Cortical semantization of autobiographical memory over subjective chronological time: An fMRI study.

The content and neural representation of autobiographical memories change over time; however, these changes are poorly understood. We hypothesize that the content of memories becomes semanticized, while the neural representation moves from mesial to cortical structures. We conducted an fMRI (functional magnetic resonance imaging) study on the effects of time on autobiographical memory retrieval. Twenty healthy participants were cued by a selection of photographs that represented distinct episodic memories from 1, 2, 6, and 14 years prior to scanning. Our behavioural data of self-report measures of memory qualia suggests a loss of episodic content over time. GLM (general linear model) results demonstrate that across all time points, visual association cortices and mesial temporal lobes were activated. However, we did not observe any GLM differences between memory time points. We used SVM (support vector machine) in order to predict memory time point based on neural activation patterns. We were able to accurately predict classification accuracy for the 1-year (66.7%), 2-year (66.7%), and 14-year (33.4%) memory time points, with an overall classification accuracy of 55.6%. We suggest that our findings can be interpreted in light of cortical semantization; as memories age, they become more semanticized and shift in representation towards cortical structures.

Novel endosomolytic poly(amido amine) polymer conjugates for systemic delivery of siRNA to hepatocytes in rodents and nonhuman primates.

The application of small interfering (si)RNAs as potential therapeutic agents requires safe and effective methods for their delivery to the cytoplasm of the target cells and tissues. Recent studies have shown significant progress in the development of targeting reagents that facilitate the recognition of, and siRNA delivery to, specific cell types. Among recently reported delivery approaches, polymers with amphipathic properties have been used to enable endosome escape and cytosolic delivery. Here, we describe a linear amphipathic poly(amido amine) polymer conjugate system for the efficient siRNA delivery in vitro and in vivo. This polymer contains a novel amine bearing bis-acrylamide monomer designed for increasing amine density, which resulted in substantial improvement in liver uptake and RNAi activity compared to our previously reported poly(amido amine disulfide) polymer.1 The activity for this liver targeted delivery system was demonstrated in rodents and nonhuman primates.

Medial prefrontal cortex hyperactivation during social exclusion in borderline personality disorder.

Frontal systems dysfunction and abandonment fears represent central features of borderline personality disorder (BPD). BPD subjects (n=10) and matched non-psychiatric comparison subjects (n=10) completed a social-cognitive task with two confederates instructed to either include or exclude subjects from a circumscribed interaction. Evoked cerebral blood oxygenation in frontal cortex was measured using 16-channel functional near infrared spectroscopy. BPD subjects showed left medial prefrontal cortex hyperactivation during social exclusion suggesting potential dysfunction of frontolimbic circuitry.

Sound stimulus qualities and severe auditory neglect.

We report the case of a patient who developed severe left auditory neglect following a cerebral vascular accident with infarction of areas in the frontal, temporal, and parietal lobes of the right hemisphere. The severity of neglect was documented using pure tones, speech, and environmental stimuli, administered binaurally and dichotically. Acuity examination and unilateral presentation of stimuli allowed exclusion of primary hearing deficit. A dichotic word test was used to evaluate the effects of implicit and explicit cuing. Contrary to our expectations, implicit semantic cues did not attenuate the neglect, and explicit manipulation of sound volume, consisting of increasing the volume in the left ear while maintaining right ear volume at a minimum did not increase the perception of neglected stimuli on the left. Explicit commands to selectively attend to the left ear also failed to improve left ear perception. These findings suggest that some manifestations of auditory neglect are not affected by attributes of the sound stimulus. Furthermore, the finding that manipulation of sound volume had no influence on the neglect supports the hypothesis that sound volume is perceived by the brain as encoded information and not as a simple analogue representation of sound magnitude mediated by variance in the firing rate of neurons in the auditory nerve.

Complex models of white and gray matter integration following training.

For many tasks, an increase in competence is associated with faster response time. Voelker et al (this issue) explore the possible role of white matter reorganization as a mechanism underlying this relationship. With such a strong focus on this possible interpretation and the limits of current neuroimaging methods, the authors constrained their options to the point of only considering simplified models of how training might result in faster responses.

Integrated zone comparison polygraph technique accuracy with scoring algorithms.

The Integrated Zone Comparison Technique (IZCT) was utilized with computerized polygraph instrumentation as part of a blind study in the detection of deception. Three scoring algorithms: ASIT Poly Suite (Academy for Scientific Investigative Training's Horizontal Scoring and Algorithm for Chart Interpretation), PolyScore 5.5, and the Objective Scoring System (OSS) were assessed in the interpretation of the charts generated. Where "Inconclusives" were excluded, accuracy for the IZCT with all three algorithms was 100%. When "Inconclusives" were counted as errors, overall accuracy for the IZCT with ASIT Poly Suite was 90% and accuracy with PolyScore and the Objective Scoring System was 72%.

Asymmetric hydrogenation of N-sulfonylated-alpha-dehydroamino acids: toward the synthesis of an anthrax lethal factor inhibitor.

A novel and highly enantioselective Ru-catalyzed hydrogenation of N-sulfonylated-alpha-dehydroamino acids has been discovered and demonstrated in the synthesis of an anthrax lethal factor inhibitor (LFI). Herein, this methodology is used to prepare N-sulfonylated amino acids in up to 98% ee. This unprecedented hydrogenation uses a chiral Ru catalyst rather than Rh as typical for acylated dehydroamino acids and esters, and this work reports the first asymmetric hydrogenation of a tetrasubstituted dehydroamino acid derivative using a Ru catalyst. [reaction: see text]

Palladium-catalyzed cyanation of aryl bromides promoted by low-level organotin compounds.

A novel method for palladium-catalyzed cyanation of aryl bromides promoted by low-level tri-n-butyltin chloride or cyanide is described. The method features low catalyst loading and mild reaction conditions. KCN is used as the cyanide source. Only trace levels of the tri-n-butyltin compound are required to achieve high conversion and yield in the cyanation of aryl bromides, iodides, and triflates.

Diffusion tensor imaging of the hippocampal formation in temporal lobe epilepsy.

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) is a noninvasive technique that can be used to assess the integrity of cerebral tissue. The purpose of this study was to assess DTI measurements in the hippocampal formation (HF) and to investigate the role of DTI in lateralizing the seizure focus in temporal lobe epilepsy (TLE). METHODS: We evaluated 12 patients with unilateral TLE and 14 healthy subjects. We collected diffusion-weighted images along six different directions with a b value of 1000 s/mm(2), as well as an image acquired without diffusion weighting (b = 0 s/mm(2)). A 1.5-T imager was used to acquire 17 (3-mm) coronal sections covering the temporal lobes. We compared the mean diffusivity (trace D) and fractional anisotropy (FA) from symmetrical voxels by sampling the anterior HF bilaterally. We compared measurements with the EEG, high-resolution MR imaging, and clinical information. RESULTS: The patient group had significantly increased diffusivity and decreased FA in the HF ipsilateral to the seizure focus, as compared with values in the contralateral HF. When compared with healthy subjects, patients had significantly higher mean diffusivity in the ipsilateral HF; ipsilateral FA values were lower and did not reach statistical significance. Measurements in the contralateral HF did not show differences. Left-right and absolute diffusivity indices lateralized the abnormal HF in eight and five of 12 patients, respectively. CONCLUSION: Abnormal DTI measurements and the epileptogenic HF are associated in unilateral TLE. This finding may reflect hippocampal sclerosis and may aid in presurgical evaluation.

An in vivo evaluation of amphiphilic, biodegradable peptide copolymers as siRNA delivery agents.

A series of amphiphilic, biodegradable polypeptide copolymers were prepared for the delivery of siRNA (short interfering ribonucleic acid). The molecular weight (or polymer chain length) of the linear polymer was controlled by reaction stoichiometry for the 11.5, 17.2, and 24.6 kDa polypeptides, and the highest molecular weight polypeptide was prepared using a sequential addition method to obtain a polypeptide having a molecular weight of 38.6 kDa. These polymers were used to prepare polymer conjugate systems designed to target and deliver an apolipoprotein B (ApoB) siRNA to hepatocyte cells and to help delineate the effect of polymer molecular weight or polymer chain length on siRNA delivery in vivo. A clear trend in increasing potency was found with increasing molecular weight of the polymers examined (at a constant polymer:siRNA (w/w) ratio), with minimal toxicity found. Furthermore, the biodegradability of these polymer conjugates was examined and demonstrates the potential of these systems as siRNA delivery vectors.

Development of a liver-targeted siRNA delivery platform with a broad therapeutic window utilizing biodegradable polypeptide-based polymer conjugates.

The greatest challenge standing in the way of effective in vivo siRNA delivery is creating a delivery vehicle that mediates a high degree of efficacy with a broad therapeutic window. Key structure-activity relationships of a poly(amide) polymer conjugate siRNA delivery platform were explored to discover the optimized polymer parameters that yield the highest activity of mRNA knockdown in the liver. At the same time, the poly(amide) backbone of the polymers allowed for the metabolism and clearance of the polymer from the body very quickly, which was established using radiolabeled polymers to demonstrate the time course of biodistribution and excretion from the body. The fast degradation and clearance of the polymers provided for very low toxicity at efficacious doses, and the therapeutic window of this poly(amide)-based siRNA delivery platform was shown to be much broader than a comparable polymer platform. The results of this work illustrate that the poly(amide) platform has a promising future in the development of a siRNA-based drug approved for human use.

Anxiety and memory test performance.

The present study examined the relationship of extra-test anxiety to memory test performance among patients undergoing cardiopulmonary bypass (N = 47) and back surgery (N = 24). These patients were chosen because they are often anxious before surgery and thus serve as a model of extra-test anxiety. This examination is important in neuropsychology because anxiety may serve as an extraneous factor compromising the validity of attention and memory scores. Anxiety level, determined from self-report and experimenter ratings, and memory performance, as measured by the Memory Assessment Scales and memory self-report, were assessed 1 to 2 days presurgery and approximately 6 weeks post surgery. The study further examined whether anxiety's influence on test performance is mediated by an impulsive cognitive style, as indicated by the Matching Familiar Figures Test. Multivariate analysis of variance (MANOVA) revealed no significant change in state anxiety during the testing interval. MANOVA did reveal significant differences between the two surgery groups on anxiety, and younger patients demonstrated greater anxiety about their upcoming surgery. An examination of the intercorrelations of anxiety and memory scores revealed that they do not share variance and are essentially unrelated. Although the subjects were moderately anxious about the upcoming surgery, this did not apparently influence their performance on memory tests.

The malingering factor.

The influence of malingering and suboptimal performance on neuropsychological tests has become a major interest of clinical neuropsychologists. Methods to detect malingering have focused on specialized tests or embedded patterns associated with malingering present in the conventional neuropsychology tests. There are two stages to the study of their validity. The first stage involves whether the method can discriminate malingering subjects from those who are not malingering. In the second stage, they must be examined for their relationship to the conventional tests used to establish impairment and disability. Constantinou, Bauer, Ashendorf, Fisher, and McCaffrey (2005. Is poor performance on recognition memory effort measures indicative of generalized poor performance on neuropsychological tests? Archives of Clinical Neuropsychology, 20, 191-198.) conducted the only study in which correlations are presented between a commonly used symptom validity test, the Test of Memory Malingering (TOMM) and the subtests of the Wechsler Adult Intelligence Scale-Revised (WAIS-R). A factor analysis was conducted using these correlations. It revealed a clear malingering factor that explained significant variance in the TOMM and the WAIS-R subtests. The relationship of malingering with cognitive tests is complex: some tests are sensitive to malingering and others are not. Factor analysis can summarize the magnitude of variance associated with each test and reveal the patterns of inter-relationships between malingering and clinical tests. The analysis also suggested that malingering assessment methods could be improved by the addition of timing the responses.

A correction for recruitment bias in norms derived from meta-analysis.

Normative comparisons are an integral component of neuropsychological test interpretation and provide the basis for an inference of abnormal function and impairment. In order to remedy a deficit of normative standards for a large number of neuropsychology tests, Mitrushina, Boone, Razani, and D'Elia (2005) used the meta-analysis of studies that incorporated normal volunteers to create a type of normative standard for many tests in neuropsychology that were not adequately normed in the past. The present study examined this method by contrasting meta-analysis norms of the Wechsler Adult Intelligence Scale-Revised (WAIS-R; Wechsler, 1981) with its published quota norms. The study examined 12 experimental studies of the WAIS-R that included normal, control volunteers (N = 2,147). These were combined by meta-analysis, and the summary scores were compared. The meta-analysis revealed a significant sampling bias with studies recruiting more White and higher educated respondents than indicated by the U.S. Census. This bias was successfully corrected using Monte Carlo simulation and adjustments for quota sampling. The corrections could be applied to all meta-analysis norms currently in use and bring them in line with the U.S. Census demographics.

Rapid conversion of API hydrates to anhydrous forms in aqueous media.

Three anhydrous polymorphs, a monohydrate and a dihydrate of an active pharmaceutical ingredient, N-{[(5S)-3-(4-{6-[(1R,5S)-6-cyano-3-oxabicyclo[3.1.0]hex-6-yl]pyridin-3-yl}phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide (Compound 1), have been crystallized and characterized. Slurry experiments and thermal data have been used to determine their relative thermodynamic stability. The hydrates of Compound 1 were found to be less stable than the most stable anhydrous Form I and converted into Form I in water within 15 min. The rate of conversion in a dry state was found to depend on the relative humidity (RH) and was highest at the two RH extremes examined, 5% and 97.5% RH.

The attenuation of auditory neglect by implicit cues.

This study examined implicit semantic and rhyming cues on perception of auditory stimuli among nonaphasic participants who suffered a lesion of the right cerebral hemisphere and auditory neglect of sound perceived by the left ear. Because language represents an elaborate processing of auditory stimuli and the language centers were intact among these patients, it was hypothesized that interactive verbal stimuli presented in a dichotic manner would attenuate neglect. The selected participants were administered an experimental dichotic listening test composed of six types of word pairs: unrelated words, synonyms, antonyms, categorically related words, compound words, and rhyming words. Presentation of word pairs that were semantically related resulted in a dramatic reduction of auditory neglect. Dichotic presentations of rhyming words exacerbated auditory neglect. These findings suggest that the perception of auditory information is strongly affected by the specific content conveyed by the auditory system. Language centers will process a degraded stimulus that contains salient language content. A degraded auditory stimulus is neglected if it is devoid of content that activates the language centers or other cognitive systems. In general, these findings suggest that auditory neglect involves a complex interaction of intact and impaired cerebral processing centers with content that is selectively processed by these centers.

Brain mapping of deception and truth telling about an ecologically valid situation: functional MR imaging and polygraph investigation--initial experience.

PURPOSE: To examine the neural correlates during deception and truth telling by using a functional magnetic resonance (MR) imaging technique and an ecologically valid task and to compare the results with those of a standard polygraph examination. MATERIALS AND METHODS: All subjects gave written informed consent for this HIPAA-approved study, which was approved by the institutional review board of Drexel University. Eleven healthy subjects (five female and six male subjects; mean age, 28.9 years) were randomly assigned to the group of guilty subjects or the group of nonguilty subjects. Each group consisted of two separate functional MR imaging conditions: "lie-only condition" and "truth-only condition." The lie-only condition was used to compare brain activity during a known lie to control questions and a subjective lie to relevant questions. The truth-only condition was used to compare brain activity during a known truthful response to control questions and a subjective truthful response to relevant questions. Functional MR images were acquired with an echo-planar sequence, and statistical analysis was performed. Physiologic responses were measured with a standard four-channel polygraph instrument. RESULTS: During the deception process, specific areas of the frontal lobe (left medial and left inferior frontal lobes), temporal lobe (right hippocampus and right middle temporal gyrus), occipital lobe (left lingual gyrus), anterior cingulate, right fusiform gyrus, and right sublobar insula were significantly active. During the truth telling process, specific areas of the frontal (left subcallosal gyrus or lentiform nucleus) and temporal (left inferior temporal gyrus) lobes were significantly active. The polygraph examination revealed 92% accuracy in deceptive subjects and 70% accuracy in truthful subjects. CONCLUSION: Specific areas of the brain involved in deception or truth telling can be depicted with functional MR imaging.

Practical synthesis of the new carbapenem antibiotic ertapenem sodium.

[reaction: see text] A practical synthesis for the large-scale production of the new carbapenem antibiotic, [4R,5S,6S]-3-[[(3S,5S)-5-[[(3-Carboxyphenyl)amino]carbonyl]-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monosodium salt (ertapenem sodium, 1), has been developed. The synthesis features the novel use of 1,1,3,3-tetramethylguanidine as base for the low-temperature reaction of a thiol, derived from trans-4-hydroxy-L-proline, with the carbapenem nucleus activated as the enol phosphate. Hydrogenolysis of a p-nitrobenzyl ester is effected using a palladium on carbon catalyst to give an overall yield for the two steps of 90%. The use of bicarbonate in the hydrogenolysis was key in providing protection of the pyrrolidine amine as the sodium carbamate improving both the performance of the reaction and the stability of the product. This discovery made processing at manufacturing scale possible. Experimental evidence for the formation of the sodium carbamate is provided. A remarkably expedient process for the simultaneous purification and concentration of the aqueous product stream relies on ion-pairing extraction for the removal of the water-soluble 1,1,3,3-tetramethylguanidine. Crystallization then affords 59-64% overall yield of the monosodium salt form of the product.

Evidence for a dysfunctional prefrontal circuit in patients with an impulsive aggressive disorder.

Humans with lesions to the orbital/medial prefrontal cortex and interconnected areas display impulsive aggressive behavior. To examine further the relationship between impulsive aggression and orbital/medial prefrontal dysfunction, we measured the behavioral performance of psychiatric patients with a disorder characterized by impulsive aggression, Intermittent Explosive Disorder (IED). Presently, no evidence exists for a localized brain lesion in IED subjects. However, on the basis of the location of brain lesions that produce acquired impulsive aggression, we hypothesized that IED subjects would exhibit test performance similar to patients with lesions to the orbital/medial prefrontal cortex. Subjects with IED and controls were administered three tests sensitive to lesions of the orbital/medial prefrontal circuit: the Iowa Gambling Task, facial emotion recognition, and odor identification, and two control tests of working memory. On the gambling task, IED subjects continued to make disadvantageous decisions throughout the 100 trials, whereas controls learned to avoid disadvantageous decisions. On the facial recognition test, IED subjects were impaired at recognizing "anger," "disgust," and "surprise," and they were biased to label neutral faces with "disgust" and "fear." On odor identification, IED subjects were mildly anosmic and were impaired relative to controls. However, on the working memory control tests, both groups performed similarly. Across tests, the performance of IED subjects resembles the performance of patients with orbital/medial prefrontal lesions in previous studies. These results extend the link between dysfunction of the orbital/medial prefrontal circuit and impulsive aggressive behavior.