Auditory neurophysiologic responses and discrimination deficits in children with learning problems.

Children with learning problems often cannot discriminate rapid acoustic changes that occur in speech. In this study of normal children and children with learning problems, impaired behavioral discrimination of a rapid speech change (/dalpha/versus/galpha/) was correlated with diminished magnitude of an electrophysiologic measure that is not dependent on attention or a voluntary response. The ability of children with learning problems to discriminate another rapid speech change (/balpha/versus/walpha/) also was reflected in the neurophysiology. These results indicate that some children's discrimination deficits originate in the auditory pathway before conscious perception and have implications for differential diagnosis and targeted therapeutic strategies for children with learning disabilities and attention disorders.

Investigating peripheral sources of speech-in-noise variability in listeners with normal audiograms.

A current initiative in auditory neuroscience research is to better understand why some listeners struggle to perceive speech-in-noise (SIN) despite having normal hearing sensitivity. Various hypotheses regarding the physiologic bases of this disorder have been proposed. Notably, recent work has suggested that the site of lesion underlying SIN deficits in normal hearing listeners may be either in "sub-clinical" outer hair cell damage or synaptopathic degeneration at the inner hair cell-auditory nerve fiber synapse. In this study, we present a retrospective investigation of these peripheral sources and their relationship with SIN performance variability in one of the largest datasets of young normal-hearing listeners presented to date. 194 participants completed detailed case history questionnaires assessing noise exposure, SIN complaints, tinnitus, and hyperacusis. Standard and extended high frequency audiograms, distortion product otoacoustic emissions, click-evoked auditory brainstem responses, and SIN performance measures were also collected. We found that: 1) the prevalence of SIN deficits in normal hearing listeners was 42% when based on subjective report and 8% when based on SIN performance, 2) hearing complaints and hyperacusis were more common in listeners with self-reported noise exposure histories than controls, 3) neither extended high frequency thresholds nor compound action potential amplitudes differed between noise-exposed and control groups, 4) extended high frequency hearing thresholds and compound action potential amplitudes were not predictive of SIN performance. These results suggest an association between noise exposure and hearing complaints in young, normal hearing listeners; however, SIN performance variability is not explained by peripheral auditory function to the extent that these measures capture subtle physiologic differences between participants.

Deficient brainstem encoding of pitch in children with Autism Spectrum Disorders.

OBJECTIVE: Deficient prosody is a hallmark of the pragmatic (socially contextualized) language impairment in Autism Spectrum Disorders (ASD). Prosody communicates emotion and intention and is conveyed through acoustic cues such as pitch contour. Thus, the objective of this study was to examine the subcortical representations of prosodic speech in children with ASD. METHODS: Using passively evoked brainstem responses to speech syllables with descending and ascending pitch contours, we examined sensory encoding of pitch in children with ASD who had normal intelligence and hearing and were age-matched with typically developing (TD) control children. RESULTS: We found that some children on the autism spectrum show deficient pitch tracking (evidenced by increased Frequency and Slope Errors and reduced phase locking) compared with TD children. CONCLUSIONS: This is the first demonstration of subcortical involvement in prosody encoding deficits in this population of children. SIGNIFICANCE: Our findings may have implications for diagnostic and remediation strategies in a subset of children with ASD and open up an avenue for future investigations.

Detection of mitochondrial DNA mutations in primary breast cancer and fine-needle aspirates.

To determine the frequency and distribution of mitochondrial DNA mutations in breast cancer, 18 primary breast tumors were analyzed by direct sequencing. Twelve somatic mutations not present in matched lymphocytes and normal breast tissues were detected in 11 of the tumors screened (61%). Of these mutations, five (42%) were deletions or insertions in a homopolymeric C-stretch between nucleotides 303-315 (D310) within the D-loop. The remaining seven mutations (58%) were single-base substitutions in the coding (ND1, ND4, ND5, and cytochrome b genes) or noncoding regions (D-loop) of the mitochondrial genome. In three cases (25%), the mutations detected in coding regions led to amino acid substitutions in the protein sequence. We then screened an additional 46 primary breast tumors with a rapid PCR-based assay to identify poly-C alterations in D310, and we found seven more cancers with alterations. Using D310 mutations as clonal marker, we detected identical changes in five of five matched fine-needle aspirates and in four of four metastases-positive lymph nodes. The high frequency of D310 alterations in primary breast cancer combined with the high sensitivity of the PCR-based assays provides a new molecular tool for cancer detection.

Identification of a mononucleotide repeat as a major target for mitochondrial DNA alterations in human tumors.

Mitochondrial DNA (mtDNA) mutations scattered through coding and noncoding regions have been reported in cancer. The mechanisms that generate such mutations and the importance of mtDNA mutations in tumor development are still not clear. Here we present the identification of a specific and highly polymorphic homopolymeric C stretch (D310), located within the displacement (D) loop, as a mutational hotspot in primary tumors. Twenty-two % of the 247 primary tumors analyzed harbored somatic deletions/insertions at this mononucleotide repeat. Moreover, these alterations were also present in head and neck preneoplastic lesions. We further characterized the D310 variants that appeared in the lung and head and neck tumors. Most of the somatic alterations found in tumors showed deletion/insertions of 1- or 2-bp generating D310 variants identical to constitutive polymorphisms described previously. Sequencing analysis of individual clones from lymphocytes revealed that patients with D310 mutations in the tumors had statistically significant higher levels of D310 heteroplasmy (more than one length variant) in the lymphocyte mtDNA as compared with the patients without D310 mutations in the tumor mtDNA. On the basis of our observations, we propose a model in which D310 alterations are already present in normal cells and achieve homoplasmy in the tumor through a restriction/amplification event attributable to random genetic drift and clonal expansion.

Aging affects hemispheric asymmetry in the neural representation of speech sounds.

Hemispheric asymmetries in the processing of elemental speech sounds appear to be critical for normal speech perception. This study investigated the effects of age on hemispheric asymmetry observed in the neurophysiological responses to speech stimuli in three groups of normal hearing, right-handed subjects: children (ages, 8-11 years), young adults (ages, 20-25 years), and older adults (ages > 55 years). Peak-to-peak response amplitudes of the auditory cortical P1-N1 complex obtained over right and left temporal lobes were examined to determine the degree of left/right asymmetry in the neurophysiological responses elicited by synthetic speech syllables in each of the three subject groups. In addition, mismatch negativity (MMN) responses, which are elicited by acoustic change, were obtained. Whereas children and young adults demonstrated larger P1-N1-evoked response amplitudes over the left temporal lobe than over the right, responses from elderly subjects were symmetrical. In contrast, MMN responses, which reflect an echoic memory process, were symmetrical in all subject groups. The differences observed in the neurophysiological responses were accompanied by a finding of significantly poorer ability to discriminate speech syllables involving rapid spectrotemporal changes in the older adult group. This study demonstrates a biological, age-related change in the neural representation of basic speech sounds and suggests one possible underlying mechanism for the speech perception difficulties exhibited by aging adults. Furthermore, results of this study support previous findings suggesting a dissociation between neural mechanisms underlying those processes that reflect the basic representation of sound structure and those that represent auditory echoic memory and stimulus change.

Comparative microsatellite analysis in discerning origin of disseminated tumor: the case of a patient with malignant ascites and a history of multiple tumors.

The origin of metastatic carcinoma is now always easily resolved on the basis of conventional dinical and pathological parameters, particularly in patients with more than 1 primary tumor. When 1 of the tumors is a renal cell carcinoma, the clinical picture is further confounded by the tendency of these tumors to be locally silent, to metastasize to unusual sites, and to disseminate long after removal of the primary tumor. We compared tumors for loss (ie, deletion) of loci on chromosomal arms 3p, 5q, 11q, and 18q in a patient with a malignant ascites fluid, a remote history of renal and colonic neoplasms, and a strong clinical suspicion of disseminated gastrointestinal adenocarcinoma. DNA from microdissected tumors and normal tissues was subjected to polymerase chain reaction-based microsatellite analysis. Even though the clinical picture suggested a gastrointestinal origin, comparison of genetic alterations clearly showed that the malignant ascites represented recurrence of the renal cell carcinoma. The malignant ascites and the primary renal cell carcinoma showed identical patterns of allelic loss at all loci tested. In contrast, the malignant ascites and colonic adenoma showed discordant patterns of allelic loss. Comparative microsatellite analysis provides a rapid genetic approach for discerning the origin of metastatic tumor spread. This may be a useful diagnostic adjunct when tumor origin is not clear on clinical or morphological grounds. In some instances, it may even provide a reasonable alternative to an extensive and costly conventional work-up.

Consequences of neural asynchrony: a case of auditory neuropathy.

The neural representation of sensory events depends upon neural synchrony. Auditory neuropathy, a disorder of stimulus-timing-related neural synchrony, provides a model for studying the role of synchrony in auditory perception. This article presents electrophysiological and behavioral data from a rare case of auditory neuropathy in a woman with normal hearing thresholds, making it possible to separate audibility from neuropathy. The experimental results, which encompass a wide range of auditory perceptual abilities and neurophysiologic responses to sound, provide new information linking neural synchrony with auditory perception. Findings illustrate that optimal eighth nerve and auditory brainstem synchrony do not appear to be essential for understanding speech in quiet listening situations. However, synchrony is critical for understanding speech in the presence of noise.

The accuracy of combined cytopathologic and flow cytometric analysis of fine-needle aspirates of lymph nodes.

We studied flow cytometry in 156 fine-needle aspirations (FNAs) of lymph nodes performed between June 1993 and September 1998. Information from flow cytometry was combined with cytomorphologic evaluation, and the diagnosis determined by using combined modalities was compared with tissue biopsy results or clinical follow-up. In 74 cases, a combined cytopathologic-flow cytometric diagnosis of lymphoma was made; histologic material was available for 52 patients; in no case was a benign process found. The lymphoma grade assigned agreed with histopathologic findings in 45 of 48 cases with a specific cytologic diagnosis. Treatment was initiated on the basis of the FNA alone for 17 of 52 patients with a history of lymphoma and in 22 additional patients with no follow-up biopsy. Among 71 cases in which the diagnosis using both modalities was benign, the only false-negative was 1 case of Hodgkin disease. Of the 156 cases, 11 were considered atypical or suggestive of lymphoma; biopsies from 8 of 10 patients revealed lymphoma. A combination of flow cytometry and cytomorphology of cells obtained by FNA of lymph nodes can distinguish between benign and malignant lymphoid infiltrates and support a diagnosis of lymphoma that permits definitive therapy in most cases.

Parathyroidectomy promotes wound healing and prolongs survival in patients with calciphylaxis from secondary hyperparathyroidism.

BACKGROUND: Calciphylaxis is a rare but life-threatening condition occasionally affecting patients with secondary hyperparathyroidism. Parathyroidectomy has been advocated as the only potentially curative intervention. METHODS: Between January 1989 and May 2000, 13 patients with pathologic/clinical criteria of calciphylaxis were treated at our institution. Of these 13 patients, 7 were managed with medical therapy alone, and 6 were referred for parathyroidectomy. The medical records were reviewed, and patients/relatives were interviewed. RESULTS: All patients had cutaneous wounds requiring local debridement predominantly located on the lower extremities or abdominal wall. Six patients underwent subtotal (3.5 gland) parathyroidectomy without morbidity. All 6 had significant reductions in parathyroid hormone levels after surgery (mean decrease, 94% +/- 0%), and all reported resolution of pain and healing of cutaneous wounds. Of the remaining 7 patients who had medical management alone, 5 eventually died of complications related to calciphylaxis. In comparing the 2 groups, patients who underwent parathyroidectomy had a significantly longer median survival than those who did not have surgery (36 vs 3 months, P =.021). CONCLUSIONS: Calciphylaxis frequently causes gangrene, sepsis, and eventual death. Parathyroidectomy can be performed with minimal morbidity and is associated with resolution of pain, wound healing, and a significantly longer median survival. Therefore, patients with secondary hyperparathyroidism and signs/symptoms of calciphylaxis should be referred promptly for consideration of parathyroidectomy.

Subcortical and cortical components of the MLR generating system.

The contributions of the auditory thalamo-cortical pathway, mesencephalic reticular formation, and inferior colliculus to the surface recorded auditory middle latency response (MLR) were assessed by selective inactivation of these areas with lidocaine. Evoked responses were recorded simultaneously from these areas and from the cortical surface. Lidocaine-induced changes were compared across recording sites. In the guinea pig, surface components measured from over the temporal lobe (waves A, B and C) and the midline (waves M- and M+) have been previously shown to reflect the activity of two distinct generating mechanisms. Effects of lidocaine injections corresponded to selective changes in components from these two systems. Injections in the medial geniculate body (MGB) were associated with total disruption of surface potentials measured over the temporal lobe, auditory cortex (AC) responses, and local activity in MGB. Thus the thalamo-cortical pathway appears to be important for the generation of MLRs recorded from the surface of the temporal lobe. These injections generally did not alter the surface midline responses or activity obtained from either the mesencephalic reticular formation (mRF) or the inferior colliculus (IC). Lidocaine injections within AC did not alter the basic response morphology of surface potentials, nor were significant changes measured within AC. Lidocaine injections into the mRF produced changes in all surface temporal potentials, the M+ midline surface potential, and in local potentials recorded from MGB and mRF. Injections into the IC changed surface and subcortical responses at all sites. This was the only injection to affect activity at the latency of surface midline wave, M-1. This wave may be the animal analogue for human wave Na. Control experiments indicated that the effects observed were specific to the neural inactivation of target areas. The MLR generating system appears to consist of contributions and interactions from multiple areas including the auditory thalamo-cortical pathway, mRF and IC. The animal model and experimental strategy described appear promising for linking the contributions from specific brain areas to surface MLR waves.

Binaural response patterns in subdivisions of the medial geniculate body.

Auditory evoked potentials (AEPs) to binaural click stimulation were examined in the ventral (MGv) and caudomedial (MGcm) subdivisions of the medial geniculate body (MG) in guinea pigs. Binaural stimulation caused a decrease in amplitude for the response component recorded from the MGv, but an increase in amplitude for the AEP component recorded from the MGcm. Findings suggest that the evoked responses recorded from MGv and MGcm are functionally distinct. The inhibitory binaural response (BR) pattern seen in MGv was similar to that of the middle latency response (MLR) component recorded over the temporal cortex, while the additive BR pattern typical of the MGcm was similar to that of the surface midline MLR component. Furthermore, these data imply that the binaural response patterns seen in the primary and non-primary auditory cortex may be processed and encoded at the thalamic level. It is concluded that the distinct BR patterns noted for the two MG subdivisions reflect the predominant type of binaurally responsive neurons within the respective pathways.

Reticular formation influences on primary and non-primary auditory pathways as reflected by the middle latency response.

Ongoing studies are aimed at identifying the neural pathways responsible for the middle latency response (MLR). These studies involve the analysis of surface and intracranial potentials following pharmacologic inactivation (with lidocaine) of discrete regions of the guinea pig brain. Previous investigations have shown that MLR surface waves recorded over the temporal lobe originate from pathways anatomically and functionally distinct from those that generate MLR waves recorded over the midline, and that both primary and non-primary auditory thalamo-cortical pathways contribute to the guinea pig MLR. The present investigation examines the role of the mesencephalic reticular formation (mRF) in the MLR generating system. Inactivation of the mRF was associated with disruption of the midline response. These waves have been shown to reflect activity from non-primary subdivisions of the thalamo-cortical pathway. Components recorded over the temporal lobe were also affected, consisting of amplitude reduction and latency prolongation without changes in response morphology. Changes in temporal MLR components with mRF inactivation were smaller than those associated with direct inactivation of primary and non-primary subdivisions of the medial geniculate body. These findings indicate that mRF input is essential for normal generation of those components of the MLR thought to reflect both primary and non-primary auditory pathway activity.

Interdigitating dendritic cell sarcoma: a rare malignancy responsive to ABVD chemotherapy.

Interdigitating dendritic cell sarcoma (IDCS) is an aggressive neoplasm of which fewer than 25 cases have been reported in the world literature. This malignancy is difficult to diagnose because of its rarity, and because of the subtle histopathologic features that distinguish IDCS from similar tumors arising from reticular cells. To date, there exists no consensus on a standard chemotherapeutic regimen for IDCS. Patients with this malignancy have been treated with chemotherapy regimens used against non-Hodgkin's lymphomas. Responses to these regimens have been variable, but mostly unsuccessful. In this article we describe a case of IDCS occurring in a 44 year old female who presented with abdominal pain and inguinal adenopathy. Staging of the tumor with CT scan, PET scan, and bone marrow biopsy demonstrated inguinal and abdominal lymphadenopathies, a large mass encasing the small bowel, and extensive liver infiltration. Morphologic and cytochemical analysis of biopsies from the abdominal mass and inguinal node were consistent with a diagnosis of IDCS, and immunohistochemical stains of the lymph node were positive for CLA, Kp-1, S-100, while negative for CD1a, CD3, CD20, CKER, and HMB45. Treatment of this patient with ABVD chemotherapy resulted in rapid clinical improvement with a marked decrease in tumor burden after two cycles of ABVD, and a complete response after six cycles of therapy.

N-methyl-D-aspartate receptors influence neuronal survival in developing spinal cord cultures.

Neuronal cell death, which exhibits precise spatial and temporal regulation, serves to remodel and optimize function in the developing nervous system. The mechanisms underlying neuronal cell death are poorly understood, but electrical activity and trophic substances appear to be among the important determinants of survival. We find that N-methyl-D-aspartate (NMDA) receptor antagonists induce neuronal cell death in developing spinal cord cultures. The magnitude of cell death is similar in amount to that produced by blocking action potentials with tetrodotoxin (TTX). The NMDA antagonists and TTX accelerate neuronal death in 2-week-old cultures but not in those that are 1 month old. Low concentrations of NMDA increased neuronal survival under conditions of electrical blockade with TTX. In addition, treatment with low levels of a calcium ionophore also decreased cell death associated with TTX. These results suggest that the NMDA receptor is an important determinant of neuronal survival and that this influence is stage-dependent and likely to be calcium-mediated.

Abnormal neural encoding of repeated speech stimuli in noise in children with learning problems.

OBJECTIVES: This study investigated whether neurophysiologic responses to repeated speech stimuli, presented in quiet and noise, differed between normal children (NL) and children with learning problems (LP). METHODS: Subjects were normal-hearing, school-age children. NL subjects scored significantly better than LP subjects on measures of reading, spelling and speech sound discrimination. Stimuli (40 ms /da/) were presented to the right ear at 80 dB SPL. Stimuli were presented in trains of four, separated within trains by 360 ms. The interval between trains was 1060 ms. Stimuli were presented in quiet and in white noise (S/N+15). Cortical responses were recorded from an electrode placed along the midline at Cz. RESULTS: Correlations between the first and 4th responses were lower in noise than in quiet for LP subjects only. Response correlations in quiet were no different between groups. There were no root-mean-square (RMS) amplitude differences between groups. CONCLUSIONS: Response correlation in noise suggested that the LP population consisted of two subgroups, one whose responses appeared relatively normal, and another whose responses were severely degraded by repetition in noise. Response correlations in noise were related to behavioral measures of auditory processing and spelling. These findings suggest that abnormal, asynchronous, auditory cortical encoding may underlie some language-based learning problems.

Neurobiologic responses to speech in noise in children with learning problems: deficits and strategies for improvement.

OBJECTIVES: Some children with learning problems (LP) experience speech-sound perception deficits that worsen in background noise. The first goal was to determine whether these impairments are associated with abnormal neurophysiologic representation of speech features in noise reflected at brain-stem and cortical levels. The second goal was to examine the perceptual and neurophysiological benefits provided to an impaired system by acoustic cue enhancements. METHODS: Behavioral speech perception measures (just noticeable difference scores), auditory brain-stem responses, frequency-following responses and cortical-evoked potentials (P1, N1, P1', N1') were studied in a group of LP children and compared to responses in normal children. RESULTS: We report abnormalities in the fundamental sensory representation of sound at brain-stem and cortical levels in the LP children when speech sounds were presented in noise, but not in quiet. Specifically, the neurophysiologic responses from these LP children displayed a different spectral pattern and lacked precision in the neural representation of key stimulus features. Cue enhancement benefited both behavioral and neurophysiological responses. CONCLUSIONS: Overall, these findings contribute to our understanding of the preconscious biological processes underlying perception deficits and may assist in the design of effective intervention strategies.

Thalamic asymmetry is related to acoustic signal complexity.

Hemispheric asymmetries in response to speech sounds are well documented. However, it is not known if these asymmetries reflect only cortical hemispheric specialization to language or whether they also reflect pre-conscious encoding of signals at lower levels of the auditory pathway. This study examined differences in neural representations of signals with acoustic properties inherent to speech in the left versus right side of the thalamus. Specifically, 2000 Hz tone bursts, clicks and synthesized forms of the phoneme /da/ were presented to anesthetized guinea pigs. Evoked responses were recorded simultaneously from aggregate cell groups in the left and right medial geniculate bodies. Results showed an asymmetric response to complex auditory stimuli between the left versus right auditory thalamus, but not to the simple tonal signal. Moreover, asymmetries differed in male versus female animals.

Complete hepatic resection of metastases from leiomyosarcoma prolongs survival.

Although liver resection has been shown to prolong survival in selected patients with metastases from colorectal cancer, the benefit for other metastatic tumors is unproved. To determine whether hepatic resection has a role in the management of metastatic leiomyosarcoma, medical records from 11 consecutive patients who underwent resection of isolated metastases from leiomyosarcoma between 1984 and 1995 were reviewed. All liver resections were for leiomyosarcomas originating in the viscera (n = 6) or retroperitoneum (n = 5). The average disease-free interval was 16 months. Five of 11 primary tumors were classified as low grade, whereas six were high grade. Hepatic resections included lobectomy or extended lobectomy (n = 4), segmentectomy and/or wedge resection (n = 5), and complex resection (n = 2). There were no operative deaths. Median survival of all patients after liver resection was 39 months. Patients who underwent complete resection of hepatic metastases (n = 6) had a significantly longer survival than those who had incomplete resections (n = 5) (P = 0.03, log-rank test). Furthermore, five of six patients who underwent complete resection are alive after hepatectomy with a median follow-up of 53 months. Therefore, in selected patients with isolated liver metastases from visceral and retroperitoneal leiomyosarcomas, complete resection of hepatic metastases results in prolonged survival.

Contributions of medial geniculate body subdivisions to the middle latency response.

Ongoing studies in our laboratory, concerned with identifying the neural pathways responsible for the auditory middle latency response (MLR), have involved analysis of surface and intracranial potentials following pharmacologic inactivation (with lidocaine) of small regions in the guinea pig brain. Previous studies indicate that MLR surface waves recorded over the temporal lobe originate from pathways anatomically distinct from those that generate MLR waves recorded over the midline. The medial geniculate body (MG) contributes to both MLR responses. At issue here are the relative contributions of ventral and caudomedial subdivisions, which have been linked to primary and non-primary auditory pathways, respectively. Ventral and caudomedial subdivisions contributed to the surface-recorded MLR in a distinctive manner. Lidocaine injections to both areas reduced the amplitude of the surface temporal response. Caudomedial injections had a much greater effect on the surface midline responses than did injections in the ventral portion. Thus, the ventral division, a part of the primary auditory pathway, contributes chiefly to the temporal response. The caudomedial portion, which may be linked to non-primary auditory pathways, contributes to both responses.