Counter-regulation of the AP-1 monomers pATF2 and Fos: Molecular readjustment of brainstem neurons in hearing and deaf adult rats after electrical intracochlear stimulation.

Expression of the immediate-early gene fos (also known as c-fos) and phosphorylation of the product of the early response gene atf2 (pATF2) in the adult auditory brainstem can be modulated by electrical intracochlear stimulation. The Fos and pATF2 proteins are competitive monomers of the heterodimeric activator protein-1 (AP-1) transcription factor that triggers the expression of genes related to neural plasticity. Our previous findings showed that the stimulation-induced spatio-temporal pattern of Fos expression in the adult auditory system depends on hearing experience. In this study, we aimed to identify a possible correlation of pATF2 and Fos expression. Adult normal hearing and neonatally deafened rats were unilaterally stimulated with a cochlear implant (CI) for 45 min, 73 min, or 2h. The numbers of Fos- and pATF2-positive neurons in the anteroventral cochlear nucleus (AVCN), the lateral superior olive (LSO), and the central inferior colliculus (CIC) were evaluated. Following stimulation, an increased Fos expression was demonstrated in all these regions in hearing and deaf rats. However, in neonatally deafened rats, significantly more Fos-positive neurons emerged that did not obey a tonotopic order. Independent of hearing experience, Fos expression correlated with a locally matching decrease of pATF2 expression in AVCN and LSO, but not in CIC. We suggest that these changes in gene expression result in a shift of AP-1 dimer composition from ATF2:Jun to Fos:Jun. This change in AP-1 constellation is expected to invoke different transcriptional cascades leading to distinct modes of tissue reorganization and plasticity responses in the mature central auditory system under stimulation.

Evolution of multi-parametric MRI quantitative parameters following transrectal ultrasound-guided biopsy of the prostate.

BACKGROUND: To determine the evolution of prostatic multi-parametric magnetic resonance imaging (mp-MRI) signal following transrectal ultrasound (TRUS)-guided biopsy. METHODS: Local ethical permission and informed written consent was obtained from all the participants (n=14, aged 43-69, mean 64 years). Patients with a clinical suspicion of prostate cancer (PSA range 2.2-11.7, mean 6.2) and a negative (PIRAD 1-2/5) pre-biopsy mp-MRI (pre-contrast T1, T2, diffusion-weighted and dynamic-contrast-enhanced MRI) who underwent 10-core TRUS-guided biopsy were recruited for additional mp-MRI examinations performed at 1, 2 and 6 months post biopsy. We quantified mp-MRI peripheral zone (PZ) and transition zone (TZ) normalized T2 signal intensity (nT2-SI); T1 relaxation time (T10); diffusion-weighted MRI, apparent diffusion coefficient (ADC); dynamic contrast-enhanced MRI, maximum enhancement (ME); slope of enhancement (SoE) and area-under-the-contrast-enhancement-curve at 120 s (AUC120). Significant changes in mp-MRI parameters were identified by analysis of variance with Dunnett's post testing. RESULTS: Diffuse signal changes were observed post-biopsy throughout the PZ. No significant signal change occurred following biopsy within the TZ. Left and right PZ mean nT2-SI (left PZ: 5.73, 5.16, 4.90 and 5.12; right PZ: 5.80, 5.10, 4.84 and 5.05 at pre-biopsy, 1, 2 and 6 months post biopsy, respectively) and mean T10 (left PZ: 1.02, 0.67, 0.78, 0.85; right PZ: 1.29, 0.64, 0.78, 0.87 at pre-biopsy, 1, 2 and 6 months post biopsy, respectively) were reduced significantly (P<0.05) from pre-biopsy values for up to 6 months post biopsy. Significant changes (P<0.05) of PZ-ME and AUC120 were observed at 1 month but resolved by 2 months post biopsy. PZ ADC did not change significantly following biopsy (P=0.23-1.0). There was no significant change of any TZ mp-MRI parameter at any time point following biopsy (P=0.1-1.0). CONCLUSIONS: Significant PZ (but not TZ) T2 signal changes persist up to 6 months post biopsy, whereas PZ and TZ ADC is not significantly altered as early as 1 month post biopsy. Caution must be exercised when interpreting T1- and T2-weighted imaging early post biopsy, whereas ADC images are more likely to maintain clinical efficacy.

The FORECAST study - Focal recurrent assessment and salvage treatment for radiorecurrent prostate cancer.

BACKGROUND: One-third of men may experience biochemical failure by 8years following radical radiotherapy for localised prostate cancer. Over 90% of men are started on androgen deprivation therapy (ADT) which is non-curative and confers systemic side-effects. Focal salvage therapy (FST) limits collateral tissue damage and may improve therapeutic ratios. In order to deliver FST, distant disease must be ruled-out and intra-prostatic disease must be accurately detected, localised and characterised. AIM: FORECAST - Focal Recurrent Assessment and Salvage Treatment - is a study designed to evaluate a novel imaging-based diagnostic and therapeutic complex intervention pathway for men who fail radiotherapy. METHODS: Men with biochemical failure following radical prostate radiotherapy, prior to salvage therapy will be recruited. They will undergo whole-body multi-parametric MRI (WB-MRI), choline PET/CT, bone-scan and pelvic-mpMRI and then MRI transperineal-targeted biopsies (MRI-TB) and Transperineal Template Prostate Mapping Biopsy (TPM). Those suitable for FST will undergo either high intensity focused ultrasound (HIFU) or cryotherapy. RESULTS: Primary outcome measures: a) the accuracy of WB-MRI to detect distant metastatic disease; b) accuracy of prostate mpMRI in local detection of radiorecurrent prostate cancer; c) detection accuracy of MRI-TB; and d) rate of urinary incontinence following FST. CONCLUSION: Focal salvage therapy may confer lower rates of morbidity whilst retaining disease control. In order to deliver FST, intra- and extra-prostatic disease must be detected early and localised accurately. Novel diagnostic techniques including WB-MRI and MRI-TB may improve the detection of distant and local disease whilst reducing healthcare burdens compared with current imaging and biopsy strategies.

[The utilization of brain plasticity by cochlear implants : Molecular and cellular changes due to electrical intracochlear stimulation]. / Nutzung der Plastizität des Gehirns durch Cochleaimplantate : Molekulare und zelluläre Veränderungen durch elektrische intracochleäre Stimulation.

BACKGROUND AND OBJECTIVES: During pre- and postnatal development, a high level of growth-associated protein 43 (Gap43) is expressed in the brain. This neuron-specific protein is expressed in somata, axons, and growth cones and plays a key role in neurite outgrowth and synaptogenesis. With maturation of the brain, Gap43 is down-regulated by most neurons, except in brain areas such as the hippocampal CA3 region or the binaural auditory regions lateral superior olive (LSO) and central inferior colliculus (CIC). This study investigated how changes in sensory activity levels and patterns can modulate the adult plasticity response. METHODS: To study the effect of sensory activity on adult Gap43 expression, mRNA and protein levels were determined in LSO and CIC of hearing-experienced rats, unilaterally and bilaterally deafened rats, or rats unilaterally stimulated by a cochlear implant (CI). RESULTS: Unilateral hearing loss of an adult auditory system causes asymmetrical expression of Gap43 mRNA between ipsi- and contralateral LSOs or CICs of the brain stem. While the mRNA level rose on the contralateral side of the LSO, CIC neurons increased their gap43 transcription ipsilaterally compared to the control level (p<0.001). Compensation of the lost sensory input by way of CI stimulation resulted in a bilaterally symmetric but increased gap43 transcription. CONCLUSIONS: Our data indicate that Gap43 is not only a marker for neuronal growth and synaptogenesis, but also reflects modified patterns of synaptic activities on auditory neurons. Thus, unilateral deafness directly results in an asymmetrical adaptation of the gap43 transcription between both sides of the auditory brain stem. This can be prevented by simple-patterned stimulation of the auditory nerve via a CI.

Phase I/II study of verteporfin photodynamic therapy in locally advanced pancreatic cancer.

BACKGROUND: Patients with pancreatic cancer have a poor prognosis apart from the few suitable for surgery. Photodynamic therapy (PDT) produces localised tissue necrosis but previous studies using the photosensitiser meso-tetrahydroxyphenylchlorin (mTHPC) caused prolonged skin photosensitivity. This study assessed a shorter acting photosensitiser, verteporfin. METHODS: Fifteen inoperable patients with locally advanced cancers were sensitised with 0.4 mg kg(-1) verteporfin. After 60-90 min, laser light (690 nm) was delivered via single (13 patients) or multiple (2 patients) fibres positioned percutaneously under computed tomography (CT) guidance, the light dose escalating (initially 5 J, doubling after each three patients) until 12 mm of necrosis was achieved consistently. RESULTS: In all, 12 mm lesions were seen consistently at 40 J, but with considerable variation in necrosis volume (mean volume 3.5 cm(3) at 40 J). Minor, self-limiting extrapancreatic effects were seen in multifibre patients. No adverse interactions were seen in patients given chemotherapy or radiotherapy before or after PDT. After PDT, one patient underwent an R0 Whipple's pancreaticoduodenectomy. CONCLUSIONS: Verteporfin PDT-induced tumour necrosis in locally advanced pancreatic cancer is feasible and safe. It can be delivered with a much shorter drug light interval and with less photosensitivity than with older compounds.

High-intensity focused ultrasound treatment of liver tumours: post-treatment MRI correlates well with intra-operative estimates of treatment volume.

OBJECTIVES: To assess the safety and feasibility of high-intensity focused ultrasound (HIFU) ablation of liver tumours and to determine whether post-operative MRI correlates with intra-operative imaging. METHODS: 31 patients were recruited into two ethically approved clinical trials (median age 64; mean BMI 26 kg m(-2)). Patients with liver tumours (primary or metastatic) underwent a single HIFU treatment monitored using intra-operative B-mode ultrasound. Follow-up consisted of radiology and histology (surgical trial) or radiology alone (radiology trial). Radiological follow-up was digital subtraction contrast-enhanced MRI. RESULTS: Treatment according to protocol was possible in 30 of 31 patients. One treatment was abandoned because of equipment failure. Transient pain and superficial skin burns were seen in 81% (25/31) and 39% (12/31) of patients, respectively. One moderate skin burn occurred. One patient died prior to radiological follow-up. Radiological evidence of ablation was seen in 93% (27/29) of patients. Ablation accuracy was good in 89% (24/27) of patients. In three patients the zone of ablation lay ≤2 mm outside the tumour. The median cross-sectional area (CSA) of the zone of ablation was 5.0 and 5.1 cm(2) using intra-operative and post-operative imaging, respectively. The mean MRI:B-mode CSA ratio was 1.57 [95% confidence interval (CI)=0.57-2.71]. There was positive correlation between MRI and B-mode CSA (Spearman's r=0.48; 95% CI 0.11-0.73; p=0.011) and the slope of linear regression was significantly non-zero (1.23; 95% CI=0.68-1.77; p<0.0001). CONCLUSIONS: HIFU ablation of liver tumours is safe and feasible. HIFU treatment is accurate, and intra-operative assessment of treatment provides an accurate measure of the zone of ablation and correlates well with MRI follow-up.

Radiofrequency ablation in the treatment of breast cancer liver metastases.

Minimally invasive, image-guided thermal ablation is gaining acceptance for the treatment of solid tumour deposits and its use is increasing. This overview discusses one method of thermal ablation in one palliative setting; the local control of breast cancer liver metastases (BCLM) using radiofrequency ablation. Breast cancer is common and over half of all women diagnosed with metastatic disease develop BCLM. The mainstay of therapy remains chemotherapy and supportive care, which may prolong survival to a median of 18-24 months. Despite breast cancer being considered a systemic disease, surgical series of metastectomy for BCLM have shown a survival advantage. Despite this, surgery for BCLM is rarely practiced due to the associated morbidity for a relatively meagre survival benefit. Similarly, radiofrequency ablation has been used for local control of BCLM; the reported series show a median survival of between 30 and 60 months, with no treatment-related deaths and only three serious treatment-related adverse events in 164 patients reported. Despite this, scepticism remains over the efficacy of BCLM ablation due to the heterogeneity of patient inclusion and selective nature of reporting. Randomised trials are needed to formulate robust evidence-based recommendations and direct the necessary allocation of health care resources. Whether or not local ablative treatment of BCLM conveys a survival advantage is an important consideration. However, in this non-curative setting, it is essential that other outcome measures are carefully evaluated in conjunction with survival, including symptoms (local and constitutional), quality of life and psychological morbidity. To these ends, a randomised, multicentre trial to assess best medical therapy alone versus best medical therapy plus radiofrequency ablation in patients presenting with newly diagnosed BCLM with or without the presence of stable extra-hepatic disease will shortly be underway.

Provision of out-of-hours interventional radiology services in the London strategic health authority.

AIM: To review the provision of out-of-hours interventional radiology (IR) services in the London Strategic Health Authority (SHA). MATERIALS AND METHODS: All 29 acute hospitals in the London SHA were contacted between November 2008 and January 2009. A questionnaire based on the Royal College of Radiologists (RCR) guidelines assessed the provision of out-of-hours IR services. An "ad-hoc" service was defined as on-call provision where not all the radiologists could perform intervention: If IR was required out of hours, an interventionalist came in when off-duty or the patient was transferred. RESULTS: Seventeen out of the 29 (59%) hospitals provided ad-hoc out-of-hours services, eight (28%) provided a 24-hour rota, and four (14%) provide no out-of-hours cover. No ad-hoc service had formal transfer arrangements to a centre providing a 24h service. Only two hospitals providing a 24h service had six radiologists on the rota. CONCLUSION: Strategic planning for out-of-hours IR across London is recommended. This is likely to be welcomed by the hospitals involved, allowing informal arrangements to be formalized, and collaboration to provide comprehensive regional networks, provided appropriate funding is made available. A national audit is recommended; it is unlikely these findings are unique to London.

High-intensity-focused ultrasound in the treatment of primary prostate cancer: the first UK series.

BACKGROUND: The use of minimally invasive ablative therapies in localised prostate cancer offer potential for a middle ground between active surveillance and radical therapy. METHODS: An analysis of men with organ-confined prostate cancer treated with transrectal whole-gland HIFU (Sonablate 500) between 1 February 2005 and 15 May 2007 was carried out in two centres. Outcome data (side-effects using validated patient questionnaires, biochemical, histology) were evaluated. RESULTS: A total of 172 men were treated under general anaesthetic as day-case procedures with 78% discharged a mean 5 h after treatment. Mean follow-up was 346 days (range 135-759 days). Urethral stricture was significantly lower in those with suprapubic catheter compared with urethral catheters (19.4 vs 40.4%, P=0.005). Antibiotics were given to 23.8% of patients for presumed urinary tract infection and the rate of epididymitis was 7.6%. Potency was maintained in 70% by 12 months, whereas mild stress urinary incontinence (no pads) was reported in 7.0% (12 out of 172) with a further 0.6% (1 out of 172) requiring pads. There was no rectal toxicity and no recto-urethral fistulae. In all, 78.3% achieved a PSA nadir < or =0.5 microg ml(-1) at 12 months, with 57.8% achieving < or =0.2 microg ml(-1). Then, 8 out of 13 were retreated with HIFU, one had salvage external beam radiotherapy and four chose active surveillance for small-volume low-risk disease. Overall, there was no evidence of disease (PSA <0.5 microg ml(-1) or negative biopsy if nadir not achieved) after one HIFU session in 92.4% (159 out of 172) of patients. CONCLUSION: HIFU is a minimally invasive, day-case ablative technique that can achieve good biochemical outcomes in the short term with minimal urinary incontinence and acceptable levels of erectile dysfunction. Long-term outcome needs further evaluation and the inception of an international registry for cases treated using HIFU will significantly aid this health technology assessment.

High-intensity focused ultrasound ablation of liver tumours: can radiological assessment predict the histological response?

Cancer therapies usually depend on cross-sectional imaging for the assessment of treatment response. This study was designed to evaluate the ability of MRI to predict zones of necrosis following the use of high-intensity focused ultrasound (HIFU) to treat liver metastases. Patients with liver metastases, who had been scheduled for elective surgical resection of their tumours, were recruited to this non-randomized Phase II study. In each case, a proportion of an index liver tumour target was ablated. The response to HIFU was assessed after 12 days using contrast-enhanced MRI and compared directly with histological analysis at the time of surgery. Eight patients were treated, of whom six were subsequently assessed with both MRI and histology. There were no major complications. MRI predicted complete ablation in three cases. In each case, histological analysis confirmed complete ablation. In one case, the region of ablation observed on MRI appeared smaller than predicted at the time of HIFU, but histology revealed complete ablation of the target region. The predominant characteristic of HIFU-ablated tissue was coagulative necrosis but heat fixation was evident in some areas. Heat-fixed cells appeared normal under haematoxylin and eosin staining, indicating that this is unreliable as an indicator of HIFU-induced cell death. This study demonstrates that HIFU is capable of achieving selective ablation of pre-defined regions of liver tumour targets, and that MRI evidence of complete ablation of the target region can be taken to infer histological success.

The safety and feasibility of extracorporeal high-intensity focused ultrasound (HIFU) for the treatment of liver and kidney tumours in a Western population.

High-intensity focused ultrasound (HIFU) provides a potential noninvasive alternative to conventional therapies. We report our preliminary experience from clinical trials designed to evaluate the safety and feasibility of a novel, extracorporeal HIFU device for the treatment of liver and kidney tumours in a Western population. The extracorporeal, ultrasound-guided Model-JC Tumor Therapy System (HAIFU Technology Company, China) has been used to treat 30 patients according to four trial protocols. Patients with hepatic or renal tumours underwent a single therapeutic HIFU session under general anaesthesia. Magnetic resonance imaging 12 days after treatment provided assessment of response. The patients were subdivided into those followed up with further imaging alone or those undergoing surgical resection of their tumours, which enabled both radiological and histological assessment. HIFU exposure resulted in discrete zones of ablation in 25 of 27 evaluable patients (93%). Ablation of liver tumours was achieved more consistently than for kidney tumours (100 vs 67%, assessed radiologically). The adverse event profile was favourable when compared to more invasive techniques. HIFU treatment of liver and kidney tumours in a Western population is both safe and feasible. These findings have significant implications for future noninvasive image-guided tumour ablation.

Cell death or survival: molecular and connectional conditions for olivocochlear neurons after axotomy.

We aimed to determine whether rat olivocochlear neurons survive axotomy inflicted through cochlear ablation, or if they degenerate. To estimate their intrinsic potential for axonal regeneration, we investigated the expression of the transcription factor c-Jun and the growth-associated protein-43 (GAP43). Axonal tracing studies based on application of Fast Blue into the cochlea and calcitonin gene-related peptide immunostaining revealed that many, but not all, lateral olivocochlear neurons in the ipsilateral lateral superior olive degenerated upon cochleotomy. A decrease of their number was noticed 2 weeks after the lesion, and 2 months postoperative the population was reduced to approximately one quarter (27-29%) of its original size. No further reduction took place at longer survival times up to 1 year. Most or all shell neurons and medial olivocochlear neurons survived axotomy. Following cochleotomy, 56-60% of the lateral olivocochlear neurons in the ipsilateral lateral superior olive were found to co-express c-Jun and GAP43. Only a small number of shell and medial olivocochlear neurons up-regulated c-Jun expression, and only a small number of shell neurons expressed GAP43. Up-regulation of c-Jun and GAP43 in lateral olivocochlear neurons upon axotomy suggests that they have an intrinsic potential to regenerate after axotomy, but cell counts based on the markers Fast Blue and calcitonin gene-related peptide indicate that this potential cannot be exploited and degeneration is induced instead. The survival of one quarter of the axotomized lateral olivocochlear neurons and of all, or almost all, shell and medial olivocochlear neurons appeared to depend on connections of these cells to other regions than the cochlea by means of axon collaterals, which remained intact after cochleotomy.

[The cochlear implant. Molecular arguments favouring early implantation]. / Kochleaimplantat. Molekularbiologische Argumente für eine Frühversorgung.

BACKGROUND: An important factor in the clinical outcome of cochlear implantation is the age of the patient. Compared to older patients, children with congenital deafness have a better outcome when the implantation is made before the age of 2 years. The cause may lie in the molecular biology of the brain, which changes during postnatal maturation. METHODS: Protein probes were obtained from tissue of the rat inferior colliculus at different ages. The probes were analyzed using 2-dimensional SDS electrophoresis. RESULTS: The expression of GAP-43, a protein expressed by neurons during axonal outgrowth and synaptogenesis, and the total number of the protein species showed a significant reduction during ontogenesis. This shows that while neurons gradually assume their specific function, they downregulate GAP-43 and the molecular complexity decreases. CONCLUSIONS: Due to a lack of neuronal pluripotency at later developmental stages, the flexibility to adapt to the afferent activation provided by a cochlear implant is increasingly limited.

In vivo visualization of the cochlear nerve and nuclei with fluorescent axonal tracers.

In recent years multichannel neuroprostheses have been developed which directly stimulate the central auditory pathway. Substantially these have been used in cases of total hearing loss caused by neurofibromatosis type 2 where bilateral damage to the auditory nerve prevents more peripheral stimulation. The electrode carrier of the auditory brainstem implant (ABI) is designed to be placed on the cochlear nucleus complex residing at the lateral brainstem surface. Despite altered anatomy due to tumor growth or preceding surgery, correct electrode placement is essential to maximize the variety of pitch percept elicited during electrical stimulation with the ABI without producing side-effects. In order to assist intraoperative identification of the proximal auditory nerve and cochlear nuclei, the non-toxic fluorescent axonal tracers Fast Blue or Fluorogold were injected into the cochlea of rats and Java monkeys. Four to seven days after tracer application, labeling of the eighth cranial nerve, its entrance into the brainstem and the primary radiation of auditory fibers into the cochlear nucleus could be demonstrated as colored fluorescence on the living brain under appropriate ultraviolet illumination. Additional histological processing revealed groups of retrogradely labeled neuronal cell bodies in both species. Our results suggest that this method could also be used in humans in order to aid surgeons with the proper positioning of the electrode array.

Modulation of P-CREB and expression of c-fos in cochlear nucleus and superior olive following electrical intracochlear stimulation.

Investigating activity-dependent plasticity in the auditory brain stem of the adult rat, we observed that electrical intracochlear stimulation led to a tonotopically localized modulation of the phosphorylation of the cAMP response element binding protein (CREB) and an equally localized expression of the immediate early gene product c-Fos in cochlear nucleus and superior olive. As P-CREB is thought to act as transcription factor on one promoter site of the c-fos gene, we compared immunolabeling for P-CREB and c-fos in adjacent brain sections. Following 2h sustained stimulation in previously deafened animals, labelling for P-CREB declined in regions where c-Fos labelling increased. This suggests that the level or state of P-CREB (e.g. whether it is phosphorylated or not) are affected by intracochlear stimulation in a process that appears to be linked to the stimulation-dependent expression of c-Fos in auditory brain stem nuclei.

Activity-dependent plasticity in the adult auditory brainstem.

Over the past few years we have studied the plasticity of the adult auditory brainstem in the rat following unilateral changes to the pattern of sensory activation, either by intracochlear electrical stimulation or by deafening. We discovered that modifications to afferent activity induced changes in the molecular composition and cellular morphology throughout the auditory brainstem, including its major centers: the cochlear nucleus complex, the superior olivary complex, and the inferior colliculus. The time window studied ranged from 2 h to over 1 year following induction of changes to afferent activity. The molecular markers employed include the NMDA receptor subunit type 1, the cAMP response element binding protein (CREB), the immediate early gene products c-Fos, c-Jun and Egr-1, the growth and plasticity-associated protein GAP-43 and its mRNA, the calcium binding protein calbindin, the cell adhesion molecule integrin-alpha(1), the microtubule-associated protein MAP-1b, and the neurofilament light chain (NF-L). As a consequence of the specific electrical stimulation of the auditory afferents or the loss of hearing, a cascade of events is triggered that apparently modifies the integrative action and computational abilities of the central auditory system. An attempt is made to relate the diverse phenomena observed to a common molecular signaling network that is suspected to bridge sensory experience to changes in the structure and function of the brain. Eventually, a thorough understanding of these events will be essential for the specific diagnosis of patients, optimal timing for implantation, and suitable parameters for running of a cochlear implant or an auditory brainstem implant in humans. In this report an overview of the results obtained in the past years in our lab is presented, flanked by an introduction into the history of plasticity research and a model proposed for intracellular signal cascades related to activity-dependent plasticity.

Plasticity of the superior olivary complex.

The superior olivary complex (SOC) is part of the auditory brainstem of the vertebrate brain. Residing ventrally in the rhombencephalon, it receives sensory signals from both cochleae through multisynaptic pathways. Neurons of the SOC are also a target of bilateral descending projections. Ascending and descending efferents of the SOC affect the processing of auditory signals on both sides of the brainstem and in both organs of Corti. The pattern of connectivity indicates that the SOC fulfills functions of binaural signal integration serving sound localization. But whereas many of these connectional features are shared with the inferior colliculus (with the important exception of a projection to the inner ear), cellular and molecular investigations have shown that cells residing in SOC are unique in several respects. Unlike those of other auditory brainstem nuclei, they specifically express molecules known to be involved in development, plasticity, and learning (e.g., GAP-43 mRNA, specific subunits of integrin). Moreover, neurons of the SOC in adult mammals respond to various kinds of hearing impairment with the expression of plasticity-related substances (e.g., GAP-43, c-Jun, c-Fos, cytoskeletal elements), indicative of a restructuring of auditory connectivity. These observations suggest that the SOC is pivotal in the developmental and adaptive tuning of binaural processing in young and adult vertebrates.

Olivocochlear neurons sending axon collaterals into the ventral cochlear nucleus of the rat.

The olivocochlear projection constitutes the last stage of the descending auditory system in the mammalian brain. Its neurons reside in the superior olivary complex (SOC) and project to the inner and outer hair cell receptors in the cochlea. Olivocochlear neurons were also reported to send axon collaterals into the cochlear nucleus, but controversies about their number and about species differences persist. By injecting the fluorescent retrograde axonal tracers diamidino yellow and fast blue into the cochlea and the ventral cochlear nucleus (VCN), we studied the distribution and number of olivocochlear neurons with and without axon collaterals into the VCN of the rat. We found that olivocochlear neurons residing in the lateral superior olive (LSO), the intrinsic lateral olivocochlear cells (intrinsic LOCs), do not send axon collaterals into the VCN. By contrast, a majority, and possibly all, olivocochlear neurons residing in the ventral nucleus of the trapezoid body (VNTB), the medial olivocochlear cells (MOCs), do have such axon collaterals. These cells may thus affect processing in the ascending auditory pathway at the level of the receptors and concurrently at the level of the secondary sensory neurons in the cochlear nucleus. Belonging to the lateral olivocochlear system, shell neurons reside around the LSO and form a third group of olivocochlear cells (shell LOCs). Like intrinsic LOCs, they innervate the inner hair cells, but like MOCs they do, by means of axon collaterals, project into the VCN. These findings have implications for understanding both auditory signal processing and the plasticity responses that occur following loss of cochlear function.

Synapses on human spiral ganglion cells: a transmission electron microscopy and immunohistochemical study.

A transmission electron microscopy (TEM) study and synaptophysin immunoreactivity analysis of neurons in the human spiral ganglion was performed with particular emphasis on the demonstration of synapses. The study was based on surgical biopsy material obtained during transcochlear meningioma surgery. Vesiculated nerve endings of unmyelinated nerve fibers occurred frequently on the small ganglion cells at all levels. The nerve terminals exhibited abundant clear synaptic vesicles but also dense-core vesicles. Multisynaptic contact sites were also seen with fibers of the intraganglionic spiral bundle (IGSB). Complex associations of synapses could be demonstrated, including several synaptic terminals in conjunction with contact sites or an adherent type of junctions on large ganglion cells. These contact sites exhibited membrane densities which were symmetric or asymmetric, changed their polarity recurrently over their extension from one cell to the other and back and lacked clear synaptic vesicles. This suggests the existence of connections between efferents, belonging to the olivocochlear bundle, and both small and large ganglion cells. Thus, both the inner and outer hair cell system may be under the influence of efferent innervation in the human spiral ganglion. The morphology and course of synaptophysin-positive nerve fibers indicated that synaptic contacts within the spiral ganglion, as observed under the electron microscope, may be abundant. These results indicate that complex neural processing may occur at the level of the spiral ganglion in man.