the case of BSC and 4.35 mg/kg in the case of Na2SeO3. The rats were sacrificed at 1, 6, 24, 72, or 120 hr to obtain biological samples. The levels of total Se were determined by graphite furnace atomic absorption spectrophotometry following microwave digestion. In serum, the highest Se level was observed at 6 hr after administration of either BSC or Na2SeO3: 1.34 +/- 0.07 (mean +/- SE), or 2.09 +/- 0.11 micrograms/ml of serum, respectively. In urine and feces, the cumulative percentages of doses excreted within 3 days of BSC or Na2SeO3 treatment were, respectively, as follows: 11.36 +/- 0.82% and 18.33 +/- 0.77% in urine; and 6.67 +/- 0.66% and 31.14 +/- 4.66% in feces. Among the tissues of BSC-treated rats, the kidneys were found to have the highest Se levels throughout the experimental period (as much as 29 micrograms/g of tissue at 72 hr), followed by liver, small intestine, large intestine, lung, pancreas, heart, and spleen. The results indicate that Se from BSC-treated animals is excreted very slowly and is retained in the organs for a much longer period compared to rats treated with Na2SeO3. Whether the slow excretion and prolonged retention of BSC and/or its metabolites play a role in its chemopreventive action is currently under investigation.

Oxidative DNA and RNA damage in rat liver due to acetoxime: similarity to effects of 2-nitropropane.

Acetoxime (ACO) and 2-nitropropane (2-NP), both industrially important chemicals and known hepatocarcinogens in rats, induced increased levels of 8-hydroxy-guanine in liver DNA and RNA of male Sprague-Dawley and F344 rats after either oral or i.p. administration. Both compounds also produced qualitatively the same patterns of other apparent modifications of liver DNA and RNA nucleosides, discernible by HPLC with electrochemical detection. Six hours after administration, the effects of 2-NP on liver nucleic acids were more pronounced in F344 rats than in Sprague-Dawley rats, suggesting that 2-NP may prove to be a stronger carcinogen in the F344 strain. The effects of ACO, a weaker carcinogen than 2-NP, were less than those of the nitroalkane in both rat strains. These results suggest that the hepatocarcinogenicity of ACO, like that of 2-NP, may depend on increased generation of reactive oxygen species capable of producing DNA and RNA base damage in rat liver. In addition, the data support the hypothesis that the hepatocarcinogenicity of ACO depends on its partial in vivo N-oxidation to 2-NP.