Postsurgical Testing Research Articles

Stool and blood biomarkers for colorectal cancer management: an update on screening and disease monitoring.

Biomarkers have revolutionized the management of colorectal cancer (CRC), facilitating early detection, prevention, personalized treatment, and minimal residual disease (MRD) monitoring. This review explores current CRC screening strategies and emerging biomarker applications. We summarize the landscape of non-invasive CRC screening and MRD detection strategies, discuss the limitations of the current approaches, and highlight the promising potential of novel biomarker solutions. The fecal immunochemical test remained the cornerstone of CRC screening, but its sensitivity has been improved by assays that combined its performance with other stool analytes. However, their sensitivity for advanced adenomas and the patient compliance both remain suboptimal. Blood-based tests promise to increase compliance but require further refinement to compete with stool-based biomarker tests. The ideal scenario involves leveraging blood tests to increase screening participation, and simultaneously promote stool- and endoscopy-based screening among those who are compliant. Once solely reliant on upfront surgery followed by stage and pathology-driven adjuvant chemotherapy, the treatment of stage II and III colon cancer has undergone a revolutionary transformation with the advent of MRD testing after surgery. A decade ago, the concept of using a post-surgical test instead of stage and pathology to determine the need for adjuvant chemotherapy was disruptive. Today, a blood test may be more informative of the need for chemotherapy than the stage at diagnosis. Biomarker research is not just improving, but bringing a transformative change to CRC clinical management. Early detection is not just getting better, but improving thanks to a multi-modality approach, and personalized treatment plans are not just becoming a reality, but a promising future with MRD testing.

Association of tumor-informed minimal residual disease (MRD) with clinical outcomes for muscle invasive bladder cancer (MIBC): A multicenter retrospective real-world analysis.

3050 Background: Muscle invasive bladder cancer is associated with a significant elevated risk of mortality and morbidity due to micro metastatic spread at the time of diagnosis. Accurate biomarkers to guide treatment determination and evaluate response are needed. Previous studies using tumor informed ct-DNA have shown that MRD assessment may be informative in these scenarios. Methods: We conducted a retrospective multicenter analysis of real-world data obtained from commercial testing (Signatera; Natera, Inc.). This cohort of MIBC patients included those who underwent radical cystectomy with a minimum follow up of 90 days. Data were collected on patient demographics, clinical and pathological staging, histologic type, and treatments. Correlation of ct-DNA status with clinical outcomes was analyzed using Cox-regression analysis to evaluate utility of the assay for detecting residual disease post-surgery and radiological recurrence. Results: A total of 109 patients with 545 plasma samples were identified that fit the inclusion criteria. The majority of the patients [79, 72.5%] were male, with a median age of 70 (range: 32-88) years. Most patients had pure urothelial carcinoma [73.4%, 80/109]. Median follow-up was 13.63 (range: 3-89.04) months. On analyzing the first time point post-surgery (median 54 days), 91.55% (65/71) of ct-DNA negative patients at the first post-surgical test remained recurrence free while 65.79% (25/38) of positive patients had recurred at data cut-off. Therefore, ct-DNA positivity at the first post-surgical timepoint was associated with shorter disease-free survival (DFS) (HR=9.9, 95%CI: 4.1-24%, p<0.001). ct-DNA detected imaging recurrence with a median lead time of 61 days (range: 12-381). Similarly, on analyzing ct-DNA positivity at any time post-surgery, of those who remained ct-DNA negative (N=63), 96.83% (61/63) showed no evidence of recurrent disease. On the other hand, 63.04% (29/46) of pts with ct-DNA positivity at any time after cystectomy recurred and experienced reduced DFS (HR=25, 95%CI: 5.9-103%, p<0.001). The assay’s sensitivity for predicting radiological recurrence at any time post-surgery was 93.55%. Notably, in the multivariate analysis, anytime ct-DNA positivity after cystectomy was found to be the only significant risk factor associated with shorter DFS (HR=23.07, 95%CI: 5.1-104.4, p<0.001). Conclusions: In this initial analysis of real-world data, MRD detection via tumor-informed ct-DNA testing was highly prognostic of patient outcomes post-surgery and may guide adjuvant treatment decisions. Future studies in this setting will explore the utility of ct-DNA testing as a predictive biomarker in response to systemic therapy.

SAT-388 Dry Cough as Only Sign of a Parathyroid Adenoma Producer of PTH

BACKGROUND: The parathyroid adenoma producing an excess of PTH is characterized by hypercalcemia, asthenia, physical weakness and renal lithiasis. This clinical case is presented only with a dry (non-productive) cough sign of long duration.CASE: 51-year-old female born in Padre Las Casas, D.R. presenting with chief complain of dry cough for about four years. Clinical findings: (03/13/2019) Height 62”, Weight 142 lbs, Temperature 36.2 Celsius, BP 90/60 mmHg, RR 16 rpm, HR 60 bpm, on her neck no adenopathies or thyroid changes. Occasional coughing. A sonographic evaluation of the neck (04/09/2019) reveals a solid, heterogeneous nodular image of 0.7 cm x 0.5 cm in the left lobe of the Thyroid (Fig. 1) which by FNAB (04/10/2019) showed a benign adenomatoid node with cystic changes (Bethesda II) (Fig. 2). TEST: (03/20/2019) anti-TG 0.10 IU/mL (NV -115), anti-TPO 9.00 IU/mL (NV -34), TG 9.41 (NV -78 ng/mL), TSH 0.34 μIU/mL (VN 0.27-4.20), free T3 2.05 pg/mL (NV 2.04-4.40), total T3 0.74 ng/mL (NV 0.83-2.00), total T4 8.46 μg/dL (NV 5.1-14.1), free T4 1.61 ng/dL (NV 0.93-1.71) Calcium 10.4 mg/dL (NV 8.1-10.4), Phosphorus 2.6 mg/dL (NV 2.5-4.5), PTH-Intact 157 pg/mL (NV 14.5-87.1) Thyroid-Parathyroid scintigraphy (Sestamibi-Technetium 99mTc04: 15 mCi) (04/23/2019) shows lower left Parathyroid Adenoma (Fig. 3). She undergoes surgery (05/23/2019) removing the left thyroid lobe and left inferior parathyroid gland whose pathology shows chronic nodular colloid goiter, with areas of hemorrhage. Parathyroid adenoma of main cells (Fig. 4-5). Post-surgical TEST (06/24/2019) PTH-intact 69.0 pg/mL (NV 14.5-87.1), Calcium 8.6 mg/dL (NV 8.1-10.4), Phosphorus 2.7 mg/dL (NV 2.5-4.5), anti-TG 10.0 IU/mL (NV <115), anti-TPO 9.00 IU/mL (NV <34), TG 8.92 ng/mL (NV <78), total T3 0.68 ng/mL (NV 0.83-2.00), free T3 1.95 pg/mL (NV 2.04-4.40), total T4 6.40 μg/dL (NV 5.1-14.1), free T4 1.02 ng/dL (NV 0.93-1.71). Post-surgical clinical evaluation (06/21/2019) Weight 142 lbs, Temperature 36.5 Celsius, BP 110/70 mmHg, RR 16 rpm, HR 60 bpm. Patient has not shown signs of coughing. Last TESTS (10/20/2019) Calcium 9.40 mg/dL, Phosphorus 3.10 mg/dL, PTH-intact 24.40 pg/mL, TG 11.90 ng/mL, total T4 6.80 μg/dL, free T4 1.23 ng/dL, total T3 0.88 ng/mL, free T3 2.66 pg/mL, anti-TPO 11.14 IU/mL, anti-TG 10 IU/mL. CONCLUSIONS: Lower left (benign) parathyroid adenoma whose clinical manifestations are not common. Dry (non-productive) cough is not known as a manifestation of elevated PTH-intact. Calcium and Phosphorus levels in normal values. In addition, histological alterations of the left thyroid lobe of benign character with few manifestations of hormonal alterations and normal antibodies. It is of crucial clinical importance to observe and document more cases with similar presentation in order to identify the possible causes of cough with an elevated PTH manifestation.

CA125 over-release behavior following a 75-g oral glucose test as a predictive biomarker of multidrug resistance in patients with ovarian cancer.

Multidrug resistance is a major cause of death in patients with ovarian cancer. To improve patient survival, we developed a novel, noninvasive and convenient tool, the 75-gram oral glucose (75gOG)-stimulated CA125 test, to monitor cancer chemoresistance in real time. Our in vitro proof-of-principal experiments revealed that post-75gOG glucose and insulin peaks can synergistically increase cancer-derived CA125 levels, and the increase in CA125 secretion (ΔCA125) is correlated with the overactivation of the insulin receptor (IR)-PI3K-Akt axis and increases (ΔIC50 s) in cisplatin/taxol IC50 s. Correspondingly, among the 93 patients enrolled, post-75gOG CA125 over-release (i.e., enhanced ΔCA125) behavior was associated with overexpression of the IR-PI3K-Akt pathway and its downstream components, namely, IR, pAkt, pS6 and GLUT4, in cancer specimens. Furthermore, both pre- and postsurgical 75gOG CA125 tests demonstrated that CA125 over-release showed excellent prediction efficacy on the chemoresistance potential of ovarian cancer; notably, the former indicated the need for an optimal debulking surgery, and the latter suggested the use of IR-PI3K-Akt inhibitors. Both test results possess independent prognostic significance for the 2-year progression-free survival (PFS) and overall survival (OS) of patients. The odds ratios and corresponding 95% confidence intervals (95% CIs) were 2.680 (95% CI: 1.393-5.156) for patients with CA125 over-release behavior evidenced by a presurgical 75gOG CA125 test or 3.822 (95% CI: 1.942-7.522) for that evidenced by a postsurgical test in PFS; and 3.320 (95% CI: 1.508-7.309) for patients with CA125 over-release behavior evidenced by a presurgical test or 5.212 (95% CI: 2.241-12.121) for that evidenced by a postsurgical test in OS.

Effects of surgical side and site on psychological symptoms following epilepsy surgery in adults.

This retrospective study examined the potential role of side and site of surgery in psychological symptom change after epilepsy surgery and determined the base rate of psychological change at the individual level. Two-hundred twenty-eight adults completed the Personality Assessment Inventory (PAI) before and after temporal (TLR; n=190) or frontal lobe resection (FLR; n=38). Repeated measures ANOVAs with bootstrapping examined differences in psychological outcome as a function of surgical site separately in patients who underwent left- versus right-sided resections. Individual's PAI score changes were then used to determine the prevalence of clinically meaningful postoperative symptom change. Following left-sided resections, there were significant group-by-time interactions on Somatic Complaints, Anxiety, and Anxiety Related Disorders. There was also a trend in this direction on the Depression scale. TLR patients endorsed greater preoperative symptoms than FLR patients on all of these scales, except the Somatic Complaints scale. After surgery, TLR patients reported symptom improvement on all four scales, while scores of FLR patients remained relatively stable over time. Endorsement of Mania-related symptoms increased in both TLR and FLR groups from pre-to post-surgical testing. Following right-sided resections, both groups endorsed symptom improvements on Somatic Complaints, Anxiety, and Depression scales following surgery. In addition, the TLR group endorsed more Mania-related symptoms than the FLR group regardless of time. Patterns of meaningful change in individual patients were generally consistent with group findings, with the most frequent improvements observed following TLR. However, there were a small subset of patients who reported symptom exacerbation after surgery. Our results suggest that surgical lateralization and localization are important factors in postoperative psychological outcome and highlight the importance of considering psychological change at the individual patient level. Further research is needed to identify potential risk factors for symptom exacerbation to aid in preoperative counseling and identify those patients most in need of postoperative psychological surveillance.

Pediatric Meningeal Tumors of the Sylvian Fissure Region without Dural Attachment: A Series of Three Patients and Review of the Literature.

Pediatric meningeal tumors are rare, but those in the region of the sylvian fissure without dural attachment are extremely rare, with only 24 previously reported cases in the world literature. In this series, we report two additional cases of sylvian fissure meningioma without dural attachment and one case of perisylvian meningioangiomatosis in the medial temporal lobe. All three patients presented with complex partial seizures, but the diagnosis was delayed in each case because the symptoms were misinterpreted to be behavioral rather than epileptic. The seizures were eventually confirmed with electroencephalogram, and subsequent imaging showed enhancing masses within the sylvian fissure region that were at least partially calcified in all three cases. Each patient underwent craniotomy. In the first case, gross total resection was achieved, and in the second case, a small residual portion of tumor was densely calcified and adherent to the middle cerebral artery branches. Both of these were World Health Organization (WHO) grade I meningiomas. The third patient underwent biopsy and limited resection of meningioangiomatosis. No dural attachments were noted in any of the tumors, but one of the meningiomas was intraparenchymal in location, surrounding the sylvian fissure in both the frontal and temporal lobes, which has been described in only a small number of these cases previously. The patients underwent pre- and postsurgical neuropsychiatric testing and did not experience any significant cognitive deficits. At 10-year follow-up, the patient who had gross total resection of the tumor has had no recurrence and is seizure-free without anticonvulsant medications. The incompletely resected intraparenchymal meningioma in the second patient recurred after 5 years, however, and at repeat surgery was found to have transformed to a WHO grade II tumor. Radiation therapy was delivered and the tumor has been stable for 2 years, but the patient continues to have occasional seizures despite medication. The patient with meningioangiomatosis has had no further growth and has excellent control of seizures but remains on medication. We review the clinical presentation of these rare tumors and discuss the treatment, outcomes, and possible relationship of meningiomas to meningioangiomatosis.

Quality of life and self-esteem in patients submitted to surgical treatment of skin carcinomas: long-term results.

BACKGROUND Cancer is a multifactorial disease and skin carcinomas are the most common type of cancer. Assessing quality of life and self-esteem outcomes in skin cancer patients is important because these are indicators of the results of the treatment, translating how patients face their lives and their personal relationships. OBJECTIVE To assess the late impact of the surgical treatment of head and/or neck skin carcinomas on quality of life and self-esteem of the patients. METHODS Fifty patients with head or neck skin carcinomas were enrolled. Their age ranged between 30 and 75 years, 27 were men and 23 were women. Patients were assessed with regard to quality of life and self-esteem, preoperatively and five years postoperatively. Validated instruments were used: the MOS 36-item Short-form Health Survey (SF-36) and the Rosenberg Self-esteem/EPM-UNIFESP Scale. The Wilcoxon signed-rank test was used for the statistical analysis. RESULTS Twenty-two patients completed the five-year follow-up, 54.5% women and 45.5% men. Compared to the preoperative assessment, patients had an improvement in mental health (p=0.011) and in self-esteem (p=0.002). There was no statistical difference with regard to the other domains of the SF-36. CONCLUSION Patients submitted to surgical treatment of skin carcinoma improved mental health and self-esteem in the late postsurgical testing.

Changes in Cognitive Function From Presurgery to 4 Months Postsurgery in Individuals Undergoing Dysvascular Amputation

ObjectiveTo describe cognition among individuals with new amputations at 3 time points: presurgical, 6 weeks postamputation, and 4 months postamputation. DesignProspective cohort. SettingMedical centers. ParticipantsReferred sample Veterans who were primarily men (N=80) experiencing their first lower extremity amputation as a result of complications of diabetes mellitus or peripheral arterial disease. Patients were screened for the absence of gross cognitive impairment using the Short Portable Mental Status Questionnaire (SPMSQ). Of those 87 individuals who were eligible, 64% enrolled; 29 were enrolled presurgically and have cognitive data for all 3 time points, and 58 were enrolled postamputation. Eighty of the 87 individuals enrolled by 6 weeks remained enrolled at 4 months. InterventionsNot applicable. Main Outcome MeasuresDemographic and general health information, general mental status (SPMSQ), and 4 brief, well-established neuropsychological measures. ResultsMost mean neuropsychological test scores fell in the low average or average range. For most participants, overall cognitive status improved from pre- to postsurgery and then remained stable between 6 weeks and 4 months. There were significant improvements between pre- and postsurgical test scores in verbal learning and memory, and these remained unchanged between 6 weeks and 4 months. Better 4 month cognitive performance was associated with higher perceived general health. ConclusionsOverall cognitive performance is poorest presurgically. Though there is improvement between pre- and postamputation, cognition appears generally stable between 6 weeks and 4 months.

Palliative hemispherotomy in children with bilateral seizure onset

Intractable epilepsy is a significant burden on families and on the cognitive development and quality of life (QOL) of patients. Periinsular hemispherotomy (PIH) for medically intractable epilepsy can benefit patients who qualify for this procedure. The ideal hemispherotomy candidate has ipsilateral ictal and interictal epileptiform activity, unilateral MR imaging abnormalities, contralateral hemiplegia, and a normal contralateral hemisphere. However, certain patients present with a mixed picture of bilateral electroencephalography (EEG) findings and severe intractable epilepsy, prompting consideration of a more aggressive treatment approach. This report introduces the possibility of surgery for patients who normally would not meet criteria for this treatment modality. In this retrospective chart review, the authors report on 7 patients with bilateral seizure onset noted on routine or video-EEG monitoring. A QOL phone questionnaire, based on the Quality of Life in Childhood Epilepsy tool, was administered to a parent. The authors reviewed each patient's chart for surgical complications, changes in examination, QOL, limited neuropsychological outcomes, and seizure outcomes. They also investigated each chart for MR imaging and EEG findings as well as the patient's epilepsy clinic notes for seizure semiology and frequency. All patients enjoyed a decrease in seizure frequency and a subjective increase in QOL after PIH. Five patients (71%) achieved Engel Class I or II seizure control. The mean follow-up was 3.64 years (2-5.3 years). One patient is now off all antiseizure medication. No patient had a decrement in Full Scale IQ on postsurgical testing, and 2 (28.5%) of 7 individuals had increased adaptive and social functioning. Postsurgical examination changes included hemiplegia and homonymous hemianopia. Hemispherotomy in patients with intractable epilepsy is generally reserved for individuals with unilateral epileptiform abnormalities or lesions on MR imaging. Seven patients in this study benefited from surgery despite bilateral seizure onset with improvement in seizure control and overall QOL. Thus, bilateral ictal onset does not necessarily preclude consideration for hemispherotomy in selected patients with severe medically refractory epilepsy.

Learning-based recovery from perceptual impairment in salt discrimination after permanently altered peripheral gustatory input

Rats lacking input to the chorda tympani (CT) nerve, a facial nerve branch innervating anterior tongue taste buds, show robust impairments in salt discrimination demonstrating its necessity. We tested the sufficiency of the CT for salt taste discrimination and whether the remaining input provided by the greater superficial petrosal (GSP) nerve, a facial nerve branch innervating palatal taste buds, or by the glossopharyngeal (GL) nerve, innervating posterior tongue taste buds, could support performance after extended postsurgical testing. Rats presurgically trained and tested in a two-response operant task to discriminate NaCl from KCl were subjected to sham surgery or transection of the CT (CTx), GL (GLx), or GSP (GSPx), alone or in combination. While initially reduced postsurgically, performance by rats with an intact GSP after CTx + GLx increased to normal over 6 wk of testing. Rats with CTx + GSPx consistently performed near chance levels. In contrast, rats with GSPx + GLx were behaviorally normal. A subset of rats subjected to sham surgery and exposed to lower concentrations during postsurgical testing emulating decreased stimulus intensity after neurotomy showed no significant impairment. These results demonstrate that CTx changes the perceptual nature of NaCl and/or KCl, leading to severe initial postsurgical impairments in discriminability, but a "new" discrimination can be relearned based on the input of the GSP. Despite losing ∼75% of their taste buds, rats are unaffected after GSPx + GLx, demonstrating that the CT is not only necessary, but also sufficient, for maintaining salt taste discrimination, notwithstanding the unlikely contribution of the small percentage of taste receptors innervated by the superior laryngeal nerve.

Rewiring the gustatory system: Specificity between nerve and taste bud field is critical for normal salt discrimination

Forty years have passed since it was demonstrated that a cross-regenerated gustatory nerve in the rat tongue adopts the stimulus–response properties of the taste receptor field it cross-reinnervates. Nevertheless, the functional consequences of channeling peripheral taste signals through inappropriate central circuits remain relatively unexplored. Here we tested whether histologically confirmed cross-regeneration of the chorda tympani nerve (CT) into the posterior tongue in the absence of the glossopharyngeal nerve (GL) (CT-PostTongue) or cross-regeneration of the GL into the anterior tongue in the absence of the CT (GL-AntTongue) would maintain presurgically trained performance in an operant NaCl vs. KCl taste discrimination task in rats. Before surgery all groups were averaging over 90% accuracy. Oral amiloride treatment dropped performance to virtually chance levels. During the first week after surgery, sham-operated rats, GL-transected rats, and rats with regenerated CTs displayed highly competent discrimination performance. In contrast, CT-transected rats were severely impaired (59% accuracy). Both the CT-PostTongue and the GL-AntTongue groups were impaired to a similar degree as CT-transected rats. These initially impaired groups improved their performance over the weeks of postsurgical testing, suggesting that the rats were capable of relearning the task with discriminable signals in the remaining taste nerves. This relearned performance was dependent on input from amiloride-sensitive receptors likely in the palate. Overall, these results suggest that normal competence in a salt discrimination task is dependent on the taste receptor field origin of the input as well as the specific nerve transmitting the signals to its associated circuits in the brain.

The pedunculopontine tegmental nucleus and the nucleus basalis magnocellularis: do both have a role in sustained attention?

BackgroundIt is well established that nucleus basalis magnocellularis (NbM) lesions impair performance on tests of sustained attention. Previous work from this laboratory has also demonstrated that pedunculopontine tegmental nucleus (PPTg) lesioned rats make more omissions on a test of sustained attention, suggesting that it might also play a role in mediating this function. However, the results of the PPTg study were open to alternative interpretation. We aimed to resolve this by conducting a detailed analysis of the effects of damage to each brain region in the same sustained attention task used in our previous work. Rats were trained in the task before surgery and post-surgical testing examined performance in response to unpredictable light signals of 1500 ms and 4000 ms duration. Data for PPTg lesioned rats were compared to control rats, and rats with 192 IgG saporin infusions centred on the NbM. In addition to operant data, video data of rats' performance during the task were also analysed.ResultsBoth lesion groups omitted trials relative to controls but the effect was milder and transient in NbM rats. The number of omitted trials decreased in all groups when tested using the 4000 ms signal compared to the 1500 ms signal. This confirmed previous findings for PPTg lesioned rats. Detailed analysis revealed that the increase in omissions in PPTg rats was not a consequence of motor impairment. The video data (taken on selected days) showed reduced lever orientation in PPTg lesioned rats, coupled with an increase in unconditioned behaviours such as rearing and sniffing. In contrast NbM rats showed evidence of inadequate lever pressing.ConclusionThe question addressed here is whether the PPTg and NbM both have a role in sustained attention. Rats bearing lesions of either structure showed deficits in the test used. However, we conclude that the most parsimonious explanation for the deficit observed in PPTg rats is inadequate response organization, rather than impairment in sustained attention. Furthermore the impairment observed in NbM lesioned rats included lever pressing difficulties in addition to impaired sustained attention. Unfortunately we could not link these deficits directly to cholinergic neuronal loss.

Nonidiopathic Focal Epilepsies: Methodological Problems for a Comprehensive Neuropsychological Evaluation

In aiming to define better practice parameters for neuropsychological assessment in patients with nonidiopathic partial epilepsies, particularly in children, we discuss the reasons for the current lack of clear answers. The relevant factors include the epilepsy itself, the complexity of the issues related to cognitive function/dysfunction and the underlying developmental processes. Another factor is the lack of availability and high cost of neuropsychological testing, even in industrialized societies. Because of these factors, the need for neuropsychological testing must be considered on an individual basis in the initial evaluation of every child with focal epilepsy; it should be left to the clinician and parents to decide which children will actually be referred. Systematic presurgical and postsurgical testing is important for surgical candidates. Comprehensive research protocols should be designed on a collaborative basis between large epilepsy centers, covering all the essential parameters to be evaluated. Children with focal epilepsies should be included in these protocols from the onset of the epilepsy.

Effects of gonadectomy and androgen supplementation on attention in male rats

Androgens are hypothesized to enhance aspects of mnemonic processing. However, it is unclear whether the memory improvement is associated with changes in earlier aspects of information processing, such as attention. The present experiments examined the effects of gonadectomy or supplementation with testosterone or dihydrotestosterone on performance of male rats in a two-lever attention task that required discrimination of visual signals and non-signals. In Experiment 1, Long–Evans rats were trained in the attention task and then underwent gonadectomy or sham-surgery. Postsurgically, animals were tested for 20 sessions in the attention task and then received manipulations designed to increase attentional demands. Gonadectomized and sham-treated animals performed similarly during immediate postsurgical testing and across all manipulations. Finally, the effects of administering the muscarinic receptor antagonist scopolamine (0, 0.1, and 0.2 mg/kg) on attentional performance were assessed for all animals. Scopolamine decreased accuracy of signal detection but did not differentially affect gonadectomized and sham-treated animals. In Experiment 2, a new group of rats (not gonadectomized) was trained to perform the attention task and subsequently administered testosterone (0, 0.1, and 0.5 mg/kg) or dihydrotestosterone (0, 0.1, and 0.5 mg/kg) prior to performing the standard version of the attention task and in the presence of a visual distractor. Testosterone (0.5 mg/kg) decreased accuracy on non-signal trials and, at 0.1 mg/kg, decreased latencies to retrieve a reward. Dihydrotestosterone (0.5 mg/kg) decreased accuracy on non-signal trials during visual distractor sessions. The present data do not support the hypothesis that alterations in attention critically mediate androgen-induced changes in mnemonic processing. Supra-physiological androgen levels appear to be capable of impairing attentional processing.

Characterization of different paresthesias following orthognathic surgery of the mandible

Paresthesia is a well known consequence of peripheral nerve injury. However, the neural mechanisms of the 2 recognized types, spontaneous and elicited, are currently unknown. This study aimed to investigate these 2 paresthesias and the possible mechanisms accompanying orthognathic surgery. Mechanical-touch thresholds and current perception threshold were measured before and 7 days after surgery in 60 chin sites (mental nerve area) of 30 patients who underwent orthognathic surgery. Similar testing was conducted on healthy volunteers (controls). All sites were classified by the presence or absence of each paresthesia: spontaneous paresthesia or no spontaneous paresthesia, and elicited paresthesia or no elicited paresthesia. Presence or absence analyses were followed-up for 6 weeks after surgery. Gender differences and maxillary surgery did not change the incidence of paresthesia during postoperative week 1 (chi-square test, P > .05). A significantly higher mechanical-touch threshold was observed with spontaneous paresthesia compared with no spontaneous paresthesia (Mann-Whitney U-test; P < .05), but not between no elicited paresthesia and elicited paresthesia (Mann-Whitney U-test; P > .05). A significant increase in postsurgery current perception thresholds values compared with presurgery values was observed at 2,000 Hz in spontaneous paresthesia, and at 2,000 and 5 Hz in elicited paresthesia (paired t test, P < .05). The incidence of spontaneous paresthesia decreased more rapidly than elicited, while the latter tended to increase again during the 6-week postsurgical test period. The results suggested that both spontaneous and elicited paresthesias are associated with damage and dysfunction in myelinated primary afferent fibers, but additional neural mechanisms are implicated during elicited paresthesia.

Nucleus accumbens dopamine and work requirements on interval schedules

Considerable evidence indicates that nucleus accumbens dopamine (DA) is involved in the regulation of instrumental response output, and that interference with DA transmission disrupts the ability of rats to overcome work-related response costs. The present experiments were conducted to assess the effects of accumbens DA depletions on the performance of variable interval schedules, to determine if the intermittence of a schedule, in itself, is an important determinant of sensitivity to accumbens DA depletions. For this purpose, two variable interval 30 s lever pressing schedules were used, each with different response requirements added to the interval requirement. For one of the schedules, the animals were reinforced for the first response after the interval elapsed (tandem variable interval/fixed ratio 1: VI/FR1). On the other schedule an additional work requirement was attached by requiring the rats to make five responses after the interval in order to receive reinforcement (tandem variable interval/fixed ratio 5: VI/FR5). Attachment of the additional work requirement led to greater response rates during baseline training. After training, rats were injected with either ascorbate vehicle or 6-hydroxydopamine (6-OHDA) into the nucleus accumbens. The effects of DA depletion on responding were highly schedule-dependent. DA depletions had no significant effect on lever pressing under the condition with low response requirement (VI/FR1), but these depletions substantially disrupted responding on the schedule with the higher response requirement (VI/FR5). The disruption of responding on the schedule with the high response requirement showed recovery over the 4 weeks of post-surgical testing. In a second experiment, the effect of 6-OHDA on spontaneous locomotion in an open field was assessed. The DA-depleted animals had impairments in locomotion and rearing compared with the vehicle treated rats when tested 8 days after surgery, but not when tested 29 days after surgery, which demonstrates recovery of locomotor function after the accumbens DA depletions. The results of these experiments support the hypothesis that nucleus accumbens DA is involved in regulating behavioral activation. The lever pressing experiment indicates that depletions of DA in the accumbens interfere with the processes that enable rats to overcome behavioral constraints such as work-related response costs, and suggest that the intermittence of reinforcement per se is not the most critical factor in determining sensitivity to accumbens DA depletions.

Nucleus Accumbens Dopamine Depletions and Time-Constrained Progressive Ratio Performance: Effects of Different Ratio Requirements

Two experiments were conducted to determine the effects of accumbens dopamine (DA) depletions on progressive ratio responding for food reinforcement. In one version of this schedule, ratio requirement increased by one response after each reinforcer was obtained (PROG1). In the other version, ratio requirement increased by five responses after each reinforcer was obtained (PROG5). For both versions, 60-min sessions were conducted. Accumbens DA depletions produced by local injections of 6-OHDA substantially decreased the number of responses on both schedules. The deficits in the response number induced by DA depletions persisted through the two weeks of postsurgical testing for both the PROG1 and PROG5 schedules. However, there were differences between the effects of DA depletions on the two schedules in terms of the time to complete the last ratio. Although time to complete the last ratio was significantly reduced by DA depletions only in the first week of testing on the PROG1 schedule, rats recovered on this measure by the second week after surgery. In contrast, DA-depleted rats on the PROG5 schedule showed a more persistent suppression of the time to complete the last ratio, which lasted through both weeks of postsurgical testing. Performance on schedules that generate low baseline rates of responding (e.g., continuous, fixed, and variable interval) is relatively unaffected by accumbens DA depletions; nevertheless, accumbens DA depletions substantially impair progressive ratio response output. The high work output necessary for responding on the PROG5 schedule may make these animals more sensitive to the effects of accumbens DA depletions.

Effects of Dopamine Antagonists and Accumbens Dopamine Depletions on Time-Constrained Progressive-Ratio Performance

Four experiments were conducted to determine the effects of dopamine (DA) antagonists and DA depletions on progressive-ratio responding for food reinforcement. On this schedule, ratio requirement increased by one response after each reinforcer was obtained, and rats were tested in 30-min sessions. Response rates and highest ratio completed were reduced in a dose-related manner by systemic injections of the D 1 antagonist SCH 23390, and also by the D 2 antagonists haloperidol and raclopride. Drug-treated rats also showed reductions in time to complete the last ratio, demonstrating that they had stopped responding before the end of the session. DA depletions produced by injections of 6-OHDA directly into the nucleus accumbens substantially decreased both the number of responses and the highest ratio completed. The deficits in response number and highest ratio completed induced by DA depletions persisted through the first 3 weeks of postsurgical testing, with some recovery by the fourth week. However, the deficits resulting from dopamine depletions were largely a manifestation of a decrease in response rate; although time to complete the last ratio was significantly reduced by dopamine depletions in the first few days of testing, rats recovered on this measure by the fifth day after surgery. Although previous work has shown that performance on several schedules (e.g., continuous, low value ratios, variable interval) is relatively unaffected by accumbens DA depletions, the present data demonstrate that such depletions do produce a substantial and persistent impairment of progressive ratio response output. Rats with accumbens DA depletions appear to have deficits in maintaining the high work output necessary for responding at large ratio values. The relative sparing of responding on some simple schedules, together with the present progressive ratio results, suggest that rats with accumbens DA depletions remain directed toward the acquisition and consumption of food, but they show deficits in work output for food.

Nucleus accumbens dopamine depletions alter relative response allocation in a T-maze cost/benefit task

This experiment was conducted to study the role of nucleus accumbens dopamine in the performance of a novel T-maze cost/benefit procedure. Rats were trained on a T-maze task for food reinforcement. Under one of the test conditions, one arm of the maze contained a high reinforcement density (4 × 45 mg Bioserve pellets) and the other arm contained a low reinforcement density (2 × 45 mg pellets). A large vertical barrier (44 cm) was placed in the arm that contained the high density of food reinforcement. In the second test condition, a separate group of rats was trained in the same T-maze, in which there were 4 food pellets in the arm that was obstructed by the barrier, yet there were no food pellets in the unobstructed arm. After training rats received intra-accumbens of injections 6-hydroxydopamine or ascorbate vehicle. Nucleus accumbens dopamine depletions substantially decreased the number of selections of the obstructed arm with the high reinforcement density when the unobstructed arm also contained 2 food pellets. Dopamine-depleted rats in this condition showed increased selection of the no-barrier arm as well as decreased entry into the arm that contained the barrier. These effects persisted throughout the 3 weeks of post-surgical testing. Nevertheless, when the unobstructed arm contained no food pellets, and the only way to obtain food was to climb the barrier, rats with nucleus accumbens dopamine depletions showed only a modest effect on selections of the obstructed arm, which recovered by the second week of testing. Dopamine-depleted rats that were tested with food in the unobstructed arm showed significantly fewer barrier crossings than dopamine-depleted rats that were tested with no food in the unobstructed arm. Thus, the present findings are not consistent with the notion that nucleus accumbens dopamine depletion rendered the animals unable to climb the barrier, or set an absolute ceiling on the number of barrier crossings the animals could perform. Instead, the present results indicate that nucleus accumbens dopamine depletions affected the relative allocation of barrier climbing responses if alternative food sources were available.

The role of brain dopamine in response initiation: effects of haloperidol and regionally specific dopamine depletions on the local rate of instrumental responding

Two experiments were undertaken to investigate dopaminergic involvement in the local rate of responding on a fixed ratio 5 (FR5) instrumental lever pressing schedule. Rats were trained to press for food reinforcement on a FR5 schedule, and a computer program was used to record the interresponse time (IRT) for each response. The IRT is the time between each lever pressing response, which is equal to the reciprocal of the local response rate. After several weeks of training, rats received i.p. injections of the dopamine antagonist haloperidol (HP; 0.1, 0.2 and 0.4 mg/kg). HP produced a dose-related decline in overall response number. In addition, HP dramatically alteref the IRT distribution. HP-treated rats showed a dose-related reduction in the proportion of IRTs with low time values (high local rates of responding), and a corresponding corresponding increase in the relative of IRTs with high time values (low local rates of responding). In the second experiment, the neurotoxic agent 6-hydroxydopamine was injected directly into the nucleus accumbens, medial neostriatum or ventrolateral neostriatum in order to determine the effects of DA depletion on lever pressing performance. Dopamine depletion in all regions significantly reduced lever pressing, and dopamine-depleted rats had substantial changes in their IRT distributions. Rats with dopamine depletions showed significant reductions in the proprtion of IRTs with low time values, and increased in the relative number of IRTs with high time values. The greatest reductions in response number and the most pronounced alterations of the IRT distribution were shown by rats with ventrolateral neostriatal dopamine depletions. In addition, dopamine levels in the ventrolateral neostriatum were correlated with the total number of responses in the first week of postsurgical testing ( r = 0.71, P < 0.05). These results demonstrate that interference with dopamine transmission by pharmacological antagonism or neurotoxic depletion produces a slowing of local response rate. Moreover, these results indicate that dopamine in the ventrolateral neostriatum is particularly necessary for maintaining very high rates of instrumental responding.