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The ability to recognize the prior occurrence of objects can operate effectively even in the absence of successful recollection of episodic contextual detail about a relevant past object encounter. The pertinent process, familiarity assessment, is typically probed in humans with recognition-memory tasks that include an experimentally controlled study phase for a list of items. When meaningful stimuli such as words or pictures of common objects are employed, participants must judge familiarity with reference to the recent experimental encounter rather than their lifetime of autobiographical experience, which may have involved hundreds or thousands of exposures across numerous episodic contexts. Humans can, however, also judge the cumulative familiarity of objects concepts they have encountered over their lifetime. At present, little is known about the cognitive and neural mechanisms that support this ability. Here, we tested an individual (NB) with a rare left anterior temporal-lobe lesion that included perirhinal cortex but spared the hippocampus, who had previously been found to exhibit selective impairments in familiarity assessment on verbal recognition-memory tasks. As NB exhibits normal recollection abilities, her case presents a unique opportunity to examine potential links between both types of familiarity. In Experiment 1, we demonstrated that NB's impairment in making recognition judgments affects cumulative frequency judgments for exposure to concept names in a recent study episode. Experiments 2 and 3 revealed, with a task borrowed from the semantic-memory literature, that NB's impairments do indeed extend to abnormalities in judging cumulative lifetime familiarity for object concepts. These abnormalities were not limited to verbal processing, and were present even when pictures were offered as additional cues. Moreover, they showed sensitivity to concept structure as reflected in semantic feature norms; we only observed them for judgments on object concepts with high feature overlap. In Experiment 4, we found that an amnesic patient (HC) with previously established deficits in autobiographical recollection, due to a selective lesion of the extended hippocampal system, does not exhibit any abnormalities in assessing lifetime familiarity. Together, these findings provide support for a functional link between the assessment of recent changes in familiarity, as probed with experimental study-test paradigms, and cumulative lifetime familiarity based on autobiographical experience accrued outside the laboratory. They argue in favor of the notion that familiarity is closely related to the representation of concept knowledge, likely through computations in perirhinal cortex.

Mental representation of the future is a fundamental component of goal-directed behavior. Computational and animal models highlight prospective spatial coding in the hippocampus, mediated by interactions with the prefrontal cortex, as a putative mechanism for simulating future events. Using whole-brain high-resolution functional magnetic resonance imaging and multi-voxel pattern classification, we tested whether the human hippocampus and interrelated cortical structures support prospective representation of navigational goals. Results demonstrated that hippocampal activity patterns code for future goals to which participants subsequently navigate, as well as for intervening locations along the route, consistent with trajectory-specific simulation. The strength of hippocampal goal representations covaried with goal-related coding in the prefrontal, medial temporal, and medial parietal cortex. Collectively, these data indicate that a hippocampal-cortical network supports prospective simulation of navigational events during goal-directed planning.

An important theory holds that semantic knowledge can develop independently of episodic memory. One strong source of evidence supporting this independence comes from the observation that individuals with early hippocampal damage leading to developmental amnesia generally perform normally on standard tests of semantic memory, despite their profound impairment in episodic memory. However, one aspect of semantic memory that has not been explored is conceptual structure. We built on the theoretically important distinction between intrinsic features of object concepts (e.g., shape, colour, parts) and extrinsic features (e.g., how something is used, where it is typically located). The accrual of extrinsic feature knowledge that is important for concepts such as chair or spoon may depend on binding mechanisms in the hippocampus. We tested HC, an individual with developmental amnesia due to a well-characterized lesion of the hippocampus, on her ability to generate semantic features for object concepts. HC generated fewer extrinsic features than controls, but a similar number of intrinsic features than controls. We also tested her on typicality ratings. Her typicality ratings were abnormal for nonliving things (which more strongly depend on extrinsic features), but normal for living things (which more strongly depend on intrinsic features). In contrast, NB, who has MTL but not hippocampal damage due to surgery, showed no impairments in either task. These results suggest that episodic and semantic memory are not entirely independent, and that the hippocampus is important for learning some aspects of conceptual knowledge.

Evidence from numerous sources indicates that recognition of the prior occurrence of objects requires computations of perirhinal cortex (PrC) in the medial temporal lobe (MTL). Extant research has primarily probed recognition memory based on item exposure in a recent experimental study episode. Outside the laboratory, however, familiarity for objects typically accrues gradually with learning across many different episodic contexts, which can be distributed over a lifetime of experience. It is currently unknown whether PrC also tracks this cumulative lifetime experience with object concepts. To address this issue, we con- ducted a functional magnetic resonance imaging (fMRI) experiment in healthy individuals in which we compared judgments of the perceived lifetime familiarity with object concepts, a task that has previously been employed in many normative studies on concept knowledge, with frequency judgments for recent laboratory exposure in a study phase. Guided by neurophysiological data showing that neurons in primate PrC signal prior object exposure at multiple time scales, we predicted that PrC responses would track perceived prior experience in both types of judgments. Left PrC and a number of cortical regions that are often co- activated as part of the default-mode network showed an increase in Blood-Oxygen-Level Dependent (BOLD) response in relation to increases in the perceived cumulative lifetime familiarity of object concepts. These regions included the left hippocampus, left mid-lateral temporal cortex, as well as anterior and posterior cortical midline structures. Critically, left PrC was found to be the only region that showed this response in combination with the typically observed decrease in signal for perceived recent exposure in the experimental study phase. These findings provide, to our knowledge, the first evidence that ties signals in human PrC to variations in cumulative lifetime experience with object concepts. They offer a new link between the role of PrC in recognition memory and its broader role in conceptual processing.

A current debate in the literature is whether all declarative memories and associated memory processes rely on the same neural substrate. Here, we show that H.C., a developmental amnesic person with selective bilateral hippocampal volume loss, has a mild deficit in personal episodic memory, and a more pronounced deficit in public event memory; semantic memory for personal and general knowledge was unimpaired. This was accompanied by a subtle difference in impairment between recollection and familiarity on lab-based tests of recognition memory. Strikingly, H.C.'s recognition did not benefit from a levels-of-processing manipulation. Thus, not all types of declarative memory and related processes can exist independently of the hippocampus even if it is damaged early in life.

Human kallikrein 1-related peptidases (KLKs) form a subfamily of 15 extracellular (chymo)tryptic-like serine proteases. KLKs 4, 5, 13 and 14 display altered expression/activity in diverse pathological conditions, including cancer. However, their distinct (patho)physiological roles remain largely uncharacterized. As a step toward distinguishing their proteolytic functions, we attempt to define their primary and extended substrate specificities and identify candidate biological targets. Heterologously expressed KLKs 4, 5, 13 and 14 were screened against fluorogenic 7-amino-4-carbamoylmethylcoumarin positional scanning-synthetic combinatorial libraries with amino acid diversity at the P1–P4 positions. Our results indicate that these KLKs share a P1 preference for Arg. However, each KLK exhibited distinct P2–P4 specificities, attributable to structural variations in their surface loops. The preferred P4–P1 substrate recognition motifs based on optimal subsite occupancy were as follows: VI-QSAV-QL-R for KLK4; YFWGPV-RK-NSFAM-R for KLK5; VY-R-LFM-R for KLK13; and YW-KRSAM-HNSPA-R for KLK14. Protein database queries using these motifs yielded many extracellular targets, some of which represent plausible KLK substrates. For instance, cathelicidin, urokinase-type plasminogen activator, laminin and transmembrane protease serine 3 were retrieved as novel putative substrates for KLK4, 5, 13 and 14, respectively. Our findings may facilitate studies on the role of KLKs in (patho)physiology and can be used in the development of selective KLK inhibitors.

It is well established that the medial-temporal lobe (MTL) is critical for recognition memory. The MTL is known to be composed of distinct structures that are organized in a hierarchical manner. At present, it remains controversial whether lower structures in this hierarchy, such as perirhinal cortex, support memory functions that are distinct from those of higher structures, in particular the hippocampus. Perirhinal cortex has been proposed to play a specific role in the assessment of familiarity during recognition, which can be distinguished from the selective contributions of the hippocampus to the recollection of episodic detail. Some researchers have argued, however, that the distinction between familiarity and recollection cannot capture functional specialization within the MTL and have proposed single-process accounts. Evidence supporting the dual-process view comes from demonstrations that selective hippocampal damage can produce isolated recollection impairments. It is unclear, however, whether temporal-lobe lesions that spare the hippocampus can produce selective familiarity impairments. Without this demonstration, single-process accounts cannot be ruled out. We examined recognition memory in NB, an individual who underwent surgical resection of left anterior temporal-lobe structures for treatment of intractable epilepsy. Her resection included a large portion of perirhinal cortex but spared the hippocampus. The results of four experiments based on three different experimental procedures (remember-know paradigm, receiver operating characteristics, and response-deadline procedure) indicate that NB exhibits impaired familiarity with preserved recollection. The present findings thus provide a crucial missing piece of support for functional specialization in the MTL.

We continuously encounter and process novel events in the surrounding world, but only some episodes will leave detailed memory traces that can be recollected after weeks and months. Here, our aim was to monitor brain activity during encoding of events that eventually transforms into long-term stable memories. Previous functional magnetic resonance imaging (fMRI) studies have shown that the degree of activation of different brain regions during encoding is predictive of later recollection success. However, most of these studies tested participants' memories the same day as encoding occurred, whereas several lines of research suggest that extended post-encoding processing is of crucial importance for long-term consolidation. Using fMRI, we tested whether the same encoding mechanisms are predictive of recollection success after hours as after a retention interval of several weeks. Seventy-eight participants were scanned during an associative encoding task and given a source memory test the same day or after ∼6 weeks. We found a strong link between regional activity levels during encoding and recollection success over short time intervals. However, results further showed that durable source memories, i.e., events recollected after several weeks, were not simply the events associated with the highest activity levels at encoding. Rather, strong levels of connectivity between the right hippocampus and perceptual areas, as well as with parts of the self-referential default-mode network, seemed instrumental in establishing durable source memories. Thus, we argue that an initial intensity-based encoding is necessary for short-term encoding of events, whereas additional processes involving hippocampal–cortical communication aid transformation into stable long-term memories.

Inhibition of return (IOR) refers to the finding that, when the time lag between a cue and a target is prolonged, the reaction to the target, when it eventually appears, is actually slower than with no cue. This phenomenon is thought to make visual search more efficient, and it is subserved by the left inferior parietal cortex and the supramarginal gyrus bilaterally. Interestingly, the very same brain structures are also involved in letter processing. Accordingly, we asked whether the two mental processes interfere with each other when simultaneously probed. The first experiment used a typical IOR procedure, but the cue/target placeholders were either simple geometric shapes or English letters. The results show that, although IOR is approximately the same across visual fields when shape placeholders are used, it is significantly lessened in the right visual field when letters are used as cue and target placeholders. To examine if this finding was due to potential spatial frequency differences between the placeholders, a second experiment using shapes and Japanese letters was conducted, and no differences in IOR were found. The supramarginal gyrus appears to be the most likely locus for the letter-IOR interference effect because it is active bilaterally in IOR, but only in the left hemisphere during letter processing. These findings provide support for the notion that IOR is not simply due to subcortical processes but also involves processing from cortical structures.

Varicocele represents the most common cause of male infertility, and most reports indicate that varicocelectomy has a beneficial effect on male fertility and pregnancy outcome. Assisted reproductive technologies (ARTs) are an alternative to varicocelec- tomy for the management of couples with a varicocele. The age of the female partner is important in the decision-making process; how- ever, the true influence of female age on pregnancy outcome follow- ing varicocelectomy or ART in these couples is unknown. We eval- uated the outcomes of 2 cohorts of infertile men with a varicocele and a female partner 35 years of age or older; one group selected varicocelectomy and the other a nonsurgical approach. We reviewed a group of consecutive infertile men who underwent microsurgical varicocelectomy and whose partners are 35 years of age or older (n 5 110). We also reviewed a consecutive group of men with vari- coceles who elected not to have surgery and whose partners are 35 years of age or older (n 5 94). The outcome measures included changes in semen parameters, pregnancy rates (assisted and un- assisted), and use of ART. The surgical and nonsurgical groups had comparable semen parameters and female ages. Mean sperm con- centration and motility increased significantly after varicocelectomy (P , .05). At a mean of 30 months follow-up, 35% of couples in the surgical group achieved a spontaneous pregnancy and an additional 6% achieved a pregnancy via ART (20% of this group attempted ART). In the nonsurgical group, 25% achieved a spontaneous preg- nancy and an additional 16% achieved a pregnancy with ART (40% of this group attempted ART). This study on the natural history of infertile men with varicocele and advanced female age suggests that the surgical and nonsurgical approaches offer comparable pregnan- cy outcome (combined assisted and unassisted pregnancy rates are about 40%). Overall, these data suggest that varicocelectomy is an acceptable option for couples with advanced female age, but other female factors must be considered in the decision-making process.

Objectives. To examine the predictive value of the gonadotropin-releasing hormone (GnRH) stimulation test in a large cohort of infertile men undergoing varicocelectomy. Methods. We examined the records of 144 consecutive infertile couples in whom the man underwent microsurgical varicocelectomy between September 1998 and December 2002. All men underwent a GnRH stimulation test before surgery. Data on the preoperative and postoperative semen parameters, pregnancy outcome, and follicle-stimulating hormone (FSH) and luteinizing hormone increase after GnRH stimulation were recorded. Results. The mean (SE) sperm concentration and motility 6 months after varicocelectomy were significantly greater than the preoperative values (25.3 2.4 versus 19.7 2.1 10 6 /mL and 29.2% 1.4% versus 25.3% 1.3%, respectively, P 0.05). Overall, 28% of the couples achieved a spontaneous pregnancy at a mean of 22 months of follow-up. The median elevation in the FSH and luteinizing hormone value 60 minutes after GnRH administration was 1.8 and 5.6 times the baseline level, respectively. No statistically significant relationship was found between the FSH or LH response to GnRH stimulation and improvement in the semen parameters or positive pregnancy outcome in our population. Conclusions. Our data showed that the FSH response to bolus GnRH stimulation does not predict improvement in semen parameters or unassisted pregnancy outcome in couples in whom the man undergoes varicocelectomy (for treatment of varicocele). The study was the largest of its type and sufficiently powered to validate these findings. The results indicate that the bolus GnRH stimulation test is of no clinical value in the treatment of infertile men with varicoceles. UROLOGY 63: 1143‐1147, 2004. © 2004 Elsevier Inc.

It is widely accepted that signal-detection mechanisms contribute to item-recognition memory decisions that involve discriminations between targets and lures based on a controlled laboratory study episode. Here, the authors employed mathematical modeling of receiver operating characteristics (ROC) to determine whether and how a signal-detection mechanism contributes to discriminations between moderately famous and fictional names based on lifetime experience. Unique to fame judgments is a lack of control over participants' previous exposure to the stimuli deemed "targets" by the experimenter; specifically, if they pertain to moderately famous individuals, participants may have had no prior exposure to a substantial proportion of the famous names presented. The authors adopted established models from the recognition-memory literature to examine the quantitative fit that could be obtained through the inclusion of signal-detection and threshold mechanisms for two data sets. They first established that a signal-detection process operating on graded evidence is critical to account for the fame judgment data they collected. They then determined whether the graded memory evidence for famous names would best be described with one distribution with greater variance than that for the fictional names, or with two finite mixture distributions for famous names that correspond to items with or without prior exposure, respectively. Analyses revealed that a model that included a d' parameter, as well as a mixture parameter, provided the best compromise between number of parameters and quantitative fit. Additional comparisons between this equal-variance signal-detection mixture model and a dual-process model, which included a high-threshold process in addition to a signal-detection process, also favored the former model. In support of the conjecture that the mixture parameter captures participants' prior experience, the authors found that it was increased when the analysis was restricted to names in occupational categories for which participants indicated high exposure.

Research has firmly established a link between recognition memory and the functional integrity of the medial temporal lobes (MTL). Dual-process models of MTL organization maintain that there is a division of labour within the MTL, with the hippocampus (HC) supporting recollective processes and perirhinal cortex (PRc) supporting familiarity assessment. An older neuropsychological literature suggested a different type of division of labour within the MTL, with left-sided structures playing a critical role in memory for verbal materials and right-sided structures being differentially involved in memory for material that cannot easily be verbalized. Research that has related predictions made by these two accounts to each other is limited. Evidence from research in patients with selective recollection impairments and fMRI data in healthy individuals suggests that lateralization of recollection for verbal materials is not clear-cut. Here we examined lateralization of familiarity processes in the MTL by asking whether selective familiarity impairments after unilateral anterior temporal-lobe removal with hippocampal sparing are material specific. We examined this issue in NB, an individual who was previously shown to exhibit selective familiarity impairments with such a lesion (Bowles et al., 2007). We administered three similar recognition memory tests in combination with the same Remember-Know procedure for three different types of novel stimuli without pre-existing semantic representations. Analyses focused on discrimination and on possible differences in response criterion, and included an ROC based approach as well. We found that NB exhibited a deficit in overall recognition of aurally presented pronounceable non-words that reflected a specific impairment of familiarity assessment with preservation of recollective processes. Examination of recognition memory for visually presented abstract pictures and faces did not reveal any impairment, neither at the level of overall recognition nor, more specifically, at the level of familiarity assessment. These findings suggest that the neural mechanisms that support familiarity assessment in the temporal lobe operate in a manner that is tied to the specific stimulus class being assessed.

Although it is well established that the integrity of the medial temporal lobe (MTL) is critical for declarative memory, the func- tional organization of the MTL remains a matter of intense debate. One issue that has received little consideration so far is whether the hippo- campus can function normally in the presence of a lesion to perirhinal cortex that produces noticeable memory impairments. This question is intriguing as the MTL forms a hierarchical system, in which perirhinal cortex represents one of the critical nodes in the reciprocal projections between neocortical association areas and the hippocampus. Here, we used functional magnetic resonance imaging to examine whether NB, an individual who underwent surgical resection of the left anterior tem- poral lobe that included large aspects of perirhinal and entorhinal cor- tex but spared the hippocampus, exhibits intact hippocampal novelty responses to auditory sentences. Our results revealed such evidence in NB's left and right hippocampus. They complement previous behavioral work in NB, indicating that recollective processes considered to rely on hippocampal integrity are also preserved. Further analyses revealed intact novelty responses in structures that provide neuroanatomical input to the hippocampus, including remaining perirhinal cortex and surgically spared parahippocampal cortex. These findings point to viable neuroanatomical mechanisms as to how functional integrity in the hip- pocampus may be maintained in the face of widespread, but incomplete removal of its input structures. V V C 2010 Wiley-Liss, Inc.

Research has firmly established that the integrity of the medial temporal lobe (MTL) is critical for recognition memory. This ability is supported by recollection, which involves recovery of contextual details of a past stimulus encounter, and familiarity assessment, which leads to awareness of prior occurrence without such recovery. Dual-process models of MTL organization posit that recollection and familiarity are supported by the hippocampus and perirhinal cortex, respectively. Alternatively, it has been argued that both structures support these recognition processes similarly as part of a more integrated declarative memory system; from this perspective, reported selective recollection impairments with circumscribed hippocampal lesions may reflect differential sensitivity to overall memory strength, rather than a deficit in a distinct recognition process. Findings from past neuropsychological research remain inconsistent and controversial, in part due to biases in patient selection, variability in clinical etiology, and limited lesion documentation. Here, we administered a verbal recognition-memory task in combination with remember-know judgements to 10 individuals who had undergone left- or right-sided stereotactic amygdalo-hippocampotomy as a surgical treatment for intractable temporal-lobe epilepsy. Comparisons with healthy control participants revealed isolated impairments in recollection with preserved familiarity, regardless of hemispheric site of lesion. In addition, we show that this impairment can be observed at a comparable level of memory strength (i.e., overall recognition performance) as the selective familiarity impairment we previously described in N.B.--an individual who underwent a tailored surgical resection of the left anterior temporal lobe with hippocampal sparing for treatment of temporal-lobe epilepsy. By revealing a double dissociation concerning temporal-lobe mechanisms for recollection and familiarity, this evidence argues against a unitary, strength-based account of MTL organization.

Objectives To examine patient compliance, complications, and significance of rare nonmotile sperm (RNMS) after no-scalpel vasectomy. Methods We reviewed the records of 690 consecutive men who had undergone vasectomy at our institution between 1996 and 2002. All men were instructed to submit two initial semen samples for analysis (3 and 4 months after vasectomy) and additional samples (at 2-month intervals) if sperm were identified on the initial and subsequent analyses. All patient complaints (telephone and clinic visit) were recorded. Results A total of 315 men (45.6%) did not submit any semen samples. Of the 295 men who submitted two samples, 176 (60%) were azoospermic, 110 (37%) had RNMS, and 9 men (3%) had rare motile sperm (the vasectomy of 1 of these 9 men subsequently failed). Of the 110 men with RNMS, 83 submitted one or more additional semen samples. Of these 83 men, 62 (75%) had become azoospermic, 20 (24%) had persistent RNMS, and 1 (1%) subsequently had a failed vasectomy (with motile sperm). The 2 patients with failure underwent a repeat vasectomy (failure rate 0.67% [2 of 295]). A total of 69 patients (10%) reported a complaint, but only 9 (1.5%) of these men returned for clinical examination. No surgical complications and no pregnancies occurred. Conclusions Our data show that despite aggressive counseling, compliance with follow-up testing is very poor. Patient-reported complaints are common but minor. We found that most men with RNMS become azoospermic and propose that the presence of RNMS is consistent with a successful vasectomy. However, long-term, prospective studies are needed to assess the risk of late failure in men with RNMS.