Faculty Bibliography

To preserve postoperative language, electrical stimulation mapping is often conducted prior to surgery involving the language-dominant hemisphere. Object naming is the task most widely used to identify language cortex, and sites where stimulation elicits naming difficulty are typically spared from resection. In clinical practice, sites classified as positive undergo no further testing regarding the underlying cause of naming failure. Word production is a complex function involving multiple mechanisms that culminate in the identification of the target word. Two main mechanisms, i.e., semantic and phonological, underlie the retrieval of stored information regarding word meaning and word sounds, and naming can be hampered by disrupting either of these. These two mechanisms are likely mediated by different brain areas, and therefore, stimulation-identified naming sites might not be functionally equivalent. We investigated whether further testing at stimulation-identified naming sites would reveal an anatomical dissociation between these two mechanisms. In 16 patients with refractory temporal lobe epilepsy (TLE) with implanted subdural electrodes, we tested whether, despite inability to produce an item name, patients could reliably access semantic or phonological information regarding objects during cortical stimulation. We found that stimulation at naming sites in superior temporal cortex tended to impair phonological processing yet spared access to semantic information. By contrast, stimulation of inferior temporal naming sites revealed a greater proportion of sites where semantic access was impaired and a dissociation between sites where stimulation spared or disrupted semantic or phonological processing. These functional-anatomical dissociations reveal the more specific contribution to naming provided by these cortical areas and shed light on the often profound, interictal word-finding deficit observed in temporal lobe epilepsy. Additionally, these techniques potentially lay the groundwork for future studies to determine whether particular naming sites that fall within the margins of the desired clinical resection might be resected without significant risk of decline.

Rationale: Cortical language mapping involves the identification of essential language cortex, which is typically spared from resection with the goal of preserving postoperative language function. Object naming is the most widely used task for this purpose; however, when stimulation impedes naming, it is unclear whether this reflects impaired access to word meaning (i.e., semantics), word sound (i.e., phonology), or both. This distinction is clinically relevant, with implications for level of disability and amenability to remediation. Two sets of psycholinguistic tasks were administered at sites where stimulation impaired naming to determine whether semantic vs. phonological processes were disrupted. Access to distinct types of word information is critical in the two tasks: information about word meaning in the semantic task, information about word sounds in the phonological task. We hypothesized that semantic and phonological naming sites would be anatomically distinct. Methods: Subjects were 12 pharmacologically intractable, TLE patients (9 female, mean age = 34.8, SD = 11.1) who underwent extraoperative language mapping prior to surgical resection for seizure control. Stimulation mapping tasks included visual object naming and auditory description naming. At sites positive for naming, two psycholinguistic tasks were administered: 1) Semantic task: patients were presented pictured items during stimulation and indicated (via "button press") whether the item belongs to a particular semantic category (e.g., edible, found indoors); 2) Phonological task: patients indicated whether the item name begins with a particular sound (e.g., "p" or "f"). Results: Across patients, we identified 53 naming sites (38 visual naming, 15 auditory naming). Semantic task performance was impaired at 3 of these sites, phonological task performance was impaired at 14 of these sites, and both semantic and phonological task performance were impaired at 7 of these sites. Topographically, phonological-naming sites were broadly distributed across left lateral temporal cortex, whereas semantic and mixed semantic-phonological naming sites were found primarily in the posterior and inferior left temporal region. There was no clear pattern evident in phonological versus semantic processing related to auditory versus visual naming sites. Conclusions: Results suggest that naming impairment related to anterior temporal abnormalities is due primarily to impaired phonological processing, whereas naming impairment resulting from posterior or inferior temporal damage reflects problems with both semantic and phonological processing. As the anterior temporal region is typically most affected in TLE, we speculate that naming difficulty in left TLE primarily reflects problems accessing information regarding word form, with relatively preserved access to word meaning

Functional magnetic resonance imaging (fMRI) is commonly used to localize brain function, but its utility in the clinical setting remains unclear. Subdural electrode implantation provides opportunities to correlate the spatial relationship of the blood oxygen level-dependent (BOLD) response to areas defined by extraoperative electrical stimulation mapping (ESM) in patients undergoing staged epilepsy surgery. 4 subjects underwent pre-operative fMRI using the analogous paradigms to those used for ESM to delineate language and motor function. Coregistration of the pre-operative MRI to a post-operative CT and MRI scan was performed in order to assess the spatial relationship between the BOLD response and the location of electrode contacts used for ESM while accounting for brain shift. fMRI was accurate in predicting the location of motor cortex with sensitivity and negative predictive value (NPV) of 1.0. Specificity was .96 with a positive predictive (PPV) value of .8. In all 4 subjects, a laterality index of the fMRI for language was accurate in predicting lateralization measured by Wada testing. While T-scores over regions where ESM-induced language deficits occurred were significantly higher (p<.05, Student's t-test) than those over regions where there was no ESM-induced deficit, sensitivity, specificity and predictive values were poor over a range of threshold criteria. Sensitivity and specificity were improved by excluding sites within 1cm of the base of the frontal and temporal bone and sites where ESM showed motor function of face. Despite this, sensitivity and specificity were .47 and .76, respectively (T score 2.5, p<.01 corrected FDR) with PPV and NPV of .40 and .77, respectively. Sensitivity for predicting areas within 1cm of ESM-defined language sites was higher at .82 with an NPV of .94. The results indicate that fMRI is clinically useful for lateralizing language and the localizing motor cortex. fMRI localizes language less accurately, but it may be useful in estimating the region of ESM-induced deficit in areas away from the base of the frontal and temporal bone.

BACKGROUND:N-Methyl-D-aspartate receptor antagonists reverse hyperalgesia during morphine infusion in male mice only. Because the melanocortin-1 receptor can act as a female-specific counterpart to N-methyl-D-aspartate receptors in kappa-opioid analgesic mechanisms, the authors assessed the contribution of melanocortin-1 receptors to the sex-specific mechanisms underlying morphine hyperalgesia. METHODS:The tail-withdrawal test was used to compare the nociceptive responses of male and female C57BL/6J (B6) mice with those of C57BL/6J-Mc(1r(e/e)) mice, spontaneous mutants of the B6 background lacking functional melanocortin-1 receptors, during continuous morphine infusion (1.6 and 40.0 mgkg(-1) . 24 h(-1)). Separate groups of hyperalgesic B6 and outbred CD-1 mice were injected with MK-801 or MSG606, selective N-methyl-D-aspartate and melanocortin-1 receptor antagonists, respectively. RESULTS:Morphine infusion (40.0 mg . kg(-1) . 24 h(-1)) reduced baseline withdrawal latencies by 45-55% in B6 mice of both sexes, indicating hyperalgesia; this increased nociception was manifest in male e/e mice only. Although MK-801 reversed hyperalgesia in male mice only, increasing latencies by 72%, MSG606 increased latencies by approximately 60% exclusively in females. A lower morphine infusion dose (1.6 mg . kg(-1) . 24 h(-1)) reduced baseline withdrawal latencies by 45-52% in B6 and e/e mice of both sexes, which was reversed by MK-801, but not MSG606, in both male and female B6 mice. CONCLUSIONS:The data indicate the sex-specific mediation of high-dose morphine-induced hyperalgesia by N-methyl-d-aspartate and melanocortin-1 receptors in male and female mice, respectively, suggesting a broader relevance of this known sexual dimorphism. The data further indicate that the neural substrates contributing to hyperalgesia are morphine dose-dependent.

Although morphine and heroin analgesia is mediated by mu-opioid receptors encoded by the MOR-1 gene, distinct isoforms are involved. Both opioids also induce dependence by acting at mu-opioid receptors, but which variants are utilized is not known. Here, we assayed morphine and heroin analgesia and dependence in mice treated with antisense oligodeoxynucleotides (AO) targeting MOR-1 exons 1-4. Whereas AOs targeting exons 1 and 4 blocked morphine analgesia, those targeting exons 2 and 3 blocked heroin analgesia. Neither morphine nor heroin analgesia was compromised 5 days after the last AO injection. In morphine and heroin dependent mice, only exon 1 AO significantly reduced jumping incidence during naloxone (50mg/kg) precipitated withdrawal. Neither analgesia nor withdrawal jumping was attenuated in controls pretreated with saline or a mismatch oligodeoxynucleotide control sequence. While these data confirm previous reports that morphine and heroin analgesia are not mediated by a single mu-opioid receptor, both opiates nonetheless apparently induce dependence via a mu-opioid receptor isoform containing exon 1. For heroin, the possibility that analgesia and dependence are mediated by distinct mu-opioid receptor isoforms offers the prospect of developing potent opiate analgesics possessing reduced dependence liability.

Heroin and morphine exposure can cause physical dependence, with symptoms manifesting during their withdrawal. Inter-individual differences in symptom frequency during morphine withdrawal are a common finding that, in rodents, is demonstrably attributable to genotype. However, it is not known whether inter-individual differences characterize heroin withdrawal, and whether such variation can be similarly influenced by genotype. Therefore, we injected mice of ten inbred strains with acute and chronic heroin doses and compared their jumping frequencies, a common index of withdrawal magnitude, during naloxone-precipitated withdrawal. The data revealed significant strain frequency differences (range after acute and chronic heroin injection: 0-104 and 0-142 jumps, respectively) and substantial heritability (h(2)=0.94 to 0.96), indicating that genetic variance is associated with heroin withdrawal. The rank order of strain sensitivity for acute and chronic heroin withdrawal jumping, and for the current heroin and previous morphine strain data, were significantly correlated (r=0.75-0.94), indicating their genetic and, ultimately, physiological commonality. These data suggest that the genetic liability to heroin dependence remains constant across a period of heroin intake, and that heroin and morphine dependence may benefit from common treatment strategies.

Morphine treatment can paradoxically increase nociception (i.e. hyperalgesia). Since there are putative sex differences in nociception and morphine sensitivity, we compared nociception in male and female mice using the tail-withdrawal test during continuous infusion of two morphine doses (1.6 and 40.0 mg/kg/24 h). Both doses caused hyperalgesia in both sexes, but onset in females always preceded that of males. Although the larger dose initially evoked analgesia, naltrexone (NTX) pellets implanted prior to morphine infusion abolished analgesia but not hyperalgesia. Distinct sex differences also characterized each morphine dose. Specifically, the lower morphine dose caused hyperalgesia that dissipated after 6 days in males but persisted in females for a minimum of 14 days. Despite this difference, N-methyl-d-aspartate (NMDA) receptor antagonists reversed hyperalgesia in both sexes. In contrast, the higher morphine dose evoked hyperalgesia that resolved concurrently in both sexes, but hyperalgesia was reversed by NMDA receptor antagonists in males only. Ovariectomy (OVX), but not OVX followed by estrogen treatment, abolished both sex differences, and resulted in females exhibiting the male-typical pattern. This study thus demonstrates NTX-insensitive morphine hyperalgesia in females as previously reported for males. However, females utilized hyperalgesic mechanisms which were distinct from those employed by males. Data from females subject to OVX/estrogen replacement further indicate that females possess functional male-typical hyperalgesic mechanisms, but are diverted from their use by ovarian sex steroids. Finally, the finding that each morphine infusion dose was characterized by a unique sex difference provides additional evidence for distinct multiple hyperalgesic systems.

Opioid and excitatory amino acid receptors contribute to morphine dependence, but there are no studies of their role in heroin dependence. Thus, mice injected with acute or chronic heroin doses in the present study were pretreated with one of the following selective antagonists: 7-benzylidenenaltrexone (BNTX), naltriben (NTB), nor-binaltorphimine (nor-BNI; delta1, delta2, and kappa opioid receptors, respectively), MK-801, or LY293558 (NMDA and AMPA excitatory amino acid receptors, respectively). Naloxone-precipitated withdrawal jumping frequency, shown here to be a reliable index of heroin dependence magnitude, was reduced by BNTX or NTB in mice injected with both acute and chronic heroin doses. In contrast, nor-BNI did not alter jumping frequencies in mice injected with an acute heroin dose but significantly increased them in mice receiving chronic heroin injections. Continuous MK-801 or LY293558 infusion, but not injection, reduced jumping frequencies during withdrawal from acute heroin treatment. Their delivery by injection was nonetheless effective against chronic heroin dependence, suggesting mechanisms not simply attributable to NMDA or AMPA blockade. These data indicate that whereas delta1, delta2, NMDA, and AMPA receptors enable acute and chronic heroin dependence, kappa receptor activity limits the dependence liability of chronic heroin. With the exception of delta1 receptors, the apparent role of these receptors to heroin dependence is consistent with their contribution to morphine dependence, indicating that there is substantial physiological commonality underlying dependence to both heroin and morphine. The ability of kappa receptor blockade to differentially alter acute and chronic dependence supports previous assertions from studies with other opioids that acute and chronic opioid dependence are, at least in part, mechanistically distinct. Elucidating the substrates contributing to heroin dependence, and identifying their similarities and differences with those of other opioids such as morphine, may yield effective treatment strategies to the problem of heroin dependency.

This paper is the 28th consecutive installment of the annual review of research concerning the endogenous opioid system, now spanning over a quarter-century of research. It summarizes papers published during 2005 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity, neurophysiology and transmitter release (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); immunological responses (Section 17).